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Issues in Risk Assessment
1
Introduction
BACKGROUND
The long-term animal bioassay for carcinogenicity was developed during the 1960s and early 1970s primarily as a qualitative screen for carcinogenic potential. Long-term animal bioassays are now used regularly to determine whether chemical agents are capable of inducing cancer in exposed animals. The bioassays are also commonly used as a basis for making qualitative inferences about the likelihood that an agent poses a carcinogenic hazard for humans as well (IARC, 1991).
Because of practical considerations, such as the cost of maintaining large numbers of animals for long periods, the number of animals used in long-term studies is generally limited to about 50 per dose-sex-species group tested. That limits the sensitivity of the carcinogenicity bioassay: it cannot detect a small increase in tumor incidence, such as an increase of 1% or less, even in experiments that use hundreds of animals. To minimize the number of false-negative results, the bioassay design was modified early in its development. The most important modifications were extension of the testing period to cover most of the lifetime of the experimental animals (which, for practical reasons, limited the test species to small rodents with lifetimes of 2-3 years) and the use of high doses.
A carcinogenicity bioassay generally involves animals exposed at two or more doses and a control group. A higher dose generally is more likely than a lower dose to produce cancer in the test animals and hence
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to increase the likelihood that a carcinogen will be detected. However, too high a dose might cause toxic effects that shorten the life of the test animals and prevent the observation of an excess tumor incidence. Those considerations led to the practice of selecting the maximum tolerated dose (MTD) as the highest dose tested (HDT) in an animal bioassay. The MTD is roughly described as the highest dose that does not alter the animals' longevity or well-being because of noncancer effects (Sontag et al., 1976; McConnell, 1989). These terms are further defined later in the report.
The MTD is generally estimated in a preliminary study by subjecting small groups of animals to a series of doses (perhaps six) for a small fraction of a lifetime (e.g., 3-months for mice and rats). The highest dose judged to cause no overt toxicity and little or no growth suppression is the estimated maximum tolerated dose (EMTD).1
Estimation sometimes results in selection of an EMTD that is too high—that causes animals to die early in life before chemically induced cancers could occur. Because it is difficult to interpret the results of animal bioassays when animals die prematurely, the bioassay design was refined to include testing at a lower dose as well—often half the EMTD (EMTD/2). Other doses (such as EMTD/5 or EMTD/10) are also used to define dose-response relationships better. Current bioassay designs have become reasonably well standardized and usually specify lifetime testing of both sexes of two species of rodents at two or more doses, the highest of which is the MTD (IARC, 1986a,b). Criteria for interpreting results obtained in these tests and for classifying them as positive, equivocal, or negative have been developed and refined (see the technical reports series of the U.S. National Toxicology Program and many others).
Although the carcinogenicity bioassay in rodents was developed primarily for qualitative screening of agents for carcinogenicity, it often provides the only quantitative information for evaluating the relationship between dose and carcinogenic response and for estimating the carcinogenic potency of an agent. Procedures for quantitative risk assessment
1
MTD will be used throughout this repeort, except where precision requires the distinction between MTD, EMTD, and HDT. A bioassay that uses an EMTD as its HDT will be refered to as an "MTD bioassay."
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were developed, beginning mainly in the 1970s, to meet the needs of regulatory agencies charged with developing reasonable limits on human exposure to agents that had been identified as potential carcinogens (Mantel and Bryan, 1961). These procedures use mathematical models and supplementary information to extrapolate data obtained from high dose animal tests to quantitative assessments of risks to humans who might be exposed to much lower doses. Numerous risk assessments by federal regulatory agencies have been based on animal carcinogenicity bioassays.
Since 1970, several hundred chemical agents have been tested for carcinogenicity in bioassays of standard designs. The National Toxicology Program (NTP) alone has reported on 382 bioassays, of which 195 (51%) identified the tested chemical as carcinogenic under the conditions of the bioassay in at least one species-sex group (R. Griesemer, NIEHS, pers. comm., 1991). That proportion is not representative of chemicals in general, however, because of how the chemicals were selected for testing. Most of the substances (255 of 382, or 67%) were selected for testing primarily because of suspicion of carcinogenicity, and 169 (66%) of the 255 were positive. The remainder (127 of 382, or 33%) was selected for testing mainly on the basis of human exposures and the lack of toxicity data, and only 26 (20%) of the 127 were positive (R. Griesemer, NIEHS, pers. comm., 1991).
Limitations inherent in using the MTD approach and suggestions for improvement have been the subject of controversy since its use became standard (Shubik, 1978). In recent years, the use of data from bioassays performed with the MTD has been called into further question. Some of the criticisms of such data are based on the following points:
A large percentage of chemicals tested by the NTP have been identified as carcinogenic in at least one species-sex group. Some observers believe that the test is labeling so many substances as carcinogenic that regulatory attention and public concern have been focused on many agents that pose only trivial hazards, while attention has been diverted from other agents that pose more important carcinogenic risks. The committee was given some evidence to support that charge. However, a high proportion of materials found positive in one or more species-sex groups have not been regulated (OTA, 1987).
At high doses (including MTD and MTD/2), some agents might
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induce cancer through mechanisms that do not occur at lower doses, thereby generating false-positive inferences of hazard and risk for humans who are exposed at lower doses. The committee was given pharmacokinetic and other mechanistic arguments, such as induced cell proliferation, that support this hypothesis.
Even in cases where effects might occur as a result of low dose exposure, the results of an MTD test might have little utility in defining the dose-response relationship. Some agents could have nonlinear dose-response relationships that reflect pharmacokinetics, induced cell proliferation, or other mechanisms. The result of the nonlinearity could be overestimation (or, in some cases, underestimation) of low dose risks. Overestimation could occur where the dose-response curve has a shallow slope at low doses and becomes markedly steeper at higher doses. Underestimation could occur where the dose-response curve flattens out or curves downward at high doses.
Statistical analysis of bioassay results for many agents has shown strong correlations between estimates of carcinogenic potency and measures of toxicity (including the MTD) that suggest that carcinogenicity is inherently related in some way to other toxic effects produced by a chemical. However, some investigators have concluded that those correlations, and possibly estimates of carcinogenic potency, are determined in some way by the bioassay design or the mathematical and statistical methods used to estimate potency and investigate the correlations, rather than by inherent biologic properties of the agents.
SCOPE OF REPORT
The above points are all addressed in various degrees in this report. Particular attention is focused (in Chapter 2) on the fourth point—questions concerning the observed correlations between measures of carcinogenic potency and the MTD. The report explores the extent to which the correlations appear to reflect some underlying biologic reality, as opposed to being determined solely by experimental design or statistical methods. It further considers the relationship of the correlations to possible biologic mechanisms of carcinogenesis and the implications of the correlations for risk assessment.
The report discusses both what bioassays conducted at the MTD can
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tell us and what they cannot tell us, qualitatively and quantitatively, regarding carcinogenic hazard in humans (Chapter 3). Several proposals are discussed (Chapter 4) for modifying the design of the bioassay, for modifying the process of selecting chemicals for testing, and for augmenting the results of the bioassay with additional testing to improve risk assessments.
The committee's conclusions are presented in Chapter 5 with the recommendations of the majority of the committee concerning the better use of bioassays, specific results from bioassays, and other types of data to assess carcinogenic hazards in human populations. The dissenting recommendations of a minority of the committee are also described.
An active discussion is in progress in the scientific community concerning the extent to which high doses produce increased mitogenesis (cell division) and how much the increase contributes to the incidence of cancer at the MTD and lower doses. That was the subject of a presentation given at the MTD workshop conducted by the committee (see the summary of the workshop at the end of the report). This report reviews and evaluates the recent research related to the issue.
Although the MTD concept is used in other contexts (e.g., tests for reproductive toxicity and teratogenicity), the committee essentially limited its investigation to the use of the MTD in bioassays for carcinogenicity associated with exposure to chemicals.
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Representative terms from entire chapter:
carcinogenic potency
