Mathematical analysis for teratogenic sensitivity.

A mathematical structure is described for determining teratogenic sensitivity or susceptibility from analysis of malformation incidence, dose-response, and pharmacokinetic data obtained during pregnancy as a result of exposure to a teratogenic agent. From the dosage or exposure of laboratory animals, embryonic and maternal concentrations of the xenobiotic are calculated using a physiologically based pharmacokinetic (PBPK) model. Malformations observed in the progeny are linked to the PBPK-derived target tissue concentrations with a model for the sensitivity calculated as a function of the embryonic age. The PBPK model for internal disposition of chemicals during pregnancy was developed previously. This report focuses on the development of the mathematical relations for the sensitivity of the embryo and effect functions on different organs. The concentrations of a xenobiotic calculated for the site of action or target tissue(s) in the embryo are weighted using both a nonlinear dose-response curve and a sensitivity distribution function that depends on the age or stage of development of the embryo. This weighted "exposure" of the target tissue is regressed with the number of observed malformations to quantify the parameters of the model. This approach lends itself to integration of diverse sources of experimental data, with hydroxyurea data taken from several sources in the literature as an example. This sensitivity function obtained from laboratory animal data serves as a vehicle for prediction and extrapolation to human pregnancy for the teratogenic potential of a substance.