REVIEW Perspectives on Comparing Risks of Environmental Carcinogens1 Frederica Perera, * Paolo Boffetta ,2,3 Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 tors are generally involved (3-5). Moreover, because of the limitations of epidemiology (6), only rarely are human data In 1987, investigators (Ames et al.) concluded that the risks available that directly link an environmental agent to hu- of man-made industrial carcinogens and pesticides (outside man cancer. For example, epidemiological studies strongly of the workplace) are trivial compared with the risks of nat- suggest, although they do not conclusively establish, an as- urally occurring carcinogens found mostly in the diet. They sociation between organic chemical carcinogens in drinking used a ranking system based on human exposure and rodent water (such as chloroform) and cancers at several sites, in- potency (HERP) data to arrive at this conclusion. As a re- cluding the rectum, colon, and bladder (7-11). Certain di- sult, they recommend that regulatory agencies, such as the etary and nutritional factors (such as dietary fat and fiber) Environmental Protection Agency and the Food and Drug have been implicated in cancer of the breast, colon, rectum, Administration, base their priorities in this area on their and stomach (12,13), but here too a direct causal association HERP system. We analyzed the assumptions and data set has not been established for specific dietary constituents. In upon which the HERPs were based, concluding that such addition to active cigarette smoking and a significant num- a simplified approach to set public health policy is inap- ber of pollutants in the workplace, established to be human propriate given the underlying uncertainties. However, we lung carcinogens (14), there is growing evidence that pas- note that when comparisons are consistently based on esti- sive smoking (75) and pollutants in the ambient air (16,17) mates of average daily exposure to common carcinogens, the contribute significantly to lung cancer mortality. However, HERP scores of many man-made pollutants are compara- because of cost and feasibility constraints and the difficulty ble to those of naturally occurring carcinogens in the diet [J Nat! Cancer lust 1988;80:1282-1293] 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 (75). Thus, for practi- cal purposes, as a matter of long-standing policy, regulatory Background agencies accept the use of positive animal data as predictive of carcinogenic hazard in human beings (19). The alterna- The majority (an estimated 60%-90%) of human can- tive, awaiting positive evidence of carcinogenicity in humans, cer is considered to be attributable to environmental factors, broadly defined to include cigarette smoking, industrial pol- lutants, radiation, diet, and perhaps other life-style factors and viruses (7). Thus, in theory most cancer is preventable 'Received May 26, 1988; revised July 1, 1988; accepted July 8, 1988. through the identification and control of causative factors, in- 2 Division of Environmental Sciences, Columbia University School of cluding exposure to carcinogens. For decades, policymakers Public 3 Health, New York, NY. concerned with the assessment and regulation of environ- We gratefully acknowledge the valuable contributions of Drs. Ian Nisbet and Karim Ahmed We also thank Drs. L B. Weinstein, Marvin Schnei- mental carcinogens have searched for a systematic way to derman, Dale Hattis, David Rail, Norton Nelson, Philip Landrigan, Devra set priorities among the many candidates. This paper criti- Davis, Lauren Zeise, Irva Hertz-Picciotto, William Pease, and Paolo Vineis cally evaluates the most recent proposal for such a ranking for helpful discussions during the preparation of this manuscript and Drs. scheme (2). Michael Waters and Frank Stack for providing results from the U.S. Envi- Identification of specific etiologic factors and estimation of ronmental Protection Agency Gene-Tox Data Base. We are grateful to Jan Roby for excellent preparation of the manuscript their relative importance constitute a formidable task. Few * Correspondence to: DT. Frederica Perera, Division of Environmental cancers are attributable to single factors or exposures; rather, Sciences, Columbia University School of Public Health, 60 Haven Ave., complex interactions between environmental and host fac- B-109, New York, NY 10032. 1282 Journal of the National Cancer Institute traditionally has been rejected as morally and socially unac- Another tool that has been used increasingly by regula- ceptable. tory agencies to set priorities and even to determine accept- A major limitation of epidemiology (and risk assess- able levels of exposure to individual environmental contam- ment) is that reliable data on human exposure to specific inants has been quantitative risk assessment Here, also, the chemicals are frequently lacking. Therefore, by necessity, lack of good information on human exposure as well as the most epidemiological studies have relied on crude or in- usual paucity of epidemiological data are compounded by direct measures of exposure. A significant number of car- uncertainties regarding the proper way to extrapolate from cinogens have been detected in drinking water, ambient air, high to low dose and from experimental animals to hu- and the food supply; however, reliable monitoring data ex- mans (37). To offset these uncertainties, the'four major U.S. ist for only a small fraction of these chemicals. For ex- regulatory agencies, including the Environmental Protection ample, while dozens of pesticides and industrial chemical Agency (EPA), the Occupational Safety and Health Admin- carcinogens have been measured routinely in surface wa- istration (OSHA), the Consumer Product Safety Commis- ter, groundwater, and drinking water, they represent only a sion, and the Food and Drug Administration (FDA), have small percentage of chemical pollutants present (10,20-23). traditionally preferred conservative models that incorporate Over 700 organic chemicals have been found to be present an assumption of low-dose linearity, regardless of the pre- in the U.S. drinking water supply, including 40 known or sumed mechanism of action of the chemical carcinogen (79). Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 suspected carcinogens (24). Numerous carcinogenic air pol- However, in certain instances, these conservative models lutants (trace metals, polycyclic aromatic hydrocarbons, and may underestimate cancer risk. For example, the widely ac- volatile organic chemicals) have been detected in ambient cepted linearized multistage model (38), considered to be air, again, there are little or no reliable monitoring data one of the most conservative of the biologically plausible on the majority of airborne carcinogens (25). Similarly, risk-assessment models, works on the assumption that the ex- many carcinogenic pesticide residues have been identified posed population is of uniform susceptibility and that interac- in the food supply, but reliable exposure data are lacking for tions do not occur between chemical exposures and other risk most (26). Testifying to the pervasiveness of environmen- factors. Yet significant intraindividual variability has been demonstrated for human metabolism and binding of drugs tal contamination are studies showing significant concen- and carcinogens (39-45) as well as for repair of DNA dam- trations of synthetic organic chemicals in the blood, urine, age (46). Moreover, a number of epidemiological studies and/or adipose tissue of the U.S. population. These include have demonstrated synergism between chemical exposures l,l,l-trichloro-2^-bis(p-chlorophenyl)ethane (DDT), dield- and host factors, such as cigarette smoking and air pollutants rin, heptachlor epoxide, polychlorinated biphenyls (PCBs), in the workplace and urban air (47,48). To further compli- and dioxin (27,28). Again, data are far from comprehensive; cate the situation, although nonlinear (both superlinear and however, they do show a decline in the concentrations of sublinear) dose-response relationships have been observed DDT and PCBs as a result of regulation. experimentally and epidemiologically, the available data do Despite their limitations, available exposure and epi- not allow low-dose linearity to be ruled out in any of these demiologic data have served as the basis for a number of cases (49). Given these uncertainties, it is reassuring that, in widely varying estimates of the proportion of human cancer a number of cases, risks observed in humans have been con- in the U.S. population that can be attributed to life-style, sistent with those calculated from high-dose animal experi- occupational exposures, or other environmental pollution. ments with the use of models that incorporated linearity at These exercises have generated significant debate, as much low dose. These include benzene, ethylene dibromide (EDB), over the underlying assumptions as the data used to gener- gasoline, asbestos, and ethylene oxide (50-56). Therefore, ate them (17,29-35). Unfortunately, various such estimates there is general agreement that the use of quantitative risk (ranging, for example, from 4% to >20% for occupational assessment, performed with appropriate and consistent as- exposures) have been cited as a basis for setting priorities sumptions and models, affords the possibility of comparing for public health protection. This approach ignores both the risks for the purpose of setting priorities among selected can- underlying uncertainties, the relative preventability of var- didates for regulation. However, most scientists do not view ious risk factors (36), and the disproportionate impact on quantitative risk assessment as capable of providing precise some segments of the population. For example, once rec- estimates of human risk from individual chemicals; general ognized, most chemical pollutant hazards can be reduced sources of chemical exposures are considered even less likely or eliminated by practical means. Moreover, the involuntary candidates for risk estimation by this method. nature of these exposures necessitates control at the source, in contrast to exposures related to life-style (e.g., diet and smoking), which can be addressed more effectively through public education regarding personal behavioral choices. An- Human Exposure/Rodent Potency (HERP) Index other inherent problem with the approach of estimates is that it obscures the much higher risks to certain subpopulations. Most recently, researchers at the University of Califor- For example, if the contribution of occupational carcinogens nia at Berkeley and Lawrence Berkeley Laboratory have to all cancer deaths in the United States were as low as 3%, suggested still another approach to priority setting (2). for male industrial workers as a group, workplace carcino- They have calculated a possible hazard index for selected gens would account for at least 25% of all identified causes carcinogens by expressing the human exposure (in mil- of cancer (33). ligrams/kilogram) as a percentage of the rodent TD50 dose Vol. 80, No. 16, October 19, 1988 REVIEW 1283 (also in milligrams/kilogram).4 They have compared the re- Table 1. Possible carcinogenic hazards, as ranked by Ames et al. (2)* sultant HERP indices for four pollutants found in drinking Possible water and indoor air, three man-made pesticides and other hazard Carcinogenic exposure residues, 10 natural pesticides and dietary toxins, two food (HERP %) additives, five drugs, and two occupational exposures (see table 1). The authors conclude that man-made environmen- Man-made chemicals in foods and beverages tal pollutants, such as pesticide residues and contaminants 0.0002 PCBs,t VS. average daily dietary intake 0.0003 DDE/DDT,t average daily dietary intake in drinking water, are "likely to be of minimal carcinogenic 0.0004 EDB, average daily dietary intake from grains/grain products hazard" relative to the background of natural carcinogens 0.0002 Furylfuramide in 2-fluorenamine, daily dietary intake before (found largely in the diet). They recommend that regulatory banning agencies that traditionally have emphasized control of expo- 0.06 Saccharint in 12-oz diet cola sures to man-made or industrial carcinogens (in addition to Natural carcinogens in foods and beverages those in the occupational setting) revise their priorities. 0.003 DMN in 100 g of cooked bacon 0.006 DEN in 100 g of cooked bacon The authors acknowledge several major limitations of the 0.003 Ureuiane in 250 mL of sake HERP system, such as the possibility of interspecies (rodent 0.03 Symphytine in 1 cup of comfrey herb tea and human) variation in susceptibility to carcinogens and 0.03 Aflatoxin in 1 peanut butter sandwich Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 0.06 DEN in dried squid, broiled in gas oven quantitative uncertainties regarding the general shape of the 0.07 Allyl isodiiocyanate in 5 g of brown mustard dose-response curve, including the possibility of synergistic 0.1 Estragole in 1 g of dried basil leaf effects and thresholds for nongenotoxic carcinogens, such as 0.1 Hydrazines in 1 raw mushroom 0.2 Safrole in natural root beer, before ban promoters (see discussion below). They caution that it would 0.008 DMN in 12-oz beer, before 1979 be a mistake to use the HERP index as a direct estimate of 2.8 Ediyl alcoholt in 12-oz beer human hazard, but they conclude that the scale provides "a 4.7 Ethyl alcoholt in 250 mL of wine 6.2 Comfrey root in comfrey-pepsin tablets, 9 daily way of setting priorities for concern." 1.3 Symphytine in comfrey-pepsin tablets, 9 daily Although this is an innovative approach, if suffers from Indoor air pollutants several inherent flaws. First, as we will show in table 2, the 0.6 Formaldehyde in conventional home air, 14 hr/day results are influenced strongly by the selection of chemicals 0.004 Benzene in conventional home air, 14 hr/day and whether one classifies them as "man-made" or "natural." 2.1 Formaldehyde in mobile home air, 14 hr/day The rationale for selection of the individual compounds in Water pollutants table 1 was not provided by the authors, but presumably it 0.001 Chloroform t in tap water, 1 L U.S. average was dictated by the nature and availability of both exposure 0.004 Tetrachloroediylenet in well water, 1 L, highly contaminated 0.0002 Chloroform! in well water, 1 L, contaminated and rodent potency data. As mentioned, the rodent potency 0.0003 Tetrachloroediylenet in well water, 1 L, contaminated data base is not comprehensive. For example, it omits a 0.008 Chloroform t in average swimming pool, 1 hr number of carcinogenic pesticides including alachlor, which Drugs is of current concern as a food contaminant (26) and has 0.3 Phenacetin, average dose been found in water supply wells at significant concentrations 5.6 Metronidazole, dierapeutic dose (67). Certainly, the four selected drinking water and air 14 Isoniazid, prophylactic dose 16 Phenobarbital, 1 sleeping pill 17 Clofibrate.t average daily dose Occupational exposure 5.8 Formaldehyde, worker's average daily exposure 140 EDB, worker's daily intake, high exposure *DMN = yV-nitrosodimethylamine, and DEN = W-nitrosodiediylamine. t Carcinogens characterized by Ames et al. as nongenotoxic and likely to 4 have thresholds. Here the TD 5 0 is the average daily dose rate to halve the percent of tumor-free animals by die end of a standard lifetime (57). The average TD 3 0 is calculated by taking die harmonic mean of. die TD5Os of the posi- tive tests in die most sensitive species. From each test, die target site widi die lowest TD 5 0 value was used. In general, the harmonic mean and die lowest TD 3 0 differ by a factor of <~2 (58). The source of TD 5 0 values is the Carcinogenic Potency Data Base (CPDB) (57-60). The data base is a compilation of results from >3,5OO experiments on 975 chemicals. It in- pollutants and the pesticides listed cannot represent the large cludes results from the Carcinogenesis Bioassay Program of the National Cancer Institute/National Toxicology Program (through May of 1986) as number of industrial chemicals and pesticides that have been well as studies published in the literature (dirough December of 1984). The detected frequently in the U.S. drinking water, air, and food data base is restricted to tests Uiat meet very stringent methodologic crite- supply and that also have evidence of carcinogenicity in ria. Thus certain human carcinogens (such as asbestos and tobacco smoke) humans and/or laboratory animals (62,63). are excluded; seven chemicals regarded by the International Agency for Re- Moreover, although we are aware that there are many search on Cancer (1ARC) as having sufficient evidence of carcinogenicity in animals (cadmium chloride, cadmium sulfate, epichlorohydrin, glycidalde- potential dietary hazards, the majority of which also are not hyde, isosafrole, mestranole, and 2-nitropropane) are recorded in die CPDB well characterized (2,64), the 10 natural dietary carcinogens as having only negative tests. The CPDB is a useful tool, but its limitations in table 1 include a number of exotic foods to which the should be kept in mind. U.S. general population has limited exposure (sake, comfrey 1284 Journal of the National Cancer Institute herb tea, dried squid, brown mustard, and comfrey-pepsin dioxin by sizeable segments of industrialized populations is tablets). Therefore, comparisons between drinking 1 L of 1 pg/kg (25), which corresponds to a HERP of 0.004. water containing average concentrations of chloroform and To avoid the problems of inconsistent exposure indices, we eating a daily serving of dried squid ignore the fact that the have adopted in table 2 the standard approach of uniformly average American adult ingests an estimated 2 L or more of providing average daily dose to the U.S. adult. We recognize water a day C65)5 and rarely, if ever, eats dried squid. both the uncertainties in available exposure data (143) and An additional problem is that several "natural pesticides the fact that the average estimates mask wide interindividual and dietary toxins" in table 1 are misclassified in that they variation in exposure depending on geographical, cultural, can result from harvesting, manufacturing, or cooking pro- economic, social, and host factors. For example, a child's cesses and therefore cannot be considered to be strictly exposure to pollutants in drinking water is proportionally natural. For example, aflatoxin in nuts and grains is par- greater than exposure of the adult, because children ingest an tially attributable to improper harvesting and storage pro- estimated 1 L of water per 10 kg of body weight compared cedures, whereas, as the authors acknowledge, nitrosamines with 2 L or more per 70 kg of body weight for the adult are formed in cured meats through the reaction of secondary (65). Children may also consume more of a contaminated amines with nitrites added as preservatives. Carcinogenic food than adults. In the case of the pesticide daminozide, nitropyrenes and nitrosamines occur in browned or burned the daily dose to the U.S. child (1-6 yr) from consumption Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 meats as a result of cooking with gas flames that generate of apples, apple juice, and peanut butter is from fivefold to NO2 (2). 15-fold higher than the daily dose to the U.S. adult (70,71.) Moreover, a number of natural substances or food addi- Thus, there are obvious drawbacks to using each of the tives in table 1 have been banned (safrole in natural root possible exposure indices (average, worst case, general pop- beer and AF-2, a Japanese food additive never used in the ulation, or sensitive subpopulation). However, it is imperative United States) (67), so that there is no current exposure to the in making comparisons that the same measure of exposure U.S. population. Several of the environmental pollutants have be used consistently. This is demonstrated by table 3 in which been regulated (chloroform, PCBs, and EDB) or even banned we compared HERPs from tables 1 and 2 for the same com- (DDT), so that postregulatory exposures (and HERPs) are pound. predictably low, testifying to the effectiveness of regulation. As mentioned above, postregulatory exposures (and A second major limitation of the approach of Ames et al. HERPs) for environmental carcinogens such as DDT/DDE derives from the fact that, as can be seen in table 1, varying (l,l-dichloro-2,2'-bis(p-chlorophenyl)ethylene) are low. exposure indices were used. For waterborne and airborne Therefore, in a number of cases we have included preregu- contaminants, daily exposure was calculated; for pesticides latory and postregulatory values for purposes of comparison. and other residues in food, daily average dietary intake was Unfortunately, any listing of chemicals such as in tables provided; for "natural" carcinogens in food, one serving was 1-3 cannot convey the reality of cumulative exposures to assumed to occur daily, for food additives and drugs, several different carcinogens in the same medium. Also, it does different measures were used. not reflect the possibility of interactions among them or the To illustrate the effect of chemical selection and of as- need to consider exposures to the same chemical via several sumptions regarding levels of exposure, we have constructed different media. For example, the individual has exposure to table 2; it includes all of the chemicals/exposures in ta- synthetic volatile organic compounds in the drinking water ble 1, except for those dietary constituents not widely con- from ingestion, from dermal absorption while bathing or sumed in the United States and those that have been banned showering, and from inhalation of the volatilized compound and have no current U.S. exposure. We have also omitted (144). Humans may be exposed concurrently to the same drugs because exposure is generally of short duration; drugs carcinogenic substance via a number of different sources and are a special case because they are prescribed when ben- media. For example, in considering the risk of EDB in grain, efits are thought to outweigh risks to the individual. Fi- the New York Department of Health reasonably chose to nally, we have included in table 2 several chemicals or sum the potential risks of the pesticide in food, ambient air sources of exposure that are encountered commonly by (from use of unleaded gas), and drinking water (145). the U.S. population and for which rodent potency (58-60) Finally, an important distinction not conveyed by either and exposure data are available. Unfortunately, in several table 1 or table 2 is that between voluntary and involuntary cases environmental chemicals of concern were in the ro- exposure. As discussed in the introduction, individuals are dent potency data base, but we could not find reliable ex- capable of voluntarily reducing exposure to substances in diet posure data for specific media. This was true for dioxin or and cigarette smoke that have been identified as carcinogenic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, ac- hazards. By contrast, individuals cannot feasibly control their cording to the EPA, a crude estimate of total daily intake of 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 5 In fact, the results of a recent water consumption survey show that for between tables 1 and 2 are largely because of these two 5% of adults 20-64 yr old, the average daily consumption of tap water is factors. In contrast to that of Ames et al. (2), our approach, 2.71 L/day, whereas the average daily total water intake is 3.79 L (66). incorporating a representative set of exposures to the U.S. Vol. 80, No. 16, October 19, 1988 REVIEW 1285 Table 2. Ranking possible carcinogenic hazards with the use of the methodology of Ames et al. (2)* Possible Average daily Potency of Carcinogenic hazard carcinogen dose carcinogen Commentt exposure (HERP %) (70-kg adult) TDJO (mg/kg) Man-made chemicals in foods/beverages 0.02 Damioozide in treated apples and apple juke (1987) 20 Mg \2 (1) 0.002 Daminozide in peanuts and peanut butter (1987) 1.9 Mg \2 (1) 0.03 DBCP in treated carrots (preregulatory, 1976) 5.1 Mg 0.24 (2) 0.003 DDT, DDD, and DDE in food (preregulatory, 29.0 Mg 13 (3) 1968-1969) 0.0003 DDT, DDD, and DDE in food (postregulatory, 2.3 Mg 13 (3) (1980-1982) 0.002 . Dieldrin in food (preregulatory, 1968-1969) 1.5 Mg 1.1 (4) 0.001 Dieldrin in food (postregulatory, 1980-1982) 11 Mg 1.1 (4) 0.004 EDB in treated apples (preregulatory) 4.1 Mg \5 (5) 0.0004 EDB in grain products (preregulatory, 1983) 0.42 m \5 (5) 0.01 PCBs in food (preregulatory, 1971) 15 Mg 1.7 (6) 0.0002 PCBs in food (postregulatory, 1980-1982) 0.2 Mg 1.7 (6) Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 0.003 Sodium saccharin in diet soda (1977-1978) 4.9 ng 2,100 (7) Natural carcinogens in foods and beverages 0.003 Aflatoxins in peanuts and peanut butter (1977) 5.8 ng 0.0026 (8) <0.0001 Estragole in basil • <3.8 Mg 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 (10) 1.3 Ethyl alcohol in hard liquor (1981) 8.1 g 9,100 (10) 0.01 Hydrazines in mushrooms (1977) 0.16 g 20,000 (11) 0.001 DMN in cured meat and bacon (1980) 0.12 Mg 0.16 (12) 0.002 DEN in cured meat and bacon (1980) 0.034 M 0.021 (12) Ambient air pollutants 0.03 Benzene (Los Angeles, preregulatory, 1968) 1.0 mg 53 (13) 0.009 Benzene (Los Angeles, postregulatory,' 1984) 0.32 mg 53 (13) 0.0005 Carbon tetrachloride (US. urban and surburban 48 Mg 140 (14) areas, 1973-1974) 0.0004 Carbon tetrachloride (U.S. urban areas, 1980) 42 Mg 140 (14) 0.0002 DDT (U.S. rural areas, preregulatory, 1972) 2.0 Mg 13 (15) 0.00003 DDT (U.S. rural areas, postregulatory, 1974) 0.24 Mg 13 (15) 0.004 EDB (U.S. urban areas, 1980-1981) 4.3 Mg 1.5 (16) 1.8 Formaldehyde (Los Angeles, 1966) 1.9 mg 1.5 (17) 0.4 Formaldehyde (Los Angeles, 1979) 370 Mg 1.5 (17) 0.002 PCBs (U.S. suburban areas, preregulatory, 1975) 2/ig 1.7 (18) 0.0001 PCBs (.MS. urban areas, postregulatory, 1979) 150 ng 1.7 (18) 0.003 Tetrachloroethylene (Bayonne, NJ, 1973) 2 2 0 Mg 100 (19) 0.001 Tetrachloroethylene (Bayonne, NJ, 1983) 9 2 Mg 100 (19) 0.001 Toxaphene (U.S. rural areas, 1972) 5.2 Mg 5.8 (20) Indoor air pollutants 0.005 Benzene (personal average, New Jersey, 1981) 173 Mg 53 (21) 0.0002 Carbon tetrachloride (personal average, New Jersey, 16.2 Mg 140 (22) 1981) 0.01 Chlordane (average in treated homes, 1976-1982) 20.5 Mg 2.4 (23) 0.6 Formaldehyde in conventional homes (average of 600 Mg \5 (24) all reported US. data) 2.1 Formaldehyde in mobile homes (US. average, 1984) 2.2 mg \5 (24) 0.02 Heptachlor (average in treated homes, 1982) 13.9 Mg \2 (25) 0.001 Tetrachloroethylene (personal average, New Jersey, 80 Mg 100 (26) 1981) Water pollutants 0.0001 Chlordane (Kansas City drinking water, 0.14 2.4 (27) preregulatory, 1965-1967) 0.003 Chloroform (average US. drinking water, 1976) 170 Mg 90 (28) 0.01 DBCP (California, postregulatory, 1984) 2.0 M 0.24 (29) 0.007 EDB (Florida, groundwater, 1983) 7.8 M 1.5 (30) 0.03 Heptachlor (South Carolina rural drinking water, 2 4 Mg 1.2 (3D preregulatory, 1977) 0.0003 PCBs (US. surface water, preregulatory, 0.4 M 1.7 (32) 1971-1974) 0.0002 Tetrachloroethylene (New Jersey water supplies, 12 Mg 100 (33) 1985) 0.00002 TCE (U.S. water supplies, 1985) 14 Mg 940 (34) 0.0002 Vinylidine chloride (New Jersey water supplies, 24 (35) 1985) 1286 Journal of the National Cancer Institute Table 2. Continued Possible Average daily Potency of Carcinogenic carcinogen dose carcinogen hazard exposure Commentt (HERP%) (70-kg adult) TD 50 (mg/kg) Occupational exposures 32.3 Benzene (rubber industry, preregulatory, 1942) 1-2 g 53 (36) 0.06 Benzene (rubber industry, postregulatory, 1980s) 2.4 mg 53 (36) 105.0 Formaldehyde (resin and paper manufacture, 1961) 110 mg 13 (37) 3.0 Formaldehyde (resin and plastic manufacture, 1980s) 32 mg 1.5 (37) 6.2 TCE (small factories, preregulatory, 1940s) 4.1 g 940 (38) 0.2 TCE (postregulatory, 1980s) 0.1 g 940 (38) "The selection of chemicals and the estimates of exposure differ somewhat from those in Ames et al., as described in the text To calculate 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 L/day, d) indoor air inhalation of 10,800 L/14-hr day, e) workplace air inhalation of 9,600 L/day, 5 days/wk, 50 wk/yr, 40/70 yr (ue., 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 20,000 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 Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 rodent (also in mg/kg). t appendix for comments. Table 3. Comparison of possible carcinogenic hazards (HERPs) as estimated by Ames et al. and with the use of average population, shows that the selected man-made or industrial exposure estimates*-t pollutants generally are comparable in terms of HERP scale to naturally occurring carcinogens in the diet. Because of the Ames et al. estimate Our estimate, Carcinogenic limitations in the HERP approach, however, we stress that average exposure Average Worst-case exposure regulatory agencies would be unwise to base public health exposure exposure policies principally on comparisons such as these. Finally, Ames et al. (2) asserted that nine of the 26 car- Man-made chemicals in foods and beverages cinogens listed in table 1 "are thought to be nongenotoxic" DDE/DDT in food and are therefore likely to have nonlinear dose-response Preregulatory — — 0.003 Postregulatory 0.0003 — 0.0002 curves or a decreased risk at lower dose. This subject has EDB in grains 0.0004 — 0.0004 been discussed frequently (146-149). The general consen- PCBs in food sus on the part of regulatory agencies and expert groups Preregulatory — 0.01 Postregulatory 0.0002 — 0.0002 has been that such policy distinctions are premature be- Sodium saccharin in diet sodas — 0.06 0.003 cause they are supported inadequately by scientific data Natural carcinogens in foods and beverages (19,63,147,150,151). Aflatoxins in peanuts and 0.03 0.003 There are few, if any, clear-cut promoters and initia- peanut butter tors; rather, there is evidence that under different condi- DMN in cured meat and bacon 0.003 0.001 DEN in cured meat and bacon 0.006 0.002 tions the same carcinogen can operate as a complete car- Estragole in basil — 0.1 <0.0001 cinogen, an initiator, or a promoter (147). For example, Ethyl alcohol in beer — 2.8 1.6 TCDD has demonstrated the ability to act both as a com- Ethyl alcohol in wine 4.7 0.4 Hydrazines in mushrooms — 0.1 0.01 plete carcinogen and a promoter (152-155). It is just as Ambient air pollutants difficult to distinguish between genotoxic and nongenotoxic agents because in most cases short-term tests for genetic Formaldehyde in conventional 0.6 0.6 home air toxicity have generated a mixture of positive and negative Formaldehyde in mobile home 2.1 — 2.1 results. This phenomenon has been observed with a vari- air ety of chemicals regarded up to this time as model "epi- Water pollutants genetic, late stage" carcinogens: asbestos, the phorbol es- Chloroform in water 0.001 0.003 ter 12-0-tetradecanoylphorbol-13-acetate, diethylstiJbestrol, Tetrachloroethylene in water — 0.0003 0.00021 and DDT. These compounds have induced a variety of ge- TCE in water 0.004 0.000025 netic effects, either indirectly or directly, in experimental sys- Occupational exposures tems or in humans (149). Formaldehyde in workplace 5.8 3.0 The nine so-called nongenotoxic carcinogens in table 1 illustrate the difficulty of making such categorical distinc- •DMN = yV-nitrosodimethylamine, DEN = W-nitrosodiethylamine, and tions. Although in most instances the majority of short-term TCE = trichloroethylene. test results have been negative, each of the compounds (with tSee tables 1 and 2 for details on daily carcinogenic dose and TD50. t Worst-case assumption: HERP % = 0.007. the exception of clofibrate) has tested positive in at least one § Worst-case assumption; HERP % = 0.1. assay for each of several different genetic toxicity end points Vol. 80, No. 16, October 19, 1988 REVIEW 1287 (156).6 For eight of the nine chemicals, although the evi- tinue to reduce involuntary exposures to carcinogens. The dence of genetic toxic effects is generally limited, it cannot dramatic decrease in estimated cancer risk following regula- be dismissed. Therefore, it is not possible to conclude defini- tion of a number of industrial chemicals illustrates this point. tively that these are nongenotoxic carcinogens that do not Controlling exposures to carcinogens such as those listed in act at some stage and under some conditions, either directly table 2 has important side benefits in that many carcinogens or indirectly, by damaging the genetic material. Viewed in a are mutagenic, teratogenic, reproductive, or neurological tox- larger context, the proposed distinction among carcinogens icants (36). 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 References rapid reduction in risk, as has been seen with postmenopausal 1. HIGGINSON J, MUIR CS. 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Results of a two-year chronic toxicity sessment for occupationally exposed workers. Regul Toxicol Pharma- and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats. col 1833:355-371. Toxicol Appl Pharmacol 1978;46:279-303. 138. BERNSTEIN RS, STAYNER LT, ELLIOTT LJ, et al. Inhalation exposure to formaldehyde: an overview of its toxicology, epidemiology, monitoring 153. National Toxicology Program. Carcinogenesis bioassay of 2,3,7,8- and control. Am Ind Hyg Assoc J 1984;45:778-785. tetrachlorodibenzo-p-dioxin in Osbome Mendel rats and B6C3F, mice (gavage study). Research Triangle Park, NC: NTP, 1982 (technical 139. Environmental Protection Agency. Technical document Formalde- report No. 209). Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 hyde. Washington, DC: EPA, Office of Pesticides and Toxic Sub- 154. PrroT HC, GOLDSWORTHY T, CAMPBELL HA, et al. 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WATERS MD, STACK HF, BRADY AL, et al. Use of computerized data water. Am J Public Health 1984;74:479-484. listings and activity profiles of genetic and related effects in the review 145. New York State Department of Health. A risk assessment for ethylene of 195 compounds. Mutat Res 1988205:295-312. dibromide. Bureau of Toxic Substance Assessment, NYSDH, Feb 21, 158. DAY NE, BROWN CC. Multistage models and primary prevention of 1984. cancer. JNCI 1980;64:977-989. Vol. 80, No. 16, October 19, 1988 REVIEW 1291 APPENDIX: TABLE 2 COMMENTS (1) Daminozide is a plant growth retardant. In 1986, the EPA adopted interim measures to reduce its use, and a ban has been proposed. The estimated residues are 0.86 ppm in peanuts, 0.47 ppm in peanut butter, 1.02 ppm in apples, and 0.38 ppm in apple juice (70). The estimated average adult daily consumption of these foods is: apples, 18.1 g; apple juice, 4.4 g; and peanuts and peanut butter, 2.9 g (71). (2) 1,2,-Dibromo-3-chloropropane (DBCP), a soil fumigant for the control of nematodes, was widely used on a variety of vegetable, fruit, and nut crops until the ban in 1979. Concentrations were highest in root crops. The DBCP concentration in peeled raw carrots 9 wlc after treatment at seeding was 0.607 mg/kg; the concentration of DBCP was 60% lower after 5 min of boiling in water (72). The average daily consumption of carrots is 8.4 g/day (71). (3) The dose calculation for DDT, l,l-dicWoro-2,2'-bis65% of the total dry cleaning solvent usage (113). Both exposure estimates refer to Bayonne, NJ, ambient air. The average daily ambient concentrations were 11.1 jig/m 3 in 1973 (98) and 4.6 Mg/m3 in 1983 (23). Studies of other urban areas reported similar average daily concentrations: Los Angeles 1976, 4.6 /ig/m 3 (U4y, Baltimore 1978-1983, 4.0 *ig/m3; and Philadelphia 1979-1982, 5.9/ig/m 3 (25). (20) Use of toxaphene has increased in the last decade, partly because of the ban on DDT. It is mainly used for the control of cotton insect pests. The average concentration measured in 1972 in the Mississippi Delta area was 0.26 /ig/m 3 (102). (21) The dose calculation for benzene is based on personal air samplers carried by ~ 6 0 0 New Jersey residents in the fall of 1981. These samplers would have integrated outdoor and indoor exposure, but in all cases outdoor concentrations were lower than personal average concentrations; hence, the personal samples would have underestimated indoor exposure. Tobacco smoke was thought to be the main source of indoor concentrations of benzene (23). (22) The dose calculation for carbon tetrachloride is based on personal air sampling in New Jersey (23). See comment 21. (23) Chlordane and heptachlor are chlorinated cyclodiene insecticides, structurally similar to dieldrin. Chlordane was widely applied to the soil below Downloaded from http://jnci.oxfordjournals.org/ at Thomas Jefferson University, Scott Library on July 23, 2015 and around the foundations of buildings to control subterranean termites until this use was terminated by agreement with the EPA in 1987. The dose calculation is based on a survey of military housing (115). Data for nonmilitary housing in the same period suggested higher average doses of 28-48 /ig/day (116,117). Chlordane is a complex mixture. The methods of measurement used in the cited studies would not have included the more volatile fractions and hence would have underestimated total exposures. Local data for 1983-1985 suggest a substantial reduction in exposure levels, perhaps resulting from unproved application techniques introduced in the 1980s (118). (24) The release of formaldehyde from urea-formaldehyde foam insulation in mobile homes as well as in conventional homes containing particle board and plywood are the most important sources of indoor exposure to formaldehyde, but it has widespread use in construction materials, wood products, and furniture, textiles, and paper. Sources of indoor contamination for benzene include tobacco smoke and solvents (95). The estimate of average daily uptake of formaldehyde in the air in conventional homes is based on the means of all reported median or mean concentrations, as estimated by Ames et al. (2). The mean concentration of formaldehyde in the air of mobile homes (0.205 mg/m 3 ) is derived from Connor et aL (119). (25) Heptachlor is a component of technical chlordane (5.8%) and is often applied with it in a 1:2 mixture. The dose calculation is based on measure- ments in homes treated with either this mixture or with technical chlordane (116). Local data for 1983-1985 suggest a substantial reduction in exposure levels, perhaps resulting from improved application techniques introduced in the 1980s (118). (26) The dose calculation for tetrachloroethylene is based on personal air sampling in New Jersey (see comment 21). Dry-cleaned clothes were thought to be a source of indoor concentrations of tetrachloroethylene (23). (27) Chlordane was used on many commercial fruit, vegetable, and grain crops, as well as in private gardening. Chlordane was detected in 21 out of 50 samples of Kansas City drinking water between 1965 and 1967 (120). Because only concentrations higher than 0.1 ng/L were listed separately in this study, a level of 0.05 Mg/L was assumed for the remaining positive samples; the average (0.07 /ig/L) is used in the table. The maximum chlordane concentration reported in the same study was 8 jig/L (HERP*, 0.01). (28) The average drinking water concentration of chloroform estimated in a 1976 nationwide study of 113 public water systems was 84 /ig/L (121). It is mainly formed through the reaction of chlorine with organic chemicals in water (122). The risk posed by chloroform must be compared with the benefits of chlorination, and its benefits should be compared with those of other water-disinfection technologies. (29) DBCP concentrations in positive groundwater samples from five states in the 1980s ranged between 0.02 and 20 /ig/L (123). The upper value corresponds to a HERP* of 0.2. A concentration of 137 Mg/L (HERP* 1.6) has been reported for a single polluted well in Arizona (10). Monitoring of wells in both small domestic and large water systems in California showed that —30% were contaminated with DBCP. The majority had concentrations > 1 ng/L; hence this value is used in the table as an average estimate (124). (30) An EPA groundwater EDB contamination study in four states found > 1 0 0 contaminated wells. Eighty-six of them were in Florida; the concentra- tion ranged between 1.0 and 15.0 ng/L. The HERP is based on the geometric mean (3.9 ttg/L). The highest concentration in this study was 100 *ig/L, corresponding to a HERP% of 0.2, and was found in Georgia (125). (31) Before being banned in 1983, heptachlor was mainly used to treat corn crops and seeds. A 1977 study of drinking water in two U.S. rural counties showed mean levels of heptachlor in positive samples of 15 and 9 Mg/L. respectively (126). The HERP is based on the average value of 12 /ig/L. (32) The estimated surface water concentration of PCBs in 17 major VS. drainage basins during 1971-1974 was 0.1-3.0 iig/L (127). The HERP is based on the average of positive results for 1974: 0.2 uglL. (33) The median concentration of tetrachloroethylene in NJ public water supplies that tested positive from July to December of 1985 was 6 ng/L; maximum concentration was 46 /jg/L (128) (HERP*, 0.001). Concentrations as high as 1,500 /ig/L (HERP*, 0.04) have been detected in polluted wells (10). (34) Trichloroethylene (TCE) is used in the vapor degreasing of lubricated metal parts, as a solvent in the textile, adhesive, and lubricants industry, as well as in some consumer cleaning products. In 1977, FDA prohibited its use as an extraction solvent in the food (coffee and spices) industry (129). The major source of environmental contamination by TCE is the metal industry (129). The median contamination of TCE in New Jersey public water supplies that tested positive from July to December 1985 was 7 jig/L (128). The same study showed a maximum concentration of 190 /ig/L (HERP*, 0.0006). Levels as high as 35,000 jig/L (HERP*, 0.1) have also been found in contaminated private drinking water supply wells (130). (35) In the New Jersey study described in comment 33, the median concentration of vinylidine chloride was 2 pg/L, and the maximum was 9 ng/L (HERP%, 0.001). Vinylidene chloride is the basis for the production of copolymers, which are used in food packaging, coatings for paper, fibers, tubes, and pipes (131). Vinyl chloride, whose polymers are also used in the production of plastics, is a known human and animal carcinogen and is strictly regulated both in the workplace and in the environment. It has been found in polluted wells at concentrations as high as 20 fig/L (132) and 10 jig/L (128). Inasmuch as the TD50 is 8.0 mg/kg, the respective HERP* values are 0.007 and 0.004. (36) Concentrations of 100 ppm of benzene or more were common in the rubber, printing, leather, and shoe industries until the 1970s (93,133). The 1942 exposure corresponded to 100 ppm. In 1980, a permissible exposure limit (PEL) of 100 ppm was issued by OS HA; today the limit is 1 ppm or 3.2 mg/m 3 . The estimated average postregulatory benzene concentration in the rubber industry is 0.20 ppm (134). (37) The estimated workplace air concentration (28.3 mg/m 3 ) is the midpoint of values obtained in a 1961 U.S. study on resin manufacture and paper production (135,136). In 1980, OSHA set the PEL at 3.7 mg/m 3 (HERP*, 13.3) on the basis of noncarcinogenic effects. In 1987, it was lowered to \2 mg/m 3 (HERP*, 4.3). Estimates of the concentration of formaldehyde (0.86 mg/m 3 ) in the resin and plastic industry during the 1980s indicates a 33-fold decrease (137-139). (38) The HERP is based on an estimated workplace concentration of 200 ppm, which was not uncommon before regulations were imposed (140). Concentrations as high as 8,000 ppm, corresponding to a HERP* of 256, have also been measured (141). Today, the OSHA PEL is 100 ppm or 538 mg/m 3 (HERP* 3.2), and the HERP is based on an estimated workplace concentration of 5 ppm (142). Vol. 80, No. 16, October 19, 1988 REVIEW 1293