<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>Sulphur dioxide</pre>

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<pre></pre>

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<pre>Gezondheidsraad                              Voorzitter
Health Council of the Netherlands
Aan de Staatssecretaris Sociale Zaken en Werkgelegenheid
Onderwerp          : Aanbieding advies ‘Sulphur dioxide’
Uw kenmerk         : DGV/MBO/U-932542
Ons kenmerk        : U-1693/JR/fs/459-P40
Bijlagen           :1
Datum              : 18 december 2003
Mijnheer de staatssecretaris,
Bij brief van 3 december, nr DGV/BMO-U-932542, verzocht de Staatssecretaris van Welzijn,
Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en Werkgelegenheid de
Gezondheidsraad om gezondheidskundige advieswaarden af te leiden ten behoeve van de
bescherming van beroepsmatig aan stoffen blootgestelde personen.
      In dat kader bied ik u hierbij een advies aan over zwaveldioxide. Dit advies is opgesteld door
de Commissie WGD van de Gezondheidsraad en beoordeeld door de Beraadsgroep Gezondheid en
Omgeving.
      Ik heb dit advies vandaag ter kennisname toegezonden aan de Minister van Volksgezondheid,
Welzijn en Sport en de Minister van Volkshuisvesting, Ruimtelijke Ordening en Milieu.
Hoogachtend,
prof. dr JA Knottnerus
Bezoekadres                                                             Postadres
Parnassusplein 5                                                        Postbus 16052
2511 VX Den Haag                                                        2500 BB Den Haag
Telefoon (070) 340 6631                                                 Telefax (070) 340 75 23
E-mail: jolanda.rijnkels@gr.nl                                          www.gr.nl
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<pre></pre>

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<pre>Sulphur dioxide
Health-based recommended occupational exposure limit
Dutch Expert Committee on Occupatoinal Standards,
a committee of the Health Council of the Netherlands
to:
the Minister and State Secretary of Social Affairs and Employment
No. 2003/08OSH, The Hague, 18 December 2003
</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...” (Section 21, Health Act).
     The Health Council receives most requests for advice from the Ministers of Health,
Welfare & Sport, Housing, Spatial Planning & the Environment, Social Affairs &
Employment, and Agriculture, Nature and Food Quality. 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.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands: Dutch Expert Committee on Occupatoinal
Standards. Sulphur dioxide; Health-based recommended occupational exposure limit.
The Hague: Health Council of the Netherlands, 2003; publication no. 2003/08OSH.
all rights reserved
ISBN: 90-5549-507-7
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<pre>    Inhoud
    Samenvatting en advieswaarde 9
    Executive summary 15
1   Scope 21
1.1 Background 21
1.2 Committee and procedure 21
1.3 Data 22
2   Identity, properties and monitoring 23
2.1 Identity 23
2.2 Physical and chemical properties 23
2.3 EU Classification and labelling (CKB99) 24
2.4 Validated analytical methods 24
3   Sources 27
3.1 Natural occurrence 27
3.2 Man-made sources 27
4   Exposure 29
4.1 General population 29
4.2 Working population 29
    Inhoud                                     7
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<pre>5   Kinetics 33
5.1 Absorption 33
5.2 Distribution 33
5.3 Biotransformation 34
5.4 Elimination 34
5.5 Possibilities for biological monitoring 34
5.6 Summary and evaluation 34
6   Effects 35
6.1 Observations in humans 35
6.2 Animal experiments 46
6.3 Other relevant studies 54
6.4 Summary and evaluation 55
7   Existing guidelines, standards and evaluation 59
7.1 General population 59
7.2 Working population 59
8   Hazard assessment 63
8.1 Hazard identification 63
8.2 The derivation of an HBR-OEL 66
8.3 Groups at extra risk 67
8.4 Health-based recommended occupational exposure limit 67
    References 69
    Annexes 77
A   Request for advice 79
B   The committee 81
C   Comments on the public review draft 83
D   Recommendations from the SCOEL for sulphur dioxide 85
E   IARC Monograph 89
F   Summary of data concerning acute physical effects in healthy humans 93
G   Abbreviations 97
H   DECOS-documents 101
8   Sulphur dioxide
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<pre>Samenvatting en advieswaarde
Vraagstelling
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid leidt de Commissie
WGD van de Gezondheidsraad gezondheidskundige advieswaarden af voor stoffen in
lucht waaraan mensen beroepsmatig blootgesteld kunnen worden. Deze aanbevelingen
vormen de eerste stap in een drietrapsprocedure die moet leiden tot wettelijke grens-
waarden, aangeduid als maximaal aanvaarde concentraties (MAC-waarden).
     In het voorliggende rapport bespreekt de commissie de gevolgen van blootstelling
aan zwaveldioxide en presenteert zij een gezondheidskundige advieswaarde voor die
stof. De conclusies van de commissie zijn gebaseerd op informatie afkomstig uit de
rapporten geschreven door de Scientific Committee on Occupational Exposure Limits
(SCOEL) van de Europese Gemeenschap (SCO93, SCO98) en op aanvullende weten-
schappelijke publicaties die vóór mei 2002 zijn verschenen.
Fysische en chemische eigenschappen
Zwaveldioxide (SO2; CAS nr. 7446-09-5) is een kleurloos gas met een sterk irriterende
geur. De geurdrempel ligt tussen 0,8 en 8 mg/m3. De molaire massa is 64,06 g/mol, het
smeltpunt -72,7 °C en het kookpunt -10,0 °C. Zwaveldioxide is zeer goed oplosbaar in
water.
     Zwaveldioxide wordt gebruikt in de chemische industrie, bijvoorbeeld als
antioxidant voor de productie van broom, als bleekmiddel bij het gieten van
Samenvatting en advieswaarde                                                          9
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<pre>   magnesiumonderdelen, als katalysator voor furfuralharsen en in de productie van
   cellulosepulp en chemicaliën. Verder wordt zwaveldioxide gebruikt in de voedings-
   industrie als conserveermiddel van groenten en fruit, als ontsmettingsmiddel in
   brouwerijen, en bij de productie van wijn- en voedingsmiddelen.
   Monitoring
   Zwaveldioxide kan zowel actief (pompsysteem) als passief (diffusie) worden
   bemonsterd. Beide bemonsteringen maken onder andere gebruik van zwaveldioxide
   absorberende vaste stoffen of vloeistoffen. Het Nederlands Normalisatie Instituut
   beveelt het gebruik van het 'voornorm' protocol (NVN2950) aan voor het monitoren van
   dampen en gassen in de werkomgeving. In het betreffende protocol wordt
   zwaveldioxide passief bemonsterd, waarna de uitslag direct weergegeven wordt op een
   display van een ‘pocket dosimeter’.
       Het Amerikaanse National Institute for Occupational Safety and Health (NIOSH)
   beveelt voor kortdurende monsternames van zwaveldioxide een ionchromatografische
   analyse aan (Methode 6004; detectiegebied: 0,5-20 mg/m3 per 100 L luchtmonster).
   Grenswaarden
   In Nederland geldt momenteel voor zwaveldioxide een wettelijke grenswaarde van 5
   mg/m3, gemiddeld over een achturige werkdag. In 1985 heeft de voorloper van de
   commissie, de Werkgroep van Deskundigen, een gezondheidskundige advieswaarde
   voorgesteld van 1,3 mg/m3 (tijd gewogen gemiddelde (TGG) van 8 uur). In 1998 heeft
   de SCOEL ook een grenswaarde van 1,3 mg/m3 geadviseerd, en een ‘short term
   exposure limit’ (STEL) van 2,7 mg/m3 (TGG 15 min).
   Kinetiek
   Zwaveldioxide wordt voornamelijk via de slijmvliezen van de neus in het lichaam
   opgenomen. Opname via de longen is echter ook mogelijk en neemt toe bij inademing
   via de mond en bij diepe inademing, zoals gebeurt bij grote lichamelijke inspanning.
       Omdat zwaveldioxide zeer goed wateroplosbaar is, zal het zodra het in contact komt
   met waterdamp die van nature aanwezig is in de ademhalingswegen worden
   omgevormd in zwaveligzuur. Dit zuur is instabiel en splitst zich snel in sulfiet- en
   bisulfietionen. De sulfietionen worden weer snel omgezet in het stabielere sulfaat. Deze
   sulfaten worden vervolgens opgenomen in het grote sulfaatdepot van het lichaam. De
   bisulfietionen op hun beurt binden zich aan lichaamseigen eiwitten tot zogenaamde S-
10 Sulphur dioxide
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<pre>sulfonaten. In het bloed komt zwaveldioxide het meest voor in de vorm van deze S-
sulfonaten.
     Het zwaveldioxide verlaat het lichaam op verschillende manieren. Als sulfaat komt
het langzaam vrij uit het sulfaatdepot, waarna het via de nieren wordt uitgescheiden. De
S-sulfonaten vallen langzaam uiteen in sulfaten of in het ‘oorspronkelijke’ zwavel-
dioxide. Dit zwaveldioxide verlaat het lichaam via uitademing, de sulfaten volgen de
route van de sulfaatdepots.
Effecten
Zwaveldioxide is irriterend voor neus, keel en ogen. Bij kortdurende hoge blootstelling
kunnen bovendien klachten optreden als rhinitis, kortademigheid, benauwdheid op de
borst en misselijkheid.
     Epidemiologisch onderzoek bij chronisch blootgestelden bracht verschillende
gezondheidsklachten naar voren, zoals bronchitis, verhoogde gevoeligheid voor
luchtweginfecties en verhoogde kans op luchtwegallergieën. Deze epidemiologische
gegevens bieden niettemin te weinig houvast om een gezondheidskundige advieswaarde
te kunnen afleiden, omdat meerdere factoren een rol kunnen hebben gespeeld bij het
ontstaan van deze klachten, zoals de mengselblootstelling. Ook is onvoldoende rekening
gehouden met de persoonlijke levensstijl.
     Naast deze epidemiologische onderzoeken is ook een aantal kwalitatief goede
onderzoeken uitgevoerd met gezonde (niet rokende) vrijwilligers in een gecontroleerde
omgeving. Daarbij ging het om acute of kortdurende blootstellingen gecombineerd met
lichte lichamelijke activiteit, met blootstellingen variërend van 0,53 mg/m3 tot ruim 20
mg/m3, waarbij de effecten op de luchtwegen centraal stonden. De belangrijkste
klachten die optraden waren irritatie aan de bovenste luchtwegen en ogen, en
verminderde longfunctie. Deze klachten waren onmiskenbaar vanaf 2,7 mg/m3, terwijl
bij 2,0 mg/m3 of lager geen noemenswaardige klachten zijn beschreven, met
uitzondering van drie onderzoeken. In twee ervan, van dezelfde onderzoeksgroep,
rapporteerden de onderzoekers een verminderde longfunctie bij 1,6-2,0 mg/m3. De
commissie laat deze onderzoeken echter buiten beschouwing, omdat de onderzoeks-
opzet te beperkt was. In een derde onderzoek met zeer lage blootstelling (0,5 mg/m3)
zijn milde effecten op de autonome hartfunctie beschreven, maar deze beschouwt de
commissie niet als een nadelig effect. Ook dit onderzoek laat de commissie buiten
beschouwing, omdat de gebruikte meetmethode zeer gevoelig was en de gemeten
effecten niet leidden tot lichamelijke klachten of hartfunctieproblemen.
     De commissie beschouwt daarom 2,0 mg/m3 als de niet-waargenomen-nadelig-
effect-concentratie (NOAEL) bij acute blootstelling. Deze NOAEL is gebaseerd op twee
onafhankelijk van elkaar uitgevoerde onderzoeken, waarbij vrijwilligers gedurende 40
Samenvatting en advieswaarde                                                             11
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<pre>   minuten of gedurende 4 uur werden blootgesteld aan zwaveldioxide, terwijl zij zich licht
   lichamelijk inspanden. Daarbij traden geen longfunctieveranderingen op.
   Ten aanzien van mensen die mogelijk een extra risico lopen geven de gegevens
   afkomstig uit epidemiologisch onderzoek onder de algehele bevolking aan dat mensen
   met astma of andere aandoeningen aan de luchtwegen gevoeliger zijn voor
   zwaveldioxideblootstelling. Dit lijkt te worden ondersteund door
   laboratoriumonderzoek. Maar de commissie heeft ook vastgesteld dat de mate van
   gevoeligheid voor zwaveldioxide in astmatici sterk wordt beïnvloed door andere (niet-
   specifieke) factoren, zoals het doen van (zware) lichamelijke krachtsinspanning en
   klimatologische factoren (droge, koude lucht). Het is bekend dat al deze factoren op
   zichzelf astma bij astmatici kunnen oproepen of verergeren. Daarom kan de commissie
   niet concluderen of astmatici gevoeliger zijn voor blootstelling aan zwaveldioxide in
   afwezigheid van deze niet-specifieke factoren. Wel wil zij haar zorg uitdrukken voor de
   gecombineerde effecten van deze niet-specifieke factoren en zwaveldioxideblootstelling
   bij astmatici.
   In dieren leidde korte en middellange blootstelling aan zwaveldioxide tot vergelijkbare
   effecten als bij de mens, zoals irritatie aan de bovenste luchtwegen en ogen. Daarnaast
   zijn verminderde afweer in de luchtwegen en afwijkingen in enzympatronen in bloed en
   lever vastgesteld. De dieren waren vaak echter aan zeer hoge concentraties blootgesteld
   (>267 mg/m3 (middellange blootstelling) tot >1.000 mg/m3 (korte blootstelling)).
   Bovendien vertoonden veel van deze onderzoeken ernstige tekortkomingen in
   onderzoeksopzet en verslaglegging.
        Ook de dieronderzoeken naar de schadelijke effecten van zwaveldioxide na
   langdurige blootstelling acht de commissie niet geschikt. Hoewel in deze chronische
   onderzoeken lagere blootstellingen zijn gebruikt (0,35 tot 133 mg/m3), zijn de gegevens
   te beperkt om een concentratie-effectrelatie te kunnen vaststellen en dus een
   gezondheidskundige advieswaarde te kunnen afleiden.
   Een paar dieronderzoeken zijn uitgevoerd om te beoordelen of zwaveldioxide kanker-
   verwekkende of genotoxische eigenschappen bezit. Hoewel tumoren zijn gevonden na
   langdurige blootstelling, acht de commissie deze onderzoeken niet geschikt om daarover
   een uitspraak te kunnen doen; naast hoge blootstellingen blijken namelijk ook zeer
   gevoelige proefdieren te zijn gebruikt. Om vergelijkbare redenen kan de commissie
   geen uitspraak doen over de vraag of zwaveldioxide de tumorontwikkeling stimuleert.
        Zwaveldioxide veroorzaakte DNA-schade in bacteriën, maar alleen onder condities
   die niet relevant zijn voor de mens. Daarnaast veroorzaakte het schade aan
   chromosomen in in vitro celsystemen en in levende muizen.
12 Sulphur dioxide
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<pre>Het aantal dieronderzoeken naar de schadelijke gevolgen van zwaveldioxide op de
vruchtbaarheid en op het nageslacht is zeer beperkt en levert onvoldoende bewijs dat, bij
lage luchtconcentraties, zwaveldioxide reproductietoxisch is.
Evaluatie en advies
De commissie beschouwt de acuut optredende irritatie aan de luchtwegen en long-
functieveranderingen als de meest gevoelige effecten na blootstelling aan
zwaveldioxide. Daarom beveelt zij een gezondheidskundige advieswaarde voor
kortdurende blootstelling aan (TGG 15 minuten). De humane gegevens afkomstig van
vrijwilligersonderzoek zijn van voldoende kwaliteit om een dergelijke advieswaarde te
kunnen afleiden.
    Als uitgangspunt neemt de commissie de NOAEL van 2,0 mg/m3, afkomstig van
twee onafhankelijk van elkaar uitgevoerde onderzoeken. Ter compensatie voor
mogelijke interindividuele verschillen corrigeert de commissie de NOAEL met een
factor 3. Deze factor van 3 vindt de commissie noodzakelijk, omdat de NOAEL is
gebaseerd op een beperkt aantal onderzoeken en een beperkt aantal vrijwilligers.
Bovendien bestaan in de literatuur aanwijzingen dat gezonde vrijwilligers verschillend
kunnen reageren bij bepaalde blootstellingen onder meer extreme omstandigheden.
Deze correctie levert afgerond een gezondheidskundige advieswaarde op van 0,7 mg/m3
voor kortdurende blootstelling (TGG 15 minuten).
    Wegens een gebrek aan gegevens van voldoende kwaliteit en betrouwbaarheid kan
de commissie geen gezondheidskundige advieswaarde adviseren, die zou kunnen
beschermen tegen langdurige blootstelling.
    De commissie is van mening dat mensen met astma in combinatie met andere
astma-inducerende factoren eerder lichamelijke klachten kunnen krijgen.
    De commissie is verder van mening dat zwaveldioxide onvoldoende is onderzocht
op kankerverwekkende eigenschappen. Zij adviseert daarom de stof niet te classificeren.
Gezondheidskundige advieswaarde
De Commissie WGD van de Gezondheidsraad stelt bij beroepsmatige blootstelling aan
zwaveldioxide een gezondheidskundige advieswaarde voor van 0,7 mg/m3 (TGG 15
minuten).
Samenvatting en advieswaarde                                                              13
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<pre>14 Sulphur dioxide</pre>

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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 Recommended Occupational Exposure Limits
(HBR-OEL) for chemical substances in air in the workplace. These recommendations
are made by the Council's Dutch Expert Committee on Occupational Standards
(DECOS). They constitute the first step in a three-step procedure, which leads to legally
binding occupational exposure limits.
     In this report, the committee discusses the consequences of occupational exposure to
sulphur dioxide and recommends a health-based occupational exposure limit. The
committee's conclusions are made on the documents produced by the Scientific
Committee on Occupational Exposure Limits of the European Commission (SCOEL;
SCO93, SCO98) and on additional scientific papers published prior to May 2002.
Physical and chemical properties
Sulphur dioxide (SO2; CAS no. 7446-09-5) is a colourless gas, with an irritating odour.
Its odour threshold ranges between 0.8 and 8 mg/m3. The molar mass of sulphur dioxide
is 64.06 g/mol, its melting point -72.7 °C and its boiling point -10.0 °C. Sulphur dioxide
is highly hydrophilic and dissolves easily in water.
     Sulphur dioxide is used in the inorganic and petrochemical industries, such as in the
production of cellulose pulp and chemicals. The substance has a lot of functions: as an
Executive summary                                                                          15
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<pre>   antioxidant in the bromine production; as a bleaching gas in casting magnesium parts
   and bleaching kaolin; as a rapid catalyst in furfural resins for manufacturing casting
   moulds; as a fruit and vegetable preservative in the food; and, as a disinfectant in the
   wine and brewery industry.
   Monitoring
   Various sampling and analysis techniques are available for determining ambient
   concentrations of sulphur dioxide in an occupational setting. Both passive and active
   samplers may be used. Samples obtained from passive sampling are analysed by
   spectrophotometry or ion exchange chromatography. The National Institute for
   Occupational Safety and Health (NIOSH) recommends the latter (Method 6004;
   detection range: 0.5-20.0 mg/m3 per 100 L air sample).
        Concerning personal exposure, direct reading pocket dosimeters may be used, as is
   described in a protocol, called ‘Voornorm NVN 2950’, from the Dutch Normalisation
   Institute.
   Limit values
   In 1985, the DECOS recommended an HBR-OEL for sulphur dioxide of 1.3 mg/m3, as
   an 8-hour time weighted average (8-hour TWA). However, due to socio-economic
   constraints, the Netherlands has set a legal occupational exposure limit (OEL) of 5 mg/
   m3 (8-hour TWA). In addition, the SCOEL has set a limit of 1.3 mg/m3 (8-hour TWA)
   and of 2.7 mg/m3 (15-minute TWA). Both in Germany and Denmark, OELs have been
   set at 1.3 mg/m3, averaged over an 8-hour period of time; and, in the United Kingdom
   and Sweden of around 5 mg/m3 (8-hour TWA) and 13 mg/m3 (15-minute TWA, for
   Sweden a Ceiling). Finally, the American Conference of Governmental Industrial
   Hygienists has proposed a TLV of 5 mg/m3 and a STEL of 13 mg/m3.
   Kinetics
   Inhaled sulphur dioxide is mainly absorbed in the body through the epithelium of the
   upper respiratory tract (nose and throat). However, the substance may reach the lower
   respiratory tract (bronchi and alveoli in lungs) when it is deeply inhaled, as happens with
   doing heavy work or physical exercise.
        Sulphur dioxide is a highly hydrophilic gas. Therefore, it reacts easily with water,
   which is present at the surface of the respiratory tract. When sulphur dioxide reacts with
   water sulphurous acid is formed. This sulphurous acid dissociates easily into sulphite
   and bisulphite ions. Sulphite ions are then rapidly converted into sulphate, whereas
16 Sulphur dioxide
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<pre>bisulphite ions bind to proteins to form S-sulphonates. In the blood most of the sulphur
dioxide is present as S-sulphonate and only a minor part as free sulphite/sulphate or
bisulphite ions. Sulphates are quickly absorbed in the large endogenous sulphate pool of
the body and then slowly released via the blood into the urine. Circulating S-sulphonates
slowly decompose into sulphates or sulphur dioxides. The latter substance is exhaled.
Effects
In humans, sulphur dioxide is irritating to the eyes and the upper respiratory tract.
Inhaling high concentrations may cause: rhinorrhae; coughing; shortness of breath;
chest tightness; and, a choking sensation.
     Epidemiological studies have associated chronic sulphur dioxide exposure with
chronic coughing; bronchitis; increased susceptibility to airway infections; and,
increased susceptibility to allergy by airborne allergens. However, because these studies
included several confounding factors, they are considered insufficient for quantitative
risk assessment.
     A number of laboratory studies have been carried out with healthy, non-smoking
volunteers, who were exclusively exposed to sulphur dioxide. These volunteers were
exposed to concentrations of as low as 0.53 mg/m3 to more than 60 mg/m3. The
exposures lasted from minutes up to several hours and were carried out with or without
physical exercise. The main adverse effects observed were irritation of the upper
respiratory tract and the eyes, and decreased lung function, such as increased pulmonary
airway resistance. These adverse effects were clearly present at exposure levels of 2.7
mg/m3 or higher. None of these effects were observed at exposure levels below 2.0 mg/
m3, with the exception of three studies (two of the same research group): these three
studies were, however, not considered for risk assessment, because of limitations in
study design or the lack of toxicological relevance of the findings. In addition, at 2.0 mg/
m3, two independent studies were performed with volunteers, who were exposed for 40
minutes and 4 hours, respectively, with moderate physical exercise. In all these
volunteers lung function remained normal. Based on these outcomes, the committee
considers 2.0 mg/m3 as the No Observed Adverse Effect Level (NOAEL) after short-
term exposure.
Epidemiological data obtained from the general population indicate that people with
asthma or with other diseases concerning the respiratory tract, are more vulnerable to
sulphur dioxide exposure than healthy people. Concerning asthma, this finding is
supported by laboratory data. However, numerous studies with asthmatics show that the
level of susceptibility is strongly influenced by non-specific factors, such as physical
activity and atmospheric conditions (dry, cold air). These factors alone may aggravate
Executive summary                                                                            17
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<pre>   asthma. Therefore, the committee cannot conclude whether or not asthmatics are more
   vulnerable to sulphur dioxide exposure in the absence of these non-specific stimuli.
   However, it is concerned that asthmatics are at higher risk when exposed to sulphur
   dioxide in combination with these non-specific asthma-aggravating factors.
   Data from experiments in animals with acute or short-term exposure support the
   findings in humans, that sulphur dioxide irritates the (upper) respiratory tract and eyes
   and reduces respiratory defence mechanisms against bacterial infections. In addition,
   changes in enzyme activities in liver and blood were observed. However, the committee
   noted that the quality of the reporting of most of these studies was insufficient. Apart
   from that, most animals were exposed to very high levels (up to 267 mg/m3 (subchronic)
   or >1,000 mg/m3 (acute)).
        The exposure levels in long-term animal studies were lower than in short-term
   animal studies (0.35 up to 133 mg/m3). However, no concentration-response
   relationships could be established, because data were too limited to be useful for
   quantitative risk assessment.
   Few animal studies have been directed towards the carcinogenicity of sulphur dioxide.
   Although tumour formation was observed, the studies showed considerable limitations,
   including: the use of animals with very high spontaneous tumour incidence; exposure to
   high levels of the substance; and, incomplete reporting on the tumour promoting activity
   of sulphur dioxide in combination with benzo[a]pyrene.
        In regard to genotoxicity, mutagenicity tests in bacteria scored positive in conditions
   not relevant for humans. Also, sulphur dioxide induced chromosomal aberrations in
   vitro, and micronuclei in vitro and in vivo.
   In a limited number of experiments, the adverse effects of sulphur dioxide have been
   studied on reproduction. Litter of rabbits and mice were exposed to 187 and 67 mg/m3,
   respectively. This resulted in minor skeletal variations and mild maternal toxicity. In
   another study, offspring of exposed mice (13.4 to 80 mg/m3) showed no defects in
   reproductive performance, and in somatic and neurobehavioral development.
   Evaluation
   From the current data, the committee concludes that the acute effects of sulphur dioxide
   on the respiratory tract, such as nose and throat irritation, depressed lung function and
   increased airway resistance, should be prevented. In order to do this, the committee
   recommends deriving a health-based occupational exposure limit for short-term
   exposure (Short-Term Exposure Limit (STEL); 15-min TWA).
18 Sulphur dioxide
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<pre>     From the human database a NOAEL of 2.0 mg/m3 was derived (see previous
paragraph). In addition, to the committee’s opinion the NOAEL needs to be adjusted for
inter-individual differences. This is needed, because the number of studies at the
NOAEL and the number of participants in those studies were limited. Also, the
committee is aware of the reporting of variable responses among healthy people at
levels near the NOAEL. To compensate for these uncertainties, a factor of 3 was chosen.
Consequently, the committee recommends a STEL for sulphur dioxide of 0.7 mg/m3
(≈0.25 ppm).
Both epidemiological and animal data suggest that chronic exposure to sulphur dioxide
may lead to chronic irritation (bronchitis) and increased susceptibility to airway
infections. However, these data were not reliable or insufficient to assess concentration-
response relationships. For this reason, the committee does not recommend an HBR-
OEL (8-h TWA).
Concerning workers with a possible extra risk, the committee likes to express its
concern that asthmatics are at a higher risk when not only exposed to sulphur dioxide,
but also to other (non-specific) factors which incite asthma.
Carcinogenicity and genotoxicity data are too limited to make a definite conclusion
about the carcinogenic potential of sulphur dioxide in humans. Therefore, the committee
recommends not classifying sulphur dioxide as a suspected carcinogen. In addition, the
database is too restricted to allow any conclusion to be drawn on the adverse effects on
fertility and development.
Health-based recommended occupational exposure limit
The Dutch Expert Committee on Occupational Standards recommends a health-based
occupational exposure limit for sulphur dioxide of 0.7 mg/m3 (≈0.25 ppm), as a 15-
minute time weighted average concentration (STEL).
Executive summary                                                                          19
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<pre>20 Sulphur dioxide</pre>

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<pre>Chapter 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 Standards
        (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 exposure limit for the atmospheric
        concentration of the substance, provided the database allows the derivation of such a
        value.
             In the next phase of the three-step procedure, the Social and Economic Council
        advises the Minister on the feasibility of using the health-based limit as a regulatory
        Occupational Exposure Limit (OEL) or recommends a different OEL. In the final step of
        the procedure, the Minister of Social Affairs and Employment sets the legally binding
        OEL.
1.2     Committee and procedure
        This document contains the assessment of DECOS, hereafter called the committee, of
        the health hazard of sulphur dioxide. The members of the committee are listed in annex
        B. The first draft of this report was prepared by AAE Wibowo of the Coronel Institute,
        Scope                                                                                           21
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<pre>    Academic Medical Center of Amsterdam, for the Ministry of Social Affairs and
    Employment.
         In 2002, the President of the Health Council released a draft of the report for public
    review. The individuals and organizations that commented on the draft are listed in
    annex C. The committee has taken these comments into account in deciding on the final
    version of the report.
1.3 Data
    In 1998, the Scientific Committee on Occupational Exposure Limits (SCOEL) of the
    European Commission published a report on the health-risk assessment of sulphur
    dioxide (SCO98), of which a draft was published in 1993 (SCO93). The summary of the
    final report is included in the current document in annex D. The committee used data of
    this report for the present evaluation. In addition, more recent literature was retrieved
    from on-line databases: Toxline, Medline, Excerpta Medica and Chemical Abstracts.
    The final search has been carried out in May 2002. The searches were performed using
    sulphur dioxide and CAS no. 7446-09-5, as key words. In addition, in preparing the
    present report the following reviews have been consulted:
    • Agency for Toxic Substances and Disease Registry, US Dept of Health and Human
         Services. Toxicological profile for sulphur dioxide. Contract no. 205-93-0606.
         Research Triangle Institute, Atlanta: 1998 (ATS98);
    • Von Burg R. Toxicology update. Sulphur dioxide. J Appl Toxicol 1996, 16: 365-
         371 (Bur95);
    • International Agency for Research on Cancer (IARC), WHO. Occupational
         exposures to mists and vapours from strong inorganic acids; and other industrial
         chemicals. IARC Monographs on the evaluation of carcinogenic risks to humans.
         Lyon, 1992; Volume 54 (ISBN 92 832 1254-1), pp 131-188;
    • World Health Organisation regional Office for Europe. In: Air quality guidelines for
         Europe. WHO Regional Publications, European Series No. 23, 1987, Copenhagen,
         pp. 338-360 (WHO87);
    • Werkgroep van Deskundigen van de Nationale MAC-Commissie. Rapport inzake
         grenswaarden zwaveldioxide. Ministerie van Sociale Zaken en Werkgelegenheid
         RA 4/85, Voorburg: 1985 (WGD85). [in Dutch]
    A list of abbreviations used in this report is given in annex G.
22  Sulphur dioxide
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<pre>Chapter 2
        Identity, properties and monitoring
2.1     Identity
        CAS name                   Sulphur dioxide
        Synonyms                   Sulphurous oxide, sulphurous anhydride, sulphur oxide, sulphurous acid
                                   anhydride, sulphur bioxide, bisulphite
        CAS number                 7446-09-5
        EEC number                 016-011-00-9
        RTECS number               WS 4550000
        EINECS number              231-195-2
2.2     Physical and chemical properties
        Molecular formula          SO2
        Molecular weight           64.06 g/mol
        Melting point              -72.7 °C
        Boiling point              -10.02 °C
        Relative density (water=1) 1.434 at –10 °C (liquid)
        Vapour pressure (20 °C)    324.24 kPa (volatility high)
        Solubility                 Soluble in water (107 g/L at 20 °C). Highly soluble in sulphuric acid,
                                   ethyl and ethyl alcohols, acetic acid, chloroform, diethyl ether, and other
                                   polar solvents.
        Odour threshold            0.8-8.0 mg/m3 (0.3-3.0 ppm)
        Conversion factors         1 ppm = 2.67 mg/m3
        (20 °C, 101.3 kPa)         1 mg/m3 = 0.37 ppm
        Identity, properties and monitoring                                                                    23
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<pre>      At normal ambient temperatures, sulphur dioxide is a colourless gas, with a strong
      pungent (suffocating) odour. The gas is very reactive: on contact with water it forms
      sulphurous acid. Certain metals and organic substances glow, burn or explode in an
      atmosphere of sulphur dioxide (Bur95).
2.3   EU Classification and labelling (CKB99)
      T symbol                           Toxic
      Risk phrases       R23             Toxic by inhalation;
                          R34            Causes burns;
      Safety phrases      1/2            Keep locked up and out of reach of children;
                          9              Keep container in a well-ventilated place;
                          26             In case of contact with eyes, rinse immediately with plenty of
                                         water and seek medical advice;
                          36/37/39       Wear suitable protective clothing, gloves and eye/face protection
                          45             In case of accident or if you feel unwell, seek medical advice;
                                         immediately (show the label where possible);
2.4   Validated analytical methods
2.4.1 Environmental monitoring
      A variety of passive and active samplers may be used to provide data on ambient
      concentrations of sulphur dioxide (SCO93). Passive samplers contain sulphur dioxide
      diffusion tubes with solid or liquid absorbents. Samples obtained in this way are
      analysed by spectrophotometry or ion exchange chromatography.
           The collecting medium for active sampling is typically a liquid bubbler, and less
      frequently solids, impregnated filters or plastic pouches. Samples are taken for a
      specified period and the volume of air is determined. The most used and reliable
      methods for analysing the collected liquid medium are: the acidimetric (total acidity)
      method (ISO1983); ion-exchange chromatography; the tetrachloromercurate method
      (ISO1990); and, the thorin method (ISO1980). The last two methods are less widely
      used because of the very hazardous reagents needed (WHO00, ATS98). The National
      Institute for Occupational Safety and Health (NIOSH) recommends method 6004 (ion
      exchange chromatography) for determination of ambient levels of sulphur dioxide
      (NIO94). This method is specific for sulphur dioxide and applicable for short-term
      sampling (range: 0.5-20 mg/m3 per 100 L air sample).
24    Sulphur dioxide
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<pre>      Concerning personal exposures, direct reading pocket dosimeters may be used, as is
      described in a protocol, called ‘Voornorm NVN 2950’, from the Dutch Normalisation
      Institute (NNI90).
2.4.2 Biological monitoring
      No method is established for assessing a biological index of exposure.
      Identity, properties and monitoring                                                25
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<pre>26 Sulphur dioxide</pre>

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<pre>Chapter 3
        Sources
3.1     Natural occurrence
        Gaseous sulphur dioxide is emitted mostly by volcanic activity and being a combustion
        product, it may be released into the atmosphere by natural fires.
3.2     Man-made sources
3.2.1   Production
        Sulphur dioxide is produced by: combustion of sulphur; roasting of sulphide ores (iron
        pyrites); and by calcination of natural sulphates. The gas thus obtained is purified,
        liquefied, and stored in special containers or converted to sulphuric acid in suitable
        industrial facilities.
            Sulphur dioxide is generally available as a compressed gas (Bur95), in industrial or
        commercial grade (99.98% pure), with a moisture content set at 100 ppm max. There is
        also a refrigeration grade with a maximum water content set at 50 ppm.
            The committee did not find information on the production of sulphur dioxide in the
        European Union countries. In the USA, in 1990, sulphur dioxide was produced at a level
        of 290 thousand tonnes (IAR92).
        Sources                                                                                  27
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<pre>3.2.2 Use
      Sulphur dioxide has various commercial uses. The dominant uses of sulphur dioxide are
      as a captive intermediate in the production of sulphuric acid and in the pulp and paper
      industry for sulphite pulping. Other uses are found within (SCO93, IAR92, Bur95):
      • the chemical industry: intermediate production of bleaches; reducing agent;
      • the food processing, beverage industry and agriculture: fumigant; preservative;
          bleach and steeping agent for grain; disinfectant; antioxidant;
      • the oil refining industry: elimination oxygen in petroleum of deep deposits;
          extraction solvent; co-catalyst;
      • the mineral industry: flotation depressants for disulphide ores; reduction of ferric to
          ferrous ions;
      • the bromine industry: antioxidant;
      • the water treatment: reduction of residual chlorine after chlorination; antioxidant.
      No quantitative data is available on the use of sulphur dioxide in the Netherlands or
      other European countries.
28    Sulphur dioxide
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<pre>Chapter 4
        Exposure
4.1     General population
        In Europe, emission of sulphur dioxide from industry and energy producing plants has
        been considerably decreased over the last two decades. In the Netherlands, the total
        annual emission of sulphur dioxide in the atmosphere decreased from 487 thousand
        tonnes in 1980 to 91 thousand tonnes in 2000. Of the latter, 55% is emitted by industry,
        26% by automobiles and 15% by power plants (RIV01).
             As a result of the reduced production and emission, the ambient air concentration of
        sulphur dioxide has also considerably decreased: in Europe with 40% over the last two
        decades. In the Netherlands in 1997, ambient air concentrations of sulphur dioxide
        averaged 6, 9 and 10 µg/m3, measured over one year in the countryside, streets and
        cities, respectively; with 24-hour peaks of 100, 90 and 60 µg/m3 and one-hour peaks of
        270, 210 and 210 µg/m3, respectively (RIV00).
             Indoor concentrations of sulphur dioxide are generally lower than outdoor
        concentrations, because sulphur dioxide absorption occurs on walls, furniture, clothes
        and in ventilation systems (WHO87).
4.2     Working population
        Sulphur dioxide may be present in industrial environments, arising from processes in
        which the gas is handled or evolved, and from combustion sources. The number of
        workers worldwide exposed to sulphur dioxide has been estimated to be several
        Exposure                                                                                  29
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<pre>   millions. For instance, in the USA, NIOSH estimated that about 500,000 workers were
   exposed in 1974; the corresponding figure in Finland was 10,000 in 1991 (IAR92). No
   data is available on the number of occupationally exposed workers in the Netherlands.
        Even though sulphur dioxide is widely used for a large number of industrial
   applications, there only have been few studies published on occupational exposure
   levels. Most of these studies are of limited use, because they are deficient in terms of
   current scientific criteria. The main limitations relate to: sizeable fluctuations in
   concentration levels in the workplace; variations in exposure duration; the quality of the
   monitoring techniques which has varied over the years; concurrent exposure to other
   gaseous chemicals or particulates; and, absence of source specification of sulphur
   dioxide release (IAR92, SCO93).
        IARC (IAR92) and the SCOEL (SCO93) reviewed papers on exposure levels of
   sulphur dioxide in the workplace. These papers were published before 1991. Below, a
   summary of their findings is given.
   In the pulp making and paper industry, mean concentrations of sulphur dioxide ranged
   from below detection level up to 68.1 mg/m3, covering the period of 1954 to 1963. The
   variation is, for instance, explained by variations in the sampling time (mainly short-
   term measurements) and the type of operation. Short-term peak values of up to
   266 mg/m3 were measured in four Norwegian pulp making and paper plants (Ska64).
        Covering the period of 1940-1986, mean levels of sulphur dioxide were lower than
   2.6 mg/m3 in nickel, zinc, aluminium smelters and steel mills, but between 2.6 and 26
   mg/m3 in copper smelters. Occasionally higher levels were measured.
        Measurements of sulphur dioxide in other types of industry have revealed large
   variations. Most of these measurement stayed below 10 mg/m3: 7.7 mg/m3 (beverage
   industry); between less than 3 and 5 mg/m3 (sulphuric acid plants, long-term
   measurements); and, <2.6 mg/m3 (e.g. close to diesel engines, photographic
   laboratories, mineral fibre plant). Moreover, in all these industries peak exposure have
   been observed. More detailed information on exposure levels can be found in the
   publications of Kangas (Kan91) and FIOH (FIO90).
        More recently, Benke et al. (Ben98) published a review on the exposure levels to
   several chemicals within the alumina and primary aluminium industry. In that review,
   the study by Chan-Yeung et al. (Cha89) was discussed. They reported a mean of
   2.0 mg/m3 (n=121, TWA 8 hours) for measurements undertaken in 1980 compared to
   2.1 mg/m3 (n=53) for the same smelter in 1986. However, Kongerud and Ramjør
   (Kon91) and Desjardins et al. (Des94) measured lower levels: 0.42 mg/m3 (breathing
   zone samples, n=75, Norway) and 1.0 mg/m3 (0.4 ppm, Canada), respectively.
        In 1999, Teschke et al. (Tes99) published the results of an international study on the
   occupational exposure to sulphur dioxide in the non-production departments of pulp,
30 Sulphur dioxide
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<pre>paper and paper product mills. The data included exposure measurements of 246
chemical agents taken from the 1950s to the 1990s. For sulphur dioxide the following
mean concentrations were measured (TWA > 1 hour): 19.0 mg/m3 (7.1 ppm,
maintenance, construction, cleaning, n=40); 19.5 mg/m3 (7.3 ppm, storage, yard,
loading, shipping, n=11); 1.9 mg/m3 (0.71 ppm, steam and power generation, n=45);
and, 0.013 mg/m3 (0.005 ppm, effluent water treatment, n=39). However, most of the
samples were below detection limit (limit not given). Hence, no further measurements
was undertaken for sulphur dioxide.
Exposure                                                                             31
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<pre>32 Sulphur dioxide</pre>

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<pre>Chapter 5
        Kinetics
5.1     Absorption
        Sulphur dioxide is a highly water-soluble gas. As a result, the substance is rapidly
        absorbed in the moist upper respiratory tract after inhalation, as was shown in both man
        and mammals (Spe66a/b, Bal60). Sulphur dioxide may reach the lower respiratory tract
        by oral inhalation and deep breathing, for instance during doing heavy work or exercise.
        When rabbits were exposed to a concentration of 2.7 mg/m3, approximately 40% of the
        sulphur dioxide was absorbed by the nasopharyngeal mucosa. This increased to 95%
        when the exposure increased from 26.6 to 266 mg/m3 (Str64).
            In the moist mucous membranes, sulphur dioxide is rapidly hydrated to sulphurous
        acid (H2SO3). This sulphurous acid dissociates easily into sulphite (SO32-) and
        bisulphite (HSO3-) ions. Sulphite ions are then rapidly converted into sulphate, whereas
        bisulphite ions bind to proteins to form S-sulphonates (IAR92).
5.2     Distribution
        In all species studied, the sulphur dioxide that is absorbed passes through the blood and
        lymph to all body tissues. When beagle dogs inhaled radio-labelled sulphur dioxide after
        tracheotomy, most of the substance concentrated in the trachea, bronchi, lungs and
        lymph nodes of the hilus, and in decreasing amounts in the kidneys, oesophagus,
        ovaries, stomach and other tissues. Only minimal amounts were found in the liver,
        spleen and cardiac muscles (Bal60).
        Kinetics                                                                                  33
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<pre>        In the blood, a main part of sulphur dioxide is bound to serum proteins as S-sulpho-
    nates (Gun71, Men86). Free sulphur dioxide is transported almost totally as bisulphite.
5.3 Biotransformation
    Sulphite ions are rapidly metabolised to sulphate by sulphite oxidase, an enzyme with
    low activity in lung tissue. Sulphate, which is also an endogenous metabolite in
    mammals, is incorporated in the large sulphate pool of the body (IAR92).
        Bisulphite ions react (sulphonation or auto-oxidation) with biomolecules, such as
    cysteine containing proteins and DNA, to form S-sulphonates. Formation of sulphonates
    prolongs the presence of sulphur dioxide in the body (Yok71).
5.4 Elimination
    Part of the inhaled sulphur dioxide is exhaled before the body absorbs it. Another part is
    eliminated by conversion into sulphurous acid on contact with moist upper respiratory
    tract (Bal69, Fra69).
        Circulating S-sulphonates slowly decompose into sulphur dioxide or sulphates. The
    sulphur dioxide is exhaled, whereas sulphates become part of the endogenous sulphate
    pool. These sulphates are slowly released via the blood into the urine (Cal81).
5.5 Possibilities for biological monitoring
    Given the toxicokinetic characteristics of sulphur dioxide described previously, no
    method has been published that allow for determination of biochemical or functional
    parameters useful for biological monitoring of occupational exposure. Also S-
    sulphonate cannot be used for biological monitoring, because it is not a specific
    parameter for sulphur dioxide exposure.
5.6 Summary and evaluation
    Sulphur dioxide is highly soluble in aqueous media. On contact with the moisture of the
    nasal mucosa, sulphur dioxide is rapidly hydrated to sulphurous acid, which quickly
    dissociates into sulphite and bisulphite ions. Once absorbed, sulphite is oxidised into
    sulphate, and bisulphite is covalently bound to plasma and cellular proteins to form S-
    sulphonates. Sulphates become part of the large sulphate pool within the body, from
    which it is slowly released and primarily excreted from the body in the urine. Circula-
    ting S-sulphonates decompose into sulphur dioxide, which is then exhaled, or into
    sulphate.
34  Sulphur dioxide
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<pre>Chapter 6
        Effects
        Numerous studies have been published on the adverse effects of sulphur dioxide
        inhalation. In addition, the committee derived data for this report primarily from the
        SCOEL documents (published in 1993 and 1997), supplemented with recent
        publications. Furthermore, the committee restricted its assessment to low exposure
        concentration data.
6.1     Observations in humans
6.1.1   Irritation and sensitisation
        Irritation
        Sulphur dioxide is irritating to the eyes and upper respiratory tract, such as the nose and
        throat (SCO93, Dou87). Inhalation of sulphur dioxide at a concentration of 10.7 mg/m3
        (6 ppm) or higher, caused instantaneous mucous membrane irritation. This is
        accompanied with symptoms, including: ocular irritation and lacrimation; rhinorrhae;
        coughing; shortness of breath; chest tightness or discomfort; and, a choking sensation
        (Sul92). At very high concentrations (SCO93, no levels reported), the absorption
        capacity of the upper respiratory airways may be exceeded, resulting in pathological
        changes that include: laryngotracheal and pulmonary oedema; and, symptoms, such as
        bronchoconstriction. These pathological changes and symptoms may result in death. In
        fact, in the general population, a clear positive association has been reported between
        Effects                                                                                     35
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<pre>      those pathologies and day-to-day changes in hospitalisation rates and deaths (And97).
      The day-to-day changes are the result of the daily variations in the outdoor
      concentration of sulphur dioxide.
           Concerning the mechanism of bronchoconstriction, it is thought that sulphur dioxide
      stimulates irritant receptors, present in the epithelium of the upper airways (Cos99).
      Stimulation of these receptors activates the nerve endings of involuntary muscles in the
      bronchi, resulting in bronchoconstriction. Atropine, a sympathetic cholinergic blocking
      agent, can completely deactivate these nerve endings, resulting in relaxation of the
      involuntary muscles. When given to normal adults, who were exposed to sulphur
      dioxide, the bronchoconstriction was completely prevented (Nad65). However, when
      given to exposed asthmatics, atropine was only partial effective (Kor79). The difference
      in reaction between normal and asthmatic people is still not clarified.
      Liquid sulphur dioxide may cause frostbite or severe corneal damage by direct contact
      on the skin and eyes, respectively (Bur95).
      Sensitisation
      No human data has been presented, suggesting that sulphur dioxide may be a sensitising
      agent through immunologic mechanisms. However, in the literature, it has been
      suggested that air pollutants, such as sulphur dioxide, promote airway sensitisation by
      modulating the allergenicity of airborne allergens. In addition, it has been suggested that
      the sulphur dioxide-induced mucosal airway damage and impaired mucociliary
      clearance may facilitate the penetration and access of inhaled allergens to the cells of the
      immune system (D’Am02a and D’Am02b).
6.1.2 Toxicity due to acute and short-term exposure
      Healthy subjects
      A summary of the most relevant studies with healthy persons is given in Annex F.
      In a double-blind study, twelve normal and twelve mildly asthmatic adults, all non-
      smokers, were exposed to clean air or to a single dose of 0.53 mg/m3 (200 ppb) sulphur
      dioxide for 1 hour during rest. No significant changes in lung function (e.g. FEV1) or in
      maximum or minimum heart rates were found in any of the exposed subjects. However,
      spectral analysis of heart rate variability with sulphur dioxide exposure in normal
      subjects showed: higher values for total power (TP); high frequency power (HF); and,
      low frequency power (LF) compared to air (p<0.05 for TP) in normal subjects. In
36    Sulphur dioxide
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<pre>asthmatics, all three indices were lower, although not statistically significant. The
authors also suggest that sulphur dioxide exposure can influence the autonomic nervous
system, which may be important in understanding the mechanism involved in sulphur
dioxide induced bronchoconstriction and of the cardiovascular effects of air pollution.
Therefore, they cannot exclude the possibility that asthmatic subjects with a heart
disease may develop serious health problems (Tun01).
     The committee noted that spectral analysis of heart rate variability is an extremely
sensitive parameter, which currently is hard to extrapolate to chronic effects observed in
humans. Moreover, the effects of sulphur dioxide on heart rate variability in healthy
subjects were more positive than negative, while for asthmatic subjects they were
uncertain. The committee, therefore, believes that this study is of little relevance for risk
assessment.
     Weir et al. (Wei72, abstract only) reported on four groups of three healthy males,
who were continuously exposed in randomised sequence for 120-hour periods to 0, 0.8,
2.7 and 8.0 mg/m3 (0, 0.3, 1.0 and 3.0 ppm) sulphur dioxide. No dose-related changes
were observed concerning subjective complaints, clinical evaluation and most
pulmonary function measurements. The only significant but minimal effect observed by
the authors was decreased airway conductance and compliance at 8 mg/m3, which
returned to normal after stopping the exposure.
     Sandström et al. (San88) exposed eight healthy, non-smoking individuals to clean
filtered air or to 1, 5 and 10 mg/m3 (0.4, 2 and 4 ppm) sulphur dioxide for 20 minutes.
During the exposure the individuals exercised on a bicycle ergometer for 15 minutes. No
differences in heart rate was observed at the different exposure, nor were there any
significant changes in lung function. A few individuals complained about mild eye
symptoms, mild breathlessness and cough. These complaints were not related to the
exposed concentration. However, a concentration-related increase in nasal and throat
irritation was observed.
     Islam et al. (Isl92) examined the acute bronchomotoric effects of a low
concentration of sulphur dioxide in twenty-six young, non-smoking volunteers (9
females, 17 males; age range: 15-26 years). Half of them performed eucapnic
hyperventilation with dry filtered air via a mouthpiece for 5 minutes. This procedure
was repeated thirty minutes later, but this time with 1.6-2.0 mg/m3 sulphur dioxide
(exact concentration not given). The other half of the volunteers did the same, but in
reverse order (first sulphur dioxide exposure and then filtered air). Specific airway
resistance measurements were taken before, immediately, 10 and 20 minutes after each
eucapnic hyperventilation. Following hyperventilation with or without sulphur dioxide,
all subjects showed variable degrees of bronchoconstriction. However, the authors
found a stronger increase of specific airway resistance with sulphur dioxide than without
(p<0.01). Also, the authors considered 13 out of the 26 subjects as responders (3
Effects                                                                                       37
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<pre>   females, 10 males), because they showed a more than 100% increase in specific airway
   resistance (sRaw). The mean increase in specific airway resistance was significantly
   higher in these responders than in the non-responders (p<0.001). All values tended to
   return to normal 20 minutes after the last exposure.
       Two years later, the same group of investigators reported on a second study with
   comparable results (Isl94). In the second study, 37 healthy non-smoking volunteers
   were exposed to 1.9 mg/m3 for 5 minutes during eucapnic hyperventilation. Three
   minutes after ending the exposure the specific airway resistance was significantly
   increased. After stopping the exposure, values returned to normal between 20 and 40
   minutes. Of the 37 subjects, 14 were considered responders (increase of sRaw ≥ 100%).
   In addition, the authors found an age dependent airway responsiveness to sulphur
   dioxide exposure, suggesting that airway responsiveness to sulphur dioxide is more
   frequent among volunteers below than above 30 years of age.
       The committee noted that in both studies by Islam et al., none of the volunteers were
   exposed to sulphur dioxide while breathing normally.
       In another study, healthy, non-smoking, Caucasian, male volunteers (n=11) were
   exposed to a single concentration of 2.0 mg/m3 (0.75 ppm) sulphur dioxide for 4 hours
   while doing two 15-min exercise sessions on a treadmill (at 2 and 4 hours into
   exposure). Just prior to exposure (air control) 2 and 4 hours into the exposure, and 24
   hours after exposure, pulmonary function was tested by spirometry. The investigators
   did not find any significant change in lung function, such as in airway resistance, lung
   volume and airflow measurement responses were observed (Sta83).
       Carson et al. (Car87), exposed seven healthy volunteers to 2.0 mg/m3 (0.75 ppm)
   sulphur dioxide for two hours. As a result of this exposure, four volunteers showed
   damage to the nasal epithelium. This damage was characterised as compounded cilia.
   Compounded cilia are fused cilia or cilia melted together, which may occur following
   viral infections or exposure to toxic substances. According to the authors, their results
   suggest that sulphur dioxide may be a causative agent in ciliary compounding in the
   upper respiratory tract.
       The committee, however, considers these findings inconclusive, because after
   exposure nasal samples were taken on the contralateral nasal turbinate instead on the
   inferior nasal turbinate, as was done before exposure.
       Fifteen healthy male subjects, four of whom were smokers, were exposed to
   2.7 mg/m3 (1 ppm) sulphur dioxide on day one; 13.4 mg/m3 (5 ppm) on day two; and,
   66.8 mg/m3 (25 ppm) on day three, for 6 hours per day on three consecutive days
   (And74). Exposure to sulphur dioxide caused a dose-dependent and significant increase
   in nasal airflow resistance and a fall in forced expiratory volume. Even the lowest
   concentration caused a significant effect (p<0.05) compared to clean air exposure. The
   authors, furthermore, observed that the volunteers, when they were exposed to the
38 Sulphur dioxide
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<pre>lowest concentration showed more pronounced airway resistance in the first three hours
of exposure than in the last four to six exposure hours.
     The committee noted that in the study no distinction was made between smokers
and non-smokers.
     Lawther et al. (Law75) conducted a series of experiments with 12 or 13 healthy
persons, who were free from respiratory symptoms. They were exposed to filtered air or
to 2.7 and 8.0 mg/m3 (1 and 3 ppm) sulphur dioxide with or without forced deep
breathing. Deep breathing was needed to increase penetration of sulphur dioxide into the
lung. Some exposures were done in an exposure chamber, whereas other exposures were
done by deep breaths from a bag containing sulphur dioxide or air. Exposure to 2.7 mg/
m3 sulphur dioxide for one hour caused no significant changes in lung function and
airway resistance, with normal breathing. However, deep breathing increased airway
resistance and this increased even more in volunteers exposed to 8.0 mg/m3 with deep
breathing. Apart from that, the authors observed a wide range of sensitivities to sulphur
dioxide among the subjects. Also, they reported that the changes in airway resistance
were short-lived.
     Frank (Fra80) published a study, in which healthy volunteers (n=7; controls, n=6)
were exposed to a mixture of 2.7 mg/m3 sulphur dioxide plus 1 mg/m3 NaCl for two
hours, while doing moderate exercise (walking on an inclined treadmill at a speed
increasing the minute ventilation five to six fold). In the exposed volunteers, the
observed a significant increase in pulmonary flow resistance compared to the control
subjects breathing clean air. Furthermore, half of the exposed subjects experienced
shortness of breath and wheezing.
     Kulle et al. (Kul84) performed a study with normal, healthy, non-smoking
volunteers (n=10/sex) to evaluate the effects of sulphur dioxide on pulmonary function
and non specific bronchial reactivity to methacholine. The subjects were exposed to
2.7 mg/m3 (1 ppm) sulphur dioxide for 4 hours. The day before and the day after sulphur
dioxide exposure all subjects breathed clean filtered air for 4 hours (control days).
During the exposure and control days, all subjects performed physical exercise on a
bicycle ergometer, two times for 15 minutes. Pulmonary function was assessed both
before and after exposure. Challenges with methacholine were performed immediately
after the end of each exposure. No significant changes in pulmonary function and
bronchial reactivity to methacholine were observed. During exposure to sulphur
dioxide, four subjects complained about upper respiratory irritation and one about eye
irritation during exposure to sulphur dioxide. In a comparable study performed by the
same authors, the lung function parameters FEF25-27% and FEV1/FVC were decreased
17 minutes after the start of the exposure. Also nose and throat irritation worsened.
However, these changes in lung function parameters and complaints about irritation
were completely gone the day after exposure (Kul86).
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<pre>       Young non-smoking adults (n=9) were exposed to a concentration of sulphur
   dioxide of 2.7 or 5.3 mg/m3 for two hours without physical exercise, or during three 30-
   min sessions of physical exercise (Bed84). Of the several lung function parameters
   measured (thoracic gas volume, maximal voluntary ventilation, functional residual
   capacity), only the specific airway resistance was significantly increased from 1.77 to
   1.95 cm H2O/sec or from 1.73 to 1.88 cm H2O/sec when exposed to 2.7 or 5.3 mg/m3,
   respectively. In a subsequent study, however, no changes in airway resistance was found
   in volunteers (n=14) exposed to 5.3 mg/m3 for 30 minutes while doing physical exercise
   (Bed89).
       In two other studies, performed by the group of Sandström (San89a and b),
   volunteers (n=12/group) were exposed to 10 or 20 mg/m3 (4 and 8 ppm) sulphur dioxide
   for 20 minutes. Before and 24 hours after the exposure, the number of alveolar macro-
   phages were measured. A significant (p<0.01) increase in total number (0.8x107/L) and
   percentage (14%) of lysozyme positive macrophages were observed in the low-dose
   group compared to the values before exposure (0.4x107/L and 5%). Even larger
   increases were observed in subjects exposed to 20 mg/m3; this was accompanied with an
   increase in macrophages and lymphocytes. All values returned to normal within 72
   hours after exposure.
   Asthmatic subjects
   Several laboratory studies have been published on exposure effects of sulphur dioxide in
   asthmatic persons. The most relevant publications are discussed below.
   In 1984, the interaction between low ambient temperature and lung function were
   studied in asthmatic persons. Eight asthmatics were exposed for successive 3-min
   periods with doubling concentrations of sulphur dioxide of 0.3, 0.7, 1.3, 2.7 and
   5.3 mg/m3, on three separate days (She84). The concentration of sulphur dioxide
   inducing a '100% increase of specific airway resistance' increased immediately with
   increasing ambient temperature: 1.36±0.53 mg/m3, cold dry air (-20°C, 0% humidity);
   1.60±1.07 mg/m3, dry warm air (22°C, 0% humidity); and, 2.32±1.09 mg/m3, warm
   humid air (22°C, 70% humidity). In these ambient conditions, breathing clean air did
   not change specific airway resistance values.
       Linn et al. (Lin84a) investigated the relation between low ambient temperature
   (5°C), relative humidity (50% or 85%) and sulphur dioxide exposure (0.5, 1.1 or
   1.6 mg/m3). Eight asthmatic persons were exposed for 5 min, while heavy exercising.
   All persons showed slight exacerbated bronchial constriction, and this was independent
   on the relative humidity and exposure level. The authors ascribed the observed effects
   totally to sulphur dioxide exposure (Lin84a).
40 Sulphur dioxide
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<pre>     The group of Linn et al. (Lin87) published another study, in which healthy
volunteers (n=24), atopics (n=21, not asthmatic), volunteers with minimal or mild
asthma (n=16) and volunteers with moderate or severe asthma (n=24) participated. They
were exposed to clean air or to concentrations of sulphur dioxide of 0.5, 1.1 and
1.6 mg/m3 for 1 hour, while doing three 10-min periods of exercises. Normal subjects
and most atopics showed little response. However, a few atopics and a lot of asthmatics
developed bronchoconstriction and respiratory symptoms. The authors could not relate
these effects reliably by clinical status, by responsiveness to sulphur dioxide or by
exercising.
     Ten volunteers with mild atopic asthma were exposed to 0.53 mg/m3 (200 ppb)
sulphur dioxide or air for 6 hours (Dev94). Ten minutes after the exposure, they were
challenged with pre-determined concentrations of extracts of house dust mite
(Dermatophagoides pteronyssinus). Sulphur dioxide did not alter the airway response
(FEV1, FVC, and cumulative breath units of D. pteronyssinus allergen required to
produce a 20% fall in FEV1 (PD20FEV1)).
     Schachter et al. (Sch84) examined the acute respiratory effects of sulphur dioxide in
ten asthmatic and ten healthy subjects. These subjects were exposed in a double-blind
random sequence to clean air, 0.7, 1.3, 2.0 and 2.7 mg/m3 (0.25, 0.50, 0.75 and 1.0 ppm)
sulphur dioxide for 40 minutes, including moderate exercise on a cycloergometer in the
first 10 minutes of exposure. On a separate day, subjects were exposed to clean air and
2.7 mg/m3 sulphur dioxide in the absence of exercise. No changes in pulmonary
function tests, including airway resistance tests, were observed in healthy subjects on
any day, or in asthmatic subjects at rest. However, when the same asthmatic subjects
performed moderate exercise, consistent decrements in most lung functions occurred in
the groups exposed to 2.0 and 2.7 mg/m3 sulphur dioxide. At 0.7 and 1.3 mg/m3,
statistically significant changes in lung function parameters were confined to small
drops in flow rates at low lung volumes.
     In another study, non-smoking males (n=28), having mild asthma and being
hyperresponsive to methacholine, were exposed to clean air, 0.7, 1.3 or 2.7 mg/m3 (0.25,
0.5 and 1 ppm) sulphur dioxide with natural breathing for 75 minutes. Each exposure
included three 10-min periods of moderate treadmill exercise. In subjects exposed to 1.3
and 2.7 mg/m3, the specific airway resistance increased twofold and threefold,
respectively, compared to the pre-exposure levels (clean air). In the first exercise period
the increase of the specific airway resistance was higher than in the two following
periods, suggesting adaptation. No significant increase was observed at 0.7 mg/m3
compared to clean air exposure (Rog85).
A comparable study was reported by Witek and Schachter (Wit85). Asthmatic persons
were exposed in double blind random order to clean air, 0.7, 1.3, 2.0 and 2.7 mg/m3
Effects                                                                                     41
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<pre>   (0.25, 0.5, 0.75 and 1 ppm) for 5 to 10 minutes. They were then asked to perform
   moderate exercise for 10 minutes, which was followed by a second exposure of 30
   minutes. Pulmonary function was measured prior to and at several time intervals after
   the second exposure. On the next day, methacholine inhalation challenges were
   performed using progressive concentrations of up to 25 mg/mL. Lung function was
   assessed before and after challenges with methacholine. A significant correlation existed
   between the concentration of sulphur dioxide and the concentration of methacholine
   required to produce bronchoconstriction (r=0.86; p<0.05): the higher the response to
   sulphur dioxide, the higher the response to metacholine. The authors concluded that
   individuals with greater non-specific sensitivity might be more vulnerable to
   bronchospasm from elevated sulphur dioxide concentrations than normal individuals.
       Young volunteers (n=24), suffering from chronic obstructive pulmonary diseases,
   including: chronic bronchitis; pulmonary emphysema; asthma; and, chronic
   bronchitiectasis, were exposed to clean air, 1.1 or 2.1 mg/m3 sulphur dioxide for one
   hour, while doing two 15-min periods of mild or strenuous exercises. No statistically
   significant changes in physiology or symptoms could be attributed to sulphur dioxide
   exposure (Lin85).
       Bethel et al. (Bet83) exposed ten persons suffering from mild asthma to 1.3 mg/m3
   sulphur dioxide for 5 minutes, while performing moderate exercise. As a result, their
   specific airway resistance increased from 2.24 (clean air control) to 13.55 cm H2Oxsec
   (p<0.005). In a subsequent study with similar experimental conditions (n=9 subjects,
   exercising more vigorously), bronchoconstriction was also induced at 0.7 mg/m3
   (specific airway resistance from 5.23 to 12.54 cm H2Oxsec). However, the authors
   found out that these inductions did not differ from the results obtained when the same
   persons were exposed to filtered air only (specific airway resistance from 6.71 to 13.59
   cm H2Oxsec). Therefore, they concluded that the effect of sulphur dioxide exposure on
   bronchoconstriction is small and largely overshadowed by the bronchoconstrictor effect
   of doing exercise alone (Bet85).
       Asthmatic subjects (n=14) were exposed to purified air or to 1.6 mg/m3 sulphur
   dioxide for 6 hours on two successive days (Lin84b). Both at the beginning (early) and 5
   hours (late) after starting the exposure, the subjects exercised heavily for 5 minutes.
   During or immediately following early or late exercise, bronchoconstriction and lower
   respiratory symptoms were observed in both groups. However, the effects in the group
   exposed to sulphur dioxide were more marked than in the group exposure to clean air.
   On the second day, the symptoms were less severe than on the first day. In addition, no
   meaningful differences in response between early and late exercise periods on either day
   were observed.
       Eleven volunteers with asthma were exposed to filtered air or to 2.0 mg/m3 (0.75
   ppm) sulphur dioxide for 10 minutes, while exercising. Sulphur dioxide increased
42 Sulphur dioxide
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<pre>      significantly the specific airway resistance and lowered, also significantly, the FEV1
      compared to air exposure. Furthermore, the total symptom score was increased
      (symptoms scored amongst others cough, sputum, dyspnoea, wheeze, chest tightness,
      and throat and eye irritation). However, the authors did not mention whether or not these
      parameters were significantly changed. No differences were found between air- and
      sulphur dioxide-exposed subjects regarding total cell counts from sputum. However, the
      percentage of eosinophils was significantly increased in sulphur dioxide-exposed
      individuals compared to clean air-exposed individuals (Gon01).
           Ten asthmatic volunteers were exposed to clean air or to sulphur dioxide at a
      concentration of 2.7 mg/m3 (26°C, 70% relative humidity) for 1 hour, while performing
      3 sets of 10-min exercises. Their specific airway resistance increased rapidly after the
      start of the exposure, which persisted during the 30 minutes of exposure: from 5.4
      (before exposure), 14.7 (after first exercise), 12.8 (after second exercise) to 11.1 cm
      H2O/sec (after third exercise). All sulphur dioxide responses were significantly higher
      than the clean air responses (Keh87).
6.1.3 Case reports
      In none of the case studies reported below, the authors mentioned the levels to which the
      workers were accidentally exposed, although they surmised that these were high.
      Overall, acute poisoning from inhalation of very high concentrations of sulphur dioxide
      is characterised by intense irritation of the conjunctiva and upper respiratory tract
      mucosa with dyspnoea and cyanosis, followed rapidly by loss of consciousness. This
      may lead to death (Ste98).
           One 25-year-old previously healthy carpenter was exposed to sulphur dioxide at
      high concentrations for 15 to 20 minutes. An immediate episode of pulmonary oedema
      was followed by a silent interval with subsequent development of a severe, irreversible
      obstructive syndrome (Woo79).
           Two maintenance workers were accidentally exposed to concentrated sulphur
      dioxide steam. Both subjects died of respiratory arrest within 5 minutes. Two other
      workers, who were near the exposure area, developed symptomatic severe airway
      obstruction and, asymptomatic mild obstructive and restrictive disease, respectively. A
      fifth subject continued to be asymptomatic with normal pulmonary function tests. The
      pulmonary function tests were performed on day 1, 50, 69 and 116 after the exposure
      (Cha79).
           In 1983, a case report was published, in which lung function was followed for 4
      years in seven Finnish men, who were exposed to sulphur dioxide in a pyrites dust
      explosion. The authors suggested that the bronchial hyperreactivity, such as observed in
      Effects                                                                                   43
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<pre>      these men, may be a frequent sequel after exposure to high concentrations of sulphur
      dioxide and, that hyperreactivity may persist for several years (Har83).
           In another case report, two non-smoking Canadian miners were followed over a
      two-year period, after being exposed to high concentrations of sulphur dioxide after a
      mine explosion (Rab89). The authors observed that: acute exposure to high levels of
      sulphur dioxide resulted in severe airway obstruction; these abnormalities are partially
      reversible; and, that most of the improvement occurred within 12 months after initial
      injury.
           These four case reports have been described briefly by Testud et al. (Tes00). In the
      same review, they reported also on six cases of sulphur dioxide-induced respiratory
      symptoms. These cases were identified during a survey of wine cellars in the French
      Beaujolais district.
6.1.4 Epidemiological studies
      General effects
      Stjernberg et al. (Stj84) performed a longitudinal study in employees of a sulphite pulp
      factory combined with a paper mill. Of the 41 workers exposed to sulphur dioxide
      (concentrations not measured) in 1966, three suffered from chronic bronchitis, whereas
      13 of them suffered from it in the1980 re-examination. For comparison, of the 10
      control workers, who were not directly exposed to irritating gases, only two had
      developed chronic bronchitis in 1980.
      Mortality and cancer
      Lee and Fraumeni (Lee69) performed a mortality study on 8,047 white males, who
      worked in copper smelters in the US. The smelter workers were simultaneously exposed
      to inorganic arsenic and sulphur dioxide. Depending on the work area, they were
      categorised according to three qualitative exposure doses: light, medium and heavy. No
      quantitative exposure data were presented. The excess of respiratory cancer showed a
      gradient in proportion to the degree of exposure to arsenic and accompanied by high or
      moderate exposure to sulphur dioxide. The authors suggested that sulphur dioxide might
      have enhanced the carcinogenic effect of arsenic.
           The committee noted that the authors could not make a distinction between arsenic
      and sulphur dioxide exposure. Also, in this study, smoking habits were not taken into
      account.
           Years later, a new study was performed on 1,800 men, who worked in the same
      factory. However, now they were classified in 4 exposure categories, with respect to
44    Sulphur dioxide
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<pre>arsenic and three exposure sulphur dioxide exposure categories: low, medium and high
(Wel82). A clear dose-response relationship was demonstrated between arsenic
exposure and respiratory cancer. The influence of sulphur dioxide exposure did not
appear to be of importance. The authors recognised that it was impossible to separate
completely arsenic exposure from that of sulphur dioxide exposure, because the workers
were always exposed simultaneously to inorganic arsenic and sulphur dioxide.
     Enterline et al. (Ent87), investigated the mortality of 6,078 male copper smelter
workers, who were employed for at least three years between 1949 and 1980. They
found a dose-dependent relationship between lung cancer and exposure to arsenic and
sulphur dioxide. However, when smoking habits were taken into account, they found
that only smoking and arsenic enhanced significantly the mortality figures of cancer.
     A historical study on 400 male workers exposed to sulphur dioxide, while employed
in a sulphuric acid plant in Sweden between 1961 and 1985, showed an increased
mortality. The increase was mainly explained by an increase of bladder cancer. No
relation could be assessed between increased mortality and the presence of non-
malignant or malignant respiratory diseases. The median of the yearly time weighted
averages was 9.1 (range 2.4-124) mg/m3 at stationary sampling and 3.6 (1.1-23) mg/m3
in the respiratory zone. Considerably higher peak levels were recorded occasionally
(Eng88).
     Abbey et al. (Abb99) studied the number of deaths in a cohort of 6,338 non-
smoking California Seventh-day Adventists from 1977 through 1992. The purpose of
this investigation was to study the relationship between long-term ambient
concentrations of air pollutants, such as sulphur dioxide, and mortality. Estimates of
monthly ambient concentrations of sulphur dioxide and other pollutants were formed for
the period 1966-1992 using fixed monitor stations. The average ambient sulphur dioxide
concentration between 1973 through 1992 was estimated to be 15 ± 7.5 µg/m3 (5.62 ±
2.81 ppb). The authors identified 1,628 study subjects who died, of which 30 died of
lung cancer. Sulphur dioxide was significantly associated with increased risk of lung
cancer mortality in both sexes (RR males, 1.99 (95% CI, 1.24-3.20); RR females, 3.01
(95% CI, 1.88-4.84)). This effect remained stable in two-pollutant models with other
pollutants. The association did not appear to be due to confounding by any of a large
number of measured risk factors (e.g. time spent indoors, time trends, smoking in the
past, food consumption) in this cohort. No associations were found for other death
causes, such as cardiopulmonary mortality. The authors realised that differences could
be due to measurement error and that some of the observed effects could be the result of
unknown correlation among pollutants and other confounding factors.
     Overall, the committee noted that, due to limitations in study design, from none of
these epidemiological studies concentration-response relationships could be assessed.
Additionally, of particular concern is the presence of confounding factors, such as co-
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<pre>      exposure, and the absence of information on smoking habits and other lifestyle factors.
      Also, the possible occurrence of adaptation to the irritant effect of sulphur dioxide is not
      well taken into account.
6.1.5 Other relevant studies
      Genotoxicity
      Chromosome breakages have been observed in lymphocyte cultures of healthy non-
      smoking human subjects exposed to various pollutants, such as sulphur dioxide, arsenic
      and lead (Bec86).
           In workers (n=40) chronically exposed to sulphur dioxide, the frequencies of
      chromosomal aberrations and sister chromatid exchanges in peripheral blood
      lymphocytes were significantly increased compared to non-exposed workers. No
      significant differences were found between smokers and non-smokers (Men90).
           Yadav and Kaushik (Yad96) investigated the genotoxic effects of sulphur dioxide
      exposure on workers of a fertiliser factory. From a total of 84 individuals, of which 42
      were exposed to an average of 41.7 mg/m3 sulphur dioxide in the ambient air, blood
      samples were taken and analysed. The frequency of sister chromatid exchanges and
      chromosomal aberrations increased significantly compared to non-exposed individuals.
      In addition, these frequencies increased significantly with the duration of exposure.
           Although the committee takes these observations as serious, the previous two
      studies have some limitations. For instance, the job history was not given. For this
      reason, the committee considers these human genotoxicity data to be insufficient to
      suggest that sulphur dioxide is genotoxic in humans.
6.2   Animal experiments
6.2.1 Irritation and sensitisation
      In animals sulphur dioxide is a respiratory irritant. As in humans, most of it is absorbed
      in the upper respiratory tract, whereas very little reaches the lungs. Detailed data on the
      irritant effects of sulphur dioxide are given in paragraph 6.2.3.
      Riedel et al. (Rie88) described the effects of sulphur dioxide exposure on local bronchial
      sensitisation to inhaled ovalbumin antigens. Perlbright-White female guinea pigs were
      exposed to ambient air or to sulphur dioxide at concentrations of 0.3, 11.5 or 44.3
      mg/m3 (0.1, 4.3 or 16.6 ppm, respectively) for 8 hours per day on 5 consecutive days.
      On days 3, 4 and 5, the exposure was followed by nebulized ovalbumin inhalation for 45
46    Sulphur dioxide
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<pre>      minutes. One week after ending the last exposure, specific bronchial provocation with
      inhaled ovalbumin, followed by plethysmographic measurements of airway obstruction
      was performed every two days during a period of two weeks. Bronchial reactions to
      inhaled ovalbumin was demonstrated in 1/14 (control), 4/6 (0.3 mg/m3), and all of the
      animals in the high-dose groups (11.5 and 44.3 mg/m3, n=5 and 6 animals, respec-
      tively). In all sulphur dioxide-exposed groups, the degree of bronchial obstruction was
      significantly higher than in the control group (p<0.05). Also, the level of ovalbumin-
      specific antibodies in serum and bronchoalveolar fluid was significantly increased
      compared to the control group (p<0.05). The authors concluded that exposure to sulphur
      dioxide at concentrations of 0.3 and 11.5 mg/m3 can facilitate local allergic sensitisation
      of ovalbumin in the guinea pig.
6.2.2 Toxicity due to acute exposure
      The SCOEL (SCO93) reviewed numerous publications on the acute exposure of sulphur
      dioxide, but stated that none of them were performed according to the codes of good
      laboratory practice. Below are described additional studies, which are not evaluated by
      SCOEL.
      Adult, male, Hartley guinea pigs (n=4/group) were exposed to clean air or to 1,070
      mg/m3 (400 ppm) sulphur dioxide for three hours. In the sulphur dioxide-exposed
      animals no damage was found in the epithelial lining or ciliated cells, although
      granulocyte invasion was observed in the tracheal basal membrane. Sulphur dioxide
      exposure significantly lowered the airway mucociliary transport velocity, a parameter
      for mucociliary clearance: 2.9±0.7 mm/min compared to 5.9±0.1 mm/min (control
      values). Even 24 hours after exposure, mucociliary transport velocity was still low
      (2.8±0.9 mm/min) (Kim99).
          Common ground squirrels (n=5/group), which were exposed to 1,350 mg/m3
      sulphur dioxide for 4 minutes, developed lung oedema. In addition, the pulmonary
      surface tension, which represents the amount of cardiac lipids, and protein content of
      cellular membranes were significantly reduced compared to controls (Ran79).
          Min et al. (Min94) investigated histopathologic changes in the olfactory epithelium
      after sulphur dioxide exposure. Female ICR mice (n=4/group) were exposed to a single
      dose of 53 mg/m3 (20 ppm) sulphur dioxide for 30, 60 or 120 minutes. The mice were
      sacrificed immediately, 24, 48 or 72 hours following exposure. Parameters measured
      included: inflammatory cell infiltration; oedema; desquamation of the epithelium in the
      nasal cavity; and, atrophy (loss of cilia). Injuries to the olfactory epithelium became
      more severe when the exposure lasted longer and were most evident at 24 hours.
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<pre>6.2.3 Toxicity due to short-term exposure
      SCOEL (SCO93) described several short-term studies on various animal species. With a
      few exceptions, the study results described in the original papers were of limited use,
      because of inadequate reporting. In addition, the experimental designs did not always
      meet the internationally accepted standards.
      Effects on the respiratory tract
      The committee noted that several studies have been carried out to investigate the
      pathogenesis of bronchitis. In these studies, bronchitis was induced after short-term
      exposure by sulphur dioxide.
           Tusl et al. (Tus83) continuously exposed mixed breed or Wistar male rats (n=not
      given) to 0.05, 0.5, 1.0 and 5.0 mg/m3 sulphur dioxide for 2, 4 or 6 weeks. The
      observations included: reduced number, viability and adhesion capacity of isolated
      alveolar macrophages; changed activities of cytoplasmic lactate dehydrogenase,
      lysosomal galactosidase, glucosidase and acid phosphatase. The committee noted that
      the results were not adequately described.
           Male Dunkin-Hartley guinea pigs were exposed to air (n=7) or to 0.27 mg/m3
      (0.1 ppm) sulphur dioxide (n=12) for 5 hours per day on 5 consecutive days. Other
      guinea pigs were also simultaneously exposed to ovalbumin aerosols. One week after
      the last exposure, all animals underwent bronchial challenge with 1% ovalbumin
      aerosols. Twenty-four hours after this challenge, bronchoalveolar lavage and
      histopathologic examinations were performed. None of the parameters tested, that is:
      airway resistance; infiltration of inflammatory cells; and, the histopathology of
      bronchial and lung tissue, were significantly changed after sulphur dioxide-exposure
      compared to animals exposed to clean air (Par01).
           Ferin and Leach (Fer73) investigated the effects of exposure to sulphur dioxide on
      lung clearance of inert particles (TiO2) in Long-Evans male rats. Lung clearance is part
      of the defensive mechanisms of the respiratory tract. The animals (n=9-10/group) were
      exposed to clean air or to 0.27, 2.7 and 53.4 mg/m3 (0.1, 1.0 and 20 ppm) sulphur
      dioxide for 7 hours/day, 5 days/week for 10 to 25 days. The day following the last
      exposure, all the animals were exposed to TiO2 aerosols (15 mg/m3) for 7 hours.
      Finally, the animals were sacrificed at several time points (1 to 136 days) after TiO2
      exposure. The clearance of particles in the groups of animals exposed to the lowest dose
      of sulphur dioxide, as determined at day 25 after TiO2 exposure, did not differ from the
      control groups (25 exposure days) or was even higher (10 and 23 exposure days). When
      exposed to 2.7 mg/m3 with 10 to 20 exposure days, the clearance was at control level or
48    Sulphur dioxide
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<pre>even higher. However, with 25 exposure days, the clearance of particles was statistically
significantly depressed. A small but significant depression in clearance was already
observed in animals exposed to 53.4 mg/m3 sulphur dioxide with 10 exposure days.
     More recently, a dose-dependent hypersecretion of the trachea was reported in male
Sprague-Dawley rats (n=not given) continuously exposed to sulphur dioxide at
concentrations of 13.4, 26.7, 53.4, 106.8 or 213.6 mg/m3 for 3 to 25 days (Wag97).
Effects on other organs
Lovati et al. (Lov96) reported changes in fat and carbohydrate metabolism in male
Sprague-Dawley CD rats (n=9/subgroup), which suffered from hypercholesterolemia
and diabetes. The animals were continuously exposed to 13.4 or 26.7 mg/m3 sulphur
dioxide for 14 days. Also they were fed standard or cholesterol enriched diets. Rats
showed a significant dose-dependent increase in serum triglycerides, but reduced HDL
cholesterol levels compared to controls. In contrast, diabetic animals exposed to 26.7
mg/m3 showed a fall in serum and liver triglycerides and an increase of plasma HDL
cholesterol. The type of diet did not influence these results.
     Male Wistar rats (n=4/group; n=8 controls) were exposed to 13.3, 133 or 267 mg/m3
(5, 50 or 100 ppm, respectively) sulphur dioxide for 5 hours a day for 7 to 28 days.
Significant evidence of lung inflammation (increase in number of neutrophil recovered
by bronchoalveolar lavage) was only observed in rats exposed to 267 mg/m3. At 13.3
mg/m3, glutathione (GSH) pools in the lungs, the heart and the kidneys were depleted.
Also, at the same exposure concentration, GSH-related enzyme activities in the lungs
were lowered compared to those in control animals. However, animals exposed to 133
mg/m3 maintained their tissue GSH status, although activities of several GSH-related
enzymes were altered in the lung tissue (Lan96).
     A study has been published in which male Swiss-Albino rats (n=16; n controls=14)
were exposed daily to 26.6 mg/m3 sulphur dioxide for 60 days (1 hour a day). Sulphur
dioxide enhanced lipid peroxidation and influenced the activities of other antioxidant
enzymes in erythrocytes. Also, GSH-related enzyme activities were altered (Güm98).
Two years later, the same authors published a study in which Swiss male albino rats
(total n=78), divided into three age groups (3, 12 and 24 months), were exposed daily to
filtered air or to 26.6 mg/m3 (10 ppm) air for six weeks (1 hour a day). At the end of the
exposure period, animals were deprived of food for 24 hours, before blood samples were
taken for analyses. Exposure to sulphur dioxide resulted in significantly lowered blood
plasma levels of the antioxidants vitamin C and ceruloplasmin in all age groups, except
for vitamin C levels in the 3-month old animals, compared to their corresponding
controls (Güm00). In addition, under the same experimental conditions, exposure to
sulphur dioxide significantly increased antioxidant enzyme activities, and decreased
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<pre>      glutathione peroxidase activity in the brains of all age groups. Catalase activity was not
      altered (Yar99).
           Male Dahl rats (n=10/group), resistant (DR) or susceptible (DS) to salt-induced
      hypertension, were exposed to 133 mg/m3 (50 ppm) sulphur dioxide for 31 weeks (6 h/
      day, 5 days/week). Subgroups of rats were maintained on either high or low salt diets.
      Only the blood pressure in the DS rats on a high salt-diet increased significantly
      compared to their air-exposed counterparts. All exposure-related differences in blood
      pressure disappeared after terminating the sulphur dioxide exposure. Based on these
      results and the fact that the authors exposed the animals at relatively high levels of
      sulphur dioxide (100 times ambient levels), they postulated that the influence of ambient
      levels of sulphur dioxide on hypertension was very low (Dre83).
           Haider (Hai85) reported that the lipid profiles in brains of guinea pigs were altered,
      after the animals were exposed to 266 mg/m3 sulphur dioxide for 21 days (1h/day). A
      few years later, the same authors published a study in which the animals, exposed to the
      same sulphur dioxide levels, also showed altered lipid profiles in other organs, such as
      in the liver, the heart, the lungs and the kidneys (Hai85).
6.2.4 Toxicity due to long-term exposure and carcinogenicity
      General effects
      Alarie et al. (Ala70) exposed Hartley albino guinea pigs (n=50/sex/exposure group) to
      clean air or to 0.35, 2.7 or 15.3 mg/m3 sulphur dioxide for 3 months or one year (22 h/
      day, 7 days/week). Biological measurements included: body weight; pulmonary
      function tests; haematology; clinical biochemical determinations; and, histopathologic
      examinations. No significant differences were observed in any of the measured
      parameters compared to the control group after 3 months of exposure or after one year.
      However, the animals exposed to 15.3 mg/m3 sulphur dioxide showed a lower incidence
      and severity of spontaneous disease normally present in those animals after one year.
      Furthermore, microscopic examinations of the liver in animals of the highest-dose group
      revealed an increase in the size of the hepatocytes, which was accompanied by
      cytoplasmatic vacuolisation.
           The committee has serious doubt about the meaning of these findings in the liver.
      Hence, it considers this study of little relevance.
           Hirsch et al. (Hir75) investigated the effects of sulphur dioxide on mucociliary
      activity. Purebred beagle dogs (n=8; n=3 controls) were exposed to clean air or to 2.7
      mg/m3 (1 ppm) sulphur dioxide by a facemask for one year (1.5 hr/day, 2 times/day, 5
      days/week). As a result of the sulphur dioxide exposure, the frequency distribution
      curve of individual disc velocities significantly changed within a single animal. This
50    Sulphur dioxide
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<pre>indicated impairment of mucociliary activity of the trachea. However, between exposed
animals and controls, no significant differences in lung function or mucociliary activity
were observed.
     The committee noted that mucociliary impairment did not differ between the
animals, but only within a single animal. In addition, the statistical power of the study is
very small. The results warrant, however, further research, because mucociliary
impairment may increase the susceptibility to bacterial or viral airway infections.
     Lewis et al. (Lew73) exposed female beagle dogs (n=4/group) to 13.4 mg/m3
sulphur dioxide on daily base for 20 months (21 h/day). No significant histological
changes were observed in the lungs and the kidneys. The only significant finding was
the increased mean nitrogen washouts of the lungs (p<0.01).
     The committee considers these findings inconclusive, because a low number of
animals were used, the description of the publication was limited, and no further details
were given.
     Cynomolgus monkeys (5 males and 4 females) were exposed to 13.7 mg/m3 (5
ppm) sulphur dioxide for 78 weeks (24 h/day, daily with two interruptions/day). No
harmful effects to lung mechanics, blood pressure, histology of the lung and other
organs, blood count and, routine clinical blood chemistry was observed (Ala75).
     The committee is uncertain about the validity of the results, because the description
of the publication was limited and no further details were given.
     Scanlon et al. (Sca87) exposed adult mongrel dogs to 40 and 133 mg/m3 (15 and 50
ppm) sulphur dioxide through cuffed tracheostomy tubes for 2 hours per day, 4 or 5 days
per week for 5 months (low exposure) or 10-11 months (high exposure). Before they
were killed, the dogs were allowed to recover for 3-4 months (low exposure) or for 7-9
months (high exposure). The dogs (n=4) exposed to 133 mg/m3 sulphur dioxide showed
hypersecretion of mucous cells and respiratory airway obstruction. Closer
histopathologic examinations revealed epithelial hypertrophy and increased size of
mucosal glands. No inflammation or changes in response to histamine was observed.
The observed effects were minimal in dogs (n=3) exposed to 40 mg/m3 sulphur dioxide
and absent in air-exposed control dogs (n not given).
     The committee noted that the dogs were only exposed to high concentrations of
sulphur dioxide and that the results did not demonstrate a concentration-response
relationship.
Carcinogenesis
So far, only one animal study has been published on the carcinogenicity of sulphur
dioxide. In this study, male and female LX mice (n = 35 males + 30 females; controls n
= 41 males + 39 females), highly susceptible to the induction of lung adenomas in
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<pre>   response to urethane, were exposed to 1,300 mg/m3 (500 ppm) sulphur dioxide for 10
   months (300 days; 5 min/day, 5 days/week) (Pea67, IARC92). The time of tumour
   appearance was shorter in exposed mice than in non-exposed mice. The percentage of
   mice over 300 days old with lung tumours are shown in Table 6.1:
   Table 6.1 Tumour development after sulphur dioxide exposure in LX mice (Pea67, IARC92).
   sulphur dioxide                no lung lesion    primary           adenoma          hyperplasia
   exposure (mg/m3)                                 carcinoma
   0         male (n=35)          69%                6%               31%               9%
             female (n=30)        77%               not given         17%              10%
   1,300     male (n=28)          46%                7%               54%              18%
             female (n=30)        53%               18%               43%              10%
   The committee noted limitations in study design, such as the use of highly susceptible
   animals, high exposure levels and the absence of statistical analysis. Therefore, the
   committee believes that no firm conclusion can be made from this study.
        In the literature, it has been suggested that sulphur dioxide may have a tumour
   enhancing effect when animals are exposed concomitantly with known carcinogenic
   agents, such as benzo(a)pyrene. As a possible mechanism, the irritant effect of sulphur
   dioxide is mentioned. Irritation can retard the pulmonary clearance of carcinogenic
   agents and increase the retention time.
   Regarding the tumour promoting potential, both the SCOEL (SCO93) and IARC
   (IAR92) evaluated the studies by Laskin et al. (1976) and by Gunnison et al. (1988).
   Laskin et al. reported the presence of squamous bronchial cell carcinoma in rats exposed
   to sulphur dioxide in combination with benzo(a)pyrene in conditions, in which the two
   substances separately did not induce bronchial cell carcinoma. The Working group of
   IARC noted the incomplete reporting of the experiment and the absence of survival data.
   In addition, Gunnison et al. concluded that the high incidence of tumours in the group of
   rats given benzo(a)pyrene alone precluded detection of an enhancing effect of sulphur
   dioxide on the incidence of benzo(a)pyrene-induced lung tumours.
        The committee noted the incompleteness of the previous studies. For this reason, the
   committee cannot make a final conclusion As for whether or not sulphur dioxide may
   enhance or promote tumour development.
52 Sulphur dioxide
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<pre>6.2.5 Genotoxicity
      Mutagenicity
      Sulphur dioxide and its sulphite and bisulphite anions, induced gene mutations in
      several bacterial (TA98, TA98NR and YA98DNP6 strains, Escherichia coli), lambda
      phage and yeast (Sacharomyces cerevisiae) systems (Pag87, IARC92, SCO93, Wol86).
      However, not all data presented in the literature were positive. For instance, in a
      Salmonella typhimurium (TA98) mutagenesis test system, sulphite was neither toxic nor
      mutagenic to the bacteria under the experimental conditions (Ree87), whereas sulphite
      enhanced the mutagenicity of a benzo(a)pyrene derivate.
      In vitro mammalian cell systems
      In vitro studies on a variety of cellular models, such as hamster foetal pulmonary cells
      and rat hepatocytes, have shown that sulphur dioxide reduces the proportion of single-
      chain DNA breakages. On the other hand, it did not amplify DNA in Chinese hamster
      cell line CO 60, whereas the known nitrosamine carcinogens did (Poo88a/b).
      In vivo tests
      Recently, Meng et al. (Men02) published the results of a study on the clastogenic and
      genotoxic effects of sulphur dioxide. Male and female Kunming mice (n=10/sex/group)
      were exposed to filtered air or to 14, 28, 56 or 84 mg/m3 sulphur dioxide for 4 hours a
      day for seven consecutive days. A full day after the end of the experimental period the
      animals were killed. In both male and female mice, the frequencies of the micronuclei in
      the polychromatic erythrocytes from the bone marrow increased significantly with
      increasing concentrations of sulphur dioxide. The authors concluded that sulphur
      dioxide has clastogenic and genotoxic properties.
      Miscellaneous
      Sulphur dioxide induced chromosomal aberrations in Tradescantia paludosa and Vicia
      faba, and micronuclei in Tradescantia paludosa (IARC92).
           Mallon and Rossman (Mal83) observed that when bisulphite (100 mM) was added
      to a reaction mixture of activated thymus DNA, it inhibited almost totally the
      incorporation of nucleotides. Based on these findings, the authors suggested that binding
      Effects                                                                                   53
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<pre>      of bisulphite to DNA polymerase enzymes reduces its activity and enhances the
      mutagenic capacity of bisulphite.
6.2.6 Reproductive toxicity
      Murray et al. (Mur79) studied the embryotoxic and teratogenic effects of sulphur
      dioxide in New Zealand white rabbits (n=20/group) and in virgin CF-1 mice (n=35-40/
      group). The rabbits and mice were exposed to 187 and 67 mg/m3 (70 and 25 ppm)
      sulphur dioxide, respectively, between GD 6-18 (rabbits) and GD 6-15 (mice). In both
      species, inhaled sulphur dioxide produced mild maternal toxicity. The few
      malformations that were observed in the sulphur dioxide-exposed litter did not differ
      from controls. However, in both species a significant increase in the occurrence of
      minor skeletal variants were observed (Mur79).
           Petruzzi et al. (Pet96) exposed male and female CD-1 mice (n total=40/sex) to 0,
      13.4, 32.0 or 80.1 mg/m3 (0, 5, 12 en 30 ppm) sulphur dioxide. The exposure was started
      9 days before the formation of breeding pairs and was ended at gestation day 12-14, for
      a total of 24 days. The exposure was near continuous, covering about 80% of the total
      time indicated. The adult mice showed acute transient behavioural effects, such as
      increased rearing and social interactions. Grooming was dose-dependently decreased.
      However, reproductive performance and postnatal somatic and neurobehavioral
      development of offspring was not affected.
           Later, the same research group used the same experimental design to study the
      offspring's social and/or agonistic behaviour in adulthood (Fio98). At adulthood,
      following a 4-week isolation period, the animals underwent an aggressive encounter
      with non-exposed CD-1 male opponents of the same age, body weight and isolation
      conditions. The levels of several responses such as rattling, freezing and defensive
      postures were reduced by sulphur dioxide exposure, whereas offensive and attack
      behaviours were not significantly modified.
6.3   Other relevant studies
      No other relevant studies are known.
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<pre>6.4 Summary and evaluation
    General toxicity
    Human data
    Sulphur dioxide irritates the eyes and the upper respiratory tract. Inhalation of high
    concentrations may cause: rhinorrhae; coughing; shortness of breath; chest tightness;
    and, choking sensation.
         Based on epidemiologic data, investigators have reported an association between
    sulphur dioxide exposure and complaints, such as chronic coughing and bronchitis.
    Also, data obtained from the general population suggest that chronic exposure may
    facilitate airway infections or airway allergy to airborne allergens. However, evidence
    of these associations is weak, because part of these studies showed limitations in study
    design and a lot of confounding factors were not taken into account. These confounding
    factors concern lack of information on combined exposure with other toxic substances,
    smoking habits and other personal lifestyle factors. For these reasons, the committee
    considers these data inadequate for the quantitative risk assessment.
         A number of laboratory studies have been performed in healthy, non-smoking
    volunteers to investigate the toxic effects of sulphur dioxide on the upper and lower
    respiratory tract. The exposures ranged from 0.53 to more than 60 mg/m3 sulphur
    dioxide and lasted from a few minutes up to a few hours, with or without physical
    exercise. The main adverse effects that have been observed were: irritation of the upper
    respiratory tract and the eyes; and decreased lung function, such as increased pulmonary
    airway resistance. These adverse effects were clearly present when the volunteers were
    exposed to a concentration of 2.7 mg/m3 or higher, but not at and below 2.0 mg/m3.
    Three studies, which concern increased airway resistance or mild effects on the
    autonomic heart function near or below 2.0 mg/m3, are not considered for risk
    assessment, because of limitations in study design or the little relevance of the findings.
    At 2.0 mg/m3 two studies, independently carried out from each other, showed no
    changes in lung function test in volunteers exposed to sulphur dioxide for 40 minutes or
    4 hours, with moderate physical exercise.
    Epidemiological data obtained from the general population indicate that people with
    asthma or with other diseases concerning the respiratory tract are likely more vulnerable
    to sulphur dioxide exposure than healthy people. Accordingly, the committee has found
    laboratory data suggesting that asthmatics are more vulnerable, even at low exposure
    levels. However, numerous studies with asthmatics showed that the level of
    Effects                                                                                     55
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<pre>   susceptibility is strongly influenced by a variety of non-exposure factors, such as by the
   presence of heart diseases or other lung diseases, (forced) physical activity and, even by
   atmospheric conditions (dry, cold air). All these factors alone may aggravate asthma.
   Therefore, the committee cannot conclude whether or not asthmatics are more
   vulnerable to sulphur dioxide exposure in the absence of these non-specific stimuli than
   healthy workers. However, the committee likes to express its concern that asthmatics are
   at extra risk when not only exposed to sulphur dioxide, but also to these non-specific
   asthma-aggravating factors.
   Animal data
   Data from experiments in animals with acute or short-term exposure support the
   findings in humans, in that sulphur dioxide causes irritation to the (upper) respiratory
   tract and eyes. Also reported are: reduced respiratory defence mechanisms against
   bacterial infections; changes in lipid metabolism; and, changes in enzyme activities in
   liver and blood. However, the main drawback of these animal studies is the poor
   reporting and the very high exposure levels used (up to 267 mg/m3 (subchronic) or
   >1,000 mg/m3 (acute)). Hence, no concentration-response relationships could be
   established. Also, no concentration-response relationships could be established from
   long-term exposure. Although in these long-term studies, the exposure levels were
   lower (0.35 up to 133 mg/m3), data were too limited to be useful for the quantitative risk
   assessment.
   Carcinogenicity and genotoxicity
   In a few epidemiological studies, sulphur dioxide was suspected to cause lung or
   stomach cancer. However, the committee considers these studies of limited use, because
   most workers were simultaneously exposed to various other toxic substances, such as
   gases, particulate compounds and metallic fumes. In addition, not always personal
   lifestyle factors were taken into account, such as smoking habits.
        Sulphur dioxide showed to be a weak carcinogen in one mouse inhalation study. In
   addition, sulphur dioxide was tested as a tumour promotor when administered with
   benzo(a)pyrene. However, the committee believes that no firm conclusion can be made
   from these studies, because of the very limited study design.
        Mutagenicity tests in bacteria showed positive results, but only in conditions not
   relevant to humans. Sulphur dioxide induced chromosomal aberrations in vitro, and
   micronuclei in vivo and in vitro.
56 Sulphur dioxide
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<pre>Reproduction toxicity
In a limited number of experiments, the potential hazard of sulphur dioxide has been
studied on reproduction. In litter of rabbits and mice exposed to 187 and 67 mg/m3,
respectively, minor skeletal variations were observed. This was accompanied by mild
maternal toxicity. In another study, offspring of exposed mice (13.4 to 80 mg/m3)
showed no defects in reproductive performance, somatic and neurobehavioral
development.
Effects                                                                              57
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<pre>58 Sulphur dioxide</pre>

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<pre>Chapter 7
        Existing guidelines, standards and
        evaluation
7.1     General population
        The Regional Office for Europe of the World Health Organisation recommended a
        guideline for sulphur dioxide of 0.5 mg/m3 (0.2 ppm; 10-minute exposure limit) not to
        be exceeded. From this guideline, a one-hour exposure limit of 0.35 mg/m3 (0.13 ppm)
        can be estimated (WHO00).
7.2     Working population
        The Netherlands
        In 1985, the committee published a criteria document on sulphur dioxide and
        recommended a health-based occupational exposure limit of 1.3 mg/m3 (0.5 ppm, 8 h
        TWA) (WGD85). In 1985 the committee concluded in its criteria document that:
        The critical organ is the respiratory tract, and in practice inhalation is also the sole route of exposure.
             The following effects were shown in human subjects after short-term exposure. The mean NOAEL on
        various lung function parameters in young healthy volunteers was higher than 1.3 mg/m3 SO2 after 2 hours
        of exposure. However, specific groups of hyper-reactive subjects were not taken into consideration in these
        experiments. The mean minimal observed adverse effect level was estimated at a level between 2 and 3
        mg/m3 after exposure during 2 hours in young healthy volunteers exercising alternate physical activities.
        Exposure to 2.6 mg/m3 SO2 during 1 to 6 hours induced a decrease of the nasal mucous flow rate and the
        forced expiratory flow of the lungs (FEF25-75%) of volunteers, which were dose and time dependent.
        Existing guidelines, standards and evaluation                                                               59
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<pre>        Experimental studies on volunteers exposed to SO2 have shown that about 10 to 20% of the so-called
   healthy subjects reacted stronger to irritants than the rest, even when asthmatics with symptoms were
   excluded.
        Epidemiological studies were less useful for determining an occupational exposure limit since in most
   cases the population was exposed to a mixture of contaminants.
        There was a report of an increased risk of chromosomal aberrations in humans, due to exposure to SO2.
   However, the results were insufficiently confirmed. The possibility of a co-carcinogenic activity of SO2 has
   been suggested, which needed corroboration. There was no information of effects on the reproduction due
   to SO2.
   Due to socio-economic constraints, however, the legally-binding Maximal Accepted
   Concentration (MAC) has been set at 5 mg/m3 (2 ppm) sulphur dioxide (8-h,TWA)
   (SZW02).
   The following evaluations were given:
   European Commission
   The SCOEL of the European Commission published its final document on sulphur
   dioxide in December 1998 (SCO98). They recommended an occupational exposure
   limit of 1.3 mg/m3 sulphur dioxide (8-h TWA) and a STEL of 2.7 mg/m3 SO2. It was
   based on a LOAEL of 2.7 mg/m3 sulphur dioxide, at which functional changes were
   found in healthy adult volunteers, and studies in asthmatics showing no appreciable
   effects at exposures from 0.7 to 2.0 mg/m3 sulphur dioxide.
   Sweden
   In 1985, the Swedish National Board of Occupational Safety and Health published a
   consensus report on sulphur dioxide (Lun85). They based their OEL on a study
   describing direct irritation of the nose and throat, and a gradual increase of pulmonary
   resistance in subjects exposed to sulphur dioxide. The critical effect was pulmonary
   resistance, although this effect was reversible in experimental animals exposed to low
   levels. The current occupational exposure limits for sulphur dioxide in Sweden are 5
   mg/m3 (8-h, TWA), and 13 mg/m3 (Ceiling) (SNB00).
   The USA - ACGIH
   The American Conference of Governmental Industrial Hygienist revised the TLV for
   sulphur dioxide in 1992. They recommended a TLV of 5.2 mg/m3 (2 ppm) sulphur
   dioxide (8-h, TWA) and a STEL of 13.4 mg/m3 (5 ppm) (ACG02), because sulphur
   dioxide was classified as a ‘mild’ respiratory irritant, and inhalation of 13.4 mg/m3
   sulphur dioxide or more induced bronchoconstriction in humans. It was estimated that a
60 Sulphur dioxide
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<pre>              worker inhaling 10.7 mg/m3 sulphur dioxide for 8 hours and performing light work
              would absorb approximately 140 mg sulphur dioxide.
              IARC
              In 1992, the IARC (IARC92) published an evaluation on the carcinogenic risks of
              sulphur dioxide, sulphites and bisulphites (see also annex E for a summary). The IARC
              concluded that ‘there is limited evidence of the carcinogenicity in experimental animals
              of sulphur dioxide. Because there is, moreover, inadequate evidence of the
              carcinogenicity in humans, IARC concluded that sulphur dioxide, sulphites and
              bisulphites are not classifiable As for their carcinogenicity to humans (Group 3)’.
              The occupational exposure limits of sulphur dioxide in other countries are presented in
              Table 7.1.
 Table 7.1 Current occupational exposure limits (OEL's) for sulphur dioxide.
Country                 OEL                              TWA            Type of OEL     Note           Year of     Reference
-organisation                                                                                          adoption
                        ppm              mg/m3
The Netherlands
- Ministry              2                  5               8h           legal MAC       -              1985        SZW02
- DECOS                 0.5                1.3             8h           HBROEL          -                          WGD85
                        1.0                2.6           15 min         Short-term      -                          WGD85
Germany
- DFG MAK-kom.          0.5                1.3             8h           MAK             Cb             2000        DFG02
                        1.0                2.7             -            Ceilinga        -              2000        DFG02
The United Kingdom      2                  5.3             8h           OES             -              1991        HSE02
                        5                13              15 min         Short-term      -              1991        HSE02
Sweden                  2                  5               8h           OEL             -              1987        SNB00
                        5                13                -            Ceiling         -              1987        SNB00
Denmark                 0.5                1.3             8h           OEL             -              1996        Arb02
The USA
- ACGIH                 2                  5.2             8h           TLV             A4c            1996        ACG02
                        5                13              15 min         STEL            A4c            1996        ACG02
- OSHA                  5                13                8h           PEL                            1993        ACG02
- NIOSH                 2                  5             10 h           REL                            1988        ACG02
                        5                13              15 min         STEL                           1988        ACG02
European Union
- SCOEL                 0.5                1.3             8h           OEL             -              1998        SCO98
                        1.0                2.7           15 min                         -              1998        SCO98
a    Momentary value should not be exceeded at any time.
b    Pregnancy risk group C: there is no reason to fear a risk of damage to the embryo or foetus when MAK and BAT values are
     observed.
c
     A4 designation refers to "not classifiable as human carcinogen" (group 3).
              Existing guidelines, standards and evaluation                                                                  61
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<pre>62 Sulphur dioxide</pre>

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<pre>Chapter 8
        Hazard assessment
8.1     Hazard identification
        Inhaled sulphur dioxide affects mainly the upper respiratory tract and to a lesser extent
        the lower part of the respiratory tract. This is caused by the fact that sulphur dioxide is
        highly water soluble and thus quickly absorbed by the nasal mucosa. However, lung
        absorption is increased when sulphur dioxide is deeply inhaled through the mouth, for
        instance during physical exercise or heavy work.
             Symptoms after acute exposure include: rhinorrhae; coughing; shortness of breath;
        and, chest tightness. Also symptoms on the eyes are reported, such as ocular irritation
        and lacrimation. Several human and animal studies have been presented, in which
        effects on lung function, including airway resistance, nasal irritation and other adverse
        health effects of sulphur dioxide have been investigated. The following paragraphs
        contain short evaluations on the relevant toxic effects of sulphur dioxide after single en
        repeated exposure.
        Single and short-term repeated exposure
        A number of laboratory studies in healthy volunteers associate acute exposure to sulphur
        dioxide with: upper respiratory tract and eye irritation; reduced lung function; and,
        enhanced pulmonary and nasal airway resistance. In more detail, volunteers were
        exposed to low concentrations of sulphur dioxide for minutes to several hours under
        controlled conditions. At 2.7 mg/m3, several investigators, but not all, reported
        Hazard assessment                                                                           63
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<pre>   increased nasal irritation or pulmonary airway resistance. No such effects on respiratory
   function have generally been described at an exposure level of 2.0 mg/m3 sulphur
   dioxide or lower, with the exception of three studies (Isl92, Isl94 and Tun01). However,
   the committee did not include these three studies, because of limitations in study design
   and lack of toxicological relevance. For instance, the mild effects on the autonomic
   heart function observed in healthy and asthmatic subjects at 0.53 mg/m3 were
   considered of little relevance, because they did not lead to visible changes in heart and
   lung functions (Tun01). Concerning the other two studies, both from the same research
   group (Isl92, Isl94), no control exposure at rest was included and the exposure itself was
   limited; subjects had been exposed to 1.6-2.0 mg/m3 (exact concentration not given) for
   only 5 minutes under forced eucapnic hyperventilation.
        Animal studies support the findings in humans, in that acute and subchronic
   exposure to sulphur dioxide causes irritation to the respiratory tract and eyes. At high
   exposure (13 and 267 mg/m3), also signs of secondary infections and systemic effects,
   such as on the cardiovascular system (>100 mg/m3) and on the lipid metabolism have
   been found. However, in none of these studies clear concentration-response
   relationships were reported.
   Long-term repeated exposure
   Epidemiological studies have reported an association between chronic exposure to
   sulphur dioxide and chronic coughing or bronchitis. Furthermore, data from the general
   population suggest that chronic exposure to air pollutants, such as sulphur dioxide, may
   facilitate airway infections or allergy to airborne allergens. However, limitations in the
   design of these studies preclude using these data for deriving a health-based
   recommended exposure limit (HBR-OEL). Of particular concern is the possibility of
   confounding from co-exposures to other toxic substances. Also failure to control
   adequately for smoking, other lifestyle factors and for adaptation is a point of concern.
   Hence, epidemiologic data are insufficient for quantitative risk assessment.
        A few long-term animal studies have been carried out with low exposure levels.
   Unfortunately, also in these type of studies clear concentration-response relationships
   were reported.
   Asthmatics
   Available data do not indicate that at low exposure concentrations, persons with asthma
   are more vulnerable to sulphur dioxide. However, when other factors are involved, such
   as the presence of other lung diseases or heart diseases, or when doing heavy physical
64 Sulphur dioxide
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<pre>exercise, asthmatic persons could be more at risk to sulphur dioxide exposure than
normal healthy persons.
Carcinogenesis
In a few epidemiological studies, sulphur dioxide was suspected to cause lung and
stomach cancer. However, for the committee it is unclear to what extent these cancers
may be attributable to sulphur dioxide exposure, since combined exposure with other
substances, smoking habits and other lifestyle factors were not taken into account. Few
animal studies have been directed at the carcinogenicity of sulphur dioxide. Although
tumour formation was observed, the studies were very limited, in that for instance
highly susceptible animals and high exposure levels were used. In addition, a few
studies on the tumour promoting activity of sulphur dioxide were incomplete. For these
reasons, the committee considers these studies inadequate to draw any conclusion about
the carcinogenicity of sulphur dioxide in humans.
    Mutagenicity tests in bacteria were positive, but only in conditions not relevant to
humans. Furthermore, sulphur dioxide induced chromosomal aberrations in vitro, and
micronuclei in vivo and in vitro.
    Overall, since data are limited, the committee is not able to make a definite
conclusion about the carcinogenic potential of sulphur dioxide in humans. It, therefore,
recommends not classifying sulphur dioxide.
Reproduction toxicity
Sulphur dioxide has been insufficiently investigated to allow any conclusion to be made,
as for whether or not the substance causes adverse effects on reproduction or on the
development of the offspring.
Conclusion
From the current data, the committee concludes that the acute effects on the respiratory
tract, such as nose and throat irritation, depressed lung function and increased airway
resistance, should be prevented. Therefore, the committee recommends deriving a
health-based recommended occupational exposure limit for short-term exposure (STEL,
15-min TWA). This STEL is derived from human data obtained from single-exposure
studies.
Hazard assessment                                                                        65
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<pre>8.2 The derivation of an HBR-OEL
    Overall, the committee considers the exposure level of 2.0 mg/m3 as the no-observed-
    adverse effect level (NOAEL) for short-term exposure (see Table in annex F). This
    NOAEL is derived from two studies, one published by Stacy et al. (Sta83) and the other
    by Schachter et al. (Sch84). In the study by Stacy et al., healthy volunteers were
    exposed for 4 hours, whereas in the study by Schachter et al., they were exposed for 40
    minutes. In both studies, moderate physical exercise sessions were included and lung
    function tests were performed before and after exposure.
        The committee adjusted the NOAEL by a factor of 3 for possible differences
    between individuals. This factor was included, because of the limited number of studies
    and the limited number of participants in those studies. In addition, referring to the
    studies by Islam et al. (Isl92, Isl94), data show variation in responses in the normal
    population under certain circumstances. Thus, the committee proposes a health-based
    recommended occupational exposure limit for sulphur dioxide to be at 0.7 mg/m3 (0.3
    ppm), as a 15-minute time weighted average concentration (15-min TWA, STEL).
        This STEL value is lower than the one recommended by the committee in 1985 (2.6
    mg/m3). However, at that time fewer data were available and variations between
    individuals were not taken into account. Furthermore, in the old report, the committee
    commented that the STEL value of 2.6 mg/m3 was probably not low enough to protect
    the most sensitive workers. Also, the STEL value differs from the one recommended
    recently by the SCOEL (2.7 mg/m3). Yet, this is well explained by the way the
    evaluations are carried out (see section 7.2, European Commission).
    Both epidemiological and animal data suggest that chronic exposure to sulphur dioxide
    may lead to chronic irritation (bronchitis) and increased susceptibility to airway
    infections. According to the committee, this warrants the need for deriving a health-
    based recommended exposure limit (HBR-OEL) to prevent chronic adverse health
    effects. However, the committee did not find reliable data from epidemiological studies.
    In addition, animal data on long- and mid-term exposure were insufficient to allow any
    scientific conclusion to be made on the concentration-response relationships. For this
    reason, the committee does not recommend an HBR-OEL (8-h TWA). Further studies
    on the long-term concentration-response relationships in both human and animals are
    needed.
66  Sulphur dioxide
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<pre>8.3 Groups at extra risk
    Workers with a history of asthma are at higher risk when not only exposed to sulphur
    dioxide, but also to other (non-specific) factors, which incite asthma. Also, the
    committee cannot exclude that workers with ischaemic heart diseases may be more
    vulnerable.
8.4 Health-based recommended occupational exposure limit
    The Dutch Expert Committee on Occupational Standards recommends a health-based
    occupational exposure limit for sulphur dioxide of 0.7 mg/m3 (≈0.25 ppm), with a 15-
    minute time weighted average (15-min TWA) (STEL).
    Hazard assessment                                                                    67
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<pre>68 Sulphur dioxide</pre>

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*Ska64  Skalpe IO. Long terms effects of sulfur dioxide exposure in pulp mills. Br J Ind Med 1964; 21:69-73.
SNB00   Swedish National Board of Occupational Safety and Health. In: Occupational exposure limit values.
        Adopted January 1, 2000, Stockholm: 2000.
74      Sulphur dioxide
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<pre>*Spe66a Speizer FE, Frank NR. The uptake and release of SO2 by the human nose. Arch Environ Health 1966; 12:
        725-728.
*Spe66b Speizer FE, Frank, NR. A comparison f changes in pulmonary flow resistance in healthy volunteers exposed
        to SO2 by mouth and nose. Br J Ind Med 1966; 23: 75-79.
Sta83   Stacy RW, Seal E Jr., House DE, Green J, Roger LJ, Raggio L. A survey of effects of gaseous and aerosol
        pollutants on pulmonary function of normal males. Arch Environ Health 1983; 38: 104-115.
Ste98   Stellman JM and McCann M (eds). Encyclopaedia of occupational health and safety. 4th edition.
        International Labour Office, Geneva 1998.
Stj84   Stjernberg N, Rosenhall L and Adelroth E. Long-term effects of chronic exposure to sulphuric dioxide. Bull
        Int Union Against Tuberculosis 1984; 59: 43-45.
*Str64  Stranberg LG. SO2 absorption in the respiratory tract. Arch Environ Health 1964; 9: 160-166.
Sul92   Sullivan JB Jr and Krieger GR (eds). Hazardous materials toxicology – clinical principles of environmental
        health. Williams & Wilkins, Baltimore (USA) 1992.
SZW02   Ministry of Social Affairs and Employment. In: Nationale MAC-lijst 2002. Sdu uitgevers, Den Haag: 2001.
Tes99   Teschke K, Ahrens W, Andersen A, Boffetta P, Fincham S, et al. Occupational exposure to chemical and
        biological agents in the nonproduction departments of pulp, paper, and paper product mills: an international
        study. Am Ind Hygiene Assoc J 1999; 60: 73-83.
Tes00   Testud F, Matray D, Lambert R, Hillion B, Blanchet C, et al. Manifestations respiratoires dues à l'anhydride
        sulfureux en cave de vinification: 6 observations. Rev Mal Respir 2000; 17: 103-108.
Tun01   Tunnicliffe WS, Hilton MF, Harrison RM and Ayres JG. The effect of sulphur dioxide exposure on indices
        of heart rate variability in normal and asthmatic adults. Eur Respir J 2001; 17: 604-608.
*Tus83  Tusl M, Byskocil a, Durrer I, Aulika BV, Litvinos NN, Merkureva RV. Importance of functional state of
        alveolar macrophages of the lungs for hygienic evaluation of protective reactions and cell damage due to
        atmospheric pollution. J Hyg Epidemiol Microbiol Immunol 1983; 27: 259-263.
Wag97   Wagner U. Studien zur trachealen Muzinsekretion und Morphologie nativ sowie nach SO2- und NO2-
        induzierter Tracheobronchitis am Rattenmodell. Pneumologie 1997; 51: 393-394.
Wei72   Weir FW, Stevens DH and Bromberg PA. Pulmonary function studies of men exposed for 120 hours to
        sulfur dioxide. Toxicol Appl Farmacol 1972; 22: 319 (Abstract only).
*Wel82  Welch K, Higgins I, Oh M, Burchfield C. Arsenic exposure, smoking and respiratory cancer in copper
        smelter workers. Arch Environ Health 1982; 37: 325-335.
WGD85   Werkgroep van Deskundigen van de Nationale MAC-Commissie. Rapport inzake grenswaarden
        zwaveldioxide. Ministerie van Sociale Zaken en Werkgelegenheid RA 4/85, Voorburg: 1985.
Wit85   Witek TJ Jr and Schachter EN. Airway responses to sulfur dioxide and methacholine in asthmatics. J Occup
        Med 1985; 27: 265-268.
WHO87   World Health Organization regional Office for Europe. In: Air quality guidelines for Europe. WHO
        Regional Publications, European Series No. 23, 1987, Copenhagen, pp. 338-360.
WHO00   World Health Organization. In: Guidelines for air quality. Published by WHO, 2000, Geneva, pp 96-98.
*Wol86  Wolff GT, Siak JS, Chan TL, Korsog PE. Multivariate statistical analyses of air quality data and bacterial
        mutagenicity data from ambient aerosols. Atmos Environ 1986; 20: 2231-2241.
        References                                                                                                   75
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<pre>Woo79  Woodford DM, Coutu RE and Gaensler EA. Obstructive lung disease from acute sulfur dioxide exposure.
       Respiration 1979; 38: 238-245.
Yad96  Yadav JS and Kaushik VK. Effect of sulphur dioxide exposure on human chromosomes. Mutation Research
       1996; 359: 25-29.
Yar99  Yargiçolu P, Aar A, Gümüşlü S, Bilmen S and Ouz Y. Age-related alterations in antioxidant enzymes, lipid
       peroxide levels, and somatosensory-evoked potentials: effects of sulfur dioxide. Arch Environ Contam
       Toxicol 1999; 37: 554-560.
*Yok71 Yokohama E, Yoder RE, Frank NR. Distribution of 35SO2 in the blood and its excretion in urine of dogs
       exposed to 35SO2. Arch Environ Health 1971; 22: 389-395.
       References consulted but not used
Bor98  Borras M, Llacuna S, Gorriz A, Ndal J. Hematological and biochemical parameters in pollution-exposed
       mice. Arch Toxicol Suppl 1998; 20: 189-195.
Iwa97  Iwase N, Sasaki T, Shimura S et al. Signature current of SO2-induced bronchitis in rabbit. J Clin Invest
       1997; 99: 1651-1661.
76     Sulphur dioxide
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<pre>A Request for advice
B The Committee
C Comments on the public review draft
D Recommendations from the SCOEL for sulphur dioxide
E IARC Monograph
F Summary of data concerning acute physical effects in healthy humans
G Abbreviations
H DECOS-documents
  Annexes
                                                                      77
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<pre>78 Sulphur dioxide</pre>

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<pre>Annex 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 in
      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 in 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 for
            advice. If possible this evaluation should lead to a health based recommended exposure limit, or, in the
      Request for advice                                                                                             79
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<pre>       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.
80 Sulphur dioxide
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<pre>Annex B
      The committee
      •  GJ Mulder, chairman
         professor of toxicology; Leiden University, Leiden
      •  RB Beems
         toxicologic pathologist; National Institute of Public Health and the Environment,
         Bilthoven
      •  LJNGM Bloemen
         epidemiologist; Dow Benelux NV, Terneuzen
      •  PJ Boogaard
         toxicologist; Shell International Petroleum Company, The Hague
      •  PJ Borm
         professor of inhalation toxicology; Heinrich Heine Universität Düsseldorf
         (Germany)
      •  JJAM Brokamp, advisor
         Social and Economic Council, The Hague
      •  DJJ Heederik
         epidemiologist; IRAS, Utrecht University, Utrecht
      •  AAJP Mulder, advisor
         Ministry of Social Affairs and Employment, The Hague
      •  TM Pal
         occupational physician; Netherlands Centre for Occupational Diseases, Amsterdam
      •  IM Rietjens
         professor of toxicology; Wageningen University, Wageningen.
      The committee                                                                        81
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<pre>   •   H Roelfzema, advisor
       Ministry of Health, Welfare and Sport, The Hague
   •   T Smid
       occupational hygienist; KLM Health Safety & Environment, Schiphol and professor
       of working conditions, Free University, Amsterdam
   •   GMH Swaen
       epidemiologist; Maastricht University, Maastricht
   •   RA Woutersen,
       toxicologist and pathologist; TNO Nutrition and Food Research, Zeist
   •   P Wulp
       occupational physician; Labour Inspectorate, Groningen
   •   ASAM van der Burght, scientific secretary
       Health Council of the Netherlands, The Hague
   •   JM Rijnkels, scientific secretary
       Health Council of the Netherlands, The Hague
   The first draft of the present advisory report was prepared by AAE Wibowo, PhD, of the
   Coronel Institute, Academic Medical Center of Amsterdam, the Netherlands, by
   contract with the Ministry of Social Affairs and Employment.
   Secretarial assistance: R Aksel-Gauri en F Smith.
   Lay-out: J van Kan.
82 Sulphur dioxide
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<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2002 for public review. The following
      organisations and persons have commented on the draft document:
      • RD Zumwalde, L Murthy and GK Hatfield
          National Institute for Occupational Safety and Health, USA
      • PE Schwarze, JA Holme and M Refsnes
          Norwegian Institute of Public Health, Norway
      • JJH Koning
          VNO-NCW, The Netherlands
      Comments on the public review draft                                                 83
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<pre>84 Sulphur dioxide</pre>

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<pre>Annex D
      Recommendations from the SCOEL for
      sulphur dioxide
      SCOEL/SUM/27final, December 1998
      8 hour TWA:                           0.5 ppm (1.3 mg/m3)
      STEL (15 mins):                       1.0 ppm (2.7 mg/m3)
      Additional classification :           -
      Substance:
      Sulphur dioxide:                       SO2
      Synonyms:                              Sulphurous oxide, sulphurous anhydride, sulphur oxide,
      EINECS N°:                             231-195-2
      EEC N°:                                016-011-00-9
      Classification:                       T; R23, Xi; R36/37
      CAS N°:                                7446-09-5
      MWt:                                   64.06
      Conversion factor (20°C, 101 kPa):     2.66 mg/m3 = 1 ppm
      Occurrence/use:
      Sulphur dioxide is a colourless gas, with an irritating odour. It has a MPt of -72.7°C, a BPt of -
      10.02°C and a vapour pressure of 321 kPa at 20°C. It has a vapour density of 2.26 times that of
      air at 0°C. The odour threshold is about 3-5 ppm (8-13 mg/m3).
      Sulphur dioxide is a normal component of air due to emissions from natural sources (volcanic
      activity and forest fires) and industrial activities. It is used in the manufacture of sulphuric acid
      Recommendations from the SCOEL for sulphur dioxide                                                    85
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<pre>   and other sulphur-containing chemicals, and as a bleaching or sterilising agent. It is also released
   into the environment from industrial processes such as ore smelting, coal and oil combustion,
   petroleum refining and water and sewage treatment. Highest exposures are generally encountered
   during manufacture of cellulose pulp.
   Health Significance:
   Sulphur dioxide is highly water soluble and, on inhalation, a large proportion is absorbed through
   the nasal mucosa (Speizer and Frank, 1966). Penetration to the alveoli is greater when inhaled
   through the mouth than through the nose. During inhalation, it reacts with water to form
   sulphurous acid, which dissociates into sulphite and bisulphite ions. Sulphite is converted to
   sulphate by the action of sulphite oxidase and individuals deficient in this enzyme constitute a
   higher risk group (Calabrese et al, 1981).
   The critical effect of sulphur dioxide is irritation of the upper respiratory tract. In most
   epidemiological studies, the workers were exposed to complex mixtures of sulphur dioxide with
   particulate material, other acid gases, metallic fumes or organic compounds. Workers exposed to
   approximately 4 ppm (11 mg/m3) sulphur dioxide experienced tightness in the chest and reduced
   forced expiratory volume (FEV) (Archer et al, 1979). Bedi et al (1984) reported that exposure of
   young volunteers to concentrations of 1-2 ppm (2.7-5.3 mg/m3) for 2 hours resulted in a
   reduction in thoracic volume in non-smoking subjects. Controlled exposure of healthy adults to 1
   ppm (2.7 mg/m3) sulphur dioxide with 1 mg/m3 NaCI caused respiratory changes only in a group
   subjected to moderate exercise (Frank, 1980). Exposure of 231 healthy subjects to 0.75 ppm (2
   mg/m3) sulphur dioxide, with and without exercise, did not affect pulmonary function (Stacey et
   al, 1983). However, electron microscopic examinations of the nasal mucosa of 7 individuals
   exposed to 0.7 ppm (1.9 mg/m3) sulphur dioxide for 2 hours revealed ciliary defects (Carson et
   al, 1987).
   Asthmatic subjects are a high risk group with respect to sulphur dioxide. Effects are exacerbated
   by increasing levels of exercise. Bethel et al (1985) reported that exposure of asthmatics to 0.25
   ppm (0.67 mg/m3) sulphur dioxide during heavy exercise resulted in mild bronchoconstriction,
   but that the effect was largely overshadowed by the effects of exercise alone. Hackney et al
   (1984) exposed 17 young asthmatic volunteers to 0.75 ppm (2.0 mg/m3) for 3 hours with 10
   minutes of heavy exercise initially, followed by rest. In general, it appeared that the
   bronchoconstriction induced by exercise during exposure was reversed immediately by rest, even
   though the sulphur dioxide was still present. Development of tolerance has been observed in
   asthmatic subjects exposed repeatedly to the bronchoconstricting effects of 0.5 ppm (1.3 mg/m3)
   sulphur dioxide for short periods (Sheppard et al, 1983). Exposure of 24 young adult asthmatics
   to 0, 0.25 and 0.5 ppm (0, 0.67 and 1.3 mg/m3) sulphur dioxide for one hour with alternating 10
86 Sulphur dioxide
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<pre>minute periods of moderate exercise and rest, at exposure intervals of one week, did not induce
significant exposure related changes in pulmonary function (Linn et al, 1982). Devalia et al
(1994) studied the effect of 6 hours exposure to 0.2 ppm (0.53 mg/m3) sulphur dioxide on the
airway response to inhaled house-dust-mite antigen in 10 volunteers with mild atopic asthma. No
significant effects were observed in the lung function indices examined. Overall, these studies
suggest that asthmatics are unlikely to experience adverse effects at sulphur dioxide levels up to
0.75 ppm (2.0 mg/m3) under normal working conditions.
It has been suggested that sulphur dioxide acts as a promoter of carcinogenesis, but this is not
supported by epidemiological evidence (Enterline et al, 1987). Mutagenicity tests in bacteria
have shown positive results only under certain conditions (Pagano and Zeiger, 1987), which are
not relevant in exposed people (e.g. damage to DNA at non-physiological pH). No relevant
positive results have been identified in animal studies (Renner and Wever, 1983). Among the
human studies there are a lot of factors potentially contributing to differences among the control
and the exposed group, which makes it difficult to specifically attribute a clastogenic effect to
SO2 (Nordenson et al, 1980; Meng and Zhang, 1990; Yadav and Kaukshik, 1996). A single study
with measured SO2 mean values at "useful" ranges (only twice the TWA) was negative, but the
number of workers was low (Sorsa et al, 1982). Therefore, genotoxicity of SO2 is not relevant in
the establishment of an occupational health-based limit value.
Recommendation:
Effects on lung function in healthy people are associated with exposures in the region of 1 ppm
or more. However, individuals with compromised respiratory function (asthmatics or persons
with chronic bronchitis) represent a large and increasing proportion of the working population,
which has to be considered in setting an occupational exposure limit for the general workforce.
In this context, the study reported in Frank (1980), showed functional changes in healthy adult
volunteers exposed to sulphur dioxide at 1 ppm (2.7 mg/m3), which could be considered an
LOAEL. Studies in asthmatics have shown no appreciable effects in the region of 0.25 to 0.75
ppm (0.67 to 2.0 mg/m3). Taking into account all of the available data, an 8-hour TWA of 0.5
ppm (1.3 mg/m3) is recommended. A STEL (15 mins) of 1.0 ppm (2.7 mg/m3) is proposed to
limit peaks in exposure which could result in irritation. No skin notation was considered to be
necessary.
It should be noted that the proposed values should afford protection to most, but not all,
individuals suffering from bronchial asthma or chronic bronchitis. At the levels recommended,
no measurement difficulties are foreseen.
Recommendations from the SCOEL for sulphur dioxide                                                 87
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<pre>   Key Bibliography:
   Archer, V.E., Fullmer, C.D. and Castle, C.H., (1979). Sulphur dioxide exposure in a smelter. III. Acute effects and
   sputum cytology. J. Occup. Med. 21, 359-364.
   Bedi, J.F., Folinsbee, L.J. and Horvath, S.M. (1984). Pulmonary function effects of 1.0 and 2.0 ppm sulphur dioxide
   exposure in active young male non-smokers. J. Air Pollut. Control Assoc. 34, 1117-1121.
   Bethel, R.A., Sheppard, D., Geffroy, B., Tam, E., Nadel, J.A. and Boushey, H.A. (1985). Effect of 0.25 ppm sulphur
   dioxide on airway resistance in freely breathing, heavily exercising, asthmatic subjects. Am. Rev. Respir. Dis. 131, 659-
   661.
   Calabrese, E., Sacco, C., Moore, G. and DiNardi, S. (1981). Sulphite oxidase deficiency: A high risk factor in SO2,
   sulphite and bisulphite toxicity? Med. Hypotheses 7,133-145.
   Carson, J.L., Collier, A.M., Hu, S.C., Srnith, C.A. and Stewart, P. (1987). The appearance of compound cilia in the nasal
   mucosa of normal human subjects following acute, in vivo exposure to sulfur dioxide. Environ. Res. 42, 155-165.
   Devalia, J., Rusznak, C., Herdman, M.J., Trigg, C.J., Tarraf, H. and Davies, R.J. (1994). Effect of nitrogen dioxide and
   sulphur dioxide on airway response of mild asthmatic patients to allergen inhalation. Lancet 344, 1668-1671.
   Enterline, P.E., Marsh, G.M., Esrnen, N.A , Henderson, V.L., Callahan, C.M. and Paik, M. (1987). Some effects of
   cigarette smoking, arsenic and SO2 on mortality among US copper smelter workers. J. Occup. Med. 29, 831-838.
   Frank, R. (1980). SO2 particulate interactions: recent observations. Am. J. Ind. Med. 1, 427-434.
   Hackney, J.D., Linn, W.S., Bailey, R.M., Spier, C.E. and Valencia, L.M. (1984). Time course of exercise-induced
   bronchoconstriction in asthmatics exposed to sulfur dioxide. Environ. Res. 34, 321-327.
   Linn, W.S., Bailey, R.M., Shamoo, D.A., Venet, T.G., Wightman L.H. and Hackney, J.D. (1982). Respiratory responses
   of young adult asthmatics to sulfur dioxide exposure under simulated ambient conditions. Environ. Res. 29, 220-232.
   Meng, Z. and Zhang, L. (1990). Chromosomal aberrations and sister chromatid exchange in lymphocytes of workers
   exposed to sulfur dioxide. Mutat. Res. 241, 15-20.
   Nordenson, I., Beckman, G., Beckman, L., Rosenhall, L. and Stjernberg, N. (1980). Is exposure to sulphur dioxide
   clastogenic?, Hereditas, 39, 161-164.
   Pagano, D.A. & Zeiger, E. (1987), Conditions affecting the mutagenicity of sodium bisulfite in Salmonella typhimurium,
   Mutat Res 179, 159-166.
   Renner, H.W. and Wever, J. (1983). Attempts to induce cytogenetic effects with sulfite in sulfite oxidase-deficient
   Chinese hamsters and mice. Food. Chem. Toxicol. 21, 123-127.
   SEG/CDO/38 (1992). Criteria document for occupational exposure limit value for sulphur dioxide.
   Sheppard, D., Eschenbacher, W.L., Boushey, H.A. and Bethel, R.A. (1984). Magnitude of the interaction between the
   bronchomotor effects of sulfur dioxide and those of dry (cold) air. Am. Rev. Respir. Dis. 130, 52-55.
   Sorsa, M., Hedman, B.K. and Jarventaus, H. (1982). No effect of sulphur dioxide exposure in aluminium industry on
   chromosomal aberrations or sister chromatid exchanges. Hereditas, 95, 159-161.
   Speizer, F.E. and Frank, N.R (1966). The uptake and release of SO2 by the human nose. Arch. Environ. Health 12, 725-
   728.
   Stacy, R.W., Sea1, E.Jr., House, D.E., Green, J., Roger, L.J. and Raggio, L. (1983). A survey of effects of gaseous and
   aerosol pollutants on pulmonary function of normal males. Arch Environ. Health, 38, 104-115.
   Yadav , J.S. and Kauksshik, v.K. (1996). Effect of sulphur dioxide exposure on human chromosomes. Mutat Res. 359,
   25-29.
88 Sulphur dioxide
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<pre>Annex E
      IARC Monograph
      Summary of data reported and evaluation of sulfur dioxide and some sulfites, bisulfites
      and metabisulfites (Volume 54, 92).
      5. Summary of Data Reported and Evaluation
      5.1 Exposure data
      Sulfur dioxide is produced commercially by burning sulfur or various sulfides or by
      recovering it from flue gases or non-ferrous metal smelting gases. Large quantities are
      used as intermediates in the manufacture of sulfuric acid and sulfite pulp. It is also used
      in agriculture and in the food and beverage industries as, among other things, a biocide
      and a preservative. Sulfite pulp workers have been exposed to fluctuating levels of
      sulfur dioxide, often exceeding 10 ppm (26 mg/m3), but levels have decreased with
      modernization of facilities and processes. In metal industries, the roasting of ores and
      the combustion of various sulfur-containing fuels have resulted in mean exposures to
      sulfur dioxide in the range of 1-10 ppm (2.6-26 mg/m3) in copper smelters, but at about
      1 ppm (2.6 mg/m3) or less in other facilities. Mean levels exceeding 1 ppm (2.6 mg/m3)
      have also been reported in the manufacture of sulfuric acid and of superphosphate
      fertilizers, as weIl as at certain fire sites during fire fighting. Levels of sulfur dioxide in
      ambient air do not usually exceed 0.05 ppm (0.1 mg/m3), except in same urban areas.
           Sodium sulfite is used mainly in the pulp industry. Both sodium and potassium
      metabisulfure are used in food processing, chemical industries, water treatment.
      IARC Monograph                                                                                  89
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<pre>   photoprocessing and the textile industry. Levels of occupational exposure have not been
   reported.
   5.2 Human carcinogenicity data
   In four US and one Swedish cohort studies of copper smelters, increased lung cancer
   risks were observed in relation to exposure to arsenic, but no independent effect of
   sulfur dioxide was seen.
       One proportionate mortality Study from the USA and Canada, as well as two US
   and one Finnish cohort studies, analysed cancer risks among sulfite pulp mill workers.
   Three of them suggested an increase in risk for stomach cancer; however, potential
   confounding factors were not adequately controlled. Lung cancer risks were not
   elevated in any of these studies.
       In case-control studies performed at a chemical facility in Texas with a complex
   exposure environment, increased risks for lung cancer and brain tumours were indicated
   in workers with high exposure to sulfur dioxide; however, the findings using two
   different control groups were not consistent.
       A population-based case-control study from Canada suggested an increased risk for
   stomach cancer in men exposed to sulfur dioxide, but no excess was indicated for lung
   cancer.
       No epidemiological study was available on cancer risks associated with exposure to
   sulfites, bisulfites or metabisulfites.
   5.3 Carcinogenicity in experimental animals
   Sulfur dioxide was tested for carcinogenicity in one study in mice by inhalation
   exposure. A significant increase in the incidenc8 of lung tumours was observed in
   females.
       Sulfur dioxide was tested for enhancement of carcinogenicity when administered
   with benzo[a]pyrene in two studies in rats and in one study in hamsters. One
   incompletely reported study found an increase in the incidence of lung tumours in rats
   exposed to sulfur dioxide in conjunction with benzo[a]pyrene. The other study in rats
   suffered from limitations owing to the high incidence of lung tumours in controls given
   benzo[a]pyrene. The study in hamsters was inadequately reported.
       Potassium metabisulfite was tested for carcinogenicity in one study in mice by oral
   administration in the drinking-water and sodium metabisulfite in one study in rats by
   oral administration in the diet. No increase in tumour incidence was observed in mice,
   and there was no indication of a dose-related increase in tumour incidence in rats, but
   bath studies had same inadequacies in reporting of data.
90 Sulphur dioxide
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<pre>     Potassium metabisulfite was tested for enhancement of carcinogenicity in one study
in rats. It significantly increased the incidence of gastric adenocarcinoma after initiation
with N-methyl-N'-nitro-N-nitrosoguanidine.
     No data were available on the carcinogenicity in experimental animals of sulfites or
bisulfites.
5.4 Other relevant data
At high concentrations, sulfur dioxide irritates the upper airways and can induce acute
and chronic bronchitis. At lower levels (less than 0.25 ppm [0.65 mg/m3]), no effect of
sulfur dioxide is seen on the airways of sensitive individuals in the general population
who take exercise, presumably since this relatively hygroscopic gas is removed by the
nose and mouth.
     Conflicting results for the induction of chromosomal aberrations in lymphocytes
were obtained in two studies of workers exposed to sulfur dioxide, among other agents.
In a single study, no increase was reported in the frequency of sister chromatid exchange
in lymphocytes of exposed workers.
     Sulfur dioxide and its aqueous forms did not induce sister chromatid exchange,
chromosomal aberrations or micronucleus formation in bone marrow of mice or Chinese
hamsters. In a single study, sister chromatid exchange and chromosomal aberrations
were induced in human lymphocytes. In cultured mammalian celIs, bisulfite induced
transformation and sister chromatid exchange but not gene mutation, chromosomal
aberrations or DNA repair synthesis. In plants, chromosomal aberrations, micronuclei
and gene mutation were induced. Sulfur dioxide and bisulfite induced gene mutation but
not gene conversion in yeast. Mutations were induced in bacteria and phage.
     Bisulfite solutions at high concentrations caused deamination of cytosine in DNA in
vitro.
5.5 Evaluation
There is inadequate evidence for the carcinogenicity in humans of sulfur dioxide,
sulfites, bisulfites and metabisulfites.
     There is limited evidence for the carcinogenicity in experimental animals of sulfur
dioxide.
     There is inadequate evidence for the carcinogenicity in experimental animals of
sulfites, bisulfites and metabisulfites.
IARC Monograph                                                                               91
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<pre>   Overall evaluation
   Sulfur dioxide, sulfites, bisulfites and metabisulfites are not classifiable as to their
   carcinogenicity to humans (Group 3).
92 Sulphur dioxide
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<pre>Annex     F
          Summary of data concerning acute
          physical effects in healthy humans
          Text in italic: the same authors reported also on higher exposure concentrations.
Exposure  Duration         Subjects      Effects                                                                     Ref.
mg/m3
0.5       1 hour with      n=24         No change in lung function, including specific airway resistance.            Lin87
          exercise
0.5       1 hour at rest   n=12, non-   No changes in pulmonary function and on heart rate. Parameters of the        Tun01
                           smoking      spectral analysis of heart rate variability were increased (p<0.05 for total
                                        power).
0.7       40 minutes       n=10         No changes in lung function, including airway resistance with exercise or    Sch84
          with exercise                 at rest.
1.0       1 hour with      n=24         No change in lung function, including specific airway resistance.            Lin87
          exercise
1.0       20 minutes       n=8, non-    No significant changes in lung function, heart rate and eye symptoms.        San88
          with exercise    smoking      Two subjects reported of mild throat irritation.
1.3       40 minutes with n=10          No changes in lung function, including airway resistance with exercise or    Sch84
          exercise                      at rest.
1.6       1 hour with      n=24         No change in lung function, including specific airway resistance.            Lin87
          exercise
1.6 – 2.0 5 min eucapnic   n=26, non-   A significantly increase in specific airway resistance (sRaw) was noted.     Isl92
          hyper-           smoking      Values turned to normal between 20-40 min after exposure. Thirteen
          ventilation                   individuals were considered to be responders (increase of sRaw ≥ 100%).
                                        No SO2-exposure data were presented without hyperventilation.
          Summary of data concerning acute physical effects in healthy humans                                              93
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<pre>1.9        5 min eucapnic   n=37, non-      Specific airway resistance was increased significantly 3 minutes after      Isl94
           hyper-           smoking         exposure. Values turned to normal between 20 and 40 minutes after
           ventilation                      exposure. Fourteen volunteers were considered responders (increase of
                                            sRaw 100%). No SO2-exposure data were presented without
                                            hyperventilation.
2.0        4 hours with     n=11            No changes in airway resistance, lung volume and air flow responses.        Sta83
           exercise
2.0        40 minutes       n=10            No changes in lung function, including airway resistance with exercise or   Sch84
           with exercise                    at rest.
2.7        10 minutes       n=4             Slight increase in respiratory rate and cardiovascular pulse rate.          SCO93
           (face mask)                                                                                                  (Amdur
                                                                                                                        et al.,
                                                                                                                        1953)
2.7        30 minutes       n=6             No changes in pulmonary flow resistance during exposure or after 15         Fra64
           at rest                          minutes of recovery period.
2.7        6 hours          n=15, including Significant decrease in nasal airway resistance, but decrease in forced     And74
                            four smokers    respiratory flow. No effects on nasal mucociliary flow rate.
2.7        1 hour           n=12-13         No significant changes in lung function and airway resistance with          Law75
                                            normal breathing. Twenty-five maximum deep breaths lowered airway
                                            resistance.
2.7        2 hours with     n=7             Significantly increased pulmonary flow resistance. Half of the exposed      Fra80
(+ 1 mg/m3 exercise                         subjects experienced shortness of breath and wheezing.
NaCl)
2.7        2 hours with     n=9, non-       Significant increase in specific airway resistance.                         Bed84
           and without      smoking         No changes in airway resistance.
           exercise         n=23, non-
                            smoking
2.7        4 hours with     n=10/sex,       No significant changes in pulmonary function and non-specific bronchial     Kul84
           exercise         non-smoking     reactivity to metacholine. Four subjects reported of upper respiratory
                                            irritation and one reported of eye irritation during exposure.
                                            At t = 17 minutes: significant decrement of FEF25-75% and FEV1/FVC.
                                            Also, statistically significant increases in nose and throat irritation.
                            n=10/sex,       No statistically significant changes in pulmonary function, and nose and    Kul86
                            non-smoking     throat irritation, were observed 24 hr postexposure.
2.7        40 minutes       n=10            No changes in lung function, including airway resistance with exercise or   Sch84
           with exercise                    at rest.
5.0        20 minutes       n=8, non-       No significant changes in lung function, heart rate and eye symptoms. Six   San88
           with exercise    smoking         subjects reported of mild throat irritation, four subjects reported of mild
                                            nasal irritation.
5.3        2 hours with and n=9, non-       Increased specific airway resistance.                                       Bed84
           without exercise smoking
5.3        30 minutes       n=14, non-      No changes in lung function, including airway resistance following          Bed89
           with exercise    smoking         normal breathing, forced oral or forced nasal breathing.
8.0        Eight deep       n=12-13         Significant increase in airway resistance following deep breathing. No      Law75
           breaths                          changes in subjects breathing normally.
94         Sulphur dioxide
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<pre>10.0 20 minutes        n=12            Significant increase in lung macrophages and lymphocytes.                    San89a
                                                                                                                    San89b
10.0 20 minutes        n=8, non-       No significant changes in lung function, heart rate and eye symptoms.        San88
     with exercise     smoking         Eight subjects reported of mild throat irritation, five subjects reported of
                                       mild nasal irritation.
13.4 30 minutes        n=6 males       A small but statistically significant increase in mean Raw. The increase     Fra64
     at rest                           was maximal after 10 min of exposure (mean %Raw: 38% (after 10 min),
                                       30.0% (after 20 min), 24.8% (after 30 min) and 26.6% (after 15 min
                                       recovery period) compared to control values).
13.4 15 minutes with n=9               Small but significant decrease in expiratory flow in the middle of expired   SCO93
     forced inhalation                 vital capacity.                                                              (Snell et
                                                                                                                    al.,
                                                                                                                    1969)
13.4 6 hours           n=15, including Significant decrease in nasal airway resistance, but significant decrease in And74
                       four smokers    respiratory forced flow and nasal mucociliary flow rate.
20.0 20 minutes        n=12            Significant increase in lung macrophages and lymphocytes.                    San89a,
                                                                                                                    San89b
40.5 30 minutes        n=6             A statistically significant increase in mean Raw. The increase was maxi-     Fra64
                                       mal after 10 min of exposure (mean %Raw: 139% (after 10 min), 99.3%
                                       (after 20 min), 64.7% (after 30 min) and 50.4% (after 15 min recovery
                                       period) compared to control values).
66.8 6 hours           n=15, including Increased nasal airway resistance, but decreased forced expiratory flow      And74
                       four smokers    and volume. Nasal mucociliary stasis occurred in 14 of 15 subjects with 4
                                       having developed colds during the week following exposure.
     Summary of data concerning acute physical effects in healthy humans                                                  95
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<pre>96 Sulphur dioxide</pre>

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<pre>Annex G
      Abbreviations
      bp        boiling point
      EC50      concentration at which a described effect is found in 50% of the exposed animals or at which
                the effect is decreased up to 50% of the control value
      HBR-OEL   health based recommended occupational exposure limit
      h         hour
      IC50      concentration at which inhibition of a certain function is found up to 50% of the control value
      LC50      lethal concentration for 50% of the exposed animals
      LC10      lowest lethal concentration
      LD50      lethal dose for 50% of the exposed animals
      LD10      lowest lethal dose
      LOAEL     lowest observed adverse effect level
      MAC       maximaal aanvaarde concentratie (maximal accepted concentration)
      MAEL      minimal adverse effect level
      MAK       Maximale Arbeitsplatz Konzentration
      MOAEL     minimal observed adverse effect level
      MTD       maximum tolerated dose
      NAEL      no adverse effect level
      NEL       no effect level
      NOAEL     no observed adverse effect level
      OEL       occupational exposure limit
      PEL       permissible exposure limit
      ppb       parts per billion (v/v)10-9
      ppm       parts per million (v/v)10-6
      Abbreviations                                                                                             97
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<pre>   RD50         concentration at which a 50% decrease of respiratory rate is observed
   REL          recommended exposure limit
   STEL         short term exposure limit
   tgg          tijd gewogen gemiddelde
   TLV          threshold limit value
   TWA          time weighted average
   Vmax         maximal reaction velocity of an enzyme
   Organisations
   ACGIH        American Conference of Governmental Industrial Hygienists
   CEC          Commission of the European Communities
   DECOS        Dutch Expert Committee on Occupational Standards
   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)
   INRS         Institut National de Recherche et de Sécurité (France)
   NIOSH        National Institute for Occupational Safety and Health (USA)
   NTP          National Toxicology Programme (USA)
   OECD         Organisation for Economic Cooperation and Development
   OSHA         Occupational Safety and Health Administration (USA)
   RTECS        Registry of Toxic Effects of Chemical Substances
   SER          Social and Economic Council (Sociaal-Economische Raad NL)
   WATCH        Working Group on the Assessment of Toxic Chemicals (UK)
   WHO          World Health Organisation
   Toxicological terms
   bid          bis in diem (twice a day)
   bw           body weight
   CARA         chronic non-specific respiratory diseases
   CHD          coronary heart disease
   CNS          central nervous system
   ECG          electrocardiogram
   EEG          electro encephalogram
   FCA          Freunds Complete Adjuvans
   FEV          forced expiratory volume
   FSH          follicle stimulating hormone
   GD           gestation day(s)
   GPMT         guinea pig maximisation test
   GSH          glutathione
98 Sulphur dioxide
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<pre>HLiA           hamster liver activated
IHD            ischaemic heart disease
im             intramuscular
ip             intraperitoneal
ipl            intrapleural
it             intratracheal
iv             intravenous
LH             lutheinising hormone
MAC            minimal alveolar concentration
MFO            mixed function oxidase
NA             not activated
PNS            peripheral nervous system
po             per os (= oral)
RBC            red blood cells
RLiA           rat liver activated
SCE            sister chromatid exchange
sc             subcutaneous
UDS            unscheduled DNA-synthesis
Statistical terms
GM             geometric mean
OR             Odds Ratio
RR              Relative Risk
SD             standard deviation
SEM            standard error of mean
SMR            standard mortality ratio
Analytical methods
AAS            atomic absorption spectroscopy
BEEL           biological equivalent exposure limit
BEI            biological exposure index
BEM            biological effect monitoring
BM             biological monitoring
ECD            electron capture detector
EM             environmental monitoring
FID            flame ionisation detector
GC             gas chromatography
GLC            gas liquid chromatography
GSC            gas solid chromatography
HPLC           high performance liquid chromatography
IR             infrared
Abbreviations                                         99
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<pre>    MS           mass spectrometry
    NMR          nuclear magnetic resonance
    PAS          personal air sampling
    TLC          thin layer chromatography
    UV           ultraviolet
    Additional abbreviations in the present report
    ERV          expiratory reserve volume
    FEF25/50/25-
                 forced expiratory flow at 25, 50 or between 25 and 75% of FVC
    75
    FEV1         forced expiratory volume in 1 second
    FIF25-75     forced inspiratory flow between 25 and 75% of FIVC
    FIF200-1200 forced inspiratory flow between inspired volumes of 200 to 1200 mL
    FIV1         forced inspiratory air at 1 second
    FIVC         forced inspritory capacity
    FVC/VC       forced vital capacity/vital capacity
    IC           inspiratory capacity
    PEF/PIF      peak expiratory flow/peak expiratory flow
    SRaw         specific airway resistance
100 Sulphur dioxide
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<pre>Annex H
      DECOS-documents
      Aanpassing van grenswaarden bij flexibele werktijden 2001/06OSH
      Acetone cyanohydrin                                  1995/05WGD
      p-Aramid fibres                                      1997/07WGD
      Azathioprine                                         1999/04OSH
      Aziridine (ethyl imine)                              2000/13OSH
      Azobisisobutyronitril                                2002/01OSH
      1,2,3-Benzotriazole                                  2000/14OSH
      Bisphenol A and its diglycidylether                  1996/02WGD
      Bromoethane                                          1998/10WGD
      1,2-and t-Butanol                                    1994/10WGD
      n-, iso-, sec-, tert-Butylacetaten                   2001/03OSH
      β-Butyrolactone                                      1999/05OSH
      Cadmium and inorganic cadmium compounds              1995/04WGD
      Calculating cancer risk                              1995/06WGD
      Carbadox                                             1999/06OSH
      Carbon disulphide                                    1994/08
      Chlorine dioxide                                     1995/07WGD
      p-Chloroaniline                                      1998/09WGD
      4-Chloro-o-toluidine                                 1998/08WGD
      Chlorotrimethylilane                                 2001/05OSH
      Chromium and its inorganic compounds                 1998/01WGD
      Chromium VI and its compounds                        2001/01OSH
      Cresols                                              1998/15WGD
      DECOS-documents                                                 101
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<pre>    Copper sulphate                                                                   1999/01OSH
    1996-1997 WGD-rapporten/1996-1997 DECOS reports                                   1999/01WGD
    1,2-Dibromoethane                                                                 1999/07OSH
    1,2-Dichloroethane                                                                1997/01WGD
    Diethylsulphate                                                                   1999/08/OSH
    Diglycidyl resorcinol ether                                                       1999/09OSH
    Diphenylamine                                                                     1997/05WGD
                                                                                      1998/03WGD
    Epichlorohydrin (1-Chloro-2,3-epoxypropane)                                       2000/10OSH
    1,2-Epoxybutane                                                                   1998/11WGD
    1,2-Ethanediamine                                                                 1996/03WGD
    Ethyleneglycol ethers                                                             1996/01WGD
    Ethylene oxide                                                                    2001/11OSH
    Ethylene thiourea                                                                 1999/03OSH
    Formaldehyde                                                                      2003/02OSH
    Formamide and dimethylformamide                                                   1995/08WGD
    Halothane                                                                         2002/14OSH
    Hydrazinoethanol, phenylhydrazine, isoniazid, maleic hydrazide                    1997/03WGD
    Hydrogen cyanide, sodium cyanide, and potassium cyanide                           2002/15OSH
    Isopropyl acetate                                                                 1997/04WGD
    Lactate esters                                                                    2001/04OSH
    Lindane                                                                           2001/07OSH
    Man made mineral fibers                                                           1995/02WGD
    Manganese and its compounds                                                       2001/02OSH
    2-Methylaziridine (propylene imine)                                               1999/10OSH
    Methyl Methacrylate                                                               1994/09
    Methacrylates. Ethyl methacrylate, n-butyl methacrylate and isobutyl methacrylate 1994/11
    Methyl-t-butylether                                                               1994/23
    Methyl chloride                                                                   1995/01WGD
    4,4'-Methylene bis (2-Chloroaniline)                                              2000/09OSH
    4,4'-Methylene dianiline                                                          2000/11OSH
    Metronidazole                                                                     1999/11OSH
    2-Nitropropane                                                                    1999/13OSH
    N-Nitrosodimethylamine (NDMA)                                                     1999/12OSH
    2-Nitrotoluene                                                                    1998/12WGD
    Pentaerythritol                                                                   1997/06WGD
    Phenol                                                                            1996/04WGD
    o-Phenylenediamine                                                                1998/06WGD
    Piperidine                                                                        1997/08WGD
    Procarbazine hydrochloride                                                        1999/14OSH
    1- and 2-Propanol                                                                 1994/24
102 Sulphur dioxide
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<pre>Propylene oxide            1997/02WGD
Ronidazole                 1998/05WGD
Styrene                    1998/07WGD
Styrene                    2001/08OSH
Tetrachloroethylene (PER)  2003/01OSH
Quartz                     1998/02WGD
Toluene                    2001/09OSH
1,1,1-Trichloroethane      1995/03WGD
1,2,3-Trichloropropane     1994/25
1,2,3-Trichloropropane     1998/14WGD
Urethane (ethyl carbamate) 2000/12OSH
Vinylbromide               1999/15OSH
Xylene                     2001/10OSH
Wood dust                  1998/13WGD
DECOS-documents                       103
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<pre>104 Sulphur dioxide</pre>

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<br><br>