Recent advances in mathematical modeling of developmental abnormalities using mechanistic information.
During the last several years, significant changes in the risk assessment process for developmental toxicity of environmental contaminants have begun to emerge. The first of these changes is the development and beginning use of statistically based dose-response models [the benchmark dose (BMD) approach] that better utilize data derived from existing testing approaches. Accompanying this change is the greater emphasis placed on understanding and using mechanistic information to yield more accurate, reliable, and less uncertain risk assessments. The next stage in the evolution of risk assessment will be the use of biologically based dose-response (BBDR) models that begin to build into the statistically based models factors related to the underlying kinetic, biochemical, and/or physiologic processes perturbed by a toxicant. Such models are now emerging from several research laboratories. The introduction of quantitative models and the incorporation of biologic information into them has pointed to the need for even more sophisticated modifications for which we offer the term embryologically based dose-response (EBDR) models. Because these models would be based upon the understanding of normal morphogenesis, they represent a quantum leap in our thinking, but their complexity presents daunting challenges both to the developmental biologist and the developmental toxicologist. Implementation of these models will require extensive communication between developmental toxicologists, molecular embryologists, and biomathematicians. The remarkable progress in the understanding of mammalian embryonic development at the molecular level that has occurred over the last decade combined with advances in computing power and computational models should eventually enable these as yet hypothetical models to be brought into use.
Kavlock
R J
RJ
Reproductive Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA.
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure; D006801:Humans; D015233:Models, Statistical; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens