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Chapter 5 EPIDEMIOLOGIC ASPECTS OF EXPOSURE TO AROMATIC AMTNES The studies of Case et al.~1954a,b) in Great Britain provided the first systematic evidence of the carcinogenicity of specific aromatic amines. More recently, Clayson (1976 I, Clayson and Garner (1976), and the working group for the International Agency for Research on Cancer (1972, 1974a, 1978a) have concluded that bladder cancer is caused in workers who manufacture and use 2-naphthylamine, benzidine, and 4-aminobiphenyl. It is difficult to identify persons exposed only to 1-naphthylamine, auramine, magenta, and N-phenyl-2-naphthylamine (International Agency for Research on Cancer, 1972, 1974a, 1978a); thus, it has not been possible to determine whether any one compound alone is carcinogenic in humans. It is generally accepted that aniline has not been shown to cause bladder cancer in humans (International Agency for Research on Cancer, 197 4a) . The da ta f rom the stud ies of Case et al. are presented in Table 5-1. The largest increase in fatalities occurred among men exposed to a mixture of compounds. Increased mortality rate is statistically significant and has been interpreted as causal for 2-naphthylamine and benz idine . The increased mortal ity rate among workers exposed to 1-naphthylamine is complicated by the fact that 1-naphthylamine contains 4-10% of 2-naphthylamine. 102

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Table 5-1 Observed and Expected Deaths from Bladder Cancer According to , , . ~ _clf to Substancesa #D Class Aniline without benzidine, naphthylamine, 1 magenta, or auramine outact Ani line with magenta contact An iline with auramine contact Benz idine 1-Naphthylamine 2-Naph thylamine Mixed exposure Observed Expected 3. 6 10 6 26 81 0.83 0.13 0.45 0.72 0.70 0.30 1.48 a From Case et al., 1954a,b, with permission. ~ _ _ Expected numbers derived from age-time specific mortality rates for BE itish ma les . 103 i

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The excess mortality among persons having had contact with magenta or auramine has been interpreted as indicating that bladder cancer is associated with the manufacture of these chemicals, not necessarily with the substances themselves (Case and Pearson, 1954b). Melick _ al. {1971) concluded that 4-aminobiphenyl is carcinogenic in humans from their study that 53 of 315 men exposed to the substance developed bladder cancer. Studies of persons in the chemical and rubber industries, who were exposed during the manufacture and use of the compounds, have provided evidence that aromatic amines are carcinogenic. Benzidine and naphthylamines are used to manufacture dyes; naphthylamines and 4-aminobiphenyl are antioxidants used to manufacture rubber. Persons who were exposed only to benzidine, 2-naphthylamine, or 4-aminobiphenyl, and who developed bladder cancer can be identified; from this, a causal association between exposure to these chemicals and bladder cancer has been derived. Another reason the above aromatic smines are accepted as a cause of bladder cancer in humans is that the rate of bladder cancer among those exposed is many times greater than the rate among persons not exposed. Not only is it relatively straightforward to detect the increased cancer incidence among a comparatively small group of 104

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exposed persons, it is also clear that apart from the possible effects due to cigarette smoking and certain drugs no other cause of bladder cancer is responsible for the increase. His situation is in contrast to the usual one in epidemiology where, among a group of exposed persons, the rate of the disease of interest is elevated by perhaps only 50-100 %. Also, it is of ten impossible to el iminate or control for the possible ef feats of other causes of the disease. Tables 5-2 through 5-S contain data on mortality and incidence of cancer in the rubber industry from 1940 to 1973. These data were assembled by Monson (1978 ~ from studies of rubber war kers in the United States and Great Britain (And jelkovich et al., 1976; Fox and Collier, 1976; McMichael et al., 1976; Monson and Fine, 1978), who died between 1964 and 1974. In the united Kingdom, the rubber industry used as a rubber-compounding ingredient a mixture containing a condensate of acetaldehyde with 1-naphthylamine and 2-naphthylamine (Nonox S). The discovery that there was an increased incidence of bladder cancer mortality in those who worked with these compounds {Case and Hosker, 1954 ~ and an associated increased mortality rate in electric cablemakers (Davies, 196S) using contaminated rubber led, in 1949, to the abandonment of the use of Nonox S and other related bladder carcinogens by the rubber industry. Fox and Collier (1976 ~ reported on a survey designed to determine whether the action taken in 1949 had removed the bladder cancer hazard from the industry, but 105

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Table 5-2 Cha ranter ist ics of Four Groups of Male Rubber Workersa Number of Initial Group Locat ion Ethn ic ity Workers Ages All 6, 678 A Ak ran 40-84 10 Min imum Years Emploved Years Fol low' 1964-' B Great Br its in All 40, 867 35-65 1 1968- C Akron White 13, 571 20-79 5 1940- D Akron Ah ite 8, 418 40-84 10 1964- a From Monson, 1978, with permission. 106

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Table S-3 General Mortality Among Four Groups of Male Rubber Wor kerea Group A _ Group B Group C Group D Cause of dea thsb ObsC Id Obs ~ Obs ~ Obs ~ All causes 1873 1798.5 4079 4055.7 5079 6186.9 2373 2524.5 All ca ncer s 351 336.9 1256 1106.0 980 1046.4 457 456.3 Circulatory disease 953 940.0 1999 2022.6 2938 3482.8 1311 1351.7 External causes 59 Res idual 83 ~ 6 118 138 ~ 4 278 446 ~ 8 91 111 e 0 420 438 ~ 0 706 788 ~ 7 833 1210 ~ 9 514 605 ~ 5 a From Monson, 1978 ~ with permission. Expected numbers based on mortality rates for A - O.S males B - English and Welsh males C - U.S white males D - U.S white males b Slight differences exist in classification c Observed. d Expected. : of ca use of dea th . 107

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Table 5-4 Mor ta 1 from Specific Types of Cancer Among Four Groups of Male Rubber Workersa ID Group A Group B Group C Group D Type of Cancers Obs . c A. c Obs . Exp. Obs . Ad. Obs . Exp . Stomach 39 20 .9 153 122 .3 98 93 .9 34 27 . 6 Large Intestine 39 31.8 e e 104 103.1 53 45. 7 Lung 91 109.3 585 493.5 234 253.1 116 139. 8 Prostate 49 34 .4 e e 82 89 .0 50 45 . 9 Bladder 9 12.3 60 38.9 48 39.5 21 18.1 Leukemia 16 12.5 28 23.3 5S 43 .0 25 18.1 From Monson, 1978, with permission. b Expected numbers based on mortality rates for A - U. S males B - English and Welsh males C - U. S. white males D - U. S. white males C 0bs. = Observed Exp. = Expected d Slight differences exist in classif ication of type of cancer . e Da ta not 9 iven . 108

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Table 5-5 Observed and Expected Numbers of Bladder , . Cancers in Selected Work Areasa _ Group Work Area Observed Expected A Receiving and shipping 2 0.7 Tire bu ilding 1 2 .5 B Tires 20 15.3 C Warehouse/shipping 8 2.6 Tire building 9 4.8 D Product fabr icationb 5 2 . 6 a From Monson, 1978, with permission. Product fabr ication is subset of tire building. 109

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they re f ra ined f rom reach ing a conclus ion because the number of tumors occurring in workers employed after 1949 still bad not reached a sufficient level for a statistically valid comparison. Table 5-3 shows that there is little to suggest a substantial increase in fatal cancer among rubber workers.^ The greatest increase in bladder cancer has been observed among British rubber workers (Table 5-41. However, compared to the data in Table 5-1, the increment is relatively small. In the U.S. studies, it has not been possible to obtain detailed exposure histories as did Case et al.(l954a, 1954b). It was only possible for the investigators to group workers on the basis of where they worked within the factory. The da ta in Table 5-5 show the observed and expected number s among men who make tires and who have close contact with uncured rubber. There is minimal evidence that these men have an increased incidence of bladder cancer. Also, among men who make rubber and who might be expected to come into contact with antioxidants such as 2-naphthylamine or phenyl-2-naphthylamine, no increased incidence of fatal bladder cancer was identif led. On balance, there is minimal evidence of an increased incidence of bladder cancer among American rubber workers . Rather than using 1- or 2-naphthylamine as antioxidants, the American rubber industry has used phenyl-2-naphthylamine. Ingestion of phenyl-2- naphthylamine has been shown to be associated with the appearance of minimal amounts of 2-naphthylamine in the urine 110

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(Kommer and Tordoir, 1975) . Among an unknown number of men who worked for at least 15 years with a phenyl-2-naphthylemine autoclave, two developed bladder cancer (Monson and Fine, 1978) . HAIR DYES - A number of aromatic amines are used in the manufacture of hair dyes. It has been speculated that users and appliers of hair dyes might be at an increased r isk of developing cancer; however, it has not been possible to assess with certainty the effects on humans of specific substances used in hair dye. mese are not the only substances to wh ich humans are exposed, and therefore it is not pass ible to identify persons with isolated exposure . Furthermore, since the adverse effect most postulated is cancer, any substance in ha ir dyes leading to cancer in either appliers car users will require many years of observation before the effect can be detected. Unless the adverse ef feet is very strong, it may not be possible to gather sufficient data on which to base an association. Volume 16 of the TARC Monographs of the Evaluation of Carcinogenic Risk of Chemicals to Humans (International Agency for _ _ Research on Cancer, 1978b), presents a general review of the data available on the exposures of humans to ha ir dyes. For users, the results were judged equivocal. There was Snore evidence for an increased risk of cancer at certain sites (bladder, lung, larnyx) for persons with occupational exposure. However, further epidemiologic studies were recommended before any firm conclusions are drawn. 111

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Repor ts since that review have not provided more conclusive data. In a followup study of cosmetologists (Wairatb, 1978}, breast cancer occurred less often than was expected, and leukemia occurred more often than expected. Four recent case~control studies provided minimal evidence for an excess incidence of breast cancer. Crude relet ive r isks between ha it dye use and breast cancer were O .83 (Shore et al. , 1979), 1.06 tHennekens et al., 1979), l.ll (Stavraky _ al., 1979), and 1.28 (Nasca et al., 1980~. Although stronger associations were observed between subsets of each study group, all authors cautioned against overinterpretation of the results of each ind iv idual study . In summary, the epidemiologic data relating ha ir dyes and cancer are inconclusive. There is some suggestion that persons with occupational exposure to hair-care products are at increased risk of developing cancer and less evidence that users of hair dyes develop such cancer. These inconclusive studies need to be balanced by the positive results for carcinogenicity and mutagenicity found for a number of the ingredients in ha ir dyes. DRUGS l Phenacetin - Among a group of employed Swiss women, those who were regular users of compounds containing phenacetin developed increased serum creatinine levels and low urine specific gravity in comparision to those of controls (Dubach _ al., 1975; International Agency for Research on Cancer, 1977' . Abuse of analgesics has been reported to 112

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be associated with the development of renal papillary necrosis (Bengtsson _ al., 1978~. In a number of clinical and epidemiologic studies, heavy users of phenacetin-containing compounds have repor ted an inc rea sed inc idence of cancer of the k idney and of the bladder (Fokkens, 1979; International Agency for Research on Cancer , 1977~. On the basis of these reports, it seers prudent to associate heavy phenacetin use with k idney and bladder disease in humans . Ch loranapha 2 ine Chlornapha z ine (N. N-b is (2-chloroethyl} -2-naphthylamine ), a derivative of 2-naphthylamine, has been used to treat persons with polycythemia and Hodgkin 's disease. It is generality accepted that this antineoplastic agent has led to the development of bladder cancer in humans (Hoover and Fraumeni, 1976; International Agency for Research on Cancer, 1974a; Lower and Bryan, 1979; Thiede and Christensen, 1975; Thiede et al., 1964~. Tobacco Cigarette smoking is the major cause of lung cancer and is associated with the increased incidence of many types of cancer, including bladder cancer (Hammond, 1975). Arylamines and n itrosamines occur in tobacco smoke (Lower and Bryan, 1979 ~ . Although the presence of these amines may cause bladder cancer in smoker s, the 1 ink a t the moment is tenuous . 113

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Amitrole (3-amino-1, 2, 4-tr iazole ~ . Amitrole residues were found in cranberries in the United States in 1959. Sale of cranberr ies and cranberry products from 1958 and 1959 crops were prohibited because Amitrole produced thyroid tumor e in rats (International Agency for Research on Cancer 1974b). In Sweden, amitrole was used as an herbicide from the 1950's to the 1970's (Axelson et al., 1974) . Increased cancer incidence and mortality rates have been reported among Swedish railway workers who sprayed amitrole and the chlorophenoxyacetic acids (2,4-D and 2,4,5-T) (Axelson et al., 1974 , 1979 ~ . Among 348 workers , 18 cases of cancer occurred, in comparision to the ll.9 expected from the Swedish incidence rates . Because of the dif f iculty in separating the possible effects of amitrole and the phenoxy acids, and because many different types of cancer occurred among those exposed, it is dif f icult to judge whether this excess may be causally related to amitrole exposure. RECOMMENDATIONS FOR EPIDEMIOLOGIC S=DY OF NOETIC NINES Ha ir dyes and nitrosamines are the substances that are of most current interest as to their potential carcinogenicity in humans. Nitrosamines are discussed in more detail in a companion report on al iphatic amines . Hair dyes are widely used, and case-control studies have ra ised suspicions that they are associated with cancer of the breast and other sites. Nitrosamines are recognized to be potent 114

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carcinogens in animals and are present in low concentrations in many substances to Which human'; are exposed. However, there is currently little evidence upon which to judge their carcinogenicity in humans. me only realistic study design to evaluate the carcinogenicity of these substances is the prospective follow-up study. To study the effects of hair dyes, women should be interviewed to determine their life-time use of hair dyes and followed for 5-20 years to measure the rate of occurrence of cancer . For nitrosamines, persons exposed to relatively high levels in the workplace should be identif led, categor ized as to level of current (and future} nitrosamine exposure, and followed from 20 to 40 years. Retrospective studies are not as likely to provide def initive information on carcinogenicity in humans. In case~control studies of cancer, the recollection of hair dye use is subject to a high degree of recall bias. In retrospective cohort studies of persons exposed to nitrosamines, there is a very imprecise measurement of exposure to n i trosamines . Also, cross-sectional or short-term prospective cohort studies can be conducted on workers exposed to nitrosamines . Here, the health outcome would be either acute illness or physiologic abnormality. These studies would provide an initial evaluation of the assoc iation between exposure to nitrosamine and human health . However, they would not be expected to address carcinogenicity. 115

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The epidemiologic evaluation of the possible head th effects from exposure to low levels of aromatic amines as well as to other substances may not be pass ible . lo the extent the t d isease among an exposed group is increased relatively little above background, perhaps less than 50%, the excess may not be detectable against the background variability. One of the best ways to minimize this variability is to conduct prospective follow-up studies, so that at least the measure of exposure is as precise as possible. However, if this strategy is adopted, long-term follow-up is the price that must be paid. 116

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References Epidemiology And jelko~rich, D., J. Taulbee, and M. Symons. 1976. Mortality experience of a cohort of rubber workers, 1963-1973. J. Occup. Med. 18: 387-394 . . ~ Axelson , O., C. Edl ing , H. Kl ing, K. Anderson, C. Hogstedt, and L. Sundell. 1979. Uppdatering av mortaliteten has bek ampn i ng smede l sexpone r ade bane rbe tare . Lake r t idn ingen 76: 3505-3507 . Axelson, O., and L. Sundell. 1974. Herbicide exposure, mortality a nd tumor i no idence . ra i lroad workers . An epidemiological investigation on Swedish Work Environ. Health 11: 21-28. 8engtsson , U., S. Johansson , and L. Angervall . 1978. Malignanc ies of the ur inary tract and the ir relation to analgesic abuse. Kidney Int. 13:107-113. Case, R.A.M., and M.E. Hosker . 1954. Tumour of the urinary bladder as an occupational disease in the rubber industry in England and Wales. Br. J. Prev. Soc. Med. 8: 39-50 . 117

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Case, R.A.M., M.E. Hosker, D.B. McDonald, and J.T. Pearson. 1954a. Tumours of the ur inary bladder in workmen engaged in the manufacture and use of certa in dyestuff intermediates in the British chemical industry. Part I. The role of aniline. benz idine, alpha-naphthylamine, and beta-naphthylamine. Br . J. Ind. Med. 11: 75-104 . Case, R.A.M., and J.T. Pearson. 1954b. Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuf f intermed fates in the Br itish chemical industry. Part II. Further considerations of the role of aniline and of the manufacture of auramine and magenta (fuchsine) as possible causative agents. Br. J. Ind. Med. 11: 213-216. Clayson, D. B. 1976 . Occupational bladder cancer . Prev. Med. 5: 228-244 . Clayson, D.B., and R.C. Garner. 1976. Carcinogenic aromatic amines and related compounds. Pp.366-461 in C.E. Searle, ed. Chemical Carcinogens. ACS Monograph 173. Amer ican Chemical Society, Washington, D.C. Davies, J.M. 1965 . Bladder tumours in the electr ic-cable industry. Lancet 2:14 3-146 . 118

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Dubach, U.C., P.S. Levy, B. Rosner, H.R. Baumeler, A. Muller, A. Peter, and T. Ehrensperger. 1975. Relation between regular intake of phenacetin~containing analgesics and laboratory evidence for urorena 1 disorders in a work ing female population of Switzerland. Lancet 1: 539-543. Fokkens, W. 1979. Phenacetin abuse related to bladder cancer. Environ. Res . 20 :192-198 . Fox, A.J., and P.~. Collier. 1976. A survey of occupational cancer in the rubber and cablemaking industries: Analysis of deaths occurring In 1972-74. Br. J. Ind. Med. 33: 249-264. Hammond, E.C. 1975. Tobacco. Pp. 131-138 in J.F. Fraumeni, Jr., ed. Persons at High Risk of Cancer ; An Approach to Cancer Etiology and Control. Academic Press, New York. Hennekens, C.H., F.E. Speizer, B. Rosner, C.J. Bain, C. Belanger, and R. Peto. 1979. Use of permanent ha ir dyes and cancer among reg istered nurses. Lancet 1 :1390-1393 . Hoover, R., and Jew. Fraumeni, Jr. 1975. Drugs. Pp. 185-199 in J.F. Fraumeni, Jr., ed. Persons at High Risk of Cancer ; An Approach to Cancer Etiology and Control. Academic Press, New York. 119

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International Agency for Research on Cancer. 1972. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Volume 1. International Agency for Research on Cancer, Lyon. 184 PPe International Agency for Research on Cancer. 1974a. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemical to Man. Volume 4. Some Aromatic Amines, Hydrazine and Related Substances, N-Nitroso Compounds and Miscellaneous Alkylating Agents. International Agency for Research on Cancer, Lyon. 286 pp. International Agency for Research on Cancer. 1974b. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Volume 7. Some Anti-Thyroid and Related Substances, Nitrofurans and Industrial Chemicals. International Agency for Research on Cancer, Lyon. 326 pp. International Agency for Research on Cancer. 1977. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Volume 13. Some Miscellaneous Pharmaceutical Substances. International Agency for Research on Cancer, Lyon. 255 pp. International Agency for Research on Cancer. 1978a. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Volume 16. Some Aromatic Amines and Related Nitro Compounds--Hair Dyes, Colouring Agents and Miscellaneous Industrial Chemicals. International Agency for Research on Cancer, Lyon. 400 pp. 120

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International Agency for Research on Cancer. 1978b. On the Evaluation of the Carcinogenic Risk of Chemicals to IARC Monogr aphs Humans. Volume 17. Some N-nitroso compounds. International Agency for Research on Cancer, Lyon. 365 pp. Runner, R., and W.F. Tordoir. 1975. (PBNA), another carcinogenic agent? 53: 415-419. Lower, G.M., and G.T. Bryan. 1979. Phenyl-be tanaphthylamine Ti jdschr . Soc . Geneeskd. Etiology and carcinogenesis: Natural systems approaches to causality and control. Pp. 29-53 in N. Javadpour, ed. Pr inciples and Management of Urologic Cancer . Williams and Wilkins, Baltimore . McMichael , A. J., R. Spir tas , J. F. Gamble , and P.M. Pusey. 1976. Mortality among rubber workers: Relationship to specific jobs. J. Occup. Med . 18 :178-185 Melick, W.F., J.J. Naryka, and R.E. Kelly. 1971. Bladder cancer due to exposure to para-aminobiphenyl: A 17-year follow-up. J. Urol. 106: 220-226. Monson, R. R. 19 78 . Ef feats of industr ial environment on health . Environ. Law 8: 663-700 . 121

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Monson, R.R., and L.J. Fine. 1978. Cancer mortality and morbidity among rubber workers. J. Natl. Cancer Inst. 61 :1047-1053 . Nasca , P.C., C.E. Lawrence, P. Greewald, S. Chorost, J.T. Arbuckle, and A. Paulson. 1980. Relationship of hair dye use, benign breast disease, and breast cancer . J. Natl. Cancer Inst. 64: 23-28. Shore, R.E., B. S. Pasternack , E.U. Thiessen, M. Sadow, R. Forbes, and R. E . Alber t. 1979 . A case-control study of ha ir dye use and breast cancer. J. Natl. Cancer Inst. 62: 277-283 . Sta~,raky, K.M., E.A. Clarke, and A. Donner. 1979. Case-control study of ha ir dye use by patients with breast cancer and endometrial cancer. J. Natl. Cancer Inst. 63: 941-945. Thiede, T., E. Chievitz, and B.C. Chr istensen. 1964 . Chlornaphaz ine as a bladder carcinogen. Acta Med. Scand. 175: 721-725 . Thiede, T., and B.C. Christensen. 1975. induced by chlornaphaz ine treatment. in Danish; English Summary; . 122 Tunours of the bladder Ugeskr . Laeg. 137: 661-666