Gaylor, D.W. and Gold, L.S. Regulatory cancer risk assessment based on a quick estimate of a benchmark dose derived from the Maximum Tolerated Dose (MTD). Regulatory Toxicolicology and Pharmacology 28: 222-225 (1998). PDF
The proposed U.S. Environmental Protection Agency carcinogen risk assessment guidelines employ a benchmark dose as a point-of-departure (POD) for low-dose risk assessment. When information on the carcinogenic mode of action for a chemical supports a nonlinear dose response curve below the POD, this dose may be divided by uncertainty (safety) factors to arrive at a reference dose that is likely to produce no, or at most negligible, cancer risk for humans. Or, a margin-of-exposure ration between the POD and anticipated human exposure would be considered. If nonlinearity below the POD is not supported by sufficient evidence, linear extrapolation from the incidence at the POD to zero is used for low dose cancer risk estimation. The carcinogen guidelines suggest that the lower 95% confidence limit on the dose estimated to produce an excess of tumors in 10% of the animals (LTD10) be used for the POD. Due in part to the relatively narrow range of doses employed in 2-year rodent bioassays and the limited range of statistically significant tumor incidence rates, there is a high correlation between the maximum tolerated dose (MTD) used and the estimate of chemical potency for rodent carcinogens. It is shown that a simple relatively quick determination of the LTD10 for the POD is provided by the MTD/7. All that is needed is a 90-day study to establish the MTD. It is shown that the LTD10 determined by this relatively easy procedure is generally with a factor of 10 of the LTD10 estimated from expensive long-term 2-year bioassays. Estimates of the LTD10 from replicated 2-year bioassays, and hence estimates of cancer risk, can vary by a factor of 4 around a median value. Thus, there may be little gain in precision of cancer risk estimates derived from a 2-year bioassay. If the anticipated human exposure were estimated to be small relative to the MTD/7 = LTD10, there may be little value in conducting a chronic 2-year study in rodents because the estimate of cancer risk would be low regardless of the results of a 2-year bioassay. Conversely, if the anticipated human exposure were not sufficiently below the MTD/7 = LTD10 and there is a high probability that the chemical may be a rodent carcinogen, caution for use of the chemical might be raised without conducting a 2-year bioassay.
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Last updated: August 6, 2007