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Issues in Risk Assessment
2
Correlations Between Carcinogenic Potency and Other Measures of Toxicity
DEFINITIONS AND BACKGROUND
McConnell (1989) has provided a definition of the maximum tolerated dose (MTD) and explained how it is determined as follows:
Sontag et al. (1976) had defined the MTD as "the highest dose of the test agent during the chronic study that can be predicted not to alter the animals' longevity [through] effects other than carcinogenicity" and stated that it should cause "no more than a 10% weight decrement, as compared to the appropriate control groups, and … not produce mortality, clinical signs of toxicity, or pathologic lesions (other than those that may be related to a neoplastic response) that would be predicted to shorten an animal's natural lifespan." That definition has been modified, but is still essentially the same. However, the main characteristic now used in selecting the MTD is histopathologic appearance; weight is a secondary consideration.
The estimated maximum tolerated dose (EMTD) is based on a 90 day or other subchronic test, and its determination involves scientific judgment applied to the information available at the end of the test period. How well the EMTD approximates the true MTD can be evaluated only after the bioassay. The highest dose tested HDT in a long-term rodent bioassay is usually used as the EMTD. However, that was not always the
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Issues in Risk Assessment
case, especially in bioassays conducted before testing at the EMTD became the standard practice.
The MTD, by definition, is an inverse measure of the potency of an agent in causing chronic toxic effects, specifically those manifested as premature death, weight loss, or histopathologic changes after near-lifetime exposure. Potency refers to the range of doses over which a chemical produces increasing responses. Chemical A is considered more potent than chemical B if more of B than of A is required to elicit an identical response.
The LD50 (dose that is lethal to 50% of animals tested) is an inverse measure of the acute toxicity of an agent. It is defined as the dose (in milligrams per kilogram of body weight) that is expected to kill half a set of animals after a single administration.
The TD50 is an inverse measure of the carcinogenic potency of an agent and was defined by Peto et al. (1984) as follows:
For any particular sex, strain, species and set of experimental conditions, the TD50 is the dose rate (in mg/kg body weight/day) that, if administered chronically for a standard period—the "standard lifespan" of the species—will halve the mortality-corrected estimate of the probability of remaining tumorless throughout that period.
Gold et al. (1984, 1986a,b,c, 1987a, 1989a,b, 1990) have tabulated estimates of the TD50 for individual tumor sites and (in some cases) total tumors from more than 4,000 sets of tumor data on 1,050 chemicals. The criteria used by Gold et al. (1984) in deciding what chemicals to include in their Cancer Potency Data Base (CPDB) were as follows:
National Cancer Institute (NCI)/NTP bioassay, or
Bioassay in the published literature meeting all the following criteria:
Animals tested were mammals,
Administration was begun early in life (100 days of age or less for rats, mice, and hamsters),
Route of administration was diet, water, gavage, inhalation, or intravenous or intraperitoneal injection (i.e., where the whole body was
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Issues in Risk Assessment
more likely to have been exposed than only a specific site, as with subcutaneous injection or skin painting),
Test agent was administered alone, rather than in combination with other chemicals,
Exposure was chronic, with not more than 7 days between administrations,
Duration of exposure was at least one-fourth the standard lifespan of the test species,
Duration of experiment was at least half the standard lifespan of the test species,
Research design included a control group,
Research design included at least five animals per group,
Surgical intervention was not performed,
Pathology data were reported as the number of animals with tumors, rather than the total number of tumors,
Results reported were original data, rather than secondary analyses of experiments already reported by other authors.
Bioassays of particulate or fibrous matter and of mixtures of chemicals were not included (except some commercial preparations to which humans are often exposed).
The CPDB or the computerized National Toxicology Program/National Cancer Institute (NTP/NCI) database served as the data sources for the statistical analyses of correlations between carcinogenic potency and other measures of toxicity conducted by a number of investigators (Zeise et al., 1984, 1985, 1986; Bernstein et al., 1985; Crouch et al., 1987, and Rieth and Starr, 1989a,b). In particular, in a paper specifically prepared for the present committee's workshop on the MTD, Krewski et al. (Appendix F) calculated estimates of the TD50 for a subset of 191 chemicals listed in the CPDB; they used three models of the dose-response relationship: the single-stage models used by Peto et al. (1984), a multistage model, and a Weibull (in dose) model.
In addition to the TD50, carcinogenic potency can be measured on the basis of the slope of the dose-response curve in the low dose region, expressed by the parameter q1. The parameter q1 is the coefficient of the linear term in the multistage model of Armitage and Doll (1961) as adapted for risk assessment by Crump (1984). When the model is applied to experimental data on tumor frequencies, q1 is an estimate of the
