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BIOLOGICALLY BASED DOSE RESPONSE MODELS FOR DEVELOPMENTAL TOXICITY RISK ASSESSMENT
Citation:
Kavlock, R. BIOLOGICALLY BASED DOSE RESPONSE MODELS FOR DEVELOPMENTAL TOXICITY RISK ASSESSMENT. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/D-91/215 (NTIS PB91233338), 1991.
Description:
Present risk assessment procedures for non-cancer endpoints generally rely on the determination of No Observed Adverse Effects Levels (NOAELS) in animal models followed by the application of various Uncertainty Factors (UFs) to account for unknowns in extrapolating high dose toxicology studies to potentially sensitive human subpopulations. he Reference Dose (RfD) or Concentration (RfC) which results from this process is an estimate, with an uncertainty spanning an order of magnitude, of the exposure level to the human population that is likely to be without appreciable risk of deleterious effects during a lifetime. he U.S. Environmental Protection Agency, through its Research to Improve Health Risk Assessment Program (RIHRA), has embarked on a concerted effort to introduce more pharmacokinetic and mechanistic information into the risk assessment process for non-cancer endpoints and to do this in a quantitative and predictive fashion. uch approaches are collectively termed biologically based dose-response (BBDR) models, and this presentation will focus on examples of such research in the area of developmental toxicity currently being conducted or supported by the EPA. hese activities range from those projects examining interrelationships of fetal responses so as to better utilize existing data, to those attempting to model the entire progression of biological events from the arrival of a chemical at the target to the expression of the developmental disturbance at the conclusion of pregnancy. Parallel efforts are focusing on factoring absorption, metabolism and distribution into the dose-response model. uch research should collectively shed light on the characteristics of the dose response curve at the sub-bioassay range, reduce our reliance on uncertainty factors, and serve as a framework for hypothesis testing in other models. ome of these approaches will prove immediately useful in virtually all developmental toxicity risk assessments. owever, given the complexity of development and the effort needed to collect the required data, full implementation of biologically based models will be restricted in the foreseeable future to a few economically important chemicals or to those with widespread human exposure.