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REVIEW Perspective's on Comparing Risks of Environmental Carcinogens` Frederica Perenz,' Paolo Boffetta" In 1987, investigator,s (Ames et a1.) concluded that the risks of man-made industrial carcinogens and pesticides (outside of the workplace) are trivial compared with the risks of nat- urally occurring carc:inogens found mostiy in the diet. They used a ranking syster.n based on human exposure and rodent potency (HERP) datta to arrive at this conclusion. As a re- sult, they reeommend that regulatory agencies, such as the Environmental ProU:ction Agency and the Food and Drug Administration, ba&: their priorities in this area on their HERP system. We ;malyzed the assumptions and data set upon which the HERPs were based, concluding that such a simplified apprce,ch to set public health policy is inap- propriate given the underlying uncertainties. However, we ote that when comparisons are consistently based on esti- .nates of average daily exposure to common carcinogens, the .IiERl' scores of many man-made pollutants are compara- ble to those of naturally octurring carcinogens in the diet. [J Nat1 Cancer Inst 1988;80:1282-1293J Bzckground The majority (ar, estimated 60%-90%) of human can- cer is considered to be attributable- to environmental factors, tors are generally involved (3-5). Moreover, because of the limitations of epidemiology (6), only rarely are human data available that directly link an environmental agent to hu- man cancer. For example, epidemiological studies strongly suggest, although they do not conclusively establish, an as- sociation between organic chemical carcinogens in drinking water (such as chloroform) and cancers at several sites, in- cluding the rectum, colon, and bladder (7-11). Certain di- etary and nutritional factors (such as dietary fat and fiber) have been implicated in cancer of the breast, colon, rectum, and stomach (12,13), but here too a direct causal association has not been established for specific dietary constituents. In addition to active cigarette smoking and a significant num- ber of pollutants in the workplace, established tc human lung carcinogens (14), there is growing evidenct L pas- sive smoking (15) and pollutants in the ambient air (16,17) contribute significantly to lung cancer mortality. However, because of cost and feasibility constraints and the difficulty in identifying an appropriate study population, the vast ma- jority of animal carcinogens, both naturally occurring and man-made, have neither been the subject of epidemiological investigation nor are they likely to be (18). Thus, for practi- cal purposes, as a matter of long-standing policy, regulatory agencies accept the use of positive animal data as predictive of carcinogenic hazard in human beings (19). The alterna- tive, awaiting positive evidence of carcinogenicity in humans. broadly defined to include cigarette smoking, industrial pol- lutants, radiation, diet, and perhaps other life-style factors and viruses (1). Thus, in theory most cancer is preventable through the identification and control of causative factors, in- cluding exposure Ko carcinogens. For decades. policymakers, concerned with the assessment and regulation of environ- mental carcinogens have searched for a systematic way to set priorities among the many candidates. This paper criti- cally evaluates thte most recent proposal for such a ranking scheme (2). Identification of specific etiologic factors and estimation of their relative importance constitute a formidable task. Few cancers are attributable to single factors or exposures: rather, complex interactions between environmental and host fac- 'Received May 26. 1988; revised July I, 1988; accepted July 8. 1988. =Division of Environmental Sciences, Columbia University School of Public Health, New York. NY. 3We gratefully acknowledge the valuable contributions of Drs. Ian Nisbet and Katim Ahmed. We also thank Drs L B. Weinstein. Marvin Schnci- derman. Dale Hattis, David Rall. Norton Nelson, Philip Landrigan. Devra Davis, Lauren Zeise, Irva Hertz-Picciotto, William Pease. and Paolo Vineis for helpful discussions during the pttpantion of this manuscnpt and Drs. Michael Waters and Frank Stack for providing results from the U.S. Envi- ronmental Protection Agency Gene-Toz Data Base. We art grateful to Jan Roby for excellent pn:pantion of the manuscript. 'Corrrspondatce to: Dr. Frederica Perera, Division of Environmental Sciences. Columbia University School of Public Health. 60 Haven Ave.. B-1o9, New York. NY 10032. 1282 Jotunal of the National Cat.cer Institute

tradtttonatty nas oeen rejectea as moratly ana soctaily unac- ceptabie. - A major limitation of epidemiology (and risk assess- ment) is that reliable data on human exposure to specific chemicals are frequently lacking. Therefore, by necessity, most epidemiological studies have relied on crude or in- direct measures of' exposure. A significant number of car- cinogens have been detected in drinking water, ambient air, and the food supp.y: however, reliable monitoring data ex- ist for only a small fraction of these chemicals. For ex- ample, while dozens of pesticides and industrial chemical carcinogens have been measured routinely in surface wa- ter, gi•oundwater, and drinking water, they represent only a small percentage of chemical pollutants present (10,20-23). Over 700 organic chemicals have been found to be present in the U.S. drinking water supply, including 40 known or suspected carcinogens (24). Numerous carcinogenic air pol- lutants (trace metals, polycyclic aromatic hydrocarbons, and volatile organic chemicals) have been detected in ambient air: again, there axe little or no reliable monitoring data on the majority of airborne carcinogens (25). Similarly, many carcinogenic pesticide residues have been identified in the food supply, but reliable exposure data are lacking for most (26)., Testifying to the pervasiveness of environmen- tal contamination are studies showing significant concen- trations of synthetic organic chemicals in the blood, urine, and/or adipose tissue of the U.S. population. These include 1,1,1-trichloro-2,",-bis(p-chlorophenyi)ethane (DDT), dield- rin, heptachlor epoxide, polychlorinated biphenyls (PCBs), and dioxin (27,28). Again, data are far from comprehensive; however, they do show a decline in the concentrations of DDT and PCBs as a result of regulation. Despite their l:imitations, available exposure and epi- demiologic data have served as the basis for a number of widely varying estirnates of the proportion of human cancer in the U.S. population that can be attributed to life-style, occupational exposures, or other environmental pollution. These exercises have generated significant debate, as much over the underlying assumptions as the data used to gener- ate them (17,29-3'5). Unfortunately; various such estimates (ranging, for example, from 4% to >20% for occupational exposures) have been cited as a basis for setting priorities for public health protection. This approach ignores both the underlying uncertainties, the relative preventability of var- ious risk factors (36), and the disproportionate impact on some segments of the population. For example, once rec- ognized, most chemical pollutant hazards can be reduced or eliminated by practical means. Moreover, the involuntary nature of these exlx sures necessitates control at the source, in contrast to expos ures related to life-style (e.g., diet and smoking), which can be addressed more effectively through public education regarding personal behavioral choices. An- other inherent problem with the approach of estimates is that it obscures the much higher risks to certain subpopulations. For example, if the contribution of occupational carcinogens to all cancer deaths in the United States were as low as 3%, for male industrial workers as a group, workplace carcino- gens would account for at least 25% of all identified causes of cancer (33). ?,notner toot tnat nas been usea increastngly by regula- tory agencies to set priorities and even to detennine accept- able levels of exposure to individual environmental contam- inants has been quantitative risk assessment. Here, also, the lack of good information on human exposure as well as the usual paucity of epidemiological data are compounded by uncertainties regarding the proper way to extrapolate from high to low dose and from experimental animals to hu- mans (37). To offset these uncertainties, the four major U.S. regulatory agencies, including the Environmental Protection Agency (EPA), the Occupational Safety and Health Admin- istration (OSHA), the Consumer Product Safety Commis- sion, and the Food and Drug Administration (FDA), have traditionally preferred conservative models that incorporate an assumption of low-dose linearity, regardless of the pre- sumed mechanism of action of the chemical carcinogen (19). However, in certain instances, these conservative models may underestimate cancer risk. For example, the widely ac- cepted linearized multistage model (38), considered to be one of the most conservative of the biologically plausible risk-assessment models, works on the assumption that the ex- posed population is of uniform susceptibility and that interac- tions do not occur between chemical exposures and other risk factors. Yet significant intraindividual variability has been demonstrated for human metabolism and binding of drugs and carcinogens (39-45) as well as for repair of DNA dam- age (46). Moreover, a number of epidemiological studies have demonstrated synergism between chemical exposures and host factors, such as cigarette smoking and air pollutants in the workplace and urban air (47,48). To further compli- cate the situation, although nonlinear (both superlinear and sublinear) dose-response relationships have been observed experimentally and epidemiologically, the available data do not allow low-dose linearity to be ruled out in any of these cases (49). Given these uncertainties, it is reassuring that, in a number of cases, risks observed in humans have been con- sistent with those calculated from high-dose animal experi- ments with the use of models that incorporated linearity at low dose. These include benzene, ethylene dibromide (EDB), gasoline, asbestos, and ethylene oxide (50-56). Therefore, there is general agreement that the use of quantitative risk assessment, performed with appropriate and consistent as- sumptions and models, affords the possibility of comparing risks for the purpose of setting priorities among selected can- didates for regulation. However, most scientists do not view quantitative risk assessment as capable of providing precise estimates of human risk from individual chemicals: general sources of chemical exposures are considered even less likely candidates for risk estimation by this method- Human ExposureiRodent Potency (HERP) Index Most recently, researchers at the University of Califor- nia at Berkeley and Lawrence Berkeley Laboratory have suggested still another approach to priority setting (2). They have calculated a possible hazard index for selected carcinogens by expressing the human exposure (in mil- ligramsikilogram) as a percentage of the rodent TDso dose Vol. 80, No. 16, Octob+er 19, 1988 REVIEW 1283

(also in milligramsl}:ilogram).' They have compared the re- sultant HERP indict:s for four pollutants found in drinkingg water and indoor air, three man-made pesticides and other residues, 10 natural pesticides and dietary toxins, two food additives, five drugs, and two occupational exposures (see ,able l). The authors conclude that man-made environmen- .1 pollutants, such as pesticide residues and contaminants tn drinking water, are "likely to be of minimal carcinogenic hazard" relative to the background of natural carcinogens (found largely in the diet). They recommend that regulatory agencies that traditionally have emphasized control of expo- sures to man-made or industrial carcinogens (in addition to those in the occupational setting) revise their priorities. The authors acknowledge several major limitations of the HERP system, such as the possibility of interspecies (rodent and human) variation in susceptibility to carcinogens and quantitative uncertai nties regarding the general shape of the dose-response curve, including the possibility of synergistic effects and thresholds for nongenotoxic carcinogens, such as promoters (see discussion below). They caution that it would be a mistake to use the 1-IERP index as a direct estimate of human hazard, but they conclude that the scale provides "a way of setting prior,',ties for concern " Although this is an innovative approach, it suffers from several inherent flaws. First, as we will show in table 2, the results are influenced strongly by the selection of chemicals and whether one classifies them as "man-made" or "natural " The rationale for selection of the individual compounds in table I was not pirovided by the authors, but presumably it was dictated by the nature and availability of both exposure and rodent potency data. As mentioned, the rodent potency Jata base is not comprehensive. For example, it omits a number of carcinogenic pesticides including alachlor, which is of current conce,rn as a food contaminant (26) and has been found in water supply wells at significant concentrations (61). Certainly, the four selected drinking water and air 'Here the TD.o is tha: average daily dose rate to halve the percent of tumor-free animals by the end of a standard lifetime (57). The average TD.o is calculated by taking the harmonic mean of the TD,os of the posi- tive tests in the most sensitive species. From each test, the target site with the lowest TD,o value was used. In general, the harmonic mean and the lowest TDSO differ by a factor of ~2 (58). The source of TD,o values is the Carcinogenic Potency Data Base (CPDB) (57-60).'IOte data base is a comptlation of results hom >3.500 experiments on 975 chemicals. It in- cludes results from the Carcinogenesis BioasSay Program of the National Cancer InstituieiNational Toxicology Program (through May of 1986) as well as studies published in the literature (through December of 1984). The data base is restricted to tests that meet very stringent methodologic crite- ria. Thus certain human carcinogens (such as asbestos and tobacco smoke) are excluded; seven chemicas regarded by the International Agency for Re- search on Cancer (IAF:C) as having sufficient evidence of carcinogenicity in animals (cadmium chlotide, cadmium sulfate, epichlorohydrin, glycidalde- hyde, isosaftole, mestranole, and 2-nitropropane) are recorded in the CPDB as having only negative tesu. The CPDB is a useful tool. but its limitations should be kept in min1 Tabk 1. Possible carctnogentc hazards, as ranked by Ames et al. (2)• Possible hazard (HERP 9c) Carcinogenic exposure .tfan-madt cfumitals in foods and beverages 0.0002 PCBs.t U.S. average daily dietary intake 00003 DDE/DDT.t average daily dietary intake 0.0004 EDB, average daily dietaryintake from grainsigratn products 0.0002 Furylfuramide in 2-fluorenamine, daily dietary intake before banning 0.06 Saccharint in l2•oz diet cola ;Vatural earcinogens in foods and beverages 0.003 DMN in 100 g of cooked bacon 0.006 DEN in 100 g of cooked bacon 0.003 Urethane in 250 mL of sake 0.03 Symphytine in I cup of comfrey herb tea 0.03 Afiatoxin in 1 peanut butter sandwich 0.06 DEN in dried squid. broiled in gas oven 0.07 Allyl isothiocyanate in 5 g of brown mustard 0.1 Estragole in I g of dried basil leaf 0.1 Hydrazines in 1 raw mushroom 0.2 Safrole in natural root beer, before ban 0.008 DMN in 12-oz beer, before 1979 2.8 Ethyl alcoholt in 12-oz beer 4.7 Ethyl aicoholt in 250 mL of wine 6.2 Comfrey root in comfrey-pepsin tablets. 9 daily 1.3 Symphytine in comfrey-pepsin tablets, 9 daily Indoor air poUutaxts 0.6 Formaidehyde in conventional home air. 14 hr/day 0.004 Benzene in conventional home air, 14 hr/day 2.1 Formaldehyde in mobile home air. 14 hr/day Waur pollawistr 0.001 Chioroformt in tap water, 1 L U.S. average 0.004 Tetrachloroethyknet in well water. 1 L, highly contaminated 0.0002 Chlorofotirtt in well water, I L, contaminated 0.0003 Tetrachlotoethyknet in well water, I L contaminated 0.008 Chloroformt in average swimming pool, 1 hr Drugs 0.3 Phenacerin, average dose 5.6 Metronidazole, therapeutic dose 14 Isoniazid, prophylactic dose 16 Phenobarbital, I sleeping pill 17 Clo6brate,t average daily dose Occupational ezpostve 5.8 Formaldehyde, worker's average daily exposure 140 EDB. worker's daily intake, high exposure ' DMN = N-nitrosodimethylamine, and DEN = N-nitrosodiethylamine. t Carcinogens characterized by Ames et al. as nongenotoxic and likely to have thresholds. ,pollutants and the pesticides listed cannot represent the large number of industrial chemicals and pesticides that have been detected frequently in the U.S. drinking water, air, and food supply and that also have evidence of carcinogeniciry in humans and/or laboratory animals (62,63). Moreover, although we are aware that there are many potential dietary hazards, the majority of which also are not well characterized (2,64), the 10 natural dietary carcinogens in table I include a number of exotic foods to which the U.S. general population has limited ezposure (sake, comfrey 94 Journal of the National Cancer Institute

f herb tea, dried squid, brown mustard, and comfrey-pepsin tablets). Therefore, comparisons between-drinking 1 L of water containing average concentrations of chloroform and eating a daily se-ving of dried squid ignore tfJe fact that the average American adult ingests an estimated 2 L or more of water a day (65)5 and rarely, if ever, eats dried squid. An additional problem is that several "natural pesticides and dietary toxins" in table I are misclassified in that they can result from harvesting, manufacturing, or cooking pro- cesses and therefore cannot be considered to be strictly natural. For example. aflatoxin in nuts and grains is par- tiallye attributable to improper harvesting and storage pro- cedures, whereas, as the authors acknowledge, nitrosamines are formed in cured meats through the reaction of secondary amines with nitntes added as preservatives. Carcinogenic nitropyrenes and nitrosamines occur in browned or burned meats as a result of cooking with gas flames that generate NO, (2). Moreover, a number of natural substances or food addi- tives in table I have been banned (safrole in natural root beer and AF-2, a Japanese food additive never used in the United States) (67), so that there is no current exposure to the U.S. population. Several of the environmental pollutants have been regulated (chloroform, PCBs, and EDB) or even banned (DDT), so that postregulatory exposures (and HERPs) are predictably low, testifying to the effectiveness of regulation. A second major limitation of the approach of Ames et al. derives from the fact that, as can be seen in table 1, varying exposure indices were used. For waterborne and airborne contaminants, daily exposure was calculated; for pesticides and other residues in food, daily average dietary intake was provided; for "natural" carcinogens in food, one serving was assumed to occur daily; for food additives and drugs, several different measures were used. To illustrate the effect of chemical selection and of as- sumptions regarding levels of exposure, we have constructed table 2; it includes all of the chemicals/exposures in ta- ble 1, except for those dietary constituents not widely con- sumed in the United States and those that have been banned and have no current U.S. exposure. We have also omitted drugs because exposure is generally of short duration; drugs are a special cas~• because they are prescribed when ben- efits are thought -ta outweigh risks to the individual. Fi- nally, we have included in table 2 several chemicals or sources of exposure that are encountered commonly by the U.S. population and for which rodent potency (58-60) and exposure data are available. Unfortunately, in several cases environmental chemicals of concern were in the ro- dent potency data base, but we could not find reliable ex- posure data for specific media. This was true for dioxin or 2,3,7,8-tetrachlorodi,benzo-p-dioxin (TCDD). However, ac- cording to the EPA, a crude estimate of total daily intake of 'In fact, the results of a recent water consumption survey show that for 5% of adults 20-64 yr oid. the average daily consumption of tap water is 2.71 L/day, whereas the a.verage daily total water intake is 3.79 L (66). Vol. 80, No. 16, Octcbi:r 19, 1988 dioxin by sizeable segments of industrialized populations is I pg/kg (28), which corresponds to a HERP of 0.00-t. To avoid the problems of inconsistent exposure indices, we have adopted in table 2 the standard approach of uniformly providing average daily dose to the U.S. adult. We recognize both the uncertainties in available exposure data (143) anc' the fact that the average estimates mask wide interindividua, variation in exposure depeinding on geographical. cultural. economic, social, and host factors. For example, a child's exposure to pollutants in drinking water is proportionally greater than exposure of the adult, because children ingest an estimated I L of water per ! 0 kg of body weight compared with 2 L or more per 70 kg of body weight for the adult (65). Children may also consume more of a contaminated food than adults. In the case of the pesticide daminozide, the daily dose to the U.S. child (1-6 yr) from consumption of apples, apple juice, and peanut butter is from fivefold to 15-fold higher than the daily dose to the U.S. adult (70,71. ) Thus, there are obvious drawbacks to using each of the possible exposure indices (average, worst case, general pop- ulation, or sensitive subpopulation). However, it is imperative in making comparisons that the same measure of exposure be used consistently. This is demonstrated by table 3 in which we compared HERPs from tables 1 and 2 for the same com- pound. . As mentioned above, postregulatory exposures (and HERPs) for environmental carcinogens such as DDT/DDE (1,1-dichloro-2,2'-bis(p-chlorophenyl)ethylene) are low. Therefore, in a number of cases we have included preregu- latory and postregulatory values for purposes of comparison. Unfortunately, any listing of chemicals such as in tables 1-3 cannot convey the reality of cumulative exposures to different carcinogens in the same medium. Also, it does not reflect the possibility of interactions among them or the need to consider exposures to the same chemical via several different media. For example, the individual has exposure to synthetic volatile organic compounds in the drinking water from ingestion, from dermal absorption while bathing or showering, and from inhalation of the volatilized compound (144). Humans may be exposed concurrently to the same carcinogenic substance via a number of different sources and media. For example, in considering the risk of EDB in grain, the New York Department of Health reasonably chose to sum the potential risks of the pesticide in food, ambient air (from use of unleaded gas), and drinking water (145). Finally, an important distinction not conveyed by either table I or table 2 is that between voluntary and involuntary exposure. As discussed in the- introduction, individuals are capable-of voluntarily.reducing exposure to substances in diet and cigarette smoke that have been identified as carcinogenic hazards. By contrast, individuals cannot feasibly control their exposure to air, water, and workplace pollution. In tables 2 and 3, we have attempted to demonstrate the susceptibility of the HERP system (or any such simplified approach) to the effects of selection of both chemicals and exposure estimates. As is clear from table 3, the differences between tables I and 2 are largely because of these two factors. In contrast to that of Ames et al. (2), our approach. incorporating a representative set of exposures to the U.S. REVIEW 2285

Posstble hazard (HERP %) Tab4e 2. Ranking possible carcinogenic hazards with the use of the methodo+ogy of Amcs et al. (2)' Carcinogenic exposure Average daily carcinogen dqse (70-kg adult) Potency of carcinogen TD50 (mg/kg) Comment+ Man-made chemicalr in foodr/beverages 0.02 Da,minozide in treated apples and apple juice (1987) 20 ug 1.2 (I) 0.002 Da.minozide in peanuts and peanut butter (1987) 1.9 ug 1.2 tf) 0.03 DECP in treated carrots (preregulatory, 1976) 5.1 jig 0.24 ('-) 0.003 DDT. DDD, and DDE in food (preregulatory, 29.0 pg 13 (3) 1968-1969) 0.0003 DDT. DDD, and DDE in food (postregulatory. 2.3 yg 13 (3) , :1980-1982) 0.002 Dieldrin in food (preregulatory, 1968-1969) 1.5 Ag 1.1 (4) 0.001 Dieldrin in food (postregulatory, 1980-1982) 1.1 µg . 1.1 (4) 0.004 EDB in treated apples (preregulatory) 4.1 µg 1.5 (5) 0.0004 EDB in grain products (prerngulatory, 1983) 0.42 µg 1.5 (5) 0.01 PC:Bs in food (preregulatory, 1971) 15 µg 1.7 (6) 0.0002 )'C:Bs in food (postregulatory, 1980-1982) 0.2 ug 1.7 (6) 0.003 Sodium saccharin in diet soda (1977-1978) 4.9 ng 2.100 (7) Natural carcinogens in foods and bevercges 0.003 Aflatoxins in peanuts and peanut butter (1977) 5.8 ng 0.0026 (8) <0.0001 Estragole in basil <3.8 µg 52 (9) 1.6 Ethyl alcohol in beer(1981) 10:2 g 9,100 (10) 0.4 Ethyl alcohol in wine (1981) 2.7 g 9,100 (l0) 1.3 Ethyl alcohol in hard liquor (1981) 8.1 g 9.100 (l0) 0.01 Hydrazines in mushrooms (1977) 0.16 g 20.000 (11) 0,001 DMN in cured meat and bacon (1980) 0.12 µg 0.16 (12) 0.002 DEN in cured meat and bacon (1980) 0.034 Icg 0.021 (12) 0.03 Aeibient air pollutm:ts &:nzene (Los Angeles, preregulatory. 1968) 1.0 mg 53 (l3) 0.0C19 &:nzene (Los Angeles, postregulatory, 1984) 0.32 mg 53 (13) 0.0005 Carbon tetrachloride (U.S. urban and surburban 48 lag 140 (14) areas, 1973-1974) 0.0004 Carbon tetsachloride (U.S. urban areas, 1980) 42 µg 140 (14) 0.0002 DDT (U.S. rural areas, przregulatory, 1972) 2.0 µg 13 (15) 0.00003 DDT (U.S. rural areas, postregulatory, 1974) 0.24 },g 13 (l5) 0.004 EDB (US. urban areas, 1980-1981) 4.3 µg 1.5 (16) 1.8 Formaldehyde (Los Angeles, 1966) 1.9 mg 1.5 (17) 0.4 Formaldehyde (Los Angeles, 1979) 370 µg 1.5 (17) 0.002 PCBs (U.S. suburban aseas, preregulatory, 1975) 2 µg 1.7 (18) 0.000t PCBs (U.S. urban areas, postregulatory, 1979) 150 ng 1.7 (18) 0.003 Tetrachloroethylene (Bayonne, NJ, 1973) 220 µg l00 (19) 0.001 Tetrachloroethylene (Bayonne, NJ. 1983) 92 lcg 100 (19) 0.001 Toxaphene (US. rural artas, 1972) 5.2 ug 5.8 (20) 0.005 Imda®r air pol[uacT.rttt Benzene (personal average. New Jersey, 1981) 173 µg 53 (21) 0.0002 C'arbon tetrachioride (personal average, New Jersey, 16.2 gg 140 (22) 1981) 0.01 Chlordane (average in treated homes, 1976-1982) 203 gg 2> (23) 0.6 Formaldehyde in conventional homes (average of 600 µg 1.5 (24) 2.1 all reported U.S. data) Formaldehyde in mobile homes (U.S. average, 1984) 22 mg 1.5 (24) 0.02 Heptachlor (average in treated homes, 1982) 13.9 )ag 1.2 (25) 0.001 Tetrachloroethylene (personal average, New Jersey, 80 µg l00 (26) 1981) 0.0001 wattr pollutanu C:hlordane (Kansas City drinking water, 0.14 µg 2.4 (27) 0.003 prrregulatory, 1965-1967) Chloroform (average U.S. drinking water, 1976) 170 y,g 90 (28) 0.01 DBCP (California, postregulatory, 1984) 2.0 vg 0.24 (29) 0.007 EDB (Florida, groundwater, 1983) 7.8 Ng 1S (30) 0.03 Heptachlor (South Carolina tunl drinking water, 24 µg 1.2 (31) 0.0003 preregulatory, 1977) PCBs (U.S. surface water, preregulatory, 0.4 ;,g 1.7 , (32) 1971-1974) 0.0002 Tetnchloroethylene (New Jersey water supplies, 12 µg 100 (33) 1985) 0.00002 TCE (US. water supplies, 1985) 14ycg 940 (34) 0.0002 Vinylidine chloride (New Jersey water supplies, 4yAg 24 (35) 1985) 12g6 Journal of the National Cancer Institute

Possible hazard :(HERP %) Carcinogenic exposure Average daily cartinogen dose (70-kg adult) Occupational exposures Potency of carcinogen TD50 (mgikg) CommentT 32.3 13enzene (rubber industry, prere2ulatory, 1942) !2 g 53 36) 006 13enzene (rubber industry. postregulatory, 1980s) 2.4 mg 53 (36) 105.0 1=ormaldehyde (resin and paper manufacture. 1961) 110 mg 1.5 13 7) 3.0 I-ormatdehyde (restn and plasac manutacture. 1990s) 3.2 mg 1.5 (37) 6.2 TCE (small factories. preregulatory, 1940s) 44.1 g 940 (38) 0? f CE /postrt gulatory, 1980s) 0 0.1 g 940 (38) 'Thc selection of chemicals and the estimates of exposui•e differ somewhat from those in Ames et al.; as described in the text. Tocalculate average daily dose over an individual lifetime, we assumed: a) food consumption according to nationwide surveys; b) water consumption: 2 L/day: c) ambient air. inhalation of 20.000 1./day; d) indoor airr inhalation of 10,800 L/14-hr day: e) workplace airr inhalation of 9,600 Llday, 5 days/wk. 50 wk/yr. 40/70 yr (i.e.. 3.768 L/day over an average lifetime) (68).. For carcinogens listed as ambient and indoor air pollutants, the respective HERPs cannot be considered additive, since the 20.0/)Q L/day may include both types of exposure. We also calculated exposure for a 70-kg male adult, although a 60-kg adult is more reasonable (69). When only a range of values was reported in the literature, their geometric mean was used as the average exposure. The HERP is derived by dividing the daily carcinogen dose by 70 kg to provide a milligram-per-kilogram value, which is then given as the percentage of the TD50 dose in the rodent (also in mg/kg). 'See appendix for comments. TabBe 3. Comparison of possible carcinogenic hazards (HERPs) as estimated b;( Ames et al. and with the use of average exposure estimates'•t Carcinogenic exposure Average Worst-case _ `xP"S"" ezpQ'5u= policies principally on comparisons such as these. Man-,*uzdo cliemicnlr in foods and beverages DDE/DDT in food Preregulatory Postregulatory EDB in grains PCBs in food Preregulatory Postregulatory Sodium saccharin in did sodas 0.0003 0.0004 0.0002 0.06 Naturrtl carci=grns in foods and berervges AElatoxins in peanuts and peanut butter 0.03 DP/1N in cured meat and bacon 0.003 DEN in cured meat arid bacon 0.006 Estragole in basil 0.1 Ethvl alcohol in beer 2.8 Etltvl alcohol in wine 4.7 Hydrazines in mushramts 0.1 Ambiunt air pollutanes Formaldehyde in conventional home atr 0.6 - Formaldehyde in mobfle home air 2.1 - R'et:r pollueanu Chloroform in water 0.001 - Tetrachloroethylene in water - 0.0003 TCE in water - 0.004 Occar{oatfosa( esposurrs Formaldehyde in workplace air ® 5.8 Table 2. Continued average ex'posure 0.003 0.0002 0.0004 0.01 0.0002 0.003 0.003 0.001 0.002 <0.0001 1.6 0.4 0.01 0.6 2.1 0.003 0.0002t 0.00002§ 3.0 population, shows that the selected man-made or industrial pollutants generally are comparable in terms of HERP scale to naturally occurring carcinogens in the diet- Because of the limitations in the HERP approach, however, we stress that regulatory agencies would be unwise to base public health Finally, Ames et a1- (2) asserted that nine of the 26 car- cinogens listed in table 1 "are thought to be nongenotoxic" and are therefore likely to have nonlinear dose-response curves or a decreased risk at lower dose. This subject has been discussed frequently (146-149). The general consen- sus on the part of regulatory agencies and expert groups has been that such policy distinctions are premature be- cause they are supported inadequately by scientific data (19,63,147,150,151). . There are few, if any, clear-cut promoters and initia- tors; rather, there is evidence that under different condi- tions the same carcinogen can operate as a complete car- cinogen, an initiator, or a promoter (147). For example, TCDD has demonstrated the ability to act both as a com- plete carcinogen and a promoter (152-155). It is just as difficult to distinguish between genotoxic and nongenotoxic agents because in most cases short-term tests for genetic toxicity have generated a mixture of positive and negative results. This phenomenon has been observed with a vari- ety of chemicals regarded up to this time as model "epi- genetic, late stage" carcinogens: asbestos, the phorbol es- ter 12-O-tetradecanoylphotboI-13-acetate, diethyistilbestrol, and DDT. These compounds have induced a variety of ge- netic effects, either indirectly or directly, in experimental sys- tems or in humans (149). The nine so-called nongenotoxic carcinogens in table I illustrate the difficulty of making such categorical distinc- "D14tN = N-nirrostidimethylamine, TCE = trichloroethyiette% DEN = N-nitrosodiethylamine, and tions. Although in most instances the majority of short-term tSee tables I and 2 for details on daily carcinogettic dose and TD50. :t Worst-case assumption: HERP % = 0.007. $ Worxt-case a.ssumption: HERP % = 0.1. Ames et al. estimate Our estimate, test results have been negative, each of the compounds (with the exception of clofibrate) has tested positive in at least one assay for each of several different genetic toxicity end points Voi. 80, No. 16, October 19, 1988 REVIEW 1287

J 1288 (156).6 For eigl t of the nine chemicais, aitnougn tne evt- drnee of genetic toxic effects is generally lim-ited, it cannot be dismissed. Therefore, it is not possible to'coitclude defini- tively that these are nongenotoxic carcinogens that do not act at some stage and under some conditions, either directly or indirectly, by damaging the genetic material. Viewed in a larger context, the proposed distinction among carcinogens on the basis of presumed mechanism or stage at which they act is belied by the observation that control of late-stage carcinogens that may not be genotoxic may lead to the most rapid reduction in risk, as has been seen with postmenopausal estrogen therapy and cigarette smoking (158). In summary, there is no question that both occupational and food carcinogens are real concerns. However, while the hazards of the workplace are relatively well characterized (68), there is cat:ariy a need for more research on dietary carcinogens. At ,he same time, there is evidence from epi- demiologic, experimental, and monitoring sources that the cumulative risks of environmental pollution are important. Despite its limitations, the HERP analysis for a selection of exposures prevalent in the U.S. environment tends to support this conclusion.. Although it is not possible to estimate the magnitude of these risks with certainty, it is prudent to con- 6As summarized by the IARC, chloroform has been positive in only one of many assays for gene mutation in bacteria and has been largely negative in other systems used. I-,Iowever, it has tested positive in lower eukaryotic sys- tems (inducing diffe:re:ntial toxic effects in DNA rrpair-deficient strains, gene conversion, and/or recombination and reverse mutation). Trichloroethylene has been positive in a number of assays. It has induced genetic toxic ef- fects in bacteria (mutation), in yeast (gene conversion or recombination and mutation), in Tradescantfa (mutation), in rodent cells (transformation), in hu- man cells in vitro (unscheduled DNA synthesis (UDS) and sister chromatid exchanges (SCEs)J„ ui animals in vitro (DNA damage), and in animal cells in vivo (mutation and micronuclei). Tetrachloroethylene. PCBs, and DDT have been largely negative in assays for genetic toxic effects; however, for tetaachloroethylene tlterz have been positive results in yeast (recombination or gene conversion), in Tracescanaa (mutation), and in animal cells (trans- formation and DNA damage). PCBs have induced DNA damage in animal cells in vitro and UDS in rat primary hepatocytes DDT has been positive in insect systems (dominant lethal mutation and aneuploidy), animal cells in vitro (chromosome aberrations), and animal cells in vivo (chromosome aberrations and dominant lethal mutation). Ethyl alcohol has been studied extensively; a significant number of positive results were found. Evidence of genetic toxic effiecas includes gene conversion or tzcombination, muta- tion, and aneuploidy in lower eukaryotic systems: SCE, micronuclei, andd chromosome aberrations in plant systems; SCE, chromosome aberrations, and aneuploidy in animal cells in vitro; SCE, chromosome aberrations, mi- cronuclei. dominant lethal mutations, and aneuploidy in animal cells in vivo; and SCE and chromusome aberrations in human cells in vivo. Alcoholism is associated with increased incidence of chromosome aberrations (157). For phenobarbitoL the preponderance of results has been negative. How- ever, there is evidence for the induction of gene mutation in bacteria and aneuploidy in yeast: gene mutadon. SCE, and chromosome aberrations in rodent cells in vitrn: cell transformation in rodent cells, as well as gene mu- tadon and chromosome aberrations in human cells in vitro. 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