MATHEMATICAL-ANALYSIS FOR TERATOGENIC SENSITIVITY

A mathematical structure is described for determining teratogenic sens itivity or susceptibility from analysis of malformation incidence, dos e-response, and pharmacokinetic data obtained during pregnancy as a re sult of exposure to a teratogenic agent. From the dosage or exposure o f laboratory animals, embryonic and maternal concentrations of the xen obiotic are calculated using a physiologically based pharmacokinetic ( PBPK) model. Malformations observed in the progeny ave linked to the P BPK-derived target tissue concentrations with a model for the sensitiv ity calculated as a function of the embryonic age. The PBPK model for internal disposition of chemicals during pregnancy was developed previ ously. This report focuses on the development of the mathematical rela tions for the sensitivity of the embryo and effect functions on differ ent 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 w eighted ''exposure'' of the target tissue is regressed with the number of observed malformations to quantify the parameters of the model. Th is approach lends itself to integration of diverse sources of experime ntal data, with hydroxyurea data taken from several sources in the lit erature as an example. This sensitivity function obtained from laborat ory animal data serves as a vehicle for prediction and extrapolation t o human pregnancy for the teratogenic potential of a substance. (C) 19 97 Wiley-Liss, Inc.