EnVIROnmEnTAL POLICY ANALYSIS
RISK
ASSESSMENT
Is There a Safe Level of Exposure to a Carcinogen? S T E V E E. H R U D E Y Department of Public Health Sciences, Faculty of Medicine, University ofAlberta Edmonton, Alberta T6G 2G3 Canada DANIEL KREWSKI Environmental Health Directorate, Health Protection Branch, Health Canada Ottawa, Ontario K1A 0L2 Canada Estimating the contribution of environmental contaminants to the human cancer burden has been a contentious issue in environmental risk management. Low-level carcinogen exposures have been particularly controversial. Most people believe there is no safe level of carcinogen exposure, a view shared by one in five toxicologists. This suggests that extrapolating downward from high exposures in search of a de minimis cancer risk level has not provided a universal answer to the title question. In search of a rational answer, we present an approach of working upward from the smallest conceivable chronic dose. Using conservative assumptions, calculating the risk from lifetime exposure to one molecule a day of the most potent known carcinogen shows that exposing the entire world population to the smallest nonzero dose likely would not yield a single case of cancer. Less potent carcinogens present correspondingly lower risk. These calculations suggest that, within a realistic concept of safety, there is a safe level of exposure. This simple analysis applies the no-threshold cancer risk estimation methods used by EPA and provides a rationale to answer the title question. Ultimately, this perspective may open dialogue on the more difficult question of how much carcinogen exposure could be considered safe.
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The recognition that chemical substances in the environment can cause cancer in humans has dominated the environmental agenda since the 1970s. Nearly one-third of all North Americans will contract cancer during their lifetimes and about onequarter will die of some form of this group of dreaded diseases. Thus, public concern about the causes of cancer is understandable. However, the role of environmental exposure to carcinogens as factors in the causation of cancer has been controversial. A 1964 World Health Organization report concluded that three-quarters of all human cancers are caused by extrinsic factors (causes other than genetic predisposition) (i). Extrinsic includes the whole range of environmental factors involved in living, including but not limited to exposure to chemical carcinogens. Yet, the view that chemicals made by humans are responsible for the majority of h u m a n cancers became popular in the 1970s with the aid of such literature as Epstein's book The Politics of Cancer. This view remains common: A survey of Pennsylvania adults found one in five respondents believed that between 25% and 50% of all new cases of cancer were caused by toxic chemicals from waste sites (2). In contrast, a 1981 scientific review estimated that perhaps only 2%—within a range from < 1% to 5%—of human cancers arise from pollution sources, as distinct from tobacco, alcohol, diet, food additives, occupation, industrial products, medicines, and geophysical factors (3). This finding was consistent with a 1989 analysis that found a summation of all EPA upper bound cancer risk assessment values for "pollution" causes would account for between 1% and 3% of all human cancer cases in the United States (4). Regardless of the portion of total cancer risk that can be directly attributed to environmental contaminant exposures, cancer causation remains a primary concern that is likely to occupy a prominent place in the environmental agenda for the foreseeable future. As much consensus as possible must be found among the divergent views, particularly with respect to low levels of exposure to substances with carcinogenic potential. First, we should ask: Is there a safe level of exposure to a carcinogen? Expert and public opinion Given the advancement of knowledge about cancer resulting from expending billions of dollars on biomedical research, the public has reasonable grounds to expect that the scientific community could provide a clear and unequivocal answer to such an apparently fundamental question. However, a survey found substantial divergence of responses among members of the U.S. Society of Toxicology to the sur0013-936X/95/0929-370A$09.00/0 © 1995 A m e r i c a n Chemical Society
vey statement: "There is no safe level of exposure to a cancer-causing agent" (5). Among toxicologists, 18.7% either agreed or strongly agreed that there is no safe level of expo sure; another 6.6% responded that they did not know or had no opinion. In a comparison group of Port land, OR, citizens, more than 50% agreed with the assertion that there is no safe level of exposure and 11.3% did not know or had no opinion. Similar an swers to comparable questions recently have been reported for members of the Canadian public (6) and the Society of Toxicology of Canada (7). The fact that 75% of toxicologists disagreed with the survey statement might normally be regarded as a substantial level of scientific consensus, were it not for the apparently fundamental nature of this ques tion and the clear divergence of the public view from the majority of the experts. Considerable diver gence of opinion also occurred a m o n g experts, grouped in terms of employment. Thirty-four per cent of academic toxicologists agreed that there is no safe dose compared with 19% of regulatory toxicol ogists and only 5% of industry toxicologists. Much of the disagreement among toxicologists likely is related to the wording of the question, which asks about a "safe" level of exposure. What an indi vidual considers safe involves some degree of value judgment (8). In this case, the different groups' val ues apparently influenced their judgment. This implied controversy among scientists con cerning the assessment of carcinogen risk likely will be interpreted by the public as chaos among the ex perts and, unless rational bounds can be placed upon the apparent disagreement, will lead to increased anx iety, distrust, and difficulty in risk communication (9). Arguments based on a belief that there is no safe dose for a carcinogen have prevailed and have driven pub lic policy (10). Other differences of opinion among experts and the public may also be cited. Ames and Gold argue that fruits and vegetables contain natural pesti cides that exhibit carcinogenic potential, and the car cinogenic risks of these may be greater than those of synthetic pesticide residues in food (11). Of the So ciety of Toxicology of Canada members, 73.3% agreed with the statement: "Fruits and vegetables contain natural substances that can cause cancer." Only 25.6% of the Canadian public supported this view (6, 7). About 88% of the experts disagreed with the state ment: "Natural chemicals are not as harmful as manmade chemicals," but 56.1% of the public strongly agreed with it. On the question of safety, the survey stated, "I believe that a risk-free environment is an attainable goal for Canada." Some 61% of the Cana dian public agreed with die statement, whereas 78% of Canadian toxicologists surveyed disagreed. This
FIGURE 1
Potency distributions Potency distributions of 343 carcinogens, after Flamm et al. {61), reprinted with permission. AFB1 is aflatoxin B1,TCDD is 2,3,7,8 tetrachlorodibenzo-pdioxin. Potency values are not based on q,* but on an approximation (62) obtained by linear extrapolation from TD50 values {63, 64). 50 -Nonlinear least squares best fit Gaussian
40 -
ΰ 30
20
10
10-1
10"" 10"2 1 Potency, (mg/kg/day)~
suggests that public expectations for safety exceed what realistically can be achieved. The linear, no-threshold hypothesis Quantitative cancer risk assessment, in large part, is based on an evaluation of the dose-response (risk) curve. The calculation of cancer risk at extremely low doses has attracted considerable discussion and con troversy (12-16). The premise underlying linear ex trapolation of risk to zero carcinogen dose is that a single molecule of a DNA-reactive carcinogen can damage a single DNA molecule. Furthermore, sin gular DNA damage can multiply through cell repli cation from an insignificant molecular anomaly into a p o p u l a t i o n of d a m a g e d clone cells t h a t ulti mately may become a malignant tumor. This out come clearly is not certain; everyone has been ex posed to countless carcinogens, yet not everyone develops cancer. For example, up to 90% of lung can cer is attributable to tobacco smoking (17, 18), but only a minority of smokers ever develop lung can cer. Cancer development involves a number of stages, influenced by one or more contributing causal fac tors (19-21). Detoxification and repair mechanisms defend the body against adverse toxic effects includ ing carcinogenesis (22). Recent advances in under standing the body's DNA repair capacity suggest that cancer occurrence may be related more to the fail ure of DNA repair capability than to the degree of trace exposures to DNA-damaging contaminants (23). Even allowing for repair of pre-cancerous lesions, the VOL. 29, NO. 8, 1995 / E N V I R O N M E N T A L SCIENCE & TECHNOLOGY • 3 7 1
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linear no-threshold hypothesis holds that there is some nonzero probability of a singular molecularlevel event developing into a tumor. This concept of the probability of an adverse outcome following a complex sequence of stochastic events is analogous to infectious disease transmission. Some probability, but not certainty, exists that exposure to a single biological agent, which can replicate itself—a viable, pathogenic bacterium or virus— will generate sufficient numbers of "offspring" to ultimately cause disease. The probability of developing the active disease will be determined by the likelihood that the replicating pathogen can survive the host's immune defense. Several theoretical arguments have been forwarded supporting the hypothesis of low-dose linearity for chemical carcinogens. Mathematical carcinogenesis models such as the Armitage-Doll multistage model (24) or the Moolgavkar-VenzonKnudson two-stage clonal expansion model (25) predict linearity at low doses when mutation rates associated with one or more stages relate linearly to dose. Low-dose linearity should hold whenever tumors are produced by an acceleration of an ongoing background process in a dosewise additive fashion (26, 27). Empirical evidence supporting low-dose linearity is difficult to obtain because the low risk levels associated with low exposure levels are outside of the directly observable response range (28). The U.S. National Center for Toxicological Research ED01 study, done in the 1970s, involved more than 24,000 mice and was designed to define the dose-response curve for the experimental carcinogen 2-acetylaminofluorine (2-AAF) down to a one-in-100 excess risk level (29). Extrapolation of 2-AAF data below this point proved inconclusive (30, 31). A subsequent largescale rodent bioassay of several nitroso compounds conducted by the British Industrial and Biological Research Association also failed to define the shape of the dose-response curve at very low doses (32). Large-scale epidemiological investigations also are unlikely to resolve uncertainties about low dose risks. Uranium miners exposed to high concentrations of radon gas before the introduction of improved ventilation techniques were at increased risk of lung cancer (33), but large-scale case control studies have failed to clarify the level of risk associated with much lower radon concentrations in homes (34). With the possible exception of chronic lymphocytic leukemia, combined data analysis on more than 96,000 nuclear workers from several countries failed to establish a clear cancer risk associated with low levels of exposure to ionizing radiation (35). Recent advances in molecular biology may provide some information on the shape of the doseresponse curve for DNA-reactive carcinogens at low doses. DNA adducts have been observed to be related linearly to dose even at levels much lower than those studied in the large-scale animal cancer tests (36-38). Mutation frequency also has been observed to be related linearly to dose below cytotoxic levels in the Ames salmonella/microsome assay (39). But the relevance of these observations to human cancer risk is not clear in light of detoxifica372
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tion and other protective mechanisms that may prevent the reactive metabolite from entering the nucleus or even reaching the target tissue. Many carcinogens require metabolic activation before posing a cancer risk. Saturating activation or detoxification pathways can lead to a nonlinear doseresponse curve, such as occurs with methylene chloride when the glutathione-S-transferase pathway is saturated (40). Physiologically based pharmacokinetic models now are used commonly to predict biologically relevant tissue doses (41) and afford an opportunity for more accurate cancer risk estimates, particularly when extrapolating from animals to humans. However, many nonlinear kinetic processes, such as Michaelis-Menten kinetics, essentially are linear at low doses and thus are compatible with the low-dose linearity hypothesis. Arguments may be made against the hypothesis of low-dose linearity and zero intercept for nonDNA-reactive carcinogens. Ames and Gold noted that certain chemicals may increase cancer risks indirectly by stimulating cell division, increasing the possibility of DNA damage during mitosis at high doses but not necessarily at low doses (42). The International Agency for Research on Cancer recently prepared a detailed review of the mechanisms by which carcinogens act (20). More than 50% of the chemicals tested under the U.S. National Cancer Institute's National Toxicology Program during the past two decades were observed to cause tumors in rats or mice subjected to high exposure levels over die course of a lifetime (43). Quantitative estimates of cancer risk are highly correlated with the maximum tolerated dose (MTD) used in such experiments (44), which raises questions about the suitability of current protocols of carcinogen evaluation (45). Gaylor suggested exploiting this correlation to obtain preliminary risk estimates based on the MTD (46). A recent U.S. National Research Council report on this issue gives a detailed discussion of this point (47). It is not yet possible to determine with certainty whether a threshold for chemical carcinogenesis exists. Faced with this uncertainty, regulatory agencies have entertained the hypothesis of low-dose linearity with a zero intercept as a prudent default assumption in the absence of evidence to the contrary (48, 49). Seeking a definition of safety Although the uncertainty about low-dose cancer risks is not easily resolved, it may still be possible to develop a reasoned response to the dichotomous question: Is there a safe level of exposure to a carcinogen? To answer this question, we must consider what constitutes a safe dose. Much of the safety and risk debate concerning carcinogens has been directed at policies seeking a de minimis risk. The value of onein-a-million lifetime risk as a definition of de minimis or acceptable risk has achieved virtual folklore status in the United States (50). However, regulatory applications have been less precise, with a range of risk levels now generally preferred to a single risk number (51). Most risk analysts can easily convince them-
TABLE 1
Estimates of risk for the smallest indivisible daily dose of a carcinogen Carcinogen
2,3,7,8-TCDD Benzolalpyrene Vinyl chloride Benzene
Molecular weight. g/mol 322 252 62.5 78
1 molecule per day dose equivalent, d (mg/kg/day)
Potency factor n,* (mg/kd/dayf 1
o.9 χ 1er20
1.56 x 1 0 5 5.8 1.9 2.9 χ 10~ 2
0.71 χ 10" 2 0 0.18 χ 10~ 2 0 0.22 χ 10~ 2 0
Upper bound lifetime cancer risk estimate, r
1.4 4.1 3.3 6.3
χ χ χ χ
ΙΟ" 1 5 10~ 20 10~ 21 10" 2 3
Global lifetime population cancer risk (number of cases of cancer) 1 χ 10-5 3 χ ΙΟ" 1 0 2 χ 10" 1 1 4 x 10~ 1 3
2,3,7,8-TCDD is included in this analysis only because its potency q,* exceeds that of other known carcin Sources: References 58-60.
selves that lifetime one-in-a-million risk is truly de minimis, given that everyone has a cumulative risk of death that ultimately must equal one and the an nual risk of death for most of one's life is about one in 1000. In comparison, many will spend consider able money on lottery tickets that offer much lower odds, given the certainty that somebody will win. Of course, in the carcinogen lottery, the prize is not one that we wish to "win" for ourselves or our loved ones. But it is not surprising to find many who do not con sider a de minimis standard of one-in-a-million life time risk to be safe. The negative reaction to the implied value judg ment of de minimis caused regulatory agencies to abandon the term "virtually safe dose" for carcino gens in favor of the more nondescript "risk-specific dose" (RSD) {52). Although RSD is defined as the dose corresponding to a specified, presumably low risk level, it carries no connotations about the accept ability of that risk. Nor does it necessarily carry clear indications of safety. Although de minimis risk has been imple mented explicitly or implicitly for a variety of regu lations on exposure to potentially carcinogenic sub stances, the debate over what constitutes a de minimis risk has not resolved, for many people, whether a safe carcinogen dose is possible. Per haps we need a pragmatic expression of safety like that articulated by Yukon First Nation leader Mal colm Dawson, who said, "a safe level is one that you do not need to worry about" (53). This statement pro vides another way of expressing de minimis risk, which may assist in discerning what level of infor mation is required to make a personal decision about safety. Whether any citizen or scientist will worry about a given cancer risk obviously is a personal choice with implicit value judgments. However, few in our soci ety have been provided with the information, in un derstandable form, to enable them to judge this ques tion for themselves. The conventional approach to quantitative can cer risk assessment has been to extrapolate down wards toward lower doses to calculate correspond ingly small risk levels. However, to find whether there is a dose level that we need not worry about, a more useful approach is to work upwards from the small est conceivable dose that could be experienced. Estimating cancer risks At the technical level, extrapolating dose-response data on carcinogenesis from high to low dose may
be done using different statistical techniques. Crump used an upper confidence limit (q^) on the linear term in the multistage model as the basis for lowdose risk assessment in accordance with what has come to be known as the "linearized multistage" (LMS) model (54). Krewski et al. proposed a modelfree method of low-dose extrapolation (MFX) that in vokes the assumption of low-dose linearity and zero intercept, but makes no further assumptions about the underlying dose-response model (55). Gaylor ob served that linear extrapolation will provide an up per bound on risk should the dose-response curve be nonlinear and curve upwards at low doses (56). The EPA approach to calculating the RSD usu ally is based on Crump's LMS model (which is gen erally equivalent to MFX) and is explained as pro viding an upper bound estimate of cancer risk. Accordingly, we can ask what this method, gener ally accepted as conservative, will predict as the risk for the smallest indivisible daily dose of a carcino gen. EPA-calculated RSDs are based on chronic life time exposure. Hence, the appropriate value for the smallest indivisible chronic daily dose would be one molecule of carcinogen per day for an entire life time. However, the risk for a one-time exposure to a single molecule would be 25,550 (i.e., 365 days/
FIGURE 2
Risk estimates above zero exposure for Table 1 carcinogens Arithmetic plots of the four carcinogens listed in Table 1 illustrate the substantial difference in risk estimates from the extremely low nonzero exposures. The first data point for TCDD will plot at a point 14,000 times above the chart's maximum risk (vertical axis) value.
2,3,7,8-TCDD Benzo[a]pyrene Vinyl chloride Benzene
3 4 5 6 7 8 Lifetime carcinogen dose, molecules/day
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year x 70 years) times lower than the calculation we present below. Calculating the corresponding risk requires sim ple arithmetic based on the formula r = qx* χ d. Here, risk (r) is the probability of cancer occurrence asso ciated with exposure to a daily dose (d) for life (say 70 years). To illustrate, consider the case of 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD). A dose of one mol ecule per day translates into mass by dividing the mo lar mass (322,000 mg) by Avogadro's number (6.02 χ 10 23 molecules/mole) and by a lifetime average body mass of 60 kg (57) to yield an equivalent dose of 0.9 χ 10 20 mg/kg per day. This dose is multiplied by the qi* value of 1.56 χ 10 5 to yield a lifetime cancer risk of 1.4 χ 10~15. Similar calculations for a few selected carcinogens with published qT* values are s u m m a rized in Table 1 (58-60). What conclusions can be drawn from these cal culations? First, it is worth noting the enormous range of chemical carcinogen potencies. As illustrated in Figure 1, these cancer potency values vary by more than 10 million-fold (61, 62). The potency values shown in Figure 1 are not based on q ^ , but rather on an approximation obtained by linear extrapola tion from the TD50 values (63, 64). By itself, this enor m o u s range suggests that exposure to low-potency carcinogens will be inherently less dangerous than exposure to high-potency carcinogens. Because it has the highest reported potency by a substantial mar gin, TCDD was included in our analysis even though it is not DNA reactive. Although TCDD may not be genotoxic, EPA failed to rule out the possibility of lowdose linearity in its recent reassessment of TCDD health risk (65). The probability of developing cancer from expo sure to one molecule of TCDD a day over a lifetime is calculated by EPA's upper bound approach as less than 2 χ 10~15. Given the astronomical numbers of cells and molecules in the h u m a n body and the myr iad factors that could prevent the interaction of a car cinogenic molecule with a strand of DNA from ul timately creating a tumor, it is not surprising that we should calculate an extremely small risk for such an infinitesimally small exposure. For individuals to decide whether a safe level ex ists, exploring the dimensions of this calculated risk for the smallest possible indivisible daily dose is in structive. Using the calculated risk value and assum ing the same lifetime exposure to TCDD for the en tire world population indicates that there would be a less than 1 in 100,000 chance of even a single can cer case arising from that exposure level. From an other perspective, the calculated risk value indi cates that all h u m a n s who have ever lived on the planet could have been exposed to this infinitesi mal level without producing a single cancer case in h u m a n history. This analysis does not attempt to consider the cur rent exposure levels to TCDD nor to evaluate what risk levels may be associated with those exposure lev els because different mechanisms likely apply. Fur thermore, this calculation for a hypothetical infini t e s i m a l e x p o s u r e n e i t h e r s u p p o r t s n o r refutes arguments on the contentious issues surrounding the h u m a n health significance of TCDD as an environ 3 7 4 A • VOL. 29, NO. 8, 1995 / ENVIRONMENTAL SCIENCE & TECHNOLOGY
m e n t a l c o n t a m i n a n t (65). However, it does illus trate that there is a quantifiable level of exposure, which most individuals likely would consider be low their worry threshold. The TCDD e x a m p l e involves t h e highest re ported potency of any known carcinogen; similar cal culations for other carcinogens yield substantially lower risk levels. To further illustrate the potency range of carcinogens according to their qj* values, consider the plots in Figure 2 of the dose—response relationships, using an arithmetic scale, for the car cinogens s u m m a r i z e d in Table 1. This depiction shows the m a g n i t u d e of divergence of the d o s e response relationships for individual carcinogens be cause of differing potencies. Conclusions This highly simplified analysis clearly suggests that, without great philosophical difficulty, an individual can reconcile the existence of a safe exposure level for a n y k n o w n c a r c i n o g e n w i t h t h e linear, n o threshold (zero intercept) hypothesis for carcino gen risk assessment. This reconciliation can be made without endorsing or disputing the merits of cur rent regulatory policy, which favors this hypothesis, at least for DNA-reactive carcinogens. Regardless of the merits of any specific exposure value, there is merit in reconciling the boundaries of concern about carcinogens. The premise that there are no safe exposure levels to a carcinogen has pro found implications. As noted previously, a majority of the Canadian public believes that a risk-free en vironment is attainable. To achieve a zero-risk en vironment would require total elimination of expo sure to e v e n a single m o l e c u l e of any c a n c e r causing agent, if we accept the linear, no-threshold hypothesis. In reality this is not possible. Rather, we need an operational concept of environmental safety that is more practical than zero risk. The prevalent belief that there can be no safe level of exposure to a carcinogen because there may be no zero-risk ex posure level may hinder progress in achieving effec tive public policy o n this issue. The main point of this article is to establish that, under any realistic concept of practicality, there is in deed a safe level of exposure to cancer-causing chem icals. The essence of our argument is that lifetime daily exposure to the smallest possible amount (one molecule) of even the most potent cancer-causing chemical known to date would pose a de minimis risk by even the most cautious standards. The more difficult question of what exposure level should be tolerated for cancer-causing chemicals in the environment cannot be answered by our anal ysis. In practice, the degree to which exposure to en vironmental carcinogens should be controlled is a complex issue that requires careful consideration of risks, costs, and benefits, in accordance with the le gal statutes underlying carcinogen regulation (66). We argue that an operational definition of safety, which is consistent with conservative cancer risk estima tion hypotheses, can be satisfied by extremely lowexposure levels above zero, thereby admitting risk management options other than complete elimina tion of exposure. On an individual level, interested scientists who
may be asked if there is a safe level of exposure to a carcinogen can use this analysis to develop their own clear and reasoned response. Thus they may avoid contributing to impossible expectations or unwar ranted fears in our society. Acknowledgments T h i s w o r k w a s s u p p o r t e d by f u n d i n g for t h e Eco-Research Chair in E n v i r o n m e n t a l Risk M a n a g e m e n t p r o v i d e d by t h e Tri-Council Secretariat r e p r e s e n t i n g t h e Medical R e s e a r c h Council of C a n a d a , t h e N a t u r a l Sciences a n d E n g i n e e r i n g R e s e a r c h Council of C a n a d a , a n d t h e Social Sciences a n d H u m a n i t i e s R e s e a r c h C o u n c i l of C a n a d a ; t h e Alberta Her itage F o u n d a t i o n for M e d i c a l Research; Alberta E n v i r o n m e n t a l Protection; Alberta Health; a n d t h e City of E d m o n ton.
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