Quantitative Risk Assessment for Teratological Effects

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Abstract
This article presents a quantitative procedure for using a “benchmark dose” to obtain low-dose risk estimates for reproductive and developmental toxic effects. This procedure combines the best features of the previously proposed methods for handling litter effects for teratology data and the currently used methods for quantitative risk assessment. The beta-binomial distribution is used to account for litter effects, and the Weibull dose—response model is used for modeling teratogenic effects. A benchmark dose, defined to be the lowest dose at which the excess risk does not exceed 1% with 95% confidence, is proposed to replace the no-observed-effect level (NOEL). The NOEL is generally the highest experimental dose that is not statistically different from the control; the NOEL approach does not use experimental data effectively for quantitative risk estimation. In this article, a lower limit on the safe dose is estimated by linearly extrapolating downward from the benchmark dose; this procedure is recommended because it is not strongly dependent on the model used in the data range. Linear extrapolation from a benchmark dose is essentially equivalent to the use of a safety factor in determining a safe dose from a NOEL. However, the linear extrapolation procedure reflects the risk at the estimated safe dose. Confidence limits on excess risks and safe doses are based on the beta-binomial likelihood ratio criterion rather than on the asymptotic distribution of the maximum likelihood estimates, because the latter have been shown to exhibit poor properties in the low-dose extrapolation problem. The proposed method is illustrated by application to a real data set.

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