BIOLOGIC BASIS FOR A RISK ASSESSMENT MODEL FOR CLEFT-PALATE

A biologic model for palatogenesis is presented, intended as a basis for risk assessment. It comprises a sequence of developmental stages: growth and migration of neural crest cells, downward growth of palatal buds, elevation of palatal shelves, and differentiation of the epithelium followed by shelf fusion. Several events representing these stages and amenable to mathematical translation may be measurable in the form of biomarkers such as DNA and protein synthesis, phospholipid metabolism, and signal transducing systems. Interrupting components of the model will result in cleft palate. Teratogens with known mechanisms of action are compared with the model. The quantitative risk of cleft palate is conceived as a sequence of mathematical probabilities that any stage of the model runs an abnormal course. Stage-specific probabilities are determined by a chemical's potency and dose, and by duration of exposure and gestational age. Species or strain sensitivity may be expressed as quantitative differences in model parameters. Although the model is designed for cleft palate, the risk model may also estimate a multiple response risk to the same exposures.