Document DGrXVoLaGdr0gRrKp7Z4ma3YM

-. 'r General Summary* An International WorkshopConference under the know71 chemistq and biochemical effects of m e * i joint chairmanship of DE. LZS Friberg of the compounds. Participants were divided into five );arolinsh Institute and Norton h'elson of Er'ew working subgroups concerned Hith: 1n:roauctjon Tork University hledical Center, jointly sponsored and General Findings, Epidemiology, -4nimal Bio- by the Xational Institute for Occupational %ety assays. Chemistrl\., and Cellulac Xlechanisms. Re- and Health, h'ationd Cancer Institute, and the p0-c generated by these g ~ o u p sformed the basis Kational Institute of Environmental Health Sd- for general conclusions on meals of carcinogenic ences, and planned in consultation uith the Scientific concern. Committee on the Toxicology of Metas of the The carcinogenicitis of arsenic. chromiun, and Pennanent Commission and International Associa- nickel compounds were again reviewed and a p e e d tion on Occupational Health, was held March 2-38, upon. In addition, the aggregate of consistently 1980, in Atlanta, Georgia, to evaluale the present positive findings from several epidemiological stud- state of scientific knowledge concerning metal ies on workers exposed-to cadmium or ber?.llium carcinogenicity and.to seek underlying principles compounds combined uith experimenta! o b s m a - for mechanisms of metal carcinogen action in relation tions led meeting puticipzztt to conclude thai fo public health. N e e dcarcinogenesis is considered accep*abie evidence n o u exists to regard some of m. imponant area of health research due to the these compounds as contrjbutkrg tc, the develop ubiquity of human exposure under occupational ment of m c e r in man. andlor environment;rl circumstances, and the per- The p a h a p a n t s concluded that evaluation of sistence of m e t d i c carcinogenic compounds in the carcinogenic effects for metallic carcinogens were environment. p a t l y hindered by the lack of data or,exposure to Tne Works'nop was attended by 34 exper!! from these substances in both the occupa5onal and 11 countries. inciuding Belpum. Canada.. Denmark, general environment and it was thereiore s:rongiy Finland, Fmce, Japan, the h'etherlands. Xo!-way, recommended that monitoring pr0gmn.t be planned Sweden, the United Kingdom, and the United and implemented t o assess human exposure. Sates, who formulated recommendations for fu- The puticipants PJSo recognized tha: human ture research on compounds of arsenic, beryllium, exposure sirnations ir, both the work anc! general cadmium, chromium, nickel, and other metals and envkronmcn: are frequently complex and tna: s:ud- their compounds. During the course of the meeting, i t s of single m e u l compoznds are frequently the proup considered the history of cancer related insufficient for cancer risk assessmen: since con- to metals as well os reviews of data from epidemio- comitant exposure to other carcinogenic or lo~iczla, nkmal bioassay, and in vitro studies. Dau coclrcinogenic substances, as well as thek spedfic from these sudies were evaluated in relation to the chemical forms, must dm be evaluated. Deailed recommendations for f u * mstcdies were developed in each of the Workhop Groups. August 1981 I 3 Introduction, General Findings and General Recommendations" Objectives The WorkshopConference, the deliberations of which are reponed here, has sought to assess the present state of knowledge in metal carcinogenicity as the basis for seeking unifying principles and nuking recommendations for research needed to fill gaps in our present understanding of metal carcinogenicity relevant to public health. Althougn the ultimate aim of the recommendations put f o m d concerns knowledge which will be applicable to the prevention of human cancer, it is recognized that this requires an undersanding of the mechanisms of action ranging h m the molecular level to organ response, as well as methods for the epidemiological study of human disease. Ac- cordingly, the WorkshoplConference brought together a multidisaplinaq- group in order to underu k e a concepl;aily linked examination of the prom i o n of tumors h m their initiation to dgnancy. In this examination, specific attention was given to tht role of potential intemction uith other agents. Attention has also been given to predictive m d n g for carcinogenic meullic compounds by both whole animal and in t i f m methods. Although the Workshop u-as not charged with a formal evaluation as to whether a specific metallic compound is or is not carcinogenic, as,for example, in the IARC Monographs, it was felt that the data at hand made k possible to reach conclusions for a number of the m e a . In addition, the Workshop took as one of i u major objectives the development of recommendations to improve our understanding of metal carcinogenicity. There has been no attempt to review safety standards for h u m u c p sure or techniques involving quantiative e s t r a p dation to man from high to low doses whether based on human data or laboratoq tests. On the other hand, the qualitative meaning of laboratoqt e s s for man, both shoz-tern and long-term, has been examined. Historical Review The chronology of observations of the carcino- genicity of some meullic compounds is illustrated in F i y n 1. In most but not all instances, a clinical report of a duster of cancer cases was the signal for subsequent epidemiologic and animal studies. Thus, cancer from m e n i c was reponed in lssb (11 in a p o u p of persons m a t e d with Fowler's solution. The tirst s,vstematic epidemiologic study was not underaken until 1948 (2). Despite many GLempu to reproduce cancer in animals uith arsenic com- pounds, failure has been the rule. Recently, how- ever. suggestive evidence of carcinogenicity in rats was reponed. They were dosed uith a Bordeaux mixture contlining arsenic (3). It may be noted that in the earlier instances (Fig. 1)the first suspiaon m e from czse repolu. In two more recent cases,the fvst signal came from animal studies (Fig. 1). As for beqllium and cadmium. the most reasonable interpretation of available data is that compounds of these metals have con;ributed to the development of lung cancer in the of beryllium and prostatic cancer in the case of cad- mium in exposed workers. In g e n e d , systcmatic epidemiologic investiga- tion k required to validate an association of oneor several possible etiologic factors. Hormally sucb studies are weak in, or even incapable of, identify- ing spedtic causal agents. At this level, aninul studies are of p&cular value; it map be that in vilm.testscan increasingly aid in such identification. W o r k p u p I recognized the prudence d the approach u k e n by XARC in suggesting that sub- stances for which there is suficient evidence of 5 I The I art I t be dis zch a fthe Lis>, ; are lofa ntermid b not lead, ih. at els to %dS, tantly . risk I and itions I ! 1 nee of Mer- OOPS I I 3 ! 1 I .I 6 ! ! I 1 I mting to nted out -6 am ctives ! I .. . . ' cz-cin'oyen:=it\- in animal studies should be gartied as ic the? were cuanogenic in man. re- Importance of MetaIs in Carcincgenesis Of aboui 80 metals there are at leas: 20 wnich have compounds that have been reponed to give rise to well-defined toxic effects in man. Onlv a few of these metals have been shown or are suspected t o be carcinogenic. The importance of metal cvanopenesis does not so much concern the number of carcinogenic compounds, but rather h e ubiquity of exposure, their wide industrial use, and their persistence in the environment. Thus, implementation of appropriate protective measures for metallic compounds proven to be carcinogenic may be difficult in comparison with organic carcinogens which are likely to be less persistent. Tnus,arsenic (a recognized carcinogen) is found to occur in high concen*ations in drinking water in some part-2 of the world. In 'Sese areas, skin cancer has been a sme!tet sevezi! y e a s before their acarr.. Tine dimcukies in tvaisating causal reiationsn:gs arc obvious; in sucn ins'xncts the interactions mas: be considered. Furthennore, u k n e v e r a m e e d is classified as carcinogenic o r noncarcinogenic, such a soatemen: should only apply to specific forms of the me'&. Tnere is ample evidence tho: meuholism. toxic^ in g e n e d , and also carcinogenicity are dependen: on the chemical and phycica! forms of a metal. hlet?l compounds may =use alteration or interfere with a number of intracehlar biochemical mechanisms and may dso induce toxic effects not related to carcinogenesis. Some metals, e.g.. lead, exert tclric effectson the nervous system,which, at the present, determine accepted exposure levels to a large extent. On the other hand, other me++, e.g., Cfl'I) and h'i compounds.induce predominantly carcinogenic effects. In evaluation of health risk and in setting priorities for epiaemiologkal and experimend cancer studies, these considentions should be d e n into account. ! t ! I f tially. In indus*q, exposure I often not to a single me*A only, but instead to mixzures. Significant amounts of a large number of m e a have been found at a u t o p q in the lungs of workers with a high difor lung cancer who retired fromtheir work in Epidemiological Studies Epidemiological studies identify the incidence of cancer in groups of humans who experience different envhnmen*L?1 condhions. If different n o u p s we exposed to different amounts of a carcinogenic eompvison of the carcinogenic potency by vuious agent. it may be possible to determine the nhtion- mxes, and different compounds of the same me*A ' . ship between the amount of exposure and the admnistered is possible. Animal studies simuiamg =stilting cancer incidence and thence to make the usual route of human exposure may be pacicu- quantirative estimates of the risk invoived. Be- l u l y useful in an evaiua:ion of the physical and -use the studies are always cartied out in real life chemical forms most hazardous for humans. For situations, it is seldom, if ever, possible to design example. animal studies nave shown that the most them in such a way 15 to satisfy the svict require- active chromium compounds for the development of ments of expei-;.men*aldesign that are normal in the lung cancer are the nexavdent salts of intermediate laboratory'; and there may be some doubt about the, solubility. interpretation that should be atbched to their Those animal studies which use routes of admin- results. Xevetcheless. epiderniolog.lca1studies have istration different from those by which man is the ovewnelming advantage that they refer di- usrully exposed have limitltions for extrapolating rectly to humans and they provide the only c e ~ & the results to man; nevertheless. such studies may means for designating a metal compound as a provide useful infomation on internal factors (ab- human carcinogen. sorption, distribution, immunolopcal status, etc. ) C h i d case r e p o m have served as useful warn- and external factors (e.g., interaction with other ing signals of the existence of risk cn a number of m e * A ccompounds or organic chemicals) influencing occasions in the past, and they may still do so the carcinogenic or cocvtinogenic potency of metal- occasionally in the future. It ought :o be possible, lic compounds. For example, it has been demon- however, to organize the collection of observations strated that the combined injection of Mn and Xi& on humans in such a way that any risk that have reduced the numbers of Id sarcomas reiative to inadvertently been caused are picked up more IXI injection of Ni& alone. quicklv and more cerrainl: b! planned inquiry. One Unfortunately, whole animal carcinogenesis stud- form of ins- is the case-control study. Such ies with metals and their compounds are still very studies have proved vduabie in establishing the limittd. Data on speciesrYiation and dose-response reality of a risk, but the method that is most relationships are Licking for ~e majority of metals. g e n e d l y appliczble to the detection of occupational One imponant disadvantage of animal experiments h v v d s is the cohort study, in which groups of is that they can be time and space consuming. In exposed workers are followed up to detennine their some cves whole animal models are less useful experience of disease The problems involved in than in vitro systems for investigating *e molecu- using cohort studies to obtain evidence about the lar mechanisms of action of carcinogens. carcinogenic effect of metals on humans,or the lack of any such effect, are discussed in the in2oductian to the repor, of Workgroup IB. In Vitro Mutation Test Systems In Oitm bacte* mutation test systems have Whole -4nimal Experiments proven highly useful for stud-ving a number of meutional mechanisms involving direcr effects of Several in vivo e x p 6 m e n t a l models have been metals on DNA metabolism. Alteration of DNA used to evaluate the potential carcinogenicity of structure,infidelity of DSA synthesis, and excision pure metals or some of their inorganic and organic repair processes have all been reported following in compounds and to investigate the factors modifying vitro incubation with me& of carcinogenic con- their activity. cern. Studies using metals with mammalian cells in Several endpoints may be considered, such as the vitro have demonstmted in some instances in- development of a tumor at the site of conzact or at a crewed virzl or morphologic transformation of distvrce in the treated animals or their offspring some cell lines following incubation with a number (transplacental carcinogenesis) and chromosomal of me&. One potential problem with such tests is damage in geminal or somatic cells. The last two the fact that at present each system measures only types of &e& (transplacental carcinogenesis and those types of mutational events to wnich it is chromosomal w t i o n s ) have ~ e l byeen looked specifidly sensitive and, hence, comparative stud- for in animals trut.ed with me*&e compounds. ies of different mutational mechanisms in one One important advantage of animal expviments Qxtem are lacking. Another area of concern in- is the fact that the chemical and physical proputies volves the q u e s ~ o nas to what extent the mutational of the administered m e d l i c compounds can be well mechanisms observed in these lest systems may be defaned. The investigation of the carcinogenic po- expeezed to operate in n o d mammalian cells in tential of weIl c b t c r i z e d complex mixtures, the v h The degree to which potentidy toxk metais August 1981 7 are sequestered from direct i n t e n d o n with DSA in vivo by binding to high affinity intmcellular ligands or trips is also presently unknown. Other studies involving effecu of metals on subcellular systems of essentiai imporstnce to celluhr viabi!jty or metabolism of organic carcinogens showed tha: these systems were a h hignly susceptible to metll toxicity. Potential nmifications of these observations are that metals may act z promoters of the carcinogenic response by stimulating cell turnover andlor altering cellular susceptibility to organic carcinogens or their metzbolic derivatives. The effects of me*& alteration of microsomal or S, fraction on activation of in t i t t o mu'ation test s_vstemsare also presently unknown. Studies of mew1 effecs on subcellular s y s t e m which metabolize organic carcinogens are also cumently largely lacking and hence the potential cocarcinogenic effects of these metals on the carcinogenic response from organic carcinogens are unknowh General Findings and Recommendations General Finding 1 There exists a serious lack of quantirative data that can be used for dose-response evaluations on occupa:ional exposure to potentially carcinogenic mew1 compounds. Recommendations Monitoring programs should be planned and implemented to measure exposures in the work environment. In addition to measurements of total exposure levels to metal compounds, means should be sought to develop and apply procedures for the characterization of the biologically i m p o r ! : physi d and chemical chlncteristics of metal compounds in the work environment. Whenever a p p m p&e, possible cocaminogenic agents should also be measured. k e s s m e n t of exposure to suspected metll compounds in workroom air shouid take into account inuke by (I)'inhalation, including, where pnctiable, estimated mucociliu3. transport with rubquent ingestion, (2) direct ingestion, e+, direct c c m c t with fingers, cigaretw, ctc, or (3) skin contlct. Where possible. exposure to suspected metal compounds should be estimated through analysis of biological samples of blood. urine, saliva, hair and fcccs, and autopsy specimens. 8 General Finding 2 For several potentially carcinogenic metal compounds there are ais0 inadeqGate cat? on exposllre levels of the general population. Recommendations Monitoring programs should be planned to estimate exposure of t h e general population to carcinogenic metlis. Due attention should be given to all routes of exposure and to measurement through bioiogical monitoring and measurement in biopsy and autopsy specimens wherever feasible. Jn instances of probable exposure of the gene-al population to compounds of carcinogenic concern, identification of specific chemical species. in addi`tion to the total metll concentration, should be undenaken. General Finding 3 Several repons indicate g ~ o s sanal?.tical errors of i m p o r a c e for evaluation of exposure to me*&. - .. Recommendation Internationally accepted analytical methods and smaard reference material should be developed for measwements of carcinogenic metals in environmentll and biological samples. These can serve for valickion of r o u ~ n eanai>tical procedures. International progxms for anairical hamonization should be promoted. and reference mareriais should be made available. General Finding 4 Environmental exposure to carcinogenic metlls results generzlly in cancer in a small fraction of exposed individuals. This indicates :hat factors detennining the susceptibility to cancer induction play a decisive role. Recommendat ion Effortshould be made to identify factors deter- mining susceptibility and to identify susceptible POUP General Finding 5 For both occupationally exposed groups and the general population very feu. studies are available on the relationship between tissue concentntion of the carcinogenic m c U compound ;urd the cucinogenic Environmental Health Perspectives ,- 1111- In , sti- 2 to ;en ent :in $le. ..?.31 Srn. idibe 'S of .Is. and *ped .nvi- -we res. 1iU- rials tAS nof tors tion Iier.tible 1 the hble on of genic lives 6 response. D i u are also lacking for experimentd anid. Recommendation Concenmtions of metlls or, whenever possible, their suspected ac:ive species should be measured in b i o l o p d samples (blood,urine. biopsy or autopsy m a t e d ) from exposed popu!ations and experimen'd animais in order to detetz possible correiations between such concentrations and ef- fects in t e r n of precancerous lesions or fully developed cvcinogenic effects. Such studies would &o, aid in reaching quantitative estimates of rela- tionships between tissue concentrations and carcinogenic response. General Finding 6 d Mctak are elements and. as such, they have been an intrinsic component of the environment to which man is adapted. Specific compounds of some metals are required for human life, and some met& are thus designated "essential metals." With several metals a distinct possibility exists that metals essential at one level or route of intake might be carcinogenic at another level or route. At difierent levels it is n e c e s s r q to consider changes in chemical speciation and whether or not the levels exceed the apacity of the normal homeostatic mechanisms. General Finding 8 There are exampies of biological interactions involving metals that lead to alteration of tumor response, e.8.. die-: zinc i n d e in 1abor;ltoq animals or a number of organic carcinogens. Also, exposure situations are often complex. In environments which have been demonstrated to cause an excess risk of cancer, a number of possible interactions may be operating (e.g., SOTarsenic interactions in smelter environmenfs). Recommendation Possible enhancing or inhibiton. effects of e x p e sure to various metal compounds in combination with other carcinogens or cocarcinogenic compounds should be examined in appropfiate animal, cellular, in tifro, and epidemiological studies. The mecnanisms by which metals cause such effecs should be elucidated. Genera1 Finding 9 Lifetime studies in animals have been found to be predictive of probable carcinogenicity in man especially when the routes of exposure and the sites of the tumors are the same. However, a positive outcome, even sith different routes of exposure o r differences in the tumor site, yields suggestive evidence of possible carcinogeniaty for man. Recommendation Systematic investigations are' necessaq: to identify the carcinogenic chemical species or, for the same chemical species, the role of the physical sute-panicle size and surfice propetties, as well a*concentration. Attention should be given to their biochemical interconversions in solution and biotransfonnations, and to compare these forms with their nutritionally essential states. These investigations should be explored on a quantiative bask General Finding 7 It has been suggested that chromosomal abemtions. sister chromatid exchange, and DNA repair are of predictive value in relation to cancer development. Recommendation When used for predictive testing, whole animal studies should, as a rule, employ a simiiar route of exposure as the one encountered in humans. Other mutes of administration may be usefully employed especially in the investigation of mechanisms of action. General Finding 10 Negative epidemiological studies should be cvduated in the same wag as positive studies and their results taken fully into account when assessing the human evidence. The acquisition of sufficient and adequate date with which to evaluate the caranogeniaty or lack of carcinogenicity of metals in humans requires a study period at least comparable b ?he induction time for carcinogenesis. Recommendation Further studies should be conducted 'at the epidcmiologid and laboratory levels to e r d u a t e the reliability of these approaches. August 1981 Recommendation Negative epidemiological studies of adequate dumtjon should be published and the confidence limits of risk estimates included when relevant. 9 t3ys2 A*d REFERENCES 1. Huuhiwn. J. Arzcnic-kerrrorir and u w n i c u n c e r . Trans. Patnoi. Soc. J9: 353 (1W). 2 Hill. A. C.. ud Frrunc. E. L. Studies m the incidence of cancer in a factory b n d l i n ~inorganic comwunar of arsenic. 1.MonJIty crpenenee in the faaoq. BnL J. Ind. Mcd. 5: I (198). S. Ivuritovit. 8. C i n b n n d . C., and Prcuvmul .!I Lung c v ~ o r mindumon UI BD mu a h r a ringie rnrnvichul instilktlon d an m c n i c c o n u l m n g pauode llll~tureformerly urcd m nm?-ards.Int. J. Cancer U :786 (1973). 4. Bactjc-. A. Y. P u l m o M~ i n o n u in chromate w r k m . I. A Rev* of litenrun and repon of e a e . A&. I d . Hyg. Z 487 11950). 5. Machle. W.. and Creporiur. F. Gncet of the r e s p i n t o y system in the United SOLCSchromate-produang indumy. Public Hatth Repu. 63:I114 (19481. &.Hueper. W. C. Experimenul studies in meul arcin+ genesis. VU. Gncerogenic deca of nw~dchromte ore deposited in muscle tissue and pleural cavity of rats. A d i d . ~ ~ dlet: xhu (1958). 7. Lmidn. S.J w h n e r . M.. and Drew. R. T. In: Inhalation h n o p e m w . M. C. Hanna. P. Xicstesntim. and R. Cdkn. &ISU. .&.Atomic Energy Commission. fir. T e c n m d hfonnrtion. Wdtinpon. D.C.. pp. 33-33(1970). L Bnagc. J. C. Health. In: Annual Report of the Chief 1n.prmr of Factories and Workshop for the Year 1932. HhISO. tondon. 1933, pp. 1 M l M . 9. Dall. R. CIIlrrr of the lunp and nose in nickel workers. Bri+ J. Ind. bled. 15: 215 (1958). 10. Sundennra F. W., Donmlly. A. J.. and West. B. Nickd poironmg. 1X. Careinoptnuis in nu exposed LO nickel carbonyl. Arch. Id.H u l t h 20: 36 0959). 11. Cudncr. tJ.. md Hesliopurn. F. F. oItcoxvcorm fram i r & a v e n U bevliium compoundr in rabbiu. Fed. Proc 5: =I (1W6). rZ Vowdid. A. J.. Pntt. P. C.. and L'rban. E. prarunion of p u l m o n a ~cancer in albino raw exmmhaaoon u)an aerosol of &@km sulfate. A c a U R I C Conrm Gntrum 11: t3j (1933). 13. 3lmcuso. T.F. Oceuprtional lunp canref m o n c ki:: roriccn. In: Conference on octupauorui &XUO.CU~C Fibrous and Pamcie h t and Their Exienrion : x o t n w o n m e n t . R. Lemen and J. Dement. E&.. Socrc:. ~ J P dW6nnmrunenuJ H d r h . nap^.. 2 1979. 14. Wagoner. J. K.,Infante. P.F..m d Baviiu. D. t.Bcr urn: An etiologrc agent in Be induction of lung can no*neoplastic respimtory disease and he-. drrcace am hdwvlolly UDOwAorken. Ennmn. Res. 3:15 :IC 15. Mmnrs~,T. F. 31onriity rtudy of beTIlium indul worken' oeupationrl lung cancer. Enwon. Res. 2:. r.,(1990). 16. Infan& P. Wagoner. J. fc. and Sprincc. h'. L. M o r a p t ~ ~ mfrosm lung cancer urd non-ncopiastic resp:.?: d i m among white d e s in the ber?.ilium CUC my: Ennron. Res. 21: 35 (1980). 17. H u b . J. F.. Daniel. M. R.. Dinple. J. T.. and Webb. G a m u m as P ordnoprn N u u n 192 S92 (19621. 18. Potu. C. L. Cadmium pmteinurk-the health of k . : c work- exposed Lo admiurn oxide OUSL Am. k p ti. 8: 55 11965). 1% Kipknp. M. D.. and Wa~rhouse.J. A. H. Gdmium a prortrtlc arcinom htte?,. &met 1: ;30 (1967. a.k r m n . R A.. kc.J. S..Waponer,J. L.and Blejer. S . Cancer moraiity amongcadmium producrron u'orsers. hr: h'. P.A a d . Sei. 271: -33 (1976). 21. JGeUluom.7..Fn-. L.and Rrhnrru. B.Mor&? E anew morbidky among crdmiumupowd workers. En\ ran. H d t b P e r s p n 28: 199 (19791. 10 Environmental Health Perspectives Problems of Epidemiological Evidence" Problemsassociated uith the use of epidemiological information may be available on 'he previous e x p e evidence to evalcate the carcinogenicity of meuls sure of individual workers, and cornpansons may be ;ve. in the main. those associated uith epidemiological praciicable only between groups of workers employed enquiry in general. There are. however, some in panicukr occupations or on specific processes. additional difficulties that arise from the v d e t y of Sometimes, when measuremenu of the intensity of ways in which exposure to metals can occur. &e past exposures are no: asaiiable, these may nave to variety of metal species and compounds. and the be estimated from the intensity of current exposure frequency of mixed exposure. We shall, therefore. in the same occupation or the length of employment review some of these problems, and the ways in m a y have to be used as a substitute for rneasure- which they can be overcome, before revieHing the ment on the assumption that exposure has been esidence relating to individual elements. cons'ant over time. Exceptionally, however, if One of the greatest difficulties is to obtain a exposure was panicularjy heavy at a time when population for study that is large enough to distin- labor turnover was high, duration of employment F i s h the effects of a specific hazard from the ---be dissociated from intensity of e..posure and effects of the random variation of small numbers or pacadoxid results may appear LO be obtained. alternatively to be confident that no material risk A s p e d problem in the study of metals is that exists. when negative results are obtained (the mixed exposures to more than one metal a r t to problem of statistical power and its reiation to different valencies or oddatior! states of the zxtal sample size). These cannot always be overcome by under investigation are frequent, and precise increasing ~e size of the population. 1s the number spei55ca5onsof individual components of the ambi- of people exposed to high concentra:ions of the ent pollution may not be available because of agent may be small and extension of 6 e study to Iimitauons in the uul>zic method. Changes in the include larger numbers will only dilute the results. nature of the process and in the consequent e s p if the additional subjects have not been intensively sure patterns may ais0 have occurred over time exposed. In studies of cancer, there is also the without being recognized. problem that the first ten years after exposure to a Two other considerations which have to be taken cvcinopen seldom provide much evidence of risk. into account are Me udequaq of the mca..ure of n.4 Longer periods, even 30 yean or more. may be and the possible esistence of confounding factors. required before the existence of a risk M be The endpoint that has most commonly been used in properiy assessed, and the inclusion of large num- studies of metal carcinogenesis is cancer moraIiry; bers of subjects who have been observed for only a this k adequate for types of cancer uith a high short period uill serve to dilute the results still htdity nte (e.:. cancer of the lung) but is a poor furrher. The analysis should, therefore, be identified measure for assessing the risk of developing tumors whenever possible, both by intensity of exposure with low fatality rates (e.g., cancer of the lapnx). and by length of time since exposure began. P0ten.d confounding faciors such as personal The exac nature of put exposure at the workplace habits, socioeconomic satus, and other occupa- is often difficult to determine and, in the case of tional exposure are seldom taken adequately into exposure to metals, may be quite complex. Little account due to lack of information. Smoking habits constitute one important confounding factor when the hazard of lung MCV is being considered. Thir Kaion Nprepared by a U'orkpoup c h i d by Sir Richrd Doll (L'nivemty of Oxford. Englmd). other memkn of thc vwkcmup were: t m m Fishbein. Peter Infante. h i i i p kndngm. J. Willurn Lloyd. Thomas 1. Mruur. Ernat ~ ~ U CTwD S.cm& GaM Penbgtn, Umbma SdIhttL Differences in smoking habits are unlikely to be h e enough to account for a relative risk of lung MCV more than tuice that of the penem! population. bu: in the absence d detailed information, it is ud Rod~Kosrrud. a matter of judgment as to how far smalier relative August 19SI 11 2 *' 7 5 .a risks *&atare no: due to chance can be attributed to excess smoking. exposure to the m e * l , or a combined effect of k h . As with dl otner epidemiologica! studies. the most imporant mwrion for the cvduation of those relating to metal carcinogenesis is the consistency of the results between studies (i.e.. do they all point in the same direc9on1, within each individd study (Le., does the risk v v y with the degme of exposure), and with the results of laboratory tests concerning carcinogenicity in animals and the absoqtion. distribution, metabolism and mechanism of action of the metal under investigation. It must, however, be borne in mind that there are many ways in which apparent inconsistency can be produced, and it m a y be difficult to sort out how far it a n 'be due to differences in the design, method of investigation, or analysis of the studies, or to differences in the exposure of the subjects, or biological variation. Positive results in one set of circumstances are not necessarily contradicted by negative results in another, nor vice versa. When major inconsis;encies prevent an unequivocal interpretation of the totality of the data, this snould be regarded as constituting urgent grounds for Wher research. In the rest of our report we have considered in detail the evidence relating LO eight metals (in d p i u b e t i d order) and follow this with a brief note on other metals. Specific recommendations concerning mcii\-idual metals and recommendations conce-ning the detection of occupational hazards of cancer in general are brougnt together at the end. Arsenic There is condusive epidemiological evidence of an increased risk of lung cancer in the manufacture of arsenic con'uining pesticides (1-8).The exposure has been mainly to inorganic arsenic compounds. K O conclusions can be drawn with regard to the cudnogenicity of trivalent versus pentlvalent compounds as both forms have O C C in~the &urnstanns in which individuals have been occupationally exposed. The use of ustnic+mtahing pesticides, often as arsenates of low solubility, has been associated w i t h lung cancer among vintners in Germany (4) and in Fmce (51, but the dam are not conclusive. The carcinogenicity of inorganic, mainly trivalent vscnic is d m evident from many epidemiological studies of men employed in smelters (6-JI). As 8 rule, an increase in lung cancer m o d i t g with incrtasing dose of arsenic has brtn observed (6, 8, 10). It should be recognized that the smelter environment is v e q complex, and the intenction 12 between anenic and other environmen'al pollu- turs 60,.hetry me&. etc.) as well ?s with to'bacco smoking is poorly understood. Some studies nave indicated an increased mord- ity from lung cancer in popu!ations living near point emission sources of arsenic to air (111, but h e role of arsenic cannot be assessed because of lack of measurements of exposure and effectsof confounding factors. Exposure to inorganic arsenic can cause nonmelanotic skin cancer. This has been observed following the ingestion of vsenic in drinking water and in arsenical medications in doses a m o u n ~ n gto seve2.11 grams (12-15). The form of arsenic in the drinking water has pet to be determined, bu: in medication the evidence dehirely relates to the inorganic trivalent form (12). Cases of hemangioendothelioma of the liver have been reported follouing exposure to inorganic arsenic from medicinal prepaations (16-291, c o n x m b nated drinking water (%anId)w,ine (3).T h e evidence that arsenic was a causative factor in these cases is thought to be conclusive. A possible association between arsenic and cancf- of other %Xis, most notably of the lympnatic and hematopoietic systems (2, 10).needs furrher inves- tigation. No epidemiological d a a are available n i a h g to the carcinogenicity of organic arsenic compounds. Beryllium Although numerous experimen'd studies had indicared that a number of 'wryilium compounds were carcinogenic in experimen-a1 animals by sev- e d routes of adrninistntion (3th,e results of epidemiologic study up to the end of 1970 ( 3 - 9 6 ) had not demons*ated any consistent evidence of carcinogenicity in men and women employed in p r i m q beqllium production works. or among *subjects enrolled in the US. Beryllium Case Regis(BCR).Results of follow-up studies of these populations h u g h the mid-1970s have been recently reponed (27-90).The study populations somewhat overlap, as three npons concern the workers in two factories (_07-_09w), hile the f o u f h concerns the mortlfity of individuals in the Regism (901, many of wnom wen employed in the same factories. Each study dcmonstntcs a significant excess of lung MCV. The lung cancer mortllity observed in the beryl- h m exposed workers was excessive compared with the morality recorded for the U.S. general population ( 2 ) and that in a .second i.~dustri?lpopulation located in the same gtrojpphic redon (29). The studies Jemowtnte an excess lung cancer Environmcntr! Health Penpectivcr I k ~ *hi- uith - d- .Ant ss role . -ii of ding ! *ion- ved :ater .:& to '1 the :it in 1 the ime z aramiThe )r in -can- and rv* .!able -enit had unds sev- ts of .:-,06) ce of ad in lmng eps* hese ently what sin .s the nany Each lung eryE ulth *pub- ation mcer Lives njk fonowing shofi-tcnn but heavy exposure LO bcpllium (28). T)us same phenomenon was o b served for indi\iauals who died from beFIlium disease, a dinical endpoint previously demonsvlted to be associated with occupationabenvironmen%l exposure to beryllium (311. Our inteqretation of the total evidence is that beqllium is the cause of the excess cancer moraiity in these groups of employees. Cadrnium Occupational exposure to cadmium oxide fumes occurs in the smelting and refining of the metal and in the production of copper-cadmium and bndng alloys. Exposure to cadmium oxide dust occlvs in cadmium-nickel battery manufacture and in the production and use of cadmium oxide for piating, chemical and plastics industries. Exposure to cadmium sulfide occurs in pigment manufacture. Lesser exposures to cadmium stearates and other compounds also occur. While cadmium has been used increasingly in industry over the p u t 50 to 60 years, the toul number of workers exposed to the compounds of this m e a has not been iarge. In the ear!ier pears of cadmium usage, occupational expusure was often heavy and prolonged, for neither the fume nor the dust are highly irriran: unless e x p sure is massive. With the recognition of chronic cadmium poisoning, m y processes were redesigned in the 1960's uith enclosure and the inssd!ation of cxhaus: v e n ~ l a t i o nAs a result, occupational exposure over the past 10-15 years has been greatly reduced from concentrations measured in millirams per cubic meter to levels measured in micrograms per cubic meter. The first intimation that cadmium might be a human carcinogen came from a small study in Briain of men exposed t o cadmium oxide dust for a minimum period of one year in cadmium-nickel barter?. manufacture (82. $31, where there were four deaths from carcinoma of the prostate when less than one w m expected. Exposure to cadmium oxide dust had been heavy and had given rise to chronic poisoning in the work force. In a similarsized group tngaged for a minimum period of two gears on the refining of cadmium in the U.S., also . under heavy exposure conditions. four deaths from prostate cancer were again observed, all of which occurred more than 20 years after tkst exposure (34).This number is significantly greater than that expected (0.88) h m national morality statistics. In this cohon there wai also a significant excess of lung cancer. However, smoking habits were not determined, and there was concurrent exposum to other compounds, in puticuiar to arsenic. Concentmtions of arsenic were low when measured at ';ne time of the survey. but there is no infomtion or. arsenic levels in the eariier Fears. In a Sweaisn ucmium-nickel b a t t e q facron, where again h e a q exposure to cadmium oxide and nickel hydroxide dusts had occuned in earlier years pving rise *a the firs: repozed cases of chronic cadmium poisoning,all workers with more than five years exposure who developed cancer between 1959 and 19ij (95) were identified. S o significant excess of prostatic or lung cancer was found. Finally, in a Swedish copper-cadmium alloy plant, a small increase in prostltic cancer mohality, but not reacning a significant level, was found in a s o u p of workers with at least five years heavy exposure to cadmium' oxide fume (005). In each of these studies the number of workers investigated was small,with. in 4 . 1 4 cases of prostatic cancer against 5.4 espected. The most reasonable interpretation of these results is that esposure to cadmium had conuibuted to the development of prostatic cancer in tbe exposed workers.? Injection site sarcomata and interstitial ceU tu- mor~of the testis have followed the injection of s e v e A cadmium compounds (3C-Lsl. Prosatic tumors have not been observed, but it is questionabie whether the animals studied provide adequate models (U). Chromium An increased risk of lung cancer has been e s b lisned for worksrs in the primary chromate production i n d u s t q ( t 5 , L6). This increased risk has been atui'outed to exposure to an incompietely defined xrhure of cfuomates. An excess risk of lung cancer has also been observed in workers in the chrome pigment production industq (47, 48). Secondaq users of chromates other than the chrome pigment indust? and s e c o n d q users of chrome pigments must be regarded as possibly being at risk, but the epidemiological evidence (46, 49-51) is not conclusive. Both results from the p r i m q chromate produc- tion industry and from chrome pigment protiuction are not inconsistent with the concept that slightly soluble chromates are more carcinogenic than the soluble compounds. Increased risk of lung cancer has been repofled in platers exposed to soluble compounds (S?), but the results in two studies August 1981 13 i I I - . - _ .(53-35) are inconclusive.: Animal experiments also and rhabdomyosarcoma (72)at injection sites in the suppofi the assumprion that the sligntly soluble rat. compounds are the more active IW, bu: soluble and Cobalt. as the $valent ion, has been shown LO sligntly soluble compounds are equally parent mu- substitute for 3 1 r - as zn activator for DS.4 poly- ugens in ~ t r (o57, 58). m e m e ( i 5 ) . Cobalt chioride has deceased ';ne There is very little epidemioloficll evidence fiaeii::; of DSA synthesis in vitm (7;. 76). relating t o workers exposed to trivalent chromium, but such as there is does not suggest an increased risk A suggestion of an increased risk of lung Iron cancer in fermchromium production can be attniuted This most abundant metal in the catch's m s t is to exposure to hexavalent chromium in the process present in its natural state in the form of oxides and (50). The assumption that exposure to Vivalent ar'oonate. Occupational exposure, dating back to chromium does not constitute an increased risk of prehistoric times, is both common and heavy in iron u n c e r is indirectly supported by in titro tests for ore mining, iron refining, steel production and mutagenicity (59, 60)and by the observation that welding. only hexavalent chromium passes the cell mem- The injection of certain iron carbohydrate brane (611,althougn the trivaient form may be the complexes in large doses has been followed by local active agent at the site of action CSJ-65). - o m production in several animal species (77-82) No reiation between dose and response can yet with evidence of a dose response relationshi?. be detennined for the cancer causing effect of Millions of doses ofsuch complexes have been given hexavalent chromium in men. This is pazly be- parenterally over the p u t 30 years in the trea:- cause the active agent in the actual circumstances ment of iron deficiency anemia, but no more than a of exposure is unknown. and partly 'because only handful of tumors at the site of injection (where limited and unreliable dose estimates a n be obtained tumors are also known to occur spon*aneously) for workers wno 'have been found at risk for the last have been reponed (89). In one study of dl soft 20-30years. The imporance of the chromium that tissue sarcomas which occurred over a defined is found in tooacco for the development of lung interval. no history of paremtend iron therapy couid cancer is not known,nor is it known wheber there be obtained (84). In another study covering dl are s-vnergistic effects between chromate exposure u s e s of sarcoma of the buttock notified to U . L and smoking. Some published data suggest an cancer registries over a two-year period, four ca5.s increased risk of ~ m i n t e s t i n a lcancer (5% 59. were discovered (85). but only one of them is 66-69). but the results are inconclusive. considered acceptable asa sarcoma that could have arisen in response to iron injection (8G).The possi- Cobalt bility that iron dextran injection may give rise o: sarcoma cannot be entirelg discounted. but *e risk Occcpational exposun to cobalt occ~vsin the (if any) appears to be extremely small. tungsten carbide hard metal industq, in mining The administration of iron oxide to the respinto? and refining of cobalt. in the production of cobalt tract of h t e n by intratracheal instillation b alloys, and in the handling of cobalt salts. Pulmo- gether u-ith benzo(a)ppne or by inhalation follow- r s q fibrosis has been reponed in workers from the ing systemic administration of aietnyi nitrosamine hard metal indus:ry (70, 71). Despite these exces- has resulted in an increased yield of tumors, whiie sive exposures, there have been feu- repom of tumors were not obtained with iron oxide alone. cancer morality occumng in these worken. One 'This effect is considered to be nonspecific. epidemiological study of cobalt refinen worken An excess morulity h m lung cancer has been has reponed an excess of deaths from lung cancer observed in iron ore miners from a number of ( Z ) .However, interpretation is complicated by the countries. The o r i g h l observations were repozed fact that there was Olso heavy exposun to ysenic, fromCumberland. England (81),and confumed in a mainly as arsenic trioxide, and probably Jso to later study in 1970, in which the miners of h a e m - nickel. There are no convincing rccporrs of cancer tite showed a d w excess moxtaiiry from lung arising from the use of cobalt-containing prosthetk cancer compared with national and regional figures devices in patients. (88).An excess lung cancer m o d i t y has also been Finely divided cobalt metal powder, Cobak oxide, reponed amongst iron ore miners from some other and cobalt sulfide have produced fibrosarcoma (731 countries (89-99). The in-4 lung cancer risk in haematite .. . c. miners mag be attributed to a number of possible -, factors. Although a carcinogenic effect of iron oxide Environmental Health Pcrspectivu J. : the '. I to ,olythe 1 I -' I;t is - and ;;to iron ', and rate io d '-83 -nip. wen -eatkn a nere uly) soft hed ouid :dl '.Ii yes ' 11 is ;ave tssi..to risk wry I tct lownine :nile one. *en r of ?Led in a maung 1nS een :her ltite ible side ives - ,,;.mcIes alone. possibly acting in a nonspecific way, Cannot be e n b e i y discounted. the t o d i t y of the (I\.idcnce strongly suggesu that the excess lung cancer risk could be attributed to ionizing ndia:ion from the d o n and radon daughters present in the ,tmosphere of the mine. The reiationship between the excess morality from lung cancer and the level of ndiauon in the C u m b e r h a h e m a t i t e mines wls comparable to that found in other mining situations where radioactivity is held to be respon- . sible for an occupationd lung cancer risk (88). However. ndioactikity levels have not been determined in dl other mines where an increased lung Cancer risk has been shown to exist. TWOearly studies in Britain showed an increased lung cancer morality in foundrf workem (94, 951, but this a n n o t necessariiy be attributed to iron oside, as exposure to polycyclic hydrocarbons also occurred. Lead Inorganic lead has been shown to produce renal tumors in a number of experimental studies, at least sill in mts (96-100) 'u?d"o5e in mice (103). Dosage was by several routes including o d Levels of exposure in all of the studies far exceeded the maximum doses tolerated by man and caused gross morpholopcal h g e to the kidney. Lead isreported t o have produced lung tumors in hamsters (104)and cerebrz! gliomas in nts (101). In titm, lead oxide has beer: found to induce dose-related Lmsformation in S-yrian harnster embryo cells (105). Lead oxide also enhanced the tansfonnation produced in Syrian hamster cells by SA; virus (106). In an early epidemiological study, an excess proporionate morality ratio was noted for malignvlt neoplasms (dl sites combined) in batten workers with so-called 'negligible exposure uith lead in urine values within the normal m g e " (25 deaths observed vs. 14.2 expected; p c 0.05), but no excess morality was noted among workers with "heavy" exposure to lead (102. No comment was made in that study as to any si-specific occrrrrenn of excess malignancy. In a more recent study of lead smelter and batteq workers (108, 1091, a significant excess of malignancies at 111 sites combined was found in smelter workers but not in htteq workera. In both p u p s . mortllit;v from digestive and respintory a n c e r was greater than national RKS predicted. A five-year follow-up study leaves the interpretation of these findings in doubt. This pattern w m not rmintlined, malignant neoplasms shouing a slight deficiency in smelters and slight excess in battery workers (109, 110). August 1981 From the d a a it m a y be conciuded *a: there is evidence tha: lead in hi@ dose can produce cancer in experimen'al animals. However, insuf5cier.t obsexitions on man have been reponed to enable a definite conciusion to be reacned as to whetner lead cruses human cancer. Nickel Nickel: is used chiefly in the production of dloys including st;linless steels. Other uses include: electroplating, ca*Aysts, coinage, and pigmenu. Kickel alloys are also used in jewelry and in dental and surgigicai prostneses. Occupational exposure occurs in mining. refimng, alloy production and use, electroplating. welding, and in'the handling of nickel salts. Increased risk of lung and nasal sinus a n c e r in nickel refining workers was h t noted in 1986 from Clydach. Wales (111). a refiner?. using the 3lond process which began opeation in 1902. The 31ond process made use of nickel carbonyl in the refining of nickel. Because of this, it has often been beiieved that nickel carbonyl wzs the sole carcinogen. Subsequent epidemiological studies from Canada (112, 113). Somay (iit.115). the U.S.S.R. (72).and S e w Caledonia (1161have shown that the increased risk also occulied in refineries where the Xond process was not used. In addition, continuing studies have snoum t h the increased risk a t the Clydach refin- has dropped markedly in workers entering employment &er 1932 despite con:inuing use of the carbonyl process (IJ J ) . Studies in Canada (102. 113) and in Wales (in.117) suggest that exposure to furnace fumes and dust. from the high tempexturn sintering or calcining of impure nickel sulfide mattes was the source of the increased risk These same operations were tamed out in the Eionuegian refinery (118)and, although some risk appeared to be associated in the eleczolytic workers, mixed exposures of these workers cannot bc mled out. The Norwegian studies also demonstrated an increase in the observed incidence of IqngeaI cancer, as well as an increase in incidence. of lung and 4 sinus cancer. Mining, smelting, and refining of laterite (nickel oxide) o m have been cYried out for about 100 y w . It was believed that the increased risk of respiratory cancer did not occur in laterite opera- fions. A single cvecontrol study, however, reported an increase among workers and residents living near a nickel smelter in Sew Caledonia (116). I t w s also assumed that increased risk of respiratory cancer did not occur among nickel users, e-6.. in nickel alloy manufacture and use, use of nickel powder, nickel plating, nickel welding, c t c , but 15 *. - -*-- 1. I* l 2 : 1 . -* . . dehitivc studies on this have been lacking. A m v n t s ~ ~ daidynot iclaiate an in- in respultorlr. a n c e r among a conort exposed to nickel powder and followed for a minimum of 19 years (119). Another recen: case control study did not indicate an increase of risk in workers engaged in gnnding and welding operations with nickel alloys (120). Studies with experimental animals have demon- strated *at nickel subsulfide (Si&) produced local tumors at a wide variety of injection sites and by inhalation in rats (121). Ni& also enhanced the carcinogenic effects of benro(a)plmne (123 and 20-methylcholanthrene in experimental animals (123).In vitro mammalian cell tests demonstmte that Ni3& and NiSO. compounds give rise to mammalian cell tansformation (1%-~8p). Other Metals Epidemiological evidence relating to exposure to a va7ety of other metals should be sought if at all possible, either because large numbers of workers are involved or because laboratoq tests suggest the possibiiity that a cancer hazard migiit.exist. These metals include copper. manganese, mercury, piatinum. seienium, titanium, vanadium. and zinc. Studies of copper refiners are panieulariy desirable, but it may be aificult to define groups who have not also had material Exposure to arsenic. In view of the small numbers of workers exposed. it will be necesswi to obtain the collabomtion of industry on an interna.Liorwl scene if any worthwhile human evidence is to be obtained relating to platinum. selenium, and vanadium. The possibijity of es'clblisning specialized registers of men who have worked with these met& should be considered. Recommendations Specific The epidemiological evidence strongly impliates inorgacic triyalent arsenic as the responsible agent when an excess of lung cancer is attributed to exposure to arsenic. There is, however, no reason to exonerate pentavalent arsenic, and workers exposed solely to other forms of arsenic should be investigated further. Experimental work should be undertlken on the effect of exposure of the respiratov tmct to arsenic compounds of low solubility. The incidence of lung cancer in areas w h e n theare unusually high concentsitions of arsenic in the air should be studied in order to w e s s possible 16 risks to the f i n e d public. Airborne icveis and personal excretion patterns snouid be rnonkored in sucn ares. There is a need to study dose-response reiationships for arsenic in water and skin cancer. P u r i m lar emphzsis snould be given to difierences in relation to valence state. The conclusion that ben.llium and cadmium contribute to the development of some cancers in man was reached because this seemed to be the most reasonable interpretation of the availabie facts. The numbers of observations on .?ran are small. however, in both cues, and it is imporrant to cneck that the conclusion is correc: by con::nued observation of the cohorts of workers exposed to beTllium in the U.S. and by collecting observations on k 3 e r numbers of men who have been esposed to subs-anti?i amounu of cadmium whenever they can be found: Furrher studies are required to determine which compounds of chromium are carcinogenic to man and, puticularly, to determine if there is any hazard associated uith exposure to soluble compounds in the plating industry. Cohorts of workers exposed to airborne r e s p h ble cobalt and its inorganic compounds shouid be identified and foollowed up to derennine their cancer morality ntes. Long-tenn exposure of experimentai animals to both insoluble and soluble forms of cobalt isuch as cobalt oxide or cobalt sulfide and cobalt chloride or cow: nkaate) via the respiratoq trap- snouid be induded. Further epidemiological studies of iron miners. steel workers. foundq workers. and welders are required in which attempts are made to characterize the extent to which the men are exposed to ionizing rodiation and possible carcinogens as well as to iron and iron compounds. More studies are needed of men wno have had long term occupational exposures to lead. Caseconml studies of adults with kidney tumors and follow-up studies of people who suffered from lead poisoning in chiidhood could also heip to d d y the extent to which lead m a y con;ribute t o the development of a n c e r in m. F u d u epidemiological studies of workers exposed to soluble and siightly soluble forms of nickel and nickel alloys in the nickel processing and mining indusuies are needed.? These should in- Environmental Heallh Pcrspectivcz I .arid 4 in ~ :ionticu-5 in con;m * most The xevthat ation ;m in `rs- . :tannbe 3:nich man =Y com- :ph- Id be lnCet 11s to ch as de or :d be ;res, i are I cter- .:d LO well ",.ahs+a?d- < and I lead `y the level- -;exlickel and Id in- rrrntfy uld bc du d tives - cjode industries involving mixed exposure!: to nickel . and other meals. e&. nickel and cadmium in btteyv manufactures and nicke! and chromium in SmtnIess steei manufactures. weiding. nickel phting. and cnrome phtinp. Additional long-term innaiation studies in experimen*danimals are needed to determine the potentia] carcinogenicity of nickel m e d and nickel compounds. P n o n t y should be given to testing nickel m e d . nickel sulfate. and nickel oxide. because of. the large number of workers esposed and the lack of conclusive information concerning these s u b sunces. G e n era1 The possibiHtg of interactions between meals (particularly Aenic). other industrial poUur.ants and tobacco smoke in the production of lung cancer should be further investigated. Epidemiological studies should. whenever p n r tical. include comparison of the rjsk of cancer in groups of inciustrd worken exposed to a particular :lcent with that in unesposed workers in the same industF or in residence in the same g t o p p h i d area as well as with those in the count? zsa whole. In epidemiological studies, identification of COh o m with past exposure is often difficult or imps- sibie because: .a) employment records are often ciestrrpd after a minimal time internal. and (b)job descriptions in company o r medical records may be nonesistent or badequate. E m p l o p e n t records adequate for the identification of workers for the rlctcrminatjon of their \ital studiessnor\ld `ber e b i n d by companies and medical or industrial hygiene dcyr;lruncnts where these exist for a minimum of 30 years. Because of the long period that may elapse between initial esposure and the development of mncer, these records should include job description, with qualitative and quantitative information on exposure. Whenever possible, informition on othcr poten:ial exposures, e.g., cigarette smoking. should be reconled. In the interest of public health, facilities should be provided in all industrialized countries LO allow Lonafide re.search workers LO linkrecordsmaintained in intlustr?. with national records of binh (when 1Jrdcticabk). sickness, and causes of death. subject lo appropriate safeguards to insure that personal records are never used to the detiment of the individual, 2 0.:-M. C.. Holder. B.B.. and Gordur.. H . L. Rcapirrtoq- a n e w mil a r u p a t i o d exposurr to m n i c a i s . Artn. E n w o n . Health 3 (19541. 3. Barye:. A. $1.. Lilicnfrld. A. SI.. and Levin. U.L. and aceuprL~odexDosuR lo i n 0 r r - c amcnrc. In: A b IVICJ. 18th inrematiod Canpress on h r u t i o d Helie.. Bnrnton. Enrund. Scptemkr 14-19. 19;:. 4. Roth. F. U k r den Bronchidkrebr arwnccxMimcr Winzer. \`irenow Arch. Pamol. a!.119 (13%). 5. Gdy. P.. Toumne. R.. Bmnc. J.. Roudicr. P.. and CJloir. P. Le a n m pulmonurr donmnr a n e n d dcr r i ~ m m du k a u j o i w . J. F n n c . ,\fed.Chir. Thonc. 1.; 303 (1Wi. 6. Lee. A. U.. and Fnumeni. J. F.. Jr. A m n i c uwf r e s p m t o v cancer in naan: an orruprtiorul srudy. J. Natl. Cancer l m ~ r.?: 1045 ( I ~ Y I . s.7. Tokudome. and Euntsune. N. A ruhor. study on moruhty fromcancer and other causes amunr worKerS at a m e a refiner?.. lnt. J. Cancer 17: 31U (195t). 8. Pinto. S.S.. Enterline. P. E.. Hcntlcrsan. V.. and Vamcr. PI. 0. Slordity cxpenenrc in rchtion to a mcwured arsenic tnoxide exposure. Enriron. Health 19: 15 (197. 9. Renrher. A. C.. Cuter. 51. W.. md 31cKee. D. W. Morulity at a large western copper smelter. J. Occup. Sled. fy: 7-54 (1YZ). IO. Axelson. 0.. D a h l p n . E.. Jansxm. C. D., and Hebnlund. S. 0. Arsenic exposure anti rnofirlitt.: a mw-refrren: RtUay fmm a Swedish copper meher. Snt J. Id %led. 35,Y (1976). 11. Pcrstuuen. G. cucinsrCniciry orm n i c . Envim. ~ 4 t h Perspm ro: 93 IlyLIl). E.Arputllo, R. A.. C e n m . D. D.. and fcllo. E. E.Caner ameninrmo ~ o n emd lemico en Corciotu. Re\..ArL-nt hmtorifilol. 9 141: 4GJ (I-). 13. Seubuer. 0. A n c n i d cancer. A nrkw. Brit. J. Canmr 14. 1: 1% fiar, (lcM.7`L::rumn+rtisehe Cnirrrucbunmn u k r die h'ebenwidcuncen der fhrrapic mt a n u ~ w u ~ c h e m Amen bei Huutkrmkherrrn. r)ermatoiupo 131: I1 (1%51. 15. fwng. W. P. Eff- and dmr-mqmnw rc~brrnnzhir~orf skin cancer and blackfoot diiraw w t h arwmc. Lnviron. Health Pcrspccl 19: 1W IlYZj. 16. Rmwt. Y. A r r c ~ nkl entu*c?i~ ~ u r u c i a r nulitn carcinomas of the internal o m w . can. Md.AIWJC. .I.7s:O f ; (IY.%l. 17. Rcpeiron. W.. Em. L.Ospina. J.. and Hulhnil. J. F. Hemanplandothriul urcortu of liver h m chronic arsenic intosication by Fowkr`s miutiun. Cancer 1 2 3 1 (lWl. 18. Lander. J. J.. Sunlcy. R.J.. Sumnrr. H. JV.. Uowtll. D. C.. and Aach. I?. 0.Anmo.urtonu of thr liver rwmated with Fowler's d u t i u n (potassium iuw*nitr). Gastmnmr- O I O F cia: 1%' IlY75l. 1Y. Popper. H.. Thomas. L. 8.. T e 1 h . S . C.. Fdk. H.. and Seiikoff. 1. J. Derrlu~immtof hc.~atuanL+wanunwin m . imlurrd by vinyl chlurick. thorotrut.and rrunic. A m J. Pathnl. 9 2 349 (1Y78). .20. aRncdnnDkotn.oH*o...Psm.tb.1Ga.iiAL.m. :EthcchrefvUemn~yw. mP.iutLl..heLlivUnu.Ro.f U.. the mi.liver and ehmnie vvcniam Re\.. Mcd. 9 ~ 1 c:trl 119fll a.Woth. F. Arrcn-kkr-fumoren (Hamangiwenlotheiiom). 2. Krebsfvrneh. 61: 4Cs (1957). E. Kuschnrr. U. Grcinoccnicity of Beryllium. Snviron. 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