Document 2RozDNRe7gB79MdK3prKBGm1b

CancerCausesand Contra( 1997,8,pp. 346-355 Aromatic amines and cancer Paolo Vineis and Roberta Pirastu Received 15 April 1996; accepted in revised form 22 August 1996 Epidemiologicalevidence on the relation between aromatic amines and cancer risk is reviewed. In particular, cancer risk in humans resulting from exposure to aromatic amines from occupational sources and tobacco smoking is assessed with reference Lo ecologici cohort, and case-control studies. Sev& arylamines have been classified by the International Agencyfor Research on Cancer:benzidine-baseddyes and MOCA (4,4'-methylene bis 2-choloroaniline) were considered `probably' carcinogenic, Group ZA,because of a high level of evidence in experimental animals; two occupational chemicals (&naphthylamine and benzidine), one drug (Chlornaphazine), and two manufacturing processes (manufacture of auramine and magenta) were included in Group 1 on the basis of `sufficient' evidence of carcinogenicity in humans. Occupational exposures to aromatic amines explain up to 25 percent of bladder cancers in some areas of Western countries; these estimates might be higher in limited areas of developing countries. Aromatic amines contaminate the ambient air as a component of environmental tobacco smoke. There is increasing evidence that the excess of bladder cancer in smokers is attributable t o aromatic amines rather than t o other contaminants of tobacco smoke such as polycyclic aromatic hydrocarbons (PAH). A modulating role in the risk of bladder cancer associated with exposure to aromatic amines is played by metabolic polymorphisms, such as the N-acetyltransferase genotype, raising important social and ethical issues. The consistent observation of a difference between men and women in bladder cancer risk, after allowing for known risk factors, suggests consideration of gender-related biological determinants for future investigation. Cancer Causes and Control 1997,8, 346-355 K e y words: Arylamines, bladder cancer, occupational exposure, tobacco. Introduction Exposure to aromatic amines (arylamines) occurs in different industrial and agricultural activities. Aromatic amines have been used as antioxidants in the production of rubber and in cutting oils, as intermediates in azo dye manufacturing, and as pesticides. They are a common contaminant in several working environments, including the chemical and mechanic industries and aluminum transformation. Arylamine-based dyes are used widely, particularly in the textile industry. An important problem is the transfer of aromatic amines (including carcinogenic compounds) from developed to developing countries.' Arylamines contaminate the ambient air where smokers are present.2 The site which has been associated causally with an increased risk of cancer in subjects exposed to aromatic amines is the bladder; we will not systematically review the evidence concerning other sites. The most stringent evidence comes from large cohort investigations conducted in the 1950s in the British chemical industry. We will consider cohort studies in detail, andcase-control and ecologic studies only when clear information on exposure to aromatic amines was available. Carcinogenic arylamines such as 2-naphthylamine have been banned in the United Kingdom since 1967 (Carcinogenic Substances Regulation)' and in other Western countries subsequently.` The International Labour Office had Dr Vineis is with the Unit of Cancer Epidemiology, Dipartimento di Scienze Biomediche e Oncologia Umana, via Santenaz, 10126, Torino, Italy. Dr Pirastu is with the Dipartimento di Biologia Animale e dell'llomo, Universita La Sapienza, Roma, Italy. Address correspondence to Dr Vineis. This work has been partially funded by the Associazione Italiana per La Ricerca sul Cancro and by Minister0 del Lavoro. 346 Cancer Causes and Control. Vol 8. 1997 01997 Rapid Science Publishers - Aromatic amines and cancer already concluded in 1921, based on early observations in huma'ns, that 2-naphthylamine and benzidine were carcinogenic.' Ecologic studies Bladder cancer was found to be increased in ecologic studies of geographic areas contaminated with carcinogens, such as the Drake Superfund site in Pennsylvania (United States), an area where different chemical companies had manufactured or stored over decades carcinogens as 2-naphthylamine and benzidine.` A study by Dolin' computed standardized mortality ratios (SMR) for bladder and lung cancer in 400 districts in England and Wales (UK) in the years 1969-80 and detected an increase in bladder cancer risk among males for textile related occupations (involving exposure to azo dyes) and amongfemalesfor engineering trades (involving exposure to aromatic amines in cutting fluids). A death certificate study conducted among 2,457 males deceased for bladder cancer in Great Britain' in the years 1965-80 used a job-exposure matrix to infer exposure to aromatic amines. The SMRs for aromatic amines were 120 (95 percent confidence interval [CI] = 101-141) for `some exposure,' 123 (CI = 102-147) for low exposure, and 108 (CI = 70-160) for high exposure. A French study' of male farmers and farm laborers in 89 geographic units, in the years 1984-86, was based on a pesticide exposure index (PEI), and found a relative risk (RR) for bladder cancer of 1.14 (CI = 1.07-1.22) among the heavily exposed. The authors claim that herbicides used in vineyards include diuron which can be contaminated by aromatic amines. Cohort studies Following anecdotal observations in humans and experimental work in dogs," the carcinogenicity of arylamines such as 2-naphthylamine and benzidine was demonstrated clearly in the 1950sin a large epidemiologic investigation of British chemical workers." Case and colleagueswere able to obtain from the chemical industry nominal rolls for all workers, including information on job titles and the chemicals they manufactured. Overall, 4,622 men in 21 firms were enrolled, and mortality from bladder cancer was ascertained. The observed (Obs) deaths exceeded by far those expected (Exp) among workers exposed to 2-naphthylamine (Obs/Exp Ratio = 87) and benzidine (O/E = 14),while lower excesseswere reported for aniline (O/E = 4.5) and I-naphthylamine (O/E = 9). However, subsequent studies did not confirm that the latter substances were carcinogenic, and the apparent excess was probably due to contamination from 2naphthylamine." Other studies have reported considerable increased risks of bladder cancer in workers exposed to 2-naphthylamine, benzidine, and 4-amin0biphenyl;l'-*t~he results of such studies are summarized in Table 1. Some of the studies did not have a formal epidemiologic design and/or were based on very small numbers. In one case, all 15 workers involved in distilling of 2-naphthylamine in a small plant in England developed bladder cancer.''This observation is important, because it shows that in exceptional situations (high levels of exposure to potent carcinogens), individual susceptibility is irrelevant. An interesting observation that has been made both in the UK and in the US is that after banning of carcinogenic arylamines, the incidence of bladder cancer in the chemical industry has decreased considerably.".*' Other arylamines, in addition to those in Table I, have been shown to be carcinogenic to humans. Chlornaphazine, a chloroethyl-derivative of 2-naphthylamine, has been used as a drug for the treatment of polycythemia vera. Among 61 patients treated in 1954-62,13 developed cancer of the bladder and eight had abnormal urinary cytology;'*this chemical is included in Group 1 (human carcinogens) according to the International Agency for Research on Cancer (IARC)." 0-toluidine has also been suggested as a bladder carcinogen. In their study, Rubino et a1``found a 62-fold increase in bladder cancer risk in workers exposed jointly to o-toluidine and 4,4'-methylene bis(2-methylaniline) both carcinogenic to experimental animals." The excess was based on five cases. Stasikz6reported a 72-foldincrease (eight cases) among workers exposed both to o-toluidine and to 4-chloro-o-toluidine. More recently, a study conducted by the US National Institute for Occupational Safety and Health: concerning a cohort of workers exposed jointly to o-toluidine and aniline, found high RRs (up to 27 for those exposed for 10 or more years). None of these investigations enables us to evaluate separately the contribution of o-toluidine to the excess of bladder cancer. 0-toluidine is clearly carcinogenic in experimental animals,whereas the data are less convincing for aniline." In Germany, in a group of 49 workers exposed to 4-chloro-o-toluidine in the synthesis of chlordimeform, seven cases of bladder cancer occurred, a number about 50 times higher than expected." Also, two industrial processes (manufacturing of auramine and magenta) have been included in Group 1 (human carcinogens) by IARC Working Groups, although the single responsible carcinogens are not known. In the case of magenta, ortho-toluidine and 4,4'-methylene bis (2-methylaniline) have been suspected." In addition to bladder cancer, esophageal tumors have been found in excess in two of the studies shown in Table 1: Rubino et al,16ina plant where workers were exposed to different aromatic amines, reported an O/E ratio of Cancer Causes and Conrrol. Vol 8. 1997 347 J! Vineis and R.Pirastu Table 1. Occupational arylamines with clear evidence of carcinogenity to humans; cohort size is based, whenever possible, on subjects exposed to the specific chemical Study (ref) 2-naphthylamine Case et a/" Mancuso & El-AttaC3 Goldwater et a/ Schulte et a/ l5 Rubino et a/ l6 Bulbulyan et a/ l7 Year 1954 1967 1965 1985 1982 1995 No. of observed deaths or cases 26 18 12 13 6 9 Benzidine Case et ai l1 Mancuso & El-Attar13 Zavon et a/" Tsuchiya et a/ l 9 Rubino et a/ l6 Horton et a/'' Meigs et aI2' Bi et a/'` Bulbulyan et a/ l7 1954 1967 1973 1975 1982 1977 1986 1992 1995 10 16 13 72 5 13 6 9 17 4-aminobiphenyl Melan~ed*~ Melick et Zack & Gaffe#5 1972 1971 1983 a OIE = observedlexpected. Total cohort, with miscellaneous exposure to arylamines. Heavy exposure. 43 53 9 OIE a 87 30 3.9 150 18.9 14 30 83 130 45.7 13.2 10 Cohort size (No.) 4,622b 640 48 1,385b 30 514 men and 87 women 4,622' 640 25 1,015 65 5 105' 266 514 men and 87 women 541 315 884 4.72 (statistically significant, based on five cases); and Bulbulyan et af " reported a ratio of 3.48 (five cases in a group exposed to benzidine and 2-naphthylamine). In contrast, the cohort study by Meigs et a f '' on US workers exposed to benzidine did not find any excess in addition to bladder cancer. Case-control studies and other relevant epidemiologic evidence Many case-control studies have considered job titles and industrial activities potentially involving exposure to aromatic aminesf"' only those studies relying on some form of assessment of exposure to aromatic amines have been included in Table 2. Increased RRs are obvious in investigations by Bonassi et a f29 in Italy, Schumacher et a1 'O in the US, and Steineck et ai " in Sweden; whereas, results are equivocal in the large study by Siemiatycki et afJJin Montreal (Quebec, Canada). The latter observation may be attributed to imperfect knowledge of specific exposures or to the actual absence of carcinogenic arylamines among the industrial activities surveyed. 348 Cancer Causes and Control. Vol 8. 1997 One of the major limitations of many epidemiologic studies is the lack of detailed information on exposure to individual chemicals. However, a few clues are worth mentioning because of the consistency of the high prevalence of exposure, and the possible contamination of exposure by arylamines. One is represented by jobs with exposure to combustion gases and soot from coal; in addition to polycyclic aromatic hydrocarbons, such jobs involve exposure to arylamines (Table 3).34-'yFe~xrample, in a cohort study of coal carbonizing workers, 2-naphthylamine was found in a sample from tar volatile~.'A~ peculiar observation is represented by the high RRs found by Tremblay and colleagues in Canada for exposure to benzopyrene." In fact, contamination from 2-naphthylamine and 4-aminobiphenyl was documented in the same working environments. Another type of exposure with likely contamination by arylamines (e.g., phenyl-lnaphthylamine) is exposure to cutting oils and cutting fluids, where excess risks of bladder cancer have been repeatedly shown.50 Occupation as hairdresser or barber is classified in Group 2A (probable carcinogen) by IARC." The pres- Aromatic amines and cancer Table 2..Bladder cancer and occupational exposure to aromatic amines (AA): case-control or linkage studies 1989-95 - Study (ref) Country Gender Cases/controls Results Year ORlRRlMOR (CI or P value) Bonassi et a / 2 9 1989 Italy M 1211342 High exposure to AA adjusted for PAH exposure: OR = 3.6 (CI = 1.6-.8.1) High exposure to AA and possible exposure to PAH: OR = 3.8 (CI = 1.99-7.29) High exposure to AA and definite exposure to PAH: OR = 4.8 (CI = 0.6-36.1) Schumacher et 1989 USA M + F 4171877 'Steineck et a/313 1989 Hours et a/32 1994 Sweden France M 10,123 cases M + F 1161232 Males: Exposure to benzidine and 2-naphthylamine: 21 cases, 38 controls: < 10 years duration: OR = 1.0 (CI = 0.5-2.1) 2 10 years duration: OR = 1.6 (CI = 0.6-4.1) Exposure to dyes: RR = 1.8 (CI = 1.2-2.6) Cutting fluids: OR = 2.6 (CI = 1.2-5.4) Inks: women OR = 14.0 (CI = 1.8-106.5) Pyrolysis and combustion products: OR = 2.3 (CI = 1.O-4.0) Siemiatycki et a/33 Canada M 48411,879 1994 (i) Probable exposure to aromatic amines: OR = 1.3 (CI = 0.9-2.0) (ii) Textile dyers and finishers > 10 years of exposure: OR = 10.8 (CI = 1.0-120) a Abbreviation: RR = relative risk; OR = odds ratio; MOR = mortality odds ratio; CI = 95 % confidence intervals; PAH = polycyclic aromatic hydrocarbons. Swedish Cancer-Environment Study (a linkage study using a job-exposure matrix). ence of aromatic amines with different degrees of evidence of carcinogenicity is documented in some cosmetic products, such as auramine (2B) in brilliantines, CI Disperse Blue 1 (2B) and H C Blue No. 1 in semipermanent hair dyes used in the past. The contribution of studies in animals The first demonstration of an excess risk of bladder cancer after exposure to some arylamines came from anecdotal observations in humans and, almost at the same time, from studies in animals. This occurred before formal epidemiologic studies were conducted. Arylamines are one of the best examples of the predictivity of animal experiments for human risk. A recent review has reported that 25 to 30 percent of all agents that have been associated causally with human cancer were identified first as carcinogens in experimental ani mal^.^' These authors have suggested that a clearer understanding of cancer induction at the molecular level will allow the design of more predictive animal models. The reference to evidence in experimental animals has been crucial in the classification of some aromatic amines for their carcinogenicityto humans. Benzidine-based dyes and MOCA (4,4'-methylene bis 2-choloroaniline) have been classified by IARC Working Groups as 'probable' carcinogens, and para-chloroaniline and ortho-toluidine as `possible' carcinogens, on the basis of strong evidence in animals. More specifically, the evaluation for MOCA was justified (even in the absence of direct evidence of carcinogenicity in humans) by sufficient evidence of carcinogenicityin animals and by mechanistic data show- ing that the same DNA adduct (a deoxyadenosin-8-yl derivative) can be found in rats and in heavily exposed worker~.~T'hree benzidine-based dyes (Direct Black 38, Direct Blue 6, and Direct Brown 95) were considered as `probably' carcinogenic to humans because their metabolism in humans leads t o the formation of free benzidine," and on the basis of `sufficient' evidence of carcinogenicity in animals. Studies in animals (rats and mice) have shown excesses of hepatocellular carcinomas after exposure to benzidine, benzidine-based dyes, 4-aminobiphenyl, or 2-naphthylamine. The rarity of this cancer in Western populations has implied very low statistical power to detect an excess in epidemiologic studies. In contrast, human studies have shown an excess of esophageal cancers that has not been observed clearly in animals. Cancer Causes and Control. Vol 8. 1997 349 I? Vineis and R. Pirastu Table 3. Combustion gases/soot from coal, exposure to policyclic aromatic hydrocarbons: relative risk (RR) and 95% confidence intervals (CI) for bladder cancer in epidemiologic studiesa Study (ref) Cohort studies DOII et a/34 Redmond et a/35 Hammond et a/36 Gustavsson et a/37 Steineck et a/3* Year 1972 1972 1976 1988 1988 Titlelexposure Coal carbonizers Coke oven workers Roofers and waterproofers Duration= 9-19 yrs Duration= 20+ yrs Chimney sweeps Combustion gases from coal RR GI) 2.4 (1.1-4.3) 1.2 (0.1-4.2) 0.8 (0.1-3.0) 1.7 (0.9-2.9) 2.3 (1.4-3.4) 1.2 (1.o-1.4) Case-referent studies Population-based Howe et a/39 1980 Glass processors 6.0 (0.7-276) McLaughlin et 1983 Coalhatural gas 2.9 (1.O-8.2) soot 3.0 (0.9-8.9) Silverman et a/41 1983 Stationary firemen 1.8 (0.7-5.0) Ore refining and foundry occupations 0.5 (0.2-1.4) Metal heaters 3.0 (0.3-28) Glass manufacture 5.9 (0.7-50) M~mmsen~~ 1984 Blacksmiths 5.0 (0.6-236) I Schoenberg et a/43 1984 Cooks 1.3 (0.8-2.3) Theriault et a/44 1984 Documented exposure to benzopyrene Duration= 10-19 yrs 6.8 (2.6-17.8) Duration= 20+ yrs 2.4 (3.3-46.1) Morrison et a/45 1985 England, cooks 1 .o (0.7-1.6) Japan, cooks 1 .o (0.4-2.4) US,cooks 1.2 (0.7-2.1) England, coal and coke 0.8 (0.6-1.3) Japan, coal and coke 1.3 (0.6-2.6) US,coal and coke 1.1 (0.5-2.0) Hospital-based Tola et a/47 Vineis and Magnani4' Tremblay et 1968 1980 1985 1995 Smiths Smiths Foundry workers Brickyards Foundries Benzo-a-pyrene (BaP) pg/m3 years -99.9 - 1 99.9 -299.9 300+ 7.6 (0.4-128) 0.4 1 2.0 - 2.0 (0.9-4.5) 0.7 (0.4-1.3) 1.9 (1.1 -3.4) 6.1 (3.1-12.3) 5.6 (2.9-10.4) 3.8 - (1.9-7.8) a Four studies for which the study base was not defined were deleted from the table. b Presence of 2-naphthylamine and 4-aminobiphenyl; 4-aminobiphenyl TWA (time-weighted average) concentration.range in 1990:< 1 to 410 n g l r r ~N. ~o confounding from smoking. The risk for each year of exposure to BaP at a concentration of 1 pg/m3 increased by 1.7% (0.8%-3.2%). The contribution of occupational exposure to bladder cancer (attributable risks) A legitimate question is how many bladder cancers are attributable to occupational exposure to arylamines. The answer is quite uncertain, since well-documented exposure to arylamines has been associated with increased risk of bladder cancer in cohort studies, which do not easily 350 Cancer Causes and Control. Vol 8. 1997 allow the estimation of attributable risks. This is due to the fact that, generally, an estimate of the proportion exposed in the general population (exposure prevalence) is not available from cohort studies. In other investigations, particularly of the case-referenttype, increased risks for job titles, without knowledge on arylamine exposure, were measured. . w1 -. 4% Aromatic amines and cuncer An attempt to estimate systematically the population attributable risks (PAR) was made by Vineis and Sim~nato,~'usinegvidence from the published case-control studies which adjusted the estimates by smoking habits. In all the PAR estimates, workers of dye-producing plants, rubber workers, and gas workers were included, under the assumption that they were exposed to arylamines. In addition, three criteria to include job titles into the PAR estimates were used. According to the first (the less stringent) criterion, the job titles associated to bladder cancer risk (OR greater than 1.0) in all the published studies, and showing a statistically significant association in a t least ,one study, were included. According to the second criterion, a further condition was that the proportion of exposed controls was at least five percent. According to the most stringent criterion, the same conditions applied but only associations which reached statistical significance in at least two studies were considered (Criterion 111). As a result of this exercise, the PAR estimates varied more between t h a n within studies, suggesting that the criteria used to estimate the PAR are less important than the proportion of workers considered to be exposed in different geographic areas. These estimates suffer from several limitations: (i) the classification of 'exposed' workers is based on job titles and not on actual knowledge of chemical exposure; (ii) the classification of workers within job categories is affected by errors which tend to entail underestimation of risks; and (iii) different studies have been conducted with different methods and different classification schemes. Nevertheless, the epidemiologic exercise suggests that the proportion of bladder cancers attributable to occupation varies across geographic areas, depending on the prevalence of exposed workers, from a minimum of about zero to a maximum of 20 to 25 percent. The estimates described refer exclusively to developed countries. An important problem, however, is the bladder cancer burden from arylamine exposure in developing countries. Information is scanty, but it is reasonable to think that such exposures may be widespread due to transfer from developed countries. Tire production involving the use of aromatic amines increased about sevenfold in Brazil and more than 20-fold in India, between 1961 and 1987.5' India, Mexico, and Brazil are major producers of magenta and para-~hloroaniline.~'.~~ Epidemiologic studies have documented the relevance of the problem. Two investigations in Shangai (China) identified occupational exposure to benzidine as the main cause of bladder cancer in some industrial settings. A retrospective cohort study in seven dyestuff factories" showed a standardized incidence ratio (SIR) of 3,500 (14 observed cases)among 354 men in the presynthesis group, Figure 1. Meta-analysis: N-aceiyltransferaseand bladder cancer. rza ' 0.12 A 04 . 016. 4n 35 2 82 26 + :in 143 I105 4 091 I lU - - -Numbers in I1 arm power of fha atudy la = 0.05, OR 2) 9. mgenotypinp. ph. phenotyping. C I Caucasian., A Awns. Cancer Causes and Control. Vol 8. 1997 351 E! Vineis and R. Pirastu Table 4. Correlation coefficients (Pearson) and P-values (in parentheses): urinary cotinine-nicotine, urinary 1-hydroxyprene, levels of 4-aminobiphenyl-hemoglobin adducts, and log DNA adducts in exfoliated bladder cells (39 healthy men) (from ref. 64) Adduct No. 1 2 3 4 5 6 7 8 9 10 11 12 Total diagonal zone All subjects 1-hydroxyprene 4-ABP -0.01 (0.95) 0.44 (0.01) -0.22 (0.17) 0.02 (0.90) 0.08 (0.62) 0.06 (0.70) 0.42 (0.01) -0.03 (0.84) 0.33 (0.04) 0.07 (0.67) -0.01 (0.93) -0.1 0 (0.52) -0.04 (0.77) -0.14 (0.39) -0.09 (0.58) -0.03 (0.87) 0.14 (0.38) 0.09 (0.57) 0.01 (0.96) -0.02 (0.88) -0.10 (0.53) 0.05 (0.75) 0.37 (0.02) -0.14 (0.40) -0.13 (0.42) 0.17 (0.29) Smokers ( n = 18) 1-hydroxyprene 4-ABP 0.02 (0.92) 0.37 (0.12) -0.19 (0.44) 0.01 (0.97) 0.16 (0.53) 0.09 (0.72) 0.52 (0.03) 0.37 (0.13) 0.54 (0.02) 0.28 (0.26) -0.08 (0.74) -0.17 (0.49) - 0.09 (0.09) -0.28 (0.27) - -0.22 (0.36) -0.15 (0.55) 0.09 (0.71) 0.05 (0.84) 0.13 (0.61) -0.35 (0.14) 0.34 (0.16) 0.06 (0.82) -0.17 (0.48) 0.45 (0.06) Abbreviations: 4-ABP = 4-aminobiphenyl-hemoglobinadducts. and the SIR was up to 7,500 (six cases) in a subgroup of 69 subjects who mixed and transported benzidine. In a case- control a significantly increased risk was observed (SIR = 167) for textile bleachers, dyers, and finishers. A case-control investigation in Bombay (India)58showed a fivefold bladder cancer risk (OR = 4.48, CI = 1.2-16.2) among employees in companies manufacturing dyes. Non-occupational sources of arylamines: tobacco smoking Tobacco smoking is a well-known cause of bladder cancer accounting for more than 50 percent of bladder cancers in men and 20 percent in women, in Western societies and is a source or ar~lamines.A5~ir-cured (black) tobacco, is particularly rich in arylamines such as +aminobiphenyl; smokers of black tobacco have a risk of bladder cancer which is about 2.5-fold compared with smokers of flue-cured tobacco.60Studies of 'molecular' epidemiology have suggested that smokers of air-cured tobacco have higher levels of 4-aminobiphenyl-hemoglobinadducts (a 352 Cancer Causes and Control. Vol 8. 1997 marker of internal dose) in their blood, compared with smokers of flue-cured tobacco.61Biopsies of bladder cancer from smokers contain a DNA adduct identified as a derivative of 4-amin0biphenyl.~'This same D N A adduct was present in exfoliated bladder cells of smokers;bf the presence and concentration of the D N A adducts was correlated strongly with 4-aminobiphenyl-hemoglobin adducts but not with urinary l-hydroxypyrene-glu- curonide, a metabolite of benzopyreneTas shown in Table 4; where the derivative of 4-arninobiphenyl is adduct 4. The latter observation suggests that arylamines and not polycyclic aromatic hydrocarbons in tobacco smoke might be responsible for bladder cancer in smokers, but this is still an attractive hypothesis which warrants further evidence. The concentration of 4-aminobiphenyl-hemoglobin adducts in both smokers and nonsmokers is modulated by the N-acetylation phenotype: irrespective of the smoking status of the subjects, the genetically based slow-acetyla- tor phenotype was associated with higher concentrations of the N-acetyltransferase deactivates carcino- Aromatic amines and cancer genic arylamines and has a genetically based polymorphic Conclusions distribution in the population, with about 50 percent of Caucasians being `slow' acetylators. Slow acetylators have According to the Working Groups of the IARC Mono- been shown to be at high risk of bladder cancer in graphs Program, seven arylamines have been classified as epidemiologic investigations.66 carcinogenic to humans (Group 1) or `probably' carcino- Figure 1 shows the individual investigations, and a genic to humans (Group 2A). In addition to three specific meta-analysis of the studies, on the N-acetylator genotype or phenotype and bladder cancer. The consistency occupational chemicals (2-naphthylamine, benzidine and MOCA), and one drug [N,N-bis(2-chloromethyl)-2- - among the results obtained in different Caucasian populations and with different study designs seems to suggest that N-acetyltransferase exerts a causal role in modulating the risk of bladder cancer in arylamine-exposed subjects. An exception is represented by two studies in Asians, which show low RRs in slow acetylators. naphthylamine], Chlornaphazine), also one group of industrial compounds (benzidine-based dyes, i.e., Direct Black 38, Direct Blue 6 and Direct Brown 95), and two manufacturing processes (manufacture of auramine and magenta) have been listed. Whereas for the other chemicals or industrial processes, the evidence of carcinogenicity in humans was sufficient, benzidine-based dyes and MOCA Overall, epidemiologic observations suggest, as a were considered `probably' carcinogenic because of a high working hypothesis, that arylamines such as +amino- level of evidence in experimental animals. biphenyl might be responsible for the excess risk of Occupational exposures to aromatic amines explain up bladder cancer in smokers. In addition, the risk appears to be modulated by genetically-based metabolic polymorphisms such as N-acetyltransferase. to 25 percent of bladder cancers occurring in some areas of Western countries. Estimates of the attributable fraction are strictly space- and time-specific, and might be higher in limited areas of developing countries. Aromatic Gender differences amines contaminate the ambient air as a component of environmental tobacco smoke. There is increasing A difference between men and women in bladder cancer risks has been shown consistently in epidemiologic studies. For tobacco smoking? most studies documented a positive association, but with RRs for women generally lower than for men. Some investigations also hzve shown a lower RR in women after allowing for differences in exposure to specific risk factors. In the cohort analysis of lung and bladder cancer mortality in Denmark, 1943-87: both genders had the same overall lung cancer risk, while for bladder cancer, women showed a smaller increase associated with 4smoking compared with men (3.7 6.1-fold). A case- control study (2,806 cases and 5,258 controls) in the US6' evidence that the excess of bladder cancer in smokers is attributable to aromatic amines rather than to other contaminants of tobacco smoke such as PAHs.A modulating role in the risk of bladder cancer associatedwith exposure to aromatic amines is played by metabolic polymorphisms, such as the N-acetyltrasferase genotype. Greater susceptibility of slow acetylators to the carcinogenic effect of aromatic amines raises important social and ethical issues that have been addressed elsewhere." The consistent observation of a difference between men and women in bladder cancer risk, after allowing for known risk factors, suggests consideration of gender-related biological determinants for future investigation. showed, in 1978, a male/female ratio of 2.7 after adjust- ment for occupational exposures and cigarette smoking. An incident case-control study carried out in Orange References County, California (US) for the years 1984-8769showed that the O R for men relative to women was 5.95 (CI 4.36-8.12), after adjustment for age, ethnicity, smoking status, and occupation. Therefore, the male/female ratio in bladder cancer is not explained completely by gender differences in smoking habits or occupational exposures. A case-control study in the US using mailed questionnaire~s'h~owed a decreased risk for parous c f nulliparous 1. Jeyaratnam J. Transfer of hazardous industries. In: Pearce N, Matos E, Boffetta P, Kogevinas M, eds. Occupational Cancer in Developing Countries. Oxford, UK Oxford University Press, 1994; IARC Sci. Pub. No. 129 23-9. 2. Maclure M, Katz RB, BryantMS, SkipperPL, Tannenbaum SR. Elevated blood levels of carcinogens in passive smokers. A m J Public Health 1989; 79: 1381-4. 3. International Agency for Research on Cancer. Some Aromatic Amines, Hydrazine and Related Substances, N- women (OR = 0.67, CI = 0.44-1.0), the reduction in risk being restricted to never-smokers (OR = 0.51, CI = 0.30- 0.88). There was no apparent effect of parity in nonsmokers (OR = 0.93). A further hint, that suggests genuine biological differences between genders, is the different spontaneous background frequency of micronuclei in exfoliated bladder cells in men and women.71 nitrosocompounds and Miscellaneous Alkykating Agents Lyon, France: IARC, 1974; IARC Monogr Eva1 Risks Humans, Vol. 4. 4. US Government. Occupational Safety and Health Standards. Washington DC: US Federal Register 38, 1973; No. 85, 10929. 5. International Labour Office. Cancer of the Bladder among Workers in Aniline Factories. Geneva, Switzerland: ILO, Cancer Causes and Control. Vol 8. 1997 353 P Vineis and R. Pirastu 1921; Studies and Repo~tsS, eries F, N o 1. 6. Budnick LD, SokalDC, Falk H, Logue JN, FoxJM. Cancer and birth defects near the Drake Superfund site, Pennsylvania. Arch Environ Health 1984; 39: 409-13. 7. Dolin PJ. A descriptive study of occupation and bladder cancer in England & Wales. BYJ Cancer 1992; 65: 476-8. 8. Dolin PJ, Cook-Mozzafari P. Occupation and bladder cancer: a death certificate study. BYJ Cancer 1992; 66: 568-78. 9. Vie1JF, Challier B. Bladder cancer among French farmers: does exposure to pesticides in vineyards play a part? Occup Environ Med 1995; 52: 587-92. 10. Hueper WC, Wiley F, Wolfe HD. Experimental production of bladder tumors in dogs by administration of betanaphthylamine. J Ind Hyg Toxic01 1938; 20: 46-84. 11. Case RAM, Hosker ME, McDonald DB, Pearson JT. Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. Part I. B r j I n d Med 1954; 11: 75-104. 12. International Agency for Research on Cancer. Overall Evaluations of Carcinogenicity: an Updating of I A R C Monographs Volumes 1 to 42. Lyon, France: IARC 1987; IARC Monogr Eval Risks Humans, Supplement 7. 13. Mancuso TF, El-Attar AA. Cohort study of workers exposed to beta-naphthylamine and benzidine. j Occup Med 1967; 9: 277-85. 14. Goldwater LJ, Rosso AJ, Kleinfeld M. Bladder tumors in a coal tar dye plant Arch Environ Health 1965; 11: 814-7. 15. SchultePA, Ringen K, Hemstreet GP, et al. Risk assessment of a cohort exposed to aromatic amines.] Occup Med 1965; 2 7 115-21. 16. Rubino GF, Scansetti G, Piolatto G, Pira E. The carcinogenic effect of aromatic amines: an epidemiologic study on the role of o-toluidine and 4,4'-methylene bis(2-methylaniline) in inducing bladder cancer in man. Environ Re5 1982; 2 7 241-54. 17. Bulbulyan MA, Figgs LW, Zahm SH, et al. Cancer incidence and mortality among beta-naphthylamine and benzidine dye workers in Moscow. Int J Epidemioll995; 24: 266-75. 18. Zavon M.R, Hoegg U, Bingham E. Benzidine exposure as a cause of bladder tumours. Arch Enwiron Health 1973; 27: 1-7. 19. Tsuchiya K, Okubo T, Ishizu S . An epidemiological study of occupational bladder tumors in the dye industry inJapan. A m j Znd Med 1975; 32: 203-9. 20. Horton AW, Bingham EL. Risk of bladder tumors among benzidine workers and their serum properdin levels.jNCZ 1977; 58: 1225-8. 21. Meigs JW,Marrett LD, Ulrich FU, Flannery JT. Bladder tumor incidence among workers exposed to benzidine: a thirty-year follow-up. JNCI 1986; 76: 1-8. 22. Bi WF, Hayes RB, Feng P, et al. Mortality and incidence of bladder cancer in benzidine-exposed workers in China. A m j l n d Med 1992; 21: 481-9. 23. Melamed MR. Diagnostic cytology of urinary tract carcinoma. A review of experience with spontaneous and carcinogen induced tumors in man. E u r j Cancer 1972; 8: 287-92. 24. Melick WF Bladder carcinoma and xenylamine. N e w Engl j Med 1972; 2 8 7 1103. 25. Zack JA, Gaffey WR. A mortality study of workers employees at the Monsanto Company plant in Nitro, West Virginia. Enwiron Sci Res 1983; 26: 575-91. 26. StasikMJ. Carcinomas of the urinary bladder in a 4-chloro- 354 Cancer Causes and Control. Vol 8. L997 o-toluidine cohort. Int Arch Occup Environ Health 1988; 60: 21-4. 27. Ward E, Carpenter A, Markowitz S, Roberts D, Halperin W. Excess number of bladder cancers in workers exposed to ortho-toluidine and aniline. JNCZ 1991; 83: 501-6. 28. Popp W, Schmieding W, Speck M, Vahrenholz C, Norpoth K. Incidence of bladder cancer in a cohort of workers exposed to 4-chloro-o-toluidine while synthesising chlordimeform. B r ] Znd Med 1992; 4 9 529-31. 29. Bonassi S, Merlo F, Pearce N, Puntoni R. Bladder cancer and occupational exposure to polycyclic aromatic hydrocarbons. ZntJ Cancer 1989; 44: 648-51. 30. Schumacher MC, Slattery ML, West DW. Occupation and bladder cancer in Utah. Am J Ind Med 1989; 16: 89-102. 31. Steineck G, Plato N, Alfredsson L, Norell SE. Industryrelated urothelial carcinogens: application of a job-exposure matrix to census data. Am J 2nd Med 1989; 16: 209-24. 32. Hours M, Dananche B, Fevotte J, et al. Bladder cancer and occupational exposure. Scand J Work Enwrron Health 1994; 20: 322-30. 33. SiemiatyckiJ, Dewar R, Nadon L, Gerin M. Occupational risk factors for bladder cancer: results from a case-control study in Montreal, Quebec, Canada. Am J Epidemiol1994; 140: 1061-80. 34. Doll R, Vessey MP, Beasley RWR, et al. Mortality of gas- workers - final report of a prospective study. B Y ] Ind Med 1972; 29: 394-406. 35. Redmond CK, Ciocco A, Lloyd JW, Rush HW. Long-term mortality study of steelworkers. VI. Mortality from malignant neoplasms among coke oven workers. j Occup Med 1972; 1 4 621-9. 36. Hammond EC, Selikoff IJ, Lawther PL, Seidman H. Inhalation of benzpyrene and cancer in man. Ann N Y Acud Sci 1976; 271: 116-24. 37. Gustavsson P, Gustavsson A, Hogstedt C. Excess of cancer among Swedish chimney sweeps. B Y ] Ind Med 1988; 45: 777-81. 38. Steineck G, Norell SE, Feychting M. Diet, tobacco and urothelial cancer: a 14-year follow-up of 16,477 subjects. Acta Oncol 1988; 2 7 323-7. 39. Howe GR, Burch JD, Miller AB, et al. Tobacco use, occupation, coffee, various nutrients and bladder cancer. J N C I 1980; 64: 701-13. 40. McLaughlin JK, Blot WJ, Mandel JS, Schuman LM, Mehl ES, Fraumeni JF Jr. Etiology of cancer of the renal pelvis. J N C I 1983; 71: 287-91. 41. Silverman DT, Hoover RN, Albert S , Graff KM. Occupation and cancer of the lower urinary tract in Detroit. J N C I 1983; 70: 237-45. 42. Mommsen S, Aagard J. Occupational exposures as a risk indicator of male bladder carcinoma in a p;edominantly rural area. Acta Radio1 Oncol 1984; 23: 147-52. 43. Schoenberg JB, Stemhagen A, Mogienicki AP, Altman R, Abe T, Mason TJ. Case-control study of bladder cancer in New Jersey. I. Occupational exposures in white males. J N C I 1984; 72: 973-81. 44. Thtriault G, Tremblay C, Cordier S , et al. Bladder cancer in the aluminum industry. Lancet 1984; 1: 947-50. 45. Morrison AS, Ahlbom A, Verhoek WG, Aori IL, Ohno Y, Obata K. Occupation and bladder cancer in Boston USA, Manchester, UK and Nagoya, Japan. J Eprdernzol Cotnm Health 1985; 39: 294-300. 46. Dunham LJ, Rabson AS, Stewart HL, etal. Rates, interview, and pathology study of cancer of the urinary bladder in - Aromatic amines and cancer New Orleans, Louisiana. JNCI 1968; 41: 683. 47, Tola3, Tenho M, Korkala ML, Jarvinen E. Cancer of the urinary bladder in Finland. Int Arch Occup Environ Health 1980; 46: 43-51. 48. Vineis P, Magnani C. Occupation and bladder cancer in males: a case-control study. Int J Cancer 1985; 35: 599-606. 49. Tremblay C, Armstrong B, Thiriault G, Brodeur J. Estimation of risk of developing bladder cancer among workers exposed to coal tar pitch volatiles in the primary aluminum industry. A m J Ind Med 1995: 27: 335-48. 50. Steineck G, Plato N, Norell SE, Hogstedt C. Urothelial cancer and some industry-related chemicals: an evaluation of the epidemiologic literature. A m J Ind Med 1990; 17: 371-91. 51. International Agency for Researchon Cancer. Occupational Exposures of Hairdressers and Barbers and Personal Use of Hair Colourants; Some Hair Dyes, Cosmetic Colorants, Industrial Dyestuff and Aromatic Amines. Lyon, France: IARCJ993; IARC Monogr Eval Risks Humans, Vol. 57. 52. Huff J. Chemicals and cancer in humans: first evidence in experimental animals. Environ Health Perspect 1993; 100: 201-10. 53. Vineis P, Simonato L.Proportion of lung and bladder cancers in males resulting from occupation: A systematic approach. Arch Environ Health 1991; 46: 6-15. 54. Vainio H, Matos E, Boffetta P, Kogevinas M. Occupational cancer in developing and newly industrialized countries. Ann Acad Med Singapore 1993; 22: 170-81. 55. Kogevinas M, Boffetta P, Pearce N. Occupational exposure to carcinogens in developing countries. In: Pearce N, Matos E, Boffetta P, Kogevinas M., eds. Occupational Cancer in Developing Countries. Oxford, UK: Oxford University Press, 1994; IARC Sci. Pub. No. 129: 63-95. , 56. Xue-Yun Y, Ji-Gang C,Yong-Ning H. Studies on the re- lation between bladder cancer and benzidine or its derived dyes in Shanghai. BYJ Ind Med 1990; 4 7 544-52. 57. Zheng W, Mc Laughlin J, Gao Y, Silverman DT, Gao R, Blot WJ. Bladder cancer and occupation in Shanghai, 198084. Am J Ind Med 1992; 21: 877-85. 58. Notani PN, Shah P, Jayat K, Bdakrishnan V. Occupation and cancers of the lung and bladder: a case-control study in Bombay. Znt J Epidemioll993; 22: 185-91. 59. International Agency for Research on Cancer. Tobacco Smoking. Lyon, France: IARC,1986; I A R C Monogr Eval Risks Humans, Vol. 38. 60. Vineis P. Epidemiological models of carcinogenesis: the exampleof bladder cancer. CancerEpidemiol Biomark Prev 1992; 1: 149-53. 61. Bartsch H, Malaveille C, Friesen M, Kadlubar FF, Vineis P. Black (air cured) and blond (flue cured) tobacco - Cancer risk IV: Molecular dosimetry studies implicate aromatic amines as bladder carcinogens. Eur J Cancer 1993; 29A: 1199-207. 62. Talaska G, Al-Juburi AZSS, Kadlubar FF. Smoking-related carcinogen-DNA adducts in biopsy samples of human urinary bladder: identification of N-(deoxyguanosin-8-y1)4-aminobiphenyl as a major adduct. Proc Natl Acad Sn' U S A 1991; 88: 5350-454. 63. Talaska G, Schamer M, Skipper P, et al. Detection of carcinogen-DNA adducts in exfoliated urothelial cells of cigarette smokers: association with smoking, hemoglobin adducts, and urinary mutagenicity. Cancer Epidemiol Biomark Prev 1991; 1: 61-6. 64. Vineis P, Talaska G, Malaveille C, et al. DNA adducts in urothelial cells: relationship with biomarkers of exposure to arylamines and polycyclic aromatic hydrocarbons from tobacco smoke. Int J Cancer 1996; 65: 314-6. 65. Vineis P, Bartsch H, Caporaso N, et ai. Genetically-based N-acetyltransferase metabolic polymorphism and lowlevel environmental exposure to carcinogens. Nature 1994; 369: 154-6. 66. D'Errico A, Taioli E, Chen X, Vineis P. Genetic metabolic polymorphisms and the risk of cancer: a review of the literature. Biomarkers 1996; 1: 149-73. 67. Skov T, Sprogel P, Engholm, Frolund C. Cancer of the lung and urinary bladder in Denmark, 1943-87:a cohort analysis. Cancer Causes Control 1991; 2: 365-9. 68. Hartge P, Harvey EB, Linehan WM, et al. Unexplained excess risk of bladder cancer in men. JNCI 1990; 82: 1636- 40. 69. Anton-Culver H, Lee-Feldstein A, Taylor TH. The association of bladder cancer risk with ethnicity, gender and smoking. Ann Epidemiol 1993; 3: 429-33. 70. Cantor KP, Lynch CF, Johnson D. Bladder cancer, parity and age at first birth. Cancer Causes Control 1992; 3: 57-62. 71. Fenech M, Neville S, Rinaldi J. Sex is an important variable affecting spontaneous micronucleus frequency in cytokinesis-blocked lymphocytes. Mutation Res 1994;313: 203-7. Cancer Causes and Control. Vol 8. 1997 355