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Issues in Risk Assessment
4
Options Considered
The committee considered several options relative to the use of the MTD as the highest dose for use in carcinogenicity screening studies. These options were initially proposed by the participants in the MTD workshop organized by the committee in consultation with the federal liaison group. The first option would retain the status quo, with the possible addition of lower doses in addition to the MTD. The second option would use a high dose that is an arbitrary fraction of the EMTD. The third option would redefine the MTD, basing it on studies of the dose dependence of physiologic effects expected to alter carcinogenic response. The fourth option would use MTD testing as part of an overall testing strategy that separates carcinogens from noncarcinogens and provides information useful for determining human relevance; this could take one of two forms—a two-track system that comprises full testing and limited testing and a system of sequential studies. These options are presented below and are followed by discussions of their advantages and disadvantages.
OPTION 1
Continue carcinogenicity screening studies with the MTD as the highest dose according to current practice (with the inclusion of lower doses as well).
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This option has the advantage that the MTD bioassay is the only currently standardized method in the United States for identifying carcinogens. Continuing the bioassay as it is currently used allows comparisons with the results of similar studies conducted in the past. The test is designed to achieve high sensitivity. Compounds found to be negative in a standard set (two species and both sexes) of bioassays conducted at the MTD can be designated as noncarcinogens with a relatively high degree of confidence.
The negative aspects of the test are that its results indicate only whether a chemical is a rodent carcinogen under the conditions of the assay. The current screening system is oriented toward identifying potential carcinogens. Without additional studies, the bioassay does not indicate how predictive the results of the rodent bioassay are for humans, and it provides little information with which to estimate responses at low doses—which might be of particular concern to humans. For materials for which the evidence of carcinogenicity is weak (i.e., related to only one sex-species group or to the highest dose) and that are economically important, further studies to elucidate the metabolism or mechanisms of action, particularly regarding effects on cell proliferation, are in order.
OPTION 2
Redesign the bioassay so that the highest dose is some small fraction of the EMTD.
When human exposures were reasonably anticipated to be within a factor of 10 or 100 of the animal MTD or when the test substance was judged to have a high potential for direct interaction with DNA (as judged by results of short-term tests for genotoxicity), the MTD would continue to be used as the highest dose.
For materials that did not meet those criteria, however, the MTD would not be routinely used as the highest dose in chronic bioassays. Instead, a fraction of the EMTD (e.g., MTD/3) would serve as the highest dose for bioassays. Additional doses would be spaced geometrically below the high (MTD/3) dose at half-log intervals (i.e., the second dose would be MTD/10, the third dose would be MTD/33, etc.).
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If the numbers of animals in a test were not substantially increased, agents that were formerly found to be carcinogenic only at the MTD would not be identified as positive in this procedure. Thus, this procedure would focus attention on agents that had high carcinogenic potency relative to their subacute toxicity (Region C carcinogens in Figure 1).
An advantage of this procedure is a flexibility that reflects differences between potentially hazardous substances themselves or the expected exposures of humans to them. Most such chemicals will never be tested in chronic animal bioassays; current evidence suggests that, if they were, about half would be identified as carcinogens and almost all, by definition, would be in Region B. It would clearly pose a dilemma for regulators to be faced with decisions on a multitude of chemicals that would be identified as carcinogens under today's regulatory standards. However, substances with low toxicity but high carcinogenic potency (Region C carcinogens) might well present an unusually high cancer risk to human populations but not produce toxicity in the bioassay that serves to warn people of a hazard; that is apparently what happened with vinyl chloride workers (Fox and Collier, 1977; IARC, 1979).
A disadvantage of this option is that it would decrease the sensitivity of the assay, thus reducing its usefulness as a means of hazard identification. This disadvantage can be compensated for by increasing the numbers of animals in test groups; however, the expense of increasing the number of animals to a point necessary to retain the same power would probably be prohibitive. Furthermore, the choice of a lower dose, such as MTD/3, as the highest dose is arbitrary. Although implementation of this option would identify primarily Region C carcinogens, there is little evidence that Region C carcinogens contribute a predominant portion of chemically induced cancer risk to human populations. Future uses of a chemical cannot always be anticipated. If the HDT were based on current uses, a future use that entailed high human exposures could necessitate a new bioassay.
OPTION 3
Base the HDT on preliminary studies that determined the dose dependence of physiologic effects induced by the chemical and the dose dependence of its metabolism.
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In this option, a comprehensive series of tests would be conducted before the bioassay were initiated. The tests would be designed to provide information about mechanisms of toxicity, as well as the dose-response curve for such toxicity. Microscopic examination of tissues would continue to be a part of studies, as would clinical chemistry (e.g., serum enzyme measurements and urinalysis.) However, the studies would be expanded to include measurement of physiologic and biochemical effects (e.g., alterations in hormone status) and quantitative measurements of cell proliferation. In addition, extensive pharmacokinetic studies (quantitative measurements of uptake, distribution, metabolism, and elimination) would be carried out.
An expert panel would be convened to evaluate preliminary data before doses for the bioassay were selected. The panel would select the HDT and lower doses on the basis of evaluation of the preliminary studies. The objective would be to design a study that could be expected to yield results that would be useful for human risk assessment and not simply to administer as much chemical as possible without causing early mortality from causes other than cancer. This approach constitutes a change in emphasis of the bioassay. Studies that use the MTD as currently defined are designed to maximize the sensitivity of the bioassay (i.e., to prevent false-negative results). The objective of the new approach would be to increase the selectivity of the bioassay (i.e., to decrease the number of false-positive results).
In some cases, adoption of this option would not change the selection of the MTD as the HDT. For example, if human populations were reasonably expected to encounter high concentrations of the test substance, the MTD would continue to be used. In many cases, however, the HDT would be lower than the MTD as currently defined, and the spacing of doses could be much wider than commonly adopted by programs such as the National Toxicology Program (NTP).
An advantage of this modification is that the mechanisms underlying any observed carcinogenic response would be more likely to be qualitatively and quantitatively similar to those operating at lower doses than mechanisms underlying responses observed at the MTD.
A disadvantage of this modification might be that doses that caused a physiologic change in one organ might not cause physiologic changes in other organs. Without knowledge of the target sites for carcinogenicity, it would be unclear whether a physiologic change that is being avoided
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by testing at lower doses has any relevance to those other target sites. For example, if an HDT were selected to be below a dose that caused a physiologic change in the liver but not the lung, one could miss a carcinogenic effect on the lung at a dose that does not alter lung physiology.
OPTION 4
Use MTD testing as part of an overall testing strategy.
The animal bioassay that uses the MTD is one part of a complete program for identifying human carcinogens. It generally is conducted after some indication that a substance merits examination—e.g., information that a chemical has a structural similarity to a known carcinogen, results of a test for mutagenicity, or a suggestion that there will be extensive human exposure to the substance. It is then used as a screening technique to separate carcinogens from noncarcinogens it can be followed by tests to determine mode of action, pharmacokinetics, and applicability of results to the human experience. The workshop participants and the committee discussed two-ways to use the MTD test in a complete program. They are described below.
Option 4A
Use a two-track system that comprises full testing and limited testing.
In this option, chemicals would be placed into two-tracks for testing. A small number of selected chemicals would be subjected to rigorous testing (the full-testing track). All the remaining chemicals would be subjected to less rigorous testing (the limited-testing track). The option is based on three premises:
A large amount of additional information might be needed to assist in understanding the importance of positive results at the MTD.
It might not be feasible to collect the additional information for all the chemicals whose regulation is appropriate.
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Without accompanying information on mechanisms or results at low doses, animal bioassay results alone (i.e., without parallel data on mechanisms and dose-response relationships) do not add greatly to our ability to make regulatory decisions because of the uncertainty about the human implications of positive results in animal bioassays.
Chemicals could be chosen for full testing on the basis of expected human exposures, importance in commerce, structural similarity to a known carcinogen, or results of mutagenicity tests—i.e., in much the same way that chemicals are currently chosen for testing. The method of Gaylor (1989), basing a preliminary estimate of the carcinogenic potency of a chemical on its MTD, could also be used to select chemicals for full or limited testing. As described earlier, given the relationship between the carcinogenic potency of chemicals and their MTDs, Gaylor pointed out that a preliminary estimate of the dose corresponding to a carcinogenic risk of one in a million human lifetimes could be found by dividing the MTD by 380,000. If human exposures were unlikely to be greater than the quotient, the chemical would not be assigned to full testing on the grounds that, even if it were a carcinogen, human risk would be unlikely to be greater than one in a million per lifetime. (A different divisor could be selected if a level of safety different from one in a million per lifetime were required.)
When a class of structurally similar chemicals that are thought likely to have similar mechanisms of action is being considered, it might be a good use of resources to test fully only a small number (perhaps only one) of representative chemicals in the class and to evaluate the others in the class for relative potency on the basis of data from short-term, less-expensive studies.
Chemicals chosen for full testing would be tested in a standard bioassay that used the MTD and an array of doses below the MTD. If a chemical were positive, additional testing would be performed as needed to clarify the dose-response relationship and to improve the predictive value of the positive findings for humans.
Chemicals chosen for limited testing would be considered for regulation without testing in a long-term cancer bioassay. Regulatory decisions for these chemicals would be based on more limited data, such as estimates of the MTD from short-term studies, mutagenicity information, and other data that can be gathered much more quickly and cheaply than results from a lifetime bioassay.
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Such a strategy could best be implemented by a program, such as the NTP, that has general responsibility for assaying a large number of chemicals. Special-interest groups concerned with chemicals assigned to the limited-testing track would have the option of conducting more rigorous tests.
An advantage of this approach is that it would provide a strong data base for evaluating carcinogenic potency for the few chemicals that undergo full testing. It also has the potential to permit more effective use of testing resources.
A disadvantage is that chemicals in the limited-testing track might be evaluated inadequately, and that might result in overregulation or under-regulation of individual chemicals. Furthermore, criteria for assigning a chemical to a track might not be reliable. For example, mutagenicity does not always correlate with carcinogenicity, and some structurally similar chemicals might not have similar mechanisms of action.
Option 4B
Perform sequential studies.
In this option, pharmacokinetic studies would be included as part of the early short-term toxicity studies that are used to determine the EMTD. Relatively simple pharmacokinetic studies could determine the approximate dose that exceeds the ability of an animal to absorb and metabolize the test chemical. The usefulness of such data in the design of a long-term study can be illustrated by the pharmacokinetics of inhaled methyl bromide (Medinsky et al., 1985). Doubling the exposure concentration from 5,700 to 10,400 nmol/L in a 6 hour exposure did not increase the internal dose received by rats. The higher concentration caused a decrease in minute volume and in the percentage absorbed, the animals did not receive any more of the test compound than at the lower concentration. Obviously, there would be no point in designing a long-term study at a concentration that the test animals could not absorb. Similar studies could determine the dose at which the animals' capacity to metabolize the internal dose is overwhelmed, as indicated by increased excretion of the parent chemical. With such information, long-term studies could be designed that include at least one dose that does not exceed the metabolic capacity of the animal.
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After the short-term toxicity studies, which would be used to find both the EMTD and the pharmacokinetic characteristics of the test chemical, the long-term bioassay would be conducted with the MTD and lower doses, one of which did not exceed the capacity of the animals to absorb and metabolize the chemical. Additional animals might be required for the latter dose. If the results of the long-term bioassay were negative, no further studies would be conducted. If the results were positive, studies to determine the relevance of the animal responses to human risk would be conducted. Such studies would be aimed at determining the shape of the dose-response curve for events that can lead to cancer. Additional work might include more detailed pharmacokinetic studies, such as studies of the effect of dose on the kinetics of specific metabolic pathways and the identification of metabolites; studies of the effects of the test chemical on primary physiologic control systems, such as the endocrine, renal, and cardiovascular systems; studies of the effects on growth-regulating systems in target organs and cells (such as perturbation of oncogene products, alteration of protein kinases, activation of cytokines, and alteration of hormones); studies of mechanisms of mutagenesis; and studies of the induction or reduction of detoxifying enzyme systems. Epidemiologic evidence of carcinogenicity would also be important in determining the relevance of the animal response to human risk. The results of those studies, in conjunction with bioassay data, should provide the framework needed to understand the events that lead to cancer, improve predictability across species (particularly from rodents to humans), and provide a biologic basis for low dose extrapolation.
An advantage of this approach is that it systematically contributes information needed for risk assessment.
A disadvantage is that it will take longer to complete the evaluation of a chemical, and it will be possible to test only a few chemicals in such a thorough program.
Representative terms from entire chapter:
carcinogenic potency
