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.
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.
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.