<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Arsenic and inorganic
arsenic compounds
    Health-based calculated occupational cancer risk values
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Arsenic and inorganic arsenic compounds
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7493/BvdV/fs/459-X67
Bijlagen               :1
Datum                  : 11 december 2012
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
arseen en anorganische arseenverbindingen.
Dit advies maakt deel uit van een uitgebreide reeks waarin concentratieniveaus in lucht
worden afgeleid die samenhangen met een extra kans op overlijden aan kanker van 4 per
1.000 en 4 per 100.000 door beroepsmatige blootstelling. De conclusies van het genoemde
advies zijn opgesteld door de Commissie Gezondheid en beroepsmatige blootstelling aan
stoffen (GBBS) van de Gezondheidsraad en beoordeeld door de Beraadsgroep Gezondheid
en omgeving.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                             Postadres
Parnassusplein 5                                                        Postbus 16052
2 5 11 V X D e n          Haag                                          2500 BB Den     Haag
E - m a i l : b . v. d . v o e t @ g r. n l                             w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Arsenic and inorganic
arsenic compounds
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety (DECOS)
a Committee of the Health Council of The Netherlands
to:
the Minister of Social Affairs and Employment
No. 2012/32, The Hague, December 11, 2012
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Arsenic and inorganic arsenic compounds.
Health-based calculated occupational cancer risk values. The Hague: Health
Council of the Netherlands, 2012; publication no. 2012/32.
all rights reserved
ISBN: 978-90-5549-923-6
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<pre>   Contents
   Samenvatting 11
   Executive summary 17
   Scope 23
.1 Background 23
.2 Committee and procedure 24
.3 Data 24
   Identity, properties and monitoring 27
.1 Chemical identity 27
.2 Physical and chemical properties 30
.3 EU Classification and labeling 30
.4 Validated analytical methods 33
   Sources 39
.1 Natural occurrence 39
.2 Man-made sources 40
   Exposure 43
.1 General population 43
.2 Working population 45
   Contents                               7
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<pre>    Kinetics 49
 .1 Absorption 49
 .2 Distribution 51
 .3 Biotransformation 54
 .4 Elimination 57
 .5 Possibilities for biological monitoring 59
 .6 Possibilities for biological effect monitoring 61
 .7 Summary 62
    Mechanisms of action 65
 .1 Mechanisms of toxicity and carcinogenicity 65
 .2 Summary 73
    Effects 75
 .1 Observations in humans 75
 .2 Animal experiments 110
 .3 Summary and evaluation 127
    Existing guidelines, standards and evaluations 131
 .1 General population 131
 .2 Working population 132
    Hazard assessment 137
 .1 Assessment of the health hazard 137
 .2 Quantitative hazard assessment 139
 .3 Recommendation 143
 .4 Groups at extra risk 143
 0  Recommendation for research 145
    References 147
    Annexes 163
A   Request for advice 165
B   The Committee 167
C   The submission letter 169
D   Comments on the public review draft 171
E   Abbreviations 173
    Arsenic and inorganic arsenic compounds
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<pre>F WHO/ATSDR References 175
G Human data 197
H Animal data 217
  Evaluation of the Subcommittee on Classification of carcinogenic substances 223
  Carcinogenic classification of substances by the Committee 227
K Evaluation of the Subcommittee on the Classification of reprotoxic substances 229
L Derivation of health-based calculated occupational cancer risk values (HBC-OCRV) 241
  Contents                                                                             9
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<pre>0 Arsenic and inorganic arsenic compounds</pre>

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<pre>Samenvatting
Vraagstelling
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid leidt de
Commissie Gezondheid en Beroepsmatige Blootstelling aan stoffen (GBBS) van
de Gezondheidsraad gezondheidskundige advieswaarden af voor stoffen in lucht
waaraan mensen beroepsmatig blootgesteld kunnen worden op de werkplek.
Deze advieswaarden vormen vervolgens de basis voor grenswaarden – vast te
stellen door de minister – waarmee de gezondheid van werknemers beschermd
kan worden.
In het voorliggende rapport bespreekt de commissie de gevolgen van
blootstelling aan arseen en anorganische arseenverbindingen en presenteert zij
concentratieniveaus in de lucht (HBC-OCRV) die samenhangen met een extra
kans op overlijden aan kanker van 4 per 1.000 en 4 per 100.000 door
beroepsmatige blootstelling. De conclusies van de commissie zijn gebaseerd op
wetenschappelijke publicaties die vóór 3 september 2012 zijn verschenen.
Fysische en chemische eigenschappen
Arseen (As; CAS nr. 7440-38-2) is een in de natuur voorkomend, grijs vast
metalloïde met een molecuulgewicht van 74,92. Elementair arseen sublimeert bij
613°C, heeft een erg lage dampspanning en een log Poctanol/water van 0,680.
Samenvatting                                                                   11
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<pre>  Arseenverbindingen kunnen voorkomen als drie- en vijfwaardige verbindingen.
  Arseen trioxide (CAS nr. 1327-53-3), de belangrijkste arseenverbinding met
  betrekking tot blootstelling voor werkers, heeft een molecuulgewicht van 197,84,
  een smelttemperatuur van 312°C, een kooktemperatuur van 465°C, een erg lage
  dampspanning en een log Poctanol/water van -0,310.
  Gebruik
  Arseen en anorganische arseenverbindingen worden gebruikt als
  houtconserveringsmiddelen, als bestrijdingsmiddel in de landbouw (vooral in het
  verleden), als droogmiddel van katoen, in halfgeleiders, bij de fabricage van glas,
  bij de productie van niet-ijzerhoudende metaalmengsels en als medicatie voor
  mensen en dieren.
  Monitoring
  Voor monitoring van arseen en arseenverbindingen in omgevingslucht zijn
  gevalideerde meetmethoden beschikbaar (NIOSH methoden 5022, 7300, 7900
  en 7901 en OSHA methode ID-105). Er bestaan verschillende methodes voor
  biologische monitoring van arseen en arseenverbindingen, deze methoden zijn
  echter niet door NIOSH of OSHA gevalideerd.
  Grenswaarden
  Voor blootstelling aan de combinatie van alle anorganische arseenverbindingen
  gedurende gemiddeld een achturige werkdag (tgg 8 uur) geldt in Nederland een
  wettelijke grenswaarde van 0,05 mg As/m3. Bovendien geldt in Nederland een
  grenswaarde van 0,1 mg As/m3 voor kortdurende blootstelling (tgg 15 minuten)
  aan de combinatie van alle anorganische arseenverbindingen.
      De huidige wettelijke grenswaarden voor wateroplosbare anorganische
  arseenverbindingen in Nederland zijn 0,025 (gemiddeld over een achturige
  werkdag; tgg 8 uur) en 0,05 mg As/m3 (tgg 15 minuten). Er is momenteel geen
  Europese norm vastgesteld door de SCOEL. In Duitsland is een TRK
  (Technische Richtkonzentration) voor 8 uur en 15 minuten vastgesteld (0.1
  respectievelijk 0.4 mg/m3). In het Verenigd Koninkrijk, Denemarken en Zweden
  zijn grenswaarden (tgg 8 uur) vastgesteld van respectievelijk 0,1 mg/m3, 0,01
  mg/m3 en 0,03 mg/m3. De grenswaarde (tgg 8 uur) in de Verenigde Staten is 0,01
  mg/m3. NIOSH beveelt een 15 minuten waarde aan van 0,002 mg/m3 voor
  anorganische arseenverbindingen.
2 Arsenic and inorganic arsenic compounds
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<pre>Kinetiek en toxisch werkingsmechanisme
Arseen en arseenverbindingen worden snel opgenomen na orale blootstelling.
Opname na inhalatie van arseen partikels is afhankelijk van de oplosbaarheid en
omvang van de partikels. De dermale opname verloopt veel trager. Na opname
vindt een verdeling plaats over alle organen. Arseen passeert gemakkelijk de
placenta. Het metabolisme wordt gekarakteriseerd door twee afwisselende
reacties: reductie van vijfwaardige naar driewaardige arseenverbindingen en een
oxidatieve reactie waarbij driewaardige verbindingen overgaan in vijfwaardige
en (een) methylgroep(en) krijgen. Arseen en arseen metabolieten worden
voornamelijk uitgescheiden via de urine. Verschillende studies tonen aan dat
arseen uitgescheiden kan worden via de moedermelk.
    Driewaardig arseen reageert met sulfhydryl groepen in eiwitten en inactiveert
verschillende enzymen. De mitochondriën in het bijzonder zijn gevoelig voor
arseen. Vijfwaardig arseen kan werken als een fosfaat analoog en mogelijk
verschillende biologische processen beïnvloeden, zoals ATP-productie,
botvorming en DNA-synthese (ontkoppeling van de oxidatieve fosforylering).
Effecten bij mensen
Er is relatief weinig informatie beschikbaar betreffende de lokale effecten van
arseen. Arseen trioxide is een corrosieve stof en kan schade veroorzaken aan de
huid, ogen en luchtwegen.
    Er zijn geen gevallen van sterfte bij mensen beschreven na acute inhalatoire
blootstelling aan anorganische arseenverbindingen, zelfs niet bij hoge
blootstellingniveau’s (1-100 mg As/m3) die voorheen gevonden werden op
werkplekken.
    Acute orale inname van grote hoeveelheden arseen kan effecten veroorzaken
in het maagdarmkanaal en in het cardiovasculaire- en zenuwstelsel met
uiteindelijk de dood als gevolg. Verder zijn beenmergdepressie, haemolyse,
leververgroting en melanose waargenomen.
    Arseen en arseenverbindingen worden als niet-stochastisch genotoxische
verbindingen beschouwd. Er worden voornamelijk chromosoomafwijkingen
waargenomen. Remming van DNA repair enzymen, hypo- en hypermethylering
van DNA en oxidatieve schade door reactieve zuurstofradicalen zijn de
belangrijkste genotoxische werkingsmechanismen van arseen.
    Chronische blootstelling aan arseen in drinkwater kan huid-, lever-, long-,
blaas-, en nierkanker en overmatige verhoorning en pigmentatie van de huid
veroorzaken. Verhoogde risico’s voor long- en blaaskanker en voor huideffecten
Samenvatting                                                                      13
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<pre>  zijn geassocieerd met een arseen blootstellingcategorie van ≤ 50 µg/l in
  drinkwater. Arseen blootstelling via drinkwater kan verschillende perifere
  vasculaire aandoeningen veroorzaken. Of enkel arseenblootstelling de extreme
  vasculaire aandoening, ‘blackfoot disease’, kan veroorzaken, is niet bekend. Of
  arseen andere nadelige gezondheidseffecten (hypertension, diabetes,
  cerebrovascular disease) kan veroorzaken is minder duidelijk.
       Beroepsmatige inhalatoire blootstelling aan arseen kan longkanker
  veroorzaken. Er zijn meerdere studies waar verhoogde risico’s zijn waargenomen
  bij relatief lage cumulatieve blootstellingen in smelterij cohorten in Zweden
  (Zweden, Rönnskär; arseen blootstellingcategorie < 250 µg/m3·jaar) en de
  Verenigde Staten (Tacoma; arseen blootstellingcategorie < 750 µg/m3·jaar).
  Studies tonen aan dat roken een synergistisch effect heeft op het optreden van
  longkanker door arseen blootstelling.
       Verschillende studies zijn uitgevoerd om te onderzoeken of arseen
  reproductietoxische eigenschappen heeft. Er werd geen duidelijk verband tussen
  inhalatoire blootstelling aan arseen en reprotoxische effecten waargenomen.
  Echter, studies naar orale blootstelling aan arseen via drinkwater laten zien dat
  arseen niet uitgesloten kan worden als een causale factor voor reprotoxische
  effecten (spontane abortus, neonatale en postnatale sterfte, vroeggeboorten en
  verlaagde geboortegewichten) (zie Annex K).
  Effecten bij dieren
  Natrium arseniet and natrium arsenaat zijn niet sensibiliserend. Verder is er
  relatief weinig informatie aanwezig met betrekking tot lokale effecten van arseen
  en arseenverbindingen.
       In een ontwikkelingstudie trad 100% sterfte op in groepen van 10 zwangere
  ratten na 1 dag blootstelling aan arseen trioxide ≥ 100 mg/m3 (76 mg As/m3). De
  acute dermale dosering van calcium arsenaat en lood arsenaat die 50% sterfte
  veroorzaakte in ratten is ≥ 2.400 mg/kg bw (≥ 400 mg As/kg bw). Orale letale
  doseringen variëren van 15 tot 960 mg As/kg lichaamsgewicht/dag.
  Arseen veroorzaakt chromosoomafwijkingen in vivo en in vitro.
  In een recente studie werd een verhoogde incidentie waargenomen van long,
  lever, maagdarm en huid tumoren in vrouwelijke muizen die via drinkwater
  blootgesteld waren aan 500 µg AsV/l* gedurende twee jaar.
  vijfwaardig arseen (Asv) itt driewaardig arseen (AsIII)
4 Arsenic and inorganic arsenic compounds
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<pre>     In studies met muizen, ratten en hamsters werden reprotoxische effecten
waargenomen (o.a. verlaagde geboortegewichten, foetale misvormingen en
foetale sterfte) na inhalatoire, orale en parenterale toediening van relatief hoge
arseen doseringen die gewoonlijk toxisch (en vaak bijna fataal) waren voor de
moederdieren. Er zijn geen reprotoxische effecten waargenomen in ratten na
inhalatoire blootstelling (20 mg As/m3) en orale blootstelling (8 mg As/kg
lichaamsgwicht/dag).
     Er zijn weinig gegevens beschikbaar over immunologische effecten van
arseen en arseenverbindingen in dieren.
Evaluatie en advies
Carcinogeniteit van arseen is het kritische effect. Omdat er voldoende adequate
humane gegevens beschikbaar zijn betreffende arseen en arseenverbindingen zal
voor het afleiden van de gezondheidskundige advieswaarde uitgegaan worden
van de humane data.
     Arseen en arseenverbindingen worden als kankerverwekkend beschouwd
voor mensen (classificatie categorie 1A, zie Annex I en J). Longkanker is het
kritische effect na inhalatoire blootstelling. Er is voldoende kwantitatieve
informatie beschikbaar over blootstelling aan arseen afkomstig van een drietal
cohorten van werknemers in kopersmelterijen (Tacoma, Washington (USA),
Anaconda, Montana (USA) and Rönskär (Zweden)) om de blootstellings-respons
relatie kwantitatief te kunnen evalueren.
     Arseen en anorganische arseenverbindingen hebben een non-stochastisch
genotoxisch werkingsmechanisme (zie Annex I). De commissie besluit om voor
arseen concentratieniveaus in de lucht af te leiden die samenhangen met een kans
op 4 extra sterfgevallen door kanker per 1.000 en 4 per 100.000 (HBC-OCRV).
     De commissie beoordeelt de kwaliteit van een viertal epidemiologische
studies over long- en respiratoire kanker in werknemers van bovengenoemde
kopersmelterijen (Lubin et al. 20001, 20082, Järup et al. 19893 en Enterline et al.
19954) en de geschiktheid voor kwantitatieve risicobeoordeling. Uiteindelijk
selecteert de commissie de studie van Lubin et al. 20001 voor de afleiding van
risicogetallen (HBC-OCRV).
De commissie berekent op grond van de gegevens uit deze studie dat de
concentratie van arseen in lucht , die samenhangt met een extra kans op
overlijden aan kanker van
• 4 per 1.000 (4x10-3), bij 40 jaar beroepsmatige blootstelling, gelijk is aan 28
     µg arseen/m3
Samenvatting                                                                        15
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<pre>  •  4 per 100.000 (4x10-5), bij 40 jaar beroepsmatige blootstelling, gelijk is aan
     0,28 µg arseen/m3.
  Het afleiden van een ‘Short Term Exposure Limit’ (STEL) of ‘ceiling value’
  wordt niet nodig geacht op basis van de beschikbare informatie.
  Een huidnotatie wordt niet nodig geacht.
6 Arsenic and inorganic arsenic compounds
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<pre>Executive summary
Scope
At the request of the Minister of Social Affairs and Employment, the Health
Council of the Netherlands sets Health-Based Calculated Occupational Cancer
Risk Values (HBC-OCRVs) for chemical substances in air at the workplace.
These recommendations are made by the Council’s Dutch Expert Committee on
Occupational Safety (DECOS). These recommendations serve as a basis in
setting legally binding occupational exposure limits by the Minister .
    In this report, the Committee discusses the consequences of occupational
exposure to arsenic and arsenic compounds and presents HBC-OCRVs
associated with excess mortality levels of 4 per 1,000 and 4 per 100,000 as a
result of working life exposure. The Committee’s conclusions are based on
scientific papers published prior to September 3, 2012.
Physical and chemical properties
Arsenic (As; CAS no. 7440-38-2) is a naturally occurring grey, crystalline solid
with metallic luster and has a molecular weight of 74.92. Elemental arsenic
sublimes at 613°C, has a very low vapour pressure and a log Poctanol/water of 0.680.
Arsenic compounds, crystalline, amorphous or hygroscopic substances, occur in
trivalent and pentavalent forms. Arsenic trioxide (CAS no. 1327-53-3), the major
arsenic compound with regard to occupational exposure, has a molecular weight
Executive summary                                                                    17
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<pre>  of 197.84, melts at 312°C, boils at 465°C, has also a very low vapour pressure
  and a log Poctanol/water of -0.130.
  Use
  Arsenic and/or arsenic compounds are used as wood preservative, in agriculture
  (mainly in the past), as a cotton desiccant/defoliant, in a variety of semiconductor
  applications, as a decolouriser and fining agent in the production of bottle glass
  and other glassware, in the production of non-ferrous alloys and as a medication.
  Monitoring
  Arsenic and arsenic compounds in air are usually associated with particulate
  matter and therefore standard methods of the National Institute for Occupational
  Safety and Health (NIOSH) and the Occupational Safety and Health
  Administration (OSHA) involve collection of air samples on glass fibre or
  membrane filters, acid extraction of the filters (digestion with nitric, sulphuric
  and/or perchloric acids) and arsine generation. Hydride generation atomic
  absorption spectrometry and graphite furnace atomic absorption spectrometry
  are the major analysis techniques (NIOSH method 5022 (particulate
  organoarsenicals), NIOSH method 7900 (arsenic and compounds as As, except
  AsH3 and As2O3), NIOSH method 7901 (arsenic trioxide, as As) and OSHA
  method ID-105 (arsenic)). Furthermore, inductively-coupled argon plasma,
  atomic emission spectroscopy is used to analyse arsenic (NIOSH method 7300
  (arsenic)).
      Although different methods for biological monitoring are available, none of
  these methods is validated.
  Guidelines
  Currently, the legal time weighted average (TWA) (8 hr) and short-term (15 min)
  occupational exposure limits for the combination of all inorganic arsenic
  compounds in the Netherlands are 0.05 and 0.1 mg As/m3, respectively. The
  legal TWA (8 hr) and short-term (15 min) occupational exposure limits for the
  watersoluble inorganic arsenic compounds are 0.025 and 0.05 mg As/m3,
  respectively. There is currently no limit value for exposure to arsenic and arsenic
  compounds at the European level. In Germany, an 8 hr TRK (Technische
  Richtkonzentration) and a short time (15 min) TRK of 0.1 mg/m3 and 0.4 mg/m3
  are established, respectively. The United Kingdom, Denmark and Sweden have
8 Arsenic and inorganic arsenic compounds
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<pre>set an occupational exposure limit (8 hr TWA value) for arsenic and compounds
(as As) of 0.1 mg/m3, 0.01 mg/m3 and 0.03 mg/m3, respectively. The American
Conference of Governmental Industrial Hygienists (ACGIH) has specified a
threshold limit value (TLV) of 0.01 mg/m3 (as As) (8 hr TWA value). The
permissible exposure limit (PEL) for inorganic arsenic of the Occupational
Safety and Health Administration (OSHA) is 10 µg/m3. Furthermore, the
recommended standard of NIOSH amounts to 0.002 mg/m3 as determined by a
15-minute sampling period (inorganic compounds, as As).
Kinetics and mechanism of action
Both pentavalent and trivalent soluble arsenic compounds are rapidly and
extensively absorbed from the gastrointestinal tract. Absorption of arsenic from
inhaled airborne particles is highly dependent on the solubility and the size of
particles. Dermal absorption appears to be much less than absorption by the oral
or inhalation routes. Arsenic and its metabolites distribute to all organs in the
body; preferential distribution has not been observed. Arsenic readily crosses the
placenta.
    Arsenic metabolism is characterised by alternation of two main types of
reactions: (1) two-electron reduction reactions of pentavalent to trivalent arsenic
and (2) oxidative methylation reactions in which trivalent forms of arsenic are
converted to (mono-, di- or tri-) methylated pentavalent products. Arsenic and its
metabolites are largely excreted via the renal route. Excretion can also occur via
faeces; minor excretion pathway are nails and hair. Different studies indicated
that arsenic can be excreted in human milk.
    Trivalent (in)organic arsenic reacts strongly with sulfhydryl groups in
proteins and inactivates many enzymes. A particular target in the cell is the
mitochondria. Pentavalent inorganic arsenic may exert effects by acting as a
phosphate analogue and could potentially affect a number of biological
processes, including ATP production, bone formation, and DNA synthesis
(uncoupling of oxidative phosphorylation).
Effects – Human toxicity data
Relatively little information is available on the local effects of arsenic and
arsenic compounds. Arsenic trioxide is a corrosive compound and may cause
local damage to the skin, eyes and respiratory tract.
Executive summary                                                                   19
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<pre>      No cases were located regarding death in humans from inhalation exposure
  to inorganic arsenicals following acute exposure, even at the very high exposure
  levels (1-100 mg As/m3) found previously in the workplace.
      Acute ingestion of large doses of arsenic leads to gastrointestinal symptoms,
  disturbances of cardiovascular and nervous system functions, and eventually
  death. In survivors, bone marrow depression, haemolysis, hepatomegaly,
  melanosis, polyneuropathy and encephalopathy may be observed.
      Arsenic is considered to be a non-stochastic genotoxic compound.
  Clastogenic damage was observed in different cell types of exposed humans and
  in mammalian cells in vitro. For point mutations, the results are largely negative.
  With regard to the mechanism which caused the genotoxic effects, there is
  evidence that DNA repair enzymes are inhibited by arsenicals, that DNA is
  hypo- or hypermethylated and that oxidative damage by reactive oxygen species
  plays a role in arsenic genotoxicity.
      Long-term exposure to arsenic in drinking-water is causally related to
  increased risks of cancer in the skin, liver, lungs, bladder and kidney, as well as
  other skin changes such as hyperkeratosis and pigmentation changes. The effects
  have been most thoroughly studied in Taiwan but there is considerable evidence
  from studies on populations in other countries as well. Increased risks of lung
  and bladder cancer and of arsenic-associated skin lesions have been reported to
  be associated with arsenic exposure categories of ≤ 50 µg/L. Chronic oral
  (drinking water) arsenic exposure in Taiwan may be associated with blackfoot
  disease, a severe form of peripheral vascular disease which leads to gangrenous
  changes. There is good evidence from studies in several countries that arsenic
  exposure causes other forms of peripheral vascular disease.
      Conclusions on the causality of the relationship between oral arsenic
  exposure and other health effects (hypertension, cardiovascular disease, diabetes,
  cerebrovascular disease, long-term neurological effects) are less clear-cut.
      Occupational exposure to arsenic by inhalation is causally associated with
  lung cancer. Exposure-response relationships and high risks have been observed.
  Increased risks have been observed at relatively low cumulative exposure levels
  in smelter cohorts in Sweden (Rönnskär; arsenic exposure category of < 250 µg/
  m3·year) and in the USA (Tacoma; arsenic exposure category of < 750 µg/
  m3·year). Studies indicated that smoking had a synergistic effect on the lung
  cancer effects of arsenic exposure.
      Several studies have examined a number of reproductive end-points in
  relation to arsenic exposure. Occupational exposure studies are not conclusive on
  a causal relationship between arsenic and reprotoxic effects. Studies on oral
  exposure to arsenic in drinking water show that arsenic can not be excluded as a
0 Arsenic and inorganic arsenic compounds
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<pre>causal factor for reproduction toxicity (spontaneous abortion, neonatal and
postnatal mortality, preterm delivery, reduced birth weight) (see Annex K).
Effects – Animal toxicity data
Relatively little information is available on the local effects of arsenic and
arsenic compounds in animals. Sodium arsenite and sodium arsenate were not
allergenic in the guinea-pig maximisation test.
    In a developmental toxicity study, 100% mortality in groups of 10 pregnant
rats after 1 day of inhalation exposure to arsenic trioxide concentrations ≥100
mg/m3 was observed (76 mg As/m3). The acute dermal LD50 for the pentavalent
arsenicals calcium arsenate and lead arsenate in the rat is ≥ 2400 mg/kg bw
(≥ 400 mg As/kg bw). Oral and parenteral lethal doses range from 15 to 960 mg
As/kg bw/day, depending on the compound and the animal species.
Arsenic produced chromosomal aberrations in vivo and in vitro
Several animal carcinogenicity studies on arsenic have been carried out, but
limitations such as limited time of exposure and limited number of animals make
these inconclusive. In a recent study, female C57B1/6J mice had an increased
incidence in tumours involving mainly lung, liver, gastrointestinal tract and skin
after exposure to 500 µg AsV/L* drinking water for 2 years. One study has
indicated that dimethylarsinic acid may cause cancer of the urinary bladder in
male rats at high doses.
    Studies with mice, rats and hamsters revealed that inorganic arsenic caused
reprotoxic effects (reduced birth weight, foetal malformations, increased foetal
mortality) upon inhalatory, oral and parenteral administration of relatively high
arsenic doses which were usually maternally toxic (and often nearly fatal).
Reproductive performance was not affected in female rats that received
inhalation exposures to concentrations as high as 20 mg As/m3 or gavage doses
as high as 8 mg As/kg bw/day from 14 days prior to mating through gestation
day 19.
    Little information is available with regard to immunological effects of
arsenic and arsenic compounds in animals.
pentavalent arsenic (Asv) versus trivalent arsenic (AsIII)
Executive summary                                                                  21
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<pre>  Evaluation and advice
  Arsenic and arsenic compounds are considered to be carcinogenic in humans
  (classification category 1A, see Annex I and J). Because sufficient adequate
  human data on arsenic and arsenic compounds are available the available human
  data are used for derivation of the occupational limit value.
      Lung cancer is the critical effect after inhalation exposure to arsenic and
  arsenic compounds. Sufficient quantitative information from human studies on
  the levels of arsenic exposure to ensure reliable assessment of the exposure-
  response relationship was available for three copper smelter cohorts: Tacoma,
  Washington (USA), Anaconda, Montana (USA) and Rönnskär (Sweden).
      Arsenic and inorganic arsenic compounds have non-stochastic genotoxic
  mechanisms (see Annex I). For quantitative hazard assessment the Committee
  decided not to pursue a threshold approach but to calculate excess lifetime cancer
  mortality risks (health-based calculated occupational cancer risk values (HBC-
  OCRV)), using mathematical modeling and extrapolation.
      The Committee compared the quality and suitability for quantitative hazard
  assessment of four epidemiological studies on lung and respiratory cancer
  mortality among workers in these smelters (Lubin et al. 20001, 20082, Järup et al.
  19893 and Enterline et al. 19954) and selects the study of Lubin et al. (2000)1 for
  the derivation of HBC-OCRV using a linear model.
  The Committee calculates that the concentration of arsenic in the air, which
  corresponds to an excess cancer mortality of
  • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 28
      µg/m3
  • 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to 0.28
      µg/m3.
  The available data do not warrant the setting of a Short Term Exposure Limit
  (STEL) or ceiling value.
  The rate of absorption of arsenic and arsenic compounds through the skin does
  not warrant a skin notation.
2 Arsenic and inorganic arsenic compounds
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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for chemical substances are set
        using a three-step procedure. In the first step, a scientific evaluation of the data
        on the toxicity of the substance is made by the Dutch Expert Committee on
        Occupational Safety (DECOS), a committee of the Health Council of the
        Netherlands, at the request of the Minister of Social Affairs and Employment
        (Annex A). The purpose of the Committee’s evaluation is to set a health-based
        recommended occupational exposure limit for the atmospheric concentration of
        the substance, provided the database allows the derivation of such a value. Such
        an exposure limit cannot be derived if the toxic action cannot be evaluated using
        a threshold model, as is the case for substances with genotoxic carcinogenic
        properties. In that case, an exposure-response relationship is recommended for
        use in regulatory standard setting, i.e., the calculation of so-called health-based
        calculated occupational cancer risk values (HBC-OCRVs). The Committee
        calculates HBC-OCRVs for compounds, which are classified as genotoxic
        carcinogens by the European Union or by the Committee.
            For the establishment of the HBC-OCRVs, the Committee generally uses a
        linear extrapolation method, as described in the Committee’s report ‘Calculating
        cancer risk due to occupational exposure to genotoxic carcinogens’.5
            In the next phase of the three-step procedure, the Social and Economic
        Council advises the Minister on the feasibility of using the HBC-OCRVs as
        Scope                                                                                23
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<pre>    regulatory occupational exposure limits. In the final step of the procedure, the
    Minister of Social Affairs and Employment sets the legally binding occupational
    exposure limits.
1.2 Committee and procedure
    This document contains the assessment of DECOS, hereafter called the
    Committee, of the health hazard of arsenic and arsenic compounds (as specified
    in WGD document 84-103-16 concerning inorganic arsenic (excluding arsine)).
    The members of the Committee are listed in Annex B. The submission letter to
    the Minister can be found in Annex C.
    Because WGD document 84-103-16 is rather outdated (1984) and recent
    toxicological profiles of WHO/IPCS Environmental Health Criteria (EHC 224,
    2001)6 and the Agency for Toxic Substances and Disease Registry (ATSDR,
    2007)7 were available, these were used as starting documents (see section 1.3). In
    sections 2.4-7.2, first the WHO and ATSDR data, which describe the data
    available before 2007, are mentioned. Subsequently, additional data are
    discussed (up to September 3, 2012) which were obtained from several online
    databases (see section 1.3).
    In July 2012, the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft are
    listed in Annex D. The Committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The Committee’s recommendations on the health-based occupational exposure
    limit of arsenic and arsenic compounds have been based on scientific data, which
    are publicly available. For evaluation of the available data before 2007, the
    toxicological profiles of WHO/IPCS Environmental Health Criteria (EHC 224,
    2001)6 and the Agency for Toxic Substances and Disease Registry (ATSDR,
    2007)7 were used as starting documents. Additional scientific publicly available
    data up to September 3, 2012 were obtained from the following online databases:
    Toxline, Medline, Chemical Abstracts and TSCATS. The CAS numbers of
    arsenic (7440-38-2); arsenic trioxide (1327-53-3); arsenic pentoxide (1303-28-
    2); arsenic acid (7778-39-4); arsenic trisulphide (1303-33-9); arsenic trichloride
    (7784-34-1); sodium arsenite (7784-46-5); arsenic acid, trisodium salt (13464-
 4  Arsenic and inorganic arsenic compounds
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<pre>38-5); arsenenous acid, potassium salt (13464-35-2); potassium arsenate (7784-
41-0); arsenic acid, calcium salt (10103-62-5); calcium arsenite (52740-16-6);
lead arsenate (7784-40-9); cupric acetoarsenite (12002-03-8); copper(II) arsenite
(10290-12-7); magnesium arsenate (10103-50-1) were used in combination with
the following key words: expos*, kinetic*, toxic, animal, human, adverse effects.
Literature references containing one of the following key terms were excluded:
environmental, soil, marine, pollution, pharmacology, drug effect, therapeutic.
The literature from this search was selected based on titles and abstracts. The last
search was performed on September 3, 2012.
Scope                                                                                25
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<pre>6 Arsenic and inorganic arsenic compounds</pre>

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<pre> hapter 2
        Identity, properties and monitoring
2.1     Chemical identity
        In this section, the chemical identity of arsenic and different arsenic compounds
        are described.7-9
        Chemical name: Arsenic
        Synonyms: Arsenic Black; Arsenic, elemental; Arsenic - 75; Arsenicals;
        Colloidal arsenic; Gray arsenic
        Molecular formula: As
        CAS-number: 7440-38-2
        EINECS-number: 231-148-6
        Chemical name: Arsenic trioxide
        Synonyms: AI3-01163; Arseni trioxydum; Arsenic (III) oxide; Arsenic oxide;
        Arsenic oxide (As2O3); Arsenic sesquioxide
        Molecular formula: As2O3
        CAS-number: 1327-53-3
        EINECS-number: 215-418-4
        Chemical name: Arsenic pentoxide
        Synonyms: Arsenic acid anhydride; Arsenic anhydride; Arsenic oxide; Arsenic
        oxide (As2O5); Arsenic pentaoxide
        Identity, properties and monitoring                                               27
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<pre>  Molecular formula: As2O5
  CAS-number: 1303-38-2
  EINECS-number: 215-116-9
  Chemical name: Arsenic acid
  Synonyms: Arsenate; Arsenic acid; Arsenic acid (H3AsO4); Arsenic acid, liquid;
  Crab grass killer
  Molecular formula: H3AsO4
  CAS-number: 7778-39-4
  EINECS-number: 231-901-9
  Chemical name: Arsenic trichloride
  Synonyms: Arsenic butter; Arsenic chloride; Arsenic chloride (AsCl3); Arsenic
  trichloride; Arsenic(III) chloride
  Molecular formula: AsCl3
  CAS-number: 7784-34-1
  EINECS-number: 232-059-5
  Chemical name: Arsenic trisulphide
  Synonyms: AI3-01006; Arsenic Red; Arsenic Sulphide Yellow; Arsenic Yellow;
  Arsenic sesquisulphide; Arsenic sesquisulphide
  Molecular formula: As2S3
  CAS-number: 1303-33-9
  EINECS-number: 215-117-4
  Chemical name: Sodium arsenite
  Synonyms: Arsenenous acid, sodium salt; Arsenious acid, monosodium salt;
  Arsenious acid, sodium salt; Arsenite de sodium (French); Atlas “A”
  Molecular formula: NaAsO2
  CAS-number: 7784-46-5
  EINECS-number: 232-070-5
  Chemical name: Arsenic acid, trisodium salt
  Synonyms: Sodium arsenate; Sodium orthoarsenate; Trisodium arsenate
  Molecular formula: Na3AsO4
  CAS-number: 13464-38-5
  EINECS-number: 236-682-3
8 Arsenic and inorganic arsenic compounds
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<pre>Chemical name: Arsenenous acid, potassium salt
Synonyms: Arsenenous acid, potassium salt; Arsenic acid (HAsO2), potassium
salt; Arsenious acid, (HAsO2), potassium salt (8CI); Potassium arsenite
Molecular formula: KH(AsO2)2
CAS-number: 13464-35-2
EINECS-number: -
Chemical name: Potassium arsenate
Synonyms: Arsenic acid (H3AsO4), monopotassium salt; Arsenic acid,
monopotassium salt; Macquer's salt; Monopotassium arsenate; Monopotassium
dihydrogen arsenate Molecular formula: KH2AsO4
CAS-number: 7784-41-0
EINECS-number: 232-065-8
Chemical name: Arsenic acid, calcium salt
Synonyms: Calcium arsenate
Molecular formula: Ca3(AsO4)2
CAS-number: 7778-44-1
EINECS-number: 231-904-5
Chemical name: Calcium arsenite
Synonyms: Arsenous acid, calcium salt; Arsonic acid, calcium salt (1:1);
Calcium arsonate (1:1); Calcium meta-arsenite; Mono-calcium arsenite
Molecular formula: CaAsO3H
CAS-number: 52740-16-6
EINECS-number: 258-147-3
Chemical name: Lead arsenate
Synonyms: Acid lead arsenate; Acid lead orthoarsenate; Arsenate of lead;
Arsenic acid (H3AsO4), lead(2+) salt (1:1); Arsenic acid, lead(2+) salt(1:1)
Molecular formula: Pb3(AsO4)2
CAS-number: 7784-40-9
EINECS-number: 232-064-2
Chemical name: Copper(II) arsenite
Synonyms: Acid copper arsenite; Air-flo Green; Arsenious acid (H3AsO3),
copper(2+) salt (1:1); Arsonic acid, copper(2+) salt (1:1); Copper arsenite
Molecular formula: Cu(AsO2)2
CAS-number: 10290-12-7
Identity, properties and monitoring                                          29
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<pre>    EINECS-number: 233-644-8
    Chemical name: Cupric acetoarsenite
    Synonyms: (Acetato)trimetaarsenitodicopper; (Acetato-
    O)(trimetaarsenito)dicopper; Basle Green; CI Pigment Green 21; Copper acetate
    arsenite
    Molecular formula: C4H6As6Cu4O16
    CAS-number: 12002-03-8
    EINECS-number: -
    Chemical name: Magnesium arsenate
    Synonyms: Arsenic acid, magnesium salt; Magnesium O-arsenate; Magnesium
    arsenate phosphor
    Molecular formula: Mg3(AsO4)2
    CAS-number: 10103-50-1
    EINECS-number: 233-285-7
2.2 Physical and chemical properties
    In Table 1, the physical and chemical properties of arsenic and different arsenic
    compounds are presented.7,9,10 No data on physical and chemical properties of
    the following arsenic compounds were available: arsenic acid, trisodium salt;
    arsenenous acid, potassium salt; arsenic acid, calcium salt and calcium arsenite.
2.3 EU Classification and labeling
    The classification of arsenic and arsenic compounds based on EC Regulation
    1272/2008 on classification, labelling and packaging of substances and mixtures
    is presented in Table 2.11 No concentration limits are specified for the different
    arsenic compounds.
 0  Arsenic and inorganic arsenic compounds
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<pre>                                      Table 1 Physical and chemical properties of arsenic and arsenic compounds.
                                                                                                                           Arsenic trichlo-     Arsenic trisulp-                         Potassium arse-                       Copper (II) arse-     Cupric acetoarse-
                                                                                         Arsenic pen-                                                                                                                                                                      Magnesium
                                                        Arsenic
                                                                    Arsenic trioxide
                                                                                         toxide
                                                                                                          Arsenic acid     ride                 hide
                                                                                                                                                                     Sodium arsenite
                                                                                                                                                                                         nate
                                                                                                                                                                                                             Lead arsenate     nite                  nite                  arsenate
                                      Physical   grey,            white,               white      white solid            oily,       yellow-red grey-whi- white,      white,      n.d.                                                             emerald     n.d.
                                      descript-  crystlline       amor-                hygros-    substance              colourless powder      tish pow- crystalline crystalline                                                                  green,
                                      tion       solid with       phous or             copic pow-                        liquid with            der       powder      solid                                                                        crystalline
                                                 metallic         crystalline          der                               acrid smell                                                                                                               powder
                                                 luster           powder
                                      Molar mass 74.9             197.8                229.8            141.9            181.3                246.0                129.9               180.0               347.1             277.4                 1013.8                350.8
                                      (g/mol)
                                      Melting    sublima-         312        decom-      35.5                            -16                  300-325              n.d.                288                 decom-      decom-                      n.d.                  86.3
                                      point (oC) tion at 613                 position at                                                                                                                   position at position
                                                                             315                                                                                                                           720
Identity, properties and monitoring
                                      Boiling         -           465        -           loses H2O                       130                  707                  n.d.                n.d.                n.d.        n.d.                        n.d.                  n.d.
                                      point (oC)                                         at 160
                                      Density         5,727       3,738      4,320       2,000-                          2,100                n.d.                 1,870               2,900               n.d.              n.d.                  n.d.                  n.d.
                                      kg/m3                                              2,500
                                      Solubility      insoluble soluble in soluble in soluble in                         decom-               insoluble            very                soluble in soluble in n.d.                                  soluble in soluble i
                                                      in water; water (37 water          alcohol                         posed by             in cold              soluble in          cold water water                                            acids      water
                                                      soluble in g/L at 20oC (1500 g/L                                   water;               water,               water               (190 g/L at (8.5*105                                                   (2.7*105
                                                      nitric acid and 115 g/ at 16oC and                                 soluble in           slightly             (1*106 mg/          6oC), very mg/L at                                                     mg/L at
                                                                  L at       767 g/L at                                  ethanol,             soluble in           L at 25oC);         so-luble in 25oC);                                                     17oC)
                                                                  100oC);    100oC);                                     ether and            hot water;           slightly            hot water; soluble in
                                                                  slightly   soluble in                                  concen-tra-          soluble in           soluble in          soluble in nitric acid
                                                                  soluble in alcohol;                                    ted mine-            alkali,              ethanol             acid, glyce- and in
                                                                  alcohol;   soluble in                                  ral acids            acids and                                rol and      caustic
                                                                  soluble in acid                                                             ethanol                                  ammonia alkalis
                                                                  hydrogen
                                                                  chloride
                                      Log Poctanol/   0.680       -0.130     n.d.        3.140                           1.610                n.d.                 -3.280              n.d.                -2.490            n.d.                  n.d.                  -7.290
                                      water
                                      Vapour          3.3*10-10   3.7*10 -11           n.d.             7.6*10-20        1.3                  n.d.                 8*10-19             n.d.                1.9*10-19         n.d.                  n.d.                  n.d.
                                      pressure                                                                           (23.5oC)
                                      (kPa;
                                      25oC)
31
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<pre> 2                                       Table 1 Continued.
                                                                                                                            Arsenic trichlo-     Arsenic trisulp-                         Potassium arse-                       Copper (II) arse-     Cupric acetoarse-
                                                                                          Arsenic pen-                                                                                                                                                                      Magnesium
                                                         Arsenic
                                                                     Arsenic trioxide
                                                                                          toxide
                                                                                                           Arsenic acid     ride                 hide
                                                                                                                                                                      Sodium arsenite
                                                                                                                                                                                          nate
                                                                                                                                                                                                              Lead arsenate     nite                  nite                  arsenate
                                         Relative    n.d.          n.d.                 n.d.             n.d.             n.d.                 n.d.                 n.d.                n.d.                5.79              n.d.                  n.d.                  n.d.
                                         density
                                         (air=1)
                                         Flash point n.d.          n.d.                 n.d.             n.d.             n.d.                 n.d.                 n.d.                n.d.                n.d.              n.d.                  n.d.                  n.d.
                                         Odor thres- n.d.          n.d.                 n.d.             n.d.             n.d.                 n.d.                 n.d.                n.d.                n.d.              n.d.                  n.d.                  n.d.
                                         hold
                                         n.d.: no data
Arsenic and inorganic arsenc compounds
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<pre> able 2 Classification of arsenic and arsenic compounds.
Arsenic compound                     CAS number          Classification
Arsenic                              7440-38-2           Acute Tox. 3; H331 (Toxic if inhaled)
                                                         Acute Tox. 3; H301 (Toxic if swallowed)
Arsenic trioxide                     1327-53-3           Carc. 1A; H350 (May cause cancer)
                                                         Acute Tox. 2; H300 (Fatal if swallowed)
                                                         Skin Corr. 1B; H314 (causes severe skin burns and eye damage)
Arsenic pentoxide                    1303-28-2           Carc. 1A ; H350 (May cause cancer)
                                                         Acute Tox. 3; H331 (Toxic if inhaled)
                                                         Acute Tox. 3; H301 (Toxic if swallowed)
Arsenic acid                         7778-39-4           Carc. 1A ; H350 (May cause cancer)
                                                         Acute Tox. 3; H331 (Toxic if inhaled)
                                                         Acute Tox. 3; H301 (Toxic if swallowed)
Arsenic trichloride                  7784-34-1           -
Arsenic trisulphide                  1303-33-9           -
 odium arsenite                      7784-46-5           -
Arsenic acid, trisodium salt         13464-38-5          -
Arsenenous acid, potassium salt      13464-35-2          -
 otassium arsenate                   7784-41-0           -
Arsenic acid, calcium salt           10103-62-5          -
 alcium arsenite                     52740-16-6          -
 ead arsenate                        7784-40-9           Carc. 1A ; H350 (May cause cancer)
                                                         Repr. 1A ; H360df (May damage fertility or the unborn child)
                                                         Acute Tox. 3; H331 (Toxic if inhaled)
                                                         Acute Tox. 3; H301 (Toxic if swallowed)
                                                         STOT RE 2; H373 (May cause damage to organs through prolonged
                                                         or repeated exposure)
 upric acetoarsenite                 12002-03-8          -
 opper(II) arsenite                  10290-12-7          -
Magnesium arsenate                   10103-50-1          -
2.4           Validated analytical methods
              In this chapter the analytical methods which are available for detecting and/or
              measuring and monitoring arsenic and arsenic compounds in air and in biological
              samples are described. The intent is not to provide an exhaustive list of analytical
              methods that could be used to detect and quantify arsenic and arsenic
              compounds. Rather, the intention is to identify well-established methods that are
              used as the standard methods of analysis.
              Identity, properties and monitoring                                                                      33
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<pre>2.4.1         Environmental monitoring
              WHO/ATSDR data
              Arsenic in air is usually associated with particulate matter and therefore standard
              methods involve collection of air samples on glass fibre or membrane filters, acid
              extraction of the filters (digestion with nitric, sulphuric, perchloric acids,
              hydrogen peroxide and/or hydrochloric acid) and arsine generation. Atomic
              absorption spectrophotometry (AAS) is as yet the major technique used to
              analyse arsenic and arsenic compounds in air.
                  Table 3 summarizes methods reported in the literature for detecting arsenic
              and arsenic compounds in air samples.
 able 3 Analytical methods for determining arsenic and arsenic compounds in air samples.
 ample matrix      Sampler               Sample preparation                Assay procedure     Limit of detection References
Air (arsenic and Filter (0.8 µm          Collection filter; digestion      Hydride generation 0.02 µg/sample      NIOSH,
 ompounds, as As cellulose ester         with nitric acid, sulphuric acid, atomic absorption                      1994a12
except AsH3 and membrane)                and perchloric acid               spectrometry
As2O3) (NIOSH                                                              (HGAAS)
method 7900)
Air (arsenic       Filter (Na2CO3-       Collection on filter and H2O2 Graphite furnace        0.06 µg/sample     NIOSH,
rioxide, as As)    impregnated, 0.8 µm                                     atomic absorption                      1994b13
NIOSH method cellulose ester                                               spectrometry
 901)              membrane + backup                                       (GFAAS)
                   pad)
Air (arsenic)      Filter (0.8-½ m       Collection on filter, digestion Inductively-coupled 5.6 ng/mL            NIOSH,
NIOSH method cellulose ester             with nitric acid, sulphuric acid, plasma, atomic                         200314
 300)              membrane, or 5-½ and perchloric acid                    emission
                   m, polyvinyl                                            spectroscopy (ICP-
                   chloride membrane)                                      AES)
Air (particulate   Filter (1 µm          Collection on filter              Ion chromatography, 0.02 µg As/sample  NIOSH,
 rganoarsenal)     polytetrafluoroethyle                                   hydride generation                     199415
NIOSH method ne (PFTE)                                                     atomic absorption
 022)              membrane + backup                                       spectrometry
                   pad)
Air, wipes (smear Filter (0.8 µm         Collection on filter, digestion Graphite furnace      0.003 µg/mL        OSHA,
abs) or bulks      mixed-cellulose ester with nitric acid and              atomic absorption (qualitative);       199116
OSHA method filter and backup            stabilisation by addition of      spectrometry        0.01 µg/mL
D-105)             pad)                  nickel; thereafter, hydrochloric (GFAAS)              (quantitative)
                                         acid is added; arsine collected
                                         on charcoal is extracted using
                                         a dilute nitric acid/nickel
                                         solution
 4            Arsenic and inorganic arsenic compounds
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<pre>Air (except volatile Filter (0.8 µm       Collection on filter; digestion Graphite furnace   200 ng         Nederlands-
 rsenic              cellulose-ester      with nitric acid and            atomic absorption                 Normalisatie
 ompounds) (NEN membrane)                 hydrochloric acid               spectrometry                      -instituut,
 951)                                                                     (GFAAS)                           199917
Air (arsenic and Cellulose ester          Particulate arsenic and         Continuous flow or 0.3 ng/mL      Health and
norganic             membrane filter and inorganic compounds of           flow injection     (qualitative); Safety
 ompounds except sodium carbonate arsenic collected on cellulose          analysis hydride   1 ng/mL        Executive
AsH3) (MDHS 41/ impregnated back-up ester membrane filter; arsenic        generation atomic  (quantitative) (HSE),
 )                   paper pad, mounted trioxide vapour collected by      absorption                        199418
                     in an inhalable dust reaction with sodium            spectrometry
                     sampler              carbonate on the paper pad.
                                          Digestion using nitric acid,
                                          sulphuric acid and hydrogen
                                          peroxide
2.4.2         Biological monitoring
              WHO/ATSDR data
              Atomic absorption spectrophotometry (AAS) is the most common analytical
              procedure for measuring total arsenic in biological materials. In AAS analysis,
              the sample is heated in a flame or in a graphite furnace until the element
              atomises. The ground-state atomic vapour absorbs monochromatic radiation
              from a source and a photoelectric detector measures the intensity of transmitted
              radiation. Inductively-coupled plasma atomic emission spectrometry (ICP-AES)
              and ICP-mass spectrometry (ICP-MS) are used techniques for the analysis of
              arsenic; both methods can generally provide lower detection limits than
              absorbance detection methods. Samples may be prepared for AAS in a variety of
              ways. Most often, the gaseous hydride procedure is employed. In this procedure,
              arsenic in the sample is reduced to arsine (AsH3), a gas which is then trapped and
              introduced into the flame. This approach measures total inorganic arsenic, but
              may not detect all organic forms unless preceded by a digestion step. Digestion
              or wet-ashing with nitric, sulphuric and/or perchloric acids degrades the organic
              arsenic species to inorganic arsenic so that recovery of total arsenic from
              biological materials can be achieved. For accurate results, it is important to check
              the completeness of the oxidation, however, this is seldom done.
              The arsenic concentration in biological fluids and tissues may also be determined
              by neutron activation analysis (NAA). In this approach, the sample is irradiated
              with a source of neutrons which converts a portion of the arsenic atoms to
              radioactive isotopes which can be quantified after separation from radioisotopes
              of other chemicals. Neutron activation has limited use because it depends on the
              Identity, properties and monitoring                                                                       35
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<pre>  presence of the number of nuclear reactors providing this service and the need to
  dispose of radioactive waste.
  X-ray fluorescence (XRF) is also capable of measuring arsenic in biological
  materials. This method has the advantage that no sample digestion or separation
  steps are required. Hydride generation combined with atomic fluorescence
  spectroscopy (HG/AFS) is a relatively new technique that provides freedom
  from interference offered by hydride generation with sensitivity better than to 20
  parts per trillion and linearity up to 10 ppm.
      The ATSDR in 20077 summarizes details of a number of methods for the
  analysis of total arsenic in biological samples e.g. total arsenic in blood using HG
  AAS (Foa et al., 1984; Valentine et al. 1979), total arsenic in serum using NAA
  (Versieck et al.,1983), total arsenic in urine using colorimetry (Pinto et al. 1975),
  NAA (Landsberger and Simsons,1987), HG AAS (Guo et al., 1997) or XRF
  (Clyne et al.,1989), total arsenic in hair using HG AAS (Valentine et al.,1979;
  Curatola et al., 1978), total arsenic in nails (Agahian et al.,1990), total arsenic in
  soft tissue using GF AAS (Mushak et al.,1977).
  Speciation of arsenic (i.e., analysis of organo-arsenicals or different inorganic
  species, rather than total arsenic) is usually accomplished by employing
  separation procedures prior to introduction of the sample material into a
  detection system. Various types of chromatography or chelation-extraction
  techniques are most commonly used in combination with AAS, ICP-AES, or
  ICP-MS detection methods. In one method, HPLC is combined with HG/AFS to
  quantify arsenite (AsIII), arsenate (AsV), monomethylarsonic acid and
  dimethylarsinic acid. Another approach involves selective reduction of arsenate
  and arsenite (permitting quantification of individual inorganic arsenic species),
  and selective distillation of methyl arsines to quantify monomethylarsonic acid
  and dimethylarsinic acid. Most methods for measuring arsenic in biological
  samples, are unable to measure arsenobetaine with any accuracy because it does
  not form a hydride and it gives a different response from inorganic arsenic in
  electrothermal AAS.
      The ATSDR in 20077 summarizes details of a number of methods for the
  speciation analysis of arsenic metabolites in urine. Ion exchange chromatography
  (IEC) was combined with HG-AAS (Johnson and Farmer, 1989) or ICP-MS
  (Inoue et al., 1994). HPLC was combined with HG-AAS (Norin and Vahter,
  1981) or ICP-MS (Ebdon et al., 1999). Selective distillation was combined with
  ICP-AES (Braman et al., 1977).
      Detection limits for arsenic in blood and urine are about 0.1-1 ppb for most
  techniques; limits for hair and tissues are usually somewhat higher.
6 Arsenic and inorganic arsenic compounds
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<pre>             Additional data
             Especially the recognition of the role of methylated arsenicals that contain AsIII
             in the toxicity and metabolism of arsenic (see Chapter 5, 6 and 7) emphasised the
             need for hyphenated analytical methods to detect and quantify these species in
             biological samples. Hence, a method was developed by Del Razo et al.(2001)19
             to exploit pH-dependent differences in the generation of arsines from inorganic
             and methylated arsenicals that contain either AsV or AsIII followed by
             gaschromatographic separation and atomic absorption spectrophotomery. Le et
             al. (2000)20 also developed a method for determination of methylated arsenicals:
             ion-pair chromatographic separation with hydride generation atomic absorption
             spectrometry detection. Verdon et al. (2009)21 developed a hyphenated method
             combining HPLC with ICP-MS and Dynamic Reaction Cell (DRC) technology
             allowing the separation of 7 As species in human urine.
             Table 4 summarises details of a variety of methods for measuring total arsenic
             and individual arsenic species in biological materials.
 able 4 Analytical methods for determining arsenic compounds in biological samples.
 ample matrix         Sample preparation                          Assay procedure           Limit of detection References
Urine                 Filtering of urine specimens through a      Graphite furnace atomic   0.03 µg/L          Horng et
                      0.45 µm Millipore membrane filter;          absorption spectrometry                      al., 200222
                      microwave digestion of a mixture of         (GFAAS)
                      sample and nitric and hydrochloric acids
Urine (inorganic      Reduction with sodium borohydride to        Hydride generation atomic 1 µg/L             ACGIH,
 cid plus             arsine                                      absorption spectrometry                      200123
monomethylarsonic                                                 (HGAAS)
 cid and
 imethylarsinic acid)
Urine                 Reduction with borohydride at pH 6:         Hydride generation atomic inorganic AsIII:   Del Razo et
                      generation of arsines from inorganic AsIII, absorption spectrometry   1.1 µg As/L        al., 200119
                      methyl AsIII, and dimethyl AsIII, but not (HGAAS)                     methyl AsIII:
                      from inorganic AsV, methyl AsV, and                                   1.2 µg As/L
                      dimethyl AsV; reduction with borohydride                              dimethyl AsIII:
                      at pH 2 or lower: generation of arsines                               6.5 µg As/L
                      from arsenicals that contained either AsV
                      or AsIII. Arsines are trapped in a liquid
                      nitrogen-cooled gas chromatographic trap,
                      which is subsequently warmed to allow
                      separation of the hydrides by their boiling
                      points.
             Identity, properties and monitoring                                                                        37
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<pre>Urine (determination                                              Ion-pair chromatographic   4 µg/L              Le et al.,
 f AsIII, AsV,                                                    separation/Hydride                             200020
monomethylarsonic                                                 generation atomic
 cid, dimethylarsinic                                             absorption spectrometry
 cid and                                                          (HGAAS)
monomethyl-
 rsonous acid)
Urine (AsIII, AsV,    Dilution with ammonium acetate, pH 5,       High-performance liquid    0.4-1.7 µg As/L     Verdon et
monomethyl-           centrifugation and injection of supernatant chromatography (HPLC)      for various species al., 200921
 rsonate,             into HPLC                                   with anion-exchange                            (CDC
 imethylarsinate)                                                 column/                                        method)
                                                                  Inductively-coupled plasma
                                                                  mass spectrometry (ICP-
                                                                  MS) with dynamic reaction
                                                                  cell (DRC)
Urine (AsIII, AsV,    Dilution with water, filtration and         High-performance liquid    (LODs for anion-    Suzuki et
MMA, DMA              injection of filtrate into HPLC             chromatography (HPLC)      resp. cation mode)  al., 200924
                                                                  with anion and cation-     AsIII 0.3/0.3 µg
                                                                  exchange column/           As/L
                                                                  Inductively-coupled plasma AsV 0.2/0.4 µg
                                                                  mass spectrometry (ICP-    As/L
                                                                  MS)                        MMA 0.2/0.3 µg
                                                                                             As/L
                                                                                             DMA 0.3/0.2 µg
                                                                                             As/L
Urine (AsIII, AsV,    Dilution with water, filtration and         High-performance liquid    AsIII 0.11 µg As/L  Xie et al.,
MMAV, DMAV,           injection of the filtrate into HPLC         chromatography (HPLC)      AsV 0.25 µg As/L    200625
MMAIII, DMAIII                                                    with anion and cation-     MMAV 0.18 µg
                                                                  exchange column/           As/L
                                                                  Inductively-coupled plasma DMAV 0.17 µg
                                                                  mass spectrometry (ICP-    As/L
                                                                  MS)                        MMAIII 0.61 µg
                                                                                             As/L
                                                                                             DMAIII 0.44 µg
                                                                                             As/L
  8            Arsenic and inorganic arsenic compounds
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<pre> hapter 3
        Sources
3.1     Natural occurrence
        WHO/ATSDR data
        Arsenic is the main constituent of more than 200 mineral species, of which about
        60% are arsenate, 20% sulphide and sulphosalts and the remaining 20% include
        arsenides, arsenites, oxides and elemental arsenic (Onishi, 1969). The most
        common of the arsenic minerals is arsenopyrite, FeAsS, and arsenic is found
        associated with many types of mineral deposits, especially those including
        sulphide mineralisation (Boyle and Jonasson, 1973). It has been estimated that
        about one-third of the atmospheric flux of arsenic is of natural origin. Volcanic
        action is the most important natural source of arsenic, followed by low-
        temperature volatilisation.
        The ability of arsenic to bind to sulphur ligands means that it tends to be found
        associated with sulphide-bearing mineral deposits, either as separate arsenic
        minerals or as a trace of a minor constituent of the other sulphide minerals. This
        leads to elevated levels in soils in many mineralised areas where the
        concentrations of associated arsenic can range from a few milligrams to > 100
        mg/kg. Concentrations of various types of igneous rocks range from < 1 to 15 mg
        As/kg, with a mean value of 2 mg As/kg. Similar concentrations (< 1-20 mg As/
        kg) are found in sandstone and limestone. Significantly higher concentrations of
        Sources                                                                            39
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<pre>      up to 900 mg As/kg are found in argillaceous sedimentary rocks including shales,
      mudstone and slates. Up to 200 mg As/kg can be present in phosphate rocks
      (O’Neill, 1990). Concentrations of arsenic in open ocean water are typically 1-2
      µg/L. The concentrations of arsenic in unpolluted surface water and groundwater
      are typically in the range of 1-10 µg/L. Elevated concentrations in surface water
      and groundwater of up to 100-5,000 µg/L can be found in areas of sulphide
      mineralisation (Welch et al., 1988; Fordyce et al., 1995). Elevated concentrations
      (> 1 mg As/L) in groundwater of geochemical origins have also been found in
      Taiwan (Chen et al., 1994), West Bengal, India (Chatterjee et al., 1995; Das et al.,
      1995, 1996; Mandal et al., 1996) and more recently in most districts of
      Bangladesh (Dhar et al.,1997; Biswas et al., 1998). Elevated arsenic
      concentrations were also found in the drinking water in Chile (Borgono et al.
      1977); North Mexico (Cebrian et al., 1983); and several areas of Argentina
      (Astolfi et al.,1981; Nicolli et al., 1989; De Sastre et al.,1992). Arsenic-
      contaminated groundwater was also found in parts of PR China (Xinjiang and
      Inner Mongolia) and the USA (California, Utah, Nevada, Washington and
      Alaska) (Valentine, 1994). More recently, arsenic concentrations of < 0.98 mg/L
      have been found in wells in south-western Finland (Kurttio et al.,1998). Levels
      as high as 35 mg As/L and 25.7 mg As/L have been reported in areas associated
      with hydrothermal activity (Kipling, 1977; Tanaka, 1990).
      In nature, arsenic-bearing minerals undergo oxidation and release arsenic to
      water. This could be one explanation for the problems of arsenic in the
      groundwater of West Bengal and Bangladesh. In these areas the groundwater
      usage is very high. It has been estimated that there are about 4-10 million tube
      wells in Bangladesh alone. The excessive withdrawal and lowering of the water
      table for rice irrigation and other requirements lead to the exposure and
      subsequent oxidation of arsenic-containing pyrite in the sediment. As the water
      table recharges after rainfall, arsenic leaches out of the sediment into the aquifer.
3.2   Man-made sources
3.2.1 Production
      WHO/ATSDR data
      Arsenic is presently obtained as a byproduct of the smelting of copper, lead,
      cobalt, and gold ores. Arsenic trioxide is volatilised during smelting and
      accumulates in the flue dust from the roasting of ores, which may contain up to
      30% arsenic trioxide. The crude flue dust is further refined by mixing with small
 0    Arsenic and inorganic arsenic compounds
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<pre>      amounts of galena or pyrite and roasting to yield a arsenic trioxide of 90-95%
      purity. By successive sublimations, a purity of 99% can be obtained.
      Subsequently, arsenic and arsenic compounds can be prepared by the reduction
      of arsenic trioxide with charcoal. Demand for metallic arsenic is limited and thus
      most arsenic is marketed and consumed in combined form, principally as arsenic
      trioxide which is subsequently converted to arsenic acid.
3.2.2 Use
      WHO/ATSDR data
      Arsenic and arsenic compounds have different uses6,7,26-28, e.g.:
      • as wood preservative, primarily chromium copper arsenate (CCA) (CrO3-
          CuO•As2O5). Chrome copper arsenate is a water-based product that protects
          several commercially-available species of western lumber from decay and
          insect attack. It is widely used in treating utility poles, building lumber, and
          wood foundations. 10,10’-Oxybisphenoxarsine is an antimicrobial used
          primarily in the plastics industry
      • as a cotton desiccant/defoliant
      • in the manufacture of galium arsenide and other intermetallic compounds
          that are used in a variety of semiconductor applications including solar cells,
          light-emitting diodes, lasers, and integrated circuits (high purity arsenic)
      • as a decolouriser (elimination of the green colour) and fining agent in the
          production of bottle glass and other glassware (arsenic, arsenic trioxide (e.g.,
          manufacturing of low-melting glasses, lightening glass and removing of air
          bubbles) and arsenic acid)
      • in the production of non-ferrous alloys, principally lead alloys used in lead-
          acid batteries (used in automobiles) and copper alloys (arsenic pentoxide and
          As2O3 are used as additives in alloys). Arsenic may be added to alloys used
          for bearing, type metal, lead ammunition, automotive body solder. It is also
          added to some brasses to improve corrosion resistance
      • in agriculture (mainly in the past). Organic arsenicals, namely cacodylic acid,
          disodium methylarsenate, monosodium methylarsenate, and arsenic acid are
          still used as herbicides. From the mid-nineteenth century to the introduction
          of organic pesticides in the 1940s, inorganic arsenic compounds were the
          dominant pesticides available to farmers and fruit growers. Calcium arsenate
          was formerly used to control the boll weevil and cotton worm and used as a
          herbicide. Lead arsenate was used on apple and other fruit orchards as well as
          on potato fields. Sodium arsenite was used to control weeds on railroad right-
      Sources                                                                              41
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<pre>      of-ways, potato fields, and in industrial areas, as well as in baits and to
      debark trees. Sodium arsenate had some application in ant traps. The use of
      inorganic arsenic compounds in agriculture has virtually disappeared
      beginning around the 1960s. Inorganic arsenic’s remaining allowable uses
      are in ant baits and wood preservatives (see above). All agricultural uses of
      arsenic were banned because of concerns about human health risk during
      production and application or accidental poisoning at the point of use
  •   as a medication. Inorganic arsenic was used as a therapeutic agent through
      the mid twentieth century, primarily for the treatment of psoriasis, and
      chronic bronchial asthma; organic arsenic antibiotics were extensively used
      in the treatment of spirochetal and protozoal disease. Organic arsenical drugs
      continue to be used in treating the meningoencephalitic stage of African
      trypanosomiasis and amoebic dysentery
  •   in veterinary medicine to treat parasitic diseases, including filariasis in dogs
      and black head in turkeys and chickens
  •   in dental surgery (until the early eighties)
  •   as a feed additive for poultry and swine (arsenilic acid (p-aminophenyl-
      arsonic acid) until the late nineties, and for cattle and sheep dips (sodium
      arsenite).
  Additional data
  •   Inorganic arsenic may be a part of a wide variety of traditional herbal
      medicines, often from asian origin and therefore the development and
      production of such herbal praparations requires strict control.29
  With regard to agriculture and/or (veterinary) medical purposes of arsenic and
  inorganic compounds in the Netherlands:
  • ‘Superwolmanzout-CO’ (CCA), a biocide contaning arsenic pentoxide as an
      active substance 30 was allowed in The Netherlands until 2006
  • different drugs for usage in humans are registered by the Netherlands’
      Medicines Evaluation Board which contain arsenic compounds as the active
      substance 31 e.g. arsenic trioxide is recently allowed for the treatment of
      acute promyelocytic anemia
  • according to the Netherlands’ Medicines Evaluation Board, which is also
      responsible for the authorisation of veterinary medicines, arsenic and arsenic
      compounds are not used as (active substances in) veterinary medicines 32.
2 Arsenic and inorganic arsenic compounds
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<pre> hapter 4
        Exposure
4.1     General population
        WHO/ATSDR data
        Arsenic is found naturally in the environment and therefore exposure to arsenic
        may occur by eating food, drinking water, or breathing air. The most common
        inorganic arsenical in air is arsenic trioxide (As2O3), while a variety of inorganic
        arsenates (AsO4-3) or arsenites (AsO2-) occur in water, soil, or food. Food is
        usually the largest source of arsenic (also in the Netherlands). Fish and seafood
        contain the greatest amounts of arsenic, mostly the organic form of arsenic.
        Children may also be exposed to arsenic by eating dirt.7 In some areas arsenic in
        drinking water is a significant source of exposure to inorganic arsenic. In these
        cases, arsenic in drinking water often constitutes the principal contributor to the
        daily arsenic intake. Contaminated soils such as mine tailings are also a potential
        source of arsenic exposure.6 Exposure may also occur by skin contact with water
        that contains arsenic or by contact with contaminated soil. Furthermore, arsenic
        compounds are used as a desiccant for cotton. If arsenic is retained in cotton, the
        general public may be exposed.7
        The concentration of arsenic in natural surface and groundwater is generally
        about 1 µg/L but may exceed 1,000 µg/L in mining areas or where arsenic levels
        in soil are high. Groundwater is far more likely to contain high levels of arsenic
        Exposure                                                                             43
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<pre>  than surface water. Levels of arsenic in food range from about 20 to 140 µg/kg.7
  Limited data indicate that approximately 25% of the arsenic present in food is
  inorganic, but this depends highly on the type of food ingested. Inorganic arsenic
  levels in fish and shellfish are low (< 1%). Foodstuffs such as meat, poultry,
  dairy products and cereals have higher levels of inorganic arsenic. The daily
  intake of total arsenic from food and beverages is generally between 20 and 300
  µg/day.6
      Mean total arsenic concentrations in air from remote and rural areas range
  from 0.02 to 4 ng/m3. Mean total arsenic concentrations in urban areas range
  from 3 to about 200 ng/m3; much higher concentrations (> 1,000 ng/m3) have
  been measured in the vicinity of industrial sources. Pulmonary exposure may
  contribute up to approximately 10 µg/day in a smoker and about 1 µg/day in a
  non-smoker, and more in polluted areas.6
  In addition to the normal levels of arsenic in air, water, soil, and food, exposure
  to higher levels of arsenic may occur:
  • some hazardous waste sites contain large quantities of arsenic. If the material
      is not properly disposed of, it can get into surrounding water, air, or soil. For
      people living near such a site, exposure to elevated levels of arsenic from
      these media may occur
  • when sawing or sanding arsenic-treated wood, inhalation of some of the
      sawdust may occur. Similarly, if burning arsenic-treated wood, inhalation of
      arsenic from the smoke may occur
  • in a formerly agricultural area where arsenic was used on crops, the soil
      could contain high levels of arsenic
  • in the past, several kinds of products used in the home (rat poison, ant poison,
      weed killer, some types of medicines) had arsenic in them. However, most of
      these uses of arsenic have ended, so exposure from home products is not
      likely any longer.7
  Additional data
  Data on Dutch emission registrations showed a total emission of arsenic and its
  compounds into air of 0.425 tonnes.33
4 Arsenic and inorganic arsenic compounds
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<pre>4.2 Working population
    WHO/ATSDR data
    Occupational exposure to arsenic may be significant in several industries, mainly
    nonferrous smelting, arsenic production, electronics, wood preservation, wood
    joinery, glass manufacturing, arsenical pesticide production and application, and
    pharmaceutical 6. Since arsenic compounds are used as a desiccant for cotton,
    workers involved in harvesting and ginning cotton may be exposed to arsenic. If
    any arsenic is retained in the cotton, workers in the fabric may be exposed. The
    electronics industry is expanding the use of gallium arsenide in the production of
    electro-optical devices and integrated circuits, and workers in the industry where
    gallium arsenide is used may be exposed to arsenic.7
        Exposure is primarily through inhalation of arsenic-containing particulates,
    but ingestion and dermal exposure may be significant in particular situations
    (e.g. chromium copper arsenate (CCA)-treated timber). It is extremely rare for
    workers to be exposed to arsenic alone; the exposure is usually to arsenic in
    combination with other elements.6
        The WHO stated that data on typical exposure levels of arsenic in the
    workplace are difficult to obtain and may vary considerably between different
    locations of the same industry because of the level of occupational hygiene in
    place and the chemical properties of the materials processed. Also, they are often
    out of date with regard to the current level of industrial hygiene. In workplaces
    with up-to-date occupational hygiene practices, exposure generally does not
    exceed 10 µg/m3 (8-h time-weighted average (TWA)). However, in some places
    workroom atmospheric arsenic concentrations as high as several milligrams per
    cubic meter have been reported.6
        The following data illustrate levels found in specific industries in various
    locations worldwide and provide some information on present and past
    exposures of workers to arsenic. They should not be considered as representative
    of all similar industrial sites.
        Exposure investigations indicated that the arsenic exposure concentrations
    (8-hour TWA) in copper smelters ranged from 0.8-746 µg/m3 (Vahter et al.,
    1986; Hakala and Pyy, 1995; Jakubowski et al., 1998; Ferreccio et al., 1996;
    Offergelt et al., 1992; Liu and Chen, 1996). Much higher arsenic exposure
    concentrations were reported in older exposure investigations.
        Workers in certain glass-manufacturing industries may be exposed to
    airborne arsenic through the use of As2O3 (IARC, 1993). A study in the USA of
    Exposure                                                                           45
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<pre>  35 crystal glassworkers within the mix-and-melt and batch-house areas indicated
  the potential for arsenic exposure. Personal air monitoring of 8 workers found
  airborne arsenic concentrations of 2-11 mg/m3 (Chrostek et al., 1980).
       In a study of six wood joinery shops in Sweden (Nygren et al., 1992),
  airborne arsenic concentrations between 0.54 and 3.1 µg/m3 were reported. In
  two workshops machining wood impregnated with CCA preservatives, levels of
  arsenic in personal air samples were reported to be 30-67 µg/m3 in one plant (8
  workers) and 10-62 µg/m3 in another plant (8 workers) (Subra et al., 1999).6 In a
  study performed in Denmark to evaluate arsenic exposure in workers
  impregnating wood with CCA solutions (Jensen and Olsen, 1995), the maximum
  exposure concentration was 17.3 µg/m3, found for a single worker who was
  filling an impregnation container with CCA paste.7
       Workers in coal-powered power plants may also be exposed to arsenic found
  in the coal, or more likely that found in the fly ash during cleaning. Yager et al.
  (1997) reported arsenic concentrations (8-h TWA) between 0.17 and 375.2
  µg/m3 (mean 48.3) in the breathing zone of maintenance workers in a coal-fired
  power plant in Slovakia.
       Concentrations of arsenic in the breathing zone of underground gold-miners
  in Ontario (Canada) were reported to range between 2.4 and 5.6 µg/m3
  (geometric mean) (Kabir and Bilgi, 1993). In a study relating arsenic exposures
  to lung cancer among tin-miners in Yunnan province (China), Taylor et al. (1989)
  reported mean concentrations of airborne arsenic to range from 0.42
  mg/m3 in 1951 to 0.01 mg/m3 in 1980.6
       NIOSH researchers conducted a study of arsenic exposures and control
  systems for gallium arsenide operations at three microelectronics facilities
  during 1986-1987 (Sheehy and Jones, 1993). Results at one plant showed that in
  all processes evaluated but one, the average arsenic exposures were at or above 5
  µg/m3, with a maximum exposure of 8.2 µg/m3. While cleaning the liquid
  encapsulated Czochralski (LEC) pullers, the average potential arsenic exposure
  of the cleaning operators was about 500 µg/m3. Area arsenic samples collected at
  the plant in break-rooms and offices, 6-20 meters from the process rooms, had
  average arsenic concentrations of 1.4 µg/m3. At the other two plants, personal
  exposures to arsenic were well controlled for all processes evaluated. In another
  study (de Peyster and Silvers, 1995), airborne arsenic was found in areas where
  equipment was cleaned but not in administrative areas in a semiconductor
  fabrication facility. The highest airborne arsenic level found in the study, 15
  µg/m3, was collected from the breathing zone of a maintenance employee who
  was cleaning a source housing over a period of 2 hours in an area with local
  exhaust ventilation.7
6 Arsenic and inorganic arsenic compounds
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<pre>Additional data
In a study performed at three semiconductor manufacturing facilities34, twenty of
31 personal airborne arsenic exposure samples were below the detection limit of
0.01 µg/m3. The geometric mean arsenic level of the remaining 11 samples was
1.66 µg/m3 (GSD = 2.2). The highest personal arsenic level was 7 µg/m3 and was
experienced by an engineer who was dismounting and scrubbing major parts of
the ion implanter for 4 hours.
    Smith and Coulehan (2002) reported that exposure to arsenic may also occur
when handling museum artifacts (e.g. skins, furs, baskets, feathers).35 In previous
centuries, various toxic pest control treatments and preservatives including
arsenic compounds were used to maintain the integrity of artifacts. However, no
quantitative information was reported.
    Baptiste (2000) reported exposure to arsenic in a battery manufacturing
facility. No quantitative information was reported.36
    Grillet et al. (2004) reported exposure to arsenic in the wine growing industry
(use of arsenic as a fungicide) without reporting quantitative information.37
Exposure                                                                            47
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<pre>8 Arsenic and inorganic arsenic compounds</pre>

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<pre> hapter 5
        Kinetics
5.1     Absorption
        WHO/ATSDR data
        Arsenic absorption depends on its chemical form. The rate of absorption of
        arsenic in highly insoluble forms (e.g., arsenic sulphide, lead arsenate) is much
        lower than that of more soluble forms via both oral and inhalation routes. In
        humans, AsIII, AsV, monomethylarsonic acid, and dimethylarsinic acid are orally
        absorbed ≥ 80%.
            Arsenic is also absorbed via inhalation. In lung cancer patients exposed to
        arsenic in cigarette smoke, deposition was estimated to be about 40% and
        absorption was 75-85% (Holland et al., 1959). Thus, overall absorption
        (expressed as a percentage of inhaled arsenic) was about 30-34%. In workers
        exposed to arsenic trioxide dusts in smelters, the amount of arsenic excreted in
        the urine was about 40-60% of the estimated inhaled dose (Pinto et al., 1976;
        Vahter et al., 1986). Absorption appears to be by passive diffusion in humans and
        mice, although there is evidence for a saturable carrier-mediated transport
        process for arsenate in rats.
            Absorption by the dermal route has not been well characterised, but is low
        compared to the other routes.
        Kinetics                                                                          49
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<pre>  Additional data
  Because human occupational exposure to high levels of arsenic in air has been
  associated with lung cancer, but generally not other types of cancer, Beck et al.
  (2002) investigated the relationship between airborne arsenic exposures and
  systemic uptake in rabbits.38 New Zealand white rabbits were chosen as the test
  animal because metabolism of arsenic in rabbits and humans is fairly similar,
  with the exception that humans excrete somewhat more monomethylarsonic acid
  than rabbits. The animals (n=6/sex/concentration) were exposed to one of four
  levels of arsenic trioxide in air for 8 hr/day, 7 days/week, for 8 weeks (0.05, 0.1,
  0.22, or 1.1 mg/m3; Mass Median Aerodynamic Diameter (MMAD) ranged from
  3.2 to 4.1 µm; GSD not specified). The airborne arsenic within each exposure
  chamber was reasonably well mixed, and variations in exposure concentrations
  within an exposure group are likely to have been minimal. Plasma levels of
  inorganic arsenic, monomethylarsonic acid, and dimethylarsinic acid were
  measured following the last exposure. Total arsenic calculated as the sum of
  inorganic arsenic, monomethylarsonic acid, and dimethylarsinic acid showed a
  concentration-related increase. Although there was also a concentration-related
  increase in plasma levels of methylated arsenic metabolites, statistically
  significant increases in mean inorganic arsenic levels in plasma were observed
  only in male rabbits exposed to 0.22 mg/m3, and in both males and females
  exposed to 1.1 mg/m3. Mean inorganic arsenic levels in plasma in males and
  females exposed to 0.05 and 0.1 mg/m3, and females exposed to 0.22 mg/m3,
  were not significantly elevated compared to controls. According to the authors
  these results suggest that low level arsenic inhalation has a negligible impact on
  body burden of inorganic arsenic until air levels are above ± 0.15 mg/m3. Based
  on plasma measurements of inorganic arsenic, the two lowest exposure levels in
  this study (0.05 and 0.1 mg/m3) are indistinguishable from background.
  In contrast to the others, Hazelton et al. (2001) found indications for
  accumulation of arsenic in the lung.39 In this study Hazelton et al. used the two-
  stage clonal expansion model to analyse lung cancer mortality in a cohort of
  Yunnan tin miners. As part of this study, models were tested with variable arsenic
  clearance rates. Analysis suggested that particles containing arsenic accumulate
  in the lung with very slow clearance. The best estimate was for a half-life of
  about 6 years, but the difference in likelihood for a 6-year half-life compared
  with no decay was not significant.
0 Arsenic and inorganic arsenic compounds
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<pre>5.2   Distribution
5.2.1 Distribution through the body
      WHO/ATSDR data
      Data on distribution after inhalation exposure are limited, but it appears that
      arsenic is transported to nearly all tissues. Arsenic and its metabolites distribute
      to all organs in the body; preferential distribution has not been observed in
      human tissues at autopsy or in experiments with animal species other than rat (in
      which arsenic is concentrated in red blood cells). Since the liver is a major site
      for the methylation of inorganic arsenic, a first-pass effect after gastrointestinal
      absorptionis possible; however this has not been investigated in animal models.
      Furthermore, arsenic accumulates in keratin-rich tissues such as skin, hair and
      nails.
      Additional data
      After the administration of arsenicals (route not specified) to animals, elevated
      levels were found especially in liver, kidney, spleen, and lung; several weeks
      later, arsenic is translocated to ectodermal tissues (hair, nails) because of the high
      concentration of sulphur-containing proteins in these tissues.40
      Hughes et al. examined the disposition of arsenic after repeated oral
      administration of arsenate in mice.41 Adult female B6C3F1 mice (n=10) were
      administered nine repeated oral daily doses of 0.5 mg As/kg ([73As]arsenate)
      (estimated dose regimen for attaining steady-state levels of whole-body arsenic).
      Accumulation of radioactivity (ng As/g tissue) was highest in bladder, kidney,
      and skin. Loss of radioactivity was most rapid in the lung and slowest in the skin.
          Monomethylarsonic acid was detected in all tissues except the bladder.
      Bladder and lung had the highest percentage of dimethylarsinic acid after a
      single exposure to arsenate, and it increased with repeated exposure. In kidney,
      inorganic arsenic was predominant. There was a higher percentage of
      dimethylarsinic acid in the liver than the other arsenicals after a single exposure
      to arsenate. The percentage of hepatic dimethylarsinic acid decreased and that of
      inorganic arsenic increased with repeated exposure. A trimethylated metabolite
      was also detected in the liver.
      Kinetics                                                                               51
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<pre>5.2.2 Placental transfer
      WHO/ATSDR data
      Human studies
      Case reports of arsenic poisoning in pregnant women resulting in death of the
      foetus; by toxic levels of arsenic in foetal organs and tissues demonstrate that
      arsenite readily passes through the placenta (Lugo et al., 1969; Bollinger et al.,
      1992). In a more recent study, Concha et al. (1998) reported that arsenic
      concentrations were similar in cord blood and maternal blood (~9 µg/L) of
      mother - infant pairs exposed to drinking water containing high levels of arsenic
      (~200 µg/L). Another study of an ‘unexposed’ population in the southern USA
      found that concentrations of arsenic in cord blood and maternal blood (about 2
      µg/L) were also similar, and suggests that arsenic readily crosses the placenta
      (Kagey et al., 1977).
      Animal studies
      Both older and more recent studies have documented the ability of trivalent and
      pentavalent inorganic arsenic to cross the placenta in laboratory animals.
      Lindgren et al., (1984) reported that in pregnant mice given a single intravenous
      injection (4 mg As/kg) of sodium arsenate or sodium arsenite, both forms passed
      through the placenta easily and to approximately the same extent. These
      investigators also reported that the rate of placental transfer was lower in a
      marmoset monkey (non-methylating species) injected intravenously with
      arsenite than in mice, and suggested that this was a consequence of stronger
      binding in maternal tissues.
          Hood et al. (1987) compared the foetal uptake of sodium arsenate after oral
      (40 mg/kg) or intraperitoneal (20 mg/kg) administration to pregnant CD-1 mice
      on day 18 of gestation. Arsenic levels peaked later and over 5-fold lower in
      foetuses of mice dosed orally, most likely reflecting both slower uptake from the
      gastrointestinal tract and greater opportunity for methylation in the liver before
      the arsenic reached the systemic circulation. The quantity of dimethylated
      metabolite present in the foetuses rose over time (to ~80% of total metabolites
      present for both routes of administration) and remained relatively constant from
      ~10 h after dosing until the study ended, 24 h after dosing.
          Hood et al. (1988) also compared the foetal uptake of sodium arsenite after
      oral (25 mg/kg) or intraperitoneal (8 mg/kg) administration to mice that were 18
      days pregnant. As was the case with arsenate, injected mice achieved both higher
 2    Arsenic and inorganic arsenic compounds
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<pre>foetal and placental levels of arsenic more quickly than did mice dosed orally.
Both valence forms followed similar time-course trends after oral administration.
However, levels of arsenic in foetuses of dams injected with arsenite reached a
plateau 12-24 h after dosing, whereas levels of arsenic in foetuses of dams
injected with arsenate peaked at 2-4 h after dosing and then declined quickly. The
proportion of arsenic present in foetuses as methylated metabolite increased over
time to 88% and 79% after oral and intraperitoneal administration, respectively.
A higher fraction of monomethylated arsenic was present in foetuses of dams
dosed with arsenite than with arsenate.
Older studies have demonstrated that dimethylarsenic acid is capable of crossing
the placenta of rats (Stevens et al., 1977).
Additional data
Human studies
The abovementioned study of Concha et al. (1998) also showed that arsenic
metabolites originating from inorganic As in the blood of both the newborns and
their mothers was in the form of DMA, which indicated that DMA is the major
form of arsenic transferred from mothers to their foetuses.
    In a recent study in Bangladesh (Hall et al., 2007) where people are exposed
to waterborne arsenic a study was conducted in 101 pregnant women who gave
birth.42 Maternal and cord blood pairs were collected and concentrations of total
As were analyzed for 101 pairs and As metabolites for 30 pairs. Strong
associations between maternal and cord blood concentrations were observed for
total As (r=0.93, p<0.0001), but also for DMA (0.94, p < 0.0001), MMA (r=0.80,
p<0.0001), arsenite (r=0.8, p< 0.0001) and arsenate (r=0.89, p < 0.0001). This
implies that exposure to all metabolites of inorganic As occurs in the prenatal
period.
Animal studies
Jin et al. (2006) investigated in an experimental study in mice the transfer of
arsenic species from the mother through the placenta in newborn pups, and the
speciated arsenic distribution in the liver and brain of newborn mice after
gestational maternal exposure to inorganic arsenic.43 The mother mice were
exposed to 10 and 30 ppm inorganic AsIII and 10 and 30 pm AsV in drinking
water during gestation. The livers and brains of the mother mice and their
newborn pups were collected and As, monomethylarsonic acid (MMAV),
dimethylarsinic acid (DMAV), and trimethylarsenic (TMA) were analysed.
Kinetics                                                                           53
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<pre>    Contents of inorganic arsenic As, MMA, and DMA in the liver of mother mice
    increased with the concentration of arsenite or arsenate in their drinking water.
    However, only DMA increased with the concentration of arsenate or arsenite in
    the drinking water in the brain of the mother mice. On the other hand, the
    contents of both inorganic As and DMA in the liver and brain of newborn mice
    increased with the concentration of arsenate or arsenite administered to their
    mother orally. Contents of arsenic species in the liver and brain of both mother
    mice and their newborn pups were significantly lower in the 10 ppm AsV group
    than in the 10 ppm inorganic AsIII group. Ratios of As or DMA levels between
    the brain and the liver of newborn mice were larger than 1, whereas those in
    mother mice were much smaller than 1. Arsenic taken from drinking water was
    distributed and metabolized mainly in the liver of mother mice. AsIII in low
    levels may be taken up and metabolized easily in the liver compared to iAsV.
    Both inorganic As and DMA are transferred from the mother through the
    placenta and cross the immature blood-brain barrier easily. Compared to that in
    the liver of newborn mice, DMA as an organic metabolite is prevalent in brain, a
    lipidic organ, if the blood-brain-barrier is not matured enough to prevent it from
    entering the brain.
5.3 Biotransformation
    WHO/ATSDR data
    In many species arsenic metabolism is characterised by two main types of
    reactions: (1) two-electron reduction reactions of pentavalent to trivalent arsenic,
    and (2) oxidative methylation reactions in which trivalent forms of arsenic are
    sequentially methylated to form mono-, di- and trimethylated products using S-
    adenosyl methionine (SAM) as the methyl donor and glutathione as an essential
    co-factor. Methylation of inorganic arsenic facilitates the excretion of inorganic
    arsenic from the body, as the endproducts monomethylarsonic acid (MMAV) and
    dimethylarsinic acid (DMAV) are readily excreted in urine. There are major
    qualitative and quantitative interspecies differences in methylation, to the extent
    that some species exhibit minimal or no arsenic methylation (e.g. marmoset
    monkey, guinea-pig, chimpanzee). However, in humans and most common
    laboratory animals, inorganic arsenic is extensively methylated. Factors such as
    dose, age, gender and smoking contribute only minimally to the large inter-
    individual variation in arsenic methylation observed in humans. Studies in
    humans suggest the existence of a wide difference in the activity of
    methyltransferases, and the existence of polymorphism has been hypothesised.
 4  Arsenic and inorganic arsenic compounds
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<pre>Animal and human studies suggest that arsenic methylation may be inhibited at
high acute exposures. The metabolism of inorganic arsenic may be influenced by
its valence state, particularly at high dose levels. Studies in laboratory animals
indicate that administration of trivalent inorganic arsenic such as As2O3 and
arsenite initially results in higher levels in most tissues than does the
administration of pentavalent arsenic. However, the trivalent form is more
extensively methylated.
Additional data
Monomethylarsonic acid (MMAV) may be methylated to dimethylarsinic acid
(DMAV), but neither monomethylarsonic acid nor dimethylarsinic acid are
demethylated to yield inorganic arsenic. Recent data showed that both
monomethylarsonous acid (MMAIII) and dimethylarsinous acid (DMAIII) are
persistent metabolites that can be identified in the urine of individuals
chronically exposed to arsenic in drinking water.20,19 A simplified scheme of
overall arsenic metabolism in many mammals including humans is shown in
Figure 1.
There is a variation in susceptibility to arsenic and arsenic compounds among
individuals, which is related to variation in metabolism. On average, the urine of
people exposed to inorganic arsenic occupationally, experimentally, or in the
general environment, contains 10-30% inorganic, 10-20% monomethylarsonic
acid, and 60-70% dimethylarsinic acid, but there is a considerable inter-
individual variation. Also, recent studies have identified groups with unusually
low or high urinary excretion of monomethylarsonic acid. Thus, there appears to
be a genetic polymorphism in the biomethylation of arsenic. Most likely, there is
a genetic polymorphism in the regulation of arsenic methyltransferases
(Schläwicke et al., 2009).44 However, the methyltransferases involved in arsenic
methylation have not been characterised. Possibly, arsenic metabolism is also
affected by the polymorphism in enzymes involved in the remethylation of
homocysteine.45
Kinetics                                                                           55
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<pre>                                                                                                            Dimethylarsinous
                                                                                                                        III
                                                                                                              acid (DMA )
Figure 1 Metabolism of arsenic in the liver: reduction from pentavalent to trivalent arsenic states may occur nonenzymatically
 ia glutathione or enzymatically. Oxidation and methylation are coupled in arsenic metabolism with the trivalent arsenic form
 s substrate and a methylated pentavalent form as the product. AsV, AsIII, monomethylarsonic acid (MMAV) (humans excrete a
 elatively high amount of monomethylarsonic acid in their urine), monomethylarsonous acid (MMAIII), dimethylarsinic acid
 DMAV) (the major form in many mammals; 60-80% in humans), and dimethylarsinous acid (DMAIII) are found in human
 rine. In rats, some arsenic is further metabolised to a form with three methyl groups, TMAO. Some forms of arsenic can
 eversibly change valence state from pentavalent to trivalent and back again (e.g. arsenate ↔ arsenite). SAM (S-adenosyl
methionine): serves as the methyl donor; SAH (S-adenosylhomocysteine); GSH (glutathione reduced); GSSG (glutathione
 xidised) (sources: Kitchin46 and Tchounwou et al.28). There is a considerable variation in the methylation of inorganic arsenic
 mong mammalian species. Compared to human subjects most experimental animals (mouse, rat, rabbit, hamster, dog) excrete
 ery little MMA, while the methylation to DMA is more efficient than in humans. There is an overall higher excretion of
 rsenic in urine of experimental animals than in humans except for the rat since most of the produced DMA is retained in the
 rythrocytes. The chimpanzee and the marmoset monkey however lack the ability to methylate arsenic.33
  6            Arsenic and inorganic arsenic compounds
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<pre>5.4   Elimination
5.4.1 Elimination from the body
      WHO/ATSDR data
      In humans arsenic is largely excreted via the renal route as a mixture of AsV,
      AsIII, monomethylarsonic acid, monomethylarsonous acid, dimethylarsinic acid
      and dimethylarsinous acid. This excretion mechanism is not likely to be saturated
      within the dose range expected from human exposure. The proportion of
      metabolites recovered in urine are roughly consistent in humans regardless of the
      exposure scenario. Smaller amounts are excreted in faeces. Some arsenic may
      remain bound to tissues (especially skin, hair, and nails), depending inversely on
      the rate and extent of methylation.
      Additional data
      Mice (n=5) were administered a single oral dose of 0.5 mg As/kg
      ([73As]arsenate) to estimate the half-life of the terminal elimination phase of
      arsenic-derived radioactivity (Hughes et al.).41 The half-life of the phase
      describing the rapid elimination of radioactivity following its absorption from
      the gut and entry into the plasma amounted to 2.2 h. The phase describing
      elimination of radioactivity which had first distributed throughout the whole
      animal, some of it perhaps retained, and then was released and finally eliminated
      had a half-life of ± 44 h.
          Furthermore, Hughes et al. examined the elimination of arsenic after repeated
      oral administration of arsenate.41 Adult female B6C3F1 mice (n=10) were
      administered nine repeated oral daily doses of 0.5 mg As/kg ([73As]arsenate)
      (estimated dose regimen for attaining steady-state levels of whole-body arsenic).
      Radioactivity was eliminated from mice after repeated [73As]arsenate exposure,
      primarily by urinary excretion (the urinary vs. fecal elimination of arsenic
      amounted to 9.8 ± 0.4 and 1.9 ± 0.3 µg As/day, respectively). There was no
      significant difference in the amount of arsenic eliminated in urine or faeces each
      day after administration of [73As]arsenate. After repeated dosing ceased, the
      amount of arsenic excreted decreased rapidly. Dimethylarsinic acid was the
      predominant arsenic metabolite detected (approximately 9-10 µg As/day) in
      urine during each 24 h period after administration of [73As]arsenate. Smaller
      amounts of arsenate, arsenite, and monomethylarsonic acid were detected (all
      Kinetics                                                                           57
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<pre>      <0.5/µg As/day). The amount of each metabolite excreted in urine each day did
      not vary significantly over the 9-day dosing period.
5.4.2 Elimination in human milk
      Various studies indicated that arsenic can be excreted in human milk.
      WHO/ATSDR data
      In the Bombay area (India) Dang et al. (1983) reported arsenic levels ranging
      from 0.2 to 1.1 ng/g in breast milk of nursing mothers 1-3 months postpartum.
      Arsenic was detected in human breast milk at concentrations of 0.13-0.82 ng/g
      (Somogyi and Beck, 1993). In human milk sampled from 88 mothers on the
      Faroer Islands whose diets were predominantly seafood, arsenic concentrations
      were 0.1-4.4 ng/g (Grandjean et al., 1995). Exposure to arsenic from the seafood
      diet in this population was most likely to organic “fish arsenic.” In a population
      of Andean women exposed to about 200 ng/g of inorganic arsenic in drinking
      water, concentrations of arsenic in breast milk ranged from about 0.8 to 8 ng/g
      (median 2.3 ng/g) (n=10) (Concha et al., 1998). The arsenic concentration in the
      breast milk of 35 women in Ismir, Turkey, a volcanic area with high thermal
      activity ranged from 3.24 to 5.41 ng/g, with a median of 4.22 ng/g (Ulman et al.,
      1998).
      Additional data
      Two hundred and twenty-six breast milk samples were collected from lactating
      women in arsenic-affected districts of west Bengal (Samanta et al., 2009).47 In
      only 39 (17%) samples arsenic was detected. The maximum arsenic
      concentration in breast milk was 48 µg/L. Hair and nail arsenic was highly
      correlated with drinking water arsenic concentrations. Women who had both
      high arsenic body burden and arsenical skin lesions also had elevated levels of
      arsenic in their breast milk.
 8    Arsenic and inorganic arsenic compounds
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<pre>5.5 Possibilities for biological monitoring
    WHO/ATSDR data
    The three most commonly employed biomarkers used to identify or quantify
    arsenic exposure are total arsenic in hair or nails, blood arsenic, and total or
    speciated metabolites of arsenic in urine.
    Arsenic is rapidly cleared from blood. It is for this reason that blood arsenic is
    typically used only as an indicator of very recent or relatively high-level
    exposure (e.g. in cases of poisoning), or chronic stable exposure (e.g. to drinking
    water). The limitation of blood arsenic levels as indicators of low-level exposure
    or drinking water is that it is difficult to distinguish the contributions of inorganic
    arsenic from water and organic arsenic from food (speciation of chemical forms
    in blood is difficult).
    Because arsenic accumulates in keratin-rich tissues such as skin, hair and nails as
    a consequence of its affinity for sulfhydryl groups, arsenic levels in hair and nails
    may be used as an indicator of past arsenic exposure (exposure that occurred 1-
    10 months earlier). Hair and nails have the advantage of being readily and non-
    invasively sampled, but a major issue of concern is whether external
    contamination can be removed (e.g., when exposed to water containing high
    arsenic levels, hair can bind arsenic externally which may not be removed readily
    by washing procedures). Arsenic levels in both hair and nails are elevated within
    one to a few weeks after acute poisoning, and return to background levels within
    a few months (Choucair and Ajox, 1988). Fingernail arsenic has been reported to
    be significantly correlated with hair arsenic content (Lin et al., 1998). Since the
    rate of hair growth is about 1 cm/month, the segmental distribution of arsenic
    along the hair shaft has been used to distinguish between acute and chronic
    poisoning, as well as to estimate length of time since a poisoning incident
    (Koons and Peters, 1994). The use of toenails rather than fingernails has been
    recommended in some studies because of the larger amount of sample that can
    generally be obtained (Garland et al., 1993; Karagas et al., 1996).
    Since arsenic is rapidly metabolised and excreted into the urine, total arsenic,
    inorganic arsenic and the sum of arsenic metabolites (inorganic arsenic +
    monomethylarsonic acid + dimethylarsinic acid) in urine have all been used as
    biomarkers of recent arsenic exposure. Urinary levels are generally considered to
    Kinetics                                                                                59
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<pre>  be the most reliable indication of recent exposures. In common with other
  biomarkers of arsenic exposure, levels of arsenicals in urine may be a
  consequence of inhalation exposure or ingestion of arsenic from drinking water,
  beverages, soil or foodstuffs (NRC, 1999). In many older studies, total urinary
  arsenic was used as a biomarker of recent arsenic exposure. However, this is
  increasingly uncommon because organoarsenicals present in substantial amounts
  in certain foodstuffs are also excreted in urine. Therefore, assessment of
  inorganic arsenic exposure using total urinary arsenic would result in
  overestimation of inorganic arsenic exposure. To avoid the potential for
  overestimation of inorganic arsenic exposure inherent in using total urinary
  arsenic, most studies now measure specific metabolites in urine and use either
  inorganic arsenic or the sum of arsenic metabolites (inorganic arsenic +
  monomethylarsonic acid + dimethylarsinic acid) as an index of arsenic exposure.
  Relatively recently it has been found that adding all arsenic metabolites together
  can give misleading results unless a careful diet history is taken and/or seafood
  consumption is prohibited for 2-3 days before urine collection (Buchet et al.,
  1996). There are two reasons for this. First, some seafoods contain arsenic
  metabolites MMA and DMA, particularly DMA, in fairly high amounts.
  Secondly, arsenosugars present in seaweeds and some bivalves are extensively
  metabolised to DMA (either by the body itself or the gut microbiota, which is
  than excreted in urine (Le et al., 1994, Ma and Le, 1998, WHO 20016).
  Additional data
  Hwang et al. (2002)48 analysed urinary inorganic arsenic metabolites in the urine
  of 12 office-based engineers (control group) and 30 maintenance engineers
  (exposure group) from six wafer fabrication facilities (semiconductor industry).
  No personal airborne arsenic exposure samples were taken. First morning-voided
  urine samples of each study subject were collected for 7 consecutive days. The
  levels of the various arsenic species for the exposed group were 1.7±1.4, 1.4±1.1,
  6.2±6.7, 20.2±14.1, and 29.5±17.2 µg/L for AsIII, AsV, monomethylarsonic acid,
  dimethylarsinic acid, and total inorganic arsenic, respectively. Although there
  was no significant difference in total urinary arsenic concentrations of the control
  (27.4 ± 17.7 µg/L) and the exposed group, monomethylarsonic acid content was
  significantly higher in the exposed group than in the control group (4.0± 5.5 µg/
  L; P<0.05). The data also suggested that, at low-level occupational arsenic
  exposure, the concentration of total urinary inorganic arsenic metabolites might
  be misleading due to the confounding effect resulting from intake of seafood,
  such as arsenosuger. Nevertheless, the authors concluded that using the
0 Arsenic and inorganic arsenic compounds
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<pre>    percentage change of monomethylarsonic acid in total urinary inorganic arsenic
    metabolites as an indicator for the verification of arsenic exposure is appropriate
    for monitoring of urinary arsenic species.
5.6 Possibilities for biological effect monitoring
    WHO/ATSDR data
    The effects of arsenic are mainly nonspecific, but the combined presence of
    several of the most characteristic clinical signs (e.g., nausea, diarrhoea,
    peripheral neuropathy, anaemia, vascular lesions, hyperkeratinisation,
    hyperpigmentation) is usually adequate to suggest arsenic intoxication. Although
    there are standard clinical methods for detecting and evaluating each of these
    effects, there are no recognised methods for identifying early (preclinical) effects
    in exposed persons. Neurophysiological measurements of nerve conduction
    velocity or amplitude have been investigated (Goebel et al., 1990; Jenkins, 1966;
    Le Quesne and McLeod, 1977; Morton and Caron, 1989; Murphy et al., 1981),
    but at present, this approach does not seem to offer much advantage over a
    standard neurological examination. Arsenic is known to affect the activity of a
    number of enzymes, and some of these may have potential as biomarkers of
    effect. Most promising is the spectrum of effects caused by arsenic on the group
    of enzymes responsible for heme synthesis and degradation, including inhibition
    of coproporphyrinogen oxidase and heme synthetase and activation of heme
    oxygenase. Changes in urinary excretion levels of several heme-related
    metabolites appear to be a good indication of preclinical effects of arsenic
    toxicity in animals (Albores et al., 1989; Sardana et al., 1981; Woods and Fowler,
    1978; Woods and Southern, 1989), but this has not been established in humans
    and is not specific for arsenic-induced effects.
    Additional data
    Apostoli et al. (2002) evaluated the possible effect of inorganic arsenic and of its
    species on the urinary excretion of porphyrin homologues.49 Total porphyrins
    and their homologues (copro, penta, hexa, hepta, uroporphyrins) and arsenic
    species (trivalent and pentavalent As; monomethyl arsonic acid; dimethyl arsenic
    acid; arsenobetaine) were measured respectively by HPLC and HPLC-ICP-MS
    in urine from 86 art glass workers exposed to As2O3 and from 54 controls
    (workers from tool makers without exposure to inorganic arsenic). Individuals
    with liver or kidney diseases were excluded. A significant increase in the
    Kinetics                                                                             61
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<pre>    excretion of penta and uroporphyrins was demonstrated for workers exposed to
    As; AsIII was the species best correlated with urinary porphyrin excretion. The
    increase of urinary excretion for some porphyrin homologues appears to be
    consistent with the inhibition by arsenic of uro-decarboxylase in the heme
    biosynthesis pathway.
    Wu et al. (2004) administered young female C57Bl/6J mice drinking water
    containing 0, 100, 250 and 500 µg AsV/L as sodium arsenate ad libitum for 12
    months.50 Urine was collected bimonthly for urinary arsenic methylation assay
    and porphyrin analysis. All detectable arsenic species showed strong linear
    correlation with administered dosage and the arsenic methylation patterns were
    similar in all three treatment groups. No significant changes of methylation
    patterns were observed over time for either the control or test groups. Urinary
    coproporphyrin III was significantly increased in the 8th month in 250 and 500
    µg/L groups and remained significantly dose-related after 10 and 12 months.
    Coproporphyrin I also showed a significant dose-response relationship after 12
    months.
5.7 Summary
    Absorption via both oral and inhalation routes is dependent on the solubility and
    the size of particles. Both pentavalent and trivalent soluble arsenic compounds
    are rapidly and extensively (>70%) absorbed from both gastrointestinal tract and
    the lung. Dermal absorption appears to be much less than by the oral or
    inhalation routes. Arsenic and its metabolites distribute to all organs in the body;
    preferential distribution has not been observed. Arsenic readily crosses the
    placenta.
        Arsenic metabolism is characterised by two main types of reactions: (1) two-
    electron reduction reactions of pentavalent to trivalent arsenic, which may occur
    nonenzymatically via glutathione or enzymatically, and (2) oxidative
    methylation reactions in which trivalent forms of arsenic are sequentially
    methylated to form mono-, di- and trimethylated products using S-adenosyl
    methionine (SAM) as the methyl donor and reduced glutathione (GSH) as an
    essential co-factor. Some forms of arsenic can reversibly change valence state
    from pentavalent to trivalent and back again.
    Arsenic and its metabolites are largely excreted via the renal route. Excretion can
    also occur via faeces; a minor excretion pathway is nails and hair. Different
    studies indicated that arsenic can be excreted in human milk.
 2  Arsenic and inorganic arsenic compounds
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<pre>Blood arsenic is a useful biomarker in the case of acute arsenic poisoning or
stable chronic high-level exposure. Arsenic in hair and nails can be indicators of
past arsenic exposure. Arsenic in hair may also be used to estimate relative
length of time since an acute exposure. Speciated metabolites in urine expressed
either as inorganic arsenic or as the sum of metabolites provide the best
quantitative estimate of recently absorbed dose of arsenic.
    Arsenic is known to affect the activity of a number of enzymes, and some of
these may have potential as biomarkers of effect. Most promising is the spectrum
of effects caused by arsenic on the group of enzymes responsible for heme
synthesis and degradation.
Kinetics                                                                           63
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<pre>4 Arsenic and inorganic arsenic compounds</pre>

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<pre> hapter 6
        Mechanisms of action
6.1     Mechanisms of toxicity and carcinogenicity
        WHO/ATSDR data
        Mechanisms of arsenic-induced toxicity and carcinogenicity have not been
        clearly identified. Due to the extremely large amount of mechanistic data for
        arsenic, it is not feasible to include all primary studies that address issues
        concerning proposed mechanisms. Therefore, the discussion of mechanisms is
        based on information from several review articles (Chen et al., 2004, 2005;
        Florea et al., 2005; Hughes, 2002; Kitchin, 2001; Lantz and Hays, 2006; Navas-
        Acien et al., 2005; Rossman, 2003; Roy and Saha, 2002; Thomas et al., 2007;
        Vahter, 2002).
        It is becoming increasingly evident that the toxicity and carcinogenicity of
        arsenic is likely to be closely associated with metabolic processes. Absorbed
        pentavalent arsenic (AsV) is rapidly reduced to trivalent arsenic (AsIII), at least
        partially in the blood. Much of the formed AsIII is distributed to tissues and
        taken up by cells (particularly hepatocytes). Many cell types appear to
        accumulate AsIII more rapidly than AsV. Because AsIII (as arsenite) is known to
        be more toxic than AsV (as arsenate), the reduction step may be considered
        bioactivation rather than detoxification. Glutathione appears to play a role in the
        reduction of AsV to AsIII, which is required prior to methylation. Methylation of
        Mechanisms of action                                                                65
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<pre>  arsenic ultimately forms relatively less toxic MMA and DMA; this process is
  accomplished by alternating between the reduction of AsV to AsIII and the
  addition of a methylgroup; S-adenosylmethionine (SAM) is considered to be the
  source of the methylgroup. The methylation process appears to include multiple
  intermediates, some of which are more reactive than inorganic arsenic. For
  example, reactive trivalent metabolites, MMAIII and DMAIII, have been detected
  in the urine of human subjects chronically exposed to arsenic in drinking water,
  and in vitro studies have demonstrated MMAIII to be more toxic than arsenite or
  arsenate to human hepatocytes, epidermal keratinocytes, and broncial epithelial
  cells. Additional in vitro studies have demonstrated genotoxic and DNA
  damaging properties of both MMAIII and DMAIII.
  Molecular action – Trivalent inorganic arsenic
  Trivalent inorganic arsenicals, such as arsenite, readily react with sulfhydryl
  groups in proteins and inactivate many enzymes, thereby inhibiting critical
  functions such as gluconeogenesis and DNA repair (Scott et al., 1993;
  Delnomdedieu et al., 1994a). The complex between arsenic and vicinal
  sulfhydryl reagent is particularly strong. The activity of enzymes or receptors
  essential to cellular metabolism is due in part to the functional groups on amino
  acids such as the sulfhydryl group on cysteine or coenzymes such as lipoic acid,
  which has vicinal thiol groups. Thus, if arsenite binds to a critical thiol or dithiol,
  the enzyme may be inhibited (Aposhian, 1989). Arsenite inhibits pyruvate
  dehydrogenase (Peters, 1955; Szinicz and Forth, 1988), a lipoic-acid-dependent
  enzyme involved in gluconeogenesis. The acute toxicity of inorganic arsenic
  may result in part from inhibition of gluconeogenesis and ultimately depletion of
  carbohydrates from the organism (Reichl et al., 1988; Szinicz and Forth, 1988).
  However, binding of arsenite to protein at non-essential sites may be a
  detoxication mechanism (Aposhian, 1989). Arsenite inhibits the binding of
  steroids to the glucocorticoid receptor, but not other steroid receptors (Lopez et
  al., 1990; Simons et al., 1990). The glucocorticoid receptor has vicinal thiols that
  are involved with steroid binding (Simons et al., 1990).
       A particular target in the cell for trivalent inorganic arsenic is the
  mitochondrion, which accumulates arsenic (Goier, 1991). A major mechanism
  by which arsenic exerts its toxic effect is through impairment of cellular
  respiration by the inhibition of various mitochondrial enzymes.
  Molecular action – Pentavalent inorganic arsenic
  A mechanism of toxicity of pentavalent inorganic arsenic, such as arsenate, is its
  reduction to a trivalent form, such as arsenite. The reduction of arsenate to
6 Arsenic and inorganic arsenic compounds
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<pre>arsenite occurs in vivo. Arsenite is more toxic than arsenate, as evidenced by the
lower amount of it needed to elicit a toxic response. Another potential
mechanism is the replacement of phosphate with arsenate. Kenney and Kaplan
(1988) have reported that in the human erythrocyte, arsenate can replace
phosphate in the sodium pump and the anion exchange transport system. In KB
oral epidermoid carcinoma cells, arsenate accumulates at a greater rate when the
cells are grown in phosphate-free media (Huang and Lee, 1996). Arsenate uptake
by these cells is inhibited by phosphate in a concentration-dependent manner.
Arsenate can form esters with glucose and gluconate (Lagunas, 1980; Gresser,
1981), forming glucose-6-arsenate and 6-arsenogluconate, respectively. These
compounds resemble glucose-6-phosphate and 6-phosphogluconate. Glucose-6-
phosphate and glucose-6-arsenate have similar KM and Vmax values as substrates
for glucose-6-phosphate dehydrogenase and each can inhibit hexokinase.
As a phosphate analogue, pentavalent arsenic could potentially affect a number
of biological processes, including ATP production (uncoupling of in vitro
oxidative phosphorylation), bone formation, and DNA synthesis. During
glycolysis, arsenate can substitute for phosphate to form 1-arsenato-3-phospho-
d-glycerate, instead of 1,3-biphospho-d-glycerate, from d-glyceraldehyde-3-
phosphate. The arsenic anhydride is unstable and hydrolyses to arsenate and 3-
phosphoglycerate. Normally adenosine-5'-triphosphate (ATP) is generated in this
reaction, but with arsenate present instead of phosphate, ATP is not formed
(Crane and Lipmann, 1953; Aposhian, 1989). Adenosine-5’-diphosphate-
arsenate is synthesised by submitochondrial particles from adenosine-5’-
diphosphate (ADP) and arsenate in the presence of succinate (Gresser, 1981).
ADP-arsenate hydrolyses more easily than ATP. The formation and hydrolysis of
ADP-arsenate results in arsenolysis. The depletion of ATP in rabbit erythrocytes
exposed in vitro to arsenate has been reported (Delnomdedieu et al., 1994b).
Molecular action – Organic arsenic (metabolites)
Trivalent organic arsenicals react with sulfhydryl groups, as observed with
trivalent inorganic arsenicals. In vitro binding of monomethylarsonous acid
(MMAIII) and dimethylarsinous acid (DMAIII) to protein occurs to a greater
extent than with the pentavalent organic forms (Styblo and Thomas, 1997).
Monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) have been
found to be bound to protein of rat liver cytosol incubated with arsenite (Styblo
et al., 1995) and in liver and kidney of mice administered arsenite (Styblo et al.,
1996). These compounds would be in the trivalent oxidation state when bound to
protein.
Mechanisms of action                                                                67
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<pre>       Methylated trivalent arsenicals are potent inhibitors of GSH reductase
  (Styblo et al., 1997). The activity of these chemicals is greater than that of
  inorganic trivalent arsenic and the pentavalent organic arsenicals. GSH reductase
  contains five cysteine residues in each dimeric unit (Collinson and Dawes,
  1995), which may provide a binding site for trivalent arsenic to inactivate the
  enzyme.
       Pentavalent organic arsenicals are reduced in vitro by thiols to trivalent
  organic arsenicals which then bind other thiols (Cullen et al., 1984;
  Delnomdedieu et al., 1994a). The reduction of organic pentavalent arsenicals to
  their trivalent forms, as observed with inorganic pentavalent arsenicals, is a
  potential mechanism of action of the pentavalent organic arsenicals.
  Carcinogenesis – Inorganic arsenic
  Because trivalent inorganic arsenic has greater reactivity and toxicity than
  pentavalent inorganic arsenic, it is generally believed that the trivalent form is
  the carcinogen. Arsenic is not a point mutagen but does induce chromosomal
  abnormalities including changes in structure and number of chromosomes,
  endoreduplication and sister chromatid exchanges. DNA repair is inhibited by
  arsenic, and this inhibition can result in a co-mutagenic effect with x-rays, UV
  radiation and several chemicals. However, concentrations of arsenite that are
  required to inhibit DNA ligase activity in vitro are higher than that needed to
  inhibit repair within cells. This suggests that arsenite does not directly inhibit
  DNA ligase, but affects repair processes controlled by the cell (Li and
  Rossmann, 1989; US EPA, 1997; Hu et al., 1998). Arsenic may cause
  hypermethylation of DNA, particularly the promoter region, which can result in
  inactivation of tumour suppressor genes or genes involved in DNA repair (US
  EPA, 1997).
       Rossman and Wang (1999) isolated two cDNAs from arsenite-resistant
  Chinese hamster V79 cells. One of these cDNAs is almost homologous with the
  rat tumour suppressor gene fau. This tumour suppressor gene contains a
  ubiquitin-like region fused to ribosomal protein (Michiels et al., 1993).
  Klemperer and Pickart (1989) have shown that arsenite inhibits the ubiquitin-
  dependent proteolytic pathway. Rossman and Wang (1999) suggest that the gene
  product, or a component within the ubiquitin system, is targeted by arsenic,
  resulting in alterations that may result in genotoxicity and carcinogenicity.
  Mass and Wang (1997) showed that arsenite increased the methylation of the
  tumour suppressor gene p53 and induced hypermethylation of DNA. Zhao et al.
  (1997) have shown that exposure of arsenite to rat liver cells results in DNA
  hypomethylation. The rat liver cells are transformed by the exposure to arsenite,
8 Arsenic and inorganic arsenic compounds
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<pre>which may have resulted from aberrant gene expression. With respect to
oxidative stress, arsenite induces metallothionein and heat shock protein.
Catalase and superoxide dismutase reduce arsenite-induced micronuclei in CHO
cells (Wang and Huang, 1994) and sister chromatid exchanges in human
lymphocytes (Nordenson and Beckman, 1991). Antioxidants such as vitamin E,
methylamine and benzyl alcohol reduce the killing of human fibroblasts by
arsenite (Lee and Ho, 1994).
     Induction of ornithine decarboxylase, an indicator of cellular proliferation,
was observed in rat liver after administration of arsenite (Brown and Kitchin,
1996). The co-carcinogenic effect of inorganic arsenic was proposed from the
observed co-genotoxic effect of arsenite and the inhibition of DNA repair. It is
concluded that each of the modes of action could operate, that more than one
may act at the same or different concentration levels, and there is little evidence
of favouring one over any other mode of action.
     The cell-specificity of arsenic carcinogenicity in humans has been studied in
primary human epidermal keratinocytes (Germolec et al., 1997). Low
micromolar concentrations of sodium arsenite resulted in increased mRNA
transcripts and secretion of growth factors including granulocyte macrophage-
colony stimulating factor (GM-CSF), transforming growth factor alpha (TGF-α),
and the cytokine tumour necrosis factor alpha (TNF-α). Total cell numbers were
also elevated. Arsenic in drinking water also increased the number of skin
papillomas in transgenic mice in which dermal application of phorbol esters
induces papillomas (genetically initiated mice). These results support a
hypothesis that chronic low-level exposure to arsenic stimulates keratinocyte
secretion of growth factors, the resulting increased cellular division (and
concomitant DNA replication) allows greater opportunities for genetic damage
to occur.
Carcinogenesis – Organic arsenic (metabolites)
Dimethylarsinic acid has been suggested to be an initiator, on the basis of the
DNA damage it induced in rat lung (Brown et al., 1997). Wei et al. (1999) have
reported that dimethylarsinic acid is a rat bladder carcinogen after a 2 year
drinking water exposure. Most studies have focused on the tumour-promoting
activity of dimethylarsinic acid. Dimethylarsinic acid promotes tumour
development in several different organs (Yamamoto et al., 1995; Wanibuchi et
al., 1996; Yamanaka et al., 1996). Yamanaka et al. (1996) have suggested that
dimethylarsinic acid may be a tumour progressor. The nitrosamine-initiated
tumours were primarily benign, but after exposure to dimethylarsinic acid the
tumours progressed to adenocarcinomas.
Mechanisms of action                                                                69
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<pre>      One potential mechanism of tumour promotion by dimethylarsinic acid is
  increased cell proliferation, as observed in the bladder (Wanibuchi et al, 1996),
  kidney (Murai et al., 1993) and liver (Wanibuchi et al., 1997) of uninitiated rats.
  A second mechanism could be dimethylarsinic acid-induced oxidative stress. A
  dimethylarsinic acid peroxyl radical has been detected in vitro (Yamanaka et al.,
  1990) and dimethylarsinic acid induces oxidative damage in the lung of mice
  (Yamanaka et al., 1991), in the liver of rats (Wanibuchi et al., 1997) and heat
  shock and other stress-related proteins such as metallothionein. Trivalent organic
  arsenicals inhibit GSH reductase, which might result in a decreased ability of
  cells to protect against oxidants.
  Additional data
  Molecular action
  The biomethylation of arsenic, particularly the conversion to methylated
  metabolites that contain trivalent arsenic, monomethylarsonous acid (MMAIII)
  and dimethylarsinous acid (DMAIII), should be considered as a pathway for
  activation of arsenic, rather than a mode of detoxification.51-55 The trivalent
  metabolites MMAIII and DMAIII exceed inorganic arsenic in the trivalent
  oxidation state (AsIII) in potency as cytotoxins56, enzyme inhibitors57 and
  genotoxins52,58,59.
  According to Kitchin and Wallace (2008) there are three main ways in which
  arsenic species can interact with biologically important molecules.60 First,
  trivalent arsenicals (a.o. arsenite, MMAIII, DMAIII, TMAIII, can bind to the
  sulfhydryls of peptides and proteins. For example, this may give rise to inhibition
  of DNA repair enzymes. Other arsenite binding sites such as selenocysteines,
  selenium atoms and molybdenum atoms are known. Second, arsenical exposures
  may generate free radicals and other reactive species in biological systems.
  Arsenic does not generate reactive oxygen by itself but it inhibits the scavenging
  systems of reactive oxygen species. Third, arsenic exposures can result in
  changes in the methylation state of cellular DNA. Following arsenic exposures,
  both hypomethylation and hypermethylation of DNA have been demonstrated in
  several different experimental systems. Altered DNA methylation could be
  caused by prior changes in the amount and activities of the DNA methylation
  enzymes involved in both de novo and maintenance of DNA methylation.
  Alternatively DNA methylation changes could be due to a shortage of cellular S-
  adenosylmethionine (SAM) concentration due to As.
0 Arsenic and inorganic arsenic compounds
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<pre>Genotoxicity/Carcinogenesis
In a study with Chinese hamster ovary cells involving the biomethylation,
genotoxic effects and uptake of different arsenic compounds is described by
Dopp et al. (2004).61 Biomethylation covered the subsequent conversion via
reduction (pentavalent to trivalent state) and oxidative methylation (trivalent to
pentavalent state) from arsenate (AsV) via arsenite (AsIII), monomethylarsonic
acid (MMAV), monomethylarsonous acid (MMAIII), dimethylarsinic acid
(DMAV), dimethylarsinous acid (DMAIII), trimethylarsenic oxide (TMAO) to
trimethylarsine. The potency of the DNA damage decreased in the order
dimethylarsinous acid (DMAIII) > monomethylarsonous acid (MMAIII) >
arsenate and arsenite > monomethylarsonic acid (MMAV) > dimethylarsinic acid
(DMAV)> trimethylarsenic oxide (TMAO). The cellular uptake of the
compounds was measured by ICP-MS analysis, demonstrating an uptake of
0.03% for monomethylarsonic acid and dimethylarsinic acid, 2% for
monomethylarsonous acid, AsIII and AsV, and 10% uptake for dimethylarsinous
acid. It was postulated that the induction of genotoxic effects caused by the
different arsenic species is primarily dependent upon their ability to penetrate
cell membranes.61
    Kitchin (2001)46 discussed in a review 9 different possible modes of action of
arsenic carcinogenesis: induced chromosomal abnormalities, oxidative stress and
formation of reactive oxygen species (ROS), altered DNA repair, altered DNA
methylation patterns, altered growth factors, enhanced cell proliferation
(induction of cell signaling pathways that lead to expression of genes involved in
cell growth and proliferation62), promotion of carcinogenesis and progression to
malignancy, suppression of p53 and gene amplification. As yet (in 2012), four of
these modes of action, chromosomal abnormality, oxidative stress, inhibition of
DNA repair, and a continuum of altered growth factors → cell proliferation →
promotion of carcinogenesis for arsenic carcinogenesis have a degree of positive
evidence, both in experimental systems (animal and human cells) and in human
tissues, while the remaining possible modes of carcinogenic action for arsenic
(progression to malignancy, p53 suppression, altered DNA methylation patterns
and gene amplification) do not have as much evidence (Kitchin, 200146; Kitchin
and Ahmad, 200354, Beyersmann and Hartwig; 200863; Hughes and Kitchin,
200664).
• Chromosomal abnormality.7,46 Collectively, in vitro and in vivo genotoxicity
    assays have demonstrated that arsenic cause single strand breaks, formation
    of apurinic/apyrimidinic sites, DNA base and oxidative base damage, DNA-
    protein crosslinks, chromosomal aberrations, aneuploidy, sister chromatid
    exchanges, and micronuclei.65-70 Chromosomal aberrations, characterized by
Mechanisms of action                                                               71
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<pre>     chromatid gaps, breaks and fragmentation, endoreduplication, and
     chromosomal breaks, are dose-dependent and arsenite is more potent than
     arsenate. Both MMAIII and DMAIII are directly genotoxic and are many
     times more potent than arsenite at inducing DNA damage. Inorganic arsenic
     can potentiate the mutagenicity observed with other chemicals, although
     arsenic itself does not appear to induce point mutations. Arsenic-induced
     genotoxicity may involve oxidants or free radical species.
  •  Oxidative stress.7,46,64,71 Mechanistic studies of arsenic toxicity have
     suggested a role for the generation of reactive oxygen species in the toxicity
     of inorganic arsenic. Results of both in vivo and in vitro studies of arsenic-
     exposed humans and animals suggest the possible involvement of increased
     lipid peroxidation, superoxide production, hydroxyl radical formation, blood
     non-protein sulfhydryls, and/or oxidant-induced DNA damage. Reduction of
     cellular oxidant defense by treatment with glutathione-depleting agents
     results in an increased sensitivity of cells to arsenic toxicity. Support for
     mechanisms of toxicity that involve arsenic-induced oxidative stress includes
     findings that inhaled arsenic can predispose the lung to oxidative damage,
     chronic low-dose arsenic alters genes and proteins that are associated with
     oxidative stress and inflammation, and major transcriptional regulators of
     altered genes are redox sensitive.
  •  Altered DNA repair.7,46 Arsenite is known to inhibit more than 200 enzymes.
     Early work on DNA repair enzymes showed that DNA ligases I and II were
     both inhibited by arsenite (Li and Rossman, 198972; Lee-Chen et al. 199373).
     Later work with purified human DNA repair enzymes showed that arsenite
     actually increased the activities of DNA polymerase beta, O6-
     methylguanine-DNA methyltransferase and DNA ligases I, II, and III (Hu et
     al., 199874). Human poly(ADP-ribose) polymerase (PARP) activity is also
     inhibited by arsenite (Yager and Wiencke, 199775). Especially zinc-finger
     DNA repair proteins may be sensitive tartgets for arsenicals. The theory that
     altered DNA repair is the cause of arsenic carcinogenesis is particularly
     attractive because trivalent arsenic species, such as arsenite, can bind
     strongly to dithiols as well as free sulfhydryl groups in proteins. Such protein
     binding could induce inhibition of DNA repair, mutation in key genetic sites,
     or increased cell proliferation (Kitchin, 200146; Beyersmann and Hartwig,
     200863). An association between arsenic exposure and a decreased
     expression of genes involved in nucleotide excision repair, provided a
     plausible mechanism for the inhibition of DNA-repair mechanisms.76
  •  Altered growth factors → Cell proliferation → Promotion of
     carcinogenesis.7,46 Increased concentrations of growth factors can lead to cell
2 Arsenic and inorganic arsenic compounds
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<pre>        proliferation and eventual promotion of carcinogenesis. Arsenic-induced cell
        death can also lead to compensatory cell regeneration and carcinogenesis.
        Altered growth factors, cell proliferation, and promotion of carcinogenesis
        have all been demonstrated in one or more systems exposed to arsenics.
        Altered growth factors and mitogenesis were noted in human keratinocytes.
        Cell death was observed in human hepatocytes and rat bladder epithelium.
        Cell proliferation was demonstrated in human keratinocytes and intact
        human skin and rodent bladder cells. Promotion of carcinogenesis was noted
        in rat bladder, kidney, liver, and thyroid, and mouse skin and lung.
    To date a uniform mechanism of toxicity and carcinogenicity for inorganic
    arsenic and its compounds has not been put forward. Identification and
    understanding of the mode of action of arsenic genotoxicity is helpful in
    estimating cancer risk. The overall mechanistic evidence supports the view that
    genotoxicity is not caused by a direct effect of inorganic arsenic or its
    metabolites on the DNA, but via other processes which are triggered by arsenic
    and its trivalent metabolites MMAIII and DMAIII. This implies that the genotoxic
    mechanism should be considered as non-stochastic.
6.2 Summary
    Trivalent inorganic arsenicals readily react with sulfhydryl groups in proteins
    and inactivate many enzymes, thereby inhibiting critical functions such as
    gluconeogenesis and DNA repair. A mechanism of toxicity of pentavalent
    inorganic arsenic is its reduction to a trivalent form. In addition, as a phosphate
    analogue, pentavalent arsenic could potentially affect a number of biological
    processes (uncoupling of in vitro oxidative phosphorylation).
        The trivalent organic compounds, monomethylarsonous acid and
    dimethylarsinous acid, are metabolites of inorganic arsenic and exceed inorganic
    arsenic in the trivalent oxidation state in potency as cytotoxins, enzyme
    inhibitors and genotoxins. Therefore, the biomethylation of arsenic, particularly
    the conversion to methylated metabolites that contain trivalent arsenic, should be
    considered as a pathway for activation of arsenic.
    As yet (in 2012), four of modes of action underlying carcinogenesis, i.e.
    chromosomal abnormality, oxidative stress, inhibition of DNA repair, and a
    continuum of altered growth factors → cell proliferation → promotion of
    carcinogenesis, have a degree of positive evidence, both in experimental systems
    (animal and human cells) and in human tissues, while the remaining possible
    Mechanisms of action                                                                73
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<pre>  modes of carcinogenic action for arsenic (progression of carcinogenesis, p53
  suppression, altered DNA methylation patterns and gene amplification) do not
  have as much evidence.
      Identification and understanding of the mode of action of arsenic
  genotoxicity and arsenic compounds is helpful in the assessment of the cancer
  risk. The overall mechanistic evidence supports the view that genotoxicity
  should be considered as non stochastic since is not caused by a direct effect of
  inorganic arsenic or its metabolites on the DNA, but via indirect processes which
  are triggered by arsenic and its trivalent metabolites.
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<pre> hapter 7
        Effects
        WHO/ATSDR references are summarized in Annex F.
7.1     Observations in humans
        Human data are summarized in Tables 10-15 (Annex G).
7.1.1   Irritation and sensitisation
        WHO/ATSDR data
        Arsenite can induce irritative contact dermatitis after occupational exposure
        (Goncalo et al., 1980), but dermal sensitisation to inorganic arsenic appears to be
        rare. Barbaud et al. (1995) reported on the contact hypersensitivity of arsenic in a
        crystal factory employee. A patch test was done with various compounds from
        the workplace, and arsenate was the only chemical that tested positive.
        Local effects on the respiratory tract
        Inhalation of inorganic arsenic dusts (usually containing mainly arsenic trioxide)
        is irritating to the nose, throat, and lungs, and can lead to laryngitis, bronchitis,
        and rhinitis (without an indication of an allergic response) (Dunlap, 1921;
        Lundgren, 1954; Morton and Caron, 1989; Pinto and McGill, 1953). However,
        Effects                                                                               75
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<pre>      chronic functional impairment of respiration is not usually observed in workers
      even exposed to high levels of arsenic trioxide in air (Perry et al., 1948).
      Local effects on the skin
      Relatively little information is available on effects due to direct dermal contact
      with inorganic arsenicals, but several studies indicate the main effect is local
      irritation and dermatitis, with little risk of other adverse effects. Usually the
      effects are mild (erythema and swelling) but may progress to papules, vesicles,
      or necrotic lesions in extreme cases (Holmqvist, 1951). These conditions tend to
      heal without treatment if exposure ceases. Effects of this type have only been
      observed in workplace environments where there are high levels of arsenic dusts
      (Holmqvist, 1951; Pinto and McGill, 1953), and have not been noted in people
      exposed to arsenic in water or soil (presumably because the concentrations of
      arsenic that contact the skin from water or soil are too low to cause significant
      irritation).
      Local effect on the eyes
      Chemical conjunctivitis, characterised by redness, swelling, and pain, usually in
      combination with facial dermatitis, has been observed in workers exposed to
      arsenic dusts in air (Dunlap, 1921; Pinto and McGill, 1953). No information was
      located regarding air levels of arsenic that produce this effect.
      Additional data
      No additional data on irritation and sensitisation of arsenic and arsenic
      compounds was found in literature for the period up to September 3, 2012.
      According to EC Regulation 1272/2008 on classification, labelling and
      packaging of substances and mixtures11, arsenic trioxide is labelled Skin Corr.
      1B; H314 (causes severe skin burns and eye damage).
7.1.2 Acute toxicity
      WHO/ATSDR data
      Inorganic arsenic is acutely toxic and ingestion of large doses leads to
      gastrointestinal symptoms, disturbances of cardiovascular and central nervous
      system functions, multiorgan failure and eventually death. In survivors, bone
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<pre>marrow depression, haemolysis, hepatomegaly, melanosis, polyneuropathy and
encephalopathy may be observed.
No cases were located regarding death in humans from inhalation exposure to
inorganic arsenicals following acute exposure, even at the very high exposure
levels (1-100 mg As/m3) found previously in the workplace (e.g., Enterline and
Marsh, 1982; Jarup et al., 1989; Lee-Feldstein, 1986). Dermal exposure to
inorganic arsenicals has not caused lethality in humans. Acute lethality caused by
ingestion of inorganic arsenic is usually attributable to cardiopulmonary collapse
(Levin-Scherz et al., 1987; Saady et al., 1989), while delayed lethality results
from failure of one or more of the many tissues injured by arsenic (Campbell and
Alvarez, 1989). Estimates of the minimum lethal oral dose in humans range from
1 to 3 mg As/kg bw/day (Armstrong et al., 1984; Holland, 1904; Vallee et al.,
1960), although there may be considerable variation between individuals. Facial
oedema, generally involving the eyelids, was a prominent feature of inorganic
arsenic poisoning among 220 cases associated with an episode of ingestion of
soy sauce contaminated with arsenic in Japan (Mizuta et al., 1956) and has also
been reported in poisoning cases in the United States (Armstrong et al., 1984).
The oedema developed soon after the initial exposure and then subsided.
Additional data
No case reports were found on inhalation exposure. Several human case reports
on arsenic ingestion were found in literature for the period up to September 3,
2012 (see Annex G, Table 11).77-85 The acute oral toxicity of arsenic was
summarised as follows: fatal consequences have been reported with acute doses
of inorganic arsenic between 70-300 mg, equivalent to 1-4 mg/kg bw.
    Symptoms of acute intoxication usually occur within 30 min of ingestion but
may be delayed if arsenic is taken with the food. Initially, a patient may have a
metallic taste or notice a slight garlicky odor to the breath associated with a dry
mouth and difficulty in swallowing. Early clinical symptoms at acute arsenic
intoxication may be muscular pain, weakness, with flusking skin. Severe nausea
and vomiting, colicky abdominal pain, and profuse diarrhea with rice-water
stools abruptly follow. Capillary damage leads to generalized vasodilation,
transudation of plasma, and vasogenic shock. Arsenic's effect on the mucosal
vascular supply, not a direct corrosive action, leads to transudation of fluid in the
bowel lumen, mucosal vesical formation, and sloughing of tissue fragments. The
patient may complain of muscle cramps, numbness in hands and feet, reddish
rashes in the body, and intense thirst.
Effects                                                                               77
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<pre>          In severe poisoning, the skin becomes cold and clammy, and some degree of
      circulatory collapse usually occurs along with kidney damage and decreased
      urine output. Drowsiness and confusion are often seen along with the
      development of a psychosis associated with paranoid delusions, hallucinations,
      and delirium. Finally, seizures, coma, and death, usually due to shock, may
      follow. Following the gastrointestinal phase, multisystem organ damage may
      occur. If death does not occur in the first 24 h from irreversible circulatory
      insufficiency, it may result from hepatic or renal failure over the next several
      days. Cardiac manifestations include acute cardiomyopathy, subendocardial
      hemorrhages, and electrocardiographic changes. The most common changes on
      an electrocardiogram are prolonged QT intervals and nonspecific ST-segment
      changes. 86,87,88
      According to EC Regulation 1272/2008 on classification, labelling and
      packaging of substances and mixtures11, arsenic, arsenic pentoxide and lead
      arsenate are labelled Acute Tox. 3; H331 (Toxic if inhaled) and H301 (Toxic if
      swallowed). Furthermore, arsenic trioxide is labelled Acute Tox. 2; H300 (Fatal
      if swallowed).
7.1.3 Short-term toxicity
      WHO/ATSDR/additonal data
      No data were available on inhalation exposure. The major effects of subacute
      oral exposure are gastrointestinal, haematological and dermal.
7.1.4 Long-term toxicity
      Genotoxicity
      WHO/ATSDR data
      Genotoxicity studies in relation to oral arsenic exposure have included exposed
      and unexposed individuals from several populations and analyses have been
      based on various tissues, including blood, buccal and bladder cells as well as
      sections from tumour biopsies.
          Even with some negative findings, the overall weight of evidence indicates
      that arsenic can cause clastogenic damage in different cell types, with different
 8    Arsenic and inorganic arsenic compounds
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<pre>end-points, in exposed individuals. Clastogenic effects have also been observed
in cells from cancer patients. Arsenic is thus clastogenic in humans in vivo.
    No HPRT gene mutation was seen in the single study in lymphocytes or
increases in ras or p53 gene expression in cells from cancer patients with long-
term exposure to arsenic, except for one study with increased p53 expression in
Bowen’s disease patients with such exposure compared to patients without
exposure.
Studies of humans have detected higher-than-average incidence of chromosomal
aberrations in peripheral lymphocytes, both after inhalation exposure and oral
exposure. These studies must be interpreted with caution, since in most cases there
was only a small number of subjects and a number of other chemical exposures
was possible.
Additional data
In Annex G, Table 13a (in vivo) and 13b (in vitro), the available human data with
regard to genotoxicity up to 2012 are summarised. These studies showed
chromosome aberrations and sister chromatid exchanges in different cell types of
people exposed to relatively high arsenic concentrations in drinking water.65-70,89-92
    In vitro studies with human lymphocytes and fibroblasts also showed
genotoxic effects of arsenic: nicking (unwinding) of DNA, double-stranded DNA
breaks, induction of alkaline labile sites, sister chromatid exchanges, oxidative
damage and interference with the formation and repair of DNA adducts.
Methylated trivalent arsenicals were more potent DNA damaging compounds than
the other arsenicals.58,59,91-96
Carcinogenicity
Human data on carcinogenicity of arsenic are summarised in Table 14 of Annex G.
The Table includes the key studies reported by the WHO (2001)6 and ATSDR
(2007)7 and additional material up to September 2012 (IARC 2012).97
    Because sufficient epidemiological data involving inhalation exposure to
arsenic (the most relevant route of occupational exposure) is available, the oral
studies concerning carcinogenicity, mainly epidemiological drinking water studies,
are only briefly mentioned in this section (based on the summaries from WHO6
and ATSDR7).
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<pre>  Carcinogenicity – inhalation exposure
  WHO/ATSDR data
  Studies of populations occupationally exposed (primarily by inhalation) to
  arsenic, such as smelter workers, pesticide manufacturers and miners in many
  countries, consistently demonstrate an excess lung cancer risk among the
  arsenic-exposed. Although all these groups are exposed to other chemicals in
  addition to arsenic, it is unlikely that some other common factor could explain
  the findings.
      There are three occupational cohorts (non-ferrous smelters) in which
  quantitative exposure assessments allow an evaluation of the relation between
  exposure to arsenic (arsenic trioxide) and lung cancer, those of the copper
  smelters in Tacoma, Washington (USA), Anaconda, Montana (USA), and
  Rönnskär (Sweden).
  Tacoma copper smelter
  Results from the Tacoma copper smelter have been published in a series of
  papers (Pinto and Bennett, 1963; Pinto et al., 1977 and 1978; Enterline and
  Marsh, 1980 and 1982; Enterline et al., 198798, Enterline et al., 19954). In the
  1995 update4, the vital status of 2802 men who worked at the smelter for a year
  or more during the period 1940-1964 was followed for the period 1941-1986;
  exposure assessment was extended to 1984, the time the smelter closed. The vital
  status was determined for 98.5% of the cohort, and of the 1583 known deaths,
  death certificates were obtained for 96.6%. The expected numbers of deaths for
  various diseases were calculated for white males in the state of Washington (all
  studied workers were males and nearly all were white).
      Exposure to arsenic was estimated from departmental measurements of
  arsenic in air from the annual company reports, available since 1938 (the factory
  began operation in 1913), and from measurements of urinary arsenic since 1948.
  Before 1971, the airborne arsenic concentrations came from “spot” samples and
  “tape” samples (apparently surface sampling), thereafter from personal air
  sampling. These data were combined to allow for an analysis of the relation
  between the concentrations of arsenic in air and various cancers. The conversion
  of data of urinary arsenic to airborne arsenic was made by the identification of
  departments and years for which data from both air and urinary arsenic were
  available and by the determination of the mathematical relation between the two.
  Twenty-eight pairs of data represented 11 of the 33 departments at the smelter.
0 Arsenic and inorganic arsenic compounds
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<pre>The relationship between arithmetic mean arsenic concentrations in air and
geometric mean concentrations of arsenic in the urine was described as follows:
      Air arsenic (µg/m3) = 0.0064 × (urine arsenic (µg/L))1.942
Using this equation, urinary arsenic concentrations were transformed into
airborne data for departments for which no air data were available. From the data
an exposure matrix of arsenic in air was developed by department and year from
1938 up to the time the smelter closed in 1984. For each worker, cumulative
exposure in (µg/m3) · year was then calculated on the basis of individual history
of work in different departments. For years before 1938 the exposure data for
1938 were used.98
      An increase in lung cancer risk related to cumulative arsenic exposure was
observed. The lung cancer standard mortality ratio (SMR)* was 188 in the group
with < 20 years after the first exposure, and 217 among those with > 20 years
since first exposure, indicating a rather short latency period. The SMRs for
respiratory cancer by cumulative airborne arsenic and date of hire are presented
in Table 5.
Table 5 Standard mortality ratios (SMRs) for respiratory cancer by cumulative airborne arsenic and
date of hire.
Cumulative exposure (mean                Total cohort          Hired < 1940         Hired ≥ 1940
exposure) (µg/m3·years)
<750 (405)                               154                    65                  178*
750-1,999 (1,305)                        176**                  68                  256**
2,000-3,999 (2,925)                      210**                 246*                 170
4,000-7,999 (5,708)                      212**                 150                  300**
8,000-19,999 (12,334)                    252**                 255**                244*
20,000-44,999 (28,356)                   284**                 252**                406**
45,000+ (58,957)                         316**                 339*                 -
*: P<0.05; **: P<0.01
The reason for the stratification is that for the cohort hired before 1940 only the person-years
accumulated from 1941 were followed up for deaths, whereas for the cohort hired in 1940 and later
all the person-years, to the end of the follow-up, period, were assessed. The stratification to some
extent also separated workers before 1940 with relatively high exposure and with poor respiratory
protection from workers with lower exposure, but with better quality exposure data and perhaps
better respiratory protection. According to the authors, smoking could be an important confounder in
respiratory cancer and data on the histories of the study population for smoking were collected.
Standard mortality ratio: Ratio between the observed number of deaths in a study population and the
number of deaths that would be expected in a standard population.
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<pre>  Figure 2 The SMRs for respiratory cancer for cumulative airborne
  arsenic. Copper smelter workers from Tacoma 1941-1976 and 1941-
  1986. Data are plotted at the means of exposure intervals. Fitted lines
  are from corresponding power functions. Source: Enterline et al.,
  19954.
  When the SMR is plotted against cumulative arsenic exposure on an arithmetic
  exposure scale (Figure 2), relatively larger increments in respiratory cancer risk
  are observed at low exposure levels, i.e. the exposure-response curve is concave
  downward. This had already been observed in the previous report on the same
  cohort, where the follow-up time was 10 years shorter.98 However, when lung
  cancer SMR was plotted against measured urinary arsenic concentrations, a
  linear relationship was observed.98
       An earlier publication of the Tacoma copper smelter98 contained data on
  actual daily exposure concentrations, duration of exposure and the risk on lung
  cancer. In this study, an arsenic exposure category of < 400 µg/m3 (mean 213 µg/
  m3) was associated with a statistically significant SMR of 238.7 for copper
  smelter workers who were exposed to arsenic for 30 or more years.
  Anaconda copper smelter
  An elevated risk of lung cancer among workers in the Anaconda copper smelter
  in Montana was originally reported by Lee and Fraumeni (1969). Updates and
  further cohort and nested case-referent analyses were published later (Lubin et
  al., 1981; Welch et al., 1982; Brown and Chu, 1983a,b; Lee-Feldstein, 1983,1986
  and 198999; Lubin et al., 20001).
2 Arsenic and inorganic arsenic compounds
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<pre>    The study population of the latest cohort update1 consisted of 8,014 white
males, who were employed for ≥ 12 months before 1957. Their vital status was
followed from 1 January 1938 to 31 December 1987; a total of 4,930 (63%) were
deceased, including 446 from respiratory cancer. The vital status at the end of the
follow-up period was not known for 1175 workers (15%), and they were
assumed to be alive at the end of the study period (except the 81 workers born
before 1900, who were assumed to have died).
    Industrial hygiene data (702 measurements), collected between 1943 and
1958, were used to categorise each work site to an exposure category on a scale
1-10, and work areas were then grouped as representing “light”, “medium” or
“heavy” exposure. Based in addition on estimates of workers' daily exposure
time, time-weighted average (TWA) exposures for each category were created,
and were considered to be 0.29, 0.58 and 11.3 mg/m3 arsenic for the “light”,
“medium”, and “heavy” exposure category. It should be noted that in earlier
reports (Lee-Feldstein 1986) on this cohort the TWA exposure estimates used
were different, notably for the "heavy" exposure category (0.38, 7.03, and 61.99
mg/m3, respectively). These earlier estimates were not weighted by workers’
exposure time. For each worker, the cumulative exposure was estimated from the
time of working in different work areas. The authors note that industrial hygiene
measurements were actually available for less than half of the 29 working areas;
no data were collected before 1943, and the measurements were often performed
when an industrial hygiene control measure was instituted or after a process
change occurred, and most often in areas where arsenic was thought to be a
hazard. The locations for sampling were not randomly selected.
    Altogether 446 deaths from respiratory cancer (SMR 155, 95% CI 141-170)
were observed. A trend of increasing risk with increasing estimated exposure
was seen; the risk increased linearly with time of employment in each exposure
category.
    Furthermore, it was found that estimated relative risk for respiratory cancer
declined with calendar year of follow-up. Measurements of arsenic in air were
available only for the years 1943-1958, and the exposure assessment implicitly
assumed that arsenic levels were constant over time. Available monitoring data
and anecdotal information indicated that airborne arsenic levels declined over
time in work areas with heavy and medium exposures with lesser reductions of
airborne arsenic in work areas with light exposure. These variations in exposure
probably accounted at least partly for the observed significant downward trend in
the relative risk for respiratory cancer by year of follow-up. In support of this, it
was found that the trend in the relative risks with duration of exposure declined
with follow-up for medium and heavy, but not for light, arsenic exposures.1
Effects                                                                               83
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<pre>       Although information on smoking was not available, according to the authors
  it is noteworthy that mortality from smoking-related cancers, except for chronic
  obstructive pulmonary disease, was not excessive. In a sample of 1469 workers
  from the original cohort, there was a higher proportion of smokers compared
  with US white males. However, the proportion of cigarette smokers did not vary
  significantly by extent of exposure to airborne arsenic, indicating that it was
  unlikely that smoking confounded the assessment of lung cancer risk with
  arsenic exposure according to the authors.1
  Rönnskär copper smelter
  The elevated lung cancer incidence among workers of the Rönnskär smelter in
  northern Sweden was originally reported in a population-based case-referent
  study in St Örjan parish in 1978 (Axelson et al., 1978). Since then, studies using
  both cohort and case-referent approaches have been published (Wall, 1980;
  Pershagen et al., 1981 and 1987; Järup et al., 19893; Sandström et al., 1989; Järup
  and Pershagen, 1991100; Sandström and Wall, 1993). The cohort consisted of
  3916 male smelter workers, who had worked for at least 3 months at the smelter
  between 1928 and 1967. The vital status of all but 15 (0.4%) of them was
  verified. Mortality of different causes, as defined on death certificates, was
  compared to local rates. Reference rates were not available for the period before
  1951, but the contribution of deaths during this period (89 out of a total of 1275,
  i.e. 7%) was minor.
       Air concentrations of arsenic were estimated by the factory industrial
  hygienists. The first measurements were carried out in 1945, and from 1951
  exposure data were more generally available; production figures were used to
  extrapolate exposures before 1951. Each work site was characterised by an
  exposure level during three consecutive time periods, and the workers'
  cumulative exposure was assessed on the basis of their working history in these
  different work sites.
       The SMRs were very similar whether they were calculated with no latency,
  10 years minimum latency or 10 years minimum latency with exposure lagged 5
  years. A positive dose-response relationship was found between cumulative
  arsenic exposure and lung cancer mortality with an overall SMR of 372 (95% CI
  304-450), and a statistically significantly increased risk was observed even in the
  lowest exposure category, < 0.25 (mg/m3) · year. In Table 6 the SMRs for lung
  cancer by cumulative airborne arsenic are presented.
4 Arsenic and inorganic arsenic compounds
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<pre>Table 6 Standard mortality ratios (SMRs) for lung cancer by cumulative
airborne arsenic.
Cumulative exposure (mg/m3·years) SMR (mean
                                     (95% confidence interval))
< 0.25                                 271 (148-454)
0.25-<1                                360 (192-615)
1-<5                                   238 (139-382)
5-<15                                  338 (189-558)
15-<50                                 461 (309-662)
50-<100                                728 (267-1.585)
100+                                 1.137 (588-1.986)
A sensitivity analysis showed that the SMRs were fairly robust, particularly
among the workers with low and medium exposure (Järup, 1992). Even when the
exposure estimates before 1940 were reduced dramatically (assuming there was
a large overestimation of the early exposures), these SMRs changed only
marginally. As expected, the SMRs in the highest exposure group increased as
the early exposures were reduced. An overestimation of the early exposures
would thus tend to decrease the strength of the exposure-response association.
     Little difference was observed in the SMRs for workers hired before 1940, in
1940-1949, or after 1949, when the estimated level of exposure was similar,
meaning that a longer follow-up did not increase the apparent risk.3 In most
subcohorts, and in the total cohort, the mortality increased with increasing
average intensity of exposure, but no clear-cut trend was observed for the
duration of exposure. Exposure to sulphur dioxide was also assessed. The lung
cancer risk was elevated in all groups exposed to sulphur dioxide, but there was
no exposure-response with the estimated cumulative sulphur dioxide exposure.
     In a nested case-referent study on the interaction between smoking and
arsenic exposure as lung cancer-causing agent in the cohort as described
above100, lung cancer risks were positively related to cumulative arsenic
exposure with smoking standardised relative risks ranging from 0.7 to 8.7 in
different exposure groups. A negative confounding by smoking was suggested in
the highest exposure category. The interaction between arsenic and smoking for
the risk of developing lung cancer appeared less pronounced among heavy
smokers.
     In a cancer incidence study (Sandström et al., 1989), partly overlapping with
the above described study, the cancer risk of the smelter workers over a moving
5-year period was observed to decrease steadily from 1976-1979 to 1980-1984,
showing that the later the date of first employment the lower the incidence of
cancer, especially for lung cancer. This trend may be explained by decreasing
Effects                                                                            85
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<pre>  exposure levels to arsenic. Further follow-up of an expanded Rönnskär cohort
  (n = 6,334) by Sandström and Wall (1992) showed also a decreasing trend in
  lung cancer incidence and mortality, but there was still an elevated lung cancer
  incidence among the workers when compared with Swedish men.
  Other studies
  A very high excess of lung cancer (SMR 2500; 10 observed and 0.40 expected
  cases in the heavy exposure category), which was related to duration and level of
  exposure, was observed in the copper smelter of a Japanese metal refinery
  (Tokudome and Kuratsune, 1976); the study was prompted by an earlier case-
  referent study that demonstrated an excess lung cancer rate among copper-
  smelter workers (Kuratsune et al., 1974). There was an approximately 3-fold
  increase in the relative death rate from lung cancer among employees of a copper
  smelter in Utah, in comparison to workers of the same company not employed in
  the smelter (mainly mine and concentrator workers), and also in comparison to
  Utah state figures (Rencher et al., 1977). The risk was related to all estimated
  exposure parameters (cumulative exposure to arsenic, sulphuric acid, lead and
  copper), and was similar for smokers and non-smokers. This refinery was a part
  of a cohort study in eight copper smelters (Enterline et al., 1987b), the SMR for
  respiratory cancer < 20 years since first exposure was 170 (11 deaths), and ≥ 20
  years 108 (39 deaths). In this study, the only smelter with an appreciable
  exposure to arsenic was the Utah one, and this was the only one with a
  statistically significant excess in lung cancer.
  • Pesticide manufacture and application
  Ott et al. (1974) conducted a proportionate mortality study of decedents who had
  worked at a factory producing arsenical pesticides, mainly lead arsenate, calcium
  arsenate, copper acetoarsenite and magnesium arsenate. The cause of death of
  173 workers who had worked at least 1 day in jobs with presumed arsenic
  exposure was compared to that of 1809 decedents (age- and calendar-year-
  adjusted) from the same factory, with no exposure to arsenic or asbestos. The
  exposure of the workers was analysed from a job exposure matrix covering the
  working history. The proportionate mortality ratio (PMR)* for lung cancer
  increased with estimated exposure, from a PMR of 200 at an exposure level of 1-
  1.9 (mg/m3) · month to a PMR of 700 at the highest cumulative exposure group ≥
  96 (mg/m3) · month.
  Proportionate mortality ratio: Number of deaths from a specific cause in specific period of time per
  100 deaths from all causes in the same time period.
6 Arsenic and inorganic arsenic compounds
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<pre>    Ott et al. (1974) also conducted a cohort study at the same pesticide plant.
The cohort was expanded and updated through December 1982 (Sobel et al.,
1988) to include 611 workers altogether; the mortality was compared to age- and
calendar-time standardised data on US white males. A significant excess of lung
cancer mortality was observed (35 observed vs. 15.6 expected cases; SMR 225,
95% CI 156-312). The small number of deaths made analyses by duration and
latency difficult; analysis by exposure level or cumulative exposure was not
reported.
    In a cohort study of pesticide manufacturing workers in Baltimore, the vital
status of 1050 men and 343 women was followed from 1946 through 1977
(Mabuchi et al., 1979 and 1980). The vital status was determined for 86.9% of
men and 66.8% of women; the non-traced subjects were counted as being alive at
the time of ending the follow-up. Cause-specific mortality was compared to that
of Baltimore city whites, age- and calendar time adjusted, and 23 lung cancer
deaths were identified, which represents an excess lung cancer mortality (SMR
168 based on Baltimore City whites, or 265 based on US whites; p < 0.05 for
both). There was an exposure-response relationship between presumed
cumulative exposure (no relevant measurement data on exposure were available)
and the SMR. The SMR reached 2750 in the highest exposure category (3 lung
cancer deaths). No exposure-response relationship was observed between
presumed cumulative exposure to non-arsenical pesticides and SMR.
    In an autopsy series of 163 winegrowers from the Moselle area (Lüchtrath,
1983), 130 cases of cancer in internal organs were observed. Of these, 108 were
lung cancers. In an age- and sex-adjusted control group of 163 people, there were
23 malignant tumours, out of which 14 were lung tumours. Exposure to arsenic
was considered to be by inhalation of arsenic-containing insecticide, but to a
much larger extent, by drinking arsenic-contaminated "Haustrunk" (a wine
substitute made from already pressed grapes), which was estimated to lead to a
daily intake of about 3-30 mg arsenic.
    In 1938 a cohort of 1231 people living in the Wenatchee area in Washington,
where lead arsenate was extensively used in orchards, was studied. The mortality
of this cohort was reported by Nelson et al. (1973), Wicklund et al. (1988) and
Tollestrup et al. (1995). No difference in lung cancer mortality was observed
between orchardists exposed to arsenical insecticides and consumers who were
not significantly exposed to arsenicals (hazard ratio 0.59, 95% CI 0.19-1.85)
(Tollestrup et al., 1995). It is likely that the overall exposure to arsenic for
orchardists was low. A case-control study included all white male orchardists (n
= 155) who died in Washington state between 1968 and 1980 from respiratory
cancer, using orchardists who died of other causes as controls (n = 155)
Effects                                                                           87
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<pre>  (Wicklund et al., 1988). Lead arsenate exposure did not differ between cases and
  controls, and smoking habits were similar.
  • Miners and other
  In a cohort study on tin-miners in the UK (Hodgson and Jones, 1990), 13
  workers had worked in arsenic calcining. Three of them had died of cancer of the
  trachea, bronchus, lung or pleura (0.55 expected, SMR 550, p < 0.05), and 2 of
  stomach cancer (0.2 expected, SMR 890, p < 0.05). A very high lung cancer
  mortality has been demonstrated among tin-mine workers exposed to arsenic and
  radon in Yunnan, China (Taylor et al., 1989; Qiao et al., 1997). The lung cancer
  risk increased with estimated cumulative exposure to arsenic (Qiao et al., 1997).
  A 2-fold excess (SMR 213; 95% CI 148-296) in lung cancer mortality was
  observed among workers in a gold-mine and refinery in France, mainly among
  workers with a history of exposure to arsenic, diesel exhaust, radon and silica.
  There was little change in the relative risk with length of employment, and the
  risk was similar among refinery workers and miners (Simonato et al., 1994). An
  exposure-related increase in the lung cancer mortality was also observed among
  gold-miners in Ontario, exposed to arsenic and radon daughters (Kusiak et al.,
  1991 and 1993). Similarly, lung cancer mortality among Australian gold-miners
  was higher than that expected from the experience of all Western Australian men
  (SMR 140, 59 observed and 40.8 expected cases, p < 0.01). The gold-miners
  were exposed to arsenic, radon daughters and silica, and apparently smoked
  more than the referent population (Armstrong et al., 1979).
      Female hat-makers, probably exposed to arsenic while making felt hats, had
  an elevated risk of lung cancer (6 cases versus 0 in controls) in a case-referent
  study (376 cases with 892 controls) on occupational risk factors of lung cancer in
  Italy (Buiatti et al., 1985).
      A cohort mortality study of workers in a Russian fertiliser plant, including
  2039 men and 2957 women, showed an excess mortality from all cancers
  combined (SMR 143) and lung cancer (SMR 186) for the male production
  workers (Bulbulyan et al., 1996). Excess mortality from all cancers and stomach
  cancer was found for the workers with the highest average exposure to arsenic,
  and excess lung cancer mortality was attributed to exposure to arsenic.
  • Interactions of arsenic exposure and tobacco smoking
  Hertz-Picciotto et al. assembled data from numerous published case-control and
  cohort studies with regard to lung cancer due to smoking and to occupational
  arsenic exposure to examine whether active smoking and occupational exposure
  to arsenic act synergistically to increase the risk of lung cancer.101 There were six
8 Arsenic and inorganic arsenic compounds
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<pre>studies on two overlapping smelter populations (Tacoma and Rönnskär), where a
direct evaluation of the interaction could be assessed (Rencher et al., 1977;
Pershagen et al., 1981; Enterline, 1983; Pershagen, 1985; Enterline et al., 1987b;
Järup and Pershagen, 1991100). The joint effect from both exposures consistently
exceeded the sum of the separate effects by about 70 to 130%. The calculated
excess fractions for the synergism showed that a minimum of between 30% and
54% of lung cancer cases among those with both exposures could not be
attributed to either one or the other exposure alone. Taken as a whole, the
evidence is compelling that arsenic and smoking act in a synergistic manner to
produce lung cancer. The mechanism for the synergism is however unclear.101
• Lung cancer in the vicinity of arsenic-emitting industries
Mortality rates for lung cancer for white men and women in 1950-1960 were
significantly higher in several counties of the United States with copper, lead, or
zinc smelting and refining industries (Blot and Fraumeni, 1975), and a 2-fold
increased mortality of lung cancer was observed among people with residence
near a zinc smelter, and in areas with high topsoil concentrations of arsenic,
cadmium, copper, lead and manganese (Brown et al., 1984). A slightly higher
mortality of lung cancer was observed among male residents of Rouyn-Noranda,
a community with a copper smelter, than among male residents of a referent
community (SMR 150) or Quebec (Canada) as a whole (SMR 120); no such
difference was observed among women (only 7 exposed cases) (Cordier et al.,
1983). Although the lung cancer mortality between 1935 and 1969 in women
living in three geographically defined areas in the vicinity of an arsenic-emitting
smelter was not different from that expected from nationwide expected figures,
there was a positive trend following predicted exposure levels (Frost et al.,
1987). No difference was observed between the frequency of lung cancer and
that of other cancers in the vicinity of non-ferrous smelters (a lead-zinc smelter
and 10 copper smelters) in the USA (Greaves et al., 1981).
     The lung cancer mortality among people living in the vicinity of a copper
smelter in Rönnskär (Sweden) was studied in a cohort and a case-referent study
(Pershagen et al., 1977; Pershagen, 1985). In the cohort study, a significantly
higher mortality from lung cancer was observed among men living close to the
smelter than among men in a reference area (Pershagen et al., 1977). The
difference disappeared, however, when men working in the smelter were
excluded. In the case-referent study, the odds ratio (OR)* for residence in the
Odds ratio: Ratio between the proportions of cancer deaths in the exposed cohort and the non-
exposed cohort.
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<pre>  exposed area was 2.0 (95% CI 1.2-3.4), and it was not explained by occupation
  in the smelter, or by differences in smoking habits (Pershagen, 1985). Lung
  cancer mortality was higher in men living in the vicinity of a factory producing
  arsenical pesticides in Baltimore (Maryland, USA) (Matanoski et al.,1981). No
  association between the distance from a smelter and lung cancer risk was
  observed in a case-referent study where 575 lung cancer cases were compared
  with 1490 breast and prostate cases collected from 1944 to 1973 in El Paso,
  Texas (USA), where a smelter had been operating since 1887 (Rom et al., 1982).
      In a study of lung cancer mortality in 6 Arizona (USA) copper smelter towns,
  using 185 lung cancer cases and 2 matched controls per case from deceased
  residents during 1979-1990, information on lifetime residential, occupational,
  and smoking history was obtained (Marsh et al., 1997 and 1998). Historical
  environmental exposures to smelter emissions were linked with residential
  histories to derive individual profiles of residential exposure. Occupational
  histories were characterised by potential exposure to smelter emissions, asbestos
  and ionising radiation. No statistically significant associations were observed
  between lung cancer risk and residential exposure to smelter emissions, when
  adjustment for potential confounding factors (gender, Hispanic ethnicity, and
  smoking) were made. The authors concluded that the study provided little
  evidence of a positive association between lung cancer mortality and residential
  exposure to smelter emissions.
      A Chinese case-control study including 1249 lung cancer patients and 1345
  population-based controls showed 3-fold elevated risks among smelter workers
  (Xu et al., 1989 and 1991). Soil levels of arsenic rose with increasing proximity
  to the Shenyang copper smelter, and, after controlling for smoking and work
  experience in the smelter, elevated risks of lung cancer were found among men,
  but not women, living within 1 km of its central stacks.
      It has been noted that epidemiological studies designed to detect lung cancer
  risk and other health effects in communities surrounding arsenic-producing
  copper smelters usually have insufficient statistical power to detect the small
  increases in risk that may occur (Hughes et al., 1988).
  • Exposure-response relationships
  Sufficient information on the levels of exposure to ensure reliable assessment of
  the exposure-response relationships can be found only in the three copper
  smelter cohorts: Tacoma, Anaconda and Rönnskär. Figure 3 shows the dose-
  response relation reported for the three copper smelter cohorts. The horizontal
  scale is logarithmic. Although the figure shows three lines, the dose-response
  relations are not modeled, but plotted by connecting the SMRs of the different
0 Arsenic and inorganic arsenic compounds
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<pre>exposure categories. In all, there was an increase in lung cancer risk with
increasing exposure (Figures 2 and 3). The risk seems to increase more rapidly
with dose at low cumulative dose levels than at higher exposures (which is clear
from Figure 2, but not from Figure 3 due to the logarithmic scale), and the
general form of the exposure-response is rather similar in the three studies
(Figures 2 and 3).
     The shape of the exposure-response curve has been further analysed and
discussed by Hertz-Picciotto and Smith, 1993102, who noted that all of the studies
with quantitative data are consistent with a nonlinear, i.e. supralinear (decreasing
slope), exposure-response relationship. Two of these studies (Lee-Feldstein,
1986 and Järup, 19893) are also consistent with a linear relationship over an
elevated background risk of lung cancer among arsenic-exposed workers.
Neither toxicokinetic mechanisms nor confounding from age, smoking, or other
workplace carcinogens that differ by exposure level appears likely to explain this
curvilinearity. The authors argue that a plausible explanation may be synergism
Figure 3 The SMRs for respiratory cancer (Anaconda and Tacoma) and lung
cancer (Rönnskär) for cumulative airborne arsenic. To facilitate presentation the
upper three exposure categories for Rönnskär have been combined. Anaconda
and Rönnskär are plotted at the midpoint of exposure intervals except for upper
intervals 30,000 and 57,000, which were based in part on the exposure
distributions in the data from Tacoma. Source: Enterline et al., 19954.
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<pre>  (with smoking) which varies in magnitude according to the level of arsenic
  exposure. Another possible explanation may be a long-term survivorship in
  higher-exposure jobs among the healthier, less susceptible individuals (Hertz-
  Picciotto and Smith, 1993102; Arrighi and Hertz-Picciotto, 1996). It is also
  plausible that exposure estimate errors are more prominent at higher exposure
  levels as a result of past industrial hygiene sampling or worker protection
  practices102, which is consistent with the findings of the sensitivity analysis of
  the Rönnskär data (Järup, 1992), and the update of the Anaconda cohort1.
      Using the updated data on the Tacoma smelter cohort of Enterline et al.,
  19954, Viren and Silvers (1999)103 explored the (non)linearity in the lung cancer
  dose-response in this cohort. Lung cancer risk was expressed in terms of both the
  SMR and the excess mortality rate (EMR). Analyses were undertaken by
  subcohort as there was strong evidence of confounding by year of initial hire.
  Subcohort analyses based on initial employment, prior to 1940 or thereafter,
  showed that the nonlinearity in the dose-response was strongly influenced by
  date of initial hire. Whether the cohort risk was measured by either the SMR or
  EMR, a nonlinear dose-response was evident only among workers hired prior to
  1940. This, however, was strongly related to the artifactually low lung cancer
  mortality seen among workers hired between 1930 and 1939. Among workers
  hired after 1940, analyses showed that a linear dose-response provided a clearly
  superior fit.
      Re-analysis of the Anaconda cohort1 is also in favour of a linear exposure-
  risk relationship, and ascribes the apparent non-linearity observed in other
  studies to overestimation of the high exposures. According to Lubin et al. (2000)
  the conclusion of Hertz-Picciotto and Smith102 that a concave relation existed
  between respiratory cancer and cumulative airborne arsenic exposure was
  strongly influenced by the previous analysis of the Anaconda data and analysis
  of the Tacoma data for which the exposure-response relations for the individual
  studies varied substantially in magnitude and shape.
  • Other types of cancer
  There have been occasional reports of other types of cancer (i.e., non-respiratory
  cancer) potentially associated with inhalation exposure to inorganic arsenic, but
  there is no strong evidence for any of them. Enterline et al., 19954 found a
  statistically significant increase in cancer of the large intestine and bone, and
  SMRs > 150 for cancer of the buccal cavity and pharynx, rectal cancer, and
  kidney cancer. However, neither cancer showed any relation to cumulative
  arsenic exposure, and the purported increase in bone cancer risk was based on a
  very small number of observations. Bulbulyan et al., 1996 reported an increase in
2 Arsenic and inorganic arsenic compounds
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<pre>risk of stomach cancer among workers exposed to the highest average arsenic
concentrations at a Russian fertiliser plant, but this finding, which was based on a
small number of observations and was only marginally statistically significant,
was confounded by exposure to nitrogen oxides. Wingren and Axelson, 1993
reported an association between arsenic exposure and stomach and colon cancer
in Swedish glass workers, but this result was confounded by concomitant
exposure to other metals. Lee-Feldstein, 1983 observed a small, marginally
significant increase in digestive tract cancer (SMR=125) in one study of the
Anaconda cohort, but this was not found in other studies of this cohort (Lee and
Fraumeni, 1969; Lee-Feldstein, 1986; Welch et al., 1982). Wulff et al., 1996
observed an apparent increase in the risk of childhood cancer (all types
combined) in the population living within 20 km of the Rönnskär smelter, but the
apparent increase was based on a small number of cases (13 observed vs. 6.7
expected) and was not statistically significant, and exposure to arsenic was
confounded by exposure to lead, copper, cadmium, sulphur dioxide, and possibly
other emissions such as nickel and selenium. Various case reports have
implicated occupational arsenic exposure as a potential contributing factor in
workers who developed sinonasal cancer (Battista et al., 1996), hepatic
angiosarcoma (Tsai et al., 1998), and skin cancer (Col et al., 1999; Tsuruta et al.,
1998), but provide no proof that inhaled arsenic was involved in the etiology of
the observed tumours. Wong et al., (1992) found no evidence that environmental
exposure to airborne arsenic produced skin cancer in residents living near the
Anaconda smelter.
Additional data
A small number of studies (Binks et al., 2005104; Jones et al. 2005105; Sorahan
2009106) have been published in support of the view that recent (late) exposures
can be more important than exposures received in the distant past (i.e. that
arsenic is a late stage carcinogen) and that analyses of lifetime cumulative
exposure can fail to identify a potent occupational carcinogen. Binks et al.
(2005)104 studied lung cancer mortality in employees from a tin smelter
operation (Capper Pass, North Humberside in UK). These employees were a.o.
exposed to lead, arsenic and cadmium. A cohort consisting of 1462 males who
had been employed for at least 12 months between 1/11/1967 and 28/7/1995,
followed up through 31/12/2001. Lung cancer mortality was significantly
elevated (62 death, SMR 161, 95% CI 124-206, P<0.001). Lung cancer mortality
had been enhanced by occupational exposure to one or more carcinogens.
However, this effect diminished with time since leaving exposure. Using
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<pre>  available data from the Capper Pass tin smelter cohort Jones et al. (2007)105 tried
  to explain this excess lung cancer mortality by attributing this to specific
  exposure (lead, arsenic, cadmium a.o.). They conclude that a substantial
  proportion of the excess lung cancer mortality can be attributed to the effects of
  arsenic exposure, but only if it is assumed that the resulting relative risk of lung
  cancer declines with time since exposue.
      Sorahan (2009)106 reexamined lung cancer mortality data in a cohort from a
  cadmium recovery factory facility located in the state of Colorado.107,108 These
  workers were employed for at least 6 months between 1 January 1940 and 31
  December 1969 and exposed to cadmium and arsenic. Sorahan categorized this
  cohort according to the period from leaving arsenic exposed employment (years)
  (< 9; 10-19; 20-29; 30-39; ≥40) and observed that there was a statistically
  significant (P < 0.05) negative trend in lung cancer SMR’s in relation to the
  period from ceasing arsenic exposure (SMR 300; 113; 140; 113; 75 respectively).
  These findings are consistent with the hypothesis that arsenic is a late stage
  carcinogen.
      These three studies (Binks et al., 2005104; Jones et al., 2007105; Sorahan
  2009106) suggest that simple cumulative inhalation exposure may not be a good
  predictor of excess relative risk and that when arsenic is a late stage carcinogen
  this may have consequences for the risk estimation.
      Lubin et al. (2008)2 reanalyzed the Anaconda copper smelter cohort. The
  original cohort study enrolled 8,014 workers employed for ≥ 1 year before 1957,
  with follow up starting 1 year after initial employment or 1 january 1938
  whichever was later. It should be noted that in the reanalysis, Lubin et al.2 used
  an exposure reduction factor in the higher exposure categories to account for the
  use of personal protection equipment. They showed that RR’s for respiratory
  cancer increased linearly with cumulative arsenic exposure when analyzed for
  specific concentrations and concentration ranges of arsenic (0.29 mg/m3; 0.30-
  0.39 mg/m3; 0.40-0.49 mg/m3; ≥ 50 mg/m3). In addition, they showed that the
  slope of the linear exposure-response relationship increased with increasing
  arsenic concentration. This pattern implied that for equal cumulative arsenic
  exposure, the RR of respiratory cancer mortality was greater for cumulative
  arsenic exposure delivered at higher concentration for shorter duration compared
  with cumulative exposure delivered at lower concentration for longer duration.
  As an explanation for this effect they suggest that the concentration dependent
  mechanisms involved in methylation and excretion of arsenic play an important
  role and can become rate-limited at higher concentrations.
4 Arsenic and inorganic arsenic compounds
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<pre>Carcinogenicity – dermal exposure
WHO/ATSDR/additional data
No studies were found that have associated cancer in humans with dermal
exposure to arsenic.
Carcinogenicity – oral exposure
WHO/ATSDR data
Studies in Taiwan, Chile and Argentina show consistently high mortality risks
from lung, bladder and kidney cancer, as well as other skin changes such as
hyperkeratosis and pigmentation changes among populations exposed to arsenic
via drinking water. Where exposure-response relations have been studied, the
risk of cancer for these sites increases with increasing exposure. Even when
tobacco smoking has been considered, the exposure-response relationship
remains.
    Not all studies of populations exposed to arsenic have reported positive
findings for increased lung, bladder and kidney cancer. Exposure in these studies
have not been as high as those in Taiwan, Chile or Argentina, and the sample
sizes of the study populations may not have provided the statistical power to
detect increased risks.
    Most of the studies where these effects have been observed were conducted
in Taiwan. The exposure categories of studies conducted in the blackfoot disease
(BFD)-endemic area in Taiwan have historically been rather broad (e.g. < 300
µg/L, 300-600 µg/L, and > 600 µg/L). A recent paper on the BFD-endemic area
in Taiwan, however, reported increased risks of bladder and lung cancer
mortality in persons consuming drinking water with arsenic concentrations < 50
µg/L.
    In Argentina, significantly elevated bladder, lung and kidney cancer
mortality were found in the high-exposure group where over 75% of the
measurements of arsenic in drinking water were higher than the detection limit of
40 µg/L. For the measurements above the detection limit, the average
concentration was 178 µg/L. Bladder, lung and kidney cancer mortality were
also significantly elevated for men, and lung cancer mortality was significantly
elevated for women in the < 40 µg/L-exposure groups. Thus the lowest exposure
where elevated kidney cancer risk could be observed would have to be
considerably lower than 178 µg/L.
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<pre>      In a case-control study conducted in Chile, there was an exposure-response
  relationship for the risk of lung cancer over all exposure categories, and the
  increased risk was statistically significant at exposure strata of 30-50 µg/L and
  above. In a case-control study in Finland, a statistically significantly elevated
  risk of bladder cancer was observed at ≥ 0.5-64 µg As/L drinking water
  concentration but only when exposure was 3-9 years before diagnosis.
      Arsenic ingestion in drinking water has also been shown to be associated
  with a high risk of skin cancer. Well-documented studies on skin cancer after
  arsenic ingestion from drinking water have been conducted in several
  populations in different countries, the largest of which were in Taiwan.
  Association of exposure to arsenic with skin cancer has also been observed in
  studies on patients treated with arsenicals.
      The lowest arsenic drinking water concentration where an increased risk of
  skin cancer could be observed is in the lowest exposure group in the exposed
  Taiwan population (i.e. < 300 µg/L). It should be noted that this is a very broad
  exposure category and the lowest concentration associated with skin cancer
  could have been considerably lower.
      The lowest arsenic drinking water concentration where an elevated risk of
  arsenic-associated skin lesions (hyperpigmentation and/or keratosis) has been
  found can be estimated from a study in West Bengal (India) to be less than 50
  µg/L.
      In two partly overlapping studies in Taiwan, an elevated mortality from liver
  cancer was observed in relation to arsenic exposure from drinking water. In one
  of the two studies in Chile, but not in the study in Argentina, such a relationship
  was observed.
      Cancer at other sites in relation to arsenic exposure has been little studied
  outside Taiwan. The sites that have exhibited an elevated risk include
  oesophagus, stomach, small intestine, colon, nose, larynx, bone and prostate, as
  well as lymphoma and leukaemia. A study in the USA and another in Australia,
  neither of which showed a clear-cut increase in the risk of lung, bladder, or
  kidney cancer, showed moderately elevated mortality from cancer of the
  prostate.
  Additional data
  Long-term exposure (years) to drinking water at levels as low as 0.001 mg As/
  kg/day have been recently associated with skin diseases and skin, bladder,
  kidney, liver, and also lung cancer. 109-121 The available oral studies (on arsenic in
  food and drinking water) were recently (2009) reviewed and evaluated by the
6 Arsenic and inorganic arsenic compounds
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<pre>European Food Safety Authority (EFSA) and will not be further discussed
here.122
According to EC Regulation 1272/2008 on classification, labelling and
packaging of substances and mixtures11, arsenic acid, arsenic trioxide, arsenic
pentoxide and lead arsenate are labelled Carc. 1A ; H350 (May cause cancer).
The National Toxicology Program (NTP) classified arsenic compounds as a
known human carcinogen, i.e., human studies (epidemiology studies and/or
experimental studies) provide ‘sufficient evidence’ of carcinogenicity in
humans123.
     The International Agency for Research on Cancer (IARC) rates arsenic and
arsenic compounds as carcinogenic to humans (Group 1: exposures ‘known to be
carcinogenic to humans based on sufficient human evidence, and limited
evidence in experimental animals). This evaluation applies to the group of
chemicals (i.e. arsenic and arsenic compounds) as a whole and not necessarily to
all individual chemicals within the group.124-126
     The U.S. Environmental Protection Agency (EPA), through its Integrated
Risk Information System (IRIS)127, classifies arsenic as a human carcinogen
(Group A).
Reproduction toxicity
Effects on fertility
WHO/ATSDR/additional data
No effects of arsenic on fertility in humans were retrieved from the literature.
Developmental effects-inhalation exposure
WHO/ATSDR/additional data
Several older epidemiological studies (see WHO 2000128, ATSDR 20077) have
reported an association between exposure to inorganic arsenic and increased risk
of adverse developmental effects (congenital malformations, low birth weight,
spontaneous abortion)(Nordström et al., 1978a129, 1978b130, 1979a131, 1979b132).
     The Rönnskär copper smelter in northern Sweden emitted a number of
potentially toxic substances, of which arsenic, lead and sulphur dioxide have
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<pre>  caused most public concern. Birth weights were studied in the offspring of
  women working at the Rönnskär smelter and in four populations (A-D) at
  different distances from the smelter (Nordström 1978a129). Records for all
  women living in any of these four areas were studied, the distance from the
  smelter increasing from A to D. In the offspring of employees and of women
  living in areas A and B close to the smelter statistically significantly decreased
  birth weights were found. This decrease showed a consistent parity dependence,
  affecting mainly later pregnancies. The same authors studied frequencies of
  spontaneous abortion in the abovementioned populations. In the population
  located close to the smelter (A) a statistically significant increase of the abortion
  frequency was found, compared to more distantly located populations (B, C, D)
  (Nordström 1978b130).
       In another report, Nordström et al. (1979a131) focussed more on the
  population of female employees working in the smelter. An increased frequency
  of spontaneous abortion was found in pregnancies where the mother was
  employed during pregnancy or had been employed before pregnancy and was
  still living close to the smelter. Women occupied in close connection with the
  smelting processes had a significantly higher abortion frequency than other
  employees. In the offspring of mothers working at the smelter, birth weight was
  decreased mainly in later pregnancies. The lowest birth weights were found in
  the offspring of women working in close contact with the smelting processes.
  Also the frequencies of congenital malformations were studied in the offspring
  of female employees at the Rönnskär smelter and in the population near the
  smelter. In the offspring of women who had worked at the smelter during
  pregnancy the frequency of congenital malformations was increased (Nordström
  1979b132).
       Inhalatory studies of more recent date are scarce in the literature. Ihrig et al.
  (1998)133 investigated the association between chronic inhalation exposure to
  arsenic and stillbirth. A case control study was conducted in the vicinity of a
  Texas arsenic pesticide factory. Data were collected on 119 cases of stillbirth and
  267 controls randomly selected from healthy live-births at the same hospital and
  matched for year of birth. Arsenic exposure levels were estimated from airborne
  emission estimates and an atmospheric dispersion model. A conditional logistic
  regression model was fitted including maternal age, race/ethnicity, parity, income
  group, exposure as a categorical variable, and exposure-race/ethnicity
  interaction. There was a statistically significant increase in the risk of stillbirth in
  the highest exposure category (> 100 ng As/m3, midpoint=682 ng/m3) for
  Hispanics only with an odds ratio (OR) of 8.4 (95%CI 1.4-50.1).
8 Arsenic and inorganic arsenic compounds
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<pre>Developmental effects-oral exposure
WHO/ATSDR/additional data
The association between trace element levels in community drinking water and
spontaneous abortion was studied in 286 women having a spontaneous abortion
through 27 weeks of gestation with that of 1,391 women having live birth
(Aschengrau et al.,1989134). Trace element levels were gathered from routine
analyses of public tap water supplies from the communities where the women
resided during pregnancy. After adjustment for potential confounders, the
authors conclude that an increase in the frequency of spontaneous abortions was
dose-dependently associated with levels of mercury above the detection limit and
with high levels of arsenic, potassium and silica. [The Committee observed that
the data in the original publication do not support the association with arsenic].
    In a case-control study (270 affected children and 665 healthy children) the
association was investigated between chemicals (arsenic, lead, mercury,
selenium) in maternal drinking water consumed during pregnancy and congenital
heart disease in the offspring (Zierler et al.,1988135). Contaminant levels in
maternal drinking water was available from the records of routine water analysis
of the samples taken from public taps in the communities where the mothers
resided during pregnancy. Mothers provided information on their health,
pregnancy management and demographic characteristics during telephone
interviews. None of the chemicals was associated with an increase in frequency
of congenital heart disease overall but arsenic exposure was associated with an
increase in the occurrence of coarctartion of the aorta (OR 3.4, 95% CI 1.3-8.9)
whereas selenium was associated with a lower frequency of any congenital heart
diseases (OR 0.82, 95% CI 0.4-0.97).
    Associations between developmental effects and chronic exposure of women
to arsenic in the drinking water has been reported in more recent studies in
populations in different areas of the world with elevated levels of arsenic in
drinking water e.g., Taiwan (Yang et al., 2003136), Chile (Hopenhayn-Rich,
2000137; Hopenhayn et al., 2003138; Smith et al., 2006139) and Bangladesh/
Bengal (Ahmad et al., 2001140; Milton et al., 2005141; von Ehrenstein et al.,
2006142; Tofail et al., 2009143; Rahman et al., 2009144; Rahman et al., 2010145).
    Taiwan. The well water in Lanyang Basin, which is located in the
northeastern part of Taiwan, was found to have high levels of arsenic ranging
from undetectable levels (< 0.15 ppb) to 3.59 ppm. A study was performed to
compare the risk of adverse pregnancy outcomes (preterm delivery and
birthweight) between an area with historic high well water arsenic levels
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<pre>   (arsenic-exposed area (AE)) and a comparison area with no historic evidence of
   arsenic water contamination (non-arsenic-exposed area (NAE)) (Yang et al.,
   2003136). Data from 3,872 first parity singleton live births for AEs and 14,387 for
   NAEs were included in the analysis. Babies born in AEs were on average 30 g
   lighter than those born in NAEs after adjustment for confounders. AEs had a
   higher rate of preterm delivery than NAEs (3.74% vs 3.43%). The results of this
   study suggest that, after adjustment for potential confounders, arsenic exposure
   from drinking well water was associated, although not statistically significant,
   with the risk of preterm delivery, with an odds ratio of 1.10 (0.91-1.33). The
   estimated reduction in birth weight was 29.05 g (95% CI 13.55-44.55).
       Chile. Associations were found between late foetal mortality, neonatal
   mortality, and postneonatal mortality and exposure to high levels of arsenic in the
   drinking water (up to 0.86 mg/L during more than a decade), based on
   comparisons between subjects in low- and high-arsenic areas of Chile
   (Hopenhayn-Rich et al., 2000137). The Antofagasta area has a well-documented
   history of arsenic exposure from naturally contaminated water, and Valparaíso, a
   comparable low-exposure city. Antofagasta is the second largest city in Chile and
   had a distinct period (1958 until 1971) of very high arsenic exposure that began
   when an arsenic removal plant was installed. A retrospective study design was
   used to examine time and location patterns in infant mortality showing the
   general declines in late foetal and infant mortality over the study period in both
   locations. The data also indicate an elevation of the late fetal, neonatal, and
   postneonatal mortality rates for Antofagasta, relative to Valparaíso, for specific
   time periods, which generally coincide with the period of highest arsenic
   concentration in the drinking water of Antofagasta. Poisson regression analysis
   yielded associations between arsenic exposure and late foetal mortality (rate ratio
   (RR) 1.7, 95% CI 1.5-1.9), neonatal mortality (RR 1.53, 95% CI 1.4-1.7), and
   postneonatal mortality (RR = 1.3, 95% CI 1.2-1.3) after adjustment for location
   and calendar time.
       Hopenhayn et al. (2003)138 also investigated the association between
   drinking water arsenic exposure and fetal growth, reflected in birth weight in a
   prospective cohort study in these two Chilean cities with contrasting drinking
   water arsenic levels: Antofagasta (40 µg/L) and Valparaiso (<1 µg/L). Study
   subjects completed in-depth interviews and provided urine samples for exposure
   analysis. Pregnancy and obstetric information was obtained from medical
   records. The final study group consisted of 424 infants from Antofagasta and 420
   from Valparaiso. After controlling for confounders, results of the multivariable
   analysis indicated that Antofagasta infants had lower mean birth weight (-57 g,
   95% CI: -123 to 9). This study suggests that moderate arsenic exposures from
00 Arsenic and inorganic arsenic compounds
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<pre>drinking water (<50 µg/L) during pregnancy are associated with reduction in
birth weight.
    Increased standardized mortality ratios (SMRs) were reported for lung cancer
and bronchiectasis among subjects in Antofagasta in Chile who had probable
exposure in utero or during childhood to high levels of arsenic (near 0.9 mg/L) in
the drinking water (Smith et al., 2006139). In this study, mortality rates in
Antofagasta in the period 1989-2000 were compared with those of the rest of
Chile, focusing on subjects who were born during or just before the peak
exposure period and who were 30-49 years of age at the time of death. For the
birth cohort born just before the high-exposure period (1950-1957) and exposed
in early childhood, the SMR for lung cancer was 7.0 [95% CI 5.4-8.9; p < 0.001]
and the SMR for bronchiectasis was 12.4 (95% CI 3.3-31.7; p < 0.001). For those
born during the high-exposure period (1958-1970) with probable exposure in
utero and early childhood, the corresponding SMRs were 6.1 (95% CI 3.5-9.9; p
< 0.001) for lung cancer and 46.2 (95% CI 21.1-87.7; p < 0.001) for
bronchiectasis. These findings suggest that exposure to arsenic in drinking water
during early childhood or in utero has pronounced pulmonary effects, greatly
increasing subsequent mortality in young adults from both malignant and
nonmalignant lung disease.
    Bangladesh/Bengal. In a cross-sectional study a group of 96 women in the
reproductive age (15-49 years) chronically exposed to arsenic through drinking
water in Bangladesh was studied to identify the pregnancy outcomes in terms of
live birth, stillbirth, spontaneous abortion, and preterm birth (Ahmad et al.,
2001140). In a cross-sectional study, pregnancy outcomes of exposed women
were compared with pregnancy outcomes of 96 women of reproductive age (15-
49 years) who were not exposed to arsenic-contaminated water matched for age,
socioeconomic status, education, and age at marriage. Of the women in the
exposed group, 98% had been drinking water containing ≥ 0.10 mg/L arsenic
(approx. 0.08 mg/As/kg/day) and 43.8% had been drinking arsenic-contaminated
water for 5-10 years. Frequency of the adverse pregnancy outcomes of
spontaneous abortion, stillbirth, and preterm birth rates were higher in the
exposed group than in the nonexposed group (p = 0.008, p = 0.046, and p =
0.018, respectively).
    In a mixed-design study in 533 women in Bangladesh the association was
assessed between arsenic in drinking water and spontaneous abortion, stillbirth,
and neonatal death (Milton et al., 2005)141. Information on sociodemographic
characteristics, drinking water use, and adverse pregnancy outcomes
(spontaneous abortion, stillbirth and neonatal death) was obtained through a
structured interviewer-administered questionnaire. The range of arsenic
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<pre>   concentrations in tube well water ranged from non-detectable to 1710 µg/L.
   Excess risks of spontaneous abortion and stillbirth were observed among the
   chronically exposed participants after adjusting for participant's height, history
   of hypertension and diabetes, and (for neonatal death only) age at first
   pregnancy. Comparing exposure to arsenic concentration of greater than 50 µg/L
   with 50 µg/L or less, the ORs were 2.5 (95% CI 1.5-4.3) for spontaneous
   abortion, 2.5 (95% CI 1.3-4.9) for stillbirth, and 1.8 (95% CI 0.9-3.6) for
   neonatal death.
       Pregnancy outcomes and infant mortality were studied among 202 married
   women in West Bengal, India (von Ehrenstein et al., 2006142). Reproductive
   histories were ascertained using structured interviews and arsenic exposure
   during each pregnancy, including all water sources used, was assessed; this
   involved measurements from 409 wells. Exposure to high concentrations of
   arsenic (≤ 200 µg/liter) during pregnancy was associated with a sixfold increased
   risk of stillbirth after adjustment for potential confounders (odds ratio
   (OR)=6.07; 95% CI 1.54-24.0; p = 0.01). The odds ratio for neonatal death was
   2.81 (95% CI 0.73-10.8). No association was found between arsenic exposure
   and spontaneous abortion (OR 1.01, 95% CI 0.38- 2.70) or overall infant
   mortality (OR 1.33, 95% CI 0.43-4.04).
       Rahman et al. (2009)144 conducted a prospective cohort study, based on 1,578
   mother-infant pairs, in Matlab, Bangladesh. Arsenic exposure was assessed by
   analysis of arsenic in urine collected at around gestational weeks 8 and 30. In
   analysis over the full range of exposure (6-978 µg/L), no dose-effect association
   was found with birth size. However, statistically significant negative dose effects
   were found for birth weight and head and chest circumferences at a low level of
   arsenic exposure (<100 µg/L in urine). In this range of exposure, birth weight
   decreased by 1.68 (standard error (SE), 0.62) g for each 1-µg/L increase of
   arsenic in urine. For head and chest circumferences, the corresponding
   reductions were 0.05 (SE, 0.03) mm and 0.14 (SE, 0.03) mm per 1 µg/L,
   respectively. No further negative effects were shown at higher levels of arsenic
   exposure.
       Tofail et al. (2009)143 performed a population-based cohort study with 4,436
   pregnant women in Matlab, Bangladesh (an area with high-arsenic contaminated
   tube wells). A subsample of 1,799 infants born to these mothers was assessed on
   two problem solving tests (PST), the motor scale of the Baley Scales of Infant
   Development, and behaviour ratings at 7 month of age. Arsenic concentrations in
   spot urine specimens at 8 and 30 weeks of pregnancy were 81 µg/L (range 37-
   207) and 84 µg/L (range 42-230) respectively. No significant effect of arsenic
   exposure during pregnancy on infant development (motor, PST score and
02 Arsenic and inorganic arsenic compounds
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<pre>behaviour rating) was detected. However, it is possible that other effects are as
yet unmeasured or that effects will become apparent at a later age.
     Associations of arsenic exposure with adverse pregnancy outcomes and
infant mortality were assessed in a prospective cohort study of pregnant women
(n=2924) in Matlab, Bangladesh (Rahman et al., 2010145). Spontaneous abortion
was evaluated in relation to urinary arsenic concentrations at gestational week 8.
Stillbirth and infant mortality were evaluated in relation to the average of urinary
arsenic concentrations measured at gestational weeks 8 and 30. The odds ratio of
spontaneous abortion was 1.4 (95% CI 0.96-2.2) among women with urine
arsenic concentrations in the fifth quintile (249-1253 µg/L; median = 382 µg/L),
compared with women in the first quintile (<33 µg/L). There was no clear
evidence for increased rates of stillbirth. The rate of infant mortality increased
with increasing arsenic exposure: the hazard ratio was 5.0 (95% CI 1.4-17.8) in
the fifth quintile of maternal urinary arsenic concentrations (268-2019 µg/L;
median = 390 µg/L), compared with the first quintile (<38 µg/L).
     The ATSDR (2007)7 reports that chronic oral exposure of humans to arsenic
concentrations of approximately 10 µg/kg/day (LOAEL) or more, can lead to
reproduction toxicity. For human cancer however, LOAELS are reported of
approximately 1 µg/kg/day indicating that carcinogenicity in humans may be
expected at far lower concentrations than reproduction toxicity. Although a
LOAEL after inhalation exposure to arsenic is not reported by th ATSDR (2007)
the Committee is of the opinion that effects of arsenic and inorganic arsenic
compounds on reproduction may be expected at exposure levels exceeding the
exposure levels for carcinogenicity.
Lactation
WHO/ATSDR/additional data
Different studies indicated that arsenic can be excreted in human milk. In the
Bombay area (India) Dang et al. (1983)146 reported arsenic levels ranging from
0.2 to 1.1 ng/g in breast milk (25) samples of nursing mothers 1-3 months
postpartum. Arsenic was detected in human breast milk at concentrations of
0.13-0.82 ng/g (Somogyi and Beck, 1993147). In human milk sampled from 88
mothers on the Faroer Islands whose diets included predominantly seafood,
arsenic concentrations were 0.1-4.4 ng/g (Grandjean et al., 1995148). Exposure to
arsenic from the seafood diet in this population was most likely to organic
arsenic (arsenobetaine).” In a population of Andean women exposed to
approximately 200 ng/g of inorganic arsenic in drinking water, concentrations of
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<pre>   arsenic in breast milk ranged from about 0.8 to 8 ng/g (median 2.3 ng/g) (n=10)
   (Concha et al., 1998149). The arsenic concentration in the breast milk of 35
   women in Ismir, Turkey, a volcanic area with high thermal activity ranged from
   3.24 to 5.4 ng/g, with a median of 4.2 ng/g (Ulman et al., 1998150).
       Samanta et al. (2009)47 collected 226 breast milk samples from lactating
   women in arsenic-affected districts of west Bengal. In only 39 (17%) samples
   arsenic was detected. The maximum arsenic concentration in breast milk was 48
   µg/L. Hair and nail arsenic was highly correlated with drinking water arsenic
   concentrations. Women who had both high arsenic body burden and arsenical
   skin lesions also had elevated levels of arsenic in their breast milk.
       Recently EFSA (2009) calculated for the European population that the
   average exposure of inorganic arsenic from breast milk for infants (up to 6
   months) amounted 0.0275 µg/kg/day.122
       No data on the toxic effects from arsenic in breast milk on the development
   of breastfed babies could be retrieved from the literature.
   Immunological effects
   WHO/ATSDR data
   Workers exposed to arsenic in air from burning coal (not further specified) did
   not have altered levels of antibodies in their blood (Bencko et al., 1988).
   Depression of white blood cells has not been reported in workers exposed by the
   inhalation route (e.g., Beckett et al., 1986; Bolla-Wilson and Bleecker, 1987; Ide
   and Bullough, 1988; Morton and Caron, 1989). Leukopenia is observed in cases
   of oral exposure to inorganic arsenicals (e.g., Armstrong et al., 1984; Franzblau
   and Lilis, 1989; Kyle and Pease, 1965).
   Additional data
   No additional human data on immunological effects of arsenic and arsenic
   compounds was found in literature.
   Neurological effects
   WHO/ATSDR data
   Signs of peripheral and/or central neuropathy are common in humans exposed to
   inorganic arsenicals by the inhalation and oral route. Acute, high-dose exposure
04 Arsenic and inorganic arsenic compounds
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<pre>can lead to encephalopathy, with clinical signs such as confusion, hallucinations,
impaired memory, and emotional lability (Beckett et al., 1986; Danan et al.,
1984; Morton and Caron, 1989). In fatal or near-fatal cases, this may progress to
seizures and coma (Armstrong et al., 1984; Fincher and Koerker, 1987), while
lower-level exposure can lead to significant peripheral neuropathy (e.g., Feldman
et al., 1979; Huang et al., 1985; Landau et al., 1977; Mizuta et al., 1956; Silver
and Wainman, 1952). This neuropathy is usually first detected as a numbness in
the hands and feet, but may progress to a painful “pins and needles” sensation
(Franzblau and Lilis, 1989; Jenkins, 1966; Le Quesne and McLeod, 1977). Both
sensory and motor neurons are affected, with distal axon degeneration and
demyelination (Goebel et al., 1990; Hindmarsh and McCurdy, 1986). More
advanced symptoms include weakness, loss of reflexes, and wrist-drop or ankle-
drop (Chhuttani et al., 1967; Heyman et al., 1956). These effects may diminish
after exposure ceases, but recovery is slow and usually not complete (Beckett et
al., 1986; Fincher and Koerker, 1987; Le Quesne and McLeod, 1977; Morton and
Caron, 1989; Murphy et al., 1981).
     Inhaled inorganic arsenic can produce neurological effects. A study by Gerr
et al. (2000) reported an elevated incidence of peripheral neuropathy in subjects
who lived near an arsenic-using pesticide plant (13/85=15.3%; odds ratio
[OR]=5.1, p=0.004), relative to subjects who lived farther from the plant (4/
118=3.4%). Studies of copper smelter workers at the smelter in Tacoma,
Washington (Feldman et al.,1979), a power station in Slovakia (Buchancová et
al.,1998), and the Rőnnskär smelter in Sweden (Blom et al. 1985; Lagerkvist and
Zetterlund, 1994) have demonstrated peripheral neurological effects in workers
associated with arsenic trioxide exposure. At the Tacoma smelter, the prevalence
of clinically diagnosed peripheral neuropathy was markedly higher in arsenic-
exposed workers (26/61=43%) than controls (4/33=12%), and although not
statistically significant, mean peroneal motor NCV (nerve conduction velocity)
was lower in arsenic-exposed workers than controls and all 12 cases of
abnormally low NCV occurred in the arsenic group (Feldman et al.,1979). In the
study of 70 workers in Slovakia, the investigators described 16 cases of arsenic
intoxication. Among these, 13 had signs and symptoms of sensory and motor
polyneuropathy on both upper and lower extremities, 10 were diagnosed with
pseudoneurasthenic syndrome, and 6 suffered from toxic encephalopathy
(Buchancová et al., 1998). The average length of exposure was 22.3 years (SD
±8.4 years) and the average arsenic exposure in inhaled air ranged from 4.6 to
142.7 µg/m3. Similar results were observed at the Rőnnskär smelter, where Blom
et al. (1985) reported significantly increased prevalence of workers with
abnormally low NCV in the exposed group, and lower, but not statistically
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<pre>   significant, mean NCV in five peripheral nerves. A follow-up study on the
   Rőnnskär workers 5 years later found that the prevalence of abnormally low
   NCV remained significantly increased in the exposed workers, but that the
   decrease in mean NCV was now also statistically significant in the tibial (motor)
   and sural (sensory) nerves (Lagerkvist and Zetterlund, 1994). The follow-up
   Rőnnskär study provided enough information to estimate that mean arsenic
   exposure was 0.31 mg As/m3 and lasted an average of 28 years in the exposed
   group.
       Chronic oral exposure to arsenic may be associated with intellectual deficits
   in children. Wasserman et al. (2004) conducted a cross-sectional evaluation of
   intellectual function in 201 children 10 years of age whose parents were part of a
   larger cohort in Bangladesh. Intellectual function was measured using tests
   drawn from the Wechsler Intelligence Scale for Children. The mean arsenic
   concentration in the water was 0.118 mg/L. The children were divided into four
   exposure groups, representing <5.5, 5.6-50, 50-176, or 177-790 µg As/L
   drinking water. A dose-related inverse effect of arsenic exposure was seen on
   both Performance and Full-Scale subset scores; for both end points, exposure to
   ≥50 µg/L resulted in statistically significant differences (p<0.05) relative to the
   lowest exposure group (<5.5 µg/L).
       The same group of investigators examined 301 6-year-old children from the
   same area (Wasserman et al., 2007). The children were categorized into quartiles
   based on water arsenic concentration: 0.1-20.9, 21-77.9, 78-184.9, and 185-864
   µg/L. Water arsenic was significantly negatively associated with both
   Performance and Processing speed raw scores. Analyses of the dose-response
   showed that compared to the first quartile, those in the second and third
   categories had significantly lower Performance raw scores (p<0.03 and p=0.05,
   respectively). Those in the fourth category had marginally significantly lower
   Full-Scale and Processing Speed raw scores.
   Additional data
   A cross-sectional study examined the effects of chronic inhalatory exposure to
   lead (Pb), arsenic (As) and undernutrition on the neuropsychological
   development of children living in the vicinity of a smelter complex (San Luis
   Potosi, Mexico) (Calderon et al., 2001).151 Two populations chronically exposed
   to either high (41 children) or low (39 children) levels of As and Pb were
   analyzed using the Wechsler Intelligence Scale for Children(WISC). Geometric
   means of urinary arsenic (AsU) and lead in blood (PbB) were 62.9 ± 0.03 (µgAs/
   g creatinine) and 8.9 ± 0.03 (µg/dL) for the exposed group and 40.2 ± 0.03
06 Arsenic and inorganic arsenic compounds
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<pre>(µgAs/g creatinine)and 9.7 ± 0.02 (µg/dL) for the reference group. The height for
age index (HAI) was used as an indicator of chronic malnutrition and
sociodemographic information was obtained with a questionnaire. Lead and
arsenic were measured by atomic absorption spectrophotometry. Data on full,
verbal, and performance intelligence quotients (IQ) scores, long-term memory,
linguistic abstraction, attention span, and visuospatial organization were obtained
through the WISC (Wechsler Intelligence Score for Children) . Verbal IQ (p <
0.01) decreased with increasing concentrations of AsU. The HAI correlated
positively with full-scale and performance IQ (p < 0.01). Higher levels of AsU
were significantly related to poorer performance on WISC factors examining
long-term memory and linguistic abstraction, while lower scores in WISC factors
measuring attention were obtained at increasing values of PbB.
Other effects
Vascular effects
WHO/ATSDR data
Several studies in Taiwan have demonstrated an association between arsenic
ingestion and blackfoot disease (BFD), with clear exposure-response effects
related to both the well-water arsenic levels and duration of use of arsenic-
contaminated drinking water (Chen et al.,1988b; Ch’i and Blackwell, 1968;
Tseng, 1977, 1989; Tseng et al.,1968. 1995, 1996). Several other studies and case
reports of subjects exposed to arsenic from many sources, in countries other than
Taiwan, document an association with peripheral vascular alterations. However,
the extreme form and high prevalence of BFD found in Taiwan has not been
reported in other parts of the world.
    Hypertension is associated with long-term oral exposure to arsenic, but this
evidence is limited to cross-sectional studies, one occupational and two
environmental (Taiwan and Bangladesh), all three of which found elevations in
blood pressure with arsenic exposure (Rahman et al.,1999; Wang et al., 2003;
Chen et al.,1995). The two environmental studies demonstrated exposure-
response relationships. It should be noted that although hypertension is not a very
important cause of death itself, it is a major risk factor for other vascular
diseases.
    Several studies in Taiwan show a relationship between oral arsenic exposure
and mortality from cardiovascular diseases (CVD), including exposure-response
relationships (Chiou et al.,1977; Wang et al., 2002, 2003; Chang et al., 2004;
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<pre>   Chen et al., 1996; Hsueh et al.,1998; Tsai et al., 1999; Tseng et al., 2003). Similar
   results have generally not been observed in other arsenic drinking water studies
   or in a medicinal study, in all of which the exposure levels have been lower. In
   the occupational studies, mortality from arteriosclerosis and coronary heart
   disease was elevated in the report from the Tacoma cohort (USA), but no
   statistically significant increases for these effects have been found in the
   Rönnskär (Sweden) or Anaconda (USA) smelter cohorts (Enterline et al.,1995;
   Lee-Feldstein, 1983; Welch et al., 1982; Wall, 1980). The study in Utah found an
   excess of mortality from hypertensive heart disease but there were only a small
   number of deaths.
       Only very limited evidence exists for an association between oral arsenic
   exposure and cerebrovascular disease. Some of the Taiwanese studies have
   shown an elevated risk of death from cerebrovascular disease, but the data are
   inconsistent across studies and the elevations, where present, are small compared
   with those for CVD. Studies from other countries provide only very limited
   support for the Taiwanese findings, but exposure levels were considerably lower.
   Additional data
   Wang et al. (2010) reported a 17-year follow-up of a cohort consisting of 280
   men and 355 women living in area in southwestern coast in Taiwan for 17
   years.152 Cumulative arsenic exposure was significantly associated with QT-
   dispersion (QTD) showing a dose-response relationship (p < 0.001). Significant
   associations of the QTD with coronary artery disease and carotid atherosclerosis
   existed after adjustment for potential confounders in the multiple linear
   regression analysis (all p values < 0.05). In the multivariate Cox regression
   analyses, the hazard ratios (95% confidence interval, p value) of cumulative
   cardiovascular and all-cause mortality were 3.9 (2.1-6.2, P = 0.002) and 1.4 (0.9-
   2.3, p = 0.10), respectively, for QTD > or = 65 ms compared with QTD < 65.
   Diabetes mellitus
   WHO/ATSDR data
   Two occupational studies found an association of borderline statistical
   significance between diabetes mellitus and inhalation exposure to arsenic.
   In Taiwan, the prevalence and mortality rates of diabetes mellitus were higher
   among the population of the BFD-endemic area. There was also an exposure-
   response relationship between cumulative oral arsenic exposure and the
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<pre>prevalence of diabetes mellitus. A similar exposure-response pattern was
observed in a study in Bangladesh, where prevalence of keratosis was used as a
surrogate for arsenic exposure.
Additional data
Navas-Acien et al. (2008) conducted a cross-sectional study in 788 adults aged
20 years or older who participated in the 2003-2004 National Health and
Nutrition Examination Survey (NHANES).153 The median urine levels of total
arsenic, dimethylarsinate, and arsenobetaine were 7.1, 3.0, and 0.9 µg/L,
respectively. The prevalence of type 2 diabetes was 7.7%. After adjustment for
diabetes risk factors and markers of seafood intake, participants with type 2
diabetes had a 26% higher level of total arsenic (95% CI 2.0%-56.0%) and a
nonsignificant 10% higher level of dimethylarsinate (95% CI -8.0% to 33.0%)
than participants without type 2 diabetes, and levels of arsenobetaine were
similar to those of participants without type 2 diabetes. After similar adjustment,
the odds ratios for type 2 diabetes comparing participants at the 80th vs the 20th
percentiles were 3.58 for the level of total arsenic (95% CI 1.18-10.83), 1.57 for
dimethylarsinate (95% CI 0.89-2.76), and 0.69 for arsenobetaine (95% CI 0.33-
1.48).
    The same cross-sectional data on urinary arsenic and type 2 diabetes mellitus
in 795 adults from the 2003-2004 National Health and Nutrition Examination
Survey were analyzed by Steinmaus et al. (2009) to assess this evidence.154 They
found an odds ratio (OR) near 1.0 for diabetes, comparing the 80th versus 20th
percentiles of urinary total arsenic (OR 0.88, 95% CI 0.39-1.97). This OR
increased to above 3.0 when urinary arsenobetaine was added to the logistic risk
model. The authors claim that this high OR was a statistical artifact. because
arsenobetaine, which is ingested from fish and is essentially nontoxic, is a part of
measured total urinary arsenic. Upon correction an OR of 1.15 (0.53-2.50) was
calculated. These findings show no evidence of increased risk of diabetes with
arsenic exposure in this dataset.
Anaemia
WHO/ATSDR data
Anaemia is often observed in humans exposed to arsenic by the oral route (e.g.,
Armstrong et al., 1984; Glazener et al., 1968; Mizuta et al., 1956; Westhoff et al.,
1975). This is probably due mainly to a toxic effect on the erythropoietic cells of
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<pre>      bone marrow (Franzblau and Lilis, 1989; Lerman et al., 1980; Westhoff et al.,
      1975), although increased haemolysis may also contribute (Goldsmith and From,
      1986; Kyle and Pease, 1965).
      Additional data
      The association between arsenic exposure and anemia, based on blood
      haemoglobin concentration was studied by Heck et al. (2008).155 Haemoglobin
      measures, skin lesions, arsenic exposure, and nutritional and demographic
      information were collected from 1954 Bangladeshi participants in the Health
      Effects of Arsenic Longitudinal Study. Arsenic exposure (urinary arsenic >200
      µg/L) was negatively associated with haemoglobin among all men and among
      women with haemoglobin <10 g/dL.
7.2   Animal experiments
      Animal data are summarized in Tables 16-19 (Annex H).
7.2.1 Irritation and sensitisation
      WHO/ATSDR data
      Sodium arsenite and sodium arsenate were not allergenic in the guinea-pig
      maximisation test (Wahlberg and Boman, 1986).
      No animal data on local effects on the respiratory tract was reported for arsenic
      and inorganic arsenic compounds.
      No studies were located on ocular effects in animals after inhalation exposure to
      inorganic arsenicals.
      Additional data
      Animal data with regard to irritation and sensitisation of arsenic and arsenic
      compounds are very limited.
           Fukuyama et al. (2008) used the local lymph node assay to evaluate the
      ability of chromated copper arsenate (CCA), a commonly used wood
      preservative, and its components to cause sensitizing reactions.156 After CBA/J
      mice were treated topically with 0.3 to 10% CCA, 0.3-3% chromium oxide, 0.3-
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<pre>      3% arsenic oxide, or 0.3-3% copper oxide, their auricular lymph nodes (LN)
      were weighed and used in lymphocyte proliferation assays. In addition, total
      levels of chromium and arsenic in blood samples were measured. In all groups
      treated with CCA, all parameters, including LN weight and lymphocyte
      proliferation, increased in a dose-dependent manner. The stimulation index (SI;
      the mean [3H]-TdR incorporation of the treatment group divided by that of the
      control group) showed a positive response (SI >3) in all treatment groups. In
      addition, it was confirmed that the three components of CCA – chromium oxide,
      arsenic oxide and copper oxide – each individually exerted sensitizing ability.
7.2.2 Acute toxicity
      WHO/ATSDR/additional data
      The acute dermal LD50 for the pentavalent arsenicals calcium arsenate and lead
      arsenate in the rat is ≥ 2400 mg/kg bw (≥ 400 mg As/kg bw) (Gaines, 1960).
          In a developmental study, 100% mortality in groups of 10 pregnant rats after
      1 day of inhalation exposure to arsenic trioxide concentrations of ≥100 mg/m3
      was observed (76 mg As/m3) (Holson et al., 1999).
          Oral and parenteral lethal doses range from 15 to 960 mg As/kg bw/day,
      depending on the compound and the animal species (Jaghabir et al., 1988; Kaise
      et al., 1989; NTP, 1989; Rogers et al., 1981; Stevens et al., 1979).
7.2.3 Short-term toxicity
      WHO/ATSDR/additional data
      In a developmental toxicology study, four of nine pregnant rats died and one rat
      was euthanised in extremis between days 12 and 19 of gestation after 30-35 days
      of exposure to an aerosol of arsenic trioxide at an exposure concentration of 20
      mg As/m3 (Holson et al., 1999). These animals exhibited severe hyperemia and
      plasma discharge into the intestinal lumen at autopsy.
          The lowest oral arsenic lethal level in an animal study was 1.5 mg As/kg bw/
      day in pregnant rabbits dosed repeatedly throughout gestation.
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<pre>7.2.4 Long-term toxicity
      Genotoxicity
      WHO/ATSDR data
      Inorganic arsenic did not induce point mutations in bacteria or in mammalian
      cells. However, arsenic can produce chromosomal aberrations in vitro, affect
      methylation and repair of DNA, induce cell proliferation, transform cells, and
      promote tumours.
          There have been a large number of in vitro studies of the genotoxic effects of
      arsenic. The results are mixed, but in general, it appears that the inorganic
      arsenicals are either inactive or weak mutagens, but are able to produce
      chromosomal effects (aberrations, sister chromatid exchange) in most systems.7
      Additional data
      Additional data on genotoxicity in animals is presented in Table 19a and 19b
      (Annex H). Ahmad et al. (2000, 2002)157,158 demonstrated that dimethylarsinous
      acid and dimethylarsinic acid are capable of releasing iron from horse spleen
      ferritin, inducing DNA damage via formation of reactive oxygen species (ROS).
      Furthermore, DNA-damaging activity by dimethylarsinous acid and
      monomethylarsonous acid mediated by ROS towards supercoiled ΦX174 RFI
      DNA, using a DNA nicking assay58,59,159 and towards isolated PM2 DNA was
      demonstrated94. In the DNA nicking assay, nicking and/or degradation of ΦX174
      DNA depended on concentration; monomethylarsonous acid was effective at
      nicking ΦX174 DNA at 30 mM; however, at 150 µM dimethylarsinous acid,
      nicking could be observed.
          Dopp et al. observed a significant increase in the number of micronuclei,
      chromosome aberrations and sister chromatid exchanges in cultured Chinese
      hamster ovary cells after exposure to dimethylarsinous acid and
      monomethylarsonous acid.61 AsIII and AsV induced chromosome aberrations and
      sister chromatid exchanges. Trimethylarsenic oxide, monomethylarsonic acid
      and dimethylarsinic acid were not genotoxic in the concentration range tested (up
      to 5 mM).
          Akram et al. (2009) examined the genotoxic effects of arsenite in ovarian
      tissue of rats at 56 days of age. Immature (28 days old) female rats were exposed
      to different doses (50, 100, and 200 ppm) of sodium arsenite in drinking water
 12   Arsenic and inorganic arsenic compounds
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<pre>for 28 days.160 DNA damage in ovarian tissue was measured by the comet assay.
All doses induced significant decrease in ovarian weight in a dose-dependent
manner compared to control, more prominently at (p < 0.001) 100 and 200 ppm.
All the comet assay parameters showed significant difference with arsenite
treatment compared to control group. In treatment groups, mean number of cells
with intact DNA decreased while, mean comet number increased (p < 0.001) in a
dose-dependent manner compared to control. Significant decrease (p < 0.05) was
observed in mean comet length, height, comet head diameter and %DNA in
comet head of high dose groups compared to control group. Dose dependent
increase was found in mean comet tail length, %DNA in tail, tail moment and
olive tail moment in high dose groups compared to control group. The study
indicates that arsenic caused DNA damage to ovarian cells particularly at high
doses.
    In an in vivo study, mice (Swiss albino) (n=6 females/dose) were exposed
orally to 0 and 2.5 mg/kg bw sodium arsenite (exposure for 24 h). Sodium
arsenite produced significantly high frequencies of chromosome aberrations in
bone marrow cells.161
    Yamanaka et al. observed that the amount of 8-oxodG (a biomarker of DNA
oxidation) was significantly increased not only in lung and liver, but also, though
not significantly, in urinary bladder in male ddY mice which were exposed for 4
weeks to 400 mg/L dimethylarsinic acid in drinking water (n=5/dose).162 No
increase in 8-oxodG was observed in spleen or kidney. The amount of 8-oxodG
in epidermis of the dorsal skin was also significantly increased (in female HR-1
hairless mice which were exposed for 2 weeks to 400 mg/L dimethylarsinic acid
in drinking water (n=5/dose)). Furthermore, when the same dose of As as
arsenite or dimethylarsinic acid (a single gavage dose of 15.2 mg (11.5 mg As)/
kg arsenite or 21.1 mg (11.5 mg As)/kg dimethylarsinic acid) was administered
to male ddY mice, the amount of 8-oxodG was significantly higher in the urine
after 9 hour of mice exposed to dimethylarsinic acid.
    Noda et al. (2002) conducted a study to evaluate whether arsenite or its
metabolite, DMA, could initiate carcinogenesis via mutagenic DNA lesions in
vivo that can be attributed to oxidative damage.163 A transgenic mouse model,
MutaMouse, was used in this study and mutations in the lacZ transgene and in
the endogenous cII gene were assessed. When DMA was intraperitoneally
injected into MutaMice at a dose of 10.6 mg/kg per day for 5 consecutive days, it
caused only a weak increase in the mutant frequency (MF) of the lacZ gene in the
lung, which was at most 1.3-fold higher than in the untreated control animals.
DMA did not appreciably raise the MF in the bladder or bone marrow. Further
analysis of the cII gene in the lung, the organ in which DMA induced the DNA
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<pre>   damage, revealed only a marginal increase in the MF. Following DMA
   administration, no change in the cII mutation spectra was observed, except for a
   slight increase in the G:C to T:A transversion. Administration of arsenic trioxide
   (arsenite) at a dose of 7.6 mg/kg per day did not result in any increase in the MF
   of the lacZ gene in the lung, kidney, bone marrow, or bladder. Micronucleus
   formation was also evaluated in peripheral blood reticulocytes (RETs). The assay
   for micronuclei gave marginally positive results with arsenite, but not with
   DMA. These results suggest that the mutagenicity of DMA and arsenite might be
   too low to be detected in the MutaMouse.
   Carcinogenicity
   WHO/ATSDR data
   Several animal carcinogenicity studies on arsenic have been carried out, but
   limitations such as limited time of exposure and limited number of animals make
   these inconclusive. However, in a recently reported animal study, female C57B1/
   6J mice exposed to arsenic in drinking water containing 500 µg AsV/L over 2
   years was associated with increased incidence in tumours involving mainly lung,
   liver, gastrointestinal tract and skin.7 One study has indicated that
   dimethylarsinic acid may cause cancer of the urinary bladder in male rats at high
   doses.7
       No studies were located regarding cancer in animals after inhalation
   exposure to inorganic arsenicals, although several intratracheal instillation
   studies in hamsters have provided evidence that both arsenite and arsenate can
   increase the incidence of lung adenomas and/or carcinomas (Ishinishi et al.,
   1983; Pershagen and Bjorklund, 1985; Pershagen et al., 1984; Yamamoto et al.,
   1987).
       Most studies of animals exposed to arsenate or arsenite by the oral route have
   not detected any clear evidence for an increased incidence of skin cancer or other
   cancers (Byron et al., 1967; Kroes et al., 1974; Schroeder et al., 1968).
       Application of arsenic acid to the skin of mice pretreated with
   dimethylbenzanthracene did not result in any skin tumours (Kurokawa et al.,
   1989), suggesting that arsenic does not act as a promoter in this test system.
       Arsenic has sometimes been called a ‘paradoxical’ human carcinogen
   because of these negative findings (Jager and Ostrosky-Wegman,1997). The
   basis for the lack of tumorigenicity in animals is not known, but could be related
   to species-specific differences in arsenic distribution, and induction of cell
14 Arsenic and inorganic arsenic compounds
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<pre>proliferation (Byrd et al.,1996). (This view has recently been contended by Tokar
et al. (2010).164)
Additional data
A study by the US National Toxicology Program provided clear evidence of the
carcinogenicity for gallium arsenide after inhalation in rodents.165 In female rats
exposed via inhalation to several levels of gallium arsenide (GaAs) particulate
(0, 0.01, 0.1,1.0 mg/m3 for up to 2 years, dose related lung alveolar/bronchiolar
tumors and adrenal medulla phaeochromocytomas occurred. In male rats,
though, treatment-related tumours were not observed, a dose-related increase in
the incidence of atypical hyperplasia of the lung alveolar epithelium occurred. In
the female rats, increases also occurred in leukemia at the highest dose. In a
separate component of this study, mice exposed via inhalation to several doses of
gallium arsenide particulate for 2 years did not show treatment-related tumours,
but both males and females showed exposure concentration-related increases in
the incidence of lung epithelial alveolar hyperplasia.
Especially recent work with arsenical methylation metabolites MMA and DMA
and early life exposures to inorganic arsenic has now become available.166-168
    Arnold et al. (2003) evaluated the carcinogenicity of monomethylarsonic
acid (MMAV) in male and female Fisher F344 rats and B6C3F1 mice in 2-year
feeding studies according to US EPA guidelines.166 Rats were treated with 50,
100 or 1300 ppm MMA and mice were treated with 10, 50, 200 or 400 ppm
MMA based on preliminary short studies. There was no treatment related
mortality in the mice. The primary target organ for MMA-induced toxicity in rats
and mice was the large intestine. Toxicity was more severe in rats compared to
mice and in male rats compared to female rats. The maximum tolerated dose for
chronic dietary administration of MMA in rats and mice was assessed as 400
ppm, and the no effect level with regard to intestinal toxicity was assessed as 50
ppm for rats and 200 ppm for male mice. There were no treatment-related
neoplastic effects detected in either the rat or the mouse.
    To evaluate the carcinogenic effects of DMAV, a bioassay was conducted in
rats given various doses of DMA (Yamamoto et al., 1995167). One-hundred
twenty-four male F344/DuCrj rats were divided randomly into 7 groups (20 rats
each for groups 1-5; 12 rats each for groups 6 and 7). Groups 2-5 were given
various tumour initiators followed by 50, 100, 200, or 400 ppm DMA,
respectively, in the drinking water. Groups 6 and 7, received 100 and 400 ppm
DMA during weeks 6-30. All rats were killed at the end of week 30. In the
Effects                                                                             115
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<pre>   initiated groups (groups 1-5), DMA significantly enhanced the tumour induction
   in the urinary bladder, kidney, liver, and thyroid gland, with respective
   incidences in group 5 (400 ppm DMA) being 80, 65, 65, and 45%. Induction of
   preneoplastic lesions (glutathione S-transferase placenta! form-positive foci in
   the liver and atypical tubules in the kidney) was also significantly increased in
   DMA-treated groups. Ornithine decarboxylase activity in the kidneys of rats
   treated with 100 ppm DMA was significantly increased compared with control
   values (p < 0.001). The authors conclude that DMA is acting as a promoter of
   urinary bladder, kidney, liver, and thyroid gland carcinogenesis in rats, but not of
   the lung.
        To elucidate molecular mechanisms, an 18 month carcinogenicity study was
   conducted of DMAV in p53 heterozygous (+/-) knockout mice, which are
   susceptible to early spontaneous development of various types of tumours, and
   wild-type (+/+) C57BL/6J mice (Salim et al., 2003168). Totals of 88-90 males, 7-
   8 weeks of age, were divided into three groups each administered 0, 50 or 200
   ppm. DMA in their drinking water for 18 months. Mice that were found
   moribund or died before the end of the study were autopsied to evaluate the
   tumour induction levels, as well as those killed at the end. Both p53(+/-)
   knockout and wild-type mice demonstrated spontaneous tumor development, but
   lesions were more prevalent in the knockout case. Carcinogenic effect of DMA
   was evident by significant early induction of tumours in both treated p53(+/-)
   knockout and wild-type mice, significant increase of the tumor multiplicity in
   200 ppm-treated p53(+/-) knockout mice, and by significant increase in the
   incidence and multiplicity of tumours (malignant lymphomas) in the treated
   wild-type mice. By the end of 80 weeks, tumor induction, particularly malignant
   lymphomas and sarcomas, were similar in treated and control p53(+/-) knockout
   mice. No evidence for organ-tumor specificity of DMA was obtained. Molecular
   analysis using PCR-SSCP techniques revealed no p53 mutations in lymphomas
   from either p53(+/-) knockout or wild-type mice. The authors conclude that
   DMA primarily exerted its carcinogenic effect on spontaneous development of
   tumours with both of the animal genotypes investigated here.
        Several studies have investigated exposure during the perinatal period in
   rodents.169,170 Waalkes et al. (2003)169, exposed pregnant C3H mice to different
   levels of sodium arsenite (0, 42.5 and 85 ppm) in the drinking water from
   gestational days 8 to 18, allowed to give birth, and, at weaning, offspring groups
   of males (25, 25, 25) and females (25, 25, 25) were formed and observed for
   tumour formation. Over the next 90 weeks post partum, female offspring
   exposed to arsenic in utero developed dose-related increases in lung
   adenocarcinoma (0/25, 1/23, 5/24), benign ovarian tumors (2/25, 4/23, 8/24) and
16 Arsenic and inorganic arsenic compounds
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<pre>combined benign or malignant ovarian tumours (2/25, 6/23, 9/24). Female
offspring also developed arsenic dose-related uterine and oviduct preneoplasias
after fetal arsenic exposure. After in utero arsenic exposure, male offspring
showed dose-related increases in incidence of liver adenoma (9/24, 12/23, 19/
21), hepatocellular carcinoma (3/24, 8/23, 10/21), liver adenoma or carcinoma
(12/24, 14/23, 19/21), and adrenal cortical adenoma (9/24, 15/23, 15/21).
Additionally, arsenic exposed male offspring showed arsenic-induced, dose-
related increases in liver tumour multiplicity (tumors/mouse), which was
maximally over 5.6-fold over control.
Reproduction toxicity
Effects on fertility-oral exposure
WHO/ATSDR/additional data
No studies on inhalation exposure were retrieved, only oral and parenteral
studies were available (Wang et al. 2006)171). Arsenite exposure causes male
reproductive toxicity when given through drinking water (Chinoy et al. 2004)172;
Pant et al. 2001)173, 2004174) or by ip injection (Sarkar et al. 2003175). AsIII
interferes with spermatogenesis (Pant et al. 2001173, 2004174, Sarkar et al.
2003175) and alters activities of spermatogenetic enzymes (Chinoy et al., 2004172;
Pant et al. 2001173, 2004174). Furthermore, AsIII lowers levels of testosterone and
gonadotrophin (Chinoy et al. 2004172; Sarkar et al. 2003175). In female mice and
rats, inorganic arsenic suppresses ovarian steroidogenesis, prolongs diestrus, and
degenerates ovarian follicular and uterine cells (Chattopadhyay et al. 2001176;
Navarro et al. 2004177). It also increases meiotic aberrations in oocytes, and
decreases cleavage and preimplantation development (Navarro et al., 2004177).
    Pant et al. (2001)173 administered arsenic to male mice via drinking water as
sodium arsenite at doses of 53.39, 133.47, 266.95 and 533.90 µmol/L (4, 10, 20,
40 µg As/L respectively) for 35 days. There was no difference in the uptake of
water in control and treated animals. Arsenic treated mice survived the treatment
period without any signs of clinical toxicity and showed no significant change in
the body weight and in the weight of testes, epididymis and accessory organs. A
decrease in the activity of 17 ß-hydroxysteroid dehydrogenase (17 ß-HSD) along
with increase in lactate dehydrogenase (LDH) and gamma-glutamyl
transpeptidase (γ-GT) activity were observed at 533.90 µmol/L. The observed
sperm count, motility and morphological abnormalities in sperm were similar to
control at lower dose levels. However at 533.90 µmol/L (40 µg As/L ) a
Effects                                                                             117
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<pre>   significant decrease in sperm count and motility along with increase in abnormal
   sperm were noticed. Significant accumulation of arsenic in testes and accessory
   sex organs may be attributed to the arsenic binding to the tissues or greater
   cellular uptake.
       In a chronic study Pant et al. (2004)174 administered sodium arsenite to male
   mice via drinking water at a dose of 53.39 µmol/L (4 µg As/L) for 365 days. The
   mice did not demonstrate any apparent symptoms of toxicity, or any change in
   food consumption or water intake. Arsenic caused a decrease in the absolute and
   relative testicular weight. However, epididymal and accessory sex organ weight
   was similar to control. The activities of marker testicular enzymes such as
   sorbitol dehydrogenase, acid phosphatase and 17ß-HSD were significantly
   decreased, but those of LDH and γ-GT were significantly increased. A decrease
   in sperm count and sperm motility, along with an increase in abnormal sperm,
   was observed in arsenite-exposed mice. A significant accumulation of arsenic in
   testes, epididymis, seminal vesicle and prostate gland was observed in treated
   animals.
       In mice, in addition to spermatogenesis, cholesterol metabolism and
   testicular testosterone level were affected by AsIII (Chinoy et al. 2004172). Male
   Swiss mice were given arsenic trioxide (As2O3) orally at 0.5 mg/kg for 30 days.
   Treated mice showed increased cholesterol levels and decreased protein levels in
   the testes. Testicular structural damage observed included degeneration of
   tubules and denudation of germinal epithelial cells. There was also a lack of
   sperm in the lumen of seminiferous tubules. In addition, testicular activities of
   3β-HSD and 17β-HSD, and testosterone levels in the serum were decreased.
       Chattopadhyay et al. (2001176, 2003178) gave a subchronic treatment to
   mature female Wistar-strain albino rats in diestrous phase with sodium arsenite at
   a dose of 0.4 ppm/100 g body weight/rat/day via drinking water for period of 28
   days (seven oestrous cycles). No differences in food consumption were seen in
   any of the groups of animals throughout the experimental schedule. The body
   weights of arsenic-treated rats did not differ significantly from the controls. Liver
   weights and activities of liver enzymes were increased. The treatment caused a
   significant reduction in the plasma levels of lutinizing hormone (LH), follicle-
   stimulating hormone (FSH), and estradiol along with a significant decrease in
   ovarian activities of 3ß-HSD and 17ß-HSD followed by a reduction in ovarian
   and uterine peroxidase activities. A significant weight loss of the ovary and
   uterus was also observed after this treatment, along with a prolonged diestrous
   phase and a high accumulation of arsenic in the plasma and these organs.
   Moreover, sodium arsenite was also responsible for ovarian follicular and uterine
   cell degeneration characterized by a high number of regressing follicles and a
18 Arsenic and inorganic arsenic compounds
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<pre>reduction in the uterine luminal diameter, respectively, in comparison with the
controls.
Effects on fertility – parenteral exposure
WHO/ATSDR/additional data
Sodium arsenite was given to Wistar rats via ip injections at 4, 5, or 6 mg/kg/day
for 26 days (Sarkar et al. 2003175). At 5 and 6 mg/kg/day, relative testicular
weight, accessory sex organ weights and epididymal sperm counts were
decreased. The same was true for plasma concentrations of luteinizing hormone
(LH), FSH, and testosterone. Massive degeneration of all the germ cells at stage
VII was observed at 5 and 6 mg/kg/day.
     Female CD-1 mice were ip injected with 0, 8, or 16 mg/kg sodium arsenite
every 2 days for a total of 7 injections over 14 days (Navarro et al. 2004177).
Superovulation was induced by injections of equine and human chorionic
gonadotrophins overlapping the end of the arsenite treatment. Metaphase II
oocytes from these arsenite-treated mice had increased meiotic aberrations,
characterized by spindle disruption and chromosomal misalignment.
Additionally, zygotes from arsenite-treated mice showed lower rates of cleavage,
decreased morula formation, and decreased development to blastocysts. More
apoptotic nuclei were seen in the blastocysts of arsenite-treated mice. Some of
these effects of arsenic on oocytes were observed at 8 mg/kg, a previously
established maternal NOAEL.171
Developmental effects-inhalation exposure
WHO/ATSDR/additional data
Studies in animals showed that arsenic caused reduced birth weight, a variety of
foetal malformations (both skeletal and soft tissue), and increased foetal
mortality. These effects have been noted following inhalation exposure of mice
and rats, oral exposure of mice, rats, hamsters and rabbits, and intraperitoneal or
intravenous exposure of mice, rats and hamsters.
     Holson et al. (1999)179 administered inorganic arsenic, as arsenic trioxide
    III
(As , As2O3), via whole-body inhalational exposure to groups of twenty-five
Crl:CD(SD)BR female rats for six h per day every day, beginning fourteen days
prior to mating and continuing throughout mating and gestation. Exposures were
initiated prior to mating in order to achieve a biological steady state of AsIII in
Effects                                                                             119
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<pre>   the dams prior to embryo-fetal development. In a preliminary exposure range-
   finding study, half of the females that had been exposed to arsenic trioxide at 25
   mg/m3 died or were euthanized in extremis. In the definitive study, intended
   exposure levels were 0.3, 3.0, and 10.0 mg/m3. Maternal toxicity, which was
   determined by the occurrence of rales, a decrease in net body weight gain, and a
   decrease in food intake during pre-mating and gestational exposure, was
   observed only at the 10 mg/m3 exposure level. Intrauterine parameters (mean
   numbers of corpora lutea, implantation sites, resorptions and viable fetuses, and
   mean fetal weights) were unaffected by treatment. No treatment-related
   malformations or developmental variations were noted at any exposure level.
   The NOAEL for maternal toxicity was 3.0 mg/m3; the NOAEL for
   developmental toxicity was greater than or equal to 10 mg/m3.
        Mice were exposed by inhalation to 0.22, 2.2 and 22 mg As/m3 (as As2O3)
   for 4 h on days 9-12 of gestation On day 18 the foetuses were removed and the
   number of dead fetuses, retardation in growth, osteogenesis and chromosomal
   aberrations were examined. The highest dose group (22 mg As/m3) had
   significant increases in the percentage of dead foetuses, skeletal malformations,
   and the number of foetuses with retarded growth, while those exposed to 2.2 mg
   As/m3 had only a 10% decrease in average fetal body weight, and those exposed
   to 0.20 mg As/m3 had 3% decrease in fetal weight (Nagymajtenyi et al., 1985180).
   Developmental effects-oral exposure
   WHO/ATSDR/additional data
   Schroeder and Mitchner (1971)181 found a statistically significant increase in the
   incidence of small litters and a trend toward decreased number of pups per litter
   in all generations of a 3-generation drinking water study in mice. The average
   litter size in the exposed group amounted 8.2 in the F1 generation, 9.6 in the F2
   generation and 8.1 in the F3 generation. In the control group the average litter
   size was 11 in the F1, 10.3 in the F2 and 10.5 in the F3 generation.
        Hood et al. (1978)182 administered sodium arsenate orally to mice at a dose of
   120 mg/kg on one of gestation days 7-15. The litters were examined at gestation
   day 18 and compared with litters from dams which were treated ip with a
   reference dose of 40 mg/kg sodium arsenate known to result in reprotoxic
   effects, and with litters from negative controls (dams treated orally with the
   solvent H2O). The two arsenate treatments (oral and ip) caused comparable
   maternal mortality. Foetuses from orally treated dams weighed statistically
   significantly less than those from negative controls when treatment was given on
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<pre>gestation days 10, 11 or 15, and either less than (treatment days 11 and 15) or
more than (day 9) those from positive controls. Oral arsenate treatment on
gestation day 11 increased prenatal mortality over that in negative controls (p <
0.01). Oral treatment on days 8-15 suggested an increase in prenatal mortality
but the difference with the negative controls was not statistically significant.
     The intraperitoneal treatment with the reference dose of 40 mg/kg sodium
arsenate resulted in a significantly higher prenatal mortality than the oral
treatment when given on day 7, 11, 13 and 14.
     Fetal malformations (oligodactyly, micromelia, kinked tail) were seen in
litters from dams given oral arsenate on days 7, 8, 9, 10, or 11, but the
percentages of affected foetuses (0.6-5.0 %) did not differ significantly from
those from negative controls (0 %). Skeletal defects (fused ribs, fused vertebrae)
were also seen in litters from orally arsenate treated dams, but only treatment on
gestation day 9 was associated with an incidence of defects significantly
different from negative controls. Litter from dams treated ip with the reference
dose of 40 mg/kg sodium arsenate exhibited both gross and skeletal
abnormalities. Histopathological evaluations of fetal tissues were negative.
     Baxley et al. (1981)183 treated CD-I mice with a single dose of 20, 40, or 45
mg/kg sodium arsenite by oral gavage on one of days 8-15 of pregnancy.
Controls were given equivalent volumes of water or were untreated. On gestation
day 18, the dams were weighed and sacrificed. Litters were evaluated for
prenatal mortality, and all live fetuses were examined for gross malformations
and weighed. The lowest dose of sodium arsenite (20 mg/kg) produced no
discernible teratogenic or maternal toxic effects in 8 to 15 pregnant mice exposed
per treatment day. With the 40 and 45 mg/kg arsenite doses, maternal mortalities
were 19 and 36% respectively and prenatal effects were observed. At 40 mg/kg,
a low incidence of gross malformations, consisting of exencephaly and open
eyes, was noted in fetuses from dams treated on days 8 or 9. Similar
malformations were observed in fetuses from the dams treated with 45 mg/kg, if
exposure to arsenic was on the 8th, 9th or 10th day of gestation.
     Hood and Harrison (1982)184 treated outbred golden hamsters of the Lak:
LVG (SYR) strain with single gavage doses. Groups of at least 10 pregnant
females were given a single dose of sodium arsenite. Treatment was given as
gavage with a dose of 25 mg/kg (14 mg As/kg) on gestation days 8, 11 or 12, or a
dose of 20 mg/kg (11 mg As/kg) on days 9 or 10. Controls received water. On
day 15 mated females were sacrificed and their litters were examined for prenatal
mortality, gross, visceral, and skeletal malformations and the foetal weight.
Treatment of pregnant hamsters with a 20 mg/kg oral dose of sodium arsenite on
one of gestation days 9 or 10, or with 25 mg/kg on day 11, had no significant
Effects                                                                            121
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<pre>   effect on prenatal growth or survival. When hamsters were treated similarly with
   the higher dose on days 8 or 12, however, prenatal deaths increased, and growth
   was inhibited in day 12 treated fetuses. No morphological defects were observed
   in any fetuses from orally treated mothers. Seven of 57 arsenite gavaged mothers
   died, compared with only 1 of 51 solvent controls.
        Nemec et al. (1998)185 evaluated potential effects of exposure to arsenic acid
   throughout major organogenesis in CD-1 mice and New Zealand White rabbits.
   The animals were gavaged with arsenic acid dosages of 0, 7.5, 24, or 48 mg/kg/d
   on gestation days (GD) 6-15 (mice) or 0, 0.19, 0.75, or 3.0 mg/kg/d on GD 6
   through 18 (rabbits) and examined at sacrifice (GD 18, mice; GD 29, rabbits) for
   evidence of toxicity. In the high dose group (48 mg/kg/d) in mice two dams died.
   In the surviving dams a significant increase was detected in the number of
   resorptions per litter (42% vs. 4% in controls) and significant decreases in the
   number of live pups per litter (6.6 vs. 12.3 in controls) and mean fetal weight (1.0
   g vs. 1.3 g in controls). No significant decreases in fetal weight or increases in
   prenatal mortality were seen at other dosages. Malformations occurred in all
   groups of mice, including controls with a similar incidence. In mice, 7.5 mg/kg/d
   was the maternal NOAEL; the developmental toxicity NOAEL was estimated to
   be 7.5 mg/kg/d.
        At the high dose in rabbits (3.0 mg/kg/d), seven does died or became
   moribund, and prenatal mortality was increased; surviving does had signs of
   toxicity, including decreased body weight. Does given lower doses appeared
   unaffected. Fetal weights were unaffected by treatment, and there were no effects
   at other doses. These data revealed an absence of dose-related effects in both
   species at arsenic exposures that were not maternally toxic. In rabbits, 0.75 mg/
   kg/d was the NOAEL for both maternal and developmental toxicity.
        Stump et al. (1999)186 treated rats (25 per group) with a single gavage dose of
   3.8, 7.6, 15.2 and 22,7 mg As/kg as arsenic trioxide on day 9 of gestation (GD 9).
   Seven of the animals in the 22.7 mg As/kg group died on GD 10-11; all other
   animals survived. Maternal food consumption (GD 9-10) was decreased in a
   dose-dependent manner across all treated groups. In the 22.7 mg As/kg group,
   body weight, body weight change, and net body weight change were
   significantly decreased In the 20 mg/kg (15.2 mg As/kg) group, only transient
   effects on body weight were seen. The dose of 22.7 mg/As/kg resulted in a
   significant increase in postimplantation loss and a decrease in viable fetuses per
   litter, while those treated with 15.2 mg As/kg showed no effects.
        Holson et al. (2000)187 administered arsenic trioxide orally beginning 14 days
   prior to mating and continuing through mating and gestation until gestational day
   19. Groups of 25 Crl:CD1(SD)BR female rats received doses of 0, 1, 2.5, 5 or 10
22 Arsenic and inorganic arsenic compounds
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<pre>mg/kg/day by gavage. The selection of these dose levels was based on a
preliminary range-finding study, in which excessive post-implantation loss and
markedly decreased foetal weight occurred at doses of 15 mg/kg/day and
maternal deaths occurred at higher doses. Maternal toxicity in the 10 mg/kg/day
group was evidenced by decreased food consumption and decreased net body
weight gain during gestation, increased liver and kidney weights, and stomach
abnormalities (adhesions and eroded areas). Transient decreases in food
consumption in the 5 mg/kg/day group caused the maternal NOAEL to be
determined as 2.5 mg/kg/day. Intrauterine parameters were unaffected by arsenic
trioxide. No treatment-related foetal malformations were noted in any dose
group. Increased skeletal variations at 10 mg/kg/day were observed (unossified
sternebrae #5 or #6, slight or moderate sternebrae malalignment, 7th cervical
ribs) that the researchers considered to be consequences of developmental
growth retardation. The developmental NOAEL was thus 5 mg/kg/day.
    Hill et al. (2008)188 evaluated the developmental toxicity of oral exposure on
embryonic day (E) 7.5 and E:8.5 to 4.8, 9.6, or 14.4 mg As /kg (given as sodium
arsenate) in an inbred mouse strain, LM/Bc/Fnn. This strain does not exhibit an
underlying rate of spontaneous neural malformations, but is highly sensitive to
arsenic induced neural tube defects (NTD). Control and arsenic-treated dams (20
per treatment group) were weighed daily, and evaluated for signs of maternal
toxicity. Foetuses were evaluated for soft tissue and skeletal malformations.
There was no maternal toxicity as evidenced by changes in maternal body weight
following As treatment. However, liver weights were slightly lower in all As-
treated groups. The number of litters affected with a neural tube defect (NTD)
(exencephaly) in each treatment group was: 0 in the control group and 1, 5, and 9
in the groups treated with 4.8, 9.6, or 14.4 mg/kg, respectively, which exhibited a
dose-dependent positive linear trend. There was also evidence for trends between
As dose and the number of litters displaying vertebral (p < 0.001) and calvarial
(P < 0.01) abnormalities, components of the axial skeleton. Mean fetal weight of
all As-treated groups was significantly less than in control. In this model,
maternal oral treatment with As induced NTDs. It also significantly increased the
frequency of axial skeletal anomalies in the offspring exposed in utero, and
reduced mean fetal weight, without convincing evidence of maternal toxicity.
    To characterize developmental and behavioral alterations induced by arsenic
exposure, Rodriguez et al. (2002)189 exposed Sprague-Dawley rats to arsenite
(37 mg As/L) in drinking water from gestation day 15 (GD 15) or postnatal day 1
(PND 1), until approximately 4 months old. The pregnant or lactating dams
received either the arsenic solution or regular drinking water and once pups were
weaned, they continued receiving the same solution as drinking water. Animals
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<pre>   exposed from GD 15 showed increased spontaneous locomotor activity and both
   exposed groups showed increased number of errors in a delayed alternation task
   in comparison to the control group. The latter effects were also found in rats
   exposed from postnatal day one.
       Xi et al. (2009)190 exposed rats in utero and during early life to sodium
   arsenite in drinking water and evaluated developmental neurotoxicity. The
   pregnant rats or lactating dams, and weaned pups were given free access to
   drinking water, which contained arsenic at (elemental) concentrations of 0, 10,
   50, 100 mg/L from GD 6 until PND 42. A battery of physical and behavioral
   tests was applied to evaluate the functional outcome of pups. Pups in arsenic
   exposed groups weighed less than controls throughout lactation and weaning.
   Body weight of 10, 50 and 100 mg/L arsenic exposed groups decreased
   signifcantly on PND 42, 16 and 12, respectively. Physical development (pinna
   unfolding, fur appearance, incisor eruption, or eye opening) in pups displayed no
   signifcant differences between control and arsenic treated groups. In the highest
   dose group (100 mg As/L), arsenic decreased the incidence of neuromotor
   reflexes (tail hung, auditory startle and visual placing) signifcantly compared to
   the control group (p < 0.05). In square water maze test, the trained numbers to
   finish the trials successfully in 50 and 100 mg/L arsenic exposed groups
   increased remarkably compared to control group, and there was a dose-related
   increase (p < 0.01) observed. Maternal effects were observed only in the group
   treated with 100 mg/L (annoyance, irritation, infuriated, dysporic, dystocia,
   labour elongation, bleeding, no lactation).
   Developmental effects-parenteral exposure and in vitro experiments
   WHO/ATSDR/additional data
   The experimental data in mice, rats and hamsters (Ferm and Carpenter (1968)191,
   Willhite et al. (1981)192, Beaudoin et al. (1974)193, Hood and Harrison (1982)184,
   Carpenter et al. (1987)194, Stump et al. 1999186, DeSesso195,196, WHO128, ATSDR
   20077) revealed that inorganic arsenic caused malformations (including neural
   tube defects) in offspring when injected ip or iv into pregnant animals during
   early gestation at maternally toxic (and often nearly fatal) doses. The Committee
   evaluated the parenteral studies and considered them of no further relevance for
   the classification and human risk assessment process. In addition, the Committee
   evaluated a selected number of in vitro studies showing effect of inorganic
   arsenic on embryonic development (Hanna et al., 1997197, Tabacova et
24 Arsenic and inorganic arsenic compounds
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<pre>al.,1996198, Wlodarczyk et al., 1996199) and considered them of no further
relevance for the classification and human risk assessment process.
Lactation
WHO/ATSDR/additional data
No data on toxic effects on the pups via lactation could be retrieved from the
literature.
Immunological effects
WHO/ATSDR data
Mice exposed to 250-1000 µg arsenic trioxide/m3 aerosol for 3 hours had a
concentration-related decrease in pulmonary bactericidal activity (presumably as
a result of injury to alveolar macrophages) and a corresponding concentration-
related increase in susceptibility to introduced respiratory bacterial pathogens
(Aranyi et al., 1985). Mice exposed to arsenate in drinking water did not display
any signs of immunotoxicity (Kerkvliet et al., 1980), and mice given
intratracheal doses of sodium arsenite had decreased humoral responsiveness to
antigens but no measurable decrease in resistance to bacterial or cellular
pathogens (Sikorski et al., 1989). Reports that gallium arsenide suppresses
immune function and increases the co-stimulatory activity of macrophages in
rodents treated orally or by intraperitoneal injection (Caffrey-Nolan and McCoy,
1998; Flora et al., 1998; Lewis et al., 1998a, 1998b) are confounded by the use of
gallium nitrate as an immuno-suppressing drug (Makkonen et al., 1995; Orosz et
al., 1997).
Additional data
Patterson et al. (2004) hypothesized that arsenic may modulate hypersensitivity
responses to cutaneous sensitizing agents by altering cytokine production,
LC migration, and T-cell proliferation.200 Therefore the induction and elicitation
phases of dermal sensitization were examined. Mice exposed to 50 mg/L arsenic
in the drinking water for 4 weeks demonstrated a reduction in lymph node cell
proliferation and ear swelling following sensitization with 2,4-dinitrofluoro-
benzene (DNFB), compared to control mice. LC and T-cell populations in the
draining lymph nodes of DNFB-sensitized mice were evaluated by fluorescence-
Effects                                                                            125
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<pre>   activated cell sorting; activated LC were reduced in cervical lymph nodes,
   suggesting that LC migration may be altered following arsenic exposure.
   Lymphocytes from arsenic-treated animals sensitized with fluorescein
   isothiocyanate (FITC) exhibited reduced proliferative responses following T-cell
   mitogen stimulation in vitro; however, lymphocyte proliferation from
   nonsensitized, arsenic-treated mice was comparable to controls. Arsenic
   exposure also reduced the number of thioglycollate-induced peritoneal
   macrophages and circulating neutrophils. These studies demonstrate that
   repeated, prolonged exposure to nontoxic concentrations of sodium arsenite
   alters immune cell populations and results in functional changes in immune
   responses, in this case specifically leading to attenuation of contact
   hypersensitivity.
   Neurological effects
   WHO/ATSDR data
   No studies were located regarding neurological effects in animals after inhalation
   and dermal exposure to inorganic arsenicals. With regard to oral exposure,
   Heywood and Sortwell (1979) noted salivation and uncontrolled head shaking in
   two monkeys given several doses of 6 mg As/kg bw/day as arsenate, while no
   such effects were noted in monkeys given 3 mg As/kg bw/day for 2 weeks.
   Nemec et al. (1998) observed ataxia and prostration in pregnant female rabbits
   treated with 1.5 mg As/kg bw/day repeatedly during gestation, but not in rabbits
   treated with 0.4 mg As/kg bw/day.
   Additional data
   No additional animal data on neurological effects of arsenic and arsenic
   compounds after inhalation were found.
       A number of oral studies in rats and mice has reported no symptoms of overt
   systemic toxicity from inorganic arsenic, but observed more subtle -
   neurobehavioural effects (Rodriguez et al., 2003201). In rats the most consistent
   change in behaviour after high oral inorganic arsenic administration (10, 20 mg/
   kg bw per day by gavage for 2-4 weeks) was a decrease in locomotor activity.
   Additionally rats showed a delay in execution of various task tests reflecting
   learning and memory after oral exposure to arsenic (Rodriguez et al., 2001202,
   2002189). Effects on locomotor activity, grip strength and rota rod performance
   were also observed recently in rats exposed orally to 20 mg arsenite/kg bw/day
26 Arsenic and inorganic arsenic compounds
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<pre>    po for 28 days (Yadav et al., 2009)203. Mice were exposed to 1 and 4 mg/kg bw/
    day of As2O3 subchronically for 60 days in water and significant dose-dependent
    neurobehavioural changes associated with memory (Morris Water Maze test)
    were observed. Rats exposed to inorganic arsenic in drinking water at 68 mg/L
    for 3 months showed a significant decrease in their spatial memory, while
    neurons and endothelial cells presented pathological changes, and the gene
    expression of aspartate receptors in the hippocampus was downregulated. These
    effects were not seen at 2.72 and 13.6 mg/L (Luo et al., 2009204).
7.3 Summary and evaluation
    Human data
    Relatively little information is available on the local effects of arsenic and
    arsenic compounds, except for arsenic trioxide. This corrosive compound may
    cause local damage to the skin, eyes and respiratory tract.
    No cases were located regarding death in humans from inhalation exposure to
    inorganic arsenicals following acute exposure, even at very high exposure levels
    (1-100 mg As/m3) found previously in the workplace.
    Acute ingestion of large doses leads to gastrointestinal symptoms, disturbances
    of cardiovascular and nervous system functions, and eventually death. In
    survivors, bone marrow depression, haemolysis, hepatomegaly, melanosis,
    polyneuropathy and encephalopathy may be observed.
    In vitro studies with human lymphocytes and fibroblasts showed clastogenic
    effects of arsenic. Methylated trivalent arsenicals were more potent DNA
    damaging compounds than the other arsenicals.
        In vivo, chromosomal aberrations were observed in peripheral lymphocytes
    after inhalation exposure. Furthermore, human studies involving people exposed
    to relatively high arsenic concentrations in drinking water showed chromosome
    aberrations and sister chromatid exchanges in different cell types.
    Studies of populations occupationally exposed (primarily by inhalation) to
    arsenic, such as smelter workers, pesticide manufacturers and miners in many
    different countries, consistently demonstrated an excess lung cancer risk among
    the arsenic-exposed. Sufficient quantitative information from human studies on
    the levels of occupational arsenic exposure to ensure reliable assessment of the
    Effects                                                                          127
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<pre>   exposure-response relationship was available for three copper smelter cohorts:
   Tacoma (USA), Anaconda (USA) and Rönnskär (Sweden).4,1,2,3 Exposure-
   response relationships and high risks have been observed. Increased risks have
   been observed at relatively low cumulative exposure levels in the smelter cohort
   of Rönnskär (Sweden; arsenic exposure category of < 250 µg/m3·year) and in the
   smelter cohort of Tacoma (USA; arsenic exposure category of < 750 µg/
   m3·year). Furthermore, in the Tacoma smelter, daily exposure to 213 µg/m3
   arsenic for 30 years or more was associated with a statistically significant SMR
   of 238 for lung cancer 98. Studies indicated that smoking had a synergistic effect
   on the lung cancer effects of arsenic exposure.
   Long-term exposure to arsenic in drinking-water is causally related to increased
   risks of cancer in the skin, lungs, bladder and kidney, as well as other skin
   changes such as hyperkeratosis and pigmentation changes. The effects have been
   most thoroughly studied in Taiwan but there is considerable evidence from
   studies on populations in other countries as well. Increased risks of lung and
   bladder cancer and of arsenic-associated skin lesions have been reported to be
   associated with arsenic exposure categories of ≤ 50 µg/L. Chronic arsenic
   exposure (via drinking water) in Taiwan has been shown to cause blackfoot
   disease, a severe form of peripheral vascular disease which leads to gangrenous
   changes. This disease has not been documented in other parts of the world, and
   the findings in Taiwan may depend upon other contributing factors. However,
   there is good evidence from studies in several countries that arsenic exposure
   causes other forms of peripheral vascular disease. Conclusions on the causality
   of the relationship between oral arsenic exposure and other health effects are less
   clear-cut. The evidence is strongest for hypertension and cardiovascular disease,
   suggestive for diabetes and weak for cerebrovascular disease, long-term
   neurological effects, and cancer at sites other than lung, bladder, kidney and skin.
   Several studies have examined a number of reproductive end-points in humans.
   No effects of arsenic on fertility are observed upon inhalatory or oral exposure.
   In the older inhalatory and oral human studies (Nordström et al., 1978a129,
   1978b130, 1979a131, 1979b132, Aschengrau et al., 1989134; Zierler et al., 1988135)
   the populations were exposed to a number of other chemicals beyond arsenic.
   These chemicals may have contributed to the observed effects (congenital
   malformations, spontaneous abortions, stillbirth) but a causal relationship is
   uncertain. However, the Committee observes that the recent human studies on
   arsenic exposure from drinking water in different parts of the world give strong
   indications that arsenic can not be excluded as a causal factor for spontaneous
28 Arsenic and inorganic arsenic compounds
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<pre>abortion, stillbirth, preterm delivery and reduced birth weight and also neuro-
psychological development.
Animal data
Relatively little information is available on the local effects of arsenic and
arsenic compounds. Sodium arsenite and sodium arsenate were not allergenic in
the guinea-pig maximisation test.
In a developmental study, 100% mortality in groups of 10 pregnant rats after 1
day of inhalation exposure to arsenic trioxide concentrations ≥100 mg/m3 was
observed (76 mg As/m3). The acute dermal LD50 for the pentavalent arsenicals
calcium arsenate and lead arsenate in the rat amounts to ≥ 2400 mg/kg bw (≥400
mg As/kg). LD50 values after oral and parenteral arsenic exposure range from 15
to 960 mg As/kg bw/day, depending on the compound and the animal species.
Arsenic may cause clastogenic effects in vitro. A significant increase in the
number of micronuclei, chromosome aberrations and sister chromatid exchanges
in Chinese hamster ovary cells after exposure to dimethylarsinous acid and
monomethylarsonous acid are observed. AsIII and AsV induced chromosome
aberrations and sister chromatid exchanges in Chinese hamster ovary cells, but
not micronuclei. Monomethylarsonous acid, dimethylarsinous acid and
dimethylarsinic acid are capable of inducing DNA damage via formation of
reactive oxygen species (ROS).
    No point mutations were observed in bacteria or in mammalian cells after
arsenic exposure.
    In vivo, sodium arsenite (2.5 mg/kg bw) produced significantly high
frequencies of chromosome aberrations in bone marrow cells in mice after 24 h
exposure161.
Several animal carcinogenicity studies on arsenic have been carried out, but
limitations such as limited time of exposure and limited number of animals make
these inconclusive. In a recent study, female C57B1/6J mice had an increased
incidence in tumours involving mainly lung, liver, gastrointestinal tract and skin
after exposure to 500 µg AsV/L drinking water for 2 years. One study has
indicated that dimethylarsinic acid may cause cancer of the urinary bladder in
male rats at high doses.
    Perinatal exposure to inorganic arsenic between gestational day 8-18 in mice
suggests that cancer may be induced in offspring.
Effects                                                                            129
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<pre>   In experimental animals effects on fertility of inorganic arsenic via the inhalatory
   route are not reported, but exposure to inorganic arsenic (AsIII and V) via the oral
   and ip route has shown significant effects on fertility (a.o. interference with
   spermatogenesis, degeneration of follicular cells). Exposure of experimental
   animals to inorganic arsenic via inhalation, oral and parenteral routes caused,
   usually at relatively high maternally toxic doses, reduced birth weight, a variety
   of foetal malformations (both skeletal and soft tissue), and increased foetal
   mortality. Reproductive performance was not affected in female rats that
   received inhalation exposures to concentrations as high as 20 mg As/m3 or
   gavage doses as high as 8 mg As/kg bw/day from 14 days prior to mating
   through gestation day 19. The Committee is aware that in none of the animal
   studies maternal toxicity can be unambiguously excluded. Only the study by Hill
   et al. (2008)188 administering arsenate to an inbred mouse strain, supports the
   view that foetal malformations can develop in the absence of maternal toxicity.
   Limited information is available with regard to immunological effects of arsenic
   and arsenic compounds in animals.
30 Arsenic and inorganic arsenic compounds
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<pre> hapter 8
        Existing guidelines, standards and
        evaluations
8.1     General population
8.1.1   Air quality guidelines
        Quantitative risk estimates for the occurrence of lung cancer after inhalation
        exposure of arsenic have been derived by the WHO128 and the EPA127.
        The risk estimates of the WHO128 for arsenic have been derived from studies
        describing the dose-response relationships between arsenic exposure and excess
        lung cancer mortality in workers at the Anaconda, Tacoma and Rönnskär
        smelter. Assuming a linear dose-response relationship, a safe level for inhalation
        exposure cannot be recommended. The unit risk for arsenic-induced lung cancer
        (excess risk estimate associated with lifetime exposure to a concentration of 1
        µg/m3) amounts to 1.5*10-3. This means that the excess lifetime risk level is
        1:10,000, 1:100,000 or 1:1,000,000 at an air concentration of about 66 ng/m3, 6.6
        ng/m3 or 0.66 ng/m3, respectively.
        The inhalation unit risk established by the EPA using the absolute-risk linear
        model amounts to 4.3*10-3 per 1 µg/m3 based on the dose-response relationships
        between arsenic exposure and excess lung cancer mortality in workers at the
        Existing guidelines, standards and evaluations                                     131
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<pre>    Anaconda and the Tacoma smelter. This means that the excess lifetime risk level
    is 1:10,000, 1:100,000 or 1:1,000,000 at an air concentration of about 20 ng/m3,
    2 ng/m3 or 0.2 ng/m3, respectively.127
8.2 Working population
    Currently, the 8 hr time-weighted average (TWA) and short-term (15 min)
    occupational exposure limits for the combination of all inorganic arsenic
    compounds in the Netherlands are 0.05 and 0.1 mg As/m3, respectively. The
    TWA (8 hr) and short-term (15 min) occupational exposure limits for the water-
    soluble inorganic arsenic compounds are 0.025 and 0.05 mg As/m3, respectively.
    There is currently no limit value for exposure to arsenic and arsenic compounds
    at the European level. A number of EU member countries have set a limit for
    arsenic and arsenic compounds. Furthermore, the ACGIH, OSHA and NIOSH
    have set a limit/recommended standard for exposure to arsenic (see Table 7).
    None of the referred EU members or organisations have attached a skin notation
    to arsenic and arsenic compounds.
    The Health and Safety Executive (HSE) has established an occupational
    exposure limit of 0.1 mg/m3 for the United Kingdom.206,207 This limit is based on
    cancer of the respiratory tract. Since it was not possible to identify a no-adverse-
    effect level (NOAEL), a maximum exposure limit was considered appropriate.
    According to the HSE, this maximum exposure limit was set at 0.1 mg/m3 (8 hr
    TWA value), which was below the exposure level at which raised incidence of
    respiratory tract cancer had been observed, and below the no-effect level for
    respiratory tract irritation. For most industries there should be no difficulty in
    using engineering controls to maintain exposures below this level, but in a
    minority of cases respiratory protective equipment may be necessary. Lead
    arsenate is excluded from this limit.
    According to the Deutsche Forschungsgemeinschaft (DFG), arsenic and
    inorganic arsenic compounds are carcinogenic in man.209,210 After inhalation of
    the substance, carcinogenic effects are observed in the lungs and after ingestion,
    in the bladder, kidneys, skin and lungs. However, neither the studies with
    inhalation exposure to arsenic nor those with oral administration of the substance
    can be used to derive a no observed adverse effect level (NOAEL). As a NOAEL
    for carcinogenicity cannot be derived from the epidemiological studies, no
    occupational exposure limit value has been established for arsenic and inorganic
    arsenic compounds in Germany. Arsenic and arsenic compounds therefore
 32 Arsenic and inorganic arsenic compounds
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<pre> able 7 Existing Occupational Exposure Limits (OELs) for arsenic and arsenic compounds.
 ountry / Organisation        Arsenic compound           Level (mg/m3)            Time-relation               Remarks
 he Netherlands 205           Arsenic (combination of    0.05                     TWA - value (8 hr)          C1
                              inorganic compounds, as    0.1                      Short term - value (15 min)
                              As)
                              Arsenic (water-soluble     0.025                    TWA - value (8 hr)
                              inorganic compounds, as    0.05                     Short term - value (15 min)
                              As)
United Kingdom206,207         Arsenic and compounds (as  0.1                      TWA - value (8 hr)          C
                              As) (except lead arsenate)
Denmark208                    Arsenic and inorganic      0.01                     TWA - value                 C
                              compounds, as As
                              Calcium arsenate           1                        TWA - value
Germany209-211                Arsenic and inorganic      (no OEL established)     -                           C
                              compounds
                              Arsenic trioxide, arsenic  0.1 (inhalable fraction) TRK (Technische
                              pentoxide, arsenic acid                             Richtkonzentration) - value
                                                                                  (8 hr)
                                                         0.4 (inhalable fraction) TRK - Short term - value
                                                                                  (15 min)
 weden212                     Arsenic and inorganic      0.03 (total dust)        TWA - value (8 hr)          C
                              compounds (as As)
 cientific Committee on       Arsenic and inorganic      (no OEL established)     -                           -
Occupational Exposure         compounds
 imits (SCOEL)213
ACGIH (TLV)214                Arsenic and inorganic      0.01                     TWA - value (8 hr)          C
                              compounds, as As
OSHA215                       Arsenic, inorganic         0.01                     TWA - value (8 hr)          C
                              compounds
NIOSH216,217                  Arsenic (inorganic         0.002                    Short term - value (15 min, C
                              compounds, as As)                                   ceiling)
 C: the substance is considered carcinogenic
             remain in Carcinogenicity category 1. As a result of the mutagenic effects in
             somatic cells, the formation of genotoxic and systemically effective metabolites,
             the bioavailability of the substance in the gonads and the inadequate
             investigation in germ cells, arsenic and inorganic arsenic compounds are
             classified in Category 3A for germ cell mutagens.209 Arsenic and arsenic
             Existing guidelines, standards and evaluations                                                      133
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<pre>   compounds are not designated as sensitisers.209 Arsenic acid penetrates the skin
   in vivo and in vitro in amounts of less than 10 % and sodium arsenate from
   aqueous solution or as the solid in vitro in amounts of about 30% to 60 %.
   Dermal absorption under workplace conditions does not seem to be relevant, and
   arsenic and inorganic arsenic compounds are not designated with a skin
   notation.209
   Based on the carcinogenic properties of arsenic trioxide, arsenic pentoxide and
   arsenic acid an 8 hr Technische Richtkonzentration (TRK) of 0.1 mg/m3
   (inhalable fraction) is established for these arsenic compounds in Germany. A
   TRK is the concentration of a chemical substance in air within a working area,
   which may be reached in accordance with the best available technology (state of
   art). Furthermore, a short-time TRK (15 min) is established at 0.4 mg/m3.211
   In Sweden, the 8 hr TWA limit value is 0.03 mg/m3.212 However, it is noted that
   in the planning of new facilities or the alteration of old ones, an effort shall be
   made to ensure that exposure to arsenic and inorganic compounds other than
   arsenic hydride in the course of a working day is acceptable with reference to a
   time-weighted average concentration of 0.01 mg/m3 (as As).
   The American Conference of Governmental Industrial Hygienists (ACGIH) has
   specified a threshold limit value (TLV) of 0.01 mg/m3 (as As) (8 hr TWA
   value).218 Furthermore, based on the weight of evidence from epidemiologic
   studies, arsenic and inorganic compounds are designated as an A1, Confirmed
   Human Carcinogen.
   Numerous epidemiologic studies showed lung cancer excesses with occupational
   arsenic exposures of smelter workers and pesticide workers. The quantitative air
   monitoring data presented by Enterline et al., 198798 indicate a significant excess
   of lung cancer risk for workers exposed to a mean a level of 0.2 mg/m3 of
   arsenic. This is based on an SMR of 213. According to the ACGIH this is the
   lowest level at which an excess risk of cancer in humans has been found. To
   allow some measure of safety, a TLV-TWA of 0.01 mg/m3 (as As) is
   recommended.214
   The permissible exposure limit (PEL) of the Occupational Safety and Health
   Administration (OSHA) for inorganic arsenic amounts to 0.01 mg/m3 when
   averaged over any 8-hour work shift.215
34 Arsenic and inorganic arsenic compounds
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<pre>      The recommended standard of the National Institute for Occupational Safety and
      Health (NIOSH) was established in 1975216(and reconfirmed in 2005217). In the
      criteria document for the recommendation, it was mentioned that studies
      suggested that exposure on an 8 to 24 hour TWA basis at concentrations of 2-3
      µg/m3 has resulted in increased cancer mortality. According to NIOSH, in the
      absence of information for a safe level of exposure to a carcinogen, protection of
      the worker should be effected by requiring that airborne concentrations not
      exceed minimally detectable levels. However, background atmospheric
      concentrations of arsenic up to 1.4 µg As/m3 were reported. Therefore, to
      achieve the greatest practicable reduction in worker exposure while avoiding
      spurious sampling results produced by natural background concentrations of
      inorganic arsenic, NIOSH recommended that worker exposure be controlled to
      prevent exposure in excess of 2.0 µg/m3 of air as determined by a 15 minute
      sampling period.
8.2.1 Biological monitoring
      For the purpose of biological monitoring in the Netherlands, in 1984, a
      (tentative) concentration of arsenic in urine as an individual maximum of 40 µg
      arsenic/g creatinine was specified (provided that recent intake of sea food is
      excluded)219. A remark was made that this recommended value possibly should
      be corrected when new data would become available. This value was based on a
      reference of Lauwerys (1980) in which normal urine arsenic concentrations were
      specified as < 40 µg arsenic/g creatinine, mostly much lower.
      In Germany, the Deutsche Forschungsgemeinschaft (DFG) investigates the
      relationships between the concentration of the carcinogen in the workplace air
      and that of the substance or its metabolites in biological material (EKA values,
      exposure equivalents for carcinogenic substances) and specifies the following
      EKA values for arsenic trioxide210:
      Table 8 EKA values for arsenic trioxide.
      Arsenic in air (mg/m3)                Sampling time: end of exposure
                                            or end of shift – urinea
                                            Arsenic (µg/L)
      0.01                                   50
      0.05                                   90
      0.10                                  130
      a    volatile arsenic compounds by hydrogenation
      Existing guidelines, standards and evaluations                                     135
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<pre>   The DFG has also specified a ‘Biologische Leitwerte’ (BLW) value of 50 µg for
   inorganic arsenic and methylated metabolites in urine per L urine (sampling: for
   long term exposures: after several shifts, end of exposure or end of shift).210
   According to the American Conference of Governmental Industrial Hygienists
   (ACGIH)23, monitoring of the sum of inorganic arsenic plus its two major
   organic metabolites, monomethylarsonic acid and dimethylarsinic acid, collected
   at the end of the workweek in urine is the recommended method for biological
   monitoring of occupational exposure to elemental and soluble inorganic arsenic
   compounds.
36 Arsenic and inorganic arsenic compounds
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<pre> hapter 9
        Hazard assessment
9.1     Assessment of the health hazard
        Occupational exposure to arsenic may be significant in several industries.
        Absorption of arsenic from inhaled airborne particles is highly dependent on the
        solubility and the size of particles. Different types of occupational exposures
        may result in different uptakes of arsenic because of the bioavailability of the
        form of arsenic to which workers are exposed. Both pentavalent and trivalent
        soluble arsenic compounds are rapidly and extensively absorbed from the
        gastrointestinal tract (≥ 70%). Dermal absorption appears to be much less than by
        the oral or inhalation routes. Arsenic and its metabolites distribute to all organs in
        the body. Arsenic readily crosses the placenta. Arsenic metabolism is
        characterised by alternation of two main types of reactions: (1) two-electron
        reduction reactions of pentavalent to trivalent arsenic, which may occur
        nonenzymatically via glutathione or enzymatically, and (2) oxidative
        methylation reactions in which trivalent forms of arsenic are converted to (mono-
        , di- or tri-) methylated pentavalent products, using S-adenosyl methionine
        (SAM) as the methyl donor and glutathione (GSH) as an essential co-factor.
        Arsenic and its metabolites are largely excreted via the renal route. Arsenic can
        be excreted in human milk.
        Hazard assessment                                                                      137
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<pre>9.1.1 Acute and short term toxicity
      No deaths were reported in humans from inhalation exposure to inorganic
      arsenic compounds following acute exposure, even at the very high exposure
      levels (1-100 mg As/m3) found previously in the workplace. A few case reports
      of neurological effects after acute inhalation have been described (see Section
      7.1.4.5). No more recent studies on neurological effects and other adverse health
      effects after acute inhalation exposure to arsenic were reported.
           Acute ingestion of large doses leads to gastrointestinal symptoms,
      disturbances of cardiovascular and nervous system functions, and eventually
      death. In survivors, bone marrow depression, haemolysis, hepatomegaly,
      melanosis, polyneuropathy and encephalopathy may be observed.
           With regard to animals, in a developmental study, 100% mortality in groups
      of 10 pregnant rats after 1 day of inhalation exposure to arsenic trioxide
      concentrations ≥100 mg/m3 was observed (76 mg As/m3) (Holson et al., 1998).
      Oral and parenteral lethal doses range from 15 to 960 mg As/kg bw/day,
      depending on the compound and the animal species.
9.1.2 Long-term toxicity
      In epidemiological studies respiratory cancer is the only type of effect,
      convincingly associated with long term inhalation exposure to arsenic, whereas
      skin cancer and cancers of multiple internal organs (liver, kidney, lung and
      bladder) have been observed in populations with exposure to arsenic in drinking
      water. A difference between studies of occupationally and environmentally
      exposed cohorts is that for most of the environmentally exposed cohorts
      exposure starts at birth, whereas for the occupationally exposed cohorts exposure
      starts much later in life. Bates et al. (1992) (cited in Enterline et al.4 and Lubin et
      al.1) suggested that differences in cancer risk after oral and occupational
      exposure were based on differences in cumulative exposure. From the study of
      Lubin et al.1 it may be concluded that carcinogenic mechanisms associated with
      inhaled arsenic differ from those related to ingested arsenic.
      Until recently there was a lack of clear evidence for carcinogenicity of any
      arsenic compound in animals. More recent work with arsenical methylation
      metabolites and early life exposures to inorganic arsenic has provided evidence
      of carcinogenicity in rodents after oral exposure. Only one long term inhalation
      study (2 yr) is available which indicates that gallium arsenide (NTP 2000)165 is
 38   Arsenic and inorganic arsenic compounds
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<pre>      carcinogenic in rats. No studies were located regarding cancer in animals after
      inhalation exposure to the other arsenicals.
9.2   Quantitative hazard assessment
9.2.1 Critical effect and approach to the quantitative hazard assessment
      The Committee considers lung cancer as the critical effect in humans after
      inhalation exposure to arsenic and arsenic compounds. Studies of populations
      occupationally exposed (primarily by inhalation) to arsenic, such as smelter
      workers, pesticide manufacturers and miners in many different countries,
      consistently demonstrated an excess lung cancer risk among the arsenic-exposed.
      Sufficient quantitative information from human studies on the levels of
      occupational arsenic exposure to ensure reliable assessment of the exposure-
      response relationship was available for three copper smelter cohorts: Tacoma
      (USA), Anaconda (USA) and Rönnskär (Sweden).4,1,3 Increased risks have been
      observed in relatively low cumulative exposure categories: exposure category of
      < 250 µg/m3·year (Rönnskär, Sweden) and exposure category of < 750 µg/
      m3·year (Tacoma, USA). Furthermore, in the Tacoma smelter, daily exposure to
      213 µg/m3 arsenic for 30 years or more was associated with a statistically
      significant SMR of 238.7 for lung cancer.98 Studies indicated that smoking had a
      synergistic effect on the the development of lung cancer of arsenic exposure.
      The Committee considers arsenic as a non-stochastic genotoxic compound (see
      Annex I and J). Clastogenic damage was observed in human and animal studies
      in vivo and in vitro. For point mutations, the results are largely negative. With
      regard to the mechanism which caused the genotoxic effects, there is evidence
      that arsenicals bind to thiol-groups in proteins which may lead to inhibition of
      e.g. DNA repair enzymes. There is also evidence that arsenic exposure can result
      in hypo- or hypermethylation of cellular DNA; these changes can be caused by
      e.g. an effect of arsenic on DNA methyltransferases. Furthermore, arsenic does
      not generate reactive oxygen by itself but inhibits the scavenging systems of
      reactive oxygen species, which indirectly leads to an increase of reactive oxygen
      species. Since all these processes support a non-stochastic mechanism of
      genotoxicity a NOAEL for arsenic and arsenic compounds should theoretically
      be derived using a threshold model. However, the available epidemiological
      studies do not allow derivation of such a threshold, i.e., a no-effect concentration.
      Hazard assessment                                                                     139
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<pre>          Therefore the Committee decided not to pursue a threshold approach but to
      calculate excess lifetime cancer mortality risks (health-based calculated
      occupational cancer risk values (HBC-OCRV)), using mathematical modeling
      and extrapolation.
9.2.2 Quality of the studies on occupational arsenic exposure
      The Committee selected four epidemiological studies on lung or respiratory
      cancer mortality among workers exposed to arsenic. The studies by Lubin et al.
      (2000)1, Lubin et al. (2008)2, Järup et al. (1989)3 and Enterline et al. (1995)4
      were considered for quantitative hazard assessment. First, the Committee
      evaluated the quality of these studies using a number of characteristics including
      study design, execution, analyses etc. and their usefulness for derivation of HBC-
      OCRVs (see Annex L for detailed information).
          The study of Jarüp et al. (1989)3 had an exposure assessment component for
      which the description was limited and basic documentation was lacking. The
      way exposure has been calculated was not transparent, therefore making it
      difficult to analyse the risk per unit of increase by exposure. Information on
      exposure before 1945 was unclear, and again, it was not clear how exposure was
      assigned to certain job titles. Furthermore, no exposure-response relation was
      given. However, in this study loss-to-follow-up was low. An exposure-response
      relation could be calculated by the Committee. This study analysed lung cancer
      mortality. Calculations were based on a comparison with the general population
      (SMR study).
          In the study by Enterline et al. (1995)4 the description of the exposure
      assessment component was limited and basic descriptive information was
      lacking. Information about exposure before 1938 was lacking completely. It was
      not clear how exposure was assigned to certain job titles. Loss-to-follow-up was
      low, and an exposure-response relation was given. The study used lung cancer
      mortality. Calculations were based on a comparison with the general population
      (SMR study). The dose-response relationship was described using a power
      model.
          In the studies by Lubin et al. (20001, 20082) instead of lung cancer mortality,
      respiratory cancer mortality is used, which included larynx and trachea tumours.
      According to the information given in the Lubin et al. (2000) paper (Table 2),
      this may cause a deviation in mortality rate smaller than 4%. Therefore, the
      effect on association measures like risk ratio’s is assumed to be negligible.
      Another potential limiting factor of this paper is the higher loss-to-follow-up,
      compared to the other studies under consideration. If it is assumed that this loss-
 40   Arsenic and inorganic arsenic compounds
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<pre>      to-follow-up is non-differential across exposure, which seems a reasonable
      assumption, the Lubin et al. (2000) study is the strongest study with fewest
      limitations. To describe the dose-response relationships both a power model and
      a linear model were applied. The Lubin et al. (2008) study was a follow-up to the
      2000 study, with a different modelling strategy. In the update, Lubin et al. used
      an exposure reduction factor in the higher exposure categories to account for the
      use of personal protection equipment. This is not common practice in risk
      calculations and this study was not further considered for risk assessment.
9.2.3 Calculation of HBC-OCRVs
      Lubin et al. (2000)1 used an internal exposure-response analysis (resulting in a
      relative risk, RR), whereas the studies by Jarüp et al. (1989) and Enterline et al.
      (1995) compared exposure-related mortality with mortality in the general
      population, which results in a standardized mortality ratio (SMR). The
      Committee reevaluated the exposure-response relationships in the three studies
      using both power and linear modelling (see Annex L).
      The use of a power model to describe the data of Lubin et al. (2000)1 did not
      significantly improve the fit compared to a linear model (see p. 557-558 of Lubin
      et al. 2000). Therefore the linear model was used (with risk function
      RR=1+0.19*cum.exposure) for further calculations. Life table calculations were
      performed. The Committee calculates (see Table 9) that the concentration of
      arsenic in the air, which corresponds to an excess cancer mortality of
      • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 28
           µg/m3
      • 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to 0.28
           µg/m3.
      The Committee also evaluated the studies of Jarüp et al. and Enterline et al. for
      quantitative hazard assessment.
           An exposure-response relationship was not given in the original article by
      Jarüp et al. 1989.3 Therefore the Committee calculated the relation based on the
      data given in the original article. This resulted in the following relations: RR = 1
      + 0.1002(cum. Exp.) and RR = 1 + 1.69(cum. Exp.)0.253 (RR = 1 means no
      difference in mortality when compared to reference group). The power-model
      calculated for the Jarüp et al. study has a better fit than the linear model. This
      also is said to be the case for the power model shown in Enterline et al.4
      Hazard assessment                                                                    141
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<pre>      (SMR=100+10.5 (cum exp)0,279, see p. 30 of the original article), although no
      model fit information is given.
          For both these studies it cannot be excluded that the strong fit of the power
      models is artefactual and caused by the fact that there is a clear difference in risk
      between the exposed population and the comparison group, while there is a very
      weak association among the exposed only. These studies by Jarüp et al. and
      Enterline et al. are SMR studies and are thus the result of a comparison with the
      general population and potential systematic differences in mortality between the
      general population and the exposed workers in these cohort studies. When an
      attempt was undertaken to model the exposure response curve in the low
      exposure range (steep part of the curve) the fit of linear models was very poor for
      both studies indicating that there was no clear exposure response curve
      discernible in this range. This again suggests that the comparison with the
      general population may be problematic.
          For comparison the risk estimates using the linear model are also given for
      the other two studies (see Table 9). In spite of these equations being derived from
      marginally fitting risk functions, the resulting risk estimates are in the same order
      of magnitude as those calculated from the Lubin et al. study.
      Table 9 Health-based calculated occupational cancer risk values.
      Study                    Equation                          ER*=4e-3  ER=4e-5
      Lubin et al. 20001       RR=1+0.19*cum.exposure            28 µg/m3  0.28 µg/m3
      Jarup et al. 19893       1+0.33*cum.exposure               16 µg/m3  0.16 µg/m3
      Enterline et al.19954    1+0.16*cum.exposure               33 µg/m3  0.33 µg/m3
      Considering the quality of the papers and fit of the models, the Committee
      decides to use the outcomes of the Lubin et al. (2000) study and calculates that
      exposure to 28 µg As/m3 for 40 years results in 4 additional death cases per per
      1,000 (4x10-3) deaths and exposure to 0.28 µg As/m3 for 40 years result 4
      additional death cases per per 100,000 (4x10-3) deaths.
          The Committee concludes that the concentration level of 28 µg/m3 associated
      with a lifetime cancer risk level of 4 x10-3 is well below any health based
      occupational exposure limit derived from data other than carcinogenicity.
9.2.4 Short Term Exposure Limit (STEL)
      Although arsenic, arsenic pentoxide and lead arsenate are labelled with Acute
      Tox. 3: H331 and H301 (‘toxic if inhaled’ and ‘toxic if swallowed’) and arsenic
      trioxide is labelled with Acute Tox. 2: H300 and Skin Corr. 1B (‘fatal if
 42   Arsenic and inorganic arsenic compounds
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<pre>      swallowed’ and ‘causes severe skin burns and eye damage’) according to EC
      Regulation 1272/200811, the available data do not warrant the setting of a Short
      Term Exposure Limit (STEL) or ceiling value according to the Committee.
          With regard to local effects, relative little information is available; effects on
      the respiratory tract, skin and eyes have been observed in old reports, where
      exposure was to high levels of arsenic dust. No concentrations or exposure
      duration are given, but since no recent studies on these effects were reported,
      these results are probably of no relevance for current exposure levels.
          Furthermore, no other countries/organisations have established a STEL for
      arsenic and arsenic compounds based on acute systemic or local toxicity (see
      chapter 8).
9.2.5 Skin notation
      Absorption by the dermal route has not been well characterised, but is low
      compared to the other routes. The rate of absorption of arsenic and arsenic
      compounds through the skin does not warrant a skin notation.
9.3   Recommendation
      The Committee calculates that the concentration of arsenic in the air, which
      corresponds to an excess cancer mortality of
      • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 28
          µg/m3
      • 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to 0.28
          µg/m3.
      The available data do not warrant the setting of a Short Term Exposure Limit
      (STEL) or ceiling value.
      The rate of absorption of arsenic and arsenic compounds through the skin does
      not warrant a skin notation.
9.4   Groups at extra risk
      WHO/ATSDR data
      No studies were located regarding unusual susceptibility of any human
      subpopulation to arsenic. However, since the degree of arsenic toxicity may be
      Hazard assessment                                                                      143
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<pre>   influenced by the rate and extent of its methylation in the liver (see Chapter 6), it
   seems likely that people may differ in susceptibility because of difference in
   methylating capacity and the existence of polymorphism has been hypothesised.
   While there is some evidence that methylation capacity does vary among
   individuals (e.g., Buchet et al., 1981; Foa et al., 1984; Tam et al., 1982), the basis
   of this variation and its impact on human susceptibility have not been
   established.
   Additional data
   Furthermore, smokers may be more susceptible as according to Hertz-Picciotto
   (1992)101 arsenic and smoking act in a synergistic manner to produce lung
   cancer.
44 Arsenic and inorganic arsenic compounds
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<pre>hapter 10
       Recommendation for research
       No recommendations for research were made by DECOS.
       Recommendation for research                         145
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<pre>46 Arsenic and inorganic arsenic compounds</pre>

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07 Health and Safety Executive (HSE). Occupational exposure limits 2002. HSE, Norwich UK. [EH40].
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08 Arbejdstilsynet. Graensevaerdier for stoffer og materialer. Arbejdstilsynet website.
09 Deutsche Forschungsgemeinschaft (DFG). Arsenic and its inorganic compounds.
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10 Deutsche Forschungsgemeinschaft (DFG). Senatskommission zur Prufung gesundheitsschadlicher
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11 Bundesanstalt für Arbeitsschutz und Arbeitsmedizin (BAuA). Grenzwerte in der Luft am
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12 Arbetarskyddsstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar. 2000.
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<pre>13 Scientific Committee on Occupational Exposure Limits (SCOEL). Occupational Exposure Limits.
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14 American Conference of Governmental Industrial Hygienists (ACGIH). Arsenic. Threshold limit
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15 Occupational Safety and Health Administration. Inorganic arsenic. Occupational safety and health
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16 NIOSH. Criteria for a recommended standard: Occupational exposure to inorganic arsenic. NIOSH
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17 NIOSH. Arsenic. NIOSH pocket guide to chemical hazards. Atlanta, Georgia: 2005.
18 American Conference of Governmental Industrial Hygienists (ACGIH). TLVs and BEIs based on the
   documentation of the Threshold Limit Values (TLVs) for chemical substances and physical agents
   and Biological Exposure Indices. ACGIH, Cincinnati Ohio. 2003.
19 Werkgroep van deskundigen (WGD). Rapport inzake grenswaarde anorganische arseenverbindingen
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20 Yu RC, Hsu KH, Chen CJ, Froines JR. Arsenic methylation capacity and skin cancer. Cancer
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21 Guo X, Fujino Y, Kaneko S, Wu K, Xia Y, Yoshimura T. Arsenic contamination of groundwater and
   prevalence of arsenical dermatosis in the Hetao plain area, Inner Mongolia, China. Mol Cell Biochem
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22 Haque R, Mazumder DN, Samanta S, Ghosh N, Kalman D, Smith MM et al. Arsenic in drinking
   water and skin lesions: dose-response data from West Bengal, India. Epidemiology 2003; 14(2):
   174-182.
23 Tseng C. Abnormal current perception thresholds measured by neurometer among residents in
   blackfoot disease-hyperendemic villages in Taiwan. Toxicology letters 2003; 146(1): 27-36.
24 Guo X, Fujino Y, Chai J, Wu K, Xia Y, Li Y et al. The prevalence of subjective symptoms after
   exposure to arsenic in drinking water in Inner Mongolia, China. Journal of epidemiology / Japan
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25 Wang C, Jeng J, Yip P, Chen C, Hsu L, Hsueh Y et al. Biological gradient between long-term arsenic
   exposure and carotid atherosclerosis. Circulation 2002; 105(15): 1804-1809.
26 Tseng C, Chong C, Tseng C, Hsueh Y, Chiou H, Tseng C et al. Long-term arsenic exposure and
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27 Colognato R, Coppede F, Ponti J, Sabbioni E, Migliore L. Genotoxicity induced by arsenic
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<pre>29 Matos EL, Vilensky M, Mirabelli D, Boffetta P. Occupational exposures and lung cancer in Buenos
   Aires, Argentina. J Occup Environ Med 2000; 42(6): 653-659.
30 Englyst V, Lundstrom NG, Gerhardsson L, Rylander L, Nordberg G. Lung cancer risks among lead
   smelter workers also exposed to arsenic. Sci Total Environ 2001; 273(1-3): 77-82.
31 Hopenhayn C, Ferreccio C, Browning SR, Huang B, Peralta C, Gibb H et al. Arsenic exposure from
   drinking water and birth weight. Epidemiology (Cambridge 2003; 14(5): 593-602.
32 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
   Hague, The Netherlands: 2010: publication no. A10/07E.
62 Arsenic and inorganic arsenic compounds
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E Abbreviations
F WHO/ATSDR references
G Human data
H Animal data
  Evaluation of the Subcommittee on classification of carcinogenic substances
  Carcinogenic classification by the Committee
K Evaluation of the Subcommittee on classification of reprotoxic substances
L Derivation of health-based calculated occupational cancer risk values
  (HBC-OCRV)
  Annexes
                                                                              163
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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        165
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<pre>       for advice. If possible this evaluation should lead to a health based recommended exposure limit,
       or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
       calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
       per year.
   •   The evaluation of documents review the basis of occupational exposure limits that have been
       recently established in other countries.
   •   Recommending classifications for substances as part of the occupational hygiene policy of the
       government. In any case this regards the list of carcinogenic substances, for which the
       classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
       EEG) are used.
   •   Reporting on other subjects that will be specified at a later date.
   In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
   Social Affairs and Employment the President of the Health Council agreed to
   establish DECOS as a Committee of the Health Council. The membership of the
   Committee is given in Annex B.
66 Arsenic and inorganic arsenic compounds
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<pre>nnex B
     The Committee
     •  G.J. Mulder, chairman
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  P.J. Boogaard
        Toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        Professor of Risk Assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        Occupational Hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders, Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, Maastricht, and
        National Institute for Public Health and the Environment, Bilthoven
     •  T.M. Pal
        Occupational Physician, Netherlands Centre for Occupational Diseases,
        University of Amsterdam, Amsterdam
     •  A.H. Piersma
        Professor of Reproductive Toxicology, Utrecht University, Utrecht, and
        National Institute for Public Health and the Environment, Bilthoven
     •  H.P.J. te Riele
        Professor of Molecular Biology, VU University Amsterdam, and Netherlands
        Cancer Institute, Amsterdam
     The Committee                                                               167
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<pre>   •   I.M.C.M. Rietjens
       Professor of Toxicology, Wageningen University and Research Centre,
       Wageningen
   •   G.M.H. Swaen
       Epidemiologist, Dow Benelux NV, Terneuzen
   •   R.C.H. Vermeulen
       Epidemiologist, Institute for Risk Assessment Sciences, Utrecht University,
       Utrecht
   •   R.A. Woutersen
       Toxicologic Pathologist, TNO Quality of Life, Zeist, and Professor of
       Translational Toxicology, Wageningen University and Research Centre,
       Wageningen
   •   P.B. Wulp
       Occupational Physician, Labour Inspectorate, Groningen
   •   B.P.F.D. Hendrikx, advisor
       Social and Economic Council, The Hague
   •   G.B. van der Voet, scientific secretary,
       Health Council of the Netherlands, The Hague
   The Health Council and interests
   Members of Health Council Committees are appointed in a personal capacity
   because of their special expertise in the matters to be addressed. Nonetheless, it
   is precisely because of this expertise that they may also have interests. This in
   itself does not necessarily present an obstacle for membership of a Health
   Council Committee. Transparency regarding possible conflicts of interest is
   nonetheless important, both for the chairperson and members of a Committee
   and for the President of the Health Council. On being invited to join a
   Committee, members are asked to submit a form detailing the functions they
   hold and any other material and immaterial interests which could be relevant for
   the Committee’s work. It is the responsibility of the President of the Health
   Council to assess whether the interests indicated constitute grounds for non-
   appointment. An advisorship will then sometimes make it possible to exploit the
   expertise of the specialist involved. During the inaugural meeting the
   declarations issued are discussed, so that all members of the Committee are
   aware of each other’s possible interests.
68 Arsenic and inorganic arsenic compounds
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<pre>nnex C
     The submission letter
     Subject          : Submission of the advisory report Arsenic and inorganic
                        arsenic compounds
     Your Reference : DGV/MBO/U-932342
     Our reference : U-7493/BvdV/fs/459-X67
     Enclosed         :1
     Date             : December 11, 2012
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     Arsenic and inorganic arsenic compounds.
     This advisory report is part of an extensive series in which health-based
     calculated occupational cancer risk values are derived for the concentrations of
     various substances in the workplace. The advisory report in question was
     prepared by the Health Council’s Dutch Expert Committee on Occupational
     Safety (DECOS) and assessed by the Standing Committee on Health and the
     Environment.
     The submission letter                                                            169
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<pre>   I have today sent copies of this advisory report to the State Secretary of
   Infrastructure and the Environment and to the Minister of Health, Welfare and
   Sport, for their consideration.
   Yours sincerely,
   (signed)
   Prof. W.A. van Gool,
   President
70 Arsenic and inorganic arsenic compounds
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in July 2012 for public review. The
     following organisations and persons have commented on the draft report:
     • Mr. T.J. Lentz, National Institute for Occupational Safety and Health
         (NIOSH), Cincinnati, USA
     • Mr. H.W.C.M. Flipsen, Nederlandse Vereniging Diervoederindustrie
         (Nevedi), Rotterdam.
     Comments on the public review draft                                            171
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<pre>nnex E
     Abbreviations
     AAS       atomic absorption spectroscopy
     AES       atomic emission spectroscopy
     AFS       atomic fluorescence spectroscopy
     AM        arithmetic mean
     BEM       biological effect monitoring
     BM        biological monitoring
     bw        body weight
     CI        confidence interval
     G(L)C     gas liquid chromatography
     GD        gestation day(s)
     GM        geometric mean
     GSD       geometric standard deviation
     hr        hour
     HBR-      health based recommended occupational exposure limit
     OEL
     ICP       inductively coupled plasma
     HPLC      high performance liquid chromatography
     im        intramuscular
     ip        intraperitoneal
     IR        infrared
     it        intratracheal
     Abbreviations                                                  173
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<pre>   iv        intravenous
   LOAEL     lowest observed adverse effect level
   MAC       maximaal aanvaarde concentratie (maximal accepted concentration)
   MAK       Maximale Arbeitsplatz Konzentration
   MMAD      mean mass aerodynamic diameter
   MS        mass spectrometry
   NOAEL     no observed adverse effect level
   OEL       occupational exposure limit
   OR        odds ratio
   PEL       permissible exposure limit
   ppb       parts per billion (v/v)10-9
   ppm       parts per million (v/v)10-6
   RR        relative risk
   SD        standard deviation
   SEM       standard error of mean
   SMR       standard mortality ratio
   STEL      short term exposure limit
   tgg       tijdgewogen gemiddelde
   TLV       threshold limit value
   TWA       time-weighted average
   UV        ultraviolet
   XRF       X-ray fluorescence
   Organisations
   ACGIH American Conference of Governmental Industrial Hygienists
   ATSDR Agency for Toxic Substances and Disease Registry
   CEC       Commission of the European Communities
   DECOS Dutch Expert Committee on Occupational Safety
   DFG       Deutsche Forschungsgemeinschaft
   EPA       Environmental Protection Agency (USA)
   FDA       Food and Drug Administration (USA)
   HSE       Health and Safety Executive (UK)
   IARC      International Agency for Research on Cancer (WHO)
   NIOSH National Institute for Occupational Safety and Health (USA)
   NTP       National Toxicology Programme (USA)
   OSHA Occupational Safety and Health Administration (USA)
   WHO       World Health Organisation
74 Arsenic and inorganic arsenic compounds
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<pre>nnex F
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WHO/ATSDR References                                                                                    177
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<pre> nnex         G
              Human data
              (additional data, if not further specified)
 able 10 Human in vitro studies with arsenic and arsenic compounds.
Human cell type             Procedure/Concentration tested                Effects                                      Reference
Human hepatocytes, human MTT (thiazolyl blue) assay (cell viability)      Monomethylarsonous acid species were         Styblo et
 pidermal keratinocytes,                                                  the most cytotoxic in all cell types;        al., 200056
 uman bronchial epithelial AsIII, monomethylarsonic acid,                 dimethylarsinous acid were at least as
 ells and human urinary     monomethylarsonous acid, dimethylarsinic      cytotoxic as AsIII for most cell types.
 ladder cells               acid and dimethylarsinous acid at final       Pentavalent arsenicals were significantly
                            concentrations of 0.05 to 20 µM for up to     less cytotoxic than their trivalent analogs.
                            24 hr.
                                                                          Hepatocytes exhibited the greatest
                            Capacities of cells to produce methylated     methylation capacity for AsIII followed by
                            metabolites                                   epidermal keratinocytes, and bronchial
                                                                          epithelial cells. Cells derived from human
                            Hepatocytes were exposed to 0.1-20 µM         bladder did not methylate AsIII.
                            AsIII, the other cell types to 0.05 µM AsIII;
                            incubation for 24 hr.
              Human data                                                                                                     197
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<pre> able 11 Human case reports with regard to exposure to arsenic and arsenic compounds.
Humans involved/No. of humans Procedure                             Effects                                      References/
                                                                                                                 Remarks
nhalation
No data available
Oral
 7-year old male                 Suicide attempt by ingestion of    Between 5 h and 7 days he developed          Yilmaz et
                                 4 g arsenic trioxide (for dental   nausea, vomiting, gastritis and stomach      al., 200977
                                 devitalizations).                  ulcers, anaemia. He recovered after clinical
                                                                    intervention.
 8-year old male                 Suicide attempt by ingestion of Multisystem organ failure, peripheral           Kim and
                                 arsenic trioxide (termiticide)     neuropathy. He recovered after clinical      Abel, 200978
                                                                    intervention.
 3-year old male                 Suicide attempt by drinking        Vomiting, diarrhoea, thirst, pharyngeal      Duenas-
                                 54 g arsenic trioxide              constriction, paraesthesia of the legs. He   Laita et al.,
                                                                    recovered after timely clinical intervention 200579
                                                                    but polyneuropathy remained.
 5-year old woman                Case report: root canal treatment Arsenical necrosis of the jaws affecting the  Yalcin et al.,
                                 of the teeth by a private          right and the left side of the maxilla. As a 200385
                                 practitioner, an arsenical paste   result of leakage into the tissues of an
                                 was applied to the teeth.          arsenical paste from the pulp chamber of
                                                                    endodontically treated teeth, bilateral
                                                                    oroantral fistula (OAF) occurred.
 98          Arsenic and inorganic arsenic compounds
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<pre> able 12 Human studies with regard to non-carcinogenic effects after long-term exposure to arsenic and arsenic compounds.
  tudy population              Exposure assessment          Effects (non-carcinogenic)                       References/
                                                                                                             Remarks
nhalation
 6 exposed art glass workers As2O3                          A significant increase in the excretion of penta Apostoli et al.,
 nd 54 controls (workers                                    and uroporphyrins was demonstrated for           200249
rom tool makers).                                           workers exposed to As; As(III) was the species Major objective of
ndividuals with liver or                                    best correlated with urinary porphyrin           this study was
 idney diseases were                                        excretion.                                       biomonitoring.
 xcluded.
Oral
Cases:                         Both cases and controls had Results indicated that skin lesion cases had      Yu et al., 2000220
 ubjects identified by         been exposed to drinking     higher percents of inorganic arsenic (13.1 ±     Cases and controls
  ermatologists during 1994, water from contaminated        3.7%), monomethylarsonic acid (16.4 ± 3.2%), were very similar
with basal cell carcinoma (2 well water for                 lower percent of dimethylarsinic acid (70.5 ± in terms of
 ases), Bowen’s disease        approximately 30 years but 5.8%), and higher ratio of monomethylarsonic cigarette smoking,
 squamous cell carcinoma of had changed to piped water acid to dimethylarsinic acid                          consumption of
he skin, 19 cases) or          for more than 10 years.      (monomethylarsonic acid/dimethylarsinic acid, alcohol beverages
  yperkeratosis/               Cases and controls had       0.24 ± 0.06) than matched controls (InAs: 11.43 for at least 1 year
  yperpigmentation (6 cases) ingested similar               ± 2.1%; monomethylarsonic acid: 14.6 ± 2.6%; before the study,
 rom the blackfoot disease     concentrations of arsenic in dimethylarsinic acid: 73.9 ± 3.3%;               status of hepatitis B
 ndemic area in                drinking water (0.77 and     monomethylarsonic acid/ dimethylarsinic acid: surface antigen and
 outhwestern Taiwan.           0.98 ppm, respectively (not 0.20 ± 0.04). Individuals with a higher           tea
Controls                       statistically significant    percentage of monomethylarsonic acid
 ubjects matched by gender different (p = 0.117))) and (>15.5%) had an odds ratio of developing skin
 12 female and 14 male         excreted comparable          disorder 5.5 times (95% confidence interval,
  airs) and age within 3 years urinary arsenic metabolite 1.22-24.81) higher than those having a lower
 average age: 63.4 years)..    concentrations.              percentage of monomethylarsonic acid. This
                                                            association was not confounded by hepatitis B
                                                            surface antigen, cigarette smoking, or alcohol
                                                            and tea consumption.
Residents from Hetao plain In the Wuyuan area, 96.2% The results showed the prevalence of arsenical Guo et al., 2001221
  f Inner Mongolia             of water samples from        dermatosis in the Wuyuan area was 44.8%,
Autonomous Region, China; tubule-type wells contained higher than 37.1% prevalence of arsenical
wo areas: Wuyuan: 216          arsenic above 50 µg/L and dermatosis in the Alashan area. The prevalence
males (114 patients) and 217 69.3% in Alashan area; the of arsenical dermatosis was highest in the over
 emales (80 patients) and      highest value was 1354 µg/ 40-year-old age group. There was no sex
Alashan: 610 males (222        L and 1088 µg/L,             difference in the prevalence.
  atients) and 566 females     respectively.
 214 patients).
               Human data                                                                                                     199
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<pre> ases:                       The average peak arsenic      The average latency for skin lesions was 23      Haque et al.,
persons with arsenic-        concentration in drinking     years from first exposure. A strong dose-        2003222 -
nduced skin lesions) and     water was 325 µg/L for        response gradients with both peak and average
ge- and sex-matched          cases and 180 µg/L for        arsenic water concentrations was found for
ontrols from participants in controls.                     arsenic-induced skin keratosis and
 1995-1996 cross-sectional   A detailed assessment of      hyperpigmentation.
urvey in West Bengal were    arsenic exposure that
elected. Participants were   covered at least 20 years
e-examined between 1998      was used.
nd 2000. Consensus
greement by four
hysicians reviewing the
kin lesion photographs
onfirmed the diagnosis in
7% of cases clinically
iagnosed in the field.
 ighty-five seemingly        Arsenic concentration in      BFD residents had significantly 1.28-2.23-fold   Tseng, 2003223
ormal subjects living in     drinking water in the BFD-    higher current perception threshold (CPT) than   Results showed
lackfoot disease (BFD)-      villages ranged from 0.70 to  normal controls for all frequencies at the 3     that the two groups
yperendemic villages in      0.93 mg/L;                    nerves. If the mean values + 3 standard          were comparable in
 aiwan and 75 external       the shallow well water in     deviations (SD) derived from normal controls     age, sex, body
ormal controls without       other areas had an arsenic    were used as cut-off points for defining         height and body
xposure were recruited. All  content between 0.00 and      abnormalities, 36 of the 85 (42.4%) residents in weight.
ubjects were 30-75 years     0.30 mg/L with a median of    the BFD villages had at least one abnormal
ld, without possible causes  0.04 mg/L.                    measurement. Stepwise regression analyses
f peripheral neuropathy and                                consistently showed that residency in BFD
uffered from no symptoms                                   villages was significantly associated with
f peripheral neuropathy.                                   higher CPT values after adjusting for age, sex,
                                                           body height and body weight.
nner Mongolia, China: 431 An arsenic level of 50+ µg/ Adjusted ORs of subjective symptoms,                  Guo et al., 2003224
esidents of an arsenic-      L was found in 90.6% of       including coughs (odds ratio [OR] = 12.8, 95%    Information bias
ffected village and 189      wells in the arsenic-affected confidence interval [CI]: 6.4-25.6), stomach-    cannot be
esidents of an arsenic-free village.                       aches (OR = 5.8, 95% CI 3.6-9.4), palpitations   excluded.
illage in 1996.                                            (OR = 3.6, 95% CI 1.5-8.2), urination problems
                                                           (OR = 14.7, 95% CI: 3.3-65.5) and spontaneous
                                                           abortions (OR = 2.7, 95% CI 0.8-8.4), were
                                                           markedly higher amongst residents of the
                                                           arsenic-affected village, including those
                                                           without arsenic dermatosis.
 00          Arsenic and inorganic arsenic compounds
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<pre> 99 male and 264 female        Cumulative arsenic           Three indices of long-term exposure to ingested  Wang et al.,
 dult residents who lived >6   exposure (arsenic water      arsenic, including the duration of consuming     2002225
months in the study area       well concentration * years   artesian well water, the average arsenic
rom the southwestern area      living in a village) was     concentration in consumed artesian well water,
 f endemic arseniasis in       grouped into three           and cumulative arsenic exposure, were all
 aiwan                         categories: 0, 0.1-19.9 and  significantly associated with prevalence of
                               >/=20 mg/L-years.            carotid atherosclerosis in a dose-response
A total of 436 (94%) of the                                 relationship. The biological gradient remained
 ubjects completed the                                      significant after adjustment for age, sex,
 ltrasonographic assessment                                 hypertension, diabetes mellitus, cigarette
 f extracranial carotid artery                              smoking, alcohol consumption, waist-to-hip
ECCA).                                                      ratio, and serum levels of total cholesterol and
                                                            LDL cholesterol. The multivariate-adjusted
                                                            odds ratio was 3.1 (95% CI 1.3 to 7.4) for those
                                                            who had a cumulative arsenic exposure of > or
                                                            =20 mg/L-years compared with those without
                                                            exposure to arsenic from drinking artesian well
                                                            water.
A total of 468 male and 613    History of arsenic exposure  Among the subjects, 78 cases (16.9%) were        Tseng et al.,
emale subjects living in the   was estimated through a      diagnosed as having IHD. The prevalence rates    2003226
 lackfoot disease-             structured questionnaire and of IHD for the age groups of 30-39, 40-49, 50-   Limitations:
 yperendemic villages in       the arsenic content in       59, and >/=60 years were 4.9, 7.5, 16.8, and     - no external
 aiwan                         artesian well water of the   30.7%, respectively (p < 0.001). For those with  control group;
                               villages. Cumulative arsenic CAE of 0, 0.1-14.9 and >/=15 mg/L-years, the     - diagnostic tool;
                               exposure (CAE) was           prevalence rates of IHD were 5.2, 10.9 and       (electrocardio-
                               calculated as the sum of the 24.1%, respectively (p < 0.001). The odds        gram) was missing
                               products multiplying the     ratios (95% confidence intervals) for IHD were   for about half of
                               arsenic concentration in     1.60 (0.48, 5.34), and 3.60 (1.11, 11.65),       the cases.
                               artesian well water (mg/L)   respectively, for those with CAE of 0.1-14.9
                               by the duration of drinking  and >/=15.0 mg/L-years, when compared with
                               the water (years) in         those lacking drinking water exposure to
                               consecutive periods of       arsenic after multivariate adjustment.
                               living in the different
                               villages.
                               Cumulative arsenic
                               exposure (CAE) was
                               grouped into three
                               categories: 0, 0.1-14.9 and
                               >/=15 mg/L-years.
Dermal
No data available
              Human data                                                                                                     201
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<pre> able 13a Genotoxicity of arsenic compounds in humans (in vivo data).
Humans involved/             Study type           Exposure duration /          Effects                               Referen-
No. of humans                                     Concentration tested                                               ces/
                                                                                                                     Remarks
 xposure group:              Chromosomal          Exposure group               Symptomatic individuals had a         Ghosh et
 22 inhabitants of North 24 aberrations in        (skin-symptomatic):          higher level of cytogenetic damage al., 200689
 arganas and Nadia, West     lymphocytes,         mean level of arsenic in     compared to a symptomatic
  engal, India (244 skin-    micronuclei          drinking water 242.06 µg/L individuals. Asymptomatic
 ymptomatic and 178 non      formation in oral                                 individuals had significantly higher
 ymptomatic)                 mucosa cells,        Exposure group               genotoxicity than unexposed
                             urothelial cells and (asymptomatic):              individuals.
  ontrol group 102           binucleated          mean level of arsenic in
 nexposed subjects from      lymphocytes          drinking water 202.33 µg/L GSTM1 was significantly higher in
 ast and west Midnapore                                                        asymptomatic group than in
 istrict, matched to the     Identification of    Control group:               symptomatic group.
 xposed group by age sex     mutations in         Mean level of arsenic in
 nd socio-economic status GSTT1, GSTM1,           drinking water 7.16 µg/L
                             GSTP1
 xposure group:              Micronuclei in oral Exposure group:               Chromosomal aberrations were          Chakrabo
 5 residents of Baduria      mucosal cells,       Mean (±SE) level of arsenic 3.85 fold increased in the exposed rty et al.,
 lock in Atghara, North 24 Chromosomal            in drinking water            population compared to those in the 200690
 arganas                     aberrations in       66.75±2.50 µg/L              control group.
                             lymphocytes
  ontrol group:                                   Control group: Mean (± SE) Micronuclei in oral mucosa cells in
 5 residents from Howrah,                         level of arsenic in drinking the exposed group were
Kolkata, West Bengal                              water 6.44 ± 0.21 µg/L       significantly increased to 3.34 fold
                                                                               over levels in unexposed groep.
 xposure group:              Micronuclei in       Exposure group:              Micronuclei in buccal cells were      Martinez
 05 individuals from the     buccal cells         Mean level of arsenic in     increased in the exposed group        et al.,
Antofagasta region (north                         drinking water 0.75 mg/L compared to the control group,            200592
  hile)                                                                        although statistical significance was (same
                                                  Control group:               not reached.                          popula-
  ontrol group:                                   Mean level of arsenic in                                           tion as
 02 individuals from the                          drinking water 2 µg/L                                              Martinez
 rea of Concepcion                                                                                                   et al.,
                                                                                                                     200491)
  xposure group:             Micronuclei in       Exposure group:              Micronuclei in buccal cells were      Martinez
 11 individuals from the     buccal cells         Mean level of arsenic in     increased in the exposed group        et al.,
Antofagasta region (north                         drinking water 0.75 mg/L compared to the control group,            200491
  hile)                                                                        although statistical significance was
                                                  Control group:               not reached.
  ontrol group:                                   Mean level of arsenic in
 06 individuals from the                          drinking water 2 µg/L
 rea of Concepcion
  02          Arsenic and inorganic arsenic compounds
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<pre>  xposure group:              Cross-sectional       Exposure group:              Analysis revealed that micronuclei Basu et
 63 inhabitants of North 24 biomarker study to in the district, North 24         frequencies in the exposed group     al., 200465
  arganas, West Bengal, India evaluate and          Parganas, the mean level (±  were significantly elevated to 5.33-
                              compare the           S.E.) of arsenic in drinking fold over unexposed levels for
  ontrol group                frequencies of        water (µg/L) was             lymphocytes, 4.63-fold for oral
 54 subjects residing in the micronuclei in         214.72 ± 9.03 µg/L;          mucosa cells, and 4.71-fold for
  ast Midnapur district,      peripheral blood                                   urothelial cells (increases in
ndia.                         lymphocytes, oral Control group:                   micronuclei frequencies significant
                              mucosa cells, and in East Midnapur the mean        at p < 0.01).
                              urothelial cells.     arsenic content of water
                                                    (µg/L) was 9.20 ± 0.32 µg/
                                                    L.
  xposure group:              Bio-monitoring        Exposure group:              In the exposed group the mean        Mahata et
 9 inhabitants of North 24 study using              in the district, North 24    arsenic concentrations in nails (µg/ al., 200366
  arganas, West Bengal, India chromosomal           Parganas, the mean level (±  g), hair (µg/g) and urine (µg/L)
                              aberrations (CA)      S.E.) of arsenic in drinking samples were 9.04 ± 0.78, 5.63 ±
  ontrol group:               and sister chromatid water (µg/L) was 211.70       0.38 and 140.52 ± 8.82,
 6 healthy, asymptomatic      exchanges (SCE) as ±15.28;                         respectively, which were
ndividuals (age matched       end points to                                      significantly high (p < 0.01)
 ontrols with similar socio- explore the            Control group:               compared to the corresponding
 conomic status) residing in cytogenetic effects in Midnapur and Howrah          control values of 0.44 ± 0.03, 0.30
 istricts--Midnapur and       of chronic arsenic (two unaffected districts)      ± 0.02 and 5.91 ± 0.49,
Howrah, India                 toxicity. Exposure the mean arsenic content of     respectively. Elevated mean values
                              was assessed by       water (µg/L) was 6.35 ±      (p<0.01) of the percentage of
                              standardised          0.45.                        aberrant cells (8.08%) and SCEs
                              questionnaires and                                 per cell (7.26) were also observed
                              by detecting the                                   in the exposed individuals in
                              levels of arsenic in                               comparison to controls (1.96% and
                              drinking water,                                    5.95, respectively).
                              nails, hair and urine
                              samples.
  xposure group:              In vitro cytogenetic 0-5 µM sodium arsenite        Although both the exposed groups Mahata et
  ix symptomatic individuals study was              The mean As content in       had chronic exposure to As through al.,
with arsenic-related skin     performed utilising nails and hair was 9.61 and    the drinking water, individuals with 2004a67
esions and six age- and sex- chromosomal            5.23 µg/g in symptomatic,    skin lesions accumulated more As
matched As-exposed            aberrations (CA) in 3.48 and 2.17 µg/g in          in their nails and hair and excreted
 symptomatic (no arsenic- lymphocytes treated asymptomatic and 0.42 and          less in urine (127.80 versus 164.15
elated skin lesions)          with sodium           0.33 µg/g in the control     µg/L). The results showed that
ndividuals from West          arsenite (0-5 µM) individuals, respectively.       sodium arsenite induced a
  engal, India                                                                   significantly higher percentage of
                                                                                 aberrant cells in the lymphocytes of
  ontrol group:                                                                  control individuals than in the
  ix control individuals with                                                    lymphocytes of both the exposed
 imilar socio-economic                                                           groups. Within the two exposed
 tatus residing in non-                                                          groups As induced higher
 ffected districts of West                                                       incidences of CA in the
  engal                                                                          symptomatic than the
                                                                                 asymptomatic individuals
                                                                                 suggesting that asymptomatic
                                                                                 individuals have relatively lower
                                                                                 sensitivity and susceptibility to
                                                                                 induction of genetic damage by As.
               Human data                                                                                                   203
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<pre>  ases:                     Case control study    Exposure group:              A significant difference (p < 0.01)   Mahata et
 65 symptomatic (arsenic    using chromosomal     in the district, North 24    in the frequencies of CA and SCE      al.,
nduced skin lesions)        aberrations (CA)      Parganas, the mean level of  between the cases and control         2004b68
 ubjects from North 24      and sister chromatid  arsenic in drinking water    group was shown.
 arganas, West Bengal,      exchanges (SCE) as    (µg/L) was 214.96 µg/L;
ndia;                       end points to
                            explore the           Control group:
  ontrols:                  cytogenetic effects   subjects from Midnapur
 55 age-sex matched control of chronic arsenic    (unaffected district).
 ubjects from Midnapur,     toxicity.
West Bengal.
 xposure group:             A pilot study was     Exposure group:              Analytical results from these         Tian et al.,
 9 residents from           undertaken to         high levels of arsenic in    individuals revealed that MN          200170
  ayingnormen, located in   evaluate              drinking water (527.5 ± 24   frequencies in the high-exposure
  entral West Inner         frequencies of        µg/L);                       group were significantly elevated to
Mongolia, China)            micronuclei (MN),                                  3.4-fold over control levels for
                            as measures of        Control group:               buccal and sputum cells, and to 2.7-
  ontrol group:             chromosomal           low levels of arsenic in     fold over control for bladder cells
 3 control residents from   alterations, in       drinking water (4.4 ± µg/L). (increases in MN frequency
  ayingnormen, located in   multiple exfoliated                                significant at p < 0.001 for buccal
  entral West Inner         epithelial cell types                              cells; p < 0.01 for sputum cells; p <
Mongolia, China)                                                               0.05 for bladder cells). When
                                                                               smokers were excluded from high-
                                                                               exposure and control groups the
                                                                               effects of arsenic were observed to
                                                                               be greater, although only in buccal
                                                                               and sputum cells; approximately 6-
                                                                               fold increases in MN frequency
                                                                               occurred in these tissues.
  ases:                     Investigation to the Arsenic levels in toenails    Toenail arsenic levels were           Andrew et
  cases with bladder cancer association between were grouped into two          inversely correlated with             al., 200376
ages 25-74 years, from July nucleotide excision categories: ≤ 0.2 µg/g and ≥ expression of critical members of
 , 1994 to June 30, 1998)   repair capacity       2 µg/g)                      the nucleotide excision repair
rom New Hampshire,          expression and                                     complex, ERCC1 (r(2) = 0.82, p <
United States.              arsenic exposure.                                  0.0001), XPF (r(2) = 0.56, p <
                                                                               0.002), and XPB (r(2) = 0.75, p <
  ontrols:                                                                     0.0001). The internal dose marker,
 0 controls (ages 25-74                                                        toenail arsenic level, was more
 ears, from July 1, 1994 to                                                    strongly associated with changes in
 une 30, 1998) from New                                                        expression of these genes than
Hampshire, United States.                                                      drinking water arsenic
                                                                               concentration.
 04           Arsenic and inorganic arsenic compounds
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<pre>  ases:                       A case-case study       Patients were placed into  The total number of chromosomal Moore et
 4 patients with transitional was conducted in        one of four arsenic        alterations was higher in              al., 200269
 ell carcinoma of the bladder Argentina and Chile     exposure categories        individuals exposed to higher
 etween 1996 and 2000 from    examining               according to their average arsenic levels (5.7 ± 5.1, 5.6 ± 5.1,
Union Country, Cordoba,       chromosomal             5-year peak arsenic        7.3 ± 7.4, and 9.1 ± 6.5 [mean ±
Argentina;                    alterations in          exposure.                  standard deviation] chromosomal
                              bladder tumour          Category 1: between 0 and  alterations per tumour with
 9 patients (between          DNA.                    <10 µg/L per year (n=45);  increasing arsenic exposure;
November 1994 and July        - Smoking history       category 2, 10-99 µg/L per p(trend) = 0.02, adjusted for stage
 996) with transitional cell and occupational         year (n=24); category 3,   and grade). The trend was stronger
 arcinoma who were            history were            100-299 µg/L per year      in high-grade (G2-G3) tumours (6.3
 scertained from a hospital- included.                (n=29); and category 4,    ± 5.5, 8.3 ± 4.7, 10.3 ± 7.8, and 10.5
 ased case-control study      - All statistical tests ≥300 µg/L per year (n=25). ± 6.4 alterations per tumour;
 reviously conducted in       were two-sided.                                    p(trend) = 0.01) than it was in low-
  hile.                                                                          grade (G1) tumours (3.5 ± 3.1, 1.1
                                                                                 ± 1.1, 2.5 ± 2.5, and 3.6 ± 3.2
                                                                                 alterations per tumour; p(trend) =
                                                                                 0.79). The mean number of
                                                                                 chromosomal alterations also
                                                                                 increased with tumour stage and
                                                                                 grade (p(trend) < 0.001)
                                                                                 independently of arsenic exposure
                                                                                 but was not associated with
                                                                                 smoking history. Deletion of part or
                                                                                 all of chromosome 17p
                                                                                 (p(trend)<0.001) showed the
                                                                                 strongest association with arsenic
                                                                                 exposure.
              Human data                                                                                                      205
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<pre> able 13b Genotoxicity of arsenic compounds in human cells (in vitro data).
Human cell   Study type                    Exposure duration/           Effects                                    References
ype                                        Concentration tested                                                    /Remarks
Human        Challenge of lymphocytes 0.5-4 µM AsIII                    Trivalent compounds AsIII and MMAIII       Colognato
 eripheral   with different arsenic        4-32 µm AsV                  enhanced micronuclei formation more        et al.,
ymphocytes compounds AsIII, AsV,           0.01-2 µM MMAIII             than pentavalent compounds AsV and         2007227
             MMAIII, MMAV, DMAV, 50-1000 µM MMAV                        MMAV. For DMAV and TMAOV no
             TMAOV and testing the         50-250 µM DMAV               genotoxicity was observed. MMAIII
             micronucleus formation        100-1000 µM TMAOV            showed a aneuploidogenic property.
             (cytokinesis block            Cytochalasin B blocked the
             micronucleus assay)           cytokinesis process and
             followed by fluorescence in cells were harvested after 72
             situ hybridization            hr
             (MMAIII).
Human liver Iron release from HLF by       The assay system (total      Both dimethylarsinic acid and              Ahmad et
erritin      dimethylarsinic acid and      volume 150 µl) contained     dimethylarsinous acid released iron from   al., 2002158
             dimethylarsinous acid with HLF (2 µg), ferrozine (0.5 human liver ferritin (HLF) with or
             or without ascorbic acid.     mM), dimethylarsinic acid/ without the presence of ascorbic acid.
                                           dimethylarsinous acid (each With ascorbic acid the rate of iron
                                           10 mM) with or without       release from HLF by dimethylarsinic
                                           ascorbic acid (250 µM) in acid was intermediate (3.37 nM/min, p <
                                           10 mM phosphate buffered 0.05) and by dimethylarsinous acid was
                                           saline (pH 7.4).             much higher (16.3 nM/min, p < 0.001).
                                                                        Relevance:
                                                                        Free iron causes redox cycling,
                                                                        production of ROS and oxidative stress.
Human        A single-cell gel (SCG,       AsIII: 1 ?M - 1000 mM;       Methylated trivalent arsenicals were       Mass et al.,
 eripheral   “comet”) (induction of        AsV: 1 µM - 1000 µM;         much more potent DNA damaging              200158
ymphocytes   DNA damage) (2 h              monomethylarsonic acid: 1 compounds than any other arsenicals that
             incubation at 37 oC; 5%       µM - 875 µM;                 were tested. On the basis of the slopes of
             CO2 in air)                   dimethylarsinic acid: 1 µM - the concentration-response curve for the
                                           1000 µM;                     tail moment in the SCG assay,
                                           monomethylarsonous acid: monomethylarsonous acid and
                                           1.25 µM - 80 µM;             dimethylarsinous acid were 77 and 386
                                           dimethylarsinous acid: 1.4 times more potent than AsIII,
                                           µM - 91 µM                   respectively.
Human        Supercoiled plasmid           synthetic                    Nicking (unwinding) DNA, double-           Mass et al.,
ymphocytes   unwinding assay               monomethylarsonous acid stranded breaks, and induction of               200159
                                           and dimethylarsinous acid, alkaline labile sites (methylated arsenic    Remark:
                                           as AsMeO and AsMe2I          species at concentrations much lower       Evaluation
                                                                        than inorganic As).                        of the
Human        Single cell gel (comet) assay                              AsIII methylated species doubled the tail  results was
ymphocytes                                                              moment at concentrations 30 to 300-fold    limited
                                                                        less than did inorganic As.                since only
                                                                                                                   an abstract
                                                                                                                   is
                                                                                                                   available.
 06        Arsenic and inorganic arsenic compounds
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<pre>HeLa S3 cells Induction of oxidative DNA    AsIII, monomethylarsonic      Incubations of 0.5-3 h with doses as low    Schwerdtle
               damage measuring             acid, monomethylarsonous      as 10 nM AsIII induced high frequencies     et al.,
               frequencies of DNA strand    acid, dimethylarsinic acid,   of Fpg-sensitive sites, the induction of    200394
               breaks and lesions           dimethylarsinous acid.        oxidative DNA damage after 18 h
               recognised by the bacterial                                incubation was rather low.
               formamidopyrimidine-DNA                                    Monomethylarsonic acid,
               glycosylase (Fpg).                                         monomethylarsonous acid,
                                                                          dimethylarsinic acid and
                                                                          dimethylarsinous acid showed a
                                                                          pronounced induction of Fpg-sensitive
                                                                          sites in the nanomolar or micromolar
                                                                          concentration range, respectively, after
                                                                          both short-term and long-term
                                                                          incubations. Furthermore,
                                                                          monomethylarsonous acid and
                                                                          dimethylarsinic acid generated DNA
                                                                          strand breaks in a concentration-
                                                                          dependent manner.
Human A549 BPDE-induced DNA adduct AsIII: 0 - 75 µM                       Whereas only AsIII and                      Schwerdtle
 ells          formation and repair         monomethylarsonic acid: 0 - monomethylarsonous acid increased             et al.,
                                            500 µM                        BPDE-DNA adduct formation, AsIII (>/        200393
                                            monomethylarsonous acid: =5 µM), the trivalent (>/=2.5 µM) and
                                            0 - 7.5 µM                    the pentavalent (>/=250 microM)
                                            dimethylarsinic acid: 0 - 500 metabolites diminished their repair at
                                            µM                            non-cytotoxic concentrations.
                                            dimethylarsinous acid: 0 -
                                            7.5 µM
               Effects on the zinc finger   1-1000 µM                     All trivalent arsenicals were able to
               domain of the human XPA                                    release zinc from XPAzf.
               protein (XPAzf)
               Effects on the Escherichia 0-10 µM                         Monomethylarsonous acid and
               coli zinc finger protein Fpg                               dimethylarsinous acid inhibited the
                                                                          activity of isolated Fpg.
Human          SCE assay                    dimethylarsinic acid: 0, 125, SCE frequencies were significantly          Mouron et
ibroblast      Comet assay                  250 and 500 µM                increased at all concentrations in treated  al., 200595
 ells          Proteinase K assay                                         cells in relation to controls (p < 0.001).
                                                                          In the standard alkaline comet assay, as
                                                                          well as in the control assay for proteinase
                                                                          K treatment, a significant dose-
                                                                          dependent reduction in tail moment was
                                                                          observed. Nevertheless, post-treatment
                                                                          with proteinase K induced the release of
                                                                          proteins joined to the DNA and
                                                                          consequently, a dose-dependent
                                                                          increment in DNA migration was
                                                                          observed (p < 0.001).
Human          DNA methylation              Monomethylarsonous acid Malignant transformation after 12 weeks           Wnek et
 ladder cells                               (MMAIII) 50 nM                of exposure.                                al., 201096
UROtsa)
              Human data                                                                                                      207
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<pre> able 14 Human carcinogenicity studies of arsenic and arsenic compounds (Inhalation).
 tudy population                  Exposure assessment        Effects                         References/Remarks
A cohort of 2802 Tacoma           For departments for which Respiratory cancer               Enterline et al., 19954 and
 melter workers who worked ≥ no air data were available,                                     Enterline et al., 198798
  year during 1940-1964.          exposure assessment based SMR1 for respiratory cancer      Smoking:
 or 98.5%, it was possible to     on urinary As              (total cohort, hired < 1940,    According to the authors, smoking
 etermine vital status at the end measurements using the     hired ≥ 1940) for the exposure  could be an important confounder
 f 1986. Of 1583 known            equation: air As (µg/m3) = categories:                     in respiratory cancer and data on
 eaths, death certificates were 0.0064 × (urinary As (µg/ 1) 154 - 65 - 178*                 the histories of the study
 btained for 96.6%.               L))1.942.                  2) 176** - 68 - 256**           population for smoking were
                                  This equation was based on 3) 210** - 246** - 170          collected. The publication
                                  departments and years for 4) 212** - 150 - 300**           addressing this and other
                                  which data from both air   5) 252** - 255** - 244*         covariates is however not yet
                                  (1938 - 1984) and urinary 6) 284** - 252** - 406**         available.
                                  arsenic (1948 - 1984) were 7) 316** - 339* - not
                                  available.                 available
                                  Calculation of cumulative *: p < 0.05; **: p < 0.01
                                  exposure: development of
                                  exposure matrix of arsenic 1 Calculation of expected
                                  in air by department and   deaths: only mortality of
                                  year from 1938 up to 1984 white men from Washington
                                  in combination with job    was used as all workers were
                                  histories for each worker. men and nearly all were
                                                             white.
                                  Cumulative exposure (µg/
                                  m3·years) categories (mean An earlier publication of the
                                  exposure):                 Tacoma copper smelter
                                  1) <750 (405)              contained data on actual daily
                                  2) 750-1,999 (1,305)       exposure concentrations,
                                  3) 2,000-3,999 (2,925)     duration of exposure and the
                                  4) 4,000-7,999 (5,708)     risk on lung cancer. In this
                                  5) 8,000-19,999 (12,334)   study, an arsenic exposure
                                  6) 20,000-44,999 (28,356) category of < 400 µg/m3
                                  7) 45,000+ (58,957)        (mean 213 µg/m3) was
                                                             associated with a statistically
                                                             significant SMR of 238.7 for
                                                             copper smelter workers who
                                                             were exposed to arsenic for 30
                                                             or more years.
 08          Arsenic and inorganic arsenic compounds
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<pre>A cohort of 8014 white males,   Work areas grouped as        A significantly increased       Lubin et al., 20001
who were employed in the        "light", "medium" or         SMR (using the US               Smoking:
Anaconda copper smelter for ≥   "heavy" exposure based on    population rate as the referent Information on smoking was not
 2 months before 1957. Vital    industrial hygiene data (702 population) was found for       available, according to the
 tatus was followed from 1      measurements; 1943 -         respiratory cancer (SMR =       authors, however, it is noteworthy
 anuary 1938 to 31 December     1958).                       1.55 (1.41-1.70)).              that mortality from smoking-
 987; a total of 4930 (63%)     Based on estimates of        Internal analyses revealed a    related cancers, except for chronic
were deceased, including 446    workers' daily exposure      significant, linear increase in obstructive pulmonary disease,
rom respiratory cancer, and     time, time-weighted          the excess relative risk of     was not excessive. In a sample of
 909 (24%) were known to be     average exposures for each   respiratory cancer with         1469 workers from the original
 live at the end of the follow- category were created.       increasing exposure to inhaled  cohort, there was a higher
 p.                             Estimated airborne           airborne arsenic. The estimate  proportion of smokers compared
  ost to follow-up: 15%         exposures (time-weighted     of the excess relative risk per with US white males. However,
assumed alive)                  average) were 0.29, 0.58,    mg/m3-year was 0.21/(mg/m3-     the authors stated that the
                                11.3 mg/m3 in areas of       year) (95% confidence           proportion of cigarette smokers
                                light, medium and heavy      interval: 0.10, 0.46).          did not vary significantly by
                                exposure.                                                    extent of exposure to airborne
                                Cumulative exposure:                                         arsenic, indicating that it was
                                estimated from the time of                                   unlikely that smoking confounded
                                working in different work                                    the assessment of lung cancer risk
                                areas and calculated as:                                     with arsenic exposure.
                                0.29 × L + 0.58 × M + λ
                                (=0.1) × 11.3 × H, where L,                                  Exposure assessment:
                                M, and H are years worked                                    Industrial hygiene measurements
                                in areas where exposure                                      were available for less than half of
                                was considered to be light                                   the 29 working areas; no data were
                                (or unknown), medium, or                                     collected before 1943, and the
                                heavy, respectively.                                         measurements were often
                                                                                             performed when an industrial
                                                                                             hygiene control measure was
                                                                                             instituted or after a process change
                                                                                             occurred, and most often in areas
                                                                                             where arsenic was thought to be a
                                                                                             hazard. The locations for sampling
                                                                                             were not randomly selected.
               Human data                                                                                                    209
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<pre>A cohort of 3916 smelter         Industrial hygiene            SMRs1 (95% CI) for lung         Järup et al., 19893
workers who worked ≥ 3           measurements available        cancer for dose categories      Smoking:
months in the Rönnskär smelter   from 1951; production         using age specific mortality See study of Järup et al, 1991 100
 etween 1928 and 1967 and        figures used to extrapolate   rates from the country where
were followed for vital status   exposures before 1951.        the smelter was situated were
 947-1981.                       Cumulative exposure: each     as follows:
 he vital status of all but 15   work site characterised by    < 0.25: 271 (148-454)
0.4%) of them was verified.      an exposure level during      0.25-<1: 360 (192-615)
                                 three consecutive time        1-<5: 238 (139-382)
                                 periods. Using this           5-<15: 338 (189-558)
                                 exposure matrix and           15-<50: 461 (309-662)
                                 detailed information of the   50-<100: 728 (267-1585)
                                 work history, cumulative      100+: 1137 (588-1986)
                                 arsenic exposure could be     The slope rose steeply only in
                                 computed for each worker.     the two highest exposure
                                 The cumulative exposure       categories. The overall trend
                                 levels (mg/m3 · year) were    was, however, highly
                                 categorised as follows:       significant (p < 0.001) with an
                                 < 0.25                        overall SMR of 372 (304-
                                 0.25-<1                       450).
                                 1-<5
                                 5-<15                         1 To enhance comparability
                                 15-<50                        the original SMRs were
                                 50-<100                       adjusted to the lowest
                                 100+                          intensity/shortest employment
                                                               time group.
A cohort of 3916 smelter         - Estimation of arsenic       - Lung cancer risks were        Järup et al., 1991100
workers who worked ≥ 3           exposure: see Järup et al,    positively related to
months in the Rönnskär smelter   1989 3.                       cumulative arsenic exposure
 etween 1928 and 1967 and                                      (mg/m3 · year) with smoking
were followed for vital status   - Smoking histories:          standardised relative risks
 947-1981.                       obtained by postal            ranging from 0.7 to 8.7 in
 he vital status of all but 15   questionnaires sent to a next different exposure groups. A
0.4%) of them was verified.      of kin and supplemented by negative confounding by
                                 telephone interviews.         smoking was suggested in the
 Cases: 103 subjects dying       Individuals were assigned highest exposure group.
rom lung cancer and an           to a smoking category
 dditional four cases during the depending on the amount of
 bservation period.              tobacco smoked per day.
                                 Quantitative information on
 Controls: two deceased          smoking habits was
 ontrols (deaths from all causes obtained for only 102 cases
 ther than lung cancer) per case (95.3%) and for 190
214 controls in total) from the  controls (88.8%).
 ohort; matched on year of
 irth.
 10           Arsenic and inorganic arsenic compounds
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<pre> 30 male lung cancer cases and  Cumulative total exposure      Increased risk of lung cancer  Chen and Chen, 2002 228
 27 controls from a cohort of   to dust and cumulative         was related to cumulative      A significant excess was found
 855 subjects employed at least exposure to arsenic            exposure to dust, duration of  even in the lowest exposure
  year between 1972 and 1974    calculated for each person     exposure, cumulative           category (mean arsenic
n four tin mines in China.      based on industrial hygiene    exposure to arsenic, and       concentration about 3.7 µg/m3 and
  he cohort was followed up to  records.                       tobacco smoking.               mean cumulative arsenic exposure
he end of 1994. There were 91   - Respirable concentration     The ORs (adjusted for          about 46.6 µg/m3·year).
miners (1.2% of whole cohort)   of arsenic in three tin mines  smoking) for different groups  According to the authors, the
 onsidered lost to follow-up.   in Dachang (µg/m3):            of cumulative arsenic          carcinogenic effect of crystalline
                                No: 1.1 (0.1-2.7)              exposure (µg/m3·year) were:    silica cannot be excluded in this
                                Low: 3.0 (1.0-4.9)             0.1-99.9: 2.1 (95% CI 1.1 to   study. High correlations between
                                Medium: 3.5 (2.4-4.7)          3.9)                           exposure to arsenic and exposure
                                High: 10.2 (1.9-38.3)          100-499.9: 2.1 (95% CI 1.1 to  to dust or silica prevented from
                                - Respirable concentration     3.9)                           adjustment for any of these values.
                                of arsenic in the tin mines in 500-999.9: 1.8 (95% CI 1.0 to  Furthermore, exposure assessment
                                Limu (µg/m3):                  3.6)                           for arsenic began in the 1980s,
                                Medium: 0.5 (0.36-0.7)         ≥ 1000: 3.6 (95% CI 1.8 to     while total dust concentration
                                High: 1.2 (1.16)               7.3).                          greatly decreased from the 1950s
                                                               It should be pointed that the  to the 1980s. Therefore, the
                                - Cumulative exposures to      percentages of smokers in      cumulative exposure to arsenic
                                arsenic (µg/m3·year) were      both cases and controls were   may have been underestimated or
                                derived:                       high (88.5% in lung cancer     overestimated in the earlier years.
                                0.1-99.9                       cases and 82.5% in controls).
                                100-499.9                      However, the adjusted ORs      Because the aim of this analysis
                                500-999.9                      did not differ from non-       was to show an absence of an
                                ≥ 1000                         adjusted ORs.                  association between respirable
                                                                                              silica and lung cancer and not to
                                Using questionnaires,                                         determine an exposure response
                                information was obtained                                      association between arsenic
                                on tobacco smoking.                                           exposure and lung cancer, the
                                                                                              exposure assessment to arsenic
                                                                                              should be interpreted more on a
                                                                                              relative than an absolute scale.
A cohort of 12,011 males        The two-stage clonal           Higher than expected lung      Hazelton et al., 200139
working for the Yunnan Tin      expansion model was used cancer rates for Yunnan tin          Confounding by:
Corporation, with complete      to analyse lung cancer         miners were found even in      - environmental exposure to
 xposure records, who were      mortality based on             groups with no or low          arsenic
nitially surveyed in 1976 and individual histories with        occupational arsenic           - arsenic in drinking water
 ollowed through 1988. There multiple exposures to             exposure. Detailed analysis of - poor nutritional intake (reduced
were 842 lung cancer deaths in arsenic, radon, cigarette       exposure however, showed       intake of yellow and green
his restricted group during the smoke, and pipe smoke.         that for this population more vegetables and tomatoes) cannot
 eriod of observation.                                         factors may be associated      be excluded.
                                                               with lung cancer. 15.8% of the
                                                               lung cancer deaths was
                                                               attributable to arsenic
                                                               exposure. Arsenic was
                                                               considered almost as potent as
                                                               tobacco for the risk of lung
                                                               cancer.
              Human data                                                                                                     211
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<pre>  ases:                           A full occupational history  A small, non-significant       Matos et al., 2000229
 99 men with lung cancer          was collected through        increased risk for lung cancer The risk for occupational exposure
residents in the city of Buenos   interviewing.                was observed after long-term   was adjusted for hospital of
Aires; admitted for treatment in  Exposure to arsenic,         exposure to arsenic.           admission, group of age, pack-
 ospitals of Buenos Aires city    asbestos, chromium, dust,                                   years of cigarettes, and
 uring March 1994 to March        nickel, and polynuclear                                     employment in other occupations /
 996)                             aromatic hydrocarbons was                                   industries with increased risks.
  ontrols:                        assessed by means of a job-
 93 male subjects who had         exposure matrix.                                            Selection bias and information
 een hospitalised for conditions                                                              bias cannot be excluded.
 nrelated to tobacco use during
he same period and were
esidents in the same area.
 wo male controls were
matched with the exception of
hree cases that were matched
with only one control subject.
A cohort of 3979 smelter          In the subcohorts, arsenic   Standardised Cancer            Englyst et al., 2001230
workers employed for at least 1   exposure in lung cancer      Incidence Rates (SIR) 1958-    It has not been possible to separate
 ear between 1928 and 1979,       cases was assessed in detail 1987 were calculated relative  the carcinogenic effects of lead
 nd also exposed to lead and      based on occupational        to county rates. Lung cancer   and arsenic, but a possible
ncluded in the Blood Lead         hygiene information from     incidence was raised in both   interaction between these metals
  egister that was started at the the company.                 subcohorts (Lead subcohort 1:  may be involved in explaining the
 melter in 1950. Two              A detailed study of arsenic  SIR 2.4; 95% CI 1.2-4.5;       carcinogenic risks.
 ubcohorts were formed from       exposure in the 10 lung      Lead subcohort 2: SIR 3.6;
he original cohort. One           cancer cases in these two    95% CI 1.2-8.3).
 onsists of 710 workers           subcohorts revealed that all
 mployed at the lead              but one of these cases had a
 epartments (Lead subcohort       significant exposure also to
 ), and the other of 383 workers  arsenic.
 mployed at the lead
 epartments (Lead subcohort
 ), but never at other works
where an excess lung cancer
isk was previously identified.
A cohort of 1462 males who        Exposure included lead,      Lung cancer mortality was      Binks et al., 2005104
 ad been employed in a UK tin     arsenic, cadmium.The         significantly elevated (SMR    The risk of lung cancer has been
 melter (Capper Pass, North       mortality of the cohort was  161, 95% CI 124-206, p <       enhanced by occupational
Humberside) for at least 12       compared against that        0.001, 62 deaths).             exposure to one or more
months between 1/11/1967 and      expected for both national                                  carcinogens, the effect of which
 8/7/1995, followed up through    and regional populations.                                   diminishes with time since
 1/12/2001.                                                                                   exposure
 12            Arsenic and inorganic arsenic compounds
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<pre>A cohort of 1462 males who        Exposure matrices for        No significant associations     Jones et al., 2007105
 ad been employed in a UK tin     arsenic, cadmium, lead       could be found between lung     The excess relative risk
 melter (Capper Pass, North       were established. Lung       cancer mortality and simple     diminishes with time since
Humberside) for at least 12       cancer mortality was         cumulative exposure to any of   exposure and attained age.
months between 1/11/1967 and      examined in relation to      the substances studied. When
 8/7/1995, followed up through    cumulative inhalation        cumulative exposures were
 1/12/2001 (same cohort as in     exposure.                    weighted according to time
  inks et al. 2005)                                            since exposure and attained
                                                               age, significant associations
                                                               were found between lung
                                                               cancer mortality and exposure
                                                               to arsenic, lead and antimony.
A cohort of 625 male workers      Detailed work histories      There was a statistically       Sorahan 2009106
rom a US cadmium recovery         were available providing     significant (p < 0.05) negative The findings are consistent with
 lant in Colorado; employees      data on exposure to          trend in lung cancer            the hypothesis that arsenic is a late
were employed for at least 6      cadmium and arsenic..        standardized mortality ratios   stage human carcinogen
month between 1 January 1940      Mortality (1940-2001) from in relation to period from
 nd 31 December 1969 (same        lung cancer was compared ceasing arseninc exposure.
 ohort as in Stayner et al. 1991) with US national mortality
                                  rates.
A cohort of 625 male workers      Air monitoring data on       Excess in mortality from lung   Stayner et al.,1992107
rom a US cadmium recovery         cadmium exposure were        cancer was observed for the
 lant in Colorado; employees      available. Detailed work     entire cohort (SMR 149, CI
were employed for at least 6      histories were available.    95% 95-222
month between 1 January 1940      Cumulative exposure for
 nd 31 December 1969              each worker was estimated.
A cohort of 602 male workers      Air monitoring data on       Mortality from respiratory      Thun et al., 1985108
rom a US cadmium recovery         cadmium exposure were        cancer and non-malignant
 lant in Colorado; employees      available. Detailed work     gastrointestinal disease was
were employed for at least 6      histories were available.    significantly greater among
month between 1 January 1940      Cumulative exposure for      the cadmium workers than
 nd 31 December 1969              each worker was estimated. would have been expected
                                                               from US rates.
A cohort of 8014 white males,     Reanalysis of the            RR’s for respiratory cancer     Lubin et al., 20082
who were employed in the          relationship between         increased linearly with         This pattern implied that for equal
Anaconda copper smelter for ≥     respiratory cancer mortality cumulative arsenic exposure     cumulative arsenic exposure, the
 2 months before 1957. Vital      and cumulative inhaled       when analyzed for specific      RR of respiratory cancer mortality
 tatus was followed from 1        arsenic exposure among       concentrations and              was greater for cumulative arsenic
 anuary 1938 to 31 December       copper smelter workers.      concentration ranges of         exposure delivered at higher
 987; a total of 4930 (62%)                                    arsenic (0.29 mg/m3; 0.30-      concentration for shorter duration
were deceased (Same cohort as                                  0.39 mg/m3; 0.40-0.49 mg/       compared with cumulative
n Lubin et al. 2000).69                                        m3; ≥ 50 mg/m3). The slope of   exposure delivered at lower
                                                               the linear exposure-response    concentration for longer duration.
                                                               relationship increased with
                                                               increasing arsenic
                                                               concentration.
               Human data                                                                                                      213
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<pre> able 15 Human reproduction and developmental studies of arsenic and arsenic compounds.
  tudy population       Exposure assessment            Effects                                References/Remarks
nhalation
No additional data
 vailable
Oral
 24 infants from        Drinking water arsenic levels: After controlling for confounders Hopenhayn et al., 2003231
Antofagasta (Chili)     40 µg/L (city: Antofagasta)    (gestational age, parity, infant sex,
 nd 420 from            and <1 µg/L (city: Valparaiso) maternal age, maternal height,
  alparaiso (Chili)                                    smoking, BMI, adequacy of
final study group).                                    prenatal health care and income),
  regnancy and birth                                   results of the multivariable
nformation was                                         analysis indicated that
 btained from medical                                  Antofagasta infants had lower
ecords.                                                mean birth weight (-57 g; 95% CI
  he birth weight                                      -123 to 9).
 nalysis was restricted
o liveborn, singleton
nfants born between
December 1998 and
  ebruary 2000.
 33 women from areas The range of measured arsenic Excess risks for spontaneous               Milton et al., 2005141
n Bangladesh using concentration in tube well          abortion and stillbirth were           The study had some limitations:
ube wells with known water ranged from non-            observed among the participants - recall bias with regard to
 rsenic concentrations detectable to 1710 µg/L.        chronically exposed to higher          documentation of pregnancy
                                                       concentrations of arsenic in           outcomes;
                                                       drinking water after adjusting for - the available water samples
                                                       participant's height, history of       reflected only a particular point in
                                                       hypertension and diabetes, and         time and not the historical exposure
                                                       (for neonatal death only) age at       (assumption: arsenic concentration
                                                       first pregnancy. Comparing             from the tube wells had been
                                                       exposure to arsenic concentration relatively constant over time);
                                                       of greater than 50 µg/L with 50        - information for only 1 well for each
                                                       µg/L or less, the ORs were 2.5         woman was available, and so her
                                                       (95% CI =1.5-4.3) for                  cumulative duration of arsenic
                                                       spontaneous abortion, 2.5 (1.3-        exposure could not include exposure
                                                       4.9) for stillbirth, and 1.8 (0.9-3.6) from other wells, although 1 of the
                                                       for neonatal death.                    eligibility criteria for study
                                                                                              participation was having lived in the
                                                                                              study area since their marriage;
                                                                                              - the amount of drinking water
                                                                                              consumed was also not considered in
                                                                                              this study.
  rospective cohort     Arsenic exposure was           Significant negative dose effects Rahman et al., 2009144
 tudy, based on 1,578 assessed by analysis of arsenic were found with birth weight and
mother-infant pairs, in in urine collected at around   head and chest circumferences at
Matlab, Bangladesh      gestational weeks 8 and 30.    a low level of arsenic exposure
                                                       (<100 µg/L in urine).
  14          Arsenic and inorganic arsenic compounds
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<pre> opulation-based     Arsenic concentrations in spot No significant effect of arsenic Tofail et al., 2009143
 ohort study with    urine specimens at 8 and 30    exposure during pregnancy on     It is possible that other effects are as
 ,436 pregnant       weeks of pregnancy were 81     infant development (motor, PST   yet unmeasured or that effects will
women in Matlab,     µg/L (range 37-207) and 84     score and behaviour rating) was  become apparent at a later age.
  angladesh (an area µg/L (range 42-230)            detected.
with high-arsenic    respectively.
 ontaminated tube
wells) and 1,799
nfants born to these
mothers.
             Human data                                                                                                 215
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<pre>16 Arsenic and inorganic arsenic compounds</pre>

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<pre> nnex        H
             Animal data
             (additional data, if not further specified)
 able 16 Animal in vitro studies with arsenic and arsenic compounds.
Animal cell type Procedure           Concentration      Effects                                                     Reference
                                     tested
 at hepatocytes Investigation to AsIII,                 The estimated IC(50) was >>100 µM for AsIII, approx. 10 Lin et al.,
cultured)         the effect of      monomethylarso µM for ATG, and approx. 3 µM for monomethylarsonous 200157
                  arsenicals on      nous acid: 1-50 acid. In hepatocytes exposed to 1 µM
                  thioredoxin        µM;                monomethylarsonous acid for up to 24 h, the inhibition of
                  reductase (TR) aurothioglucose TR activity was maximal (approximately 40%) after
                  (an NADPH-         (ATG, a            exposure for 15 min.
                  dependent          competitive        After exposure for 3 h [when most monomethylarsonous
                  flavoenzyme        inhibitor of TR acid has been converted to dimethylarsinic acid], TR
                  (plays an          activity): 1-100 activity in these cells had returned to control levels.
                  important role in µM                  Notably, exposure of the cell to 50 µM dimethylarsinous
                  the cellular                          acid did not affect TR activity. In hepatocytes exposed to
                  response to                           10 µM AsIII for up to 24 h, the inhibition of TR activity
                  oxidative stress)                     was progressive; at 24 h, activity was reduced
                                                        approximately 35%.
                                                        Following exposure to AsIII or monomethylarsonous acid,
                                                        the extent of inhibition of TR activity correlated strongly
                                                        with the intracellular concentration of
                                                        monomethylarsonous acid.
             Animal data                                                                                                   217
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<pre> able 17 Short-term animal toxicity studies of arsenic and arsenic compounds.
 pecies/Strain/   Exposure          Concentration      NOAELa           LOAELb (Critical) effects    References/
No. per Sex per duration            tested                                                           Remarks
Group
nhalation
New Zealand       8 hr/day, 7 days/ Arsenic trioxide: 1.1 mg/m3         -      There were no         Beck et al. (2002)38
white rabbits/    week for 8        0.05, 0.1, 0.22,                           significant clinical  Remark: Since the
 =6/sex/          weeks             or 1.1 mg/m3                               findings or           major objective of
 oncentration                       (MMAD ranged                               consistent changes    this study was
                                    from 3.2 to 4.1                            in body weight        toxicokinetics, only
                                    µm)                                        associated with any   clinical findings and
                                                                               of the exposure       body weight were
                                                                               group.                investigated.
Oral
No data available
Dermal
No data available
 NOAEL = No Observed Adverse Effect Level
 LOAEL = Lowest Observed Adverse Effect Level
 able 18 Long-term animal toxicity studies of arsenic and arsenic compounds.
 pecies/Strain/   Exposure          Concentration      NOAELa           LOAELb (Critical) effects     References/
No. per Sex per duration            tested                                                            Remarks
Group
nhalation
No data available
Oral
Mice (C57Bl/6J)/ 12 months          0, 100, 250 and 65.0 µg/kg          -      No tumours were        Wu et al, 200450
 =70 females/                       500 µg AsV/L        bw/day                 observed; no           Remark: Since the
 ose                                (13, 32.5 and                              significant effect on  major objective of
                                    65.0 µg/kg bw/                             the growth rate and    this study was to
                                    day) in drinking                           on the water           detect biomarker
                                    water as sodium                            consumption of the     changes, no more
                                    arsenate ad                                treated animals        toxicological
                                    libitum                                    compared to            investigations were
                                                                               controls; no           performed.
                                                                               abnormal appearance
                                                                               or behaviour was
                                                                               observed.
Dermal
No data available
 NOAEL = No Observed Adverse Effect Level
 LOAEL = Lowest Observed Adverse Effect Level
 18          Arsenic and inorganic arsenic compounds
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<pre> able 19a Genotoxicity of arsenic and arsenic compounds in animals (in vitro data).
 est system Procedure                       Arsenic species/Dose/       Result                               References/
                                            Concentration                                                    Remarks
 X174 RFI A DNA nicking assay (2 h          AsIII: 1 nM - 300 mM;       Both methylated trivalent arsenicals Mass et al.,
DNA         incubation at 37 oC) (pH 7.4); AsV: 1 µM - 1 M;             were able to nick and/or completely  200158
super-                                      MAsv: 1 µM - 3 M;           degrade фX174 DNA depending on
 oiled)                                     dimethylarsinic acid: 0.1   concentration. monomethylarsonous
                                            mM - 300 mM;                acid was effective at nicking фX174
                                            monomethylarsonous acid: DNA at 30 mM; however, at 150 µM
                                            10 mM - 60 mM;              dimethylarsinous acid, nicking could
                                            dimethylarsinous acid: 40   be observed.
                                            µM - 10 mM
Mice        Mouse lymphoma L5178Y           Synthetic                   Mutation by AsMeO was seen down      Mass et al.,
            TK+/- assay                     monomethylarsonous acid to 0.5 µM (30 to 100 fold more potent    200159
                                            and dimethylarsinous acid, than arsenite)
                                            as AsMeO and AsMe2I
 trains     Ames assay                      Synthetic                   -                                    Mass et al.,
 A98,                                       monomethylarsonous acid                                          200159
 A100 and                                   and dimethylarsinous acid,
 A104                                       as AsMeO and AsMe2I
            Prophage-induction assay that Synthetic                     AsMe2I induced SOS repair at ~5 µM   Mass et al.,
            detects SOS repair              monomethylarsonous acid                                          200159
                                            and dimethylarsinous acid,
                                            as AsMeO and AsMe2I
solated     Induction of oxidative DNA As(III), monomethylarsonic Only dimethylarsinous acid (> or =10       Schwerdtle
 M2 DNA damage measuring                    acid, monomethylarsonous µM) generated DNA strand breaks in      et al., 200394
            frequencies of DNA strand       acid, dimethylarsinic acid, the absence of Fpg-sensitive sites.
            breaks and lesions recognised dimethylarsinous acid
            by the bacterial
            formamidopyrimidine-DNA
            glycosylase (Fpg).
            Animal data                                                                                                219
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<pre>hinese     Cytotoxic effects by the     AsV, AsIII,                Viability was significantly decreased Dopp et al.,
amster     trypan blue extrusion test;  monomethylarsonic acid,    after incubation (1 h) of the cells with 200461
vary cells                              monomethylarsonous acid,   > or = 1 µM AsIII, > or = 1 µM AsV, >
                                        dimethylarsinic acid,      or = 500 µM monomethylarsonous
                                        dimethylarsinous acid and  acid, > or = 100 µM
                                        TMAOV:                     monomethylarsonic acid, and 500 µM
                                        0.1 µM to 10 mM for 30 min dimethylarsinic acid and > or = 0.1
                                        and 1 h                    µM dimethylarsinous acid. TMAOV
                                                                   was not cytotoxic at concentrations up
                                                                   to 10 mM.
           Genotoxic effects:                                      A significant increase of the number
           micronucleus (MN) induction,                            of MN, CA and SCE was found for
           chromosome aberrations                                  dimethylarsinous acid and
           (CA), and sister chromatid                              monomethylarsonous acid. AsIII and V
           exchanges (SCE);                                        induced CA and SCE but no MN.
                                                                   TMAOV, monomethylarsonic acid and
                                                                   dimethylarsinic acid were not
                                                                   genotoxic in the concentration range
                                                                   tested (up to 5 mM).
           Intracellular arsenic                                   0.03% monomethylarsonic acid and
           concentrations were                                     dimethylarsinic acid, 2%
           determined by ICP-MS                                    monomethylarsonous acid, AsIII and
           techniques.                                             AsV and 10% dimethylarsinous acid
                                                                   were taken up by the cells. The total
                                                                   intracellular concentration of all
                                                                   arsenic compounds increased with
                                                                   increasing arsenic concentrations in
                                                                   the culture medium.
20         Arsenic and inorganic arsenic compounds
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<pre>Horse   Iron mobilisation assays The assay system (total      Dimethylarsinic acid and               Ahmad et al.,
 pleen                           volume 2.0 ml) contained     dimethylarsinous acid significantly    2000157
erritin                          horse spleen ferritin (100   released iron from horse spleen
                                 mg), ferrozine (0.5 mM),     ferritin either with or without the
                                 and the test chemical        presence of ascorbic acid, a strong
                                 (arsenate/arsenite/mono-     synergistic agent. Ascorbic acid-
                                 methylarsonic acid/          mediated iron release was time-
                                 dimethylarsinic acid/        dependent as well as both
                                 monomethylarsonous acid/     dimethylarsinous acid and ferritin
                                 dimethylarsinous acid)       concentration-dependent. Iron release
                                 (each 10 mM)) with or        from ferritin by dimethylarsinous acid
                                 without of the ascorbic acid alone or with ascorbic acid was not
                                 (1 mM) in 10 mM phosphate    significantly inhibited by superoxide
                                 buffered saline (pH 7.4);    dismutase (150 or 300 units/mL).
                                                              However, the iron release was greater
                                                              under anaerobic conditions (nitrogen
                                                              gas), which indicates direct chemical
                                                              reduction of iron from ferritin by
                                                              dimethylarsinous acid, with or without
                                                              ascorbic acid.
        Bleomycin-dependent DNA  The assay system (total      The release of ferritiniron by
        damage                   volume 1.0 ml) contained 50 dimethylarsinous acid with ascorbic
                                 mg ferritin and              acid catalysed bleomycin-dependent
                                 dimethylarsinous acid (0-5 degradation of calf thymus DNA
                                 mM) with or without
                                 ascorbic acid (50 mM) in 10
                                 mM of phosphate-buffered
                                 saline (pH 7.4).
 lasmid Iron mobilisation assays The assay system contained No pBR322 plasmid DNA damage             Ahmad et al.,
 BR322                           500 ng pBR322 DNA,           was observed from exposure AsV,        2002158
DNA                              arsenic species (0-1.0 mM), AsIII, monomethylarsonic acid,
                                 HLF (10 µg), ascorbic acid monomethylarsonous acid or
                                 (25 µM), DTPA (5 mM) or dimethylarsinic acid alone.
                                 oxyradical scavengers (such DNA damage was observed following
                                 as SOD (150 units), catalase dimethylarsinous acid exposure;
                                 (50 units), D-mannitol (5    coexposure to dimethylarsinous acid
                                 mM), potassium iodide (5 and HLF caused more DNA damage;
                                 mM), sodium azide (5 mM)) considerably higher amounts of DNA
                                 in 10 mM phosphate-          damage was caused by coexposure of
                                 buffered saline (pH 7.4).    dimethylarsinous acid, HLF and
                                                              ascorbic acid.
                                                              Diethylenetriaminepentaacetic acid
                                                              (an iron chelator), significantly
                                                              inhibited DNA damage. Addition of
                                                              catalase (which can increase Fe2+
                                                              concentrations) further increased the
                                                              plasmid DNA damage.
        Animal data                                                                                          221
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<pre> able 19b Genotoxicity of arsenic and arsenic compounds in animals (in vivo data).
 est system              Dose / concentration     End point                Result                                References
Mice (Swiss albino) /    0 and 2.5 mg/kg bw       Total chromosome         Sodium arsenite produced              Poddar et
 =6 females/dose         sodium arsenite          aberrations and number significantly high frequencies of       al., 2000161
                         (exposure for 24 h)      of chromosome breaks chromosome aberrations as
                                                  per cell (50 clear       compared with negative control
                                                  metaphase with normal following exposure.
                                                  chromosome number,
                                                  2n=40 were examined
                                                  from each animal)
Mice (male ddY)/n=       single gavage dose: 15.2 DNA oxidation            When the same dose of As as           Yamanaka
 /dose                   mg (11.5 mg As)/kg                                arsenite or dimethylarsinic acid was  et al.,
                         arsenite;                                         administered to ddY-strain mice, the  2001162
                         21.1 mg (11.5 mg As)/                             amount of 8-oxodG (a biomarker of
                         kg dimethylarsinic acid                           DNA oxidation) was significantly
                                                                           higher in the urine after 9 hour of
                                                                           mice exposed to dimethylarsinic
                                                                           acid.
Mice (male ddY)/n=       400 ppm                  DNA oxidation            The amount of 8-oxodG (a
 /dose                   dimethylarsinic acid in                           biomarker of DNA oxidation) was
                         drinking water (for 4                             significantly increased not only in
                         weeks)                                            lung and liver, but also, though not
                                                                           significantly, in urinary bladder. No
                                                                           increase in 8-oxodG was observed
                                                                           in spleen or kidney.
Mice (female HR-1        400 ppm                  DNA oxidation            A significant increase in the amount
 airless)/n=5/dose       dimethylarsinic acid in                           of 8-oxodG in dorsal epidermis.
                         drinking water (for 2
                         weeks)
Ovarian tissue in female 50, 100, 200 ppm         DNA damage measure Decrease in mean comet length,              Akram et
ats                      sodium arsenite in       by comet assay           height, comet head diameter and       al., 2009160
                         drinking water for 28                             %DNA in comet head of high dose
                         days                                              group.
                                                                           Dose-dependent increase in mean
                                                                           comet tail lengthe, %DNA in tail
                                                                           and tail moment in high dose
                                                                           groups.
Mutamouse (a transgenic DMA 10.6 mg/day for 5 Mutation frequency in        Weak increase in mutation             Noda et al.,
mouse model)             consecutive days         lacZ transgene and cII   frequency in lung, but not in bladder 2002163
                                                  gene                     and bone marrow
 22          Arsenic and inorganic arsenic compounds
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<pre>nnex I
     Evaluation of the Subcommittee on
     Classification of carcinogenic
     substances
     Scope
     On request of the Dutch Expert Committee on Occupational Safety of the Health
     Council, the Subcommittee on the Classification of carcinogenic substances
     evaluates the carcinogenic properties of arsenic and arsenic compounds.
         In the Netherlands a special policy is in force with respect to occupational
     use and exposure to carcinogenic substances. Regarding this policy, the Minister
     of Social Affairs and Employment has asked the Health Council of the
     Netherlands to evaluate the carcinogenic properties of substances, and to propose
     a classification with reference to the appropriate EU-directive (see Annex J). In
     addition to classifying substances, the Health Council also assesses the genotoxic
     properties of the substances in question.
         The members of the Subcommittee on Classification of carcinogenic
     substances are listed at the end of this annex. The evaluation is based on the data
     summarized in the first part of the present report of DECOS.
     Carcinogenicity of arsenic and arsenic compounds
     Inorganic arsenic is the cause of human malignancies, and is classified as a
     human carcinogen (Group 1) by the International Agency for Research on
     Cancer (IARC).1,2
     Evaluation of the Subcommittee on Classification of carcinogenic substances         223
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<pre>       Inhalation is the primary route of occupational exposure to arsenic and
   occurs in industries such as mining, smelting, wood preservation, production and
   application of arsenic-based pesticides, and electronics. Non occupational
   exposure occurs mainly through food, but also in the drinking water in areas with
   high levels of arsenic (e.g. Taiwan, Bangladesh).2
       Epidemiological studies of populations occupationally exposed to arsenic
   consistently demonstrate an excess lung cancer risk.3,4 In addition,
   epidemiological studies consistently show that oral exposure to arsenic via
   drinking water increases the risk of skin and urinary bladder cancer.2,3 Evidence
   also suggests a relationship between oral arsenic exposure via drinking water and
   cancer of kidney, liver and prostate, but these studies are not consistent.2,3 Based
   on the compelling evidence from epidemiologic studies, the Subcommittee
   recommends classifying inorganic arsenic compounds as ‘known to be
   carcinogenic to humans’ (category 1A) according to the new classification
   system of the Health Council (comparable with EU category 1A according to the
   newly implemented Globally Harmonized System) (see Annex J).
   Mechanism of genotoxicity
   Several studies have been published on the genotoxic potential of inorganic
   arsenic and its methylated metabolites. Especially the trivalent metabolites
   monomethylarsonous acid and dimethylarsinous acid may play a role in the
   development of cancer.2,8 From these studies various genotoxic processes could
   explain carcinogenic activity. For instance:
   1 arsenicals can bind to thiol-groups in proteins which may lead to inhibition of
       e.g. DNA repair enzymes5
   2 arsenic exposure can result in hypo- or hypermethylation of cellular DNA.
       These changes can be caused by e.g. an effect of arsenic on DNA
       methyltransferases5
   3 arsenic does not generate reactive oxygen by itself but inhibits the
       scavenging systems of reactive oxygen species. This leads indirectly to the
       increase of reactive oxygen species.6
   All three abovementioned processes support a non-stochastic genotoxic
   mechanism. Although inorganic arsenic is able to produce chromosomal effects
   (aberrations, sister chromatid exchange) in many in vitro and in vivo systems3,7,
   no overt signs of stochastic genotoxic activity of inorganic arsenic have been
   found. Inorganic arsenic does not covalently bind to DNA7 and does not induce
   point mutations in bacterial or mammalian test systems3,7.
24 Arsenic and inorganic arsenic compounds
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<pre>     Therefore, the overall mechanistic evidence supports the view that
genotoxicity is not caused by a direct effect of inorganic arsenic on the DNA, but
via other processes which are triggered by arsenic. The Subcommittee concludes
therefore that the genotoxic mechanism of inorganic arsenic should be
considered as non-stochastic.
As arsenic and arsenic compounds have non-stochastic genotoxic mechanisms,
an exposure limit should be derived using a threshold model. However, the
epidemiological studies3,4 on arsenic and cancer do not report exposure-effect
relations that allow derivation of such a threshold. Therefore the Subcommittee
advised to apply linear extrapolation to establish a health based reference value.
References
Some drinking-water disinfectants and contaminants, including arsenic. Monograph 84, International
Agency for Research on Cancer (IARC), 2004.
Straif K, Benbrahim-Tallaa L, Baan R, Grosse Y, Secretan B, El Ghissasi F, Bouvard V, Guha N,
Freeman C, Galichet L, Cogliano V. A review of human carcinogens - Part C: metals, arsenic, dusts
and fibres. The Lancet Oncology 2009; 10: 453-454 (gives a summary of the reassessments awaiting
publication in Monograph 100, International Agency for Research on Cancer (IARC).
Toxicological profile for arsenic. Agency for Toxic Substances and Disease Registry (ATSDR), US
Department of Health and Human Services, August 2007.
Lubin JH, Moore LE, Fraumeni JF, Cantor KP. Respiratory cancer and inhaled arsenic in copper
smelters workers: a linear relationship with cumulative exposure that increases with concentration.
Environmental Health Perspectives 2006; 116 (12): 1661-1665.
Kitchin KT, Wallace K. The role of protein binding of trivalent arsenicals in arsenic carcinogenesis
and toxicity. Journal of Inorganic Biochemistry 2008; 102 (3): 532-539.
Hughes MF, Kitchin KT. Arsenic, oxidative stress, and carcinogenesis. In: Oxidative stress, disease
and cancer (K.K. Singh ed), Imperial College Press, London, 2006, pp825-850.
Scientific opinion on arsenic in food. (European Food Safety Authority (EFSA), EFSA Panel on
Contaminants in the Food Chain, october 2009), EFSA Journal 2009; 7(10); 1351-1549.
Wnek SM, Jensen TJ, Severson PL, Futcher BW, Gandolfi AJ. Monomethylarsonous acid produces
irreversibel events resulting in malignant transformation of a human bladder cell line following 12
weeks of low-level exposure. Toxicological Sciences 2010; 116 (1): 44-57.
The Subcommittee
•    G.J. Mulder, chairman
     Emeritus Professor of Toxicology, Leiden University
Evaluation of the Subcommittee on Classification of carcinogenic substances                          225
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<br><br>====================================================================== Pagina 226 ======================================================================

<pre>   •  P.J. Boogaard
      Toxicologist, Shell International BV, The Hague
   •  M.J.M. Nivard
      Molecular Biologist and Genetic Toxicologist, Leiden University Medical
      Center
   •  G.M.H. Swaen
      Epidemiologist, Dow Benelux NV, Terneuzen
   •  R.A. Woutersen
      Toxicologic Pathologist, TNO Quality of Life, Zeist, and Professor of
      Translational Toxicology, Wageningen University and Research Centre,
      Wageningen
   •  A.A. van Zeeland
      Emeritus Professor of Molecular Radiation Dosimetry and Radiation
      Mutagenesis, Leiden University Medical Center
   •  E.J.J. van Zoelen,
      Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
   •  G.B. van der Voet, scientific secretary
      Health Council of The Netherlands
   Meeting date: 07 June 2010
26 Arsenic and inorganic arsenic compounds
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<pre> nnex        J
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                67/548/EEC            EC No 1272/2008
                                                                                before                as from
                                                                                12/16/2008            12/16/2008
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be carcinogenic to humans.             2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.232
             Carcinogenic classification of substances by the Committee                                                227
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<pre>28 Arsenic and inorganic arsenic compounds</pre>

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<pre>nnex K
     Evaluation of the Subcommittee on
     the Classification of reprotoxic
     substances
     As yet only one inorganic arsenic compound, lead arsenate, has been classified
     for reproduction toxicity according to EC regulations (Repr 1A; H360DF - may
     damage fertility or the unborn child).1 However, for this compound, the
     reproduction toxicity is probably more related to lead than to arsenic. The ECHA
     website (European Chemicals Agency) recently reported that data on
     reproduction toxicity of diarsenic trioxide (AsIII) and arsenic acid (AsV) are not
     sufficient for classification for reproduction toxicity (see website European
     Chemicals Agency, http://echa.europa.eu/). Nonetheless, the ECHA website
     reports for arsenic acid a ‘self-classification’ (suspected of damaging fertility or
     the unborn child).
     Effects on fertility
     In humans no effects of arsenic on fertility have been observed upon inhalatory
     or oral exposure. No fertility effects in experimental animals have been reported
     after inhalatory exposure. However, a number of oral and parenteral studies was
     available (Wang et al. 20062) reporting effects on fertility in male and female
     animals.
         Arsenic trioxide (AsIII). In male mice, oral administration of arsenic trioxide
     (30 days) interferes with spermatogenesis (decreased sperm count, decrease of
     activity of 22 spermatogenetic enzymes 3ß- en 17ß-HSD, interference with
     cholesterol metabolism, 23 degeneration of tubules)(Chinoy et al., 20043).
     Evaluation of the Subcommittee on the Classification of reprotoxic substances        229
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<pre>       Sodium arsenite (AsV). Oral administration of sodium arsenite to male mice
   (35 days) resulted in a significant decrease in sperm count and motility, increase
   in abnormal sperm and interference with activity of spermatogenetic enzymes
   (17 ß-HSD)(Pant et al., 20014). In a chronic study Pant et al. (2004)5
   administered sodium arsenite to male mice via drinking water for 365 days. This
   caused a decrease in the absolute and relative testicular weight, a decrease in
   activity of marker testicular enzymes (sorbitol dehydrogenase, phosphatase), and
   in increase of LDH and γ-GT activity. In addition, a decrease in sperm count and
   sperm motility, along with an increase in abnormal sperm, was observed.
   Intraperitoneal administration of sodium arsenite to male rats for 26 days (Sarkar
   et al. 20036) resulted in a decrease in testicular weight, accessory sex organ
   weights and epididymal sperm counts, plasma luteinizing hormone (LH), follicle
   stimulating hormone (FSH), and testosterone. In addition, massive degeneration
   of all the germ cells was observed.
       Oral administration of sodium arsenite to female rats in diestrous phase for
   28 days (seven oestrous cycles) (Chattopadhyay et al. 20017, 20038) caused a
   significant reduction in the plasma levels of LH, FSH, and estradiol along with a
   significant decrease in ovarian activities of 3ß-HSD and 17ß-HSD followed by a
   reduction in ovarian and uterine peroxidase activities. A significant weight loss
   of the ovary and uterus was also observed.
   The effects on fertility in experimental animals are observed in oral and
   parenteral studies at relatively high dose levels in the absence of general toxic
   effects. The Subcommittee concludes that the data support the view that
   inorganic arsenic should be classified ‘as presumed human reproductive
   toxicant’ (category 1B) for effects on fertility (H360F).
   Effects on development
   A huge number of human studies, both occupational and environmental, is
   reported addressing the effect of arsenic as a developmental toxicant. Several
   (older) human studies have reported an association between inhalation or oral
   exposure to inorganic arsenic and increased risk of adverse developmental
   effects (congenital malformations, low birth weight, spontaneous abortion)(
   WHO 20009, ATSDR 200710, Nordström et al. 1978a11, 1978b12, 1979a13,
   1979b14, Aschengrau et al. 198915, Zierler et al. 198816). However, the
   Subcommittee observed that these (older) populations were co-exposed to a
   number of other chemicals beyond arsenic and that these chemicals may have
   contributed to the observed effects an that not all studies were well analyzed and
30 Arsenic and inorganic arsenic compounds
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<pre>designed (Aschengrau et al. 198915 and Zierler et al. 198816). Therefore these
studies did not unequivocally prove that arsenic is a developmental toxicant.
More recent epidemiological studies however, especially in populations in areas
of the world (Taiwan, Chile, Bangladesh/Bengal) with elevated levels of arsenic
in drinking water, report associations between developmental effects and chronic
exposure of women to arsenic in the drinking water.
     Taiwan. Yang et al. (2003)17 suggested that arsenic exposure from drinking
well water was associated, although not significantly, with the risk of preterm
delivery and reduction in birth weight.
     Chile. Associations have been found between late fetal mortality, neonatal
mortality, and postneonatal mortality and exposure to high levels of arsenic in the
drinking water (Hopenhayn-Rich et al. 200018). Hopenhayn et al. (2003)19
suggested that moderate arsenic exposures from drinking water (<50 µg/L)
during pregnancy are associated with reduction in birth weight. Significantly
increased SMRs were reported for lung cancer and bronchiectasis among
subjects who had probable exposure in utero or during childhood to high levels
of arsenic in the drinking water (Smith et al., 200620).
     Bangladesh/Bengal. Ahmad et al. (2001)21 showed that adverse pregnancy
outcomes in terms of spontaneous abortion, stillbirth, and preterm birth rates
were significantly higher in an exposed group than those in the nonexposed
group. Milton et al. (2005)22 observed excess risks for spontaneous abortion and
stillbirth among the chronically exposed study participants. Von Ehrenstein et al.
200623 observed that exposure to high concentrations of arsenic (≤ 200 µg/liter)
during pregnancy was associated with an increased risk of stillbirth and neonatal
death, while no association was found between arsenic exposure and
spontaneous abortion. Rahman et al. (2009)24 found negative dose effects with
birth weight and head and chest circumferences at a low level of arsenic
exposure (<100 µg/L in urine). Rahman et al. (2010)25 reported that the odds
ratio of spontaneous abortion was increased among women with elevated urine
arsenic concentrations and that the rate of infant mortality increased with
increasing arsenic exposure. Tofail et al. (2009)26 assessed infants born to arsenic
exposed mothers on two problem solving tests (PST) (the motor scale of the
Baley Scales of Infant Development, and behaviour ratings). No significant
effect of arsenic exposure during pregnancy on infant development (motor, PST
score and behaviour rating) was detected.
     The Subcommittee observes that these recent human studies have good
quality when compared to the earlier ones, and give strong indications that
exposure to arsenic may not be excluded as a causal factor for spontaneous
abortion, stillbirth, preterm delivery and reduced birth weight and also
Evaluation of the Subcommittee on the Classification of reprotoxic substances        231
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<pre>   neuropsychological development. The actual chemical form of arsenic in these
   human studies, be it airborne or in solution (AsIII, AsV), is never clearly reported.
   Numerous studies in animals showed that arsenic caused reduced birth weight, a
   variety of foetal malformations (both skeletal and soft tissue), and increased
   foetal mortality following inhalation exposure of mice and rats, oral exposure of
   mice, rats, hamsters and rabbits, and intraperitoneal or intravenous exposure of
   mice, rats and hamsters. The Subcommittee focussed on the evaluation of
   inhalation and oral studies in animals.
       Arsenic trioxide (AsIII). Only two inhalation studies were reported, with
   controversial results. Holson et al. (1999)27 administered as arsenic trioxide to
   rats. Maternal toxicity (rales, decrease in net body weight gain, a decrease in
   food intake during pre-mating and gestational exposure) was observed at the
   highest exposure level. No treatment-related malformations or developmental
   variations were noted at any exposure level. Nagymajtenyi et al. (1985)28
   exposed mice by inhalation to arsenic trioxide during gestation. The highest dose
   group had significant increases in the percentage of dead foetuses, skeletal
   malformations, and the number of foetuses with retarded growth. Stump et al.
   (1999)29 treated rats with a single oral dose of arsenic trioxide during gestation.
   Maternal food consumption was decreased dose-dependently. In the highest dose
   group body weight, body weight change, and net body weight change were
   significantly decreased. The highest dose resulted in a significant increase in
   postimplantation loss and a decrease in viable fetuses per litter. Holson et al.
   (2000)30 administered arsenic trioxide orally to rats beginning prior to mating
   and continuing through mating and gestation. Maternal toxicity in the highest
   dose group was evidenced by decreased food consumption and decreased net
   body weight gain during gestation, increased liver and kidney weights, and
   stomach abnormalities (adhesions and eroded areas). No treatment-related foetal
   malformations were noted in any dose group. Increased skeletal variations at the
   highest dose group were observed.
       Sodium arsenite (AsV). Baxley et al. (1981)31 treated pregnant mice by oral
   gavage and noted gross malformations (exencephaly, open eyes) in foetuses at
   the highest dose. Hood and Harrison (1982)32 treated hamsters by oral gavage
   and observed no effect on prenatal growth or survival at the highest dose on
   gestation days 9-11. However, when treated with the highest dose on gestation
   day 12, prenatal deaths increased, and growth was inhibited in the foetuses.
   Rodriguez et al. (2002)33 exposed rats to arsenite during gestation or postnatally
   and observed that animals showed increased spontaneous locomotor activity and
   increased number of errors in a delayed alternation task. Xi et al. (2009)34
32 Arsenic and inorganic arsenic compounds
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<pre>evaluated the developmental neurotoxicity of arsenic in offspring rats by
transplacental and early life exposure to sodium arsenite in drinking water and
reported that tail hung reflex, auditory startle and visual placing showed
signifcant decrease compared to the control group. In square water maze test
spatial learning and memory were affected.
    Arsenic acid /sodium arsenate (AsV). Nemec et al. (1998)35 evaluated effects
of oral exposure to arsenic acid in mice and rabbits. In the highest dose group in
mice an increase was detected in the number of resorptions per litter and
decreases in the number of live pups per litter, and mean fetal weight. At the
highest dose in rabbits prenatal mortality was increased; surviving does had signs
of toxicity, including decreased body weight. These data revealed an absence of
dose-related effects in both species at arsenic exposures that were not maternally
toxic. Hood et al. (1978)36 administered sodium arsenate orally to mice on during
gestation. Fetuses weighed significantly less than controls, prenatal mortality
was increased and fetal malformations and skeletal defects were seen. Hill et al.
(2008)37 evaluated the developmental toxicity of oral exposure of arsenate during
gestation in an inbred mouse strain, that does not exhibit spontaneous neural tube
malformations. There was no maternal toxicity as evidenced by losses in
maternal body weight following As treatment. However, liver weights were
lower in all As-treated groups, suggesting hepatotoxicity due to As exposure.
The number of litters affected with a neural tube defect (exencephaly) in each
treatment group exhibited a positive linear trend (vertebral and calvarial
abnormalities, components of the axial skeleton). Mean fetal weight of all As-
treated groups was significantly less than in control. This is the only study
proving that foetal malformations can develop in absence of maternal toxicity.
    The Subcommittee concludes that the oral and inhalatory animal studies
showed that arsenic, usually at maternally toxic doses, caused reduced birth
weight, a variety of foetal malformations (both skeletal and soft tissue), and
increased foetal mortality. In addition to the oral and inhalatory studies, the
Subcommittee evaluated a number of parenteral animal studies and observed
similar effects in offspring (Ferm and Carpenter, 196838; Willhite et al., 198139;
Beaudoin et al., 197440; Hood and Harrison, 198232; Carpenter et al., 198741;
Stump et al., 199929; DeSesso, 200142; Desesso et al., 1998,43; WHO 20009;
ATSDR 200710). The Subcommittee is aware that in none of the animal studies
maternal toxicity can be unambiguously excluded. Only the study by Hill et al.
(2008)37, administering arsenate to an inbred mouse strain, supports the view that
fetal malformations can develop in the absence of maternal toxicity.
Evaluation of the Subcommittee on the Classification of reprotoxic substances      233
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<pre>   The Subcommittee is of the opinion that, in view of the recent animal findings
   (Hill et al., 2008)37, it can not be excluded that developmental effects can occur
   in the absence of maternal toxicity. Together with the recent epidemiological
   observations from different parts of the world on associations between
   developmental effects and chronic exposure, the Subcommittee recommends
   classification of inorganic arsenic (arsenate) as ‘ known human reproductive
   toxicant’ (category 1A: H360D).
   Effects on lactation
   A small number of studies indicated that arsenic can be excreted in human milk.
   No data on the toxic effects from arsenic in human breast milk on the
   development of breastfed babies could be retrieved from the literature. No
   literature could be retrieved on toxic effects on pups via lactation.
        Dang et al. (1983)44 reported arsenic levels ranging from 0.2 to 1.1 ng/g in
   breast milk of nursing mothers 1-3 months postpartum (Bombay, India). Arsenic
   was detected in human breast milk at concentrations of 0.13-0.82 ng/g (Somogyi
   and Beck, 199345). In human milk sampled from mothers on the Faroer Islands
   whose diets were predominantly seafood, arsenic concentrations were 0.1-4.4 ng/
   g (Grandjean et al., 199546). Exposure to arsenic from the seafood diet in this
   population was most likely to organic arsenic. In a population of Andean women
   exposed to about 200 ng/g of inorganic arsenic in drinking water, concentrations
   of arsenic in breast milk ranged from about 0.8 to 8 ng/g (median 2.3 ng/g)
   (n=10)(Concha et al., 199847). The arsenic concentration in the breast milk of 35
   women in Izmir, Turkey, ranged from 3.24 to 5.41 ng/g, with a median of 4.22
   ng/g (Ulman et al., 199848). Samanta et al. (2009)49 collected two hundred and
   twenty-six breast milk samples from lactating women in arsenic-affected districts
   of west Bengal. In only 39 (17%) samples arsenic was detected. The maximum
   arsenic concentration in breast milk was 48 µg/L. Women who had both high
   arsenic body burden and arsenical skin lesions also had elevated levels of arsenic
   in their breast milk.
   Estimation of tolerable concentration for inorganic arsenic
   The Subcommittee is of the opinion that the data on exposure via lactation are
   limited as yet. However, EFSA (2009)50 calculates an average daily exposure to
   inorganic arsenic from breast milk for infants (up to 6 months) of 0.0275 µg/kg/
   day in the general European population (approx. 0.13 µg/L in breastmilk). The
   Subcommittee observes that this level is easily exceeded in specific area’s in the
   world with elevated levels in drinking water. In order to protect up to 6-month-
34 Arsenic and inorganic arsenic compounds
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<pre>old breastfed children from the effects of arsenic through intake of breast milk,
the Subcommittee used the following default values:
• body weight infant: 4.5 kg
• intake human breast milk per infant per day: 900 mL
• an infant is as sensitive to the substance as an adult.
These assumptions are used for the calculation of a tolerable level of arsenic in
human breast milk. The values are conservative figures estimated from the
growth curves for the Netherlands (Fredriks et al. 200051) and by the WHO
(2006)52, and breast milk intake (Butte et al. 200253). Of note, however, are the
indications that children might be more sensitive to the effects of arsenic than
adults (ATSDR 200754).
     The following health-based values for inorganic arsenic have been
recommended:
• ATSDR (2007)10, Minimal Risk Level (MRL) for acute exposure (1-14
     days): 5 µg/kg/day
• ATSDR (2007)10, MRL for chronic exposure (1 year or longer): 0.3 µg/kg/
     day
• US-EPA (2007)10, Reference Dose (RfD): 0.3 µg/kg/day.
(Unfortunately, the MRL for intermediate duration (15 days to 1 year) exposure
is the most appropriate limit value for suckling infants but was unfortunately not
derived by the ATSDR (2007)54 due to lack of suitable data).
     This corresponds to (MRL for acute exposure as limit):
• a tolerable intake of arsenic of 22.5 µg/infant/day
• a tolerable concentration of arsenic in breast milk of 25 µg/L.
(MRL for chronic exposure as limit):
• a tolerable intake of arsenic of 1.35 µg/infant/day
• a tolerable concentration of arsenic in breast milk of 1.5 µg/L.
The breast milk levels as reported by Samanta et al.49 (48 µg/L) exceed the
tolerable concentration of arsenic in both acute and chronic exposure situations.
When the MRL for chronic exposure is chosen for the calculation, most of the
breast milk levels reported by Grandjean et al.46, Ulman et al.48, Concha et al.47,
and Samanta et al.49 will exceed the calculated tolerable concentration (of 1.5 µg/
L). Supposing that the intermediate MRL is 2 or 3 µg/kg/day, this will lead to
tolerable concentrations in breast milk of 10 and 15 µg/L. The Subcommittee
estimates that 10 µg/L may be considered an upper tolerable concentration for
Evaluation of the Subcommittee on the Classification of reprotoxic substances       235
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<pre>   inorganic arsenic in breast milk and notes that this concentration is exceeded in
   specific area’s in the world with elevated levels in drinking water (Samanta et
   al.49).
   Therefore the Subcommittee recommends to label inorganic arsenic as a
   substance that ‘may cause harm to breasfed babies’.
   Proposed classification for effects on fertility
   The Subcommittee is of the opinion that inorganic arsenic should be classified
   ‘as presumed human reproductive toxicant’ (category 1B: H360F) for effects on
   fertility.
   Proposed classification for developmental toxicity
   In view of the recent epidemiological and animal findings the Subcommittee is
   of the opinion that the developmental effects of inorganic arsenic allow
   classification as ‘known human reproductive toxicant’ (category 1A: H360D).
   Proposed labeling for effects during lactation
   The Subcommittee recommends classifiying inorganic arsenic as a substance that
   ‘may cause harm to breastfed babies’ (H362).
   References
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36 Arsenic and inorganic arsenic compounds
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<pre>  Chattopadhyay S, Ghosh S, Debnath J, Ghosh D. Protection of sodium arsenite-induced ovarian
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3 Nordström S, Beckman L, Nordenson I. Occupational and environmental risks in and around a
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8 Hopenhayn-Rich C, Browning SR, Hertz-Picciotto I, Ferreccio C, Peralta C, Gibb H. Chronic arsenic
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9 Hopenhayn C, Ferreccio C, Browning SR, Huang B, Peralta C, Gibb H et al. Arsenic exposure from
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0 Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J, von EO et al. Increased mortality from lung
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1 Ahmad SA, Sayed MH, Barua S, Khan MH, Faruquee MH, Jalil A et al. Arsenic in drinking water
  and pregnancy outcomes. Environ Health Perspect 2001; 109(6): 629-631.
2 Milton AH, Smith W, Rahman B, Hasan Z, Kulsum U, Dear K et al. Chronic arsenic exposure and
  adverse pregnancy outcomes in bangladesh. Epidemiology 2005; 16(1): 82-86.
  Evaluation of the Subcommittee on the Classification of reprotoxic substances                         237
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<pre>3  von Ehrenstein OS, Guha Mazumder DN, Hira-Smith M, Ghosh N, Yuan Y, Windham G et al.
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   Epidemiol 2006; 163(7): 662-669.
4  Rahman A, Vahter M, Smith AH, Nermell B, Yunus M, El AS et al. Arsenic exposure during
   pregnancy and size at birth: a prospective cohort study in Bangladesh. Am J Epidemiol 2009; 26
   169(3): 304-312.
5  Rahman A, Persson LA, Nermell B, El AS, Ekstrom EC, Smith AH et al. Arsenic exposure and risk
   of spontaneous abortion, stillbirth, and infant mortality. Epidemiology 2010; 21(6): 797-804.
6  Tofail F, Vahter M, Hamadani JD, Nermell B, Huda SN, Yunus M et al. Effect of arsenic exposure
   during pregnancy on infant development at 7 months in rural Matlab, Bangladesh. Environ Health
   Perspect 2009; 117(2): 288-293. 32
7  Holson JF, Stump DG, Ulrich CE, Farr CH. Absence of prenatal developmental toxicity from inhaled
   arsenic trioxide in rats. Toxicol Sci 1999; 51(1): 87-97.
8  Nagymajtenyi L, Selypes A, Berencsi G. Chromosomal aberrations and fetotoxic effects of
   atmospheric arsenic exposure in mice. J Appl Toxicol 1985; 5(2): 61-63.
9  Stump DG, Holson JF, Fleeman TL, Nemec MD, Farr CH. Comparative effects of single
   intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development.
   Teratology 1999; 60(5): 283-291.
0  Holson JF, Stump DG, Clevidence KJ, Knapp JF, Farr CH. Evaluation of the prenatal developmental
   toxicity of orally administered arsenic trioxide in rats. Food Chem Toxicol 2000; 38(5): 459-466.
1  Baxley MN, Hood RD, Vedel GC, Harrison WP, Szczech GM. Prenatal toxicity of orally
   administered sodium arsenite in mice. Bull Environ Contam Toxicol 1981; 26(6): 749-756.
2  Hood RD, Harrison WP. Effects of prenatal arsenite exposure in the hamster. Bull Environ Contam
   Toxicol 1982; 29(6): 671-678.
3  Rodriguez VM, Carrizales L, Mendoza MS, Fajardo OR, Giordano M. Effects of sodium arsenite
   exposure on development and behavior in the rat. Neurotoxicol Teratol 2002; 24(6): 743-750.
4  Xi S, Sun W, Wang F, Jin Y, Sun G. Transplacental and early life exposure to inorganic arsenic
   affected development and behavior in offspring rats. Arch Toxicol 2009; 83(6): 549-556.
5  Nemec MD, Holson JF, Farr CH, Hood RD. Developmental toxicity assessment of arsenic acid in
   mice and rabbits. Reprod Toxicol 1998; 12(6): 647-658.
6  Hood RD, Thacker GT, Patterson BL, Szczech GM. Prenatal effects of oral versus intraperitoneal
   sodium arsenate in mice. J Environ Pathol Toxicol 1978; 1(6): 857-864.
7  Hill DS, Wlodarczyk BJ, Finnell RH. Reproductive consequences of oral arsenate exposure during
   pregnancy in a mouse model. Birth Defects Res B Dev Reprod Toxicol 2008; 83(1): 40-47.
8  Ferm VH, Carpenter SJ. Malformations induced by sodium arsenate. J Reprod Fertil 1968; 17(1):
   199-201.
9  Willhite CC. Arsenic-induced axial skeletal (dysraphic) disorders. Exp Mol Pathol 1981; 34(2): 145-
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0  Beaudoin AR. Teratogenicity of sodium arsenate in rats. Teratology 1974; 10(2): 153-157.
38 Arsenic and inorganic arsenic compounds
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<pre>1 Carpenter SJ. Developmental analysis of cephalic axial dysraphic disorders in arsenic-treated
  hamster embryos. Anat Embryol (Berl ) 1987; 176(3): 345-365.
2 DeSesso JM. Teratogen update: inorganic arsenic. Teratology 2001; 64(3): 170-173.
3 DeSesso JM, Jacobson CF, Scialli AR, Farr CH, Holson JF. An assessment of the developmental
  toxicity of inorganic arsenic. Reprod Toxicol 1998; 12(4): 385-433.
4 Dang HS, Jaiswal DD, Somasundaram S. Distribution of arsenic in human tissues and milk. Sci Total
  Environ 1983; 29(1-2): 171-175.
5 Somogyi A, Beck H. Nurturing and breast-feeding: exposure to chemicals in breast milk. Environ
  Health Perspect 1993; 101 Suppl 2: 45-52.
6 Grandjean P, Weihe P, Needham LL, Burse VW, Patterson DG, Jr., Sampson EJ et al. Relation of a
  seafood diet to mercury, selenium, arsenic, and polychlorinated biphenyl and other organochlorine
  concentrations in human milk. Environ Res 1995; 71(1): 29-38.
7 Concha G, Vogler G, Nermell B, Vahter M. Low-level arsenic excretion in breast milk of native
  Andean women exposed to high levels of arsenic in the drinking water. Int Arch Occup Environ
  Health 1998; 71(1): 42-46.
8 Ulman C, Gezer S, Anal O, Tore T, Kirca U. Arsenic in human and cow's milk: a reflection of
  environmental pollution. Water Air Soil Pollut 1998; 101: 411-416.
9 Samanta G, Das D, Mandal BK, Chowdhury TR, Chakraborti D, Pal A et al. Arsenic in the breast
  milk of lactating women in arsenic-affected areas of West Bengal, India and its effect on infants. J
  Environ Sci Health A Tox Hazard Subst Environ Eng 2007; 42(12): 1815-1825.
0 EFSA panel on contaminants in the food chain (CONTAM). Scientific opinion on arsenic in food.
  2009: EFSA Journal 2009; 7(10): 1351 [198 pp].
1 Fredriks AM, van BS, Burgmeijer RJ, Meulmeester JF, Beuker RJ, Brugman E et al. Continuing
  positive secular growth change in The Netherlands 1955-1997. Pediatr Res 2000; 47(3): 316-323.
2 WHO Child Growth Standards. Lenth/Height-for age, Weight-for-age, Weight-for-length and Body
  Mass index-for-age: methods and development. World health Organization, Geneva, Switzerland
  2006.
3 Butte NF, Lopez-Alacorn MG, Garzan C. Nutrient adequacy of exclusively breastfeeding for the term
  infant during the first six month of life. World health Organization, Geneva, Switzerland 2002.
  The Subcommittee
  •    A.H. Piersma, chairman
       Professor of Reproductive and Deveopmental Toxiclogy, Utrecht University,
       Utrecht; National Institute of Public Health and the Environment, Bilthoven
  •    D. Lindhout
       Professor of Medical Genetics, Paediatrician, Clinical Geneticist, University
       Medical Centre, Utrecht
  Evaluation of the Subcommittee on the Classification of reprotoxic substances                        239
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<pre>   •  N. Roeleveld
      Reproductive Epidemiologist, Radboud University Nijmegen Medical
      Centre, Nijmegen
   •  D.H. Waalkens-Berendsen
      Reproductive Toxicologist, Zeist
   •  J.G. Theuns-van Vliet
      Reproductive Toxicologist, TNO Triskelion BV, Zeist
   •  P.J.J.M. Weterings
      Toxicologist, Weterings Consultancy BV, Rosmalen
   •  J.T.J. Stouten, scientific secretary
      Health Council of The Netherlands, Den Haag
   •  G.B. van der Voet, scientific secretary
      Health Council of The Netherlands, Den Haag
   Meeting date: July 6, 2012
40 Arsenic and inorganic arsenic compounds
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<pre> nnex L
      Derivation of health-based
      calculated occupational cancer
      risk values (HBC-OCRV)
      M. Bos, L. Portengen, R. Vermeulen, D. Heederik
      Division Environmental Epidemiology, Institute for Risk Assessment Sciences,
      Utrecht University Utrecht, Netherlands
1     Mortality figures
      Mortality has been calculated on the basis of national data on lung cancer
      mortality in five-year age bands obtained through Statistics Netherlands
      (Centraal Bureau voor de Statistiek, www.cbs.nl) and the Comprehensive Cancer
      Centres (Vereniging van Integrale Kankercentra, www.ikcnet.nl). Mortality data
      for the years 2000 to 2010 were used, separated by age and sex. Rates for women
      and men were averaged so that the calculations would describe the average risk
      for the population. To avoid an abrupt transition between age categories, the
      mortality data were ‘smoothed’. These ‘modelled’ mortality data were employed
      in the Committee’s analysis.
          The mortality rates (deaths per 100,000 person-years) were used in a so-
      called survival analysis. Such an analysis may be thought of as involving two
      cohorts (in this case, of 100,000 people), that are followed from birth to death.
      For occupational arsenic exposure, it is assumed that exposure of the cohort
      starts at the age of twenty and lasts until the age of sixty. Every year the cohort
      reduces in size, through death as a result of the cause of death under study and
      other causes; the cohort is followed until it reaches the age of a hundred years.
      Derivation of health-based calculated occupational cancer risk values (HBC-OCRV)    241
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<pre>        The first cohort is not exposed; the second cohort is exposed to arsenic, and
    for this reason lung cancer mortality is higher in this cohort. Assuming a given
    average annual exposure to arsenic, every year that a person in the cohort is
    exposed to arsenic is another year contributing to their cumulative exposure. This
    approach employs cumulative exposure because studies of workers exposed to
    high levels of arsenic always work with cumulative exposure; the formulae
    employed are also based on cumulative exposure. Using this cumulative
    exposure, which is recalculated for each year, and the assumed exposure-
    response relationship between exposure to arsenic and death from lung cancer,
    the number of extra deaths is calculated for each year that the cohort ages. Using
    this information, first the additional risk of death per year associated with
    exposure to arsenic can be calculated and then the lifelong additional risk of
    death associated with exposure.
2   Quality of studies on occupational arsenic exposure
    Four epidemiological studies on lung or respiratory cancer mortality among
    workers exposed to arsenic are of interest. These concern Lubin et al. (2000),
    Lubin et al. (2008), Jarüp et al. (1989), and Enterline et al. (1995). In Table A
    detailed information is given on study design, execution, analyses, and additional
    remarks made by the Committee. In short, all studies show some shortcomings,
    which differ between studies.
    Lubin et al. (2000) and Lubin et al. (2008)
    In these studies, instead of lung cancer mortality, respiratory cancer mortality is
    used. According to the information given in the 2000 paper (Table 2), this may
    cause a deviation in mortality rate smaller than 4%. Therefore, the effect on
    association measures like risk ratio’s is assumed to be negligible. Another
    potential limiting factor of the 2000 paper is the higher loss-to-follow-up,
    compared to the other studies under consideration. If it is assumed that this loss-
    to-follow-up is non-differential across exposure, the Lubin et al. (2000) study is
    the strongest study with fewest limitations.
        The Lubin et al. (2008) study was a follow-up to the 2000 study, with a
    different modelling strategy. In the update, Lubin et al. used an exposure
    reduction factor in the higher exposure categories to account for the use of
    personal protection equipment. This is not common practice in risk calculations
    and this study was not further considered for risk assessment.
 42 Arsenic and inorganic arsenic compounds
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<pre>  Enterline et al. (1995)
  In this study, description of the exposure assessment component was limited and
  basic descriptive information was lacking. Information about exposure before
  1938 was lacking completely. It was not clear how exposure was assigned to
  certain job titles. Loss-to-follow-up was low, and an exposure-response relation
  was given. The study used long cancer mortality (including bronchus and trachea
  cancer). Calculations were based on a comparison with the general population
  (SMR study).
  Järup et al. (1989)
  This study had an exposure assessment component for which the description was
  limited and basic documentation was lacking. The way exposure has been
  calculated was not transparent, therefore making it difficult to analyse the risk
  per unit of increase by exposure. Information on exposure before 1945 was
  unclear, and again, it was not clear how exposure was assigned to certain job
  titles. Furthermore, no exposure-response relation was given. However, also in
  this study loss-to-follow-up was low and an exposure-response relation could be
  calculated by the Committee. This study analysed lung cancer mortality.
  Calculations were based on a comparison with the general population (SMR
  study).
3 Exposure response analysis
  Lubin et al. (2000) used an internal exposure-response analysis (resulting in a
  relative risk, RR), whereas the other studies compared exposure related mortality
  with mortality in the general population, which results in a standardized
  mortality ratio (SMR).
       As an exploratory analysis, exposure-response relations for the Järup et al.
  (1989) study were calculated based on the data given in the original article.
  Exposure-response relations based on joined data from the paper were calculated
  with PROC NLMIXED (SAS), resulting in the following relations (RR = 1
  means no difference in mortality when compared to reference group):
  • RR = 1 + 0.1002(cum exp)
  • RR = 1 + 1.69(cum exp)0.253.
  The power-model calculated for the Järup et al. study has a better fit (AIC power
  model: 43.0; AIC additive model: 68.5). This also is said to be the case for the
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<pre>   power model shown in Enterline et al. (p. 30), although no model fit information
   is given. For both these studies it cannot be excluded that the strong fit of the
   power models is caused by the fact that there is a clear difference in risk between
   the exposed population and the comparison group while there is a very weak
   association among the exposed only. These studies are SMR studies and are thus
   the result of a comparison with the general population and potential systematic
   differences in mortality between the general population and the exposed workers
   in these cohort studies. When an attempt was undertaken to model the exposure
   response curve in the low exposure range (steep part of the curve) the fit of linear
   models was very poor for both studies indicating that there was no clear exposure
   response curve discernible in this range. This again suggests that the comparison
   with the general population may be problematic. Considering the quality of the
   papers and fit of the models, the Committee decides to use the study of Lubin et
   al. (2000).
    In the study by Lubin et al. model fit did not improve significantly after fitting a
   power model (p. 557-558). Therefore the linear model was used , in line with
   previous reports, with an intercept RR=1.
   It is not completely clear from the paper how the linear relation in the paper has
   been calculated. If the published function is used the following equation is
   obtained RR = 1 + 0.19 * cumulative.exposure. However, post hoc estimation on
   the basis of the categorical data leads to the equation
   RR=1+0.09*cumulative.exposure).
   Risk calculations
   Lifetable calculations were performed by means of the software package R (in
   Windows). For the derivation of the health-based calculated occupational cancer
   risk values (HBC-OCRV), an additional risk of one extra cancer death due to
   occupational exposure per 250 (4 x 10-3) and 25,000 (4 x 10-5) is used. The
   results are shown below.
   Study                    equation                 ER*=40e-4        ER=40e-6
   Lubin                    1+0.19*cum.exposure      0.028            0.00028
   For convenience risk estimates are also given for the other two studies. Note
   however that these equations were derived from marginally fitting risk functions:
44 Arsenic and inorganic arsenic compounds
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<pre>              Study                           equation                       ER*=40e-4            ER=40e-6
              Järup                           1+0.33*cum.exposure            0.016                0.00016
              Enterline                       1+0.16*cum.exposure            0.033                0.00033
              Study characteristics
  eference                Enterline et al. (1995)    Lubin et al. (2000)        Lubin et al. (2008)       äarup et al. (1989)
  ohort name:             Tacoma                     Lee-Fraumeni               Lee-Fraumeni              Rönnskär
                                                     (Anaconda)                 (Anaconda)
Country:                  US                         US                         US                        Sweden
Cohort size:              2802                       8014                       8014                      3916
Cohort definition/source: Males working ≥ 1 year Workers employed for ≥ Workers employed for ≥ Male workers employed
                          at the Tacoma copper       12 months prior to 1957 12 months prior to 1957 ≥ 3 months between
                          smelter between 1940-                                                           1928-1967
                          1964
Number of cases:          182 (bronchus, trachea, 446 (respiratory cancers) 446 (respiratory cancers) 106 (lung)
                          lung cancer)
  ource of unexposed:     Mortality rates of white US population rates          US mortality rates for    Reference mortality rates
                          men in Washington State                               resp. cancer in white     from county, available
                          since 1941                                            males                     from 1951
  xposure period:         1940-1964                  1938-1957                  1938-1957                 1928-1967
  ollow-up period:        -1986                      One year after initial     One year after initial    - 1981
                                                     employment or 1938-        employment or 1938-
                                                     1989                       1989
  oss to follow-up:       1.5%                       15%                        Not mentioned             15 lost
  xposure assessment: - Before 1971:                 - Employment records - Employment records - After 1945
                          environment samples        - 702 measurements of - 702 measurements of measurement data +
                          - After 1971 personal      airborne arsenic between airborne arsenic between production numbers
                          samples                    1943 and 1958              1943 and 1958             - Strategy unclear
                          - Before 1938 no           - Resulting in low,        - Resulting in low,
                          exposure data              medium, high categories medium, high categories
                          - Biomonitoring data for with group-average           with group-average
                          part of the employees      estimation of exposure estimation of exposure
                          - Strategy is not clearly - Exposure estimation - Exposure estimation
                          described                  based on measurements based on measurements
                          - Resulting in 7 exposure and duration of exposure and duration of exposure
                          categories
Reported dose-response SMR = 100 + 10.5 (cum Power: RR =                        RR = 1+0.115a             None given
 elationship (give        exp)0.279                  1+1.00(cum exp)0.43
ormula):                                             Linear: RR =
                                                     1+0.19(cum exp)
s the paper valid and     Yes                        Yes, but relatively high Yes, but dose-response is Yes, but exposure
 sable for lifetable?                                loss to follow-up          adjusted for wearing air estimates before 1945 are
                                                                                filtration masks          problematic and no
                                                                                                          exposure model
              Derivation of health-based calculated occupational cancer risk values (HBC-OCRV)                                245
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<pre>emarks:          - Weaker in exposure     - Exposure most clear - Exposure most clear         - Too little information
                 assessment               and transparent          and transparent            on exposure (esp. before
                 - Exposure not clearly   - Analysis based on      - Results are adjusted for 1945), hence difficult to
                 described                limited data             wearing air masks          judge risk per unit
                 - Data on before 1938 is - No exposure            - No exposure              increase of exposure
                 missing                  measurements before      measurements before        - Details are lacking
                                          1943                     1943                       - Not clear how sound
                                          - High loss to follow-up - Calculated with          analysis is
                                          - After 1971 job history duration and cumulative - No general exposure-
                                          not complete, but only exposure- inconvenient response relation given
                                          10% was still working in for normal procedure
                                          1977                     - High loss to follow-up
                                          - Health outcome         - After 1971 job history
                                          unknown for 15% of the not complete, but only
                                          employees- could mean 10% was still working in
                                          possible methodological 1977
                                          limitations              - Health outcome
                                                                   unknown for 15% of the
                                                                   employees- could mean
                                                                   possible methodological
                                                                   limitations
46      Arsenic and inorganic arsenic compounds
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