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Pharmacokinetic-pharmacodynamic modeling of CNS drug effects: An overview

1988; Elsevier BV; Volume: 38; Issue: 1 Linguagem: Inglês

10.1016/0163-7258(88)90101-5

1879-016X

Jasper Dingemanse, Meindert Danhof, D. D. Breimer,

Analytical chemistry methods development

Health risk assessment for developmental neurotoxicants often requires the analysis and use of data collected in nonhuman mammalian species exposed to high doses, at different developmental stages, via exposure routes and scenarios different from anticipated human exposures. In such cases, the challenge of extrapolating from one test or exposure condition and dose level to another can be resolved on the basis of target tissue dose (e.g., area under the brain concentration vs. time curve and maximal brain concentration). Physiologically based pharmacokinetic (PBPK) models are scientifically sound tools that facilitate the simulation of target tissue dose for a number of developmental neurotoxicants (e.g., dioxins, polychlorinated biphenyls, organochlorine pesticides, metals, and organometallics). The construction and evaluation of PBPK models to account for prenatal and postnatal exposures is described in this chapter along with examples of their application in the risk assessment of methylmercury, atrazine, chlorpyriphos, and ethanol. The use of PBPK models in the risk assessment for developmental neurotoxicants will not only enhance the credibility of the process, but also provide a dynamic way of integrating new observations on the mode of action, biomonitoring, and high throughput screening assays as they emerge for diverse sets of developmental neurotoxicants.