<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>Hardwood and softwood dust
Evaluation of the carcinogenicity and genotoxicity
</pre>

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<pre>Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp      :   aanbieding advies houtstof
Uw kenmerk     :   ARBO/AMIL/9834631
Ons kenmerk    :   U 1395/EvV/mj/246-Z8
Bijlagen       :   1
Datum          :   18 juli 2000
Mijnheer de staatsecretaris,
Op 12 november 1998 verzocht uw Directeur Arbeidsomstandigheden, R. Laterveer,
namens u om advies over de wijze waarop toxicologische advieswaarden voor
blootstelling aan hardhout- en zachthoutstof moeten worden afgeleid (brief nr.
ARBO/AMIL/9834631).
Hierbij bied ik u - gehoord de Beraadsgroep Gezondheid en Omgeving - het advies
'Hardwood and softwood dust, evaluation of the carcinogenicity and genotoxicity' aan,
dat is opgesteld door de Commissie Beoordeling carcinogeniteit van stoffen.
Hoogachtend,
w.g.
prof. dr JJ Sixma
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<pre>Hardwood and softwood dust
Evaluation of the carcinogenicity and genotoxicity
Committee on the Evaluation of the carcinogenicity of chemical substances
to:
the Minister and State Secretary of Social Affairs and Employment
Nr 2000/08OSH, The Hague, 18 July 2000
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<pre>Preferred citation:
Health Council of the Netherlands: Hardwood and softwood dust; evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands, 2000;
publication no. 2000/08OSH.
auteursrecht voorbehouden
all rights reserved
ISBN: 90-5549-327-9
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<pre>    Contents
    Samenvatting 7
    Executive summary 10
1   Introduction 13
2   Hardwood 15
2.1 Genotoxicity and interaction with DNA 15
2.2 Carcinogenicity 16
2.3 Evaluation 20
3   Softwood 23
3.1 Genotoxicity and interaction with DNA 23
3.2 Carcinogenicity 24
3.3 Evaluation 26
4   Health hazard assessment 29
    References 34
    Contents                                 5
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<pre>  Annexes 37
A The request for advice 38
B The committee 39
C Linear extrapolation 41
D Comments on the public draft 43
  Contents                        6
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<pre>Samenvatting
Hardhoutstof is voor mensen kankerverwekkend: inademing ervan kan leiden tot het
optreden van adenocarcinoom van de neus en de neusbijholten. Onduidelijk is nog of er
ook sprake is van verhoogde kansen op andere vormen van kanker, in het bijzonder
nasofarynxcarcinoom, dieper in de luchtwegen. Uitkomsten van meta-analyses geven wél
aanwijzingen in die richting. Voor zachthoutstof gaat de evidentie voor
kankerverwekkendheid nog niet verder dan een verdenking: epidemiologische gegevens
doen vermoeden dat dit agens plaveiselcelcarcinoom van de neus en de neusbijholten kan
veroorzaken. Het bestaan van een causaal verband tussen hardhoutstof en
nasofarynxkanker en tussen zachthoutstof en plaveiselcelcarcinoom van de neus en de
neusbijholten is noch als bewezen noch als uitgesloten te beschouwen. Deze ongewisheid
is waarschijnlijk vooral het gevolg van onzekerheid over de aard van de blootstelling
(hardhout óf zachthout óf een mengsel van beide) en van een tekortschietend statistisch
onderscheidingsvermogen van het verrichte onderzoek.
     Onderzoek met proefdieren heeft tot dusver geen informatie opgeleverd over de
eventuele kankerverwekkendheid van houtstof. Slechts van één langdurig
inhalatie-experiment met hardhoutstof bij proefdieren zijn de uitkomsten gepubliceerd.
Zij duiden niet op carcinogeniteit. Over de oorzaken van de discrepantie tussen de
uitkomsten van onderzoek bij mensen en bij proefdieren is niets met zekerheid te zeggen.
    Het is onmogelijk om de genotoxiciteit van houtstof rechtstreeks te onderzoeken.
Daarom is gewerkt met extracten of condensaten als vervangende agentia. Uit de
resultaten is het beeld naar voren gekomen dat de genotoxiciteit van hard- en
zachthoutstof vergelijkbaar is, wat betreft zowel de potentie — in casu: zwak — als de
Samenvatting                                                                             7
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<pre>aard. Onbekend is echter in hoeverre de eigenschappen van de vervangende agentia
representatief zijn voor die van hard- of zachthoutstof. De commissie betwijfelt of de
gevonden genotoxiciteit betekenis heeft voor de (mogelijke) carcinogeniteit. Andere
gegevens die plausibel kunnen maken dat hier de genotoxiciteit een cruciale rol speelt in
het proces dat tot kanker leidt, bijvoorbeeld gegevens over het optreden van specifieke
mutaties bij mensen die aan houtstof blootgesteld zijn geweest, zijn verre van
eensluidend.
     Er zijn ook bevindingen die erop duiden dat houtstof ontstekingsreacties kan
veroorzaken en cytotoxisch is. De betekenis van deze bevindingen voor de
carcinogeniteit — te weten: hogere incidenties van functionele en histologische
veranderingen in de neus en de neusbijholten van aan houtstof blootgestelde mensen —
is, net als die van de bevindingen inzake genotoxiciteit, nog onduidelijk. Wél kan men
spreken van indicaties voor het bestaan van een (plaatselijke) weefselbeschadigende
werking. De waargenomen effecten zijn zwak. Omdat de waarnemingen betrekking
hebben op mengblootstellingen valt niet te zeggen of beide typen houtstof de genoemde
effecten kunnen veroorzaken. In dierexperimenteel onderzoek (met hardhoutstof) naar
plaatselijke cytotoxiciteit en regeneratieve celproliferatie zijn praktisch geen effecten
waargenomen. Juist voor een agens als houtstof, dat matig vatbaar is voor degradatie
door het immuunsysteem, zou men veel sterkere effecten verwachten dan hetgeen tot
dusver is waargenomen. Er is geen verklaring voor het feit dat de ontstekingsbevordende
en de cytotoxische eigenschappen van houtstof zich uitsluitend lijken te manifesteren als
bescheiden histologische en functionele afwijkingen in de neus en de neusbijholten.
Zowel bij mensen als bij proefdieren zijn de aangeduide waarnemingen gedaan na
(semi-)chronische blootstelling. Dit bemoeilijkt hun interpretatie: uitsluitend het vroege
optreden van de genoemde verschijnselen zou de commissie tot de overtuiging kunnen
brengen dat houtstof niet langs genotoxische weg kankerverwekkend is, maar dat het
ontstaan van tumoren door toedoen van dit agens voornamelijk berust op cytotoxiciteit
en de regeneratieve hyperplasie die op weefselbeschadiging volgt. Was dit laatste het
geval dan zou kanker goeddeels te voorkomen zijn door weefselbeschadiging te
verhinderen.
     Evenzeer tot dusver onbeantwoord is de vraag welke bestanddelen van houtstof
verantwoordelijk zijn voor de waargenomen effecten. Is dat het stof als zodanig, of zijn
het opzettelijk aan het hout toegevoegde stoffen of verontreinigingen, zoals
conserveermiddelen respectievelijk schimmels? Ook de rol van de fysische kenmerken,
zoals deeltjesgrootte, is onduidelijk.
De commissie meent dat toxicologische advieswaarden voor hard- en zachthoutstof op
gelijke wijze moeten worden afgeleid, ook al staat voor hardhoutstof de
Samenvatting                                                                               8
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<pre>kankerverwekkendheid bij mensen vast en is zachthoutstof in dit opzicht als verdacht te
bestempelen. Doorslaggevend is de overeenkomst in genotoxische eigenschappen.
    Gezien de geschetste onduidelijkheden met betrekking tot genotoxiciteit en
functionele of histologische veranderingen kan de commissie niet aangeven om welke van
de volgende, voor de keuze van de methode bepalende, mogelijkheden het gaat:
    hard- en zachthoutstof zijn rechtstreeks genotoxisch carcinogeen, met een hoofdrol
    voor de genotoxiciteit
    hard- en zachthoutstof zijn indirect genotoxisch carcinogeen, met een hoofdrol, zo
    niet een essentiële rol, voor ontstekingsachtige of regeneratieve hyperplastische
    veranderingen
    hard- en zachthoutstof zijn niet-genotoxisch carcinogeen, met en essentiële rol voor
    regeneratieve hyperplasie na herhaaldelijk opgetreden weefselbeschadiging.
    Het voorgaande houdt in dat het niet mogelijk is om te beslissen of bij de afleiding
van gezondheidskundige bovengrenzen voor beroepsmatige blootstelling aan houtstof wel
of niet moet worden uitgegaan van het bestaan van een drempelwaarde waarbeneden zich
geen gezondheidsschade voordoet. In het verleden is het voorstel gehonoreerd om in
geval van ongewisheid over het bestaan van een drempelwaarde aan te nemen dat zo’n
grens niet bestaat en — derhalve — de methode van lineaire extrapolatie toe te passen.
In dit rapport is een dienovereenkomstige berekening toegevoegd.
Samenvatting                                                                             9
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<pre>Executive summary
Hardwood dust is a human carcinogen; upon inhalation it can cause sinonasal
adenocarcinoma. Whether it is able to induce other tumours, especially nasopharyngeal
carcinoma, a cancer deeper down the airways, is unresolved, but the outcome of a
meta-analysis suggests that it is. Softwood, on the other hand, is suspected of
carcinogenic properties. The epidemiological data available suggest that it can cause
sinonasal squamous-cell carcinoma. The data do not prove or disprove a causal
relationship between hardwood dust and nasopharyngeal carcinoma, nor between
softwood dust and sinonasal squamous-cell carcinoma. This may mainly be due to
uncertainty as to the nature of the exposure (hardwood, softwood or mixed) and to lack
of statistical power of the studies concerned.
     The animal experiments do not provide any clues as to the questions of the types of
tumour caused by the two species of wood dust. From only one long-term inhalation
experiment, with hardwood dust, the results have been published. It did not provide any
indication of carcinogenicity. The cause of the discrepancy between the human and
animal findings as regards carcinogenicity is unknown.
     The genotoxicity of the wood dusts cannot be and has not been tested directly.
Preparations like extracts and condensates have been used as substitutes. The picture
emerging from the results of the genotoxicity tests is that hardwood and softwood both
possess genotoxic properties and that their genotoxicity is similar, with regard to nature
and strength (weak). It is unknown, however, to what extent the properties of the dust
surrogates represent those of the original material. According to the Committee, the
relevance of the genotoxicity observed for the (possible) carcinogenicity of the dusts is
Executive summary                                                                          10
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<pre>questionable. Other lines of evidence that could lend plausibility to the assumption that
the genotoxicity is crucial to the carcinogenic process, such as specific mutations in
adenocarcinomas from individuals with a history of wood dust exposure, are
inconclusive.
     Doubt as to their significance for carcinogenicity also holds true for the findings
pointing to inflammatory and cytotoxic potential in vivo, viz. higher incidences of
functional and histological changes in the sinonasal cavities of wood dust-exposed
individuals. Due to the mixed nature of the exposure it has not been possible to
determine whether both dusts can cause these effects. Together the findings are taken as
indications of local tissue damage. The effects observed are weak, however.
Correspondingly, animal experiments, with hardwood dust, aimed at detection of local
cytotoxicity and regenerative cell proliferation (hyperplasia), were negative or virtually
negative. A much stronger in vivo response than that observed is expected from an agent
like wood dust, that is relatively resistant to degradation by the immune system. Why the
inflammation and cytotoxicity are weak, only reflected in diminished nasal function and
mild histological abnormalities, is enigmatic. The observations on local tissue damage, in
humans and animals, have all been made upon semi-chronic and chronic exposure. It is
not known whether they occur earlier upon exposure. This hampers interpretation,
because only early presentation of such phenomena would convince the Committee that
the wood dust does not cause tumours through genotoxicity, but promotes tumour
formation predominantly by cytotoxicity and ensuing regenerative hyperplasia, and that
tumours can largely be prevented by preventing tissue damage.
     Another unresolved matter is that of the constituents to be held responsible for the
effects observed: the wood dust itself, or components added to the wood deliberately or
contaminating it, such as preservatives or moulds, respectively. Perhaps the physical
characteristics, particle size for example, also play a role.
According to the Committee toxicology-based recommended exposure limits for
hardwood and softwood dust should be derived identically, bearing in mind that
hardwood dust is a proven, softwood dust a suspected carcinogen. The decisive factor
here was the similarity of their genotoxicity.
     In view of the dubious significance of both the genotoxicity findings and the
functional and histological findings the Committee cannot answer the question whether
the wood dusts are
     direct genotoxic carcinogens with a major role for their genotoxicity
     indirect genotoxic carcinogens with a major, if not an essential role for inflammatory
     or regenerative hyperplastic changes
     non-genotoxic carcinogens with an essential role for regenerative hyperplasia
     following recurrent tissue damage.
Executive summary                                                                           11
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<pre>    Consequently, the decision how toxicology-based occupational exposure limits
should be derived, with a threshold or linear model, cannot be made. In the past the
suggestion to apply linear extrapolation to carcinogens with unresolved mechanism has
been honoured. Therefore, calculations along this line have been added.
Executive summary                                                                     12
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<pre>Chapter 1
        Introduction
        Recently, the Dutch Expert Committee on Occupational Standards (DECOS), a
        committee of the Health Council of the Netherlands, assessed the health effects of
        exposure to wood dust (DEC98). This evaluation was restricted to the carcinogenic
        properties. It was performed according to the classification system of the EU, that uses
        the strength of the evidence, and it was based on a monograph from the International
        Agency for Research on Cancer (IARC), supplemented with more recent publications
        (IAR95). Hardwoods and softwoods were separately assessed. The terms ‘hardwood’
        and ‘softwood’ refer to angiosperm and gymnosperm trees, respectively, and not
        necessarily to the hardness of the wood. According to DECOS hardwood dust has been
        found to be carcinogenic to humans and to possess genotoxic properties. They concluded
        that softwood dust, on the other hand, had been insufficiently investigated and proposed
        to classify it as a suspected human carcinogen.
             In a previous report, DECOS had assessed the health effects of exposure to wood
        dust as a whole and derived a toxicology-based recommended exposure limit based on a
        threshold, a level below which adverse effects are expected not to occur (DEC91). This
        limit was based on prevention of irritation.
             The classification outcome prompted the State Secretary of Social Affairs and
        Employment to request the Health Council for assessment of its consequences for the
        exposure limit in force, that applies to wood dust as such (see Annex A). Because of
        their specialised knowledge, the President of the Health Council asked the Committee on
        the Evaluation of the Carcinogenicity of Chemical Substances — further referred to as:
        the Committee — to answer the questions.
        Introduction                                                                             13
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<pre>    For its judgement the Committee has relied on the reviews of IARC and DECOS, as
well as on papers published more recently than the latter. These were drawn from the
databases Biosis, Embase, Elsevier Biobase, IAC Health, Pascal, Medline and Toxline
up until March 2000. If considered necessary the original papers included in the reviews
were checked. The report starts with separate evaluations of hardwood and softwood
dust. It does not mention the species of tree investigated, because species-wise evaluation
is not possible, as exposure involves dust from several species combined (in the case of
epidemiological data), or species-specific data are too scarce (the other data). In the final
chapter the health hazards of the two types of dust are compared. This is crucial for the
decision whether to propose different methods for estimation of toxicology-based
recommended exposure levels, levels that do not pose a health risk higher than a
predetermined one.
Introduction                                                                                  14
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<pre>Chapter 2
        Hardwood
2.1     Genotoxicity and interaction with DNA
        To investigate wood dust for compounds with genotoxic properties two preparative
        methods have been applied that are common for assessing the health hazards of materials
        consisting of insoluble high-molecular components, such as cellulose and lignin, and
        low-molecular ones, like terpenes. The material is heated and the fumes set free are
        collected and condensated; alternatively it is extracted with a solvent.
            In vitro genotoxicity tests were performed with both types of preparation. The
        majority were tests with bacteria, that detect gene mutations. Both condensates and
        extracts from hardwoods have been shown to cause mutations in bacteria, albeit weakly
        (Kur90, Moh86, Moh90). Addition of a metabolic activation system was not required to
        demonstrate this activity. Not all experiments of this type performed demonstrated
        mutagenicity; some were negative, with and without metabolic activation (Kub88,
        Sin95, Wei92). In one study a third method, microbial degradation, was applied to a
        hardwood dust (Moh90). The preparation proved to be genotoxic.
            Additionally, hardwood preparations were investigated for the ability to cause
        chromosomal aberrations. An extract proved positive in a test with a cell line of human
        origin, the positivity being moderate (Zho95). A condensate, on the other hand, was
        found negative in a test with human peripheral blood lymphocytes (Mar95a).
            With hardwood one in vivo genotoxicity test was performed. Intranasal application
        of a hardwood extract to rats significantly increased the frequency of micronuclei in the
        Hardwood                                                                                  15
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<pre>      nasal tissue (Nel93). Also the local formation of DNA adducts was checked by
      32
         P-postlabelling; none was observed.
           Hardwood extracts and condensates have not been investigated for interaction with
      DNA in vitro.
           Furthermore, four papers describe observations suggestive of genotoxicity in
      humans. The peripheral blood of workers employed in the plywood industry on average
      demonstrated more chromosomal aberrations than controls, the difference being small
      but statistically significant (Kur93). Similarly the peripheral blood lymphocytes of
      smoking workers exposed to hardwood dust in the furniture industry appeared to contain
      significantly more DNA breaks than unexposed smoking colleagues (Pal98). It should be
      noted, however, that there had been exposure to hard- and softwood in both cases. In the
      third paper the investigators confirmed these findings in non-smoking workers in a
      furniture plant, exposed to dust from unspecified wood (Pal99).
           The fourth paper describes a different approach: a molecular analysis of the DNA
      modifications in sinonasal adenocarcinomas, the type of tumour undoubtedly caused by
      hardwood dust (see 2.2) (Sab98). A particular mutation was observed in the k-ras
      oncogene in sinonasal adenocarcinomas from patients who had been exposed to (an
      unspecified type of) wood dust. The investigators suggest that this points to genotoxic
      properties. The Committee considers this doubtful, because the suggestion is based on
      two subjects only and the mutation described has also been observed in several types of
      animal and human tumour not associated with wood dust exposure (Cap91). More
      papers document mutations in sinonasal adenocarcinoma. Mutations in h-ras and k-ras
      were observed in five and one, respectively, out of 31 cases; n-ras was not mutated
      (Per99). Others found mutations in p53, but not k-ras, in 2 out of 11 tumours (Wu96).
      The h-ras mutations were identical; the adenocarcinomas they were detected in, came
      from patients with and without a history of exposure to wood dust. In the case of the p53
      mutations it is not known whether the patients had been exposed to wood dust
      previously.
2.2   Carcinogenicity
2.2.1 Animals
      The available animal data have been examined for indications of carcinogenicity and
      effects that may be causally related to tumour formation: local cytotoxicity and
      histological abnormalities, suggestive of regeneration of the tissue following a cytotoxic
      insult. Such lesions are for instance hyper- and metaplasia.
           Since the publication of the IARC review no new relevant data obtained in toxicity
      studies with animals have been reported. This means that only one experiment has been
      Hardwood                                                                                   16
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<pre>      carried out in which animals have been exposed to hardwood dust chronically. It is a
      two-year inhalation study in rats (Hol89). The animals demonstrated no enhanced risk of
      tumours in the nose or lungs, the organs investigated, at the end of the experiment, only
      a significantly increased histological score in the nasal tissue corresponding to
      (unspecified) light histological changes.
           From another long-term inhalation study only some preliminary results have been
      published. Female rats were exposed to dust from hardwood, untreated or preserved with
      certain chemicals, or to the chemicals themselves (Wol98a). Findings concerning part of
      the animals have been reported. As they are incomplete, the Committee does not take
      them into account.
           The remainder of the data reviewed by IARC originate from experiments with rats,
      mice and hamsters, of varying designs, and sharing a shorter duration (minimally six
      months). They provide evidence neither for carcinogenicity, nor for histological
      abnormalities, except minor ones.
           Cytotoxicity and histological changes have not been addressed at short-term
      exposures (28 days or less).
           There is evidence from one animal study that hardwood dust carries carcinogenic
      properties. The experiment has been carried out with a genotoxic extract of hardwood
      dust, applied dermally for three months (Moh89). It proved to be carcinogenic, to cause
      a significant and dose-dependent increase of tumours, most of which occurred at the site
      of application, the skin, and none in the nasal cavities. These findings demonstrate that
      tumours can be induced locally and suggest that the genotoxicity of the extract is
      associated with the carcinogenic effect observed.
2.2.2 Humans
      Hardwood dust is a proven human carcinogen; it can cause a specific type of cancer of
      the nasal cavities and paranasal sinuses: sinonasal adenocarcinoma (DEC98, IAR95). A
      sufficient number of well-performed studies on cohorts with exposure to hardwood dust
      alone or as the major source of the wood dust has demonstrated this in separate and
      pooled analyses. Support comes from various case-control studies.
           The individual studies had produced inconsistent findings with regard to other
      cancers. To address this issue two meta-analyses, taken into account by IARC
      (Dem95a) and DECOS (Dem95b), were performed. In these analyses the type of wood
      dust was not specified and crude measures of exposure to wood dust were applied.
      Industry and job titles provided information as to involvement of each type.
           The primary aim of a combined analysis of five cohorts (about 28 000 persons) was
      to detect association of wood dust with any cancer other than sinonasal adenocarcinoma
      (Dem95b). The suspected cancer sites, the respiratory, digestive and hematopoietic
      Hardwood                                                                                  17
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<pre>system, had been indicated by the previous studies. Additionally the combined analysis
sought to quantify the risk of sinonasal cancer. ‘Sinonasal cancer’ was addressed instead
of ‘sinonasal adenocarcinoma’, presumably because some of the contributing datasets
lacked histological specification of the sinonasal tumours. The aggregated data show
statistically significant increases of sinonasal cancer (SMR 3.2 [95%-CI 1.6-5.6]) and
nasopharyngeal cancer (2.4 [1.1-4.5]).
     The data were also analysed by decade of first employment, number of years since
first employment and type of industry — all surrogate measures of exposure. Analysis
by industry title confirmed that the sinonasal and nasopharyngeal cancers are
significantly enhanced in the furniture industry (4.3 [2.2-7.8] and 2.9 [1.2-5.9],
respectively). In the plywood industry they are raised, though not significantly, but show
large confidence intervals with high upper bounds (0.0 [0.0-11.5] and 4.6 [0.6-16.4]).
The furniture makers had been exposed to hardwood primarily, the plywood workers to
unknown wood species.
     Using the other exposure measures mentioned the relative risks of sinonasal and
nasopharyngeal cancer were shown to be significantly increased, like in the full cohort,
and the relative risk of multiple myeloma to be suggestively, but non-significantly
augmented. The relative risk of both sinonasal and nasopharyngeal cancer increases with
exposure; the data on multiple myeloma do not show this type of consistency in
exposure-response relationship.
     A recent cohort study also addressed the issue of other cancers than those of the
sinonasal cavities (Ste98). The risk of cancer of various origins was examined in a group
of 45,399 US. men that had been exposed to wood dust (of unspecified type). Their
follow-up was six years and exposure varied from less than 10 to more than 20 years.
They showed statistically significant excesses of all malignancies combined and tumours
of the lung, prostate and brain. The investigators offer confounding by, among others,
asbestos and formaldehyde as explanation, at least partially. A peculiarity is that the
cohort does not demonstrate an excess of sinonasal tumours. This is in line with the
(unexplained) observations that the hardwood dust-associated risk of sinonasal tumours
is raised in Europe, but not in North America (see for instance the review by Blot and
co-workers (Blo97)).
Twelve case-control studies on sinonasal cancer and wood dust have also been subjected
to pooled analysis (Dem95a). The purpose of this evaluation was to gain more insight
into the type of sinonasal tumour associated with wood dust. Occupation and industry
titles were used to construct a job exposure matrix. The exposures were ascribed to three
categories: high, moderate or low. The histological characterisation of the tumours was
crucial. In the analysis 625 of the 930 sinonasal cancers included were specified as
either adenocarcinoma (195 cases) or squamous-cell carcinoma (430 cases), the
Hardwood                                                                                   18
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<pre>remainder as tumours of other or unspecified histology. The analysis was performed for
all sinonasal cancers together, adenocarcinoma, and squamous-cell carcinoma.
     The risk of all sinonasal cancer was found to be significantly elevated when either
all jobs or all exposure categories were combined. Analyses by exposure category and
by duration of exposure demonstrated that the risk increases with the exposure. For
adenocarcinoma a similar pattern emerged, with higher relative risks though. The risk of
squamous-cell carcinoma, however, did not appear to be significantly raised in any of
these analyses. These conclusions are based on the data from the men in the study. The
outcome regarding squamous-cell carcinoma does not appear to be the consequence of a
lack of statistical power, since the number of exposed cases is about half that of exposed
cases of adenocarcinoma. Generally the women showed a pattern of relative risks similar
to that of the men, although with trends instead of significant effects, probably a
reflection of the considerably lower number of female cases compared to male ones (one
tenth or less). There is one exception: the women exposed for more than five years in all
jobs combined and those exposed equally long to moderate to high dust concentrations
demonstrated a statistically significant excess risk of squamous-cell carcinoma (5.6
[1.1.-28] and 8.9 [1.6-48.4], respectively).
     Recently, the eight European case-control studies included in the above-mentioned
analysis were subjected to another pooled analysis, taking into account occupation,
smoking and gender (Man99). In general the conclusions of the larger study are
confirmed, with OR’s and confidence intervals reflecting the difference in size.
Furthermore, some epidemiological investigations are worth mentioning, because they
may shed light on the mechanism by which the sinonasal cancers develop. They concern
histological changes in the sinonasal epithelium and indications of functional
impairment.
     IARC reviewed the results from nasal biopsies up until 1995. Higher frequencies of
various morphological changes in the nasal epithelium have been noted in nasal biopsies
from wood-dust exposed persons as compared to controls. Similar findings were
described in a more recent publication (Pis95). Some of the changes noted have also
been detected in the tumour-free nasal tissue of patients with sinonasal adenocarcinomas.
In most cases the source of the wood dust the subjects had been exposed to was
uncertain. It may or may not have been hardwood only. Only one of the studies reviewed
by IARC does not suffer from lack of insight into the exposure (Wolf et al., 1994 in
IAR95; see also Wol98b). Various histological scoring systems were used and two
pathways leading to tumours were suggested. One from metaplasia of the normal
(low-cuboidal) sinonasal epithelium through high-cuboidal epithelium, squamous
metaplasia, squamous dysplasia to squamous cell carcinoma. The other from normal
Hardwood                                                                                   19
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<pre>    through high-cuboidal epithelium, high-cuboidal epithelium with dysplasia to
    adenocarcinoma.
         IARC also reviewed the available results from tests of nasal function in humans
    exposed to wood dust, mostly employees of furniture factories exposed to both dust
    species (IAR95). Diminished mucociliary transport rates were noted, indicating that
    nasal clearance can be partly or fully inhibited in wooddust-exposed individuals. In one
    study the groups exposed to unprocessed wood did not exhibit statistically significant
    reduction of nasal clearance, whereas those additionally exposed to preservatives did,
    suggesting that these chemicals play an important role (IAR95, see also Wol98b).
         Additionally it was reported that woodwork teachers show slightly decreased nasal
    function, but no indications of inflammation (Ahm95, Ahm96). However, the data are
    incomplete with regard to the exposure: the type of wood was unknown, the wood was a
    mixture of hard- and softwood, or additional exposure to metal dust had occurred.
         Workers coating wood surfaces were examined for signs of inflammation in cells
    obtained by nasal lavage (Gra98). Only the groups that had been exposed to coatings
    and wood dust showed raised numbers of macrophages and inflammatory cells, of which
    only the former was significant. Information as to the type of wood was not provided.
         Without any exception the data on nasal histology and function have been collected
    from groups exposed to hardwood dust for upon average ten years or more, individual
    exposures lasting minimally one year.
2.3 Evaluation
    The Committee concludes that there is consistent evidence from epidemiological studies
    that hardwood dust can cause sinonasal adenocarcinoma. They agree with IARC and
    DECOS that the epidemiological data on wood dust and cancer allow this inference. It is
    primarily based on the facts that it concerns a tumour that is rare in the general
    population and that many cohorts have been investigated that leave no doubt as to the
    association with hardwood. The combined analysis of case-control studies confirms that
    the adenocarcinomas stand out, as expected from the single studies (Dem95a). Why the
    association in the cohort studies is found in the European, but not the American ones, is
    enigmatic. The outcome of the pooled cohort analysis provides evidence that exposure to
    wood dust can also lead to cancer at an other site in the airways, the nasopharyngeal
    region, as demonstrated by a statistically significant excess risk in the same order of
    magnitude as that of the adenocarcinomas (Dem95b). The inconsistency of the individual
    studies with regard to the presence or absence of excess risk had precluded this
    conclusion before. The cohort-derived findings do not point to an association of
    (hard)wood with any other cancers than those of the sinonasal and nasopharyngeal
    region.
    Hardwood                                                                                  20
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<pre>     Whereas the cohort meta-analysis has not addressed the specificity of the sinonasal
tumours, the case-control meta-analysis has. It provides some evidence that wood dust
may also be able to cause squamous-cell carcinoma, the second sinonasal type of tumour
frequently mentioned as possible consequence of exposure to wood dust. In this respect a
statistically significant excess risk of squamous-cell carcinoma demonstrated in
highly-exposed women is striking. The investigators offer several explanations, among
them sex-related differences in susceptibility or exposure. They also suggest that these
tumours are caused by softwood, not hardwood dust. The Committee agrees with these
suggestions.
Further epidemiological findings demonstrate that wood dust has histologically and
functionally detectable adverse effects on the nose. As regards the former the Committee
does not support the interpretation, given by several investigators, that specific
morphological changes in the nasal lining represent early stages in the development of
certain cancers. Although occurring significantly more frequent in wood dust-exposed
persons, the background prevalence of some of them was quite high. Additionally the
assessment of their relevance is complicated by differences and inadequacies in
histological typing and by the fact that the exposures were mostly of mixed nature.
Many of them, if correct and relevant, would point to squamous-cell carcinoma rather
than adenocarcinoma. This combined with the uncertainty as to the type of wood, the
high background prevalence of the tissue lesions, the abundance of these lesions in
patients with nasal complaints of unknown cause or arising spontaneously and the
speculative character of the sequence of histological events preceding a tumour renders
their significance, especially as indicator of specific types of tumour, dubious.
     The interpretation of the reduced nasal clearance of course also suffers from the
limitations imposed upon them by the exposure characteristics.
     Together, the histological and functional findings nevertheless demonstrate that
wood dust can have a cytotoxic effect on the cells lining the sinonasal cavities. Whether
this effect can be ascribed to hardwood dust, remains to be determined, however.
There is a discrepancy between the epidemiological and the experimental findings. In the
one animal species exposed via inhalation no carcinogenic effect in the airways has been
detected. The estimated exposure concentration in the cohort with the highest relative
risk of sinonasal adenocarcinoma, a group of British furniture workers, was 4.2 (range
0.3-53) mg per m3 in 1983 and 7.8 (range 2.0-32) mg per m3 in 1976 and 1977, whereas
the rats had been inhaling 25 mg per m3 (Hol89, IAR95, Jon86). Therefore the
nonresponsiveness of the animals does not seem to be the consequence of too low a dose.
Additionally, the animals that had been inhaling hardwood dust show at most weak signs
of cytotoxicity and tissue regeneration in the sinonasal cavities. These observations were
Hardwood                                                                                   21
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<pre>made after semi-chronic or chronic exposure. In the one experiment demonstrating
carcinogenicity in animals an extract with genotoxic properties was applied dermally and
shown to induce tumours locally (Moh89). Thus, the route of exposure (dermal) was
different from that experienced by humans (inhalation) and cannot be used as such to
imply that hardwood dust is a (genotoxic) carcinogen by inhalation. Together, the scarce
animal data available do not provide evidence that points to carcinogenicity by
inhalation.
    There is sufficient evidence that hardwood extracts and condensates can cause gene
mutations and chromosomal aberrations in vitro. Therefore, this material is considered
genotoxic in vitro. The genotoxicity is weak, however. Whether hardwood preparations
are also genotoxic in vivo has not been investigated properly. According to the
Committee the only test, performed with an extract, does not allow any inferences,
because small numbers of cells were scored (Nel93). The epidemiological studies of
genotoxicity are inconclusive as to the type of wood dust or have produced results of
doubtful relevance, as in the case of the k-ras mutation (Sab98).
Hardwood                                                                                 22
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<pre>Chapter 3
        Softwood
3.1     Genotoxicity and interaction with DNA
        Softwood has been investigated for genotoxic properties in the same manner as
        hardwood: as condensates and extracts. With regard to in vitro tests the majority of
        experiments has been performed with bacterial systems. Condensates isolated from
        softwoods were demonstrated to be mutagenic, the mutagenicity being weak, but
        observable with and without metabolic activation (Kur90, Sin95). Other investigators
        found negative results, however, even after metabolic activation (Kub88, Wei92).
             Three softwood condensates were tested for induction of chromosomal aberrations
        and sister chromatid exchanges in vitro. Two appeared to be able to cause these
        cytogenetic effects in human as well as animal cells (Mar95b, Mar95c, Mar95d). The
        third was tested only in animal cells and found positive as well (Mar95e). Like the
        mutagenicity the cytogenetic effects were weak. Additionally, an extract was tested for
        the capacity to induce chromosomal aberrations and found negative in a human cell line
        (Zho95).
             The effects in vitro on DNA and the in vivo genotoxicity of softwood condensates or
        extracts have not been investigated.
        Some epidemiological observations regarding occupational exposure of softwood dust
        suggest that it carries genotoxic properties. Among them are the observations already
        mentioned in the previous chapter, concerning people that had been in contact with
        hardwood and softwood dust (Kur93, Pal98, Pal99). An additional finding pointing in
        Softwood                                                                                 23
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<pre>      the same direction is that employees of a match factory, exclusively exposed to softwood
      dust, carry more micronuclei in their peripheral blood lymphocytes than a control group
      (Jia94). Unfortunately it was not reported whether their smoking habits were comparable
      to those of the controls. As tobacco smoke is known to cause DNA breaks, differences in
      smoking behaviour may have confounded the outcome.
3.2   Carcinogenicity
3.2.1 Animals
      The health effects of inhalation of softwood dust have not been investigated in animals,
      neither in chronic, nor in subchronic studies.
3.2.2 Humans
      Whether inhalation of softwood dust can lead to cancer is controversial. However,
      sinonasal adenocarcinomas hardly figure in the discussions; the focus is on other
      tumours. It is assumed that the adenocarcinomas that seem to be caused by softwood
      dust, in fact are due to co-exposure to hardwood. According to the Committee this is
      plausible.
           The predominant type under discussion is squamous-cell carcinoma of the sinonasal
      tissues. One of the major difficulties when interpreting the data is the uncertainty as to
      the nature of the wood from which the dust originates. Of course this also applies to
      hardwood, but there the high carcinogenic potency of the agent combined with the
      specificity of the tumours made inferences relatively easy, at least for the
      adenocarcinomas. Only few of the relevant epidemiological data concern people that had
      been exposed to softwood exclusively; and even in some of these cases some
      co-exposure to hardwood cannot be ruled out, according to Demers and co-workers, who
      reviewed the data (Dem97). The remainder, however, concern unequivocal co-exposure
      to hardwood.
           The review by Demers and colleagues describes which studies presumably concern
      softwood predominantly, the species of trees harvested locally serving as criterium
      (Dem97). The Committee endorses this analysis of the matter, except for exclusion of a
      cohort of construction workers (see below). Relevant are five case-control, several
      cohort and two other studies, one lacking a control group and the other investigating the
      morphology of the sinonal tissue instead of nasal cancer (Boysen et al., 1986 in IAR95,
      see 3.2.3). The case-control studies were directed at squamous-cell carcinomas (two
      studies) and sinonasal cancers (three studies), reflecting the absence or presence of
      histological information, respectively. Together, they concern 86 squamous-cell
      Softwood                                                                                   24
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<pre>carcinomas and 235 sinonasal cancers. Two out of three studies showed statistically
significant raises of sinonasal cancer, two statistically significant increases of
squamous-cell carcinoma in subgroup analyses. The SMRs for sinonasal tumours were
2.5 (p < 0.03), 3,4 (1.1-10.3) and 0.7 (0.3-2.0). Those for squamous-cell carcinoma
overall were 2.4 (0.8 - 6.7) and 1.7 (’not significant’, 95%-CI not given). In the
subgroups with the highest exposure they were significantly raised for at least one of the
measures used for this purpose: 7.3 (1.4 - 34.3) for more than 10 years of exposure and
2.5 (1.1.-6.0) for exposure started in 1945 or earlier, respectively. According to the
authors of the review only three cohort studies were sufficiently specific for softwood to
be included: two small ones (2283 and 1283 persons exposed) and a large one (26 487
persons exposed). The small studies demonstrated some significantly raised excesses of
tumour risk, among them no cancers of the respiratory system, but the figures were
considered unreliable due to variation associated with very small numbers. The larger
cohort will be discussed below separately (Her97). According to the reviewers the cohort
studies lacked the statistical power to address the risk of sinonasal cancer, without
specifying the relative risk they had in mind, however. They prudently conclude from the
overall data that softwood exposure possibly increases the risk of squamous-cell
carcinoma. With regard to association of softwood with any other type of cancer they
see no consistency among the cohort studies.
The results of two retrospective cohort studies have been reported after IARC published
its monograph (Don95, Her97). One concerns construction workers in the United
Kingdom, the other saw mill employees in British Columbia, Canada. Neither paper
discusses the type(s) of wood involved. Data on wood production from the United
Nations Food and Agriculture Organisation indicate that the wood produced in British
Columbia is almost exclusively softwood and in the UK for about 80% (cited in
Dem97). As saw mills and the industries supplied by them use wood produced locally,
the Committee assumes that both studies concern softwood exclusively or predominantly
(IAR95), whereas Demers and colleagues apparently regard only the saw mill workers
as exposed to softwood dust (Dem97).
     The cohort of construction workers in the UK (15 007 persons) shows a small but
significantly enhanced risk of death by cancer of any type (proportional mortality rate
1.21, 95% confidence interval 1.18-1.25), and of specific types: mesothelioma and
cancer of the stomach, pancreas, bladder and lung, but not the nasal cavities (Don95).
The last category was not subdivided any further. In the cohort more than 20 different
job titles were represented. The authors do not provide any information as to the wood
dust exposure in the various jobs held. Analysis by job titles showed a significantly
enhanced risk of cancer in general for many of the jobs; the corresponding PMRs vary
from 1.11 to 1.56. With regard to the duration of the exposure it was mentioned that the
Softwood                                                                                   25
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<pre>    median length of reckonable service was 4.9 years and that 15% had over 20 years of
    service.
         The other cohort reported upon consists of 26 487 sawmill workers in British
    Columbia, Canada, of which 23 829 had been exposed to wood preserved with
    chlorophenate fungicides and 2658 to unpreserved wood (Her97). It was set up for
    investigation of the relation between chlorophenates and (various types of) cancer. The
    group exposed to preserved wood was compared with that exposed to unpreserved wood
    and with the general population. The two groups are characterised by 9.8 and 7.3 years
    of employment on average, respectively. Their mean follow-up was 24.5 and 15.5 years,
    respectively. The comparison with the general population, detecting in fact the effect of
    chlorophenates plus softwood, showed no statistically significant increases in risk of any
    kind of cancer. The majority of cancer types investigated showed no increase at all.
    Cancers of the nasopharynx and of the nose and nasal cavities, however, showed
    increases that are non-significant and do not correlate with exposure duration. The same
    holds true for soft tissue sarcoma and non-Hodgkin’s lymphoma, the primary target of
    study.
    With regard to observations on nasal histology and inflammation there are two
    investigations reviewed by IARC concerning groups that had exclusively been exposed
    to softwood. The first is the group that had been exposed to softwood only without
    additives for at least 15 years in the study already mentioned in the previous chapter, the
    findings of which, a non-significantly higher frequence of cuboid metaplasia, are subject
    to the same objections (Wolf et al., 1994 in IAR95, see also Wol98b). The other is a
    group of 44 persons who had been exposed for 10 to 43 years and whose nasal biopsies
    showed a significantly higher incidence of dysplasia than biopsies taken from controls
    (Boysen et al., 1986 in IAR95).
         The most recent data on nasal histology and function have already been mentioned
    under hardwood, because they concern combined exposure to hardwood and softwood
    (Ahm95, Ahm96, Gra98, Pis95). In addition to the questionable relevance of the
    findings, as already discussed in 2.3, they pose the problem of exposure to a mix of
    wood species. The only finding not mentioned there is that of normal nasal function in
    individuals that had been exposed to softwood dust only (Wolf et al., 1994 in IAR95,
    see also Wol98b).
3.3 Evaluation
    The epidemiological data on softwood are harder to interpret than those on hardwood,
    because they are fewer and a large variety of cancers reported incidentally are associated
    with excess risks that are generally lower than those of the adenocarcinomas associated
    Softwood                                                                                    26
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<pre>with hardwood. The adenocarcinomas observed in the various studies on softwood
probably are due to co-exposure to hardwood. The ones with exclusive, or almost
certainly exclusive exposure to softwood do not show an enhanced risk of
adenocarcinomas. However, some of them demonstrate enhanced risk of sinonasal
tumours, without histological characterisation (Dem97). As the major question is
whether softwood exposure can lead to sinonasal squamous-cell carcinoma, this lack of
specificity complicates the matter considerably.
     The overall evidence does not show a consistent association of softwood dust with
other types of cancer — neither with squamous-cell carcinoma of the sinonasal cavities,
nor with any other. As such the epidemiological studies do not provide consistent
evidence that softwood dust possesses carcinogenic properties. On the other hand, at
least high-exposed subgroups in some of the case-control studies suggest that it does and
indeed point in the direction of squamous-cell carcinoma. Moreover, the cohort studies
carried out lack the statistical power to resolve the matter. According to the Committee
this holds true for all the cohorts investigated, the ones in the review by Demers and
colleagues (that includes the saw mill workers, discussed separately in 3.2 (Her97)) and
the construction workers (Don95). Thus, the data leave open the possibility that
softwood can cause sinonasal squamous-cell carcinoma. In the opinion of the Committee
the data have neither proven nor refuted association of softwood with squamous-cell
cancer. Like DECOS the Committee regards softwood dust as a suspected human
carcinogen (DEC98).
     The nasal histology in humans that have been exposed to softwood dust is poorly
documented. As far as it has been carried out, it shows an augmented incidence of
changes upon long-term exposure of which the meaning is elusive. These histological
changes merely indicate that softwood dust possesses cytotoxic potential.
     Decreased nasal function was observed in groups that had been experiencing mixed
exposure (see 2.2 and 2.3). The only study addressing nasal function in individuals with
a history of exposure to softwood only, showed normal clearance.
     Softwood dust has also been investigated less thoroughly in the laboratory.
Verification of carcinogenic potential in animals has not been carried out. And as far as
genotoxicity testing is concerned, the testing of preparations has been restricted to in
vitro experiments. Softwood extracts and condensates have been investigated for
genotoxicity in vitro as thoroughly as hardwood though. They appear to possess
identical properties: the abilities to cause gene mutations, chromosomal aberrations and
sister chromatid exchanges. So, like hardwood dust surrogates they are clearly genotoxic
in vitro. Moreover, the similarity extends to the strength of the genotoxicity: both
surrogates are weak genotoxins. But as far as other aspects of the genotoxicity profile
are concerned, interaction with DNA and in vivo genotoxicity testing, data are lacking.
Overall, the Committee feels that softwood dust extracts and condensates should be
Softwood                                                                                  27
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<pre>regarded as genotoxic; an opinion differing from that of DECOS and based on several
publications not considered by them, obtained by searching additional databases.
Softwood                                                                            28
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<pre>Chapter 4
        Health hazard assessment
        Hardwood dust is a human carcinogen with weak genotoxic properties and equivocal
        cytotoxic capacity in vivo. Softwood dust possesses similar genotoxic and cytotoxic
        power, but is possibly carcinogenic. The Committee reached these conclusions taking
        into account that hardwood co-exposure figures in the dataset on softwood and vice
        versa, and that the former is the stronger one.
             Hardwood dust possesses the capacity to induce sinonasal adenocarcinoma in
        humans. This is the only consensus finding so far from the overall studies of a series of
        groups of individuals exposed occupationally to dust from hardwood, softwood or, as in
        most cases, both. An unresolved, but important issue is why only the European cohorts
        investigated show an excess risk.
             The possible causal relationship between hardwood dust and other types of tumours,
        in the sinonasal cavities and elsewhere in the body, is subject to debate. With regard to a
        causal relationship between softwood dust and any cancer the situation is similarly
        unresolved. The outcomes of the meta-analyses suggest that the relative risk of
        nasopharyngeal tumours and squamous-cell tumours of the nose is elevated by exposure
        to hardwood and softwood dust, respectively, the uncertainty being partly due to the
        mixed exposure.
             There are several explanations for the difference in the epidemiological findings on
        hardwood and softwood in addition to that of sample size; they are not mutually
        exclusive. First that the follow-up in the softwood studies is shorter on average — and
        shorter than the tumour latency period. This appears to be the case: only the
        hardwood-exposed groups contain subgroups that had been exposed for more than 30
        Health hazard assessment                                                                    29
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<pre>years and sufficiently large to demonstrate a significant excess of adenocarcinoma
(Dem95a).
     An alternative explanation is that the cumulative exposure, the integral of
concentration and duration of exposure, of softwood dust-exposed groups is lower than
that of hardwood dust-exposed ones. This issue cannot be resolved, because most of the
studies have very little information, or none at all, about dust concentrations and
exposure duration. They allow inferences only from industry and job titles, occasionally
supplemented with the number of years spent in a job; the study on British furniture
workers presents a favourable exception.
     A third explanation is that the carcinogenic potency of softwood dust is smaller than
that of hardwood dust, as a consequence of, for instance, a difference in average particle
size. Airway deposition is known to depend strongly on particle characteristics. The
physical properties of hardwood and softwood differ and it is probable that this
difference together with that in woodworking processes they undergo, leads to
dissimilarity in particle size. Differences in chemical properties may also play a role
(Bia94).
     Finally, there is the matter of treated versus untreated wood. The relevance of this
issue has clearly been demonstrated by Wolf and colleagues who analysed wood samples
presumed to be untreated and found a variety of preservatives (Wol98b).
     Unfortunately, proof or refutation is lacking for all of these theories. Therefore the
Committee, like DECOS, prudently considers softwood to be a suspect carcinogen in
humans. Why the animal experiment performed to detect carcinogenicity upon inhalation
did not show evidence of carcinogenic properties is a question the Committee cannot
answer.
Several lines of evidence need to be evaluated to answer the question of the methods
appropriate to derive toxicology-based occupational exposure limits for each of the
dusts. These are the indications that shed light on the role of, on the one hand,
genotoxicity and, on the other hand, inflammation, ensuing cytotoxicity and regenerative
cell proliferation (hyperplasia).
     The wood dusts cannot be and consequently have not been tested directly for
genotoxic properties. Workable surrogates are extracts and condensates. These types of
preparation have been tested in various genotoxicity assays and have demonstrated that
the genotoxicity of the two dusts is similar, with regard to its nature and its potency.
Two aspects determine the strength of the genotoxic properties: the magnitude of the
effect and the concentration at which it is observed. The magnitude of the effect in the
various genotoxicity tests was small. Furthermore, the outcomes do not refer to neat
concentrations, as in the case of pure chemicals, but to dilutions of the extract or
condensate with unknown concentration and composition. Therefore the outcome is hard
Health hazard assessment                                                                    30
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<pre>to relate to the original material wood dust. Moreover, there are several explanations for
the genotoxicity observed under the circumstances of the tests. It may reside in
endogenous components or preservatives, that may be present even when assumed
absent (Wol98b). Alternatively, genotoxic molecules may have been formed during
preparation of the dust surrogates. At least in the case of isolation of condensates, that
requires heating of the wood, this is plausible. The bulk of the original material,
however, has escaped testing, because it does not dissolve or evaporate under the
circumstances needed for preparation of the surrogates. But this untested fraction
probably is the material that is likely to play an important role in the inflammation- and
cytotoxicity-inducing properties of the dust. Thus, whether the genotoxicity of the
surrogates bears any relevance to the carcinogenicity of inhaled wood dust in humans is
enigmatic.
     There are two more relevant lines of evidence regarding the contribution of the
genotoxicity to tumour formation. The first is the genotoxicity in the peripheral blood of
wood dust-exposed humans, the proof of which is scarce. Findings of this nature are
difficult to interpret, for any chemical. Therefore they do not play a crucial role in the
Committee’s decision.
     Furthermore, the specificity of the mutations found in the DNA of adenocarcinomas
may provide a clue to the role of the genotoxicity in carcinogenesis. A difference in
specificity between adenocarcinomas from spontaneous and wood dust-exposed
individuals would suggest that the genotoxicity is central to the genesis of
adenocarcinoma. This, however, has not been investigated properly. The publications on
mutations in sinonasal adenocarcinomas concern small numbers of biopsies and the
exposure history of most of the patients involved is not documented. Thus, the mutation
specificity hypothesis has not been sufficiently verified to allow any conclusions.
     The conclusion the Committee draws from the overall genotoxicity observations is
that it is enigmatic whether the genotoxicity observed bears any relevance to the (proven
or suspected) carcinogenicity of inhaled hardwood and softwood dust in humans.
The other relevant matter is that of the contribution of inflammation, cytotoxicity and
regenerative tissue response to carcinogenesis. These phenomena have almost
exclusively been detected in connection with mixed exposure. Therefore attribution to
one of the dusts or both, is not possible. These local tissue reactions have not been
investigated upon exposures shorter than semi-chronic, neither in humans, nor in
animals. This means that an argument in favour of these being the primary effects
responsible for carcinogenesis is lacking. If the cytotoxicity and regenerative hyperplasia
would have been overt after short exposures of humans or animals, this would have been
a strong argument to overrule the hypothesis that the genotoxicity test outcomes are
indicative of the pathway the development of cancer follows. As they have been noted
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<pre>after chronic or semi-chronic exposure, in humans as well as in animals, they may have
been the result of genotoxicity.
Which methods are suitable for deriving toxicology-based recommended exposure limits
for hardwood and softwood dust? Should the two dusts be treated with the same method?
To be able to answer these questions several characteristics need to be taken into
account. The similarity of the genotoxicity evidence is in favour of one method for both.
The data on local tissue responses are neither in favour of, nor against, a one-method
approach, as it is undecided whether both dusts can induce them. Differences in chemical
or physical properties, or in the presence of preservatives and moulds would lend
plausibility to an approach using different methods. However, differences of these kinds
are assumed to exist, not sufficiently demonstrated to support an approach with different
methods. Thus, as far as investigated similarity predominates. The Committee therefore
recommends to treat them identically when deriving toxicology-based recommended
exposure limits.
The circumstances under which the genotoxicity has been found do not allow any
conclusions as to its contribution to carcinogenesis. Additional findings, from for
instance mutation specificity of tumours, are insufficient to resolve the matter.
Furthermore, the doubt as to the contribution to carcinogenesis also applies to the
inflammation- and cytotoxicity-inducing properties. How much these contribute to
tumour formation is uncertain, as their presence has not been investigated after
exposures of short duration, which would make a strong case for a threshold. Therefore
it remains elusive whether carcinogenesis in the airways can be avoided by levels
sufficiently low to prevent local cytotoxicity. The Committee cannot propose a method
to derive figures, because the clues available are insufficient to distinguish among (a) a
direct genotoxic carcinogen with a major role for its genotoxicity, (b) an indirect
genotoxic carcinogen with a major, if not an essential role for inflammatory or
regenerative hyperplastic changes, or (c) a non- genotoxic carcinogen with an essential
role for regenerative hyperplasia following recurrent tissue damage, the first option
leading to the proposal to apply the linear model, the second and third to the proposal to
apply the threshold model. Previously the Minister of Social Affairs accepted the
recommendation of linear extrapolation in similarly elusive situations. If linear
extrapolation would be applied, the results would be 5.8 mg of inhalable wood dust per
m3 for a reference additional lifetime risk of nasal cancer — representing
adenocarcinoma — of 1 in 250, and 0.06 mg per m3 for that of 1 in 25 000, both for
workplace exposure during forty years (see Appendix C).
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<pre>According to the Committee, the assessment of the health hazards of hardwood and
softwood dust would benefit from the following research: carcinogenicity testing of
softwood dust, analysis of sinonasal histology and function in animals and humans upon
sub-acute exposure to each type of dust — all with established preservative- and
mould-free preparations — and identification of the responsible constituent(s). In
addition, exposure measurements under various working conditions and longer follow-up
in the softwood cohort studies would be helpful.
The Hague, 18 July 2000,
for the committee
dr PW van Vliet,                          dr GMH Swaen,
secretary                                 chairman
Health hazard assessment                                                               33
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<pre>       References
Ach84  Acheson ED, Pippard EC, Winter PD. Mortality of English furniture makers. Scand J Work 1984; 10:
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<pre>A The request for advice
B The committee
C Linear extrapolation
D Comments on the public draft
  Annexes
                               37
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<pre>Annex A
      The request for advice
      On 12 November 1998 the President of the Health Council of the Netherlands received
      the following letter from the State Secretary of Social Affairs and Employment
      (reference: ARBO/AMIL/9834631):
      Your evaluation report 1998/13 WGD on the subject of wood dust was completed in September. In the
      report, your Dutch Expert Committee on Occupational Standards comes to the conclusion that the dust
      from hardwood is genotoxically carcinogenic.
           In 1991, in its report RA8/91, the committee recommended a health-based exposure limit for all
      types of wood dust, based on a threshold approach. Based on this advisory opinion, a statutory exposure
      limit was established for wood dust, which came into effect on 1 January 1998.
           My question is: how do the two advisory opinions relate to each other? In order to clarify this point, I
      would request that you produce an additional advisory report explaining what implications the
      genotoxicity of hardwood has for the health-based exposure limit that was recommended in 1991.
      Essentially, I would like to know whether the threshold approach that was adopted at that time is still
      valid, or whether it needs to be replaced with a risk-based approach. The latter option could result in
      different threshold values being applied for hardwood and softwood. I would very much like to hear your
      view on this point. I look forward to receiving your advisory report within two months.
      Director, Working Conditions
      (signed R Laterveer), on behalf of
      the State Secretary of Social Affairs and Employment
      JF Hoogervorst
      Request for advisory report                                                                                   38
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<pre>Annex B
      The committee
         GMH Swaen, chairman
         epidemiologist, Maastricht University, Maastricht
         PJ Boogaard (from Februari 1, 2000 on)
         toxicologist, Shell Int. Chemicals BV, Amsterdam
         HC Dreef - van der Meulen
         animal pathologist, NV Organon, Oss
         VJ Feron
         professor of toxicology, Utrecht University, Utrecht; TNO Nutrition and Food
         Research Institute, Zeist
         GR Mohn
         professor of cellular mutation genetics, Leiden University, Leiden
         GJ Mulder
         professor of toxicology, Leiden University, Leiden
         MJM Nivard
         genetic toxicologist, Leiden University, Leiden
         PC Noordam, consultant
         Ministry of Social Affairs and Employment, The Hague
         H te Riele
         molecular biologist, Netherlands Cancer Institute, Amsterdam
         H Roelfzema, consultant
         Ministry of Health, Welfare and Sport, The Hague
      The committee                                                                   39
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<pre>    D Roos (until February 1, 2000)
    professor of immunology, University of Amsterdam, Amsterdam; Central
    Laboratory for Bloodtransfusion, Amsterdam
    W Slob
    biologist, National Institute of Public Health and the Environment, Bilthoven
    ALM Verbeek
    professor of epidemiology, Catholic University of Nijmegen, Nijmegen
    EJJ van Zoelen
    professor of cell biology, Catholic University of Nijmegen, Nijmegen
    JA van Zorge, consultant
    Ministry of Housing, Spatial Planning and the Environment, The Hague
    PW van Vliet, secretary
    Health Council of the Netherlands, The Hague
The Committee consulted PJ Slootweg, professor of pathology, Utrecht University.
Secretarial assistance: M Javanmardi.
Lay-out: J van Kan.
The committee                                                                     40
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<pre>Annex C
      Linear extrapolation
      A group of British furniture makers is the only cohort of which the relative risk and the
      exposure have been quantified (Ach84). Therefore this cohort’s data are suited best for
      calculations. The calculations will be based on the risk of nasal cancer, because
      histological specifications were not reported and the background data from the Dutch
      population concern nasal cancer as a whole, i.e., code 160 of the ‘International
      Classification of Diseases’. Alternatively, the percentage of adenocarcinomas in the
      nasal cancers would have to be estimated, but that would introduce other uncertainty.
      The nasal tumours all occurred in the group with the longest exposure, dating back to
      the forties and fifties. The SMR of this subcohort was 23.3; its members had been
      exposed for forty years or longer.
           The furniture makers had been exposed to hardwood dust exclusively, or almost
      exclusively, but as outlined in chapter 4 a distinction between hardwood and softwood
      does not have to be made for setting toxicology-based recommended exposure levels; the
      calculations are applicable to both types of dust. The actual exposure measurements
      were performed, gravimetrically, in the seventies and eighties (Jon86); the concentrations
      of (inhalable) wood dust appeared to be 7.8 and 4.2 mg per m3 on average, respectively
      (Jon86, IAR95). The decrease probably reflects exposure-reducing measures taken as
      soon as the health hazards of wood dust inhalation became known. It is reasonable to
      assume an even higher exposure in earlier days. For the calculations this average
      concentration is assumed to have been 10 mg per m3, slightly higher than the highest of
      the means measured. If, in reality, the average exposure would have been higher, the
      calculated reference concentrations would be underestimations. Levels higher by one or
      Linear extrapolation                                                                       41
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<pre>more orders of magnitude are unlikely to have occurred, however; such concentrations
are exceptional for aerosols. A tenfold higher concentration would create an environment
that is exceptionally difficult to work in, for it would reduce the sight to 2-3m, increasing
considerably the risk of accidents. Peak exposure to such a concentration, though, could
have occurred, but still be compatible with 8-hour-average exposure to 10 mg/m3.
     Reference concentrations can be calculated with the following formula, representing
the linear relationship of exposure and effect:
      y=ax +1
In this formula y is the SMR, a the slope and x the concentration. As y is 23.3 and x is
10 mg per m3 the slope is 2.2.
     In the Netherlands 31 per 100.000 (or 0.0775 per 250) men die of nasal cancer
annually (CBS93). This is the reference figure appropriate for the (male) furniture
workers. The upper and lower reference additional risk levels for occupational exposure
situations in the Netherlands are 1 in 250 and 1 in 25 000 for 40 years of exposure.
Thus, the reference SMRs for nasal cancer are 1.0775/ 0.0775 = 13.9 and
0.0875/0.0775 = 1.13. They correspond to wood dust concentrations of 5.8 and 0.06 mg
per m3, respectively.
Linear extrapolation                                                                          42
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<pre>Annex D
      Comments on the public draft
      A draft of the present report was released for public review earlier in 2000. The
      following organisations and persons have commented on that draft:
           Th van Amersfoort, Bouw- en Houtbond FNV, Woerden, the Netherlands
           O Axelson, University of Linköping, Sweden
           FA de Boer, Vereniging Van Nederlandse Houtondernemingen, Almere, the
           Netherlands
           AJM Ceelaert, Nederlandse Emballage- en Palletindustrie Vereniging EPV,
           Vereniging HAS en Vereniging van Nederlandse Borstelfabrikanten, Tilburg, the
           Netherlands
           P Demers, University of British Columbia, Vancouver, Canada
           H Savolainen, Institute of Occupational Health Sciences, Lausanne, Switzerland
           T Scheffers, DSM, Geleen, the Netherlands
           SF Vuijk, Centrale Bond van Meubelfabrikanten, Heemstede, the Netherlands
      Comments on the public draft                                                        43
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