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EXECUTIVE SUMMARY Aromatic amines and compounds related through metabolism are used widely in industry. AS a result of such applications, they are also dispersed into the environment, thereby creating a potential for human exposure. Four aromatic amines are known to lead to ur inary tract cancer in exposed humans, and some are also responsible for the induction cuff methemoglobinemia. Some other structurally similiar amines are carcinogenic to one or more tissues in laboratory animals. His report summarizes the key information concerning the occurrence, analysis, and toxicology of the aromatic amines and then considers six specif ic amines in detail. H I STORICAL PERSPECTIVE Aromatic amines compr ise one Of the ma jor groups of carcinogens. In 1895 Rehn reported that four workmen, three of whom were employed at a single plant manufacturing magenta (fuschin) from crude, coT'unercial aniline, appeared at his Olin ic with bladder cancer . He cor rectly deduced that these comparatively rare tumors were associated with the workers' occupation. Hueper (1942) suggested that a limited number of aromatic amines were human bladder carcinogens in humans. Case and his colleagues {1954} confirmed this finding in their classic investigation of the British chemical industry. Hey demonstrated that 2-naphthylamine, 1

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benzidine, and 1-naphthylamine, contaminated with between 4% and 1096 of the 2-isomer, were carcinogenic in the human bladder. Melick and his associates (1955, 1971) also showed that 4-aminobiphenyl (xenylamine) was a potent carcinogen in the bladders of those occupationally exposed and of users. The only other aromatic amine for which there is significant evidence of probable carcinogenicity in humans is 4-ethoxyacetanilide (phenacetin), which was a major component of the analgesics consumed in excessively large quantities by certa in well-defined populations. These exposed populations developed renal papillary necrosis and renal pelvic and bladder cancer (Bengsston et al., 1968; Rathert et al., 19731. Two consequences followed the identification of bladder carcinogens in occupationally exposed humans. First, the manufacture and use of 4-aminobiphenyl and 2-naphthylamine have, for all practical purposes, been phased out, although benzidine continues to be manufactured and used, even in the United States. Traces of a variety of aromatic amines, including 2-naphthylamine, still occur in the environment as the result of combustion of organic materials, including cigarettes. Second, there has been a ma jor research ef fort to determine which aromatic amines are carcinogenic in laboratory experimental animals {Clayson and Garner, 1976 ), how they may be measured in the environment, and how their m.~ charism of action operates {Miller and Mills , 19-') . Results from this effort demonstrate that many aromatic amines or their 2

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derivatives are indeed potent carcinogens in animals and that they are converted to derivatives of arylhydroxylamines during metabolic activation. me se intermediates probably dissociate to electrophilic nitrenium ions which interact with nucleophilic centers in major cell macromolecules (e.~., DNA, RNA, and protein} in exerting their carcinogenic and other toxic effects. CHARGE TO THE COMMITTEE The committee was convened by the National Research Council at the request of the Environmental Protection Agency (EPA) to assess the health and environmental effects of amines. The committee decided that the topic could be addressed best by dividing the subject into two parts: (1) aromatic amines and related compounds and (2) aliphatic amines. This report on aromatic amine s consists of chapters on the general characteristics of the class followed by chapters concerned with specif ic chemicals that illustrate problem areas . The committee reviewed the background information on aromatic amines and related compounds, stressing, for example, general analytic methods, toxicity, mutagenic and carcinogenic properties, and the utility of these substances to industry. It decided that it would exclude chemicals such as 2-naphthylamine, 4-aminobiphenyl and benzidine since they have been extensively and repeatedly reviewed in the past. Benzidine and its cogeners were especially well 3

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covered in a recent report by Shriner et al. (1978). Discussions with the EPA led to the selection of the following compounds for intensive review: aniline, 4,4'-methylenebis(2-chloroaniline), 2,4-diaminotoluene, trifluralin and oryzalin, ~cresidine, and furazolidone. Both trifluralin and furazolidone are nitro compounds, but were considered relevant to this study because of the relatively easy biological conversion of the nitro groups to the amino group and the fact that arylhydroxylamine der ivatives, in which the nitrogen is in an intermediate oxygenated state between the amine and nitro compound forms, is now generally recognized as the proximate biologically active form. The committee did not address the environmental aspects of exposure after an intensive search of the literature revealed a lack of information on this subject for the compounds selected. OCCURRENCE, CONTROL, AND ANALYTIC METHODS . Aromatic amines are used in dyes, antioxidants, polymers, explosives, pesticides, and pharmacolog ic agents. Workers in plants prod uc ing these products can be exposed to a health hazard. An evaluation of the da ta indicating that aromatic amines are potentially toxic in humans indicates that it is prudent to suggest that exposure be held to a minimum both for the worker and others who may be exposed to inadequately controlled wastes associated with 4

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manufacture of the products or who are users of the products. Low levels of exposure to aromatic amines may result from the products of destructive distillation of materials containing carbon, hydrogen, and nitrogen, as in smoke from tobacco and the gases resulting f rom the combustion of foss il fuels. Because of the anticipated changes in the consumption pattern of fossil fuels--those impl ic it in the promotion of diesel eng ines and the use of coal--occupational and environmental exposure to the aromatic amines may increase (National Academy of Sciences, 1981~. The committee recommends that both the qualitative and OCR for page 1
Other metabolic reactions, such as acetylation and ring hydroxylatiOn followed by con jugation, are detoxifying pathways. Understanding of the metabolism of aromatic amine s in laboratory animals has advanced to the point that research workers are better able to understand the process in humans. To further this objective, it is first necessary to know which animal most closely approximates the metabol ic responses of humans. Assuming that most chemical carcinogens need to be metabolized in the host to active forms in order to exer t a carcinogen ic effect, it becomes necessary to know how specif ic carcinogens are activated in animals. If the metabolism of a specif ic chemical carcinogen in human tissues is qualitatively simil far to that observed in studies of tissues from a susceptible test animal, then a potential carcinogenic effect might also be observed in humans exposed to the chemical . Al though the use of humans for testing is difficult or impossible and laboratory animals tests are expensive, it should be feasible to make inferences concerning responses in humans based on In vitro tests with Truman cell lines, mutagenicity testing with human liver S-9 fractions, and careful monitoring of blood and urine of humans accidently exposed to compounds of interest. It would be easier to assess the risk to humans from many aromatic amines if additional biological data on occupationally or otherwise exposed humans were obtained. STRUCTURE-ACTTVI TY RELATIONSHIPS Many aromatic amine and nitro compounds exhibit the ability to induce cancer in animals. Unless polar groups, such as sulfonic or 6

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carboxylic acid substituents, are present in the molecule, these chemicals should be regarded as potentially carcinogenic. FortunatelY' however ~ the most potent carcinogens among Me aromatic amines appear to possess certa in structural identifying character istics, such as: o one, two, or three conjugated aromatic ring systems, o an aromatic amino group substituted in the position pare to the conjugated aromatic system; or 0 groups, such as methyl, methoxyl, or fluorine, substituted in relative positions to the amino group. However, carcinogenicity has been associated with aromatic amines that lack one or more of these character istics. A thorough understanding of these relationships may make it possible to predict the potential toxicity of aromatic amines before they are adopted for widespread use. Furthermore, this knowledge and the ant icipated increases in the understanding of structure-activity characteristics of aromatic amines and of other chemicals may allow for the selective development of desirable chemical species without the accompanying toxicity. CARC INOGENIC POTENCY AND RISK ESTIMATION - It is not yet possible to predict the potency of a carcinogen in any species. One prudent approach is to assume that humans are at least as sensitive to these carcinogens as are the most sensitive species. For example, 2-naphthylamine should be assumed to be as 7

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potent in humans as it is in dogs. The potency of a carcinogen depends on three factors: the done of carcinogen required to induce tumors, the time to tumor induction, and the percentage tumor response. A method for expressing relative potency is described in Chapter 4. Whatever tOmor incidence-dose model is used to descr ibe a biolog ic event, the suggested means of expressing potency values discussed herein may have a considerable advantage in that these values may be derived without excessive effort or data extrapolation. Ways of predicting carcinogenic potency based on the present knowledge of the mechanisms of carcinogenesis urgently need to be improved. The use of statistical models to estimate possible risk to humans exposed to very low concentrations is filled with uncertainty. Studies of animals usually involve exposure to a high level of a single carcinogen and, sometimes, just one modifying agent. On the other hand, humans are exposed to a wide range of carcinogens and carcinogenesis-modifying agents that may enhance or inhibit the development of cancer especially if the carcinogen exposure is low. The recently completed EDo1 exper iment conducted by the National Center for Toxicological Research has forced a rethinking of. some aspects of dose-response modeling for carcinogenesis. More attention may need to be directed toward the concepts of initiation and promotion and the inherent abilities of chemicals to act in one or the other capacity as well as in both. 8

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EP IDEMIOLOGY Occupational exposure to 4-aminobiphenyl, 2-naphthylamine, and benzidine has been clearly associated with an increased rate of bladder cancer in workers. The use of 2-naphthylamine-containing ingredients in the British rubber industry was associated with bladder cancer in workers; however, U.S. rubber workers have not exhibited an increased incidence of bladder cancer as a result of exposure to that compound. There is no epidemiologic evidence from which to assess the effects on humans from exposure to the specific chemicals examined in this report. With the exception of trifluralin, the chemicals assessed in this report have induced cancer at various sites in one or more species of animals. Most toxicologists accept the concept that a demonstration of carcinogenicity in laboratory animals implies that the causative agent is a potential carcinogen in humans. Of the chemicals discussed in this report, 2,4-diaminotoluene (a component of some hair dyes) and 4,4'-methylene-bis(2-chloroaniline) (MOCA) are of most interest because they have been shown to be carcinogen ic in animals and because humans are frequently exposed to products containing them. Case-control studies have raised suspicions, while not providing conclusive proof, that the use of widely available hair dyes containing 2!4-diaminotoluene may be associated with cancer of the breast and of other sites. Because of faulty industr ial waste disposal methods, many people in Adrian, Michigan have been exposed to MOCA, which is known to be a potent carcinogen in animals. However, there is little evidence upon which to judge its carcinogenicity or other effects to humans. 9

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Retrospective studies are not as likely to provide definitive information on carcinogenicity in humans. In case-control studies of cancer, the recollection of, for example, hair dye use is subject to a high degree of recall bias. In retrospective cohort studies of persons exposed to other chemicals, there is a very imprecise measure of exposure. The prospective follow-up study is the only realistic study design to evaluate the carcinogenicity of these substances in humans. To determine the ef feats of ha ir dyes, it would be necessary to interview women (and possibly men) about their lifetime use of hair dyes and follow them for 5 to 20 years to measure the rate of cancer occurrence. To determine MOCA's health effects, persons exposed occupationally to relatively high levels of MOCA, their families, and preschool children living near the plant would have to be identified, categorized as to level of current (and future ~ exposure, and followed for 20 to 40 years. The epidemiolog ic evaluation of the possible health effects from exposure to low levels of aromatic amines as well as to other substances may be costly and time consuming. To the extent that disease 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 the measure of exposure is as precise as possible and does not, for example, depend on memory-based recall of hair dye use. If this strategy is adopted, long term and costly follow-up is the price that must be paid. 10

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ANILINE In the United States, more than 300 x 103 metric tons of aniline is produced per year. It is the parent compound for more than 300 chemical products. A metabolite of aniline, phenylhydroxylamine, is known to cause methemaglobinemis in exposed workers . Although the mechanism is fairly well understood, it now appears that some people are more susceptible to this condition than others. The mechanism of this increased sensitivity needs further investigation. The National Cancer Institute recently reported that exposure to the maximum tolerated dose of aniline led to hemangiosarcomas and other sarcomas of the 'spleen in rats, but not in mice . Mutagen ic ity tests produced negative results except in the presence of a comutagen. These findings indicate the need for fur ther research, including carcinogenic studies, possibly on dogs . There is no evidence indicating that aniline causes cancer in humans, but further epidemiologic studies are required. There is also a need to explore the mechanism by which aniline induces splenic tumors in rats and to determine why it is not carcinogenic in mice. 4,4 '-METHYLENE-BIS (2-CH=ROANILI=) Studies in laboratory animals have demonstrated conclusively that 4,4 '-methylene-bis {2-chloroaniline) (MOCA) is a carcinogen. Such activity is expected because of the chemical's structural similar ity to other carcinogenic aromatic amines. Widespread 11

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environmental contamination by MOCA is attributed to one point source in Adr fan, Michigan, thus increasing the need for epidemiologic investigations of the exposed population. There is also a need to study the metabolic fate of MOCA so that those who have been highly exposed can be identified by these metabolic indicators and prospective epidemiologic investigations can be facilitated. Z. 4-DIAMINOTOLUENE 2,4-Diaminotoluene (2,4-DT) has been used in some hair dye formulations. It is also used as an antioxidant and antiozonant in some rubber products. When administered orally, 2,4-DT is carcinogenic in rats and mice, leading to liver and mammary gland tumors. This compound is also a potent microbial mutagen, and induces mutations in Drosophila melanogaster. There is no information on the mechanism by which 2, 4-DT is activated in susceptible species, including rats and mice. Given the positive demonstration of carcinogenicity in two animal spec ies and the da ta on the genotoxic ef feats of 2, 4-Dq in In vitro systems, it is prudent to assume that humans may be under some increased risk from exposure to 2,4-DT. TRIFLURALIN At the request of the Environmental Protection Agency, tl..= report assesses only the potential mutagenic and genotoxic 12

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properties of trifluralin, a widely used herbicide. During its commercial preparation, an impurity, dipropylnitro~amine (NDPA), is produced. Since NDPA is a mutagen, it is difficult to assess this property in trifluralin. Mast mutagenicity studies of trifluralin have produced negative results. Those that are positive for chromo~omal damage and aneuploidy may be due to the presence of NDPA. Parallel studies with NDPA have not been reported. NDPA-free trifluralin and pure NDPA need to be tested, in tandem, for their abilities to induce chromosomal damage and aneuploidy. mere is an inadequate data base from which to evaluate the potential hazards of tr if luralin and NDPA, to DNA and cell spindles in laboratory animals or humans . Should HDPA be a germinal mutagen, exposures are expected to occur at such low levels that its mutagenic potential should be correspondingly low. Current manufacturing practice teas considerably reduced the level of NDPA in trifluralin and its formulations. Positive mutagenicity test results obtained with trifluralin have subsequently been attributed to a 177-ppm NDPA impurity contained in the trifluralin rather than to the test chemical itself. mere is a need for additional mutagenicity testing on NDPA-free trifluralin for comparison with the existing studies. Until these studies are performed, pure (NDPA-free) trifluralin should not be considered mutagenic. ~3

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F-CRESIDINE E'-Cresidine is used almost exclusively as a chemical intermediate in the manufacture of dyes. Other than a cancer bioassay conducted by the National Cancer Institute, there is virtually no other existing biologic data on this compound. Chronic oral exposures to E:cresidine produced bladder cancer in both male and female rats and mice as well as hepatocelluar carcinomas in male rats and female mice. In a preliminary investigation, the compound showed dose-response mutagenicity without metabolic activation in the Salmonel la assay . Because of the lack of data, it is difficult to evaluate the potential health effects of this compound. Nonetheless, it must be considered as a potential carcinogen in humans on the basis of the carcinogenicity demonstrated in rats and mice. Me preliminary mutagenicity data appear to show a positive response for p-cresidine, but con f irmation is needed. Additional data are also needed on metabolism, metabolic activation, mutagenicity, and genetic toxicity in both animal and human In vitro test systems. FURAZOLIDONE Fur azolidone is one of the S-nitrofurans currently approved for use as a systemic veterinary medicine in the United States, thereby f inding its way into some edible tissues. It has also been used to treat bacillary dysentery, typhoid, and other infectious diseases in 14

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4.O ppb with current analytical methods. Various spectrophotometric and thin layer chromatography procedures have-failed to yield satisfactory and reproducible recoveries at these levels. Furazolidine has exhibited carcinogenic effects in male and female rats and mice just as other 5-nitrofurans have done. A var iety of dif ferent tissues in each species have displayed these effects. file compound is highly mutagenic in both microbial (Escherichia coli) and insect (Drosophila melanogaster) test systems, produces chromosomal damage (breakage, sister-chromatic exchange, mitotic suppression) in human lymphocytes , and forms interstrand cross-linking in bacterial (Vibrio cholera) DNA. For the reasons discussed above, the use of furazolidone is now being reviewed by the Food and Drug Administration. Resolution of this matter awaits the development of a sufficiently sensitive and reliable analytical method. Any identified problem most certainly would be associated with the veterinary use of furazolidone. A "solution" may involve the substitution of an efficacious product known not to have the mutagenic and carcinogenic potential of furazolidone . RESEARCH RECOMMENDATI ONS - The following recommendations have been excerpted from the various chapters to highlight and focus attention on specific topics the committee felt deserved further consideration. 15

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Occurrence in the Environment . . . The anticipated changes in the use of fossil fuels, implicit in the promotion of diesel engines and coal, may raise existing environmental levels of some aromatic amines. Accordingly, it is recommended that steps be taken to evaluate both the qualitative and quantitative factors that attend these changes in practice. General Analysis Techniques must be developed to analyze for the presence of the more volatile compounds such as aniline. Furthermore, methods must be developed to determine the kinds and amounts of metabolites present in persons exposed to these compounds. Metabolism Understanding of the metabolism of aromatic amines in laboratory animals has advanced to the point that it can be extended to improve the understanding of this process in humans. First it is necessary to know which animal most closely approximates the metabol ic responses of humans. Assuming that most chemical carcinogens need to be metabolized in the host to active forms in order to exert a carcinogenic effect, it becomes necessary to know how specific carcinogens are activated in animals. If the metabolism of a specific chemical carcinogen in human tissues is qualitatively similiar to that observed in studies of tissues from a susceptible 16

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test animal, then a potential carcinogenic effect might also be observed in humans exposed to the chemical. Although the use of humans for testing is dif f icult or impossible, it should be feasible to make inferences based on in vitro tests with human cell lines, mutagenicity testing with human liver S-9 fractions, and careful mon itor ing of blood and ur ine of humans accidently exposed to compounds of interest. It would be easier to assess the potential risk to humans from many aromatic amines if additional biological data on humans were obta ined. Carcinogenic Potency and Risk Estimation More attention needs to be focused on the concepts of initiation and promotion and the inherent abilities of chemicals to act in one or the other capacity as well as in both. Also, ways of predicting carcinogen ic potency based on the present knowledge of the mechanisms of carcinogenesis urgently need to be expanded. In the absence of contrary evidence, aromatic amines which lack polar groups should be regarded as carcinogens. Epidemiology Epidemiologic methodology needs to be improved so small differences between exposed and control groups can be detected above the background variability. One of the best ways to minimize this variability is to conduct prospective follow-up studies so that the- measure of exposure is at least as precise as possible. Of all the 17

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compounds discussed in this report, the widespread exposure to 4, 4 ' -me thylene-bi s ~ 2-chloroan il ine ~ (MOCA) represents the best oppor ton i ty f or th i s approach . Aniline Although there has been considerable research on aniline, there is still much to be learned about its possible health effects. A compond of such industrial importance deserves to be studied more thoroughly. The hemangiosarcomas and sarcomas of the spleen and other organs observed at the maximally tolerated dose (MTD) in the National Cancer In s t i tu te b ioassay need to be examined fur ther in another 1 i fet ime feeding study at three or four dose levels in a different strain of rat to interpret the signif icance of previous observations. A care inogen ic ity Study us ing Syr fan golden hamsters may also be useful since these animals to develop bladder tumors after exposure to other aromatic amines. In addition, a long term (preferably 8-10 years) dog-feeding study at the MTD should allay any suspicions concerning the possible role of aniline in the causation of human bladder cancer. The only test on dogs was conducted many years ago on a few animals for too short a duration. Further studies on the metabolites of aniline in urine should be directed toward explaining the fa ilure of this compound to induce bladder cancer in dogs ~ if this fa ilure is conf irmed) . Special attention should be pa id to N-hydroxylated urinary metabolizes. Moreover, studies should be conducted on its potential for teratogenicity and reproductive toxicity. 18

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Epidemiological investigations on workers exposed to aniline should also be undertaken. Monitoring of urine for aniline metabolites to con f irm and quantitate exposures should be considered. 4, 4 ' -Me thyle ne-b i s (2-chloroan i 1 ine ) (MOCA) Tnd ividuals exposed to MOCA in Adr fan, Michigan as a result of faulty industr ial waste methods and others exposed to the compound should be studied further to learn whether or not the compound is carcinogenic in humans. First, the metabolic disposition of MOCA should be explored so that methods for evaluating exposure can be developed. Then these methods should be applied, to the population at r isk, including an evaluation of necropsy specimens from any member of this population who dies during the course of this investigation . Such studies would clarify the potential r isk to individuals, and aid in monitoring the effects of the cleanup ef for ts . The f inal step is the prospective surve illance of this population to determine whether exposure to MOCA increases their tendency to develop cancer. In addition, studies on the potential for teratogenicity and reproductive toxicity should be conducted. 2, 4-Diaminotoluene (2, 4-DT) Recommendations for future research on 2, 4-DT include studies of the mechanism by which the chemical is activated in rats, mice, and humans, testing for carcinogenic) ty in other species to obtain more data on the relationship between metabolism and carcinogenicity, and 19

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examination of the In vitro metabolism of 2,4-DT in human tissues. The resulting data would facilitate estimatation of risk to humans exposed to 2, 4-DT. Studies on the potential for teratogenicity and reproduct ive tax ici ty should also be conducted . Tr i f luralin Tandem mutagenicity studies on pure trifluralin and its contaminant, N-nitrosodipropylamine should be conducted to determine which compound is responsible for chromosomal damage and aneuploidy noted in previous studies. p-Cresidine In vitro studies of human tissues and tests with animals should be conducted to gather data on the metabolism, metabolic activation, mutagenicity, and genetic toxicity of p-cresidine. Furthermore, studies on the potential for teratogenicity and reproductive toxicity need to be performed. Furazolidone A sufficiently sensitive and reliable analytical method for fura 201 idone is needed. Moreover, studies on that compound's potential for teratogenicity and reproductive toxicity should be conducted. 20

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Re ferences Bengtsson , U., L. Angervall , H. Ekman, and L. Lehman . 1968. Transitional cell tumours of the renal pelvis in analgesic abusers. Scand. J. Urol. Nephrol . 2 :145-150. Case, R.A.M., M.E. Hosker, D.B. McDonald, and J.T. Pearson. 1954. Tumours of the urinary bladder in workmen engaged in the manufacture and use of certa in dyestuf f intermediates in the British chemical industry. Part I: file role of aniline, benz id ine, alpha-naphthylamine and beta-naphthylamine . Br . J. Ind . Hed . 11: 7 5-104 . 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. American Chemical Society, Washington, D.C. Hueper, W.C. 1942 . Occupational Tumors and Allied Diseases. Thomas, Springf ield, Ill . Melick, W.~., H.M. Escue, J.J. Naryka, R.A. Mezera, and E.P. Wheeler. 1955. m e first reported cases of human bladder tumors due to a new carcinogen--xenylamine. J. Urol. 74:760-766. Melick, W.F., H.M. Escue, J.J. Naryka, and R.E. Kelly. 1971. Bladder cancer due to exposure to para-aminobiphenyl: A 17-year followup. J . Urol. 106: 220-226 . 21

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Miller, E.C., and J.A. Miller. 1976. me metabo' ism of chemical carcinogens to reactive electrophiles and their possible mechanisms of action in carcinogenesis. Pp. 737-762 in C.E. Searle, ed. Chemical Carcinogens. ACS Monograph 173. American Chemical Society, Washington, D.C. National Academy of Sciences . 1981. Health Ef feats of Exposure to Diesel Exhaust . Repor t of the Health Ef feats Panel . Diesel Impacts Study Committee. National Research Council, Washington, D.C. 197 pp. Rathert, P., H. Melchior, and W. Lutzeyer. 197S. Phenacetin: A carcinogen for the ur inary tract. J. Urol. 113: 653-657. Rehn, L. 1895. Ueber Blasentumoren be i Fuchsinarbeitern . Arch. Klin. Chir. 50: 588-600. Shriner, C.R., J.S. Drury, A.S. Hammons, L.E. Towill, E.B. Lewis, and D.M. Opresko. 1978. Reviews of the environmental effects of pollutants: II. Benzidine. Information Center Complex, Information Division, Oak Ridge National Laboratory, prepared for Health Effects Research Laboratory, Office of Research and Development, U. S. Environmental Protection Agency, Cincinnati, Ohio, EPA-600/1-78-024, 139 pp. 22