Publications from the Carcinogenic Potency Project

Gaylor, D.W., and Gold, L.S. Quick estimate of the regulatory virtually safe dose based on the maximum tolerated dose for rodent bioassays. Reg. Toxicol. Pharmacol., 22: 57-63 (1995). PDF

With a limited subset of National Cancer Institute/National Toxicology Program (NCI/NTP) bioassays, Gaylor (1989) showed that the regulatory virtually safe dose (VSD), corresponding to an estimated lifetime cancer risk of less than 10^-6, could be estimated within a factor of 10 simply by dividing the maximum tolerated dose (MTD), estimated from the results of a 90-day study, by 380,000. The purpose of this current study was to extend the analysis to all carcinogens in the Carcinogenic Potency Database (CPDB) of Gold et al. (1984, ’86, ’87, ’90, and ’93), utilizing the TD₅₀ (average daily dose rate in mg/kg body weight/day that was estimated to halve the probability of remaining tumor-free at a specified tissue site throughout a two-year study). Using the relationship between the upper bound on the low-dose slope () and the TD₅₀ reported by Krewski et al. (1993) and the ratio of the maximum dose tested (Max-D)/TD₅₀ obtained in our present analysis, an estimate of the regulatory VSD was given by the MTD/740,000, for NCI/NTP rodent carcinogens. This was about a factor of two lower than the limited analysis conducted by Gaylor (1989). There was little difference when the chemicals were divided into mutagens and nonmutagens. Ninety-six percent (134 of the 139 NCI/NTP rodent carcinogens) of the regulatory VSDs calculated from the individual TD₅₀s obtained from the 2-year bioassays were within a factor of 10 of the MTD/740,000. Gold et al. (1989) investigated the distribution of the TD₅₀ among “near-replicate” experiments (where the same chemical was tested more than once and was positive in the same strain, sex, and species by the same route). The distribution of TD₅₀s from near-replicate experiments is similar to the distribution of the Max-D/TD₅₀. Hence, the estimate of the regulatory VSD based on the Max-D/740,000, for NCI/NTP bioassays, is about as precise as the estimate obtained from a 2-year bioassay. This questions the advisability of conducting a 2-year bioassay for purposes of regulatory risk estimation.

Since resources are available to test only a small fraction of chemicals to which humans are exposed, a preliminary estimate of the regulatory VSD can be useful in setting testing priorities. If the expected human exposure level is below the regulatory VSD estimated from the MTD, a chemical may be assigned low priority for testing in a 2-year bioassay. Based on the work of Rulis (1986, ’89, and ’92), the FDA (1993) proposed a “threshold of regulation” of a dietary concentration of 0.5 ppb for substances used in food-contact articles. Rather than setting a single dietary concentration (0.5 ppb) for the threshold of regulation for all substances, the results of the present analysis could be used to make the procedure more chemical specific based upon the MTD.

The high correlation between the MTD and estimate of cancer potency (TD₅₀) can be exploited to provide a preliminary, hypothetical upper bound estimate of cancer risk for exposure to a chemical without conducting a 2-year animal bioassay. Thus, the expected level of human exposure relative to the MTD can be used to determine the priority for further research on a chemical, such as mechanistic studies.

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Last updated: August 6, 2007