A Comparison of Regulatory Implications of Traditional and Exact Two‐Stage Dose‐Response Models

We compare the regulatory implications of applying the traditional (linearized) and exact two‐stage dose‐response models to animal carcinogenic data. We analyze dose‐response data from six studies, representing five different substances, and we determine the “goodness‐ of‐fit” of each model as well as the 95% confidence lower limit ofthe dose corresponding to a target excess risk of 10‐5 (the target risk doseTRD). For the two concave datasets, we find that the exact model gives a substantially better fit to the data than the traditional model, and that the exact model gives aTRD that is an order of magnitude lower than that given by the traditional model. In the other cases, the exact model gives a fit equivalent to or better than the traditional model. We also show that although the exact two‐stage model may exhibit dose‐response concavity at moderate dose levels, it is always linear or sublinear, and never supralinear, in the low‐dose limit. Because regulatory concern is almost always confined to the low‐dose region extrapolation, supralinear behavior seems not to be of regulatory concern in the exact two‐stage model. Finally, we find that when performing this low‐dose extrapolation in cases of dose‐response concavity, extrapolating the model fit leads to a more conservative TRD than taking a linear extrapolation from 10% excess risk. We conclude with a set of recommendations.