Document XR9LE4QdBpaax5VoqdL0NmKbR

/****% UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON. D.C. 20460 -February 16, 1979 OFFICE OF RESEARCH AND DEVELOPMENT SUBJECT: The Carcinogen Assessment Group's Type I Riyfe Asse.ssment/for Maleic Anhydride FROM: L. Ahderson, Ph.D., Executive Director inogen Assessment Group (RD-689) TO: Joseph Padgett, Director Strategies and'Air Standards Division, MD-12 Research Triangle Park, North Carolina 27711 THRU: Jack McGinnity, Staff Engineer Strategies and Air Standards Division,. MD-12 Research.Traiangle Park, North Carolina 27711 As requested in your May 18, 1978 memorandum, The Carcinogen Assessment Group has finished the Type I risk assessments for Maleic Anhydride. We are transmitting this report to you. Attachment cc: S. Gage (RD-672) S. Jellinek (TS-788) W. Barber (RTP) D. Denney (A-132) M. James (A-133) T. Murphy (RD-682) H. Beale (PM-233) AP00009139 THE CARCINOGEN ASSESSMENT GROUP'S PRELIMINARY RISK ASSESSMENT - ON MALEIC ANHYDRIDE Roy E. Albert* M.D.Chairmen Participating Members Elisabeth Anderson* Ph,D. Bernard Haberman, D.V.M., M.S. Charalingayya Hiremath, Ph.D. Robert McGaughy, Ph.D. Steven Miller, M.S. Beverly Paigen, Ph.D. Dhartn Singh, D.V.M., Ph.D. Todd Thorslund, Sc.D. Adrienne Zahner, Ph.D. i AP00009I40 TABLE OF CONTENTS * Z Summary II Introduction XII In vitro studies (none exist) IV Carcinogenesis studies A* Carcinogenicity in tats -- Dickens and Jones, 1963 * B, Anti-carcinogenic studies in alee Crabtree, 1944 Klein, 1965 Ottenbrite et al., 1977; Goodell, et al., 1978 V Unit risk assessment VI References *' 1 F AP00009141 I. Summary Maleic anhydride; 0^ Evidence for carcinogenicity The data bate for'evaluating the carcinogenicity of maleic anhydride la almost non-existent. One Inadequate .study treated 3 Wlster-derived rate for 61 weeks with maleie anhydride and 4 untreated rats of the same type. In one treated rat, 2 fibrosarcomas occurred at the site of Injection compared to mo tumors In the untreated rats. Three studies showed that maleic anhydride had anti-carcinogenic activity in mice against skin tumors Induced by polycyclic aromatic hydrocarbons, against a primary tumor system Lewis lung cells inoculated into mice* and against Friend leukemia virus. Maleic anhydride should be tested for carcinogenicity using short term mutagenesis, cell transformation and animal bioassay tests. Unit risk assessment: No adequate test of carcinogenicity has been done. ) AP00009142 ZZ Introduction Maleic anhydride dust or vapor la an acuta akin, aya, and respiratory tract Irritant. . The V.S. occupational standard for exposure Is 1 g/m? (0*25 ppa) based on its high Irritant property* Inhalation can cause pulmonary edema and Inflammatory changes In kidneys and other organs* These Changes are generally Irreversible (Bober end Began* 1970)* Direct contact with the akin may cause burns* Maleic anhydride la alao a respiratory tract sensitizer and persona may become highly sensitized to vary smell concentrations. Chronic exposure In huraen8 also caused asthma* chronic bronchitis, and dermatitis (Patterson et al*. 1976). ` III. in vitro Studies " * Ho in vitro studies for mutagenicity or ability Co transform cells exist. These tests should be done. IV, Carcinogenesis Studies A. Carcinogenicity In rats The date base for evaluating carcinogenicity Is almost non-existent. This chemical should be tested for carcinogenicity. e Only one Inadequate test has been made of the carcinogenic properties of maleic anhydride. Sicken and Jones (1963) injected 1 mg maleic anhydride In arachls oil twice weekly into 3 Vlstar-derlved male rets for 61 weeks and -- arachis oil only into 4 rats of the same type. One treated rat developed 2 fibrosarcomas at the site of injection compered to no tumors in the controls. This study is Judged to be of poor quality due to the email number of animals and the lack of hlstopathology. The difference between control and treated Is not statistically significant and the meaning of a tumor at the site of injection of a highly irritating compound la unclear* B. Anti-tumor activity in mice Three studies have shown that maleic anhydride heB an antiearcinogenlc effect* 3 AP00009143 Crabtree (1944) shoved that maleic.anhydride painted on the shin of nice previously painted vlth dlbenzanthracena or bansopyrene retarded the time at which skin tumors appeared* Ho control group treated only with maleic anhydride a was Included in the experiment* Groups of 25*30 Hybrid mice (parental stocks not" given) vara painted twice weekly for 9 months with 0*1*0.32 bensopyrene or 0.22 dlbenaanthraeene* Halele eohydride was painted over the same ares 4 times weekly on the'days between the carcinogen paintings. Tbs concentration was 1, 2, 4* or 62 maleic anhydride. Highly significant anti-tumor activity of maleic anhydride was observed both in the time at which tumors first appearad and In the number of animals vi-th tumors. Klein (1965) treated B6AF^ female mice with dlmethylbensanthracene, croton oil. and maleic anhydride In various combinations onrthe skin and measured skin tumors at least 1 am In diameter. Each experimental group contained 40 mice. No control group treated only with maleic anhydride was included* Kaleic anhydride reduced tumor incidence, delayed time of appearance to first tumor, and caused tumor regression. Ottenbrite et al.. (1977) studied the ability of maleic anhydride and Its polymers to Inhibit the growth of Levld lung cells, a primary tumor system In BDF mice, and Friend leukemia virus In Balb/C mice. One million Levis lung cells ware inoculated subcutaneously in each mouse followed by daily i.p. injections of. maleic anhydride for 10 days. Kaleic anhydride homopolymer at 25, 50, or 75 mg/kg for 10 days inhibited the growth of Lewis lung tumor up to 76Z Inhibition of the`primary tumor else at the highest dose but did not prolong survival, tlma* These authors suggest that maleic anhydride la more effective against the primary tumor than against metastatic tumor cells* Kaleic anhydride polymers of 6 different molecular weight ranges from >100,000 to <1000 inhibited splenomegaly in Friend leukemia virus-treated mica* The molecular weight fraction moan effective against Friend leukemia virus was 10,000-30,000 mw (Coodell at al., 1978). # 4 AP00009144 VI References *Bober, A,, and Sagan, J "Pathomorphology of the Internal Organs under Experimental Poisoning with Maleic Acid Anhydride.11 Biol. Slutby. Sanit. Epidemiol. Wolewodstua Ka 14 (2): 171*175 (1970). Crabtree, H.G. "Influence of Unsaturated Dibasic Acids on the Induction of Skin Tumors by Chemical Carcinogens." Cancer Res. 5: 346*351 (1945). Dickens, 7. and Jones, H.E.R. "Further Studies on the Carcinogenic end GrearthInhibiting Activity of Lactones and Related Substances." British Journal of Cancer 17: 100-108 (1963). Goodell, E.M., Ottenbrite, R.M., and Munser, A.E. "Polymalelc anhydride effects on the immune system and Friend leukemia disease of mice." J. Reticuloendothel. Soc. 23(3)i 183-193 (1978). Klein, M. ''Inhibition-of Skin Tuaorigenesls in Strain B6AF-/J Female Klee with Maleic Anhydride." J. Rati. Cancer-Inst. 34(2): 175-13 (1965). # Ottenbrite, R., Good ell, E., and Munser, A, "A Comparative Study of Antitumor and Toxicologic Properties of Related Folyanions.11 Polymer 18(5): 461-466 (1977). * Patterson, R.M., Bomsteln, M.I., and Garshiek, E. Assessment of Maleic Anhydride as a Potential Air Pollution'Problem. For the U.S. NTIS, PB Rep. Vol. XI ISS FB-258363, 1976. *Abetracted version. 6 AP00009 fas' TOE IAPC FROGRft&ME CN SHE EVALCIA1TON OF SHE CARCINOGENIC RISK OF CHEKECAIS TO MAN Lorenzo Tcmatis International Agency fox Research on Cancer Lyon* France 2a a recent paper (Murray and Axtell 1974)1 cancer mortality data in the USA were reviewed with the purpose of assessing the loss to society caused by cancer. For this reason, the years of life lost and the work years lost due to cancer mortality for cancer occurring at different ages amd at different sites were evaluated. Hie authors cane to two main/ and other obvious, conclusions: (1) that cancer occurring at an early age represents a greater loss in terns of work years lost than cancer occurring At a late age, even if at a much greater frequency; cancer of the prostate in males, for instance, ranks secorofl in frequency and yet lower than twelfth as a cause for work years lost. (It is perhaps pertinent to remember that occupational cancer is rot a disease of old age: the average age at diagnosis ' of people with haemangiosarooma of the liver due to vinyl chloride is 47 years and that of the 33 cases for which ccnplete information is available, five were diagnosed before 39, and 12 between 40 aid 44, years of age.) (2) that in view of the limited success obtained up to now with improve! diagnostic systans and therapy, the greatest potential for career control lies la preventive measures. Even if one looks at the cancer problem with an eye on costs ard benefits, it appears that the most premising and rewarding approach is AP00009147 - 2 T" that of .primary 'prevention, which means firstly the avoidance of exposure to carcinogenic agents. In addition, it does not appear that periodic health examinations give any guarantee of a longer and healthier life tfiegel 1966)2. Accordingly, an intensified health surveyance of people 2t high cancer risks, as fear Instance people exposed to high levels of :-tinyl chloride, does not guarantee a better survival car an improved outcome of the disease. T |. It has been stated repeatedly that a large raxrtoer of cancers can be attributed to environmental factors in proportions which can vary from 75% (SffiO 1964) 5 to B0% (Haddow 1967, Bcyland 1969)4 *5 to 90% (Higginson 1968)6. One can dispute these percentages and reduce than to much lower and more acceptable proportions, but the fact rsnains that a certain proportion of human cancers are certainly due to environmental factors. Of these factors, dt have been identified and their carcinogenic effect on man has been prove!, many more have been identified as possibly hazardous to man, but the actual proof of their carcinogenicity relies only on experimental evidence, and for an even larger nurrber, the available data are insufficient to build up any kind of evaluation. Hhen the IAFC was first faced with the request to provide useful information on envirormental carcinogens, our first reaction was to prepare two lists of chenical carcinogens, one for chemicals carcinogenic to ma^ and the other for chemicals carcinogenic in experimental animal a. This project was soon discarded because (1) a list was considered too rigid to take into account the multiple aspects required for a proper evaluation, and (2) because it would have been relatively easy to prepare lists of chsnicals for which results were clear and unquestionable, but it would AP00009148 -3- have been impossible to include in any given list chanicals for vfoich the quantity and/or quality of the available data varied considerably. Share was also the implicit danger that all chemicals not included in the "blade list" of carcinogens could be automatically assumed safe. For these reasons, the ZARC, following the advice of an ad hoo working group, initiated the programme on the evaluation of the carcinogenic risk of chemicals to man, which is centered on the preparation of monographs on individual chemicals. Each monograph comprises several sections in data are summarized on: chemical and physical characteristics; production, use, occurrence and analytical methods? biological data relevant to the evaluation of the carcinogenic risk of the chemical to man, covering *11 available data on carcinogenicity studies, data on the metabolism of the chemical in experimental animals and man, the carcinogenicity of the metabolites, if tested, essential data on acute toxicity and, since last year, data on mutagenicity; and observations in man covering epidaniological studies and case reports. The last section of the monograph is a brief ccmnent on the ensemble of the esqperimental and human data with, vhenever possible, an evaluation of the data in termg of a possible risk to man. Up to neight volumes7-11*, each containing several monographs, have been published. The first volume, which appeared in 1972, contained monographs on 19 chanicals pertaining to different chemical groups. Qice the feasibility of the monographs was agreed, each volume contained data on chaoicals pertaining to one or two chenical groups, plus a ron-related substance when its evaluation appeared particularly urgent. This was the ease, for instance, with vinyl chloride, which was added to the session called in Jtine 1974, when anti-thyroid substances and nitrofurans were evaluated. i i ! i1 [ ] j i i ! i j / AP00009149 The chemicals for which a mozograph is prepared are selected according to two main criteria: (1) that there is evidence of Inman exposure, and (2) that sane experimental evidence of carcinogenicity and/or sane evidence or a strong suspicion of a hunan hazard exists. The extent of the possible human exposure is assessed in mazy instances with sane approximation on the basis of the data on the use and production of a chanical. Shis information has been obtained mainly through the collaboration of the Stanford Research Institute, operating under an agreement with the NCI. The data are also intended to be of sane help to epidemiologists, as they may indicate where a study could be initiated. The NCI supports this programme financially and has helped the Agency considerably by providing surveys of available pertinent literature. It is worth noting that it has been our policy to only include for consideration work which has been published or accepted for publication, anl to disregard unpublished results and personal oanrunications. After having assetbled reprints on studies related to the chemicals selected for the preparation of a monograph, a draft monograph is prepared, either by an external consultant or by JKPC staff. These drafts are then circulated among IMC staff and a group of expert consultants for carments. An ad hoc working group of experts is then convened in Lyon and the monographs are finalized after a careful and painstaking checking of all data. Die first eight volumes cover a total of 196 chsnicala. Of these, 17 (about 9%) were found to be associated with the induction of tumours in man (Table I). These 17 chemicals are listed in Table II. Aflataxin is inclined in this list, but It must be noted that only a strong suspicion. AP00009150 -5- and not absolute evidence, of its role on the induction of liver in nan exists, She carcinogenicity for nan of the majority of these chemicals was established as a result of studies conducted on people who were occu^tionally exposed to than. In fact, with the exception of aflatoxin, on which, as mentioned before, sane doubts still exist and for which . e^osure is dietary, and of chlomafhazine and stilboestrol, for which exposure is medicinal, exposure to all others is occupational {Table IX). If we ocnpare idle effect of these human carcinogens bn experimental animals, we find that nearly all are carcinogenic in one or more animal species, the exceptions being arsenic, haematite and possibly benzene. If we then catpare target organs in man and experimental animals (Table III), we can see that often, but certainly not always, target organs coincide. This is certainly not a new observation, but it is peihaps worth stressing, as it may have seme relevance in assessing Idle value of studies on chemicals for which human data are not available. Xhat exposure levels are mostly unknown means several things: (1) that nebody really queried exposure of workers to eccpounds whidi, in most cases, before being found carcinogenic, were known to produce acute and subacute toxic effects; (2) that there was no real interest in finding out the exposure levels which produced a high incidence of cancer, as they would have shown a fantastically high difference between the present levels or the accepted levels and the levels to which workers had been exposed for a long time. The example of vinyl chloride (VC), for instance, is quite denonstrative: at present, several companies are fighting for the acceptance of a level which lies between 25 and 10 pgxn, while a few conpanies are orientated AP00009151 -6 - towards accepting levels between 1 and 5 ppo. Although there is no. evidence whatsoever that even 1 pjm would be without adverse effects/ it is wrth remembering that workers were exposed only reoently to 2,0003/000 ppm. At these levels of exposure/ it is well known that a number of lesions and diseases were caused/ but with the present upgrading of cancer as the diffuse par excellencet other sccoetunes very serious diseases are forgotten; (3) that the recent interest to establish the actual levels causing cancer in es^osed workers, could be rather suspicious. Somebody would . surely be Interested in denonstrating that cancer occurs only at very high levels of e&qposure and that low levels are "safe". Bar 94 of the 196 chsnicals, there is unquestionable evidence of carcinogenicity in experimental animals. Far 89 of then, human exposure has been confirmed (Table IV) and again in the majority of cases/ it is occupational (Table V) For 41 chemicals / a limited carcinogenic activity has been found in experimental animals. For most of these chmicals, tasnan ejqxasure has been confirmed and, as before, in a large proportion it is occupational (Table VI). For 26 chemicals/ the available data were insufficient to reach any conclusion on their possible carcinogenicity in experimental animals, while for 18 the available data did not reveal a carcinogenic effect. In general, there were more experimental than epidemiological or case reports (Table VII). This can in part be explained fcy the higher cost and longer duration of hunan than animal studies, but it also reflects the greater eiphasis which for quite a long time was put on experimental rather than on human studies. AP00009152 -7- 3he case of recognized chanical carcinogens is (or at least should be) clear, as everybody agrees that hunan exposure to carcinogens roust be avoided, although disagreement exists on how, to What extent and how quickly this should be done. A different and major problem is the evaluation of the possible carcinogenic effect of a chanical to man in the absence of epidemiological studies car case reports. Of the 196 chemicals considered in the INC Monographs, there are 124 for which such & problem exists. For 15 of these {4,4'-methylene bis (2-efhloroaniline} (M3CA), BHC, dieldrin, DDT, chlorobenzilate, aniitrole, PCBs, CCI4, hydrazine, 1,1-dimethylhydrazine, ethyloie thiourea, o-dianisidine, beryllion, lead salts, 6-prqpiolactone) the world production figure is above 500 thousand kilograms a year. Present regulations recaomend a zero tolerance in food for chemicals for which experimental evidence of carcinogenicity exists. In so far as food additives are concerned, therefore, an extrapolation for public health purposes is carried out systematically with a procedure which cbviously inplies that experimental evidence of carcinogenicity is sufficient per ee to suggest carcinogenicity in man (Taratis et at. 1973)15. However, this cautious procedure, with which most people agree, has not been applied to other situations, and certainly not to chsnicals present in and around factories. In the literature there is an evident preoccupation of warning scientists about unduly extrapolating frcm experimental data to man and alphasis is, of course, put on the fallacy of iniwprati-ng toxicity data obtained in experimental animals as automatically indicating a danger for man. Very little emphasis, if any, if put on the in the opposite direction, that is, mistakes made when results obtained in animals were not taken as indicative of a possible danger to man. AP00009153 -8- There Is no evidence that a chemical which is carcinogenic to experimental animals will not in any circunstanoes produce tumours in man (Saffiotti 1973)16. Neither is there ary scientific criteria an which to base the usual argument that as it is inpossible to extrapolate frcrn. experimental data to man, experimental evidence of carcinogenicity has no value in attempting an assessment of a possible human risk. The fact is 4 that an obvious declaration, of impotence has been used for different purposes. There are data which indicate that experimental results can be taken as indicators of a possible human hazard and that measures should be taken to warrant an immediate control of the state of health of people -who are or who have been exposed, and to adopt immediate steps to reduce or possibly eliminate exposures until the results are carefully assessed. There is really no justification to wait for the proof that a chorale?i causes cancer in man before measures to avoid exposure are taken (Doll 1967)17. The example of bis (chlorcmethyl) ether and vinyl chloride well illustrate this statement*8(Table VIII). In fact, experimental evidence of carcinogenicity of the former compound existed in 1968 and was confirmed in 1969, but it was only in 1973, after a retrospective epidaniological study showed an excess of lung cancer in workers exposed to bis (chlorcmethyl) ether that measures to reduce exposure in the working environment were adopted. Similarly, for vinyl chloride, experimental evidence of carcinogenicity existed already in 1970 and was long preceded by the evidence of toxic effects of the same type in man and experimental animals* It was only in 1974, however, that measures for drastically reducing its acceptable concentration were adopted and only after a report on the occurrence of angiosarocma of the liver among workers exposed to vinyl chloride. AP00009154 In these two cases, a a successful prevention. - One of the discr^ancies of the present situation is that an. the one hand we accept that certain population groups are exposed to relatively high risks and that certain preventive measures are in sane instances adopted once the risk is detected on the basis of the epidsaiological evidence of an unusually high incidence of cancer. On the other hand, there are objections against the use in carcinogenicity testing of experimental models which will maximize the possible carcinogenic effect of a chemical under test (ani in particular the use of high dose levels) as if this were an improper procedure which would never reflect the human situation and would give misleading results. It is difficult to accept these objections because in most instances when a chemical has been found to be closely related to cancer in nan this was because the incidence was so high that it could be easily detected. The working environment, therefoa maximized the hazard to such a macroscopic effect that epidemiologists or alert physicians could not help but detect it. The hazard, however, is not necessarily limited to the workers involved in a particular manufacturing process: they are at the forefront of the risk, but this may expand far beyond the borders of the factories. The risk nay be relatively low or at least low enough that normal epidqniological methods are unable to detect it, even if the incidence of cancer related to a given chanical be numerically important as a large proportion of the population may be esqposed. The observations of a few cases of angiosarccxna of the liver in persons with no occupational exposure to VC, but who had lived for many years in the, proximity of factories utilizing polyvinyl chloride, and the AP00009155 - 10 - clustering of cases of mesothelicma In areas close to asbestos factories (Greenberg and Davies 1974)19, Illustrate well tills eventuality. -- Ihat preventive measures are successful in decreasing cancer risks is proven, and of course not only in fVY*ip4-|onTiy^-eposea people. Die raooval or at least drastic reduction of occupational exposures to hazardous chemicals may be obtained in the majority of cases by an inprovanant in manufacturing procedures. Ibese irproveients do not represent in general too severe a blew to the econcny of a factory, but just a marginal loss of profit. An example of the success which can be obtained in this way is the disappearance of the excess of nasal sinus and lung canoar in nickel workers in the UK arti Norway, who began their work after an industrial process had undergone major changes in order to eliminate exposure of workers to dust and funes (Doll et aU 1970, Pedersen et at. 1973)20*21. Another side of the same prcblen is the possibility of preventing or reducing the incidence of cancer in people who have already been exposed. Does prevention help in such a condition? According to Doll22, "the effect of stopping exposure to & carcinogen after a prolonged period of exposure is likely to vary with the nature of the carcinogen". It also depends, for a given carcinogen, on the different target organs, as was the case of tbe persistence of the risk of developing nasal cancer and the decreasing risk of developing lung cancer up to 40 years after cessation of exposure to nickel carbonyl (Doll 1970)20. In a nan-occiipatlonal situation, the high risk of lung cancer in heavy cigarette smokers decreased if exposure to cigarette smoke was discontinued but still remained higher than in people who had never smoked22. AP00009156 -11.- Cbce a chemical is marketed and produced in large amounts, the claim is often made that its vithdrawl would be an ocormic a* aae+w far-all, and that the reshaping of the manufacturing processes in order to protect workers zon exposure would increase the cost of production to impossible levels, of course, people who use these two arguments forget about the profit already made with the chemical. Cfte can therefore explain why certain industries look at long-term toxicity tests as procedures "to satisfy v&ums rather than provide data for safety evaluation" (Gehring et al. 1973)23. Another argument is that all present health regulations are taken at the expense of the manufacturers and -that this expense finally reverberates on the consumer (Gehring et al. 1973)23. Xt is therefore obvious that the manufacturers take it far granted that if the manufacturing process became more costly to satisfy the elementary protection, of the workers and the general population, the product would have to be sold at a higher price. AP00009157 SCMMMtf Tte International Agency for Research on Cancer has initiated a program!)e to evaluate the carcinogenic risk of chemicals to man. This programme is centered cn the production of monographs on individual chemicals, consisting of data on use ani production, carcinogenicity in experimental animals, epidaniological studies and case reports, and other biological data such as mstabolian and mutagenicity, and ending with a balanced evaluation of all the data made by an international group of experts. Chemicals to be surveyed for the preparation of monographs have 80 far been selected .among those for which seme evidence or suspicion of carcinogenicity in experimental animals and/or man exists and for which human exposure is knom to occur. Of the 196 compounds already evaluated, 17 have been found to be associated with cancer in man. Ninety-four cxitpourxSs were definitely carcinogenic in eoqaerixnent&l animals and 41 were shown to have a limited carcinogenic effect in experimental animals. A ntstlber of the chanicals found carcinogenic in experimental animals are produced in very large quantities. The type of exposure to the 17 chemicals found carcinogenic to man was occupational for 14, medicinal for two and dietary for one. AP00009!58 1. MIRRAY, J.I*. 6 L.M. astftx,. 1974. Inpact of cancers years of life lost doe to cancer mortality. J. Natl. Cancer Inst. 52s 3-7. . * 2. SIEGEL, 6.S. 1966. An American dilanna - the periodic health examination. Arch. Environ. Health 13: 292-295. 3. Prevention of Cancer. Wld. Hlth. Ocg. techn. Rep. Ser. HO. 276, Geneva 1964. 4. HADDOW, A. 1967. Proceedings of the 9th International Cancer Congress, Ttokyo 1966. R.J.C. Harris, Ed. UICC Monograph Series Vol. 9i 111-115. Springer-Verlag. Berlin, Heidelberg, Hew York. 5. BOYIAHD, E. 1969. The correlation of experimental carcinogenesis and cancer in nan. 6. HIGGDGCN, J. Pzogr. exp. Timor Res. 11: 222-234. t7 J* * 4? 1968. Present trends in cancer epidemiology. Proc* Eighth Canadian Cancer Conf., Honey Harbour 1968: 40-75. Pargsmon Canada. 7. IARC Monographs on the Evaluation of Carcinogenic Risk of Ghonicals to Man. Vol. 1. IARC, lyon, 1972. 8. IARC Monographs on the Evaluation of Carcinogenic Risk of to man. Vol. 2: Sane inorganic and organcmetallic ccnpounds. IARC, lyon, 1973. 9. IARC Monographs an the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol. 3: Certain polycyclic aronatic hydrocarbons and heterocyclic corpounds. IARC, Lyon, 1973. j i ! I i j AP00009159 -14 -- 10. IARC Manographs on the Evaluation of Carcinogenic Risk of Chemicals to Han* Vol. 4: Seme arcmatic amines, hydrazine end related substances, N-nitroso oorpounds and miscellaneous alkylating agents. IARC, Iycn, 1974. 11. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vbl. 5: Seme organochlorine pesticides. IARC, Lyon, 1974. 12. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol. 6: Sex hormones. IARC, lyon, 1974. 13. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Vol. 7: Sene anti-thyroid and related substances, nitrofurans and industrial chemicals. IARC, Lyon, 1974. 14. IARC Monographs, on the Evaluation of Carcinogenic Risk of. Qiemicals to Man. Vbl. 8: Sane aranatic azo oenpounds. IARC, Iyon, 1975. 15. TOMATIS, L., C. PAKEENSK* & R. MDOTESANO. 1973. The predictive value of mouse liver turour induction in carer nogenicity testing - a literature survey. Int. J. Cancer 12: 1-20. 16. SATFIOin, U. 1973. Ocrments on Idle scientific basis for the "Delaney Clause". Preventive Med. 2: 125-132. 17. DOLL, R. 1967. Prevention of cancer: %pointers frerrt epidaniology. Whitefriars Press, London & Tonbridge. 18. TQ4ATIS, L. 1975. The validity of long-tenn bioassays in carcino genicity testing. Froc. XXth international Cancer Oongr., Florence, 1974 (in press). AP00009160 - 15 19. GREENBERG* M. & T.A. U/HD DAVIES. 1974. Mesothelioma register 1967-68. Brit. J. Industrial Med. 31* 91-104. 20. DGIXi, R., L.G. MORGAN & F.E. SFKTflFTR. 1970. Cancers of tiie lung and nasal sinuses in nickel vrorkers. Brit. J. Cancer 24 : 623-632.* 21. `B&SEESBS, ., A.C. B03EWEIT & A. ANDERSEN. 1973. Cancer of respiratory organs among workers at a nickel refinery in Norway. Int. J. Cancer 12: 32-41. 22. DOLL* R. 1973. Age. In Host Envirorment Interactions in tiie Etiology of Cancer in Man. R. Doll i I. Vodopija, Eds.: 39-48. IARC Scientific Pub. No. 7, FIC Proc. No. 18. IMC, Zyon. 23. GEHRING/'P.'J.* V.K. ROWS & S.B. McCOT.TIglER.' 1973. Toxicology: cost/time. Pd. Cosmet. Toxicol. 11: 1097-1110. AP00009161 * Table I HUMBER OF CHEMICALS EVALUATED 196 NUMBER OF CHEMICALS CARCINOGENIC TO MAN 17 AP00009162 TABLE 11 CHEMICALS FOR WHICH CARCINOGENICITY TO MAN OR A STRONG SUSPICION OF CARCINOGENICITY TO MAN HAS BfefcN FOUNO COMICAL AFUTOXIN? 4-AMINOBIPHENYL ARSENIC COMPOUNDS ASBESTOS (CROCIDOLITE, AMOSITE & CHRYSOTILE) AURAMINE BENZENE BENZIDINE BIS(CHLOROMETHYL)ETHER CADMIUM OXIDE & SULPHATE CHROMIUM (CHROMATE PRODUCING INDUSTRIES) HAEMATITE (MINING) 2-NAPHTHYLAMINE NICKEL (NICKEL REFINING) N ,N-B IS (2-CKL0R0ETHYL)2- NAPHTHYLAMINE SOOT and TARS STILBOESTROL VINYL CHLORIDE rm op exposure TARGET ORGAlt(S) ROUTE OP EXPOSURE EXPOSURE LEVEL Dlefcat*y Occupational Occupational, medicinal Occupational Occupational Occupational Occupational Occupational Occupational Occupational LIVER BLADDER SKIN, 7LUNG LUNG * PLEURAL CAVITY GASTROINTESTINAL TRACT BLADDER BONE MARROW BLADDER LUNG PROSTATE, LUNG LUNG Oral Inhalationi oral Oral, Inhalation 5-15 pg/kg bw/day Unknown Unknown Inhalation, oral - Unknown Oral, Inhalation, Inhalation, sklri Inhalation, oral, Inhalation Inhalation, oral Inhalation skin skin Unknown Unknown Unknown Unknown Unknown Unknown Occupational Occupational Occupational Medicinal LUNG {BLADDER' ' NASAL CAVITY, LUNG BLADDER Inhalation Inhalation, oral Inhalatlon Oral \ Unknown Unknown Unknown 4-350 g (total dose) Occupational Environmental Medicinal Occupational LUNG SKIN (SCROTUM) VAGINA, UTERUS LIVER, BRAIN, LUNG Inhalation Skin contact Oral Inhalation, skin ? 320 ug BaP/hr Unknown 1.5-150 mg/day 50-3000 ppm ,w * AP00009163 TABLE III CHEMICAL CARCINOGENS IN MAN AND THEIR EFFECTS ON EXPERIMENTAL ANIMALS cnmicAL SPECIES TARGET ORGAN(S) TARGET ORGAN(S) MAS AFLATOXIN - 4-AMINOBIPHENYL ARSENIC ASBESTOS AURAHINE BENZENE BENZIDINE BIS(CHLOROMETHYL)ETHER CADMIUM OXIDE & SULPHATE CHROMIUM COMPOUNDS HAEMATITE 2-NAPHTHYLAMINE NICKEL COMPOUNDS N,N-BIS(2**CHLOROETHYL)2- NAPHTHYLAMINE SOOT and TARS STILBOESTROL VINYL CHLORIDE Rat. trout, duck Rat. mouse Mouse, rabbit, dog Newborn mouse, rat Mouse* rat. dog Mouse, rat Mouse, rat Mouse Mouse, rat. hamster Dog Mouse, rat Rat Mouse, rat Guinea pig. mouse, hamster House Rat. rabbit Hamster, dog. monkey Mouse, rat Mouse Rat Mouse, rat Mouse Rat Hamster Squirrel. monkey Mouse, rat* hamster LIVER. STOMACH, INTESTINE, KIDNEY LOCAL. LIVER. LUNG. TRACHEA BLADDER LIVER, MAMMARY GLAND, INTESTINE Negative LUNG, PLEURA, PERITONEUM LUNG, LOCAL, INTESTINE 7LEUKAEMIA LIVER BLADDER SKIN, LOCAL, LUNG LOCAL, TESTIS LUNG, LOCAL Negative / LIVER, LUNG No effect BLADDER LOCAL LUNG LOCAL SKIN, LOCAL, LUNG, STOMACH* MAWARY GLANO, LYMPHORETICULAR TISSUE, TESTIS, VAGINA HYPOPHYSIS, MAMMARY GLAND, YURINARY BLADDER KIDNEY UTERINE SEROSA LUNG, LIVER, KIDNEY, ZYMBAL GLAND Produced by some polycyclic hydrocarbons tested separately YLIVER BLADDER SKIN. LUNG, LIVER LUNG, PLEURA, INTESTINE BLADDER BONE MARROW BLADDER LUNG PROSTATE. LUNG LUNG LUNG BLADDER NASAL CAVITY, LUNG BLADDER SKIN (SCROTUM), LUNG VAGINA. UTERUS LIVER, LUNG, BRAIN * ' AP00009164 Table IV NUMBER OF CHEMICALS CARCINOGENIC IN EXPERIMENTAL ANIMALS ONLY 94 HUMAN EXPOSURE KNOWN FOR 89 OCCUPATIONAL EXPOSURE KNOWN FOR 78* MEDICINAL EXPOSURE KNOWN FOR 16 GENERAL ENVIRONMENTAL EXPOSURE KNOWN FOR 49* including 15 polycyclic aromatic hydrocarbons present In soot, tar and exhaust fumes AP00009165 Table V CHEMICALS CARCINOGENIC IN EXPERIMENTAL ANIMALS ONLY Ocrapuund 1 Acetamide 2 2-Ami no-5-(5-n1tro-2- furyl)-l,3,4-thiadiazole 3 Ami trole 4 Aramlte* 5 Benz(c)acr1d1ne * 6 Benz(a)anthracene * 7 Benzo(b)fluoranthrene * 8 Benzo(j)f1uoranthene * 9 Benzo(a)pyrene * 10 Benzo(e)pyrene * n Beryl ore 12 Beryllium 13 Beryllium oxide 14 Beryllium phosphate 15 Beryllium sulphate 16 BHC (technical grades) 17 Calcium chromate 18 Carbon tetrachloride 19 Chlorobenzllate 20 Chrysene * 21 Cycasin 22 ODD 23 DDE 24 DDT 25 Diazomethane * present In soot and tars EXPOSURE General Unkncwn . Occupational Medicinal , tevironnental . . .... /+-. V. ...................... 4 .4 . .4................. ............ ..............................4 ..................... +? + + 44 +4 + 4 +4 +4 + + + + 44 4 44 4 4? 44 '4 4 4 -V'-'"'- + + !' \ v .4 44 4 fL: V : AP00009166 CHEMICALS CARCINOGENIC IN EXPERIMENTAL ANIMALS ONLY (contd. ) 2 ... Oanpound 26 D1benz(a,h)acr1dint * Unknown .............. ----------. EXPOSURE------ nnraipwf-irmal .... Medicinal . General Erwlromervfcal _. -..; v.+ .......... .. 27 D1benz(atj)acridine * . ................... ................ ............ + 2S 01benz(a,h)anthracene * ...+ .................. ............ + 29 7H-Dibenzo(c,g)carbazo1e * + 30 D1benzo(a,e)pyrene * 31 D1benzo(a*h)pyrene * . 32 Dlbenzo(a,i)pyrene * + 33 S^-Dichlorobenzidine + 34 Dieldrin ++ 35 1,2-Oiethylhydrazine 36 Diethyl sulphate + 37 Dlhydrosafrole ++ 38 3,3'-D1methoxybenz1dine (o-DlanlsIdine) + 39 trans-2[(Dimethylami no) methyl1m1no]-5-[2-(5-nitro2-furyl)vinyl]-l,34- oxadiazole + 40 33'-D1inethy1benzid1ne (o-Tol idlne) + 41 1,1-Dimethylhydrazlne 42 1,2-Dimethylhydrazine +7 43 Dimethyl sulphate + 44 Ethinyloestradiol ++ 45 Ethyl methanesulphonate + 46 2-(2-Formylhydrazino)-4(5-n1tro-2-furyl)th1azole 47 Hydrazine +? + 48 Indeno(!,2,3-cd)pyrene * + + * present in soot and tars AP00009167 CHEMICALS CARCINOGENIC IN EXPERIMENTAL ANIMALS ONLY (cont'd.) 3 Canpourd Unknown EXPOSURE Occupational Medicinal General Enviroixnentalj 49 Isonlcotlnlc acid hydrazlde .......4........... ` .-. , . .+............ 50 Isosafrole + 51 Lead acetate ++ 52 Lead phosphate + 53 Lead subacetate + 54 Lindane + . .. - + 55 Mestranol ++ 56 Methylazoxymethanol acetate 57 4,4'-Methylene bis (2chloroanillne) + 4 58 4,4`-Methylene bis (2methylanlllne) + 59 Methyl methanesulphonate 60 N-Methyl-N`-nltro-Nnitrosoguanidlne 4 + 61 Mi rex + .4 62 5-(Morphol1nomethyl)-3[(5-nltrofurfurylldlne)amlno]-2-oxaz ol1d1none +4 63 4-Nltrobiphenyl + 64 1[(5-N1trofurfurylIdene)amino]-2-1mldazol1d1none +4 65 N-[4-(5-Nitro-2-furyl)-2thiazolyllacetamlde 4 66 H-HItroso-dl-n-butylamine + 67 N-NItrosodiethylamlne 4 68 N-NItrosodimethylamine 69 Nltrosoethylurea 4 4 70 Nitrosomethylurea .4 AP00009168