Use of Biomarkers and Physiologically Based Pharmacokinetic (PBPK) Modeling in Risk Analysis for Developmental Effects of ChlorpyrifosEPA Grant Number: R833453
Title: Use of Biomarkers and Physiologically Based Pharmacokinetic (PBPK) Modeling in Risk Analysis for Developmental Effects of Chlorpyrifos
Investigators: Hattis, Dale , Andrews, Howard F. , Garfinkel, Robin S. , Ginsberg, Gary , Goble, Robert , Hoepner, Lori A. , Rauh, Virginia , Whyatt, Robin M.
Institution: Clark University , Columbia University in the City of New York
EPA Project Officer: Pascual, Pasky
Project Period: June 1, 2007 through May 30, 2010
Project Amount: $677,499
RFA: Interpretation of Biomarkers Using Physiologically Based Pharmacokinetic Modeling (2006) RFA Text | Recipients Lists
Research Category: Health Effects , Health
The primary goal is to use PBPK modeling to help derive a developmental Reference Dose (RfD) and/or Acceptable Daily Intake (ADI) for Chlorpyrifos (CPF) from an epidemiology study in which biomonitored levels of CPF in cord blood were associated with impaired fetal growth and several neurodevelopmental effects (Whyatt, et al., 2004; Rauh, et al., 2006). Other parts of the project will evaluate the internal dose-response for adverse effects in developmental and mechanistic toxicity studies in rodents for comparison with humans; use the PBPK modeling approaches to assess population exposures and risk from CPF, based on NHANES general population measurements of a specific CPF urinary metabolite; and develop more general recommendations for the collection and interpretation of dynamically changing biomarker measurements for health risk assessment modeling.
The team will enhance an existing physiologically based pharmacokinetic (PBPK) model for CPF in humans (Timchalk, et al., 2002) to estimate dosimetry in pregnancy, to incorporate information on the human interindividual variability in key metabolic parameters, and to fairly reflect uncertainties in those parameters. PBPK model enhancement will be based in part on newer metabolism measurements in human livers (Sams et al. 2004; Mutch and Williams 2006) (rather than previous rat liver measurements). This, together with exposure time pattern data (Hore et al. 2005: Whyatt et al. 2002), will be used to convert observed CPF levels in cord and maternal blood to both intake doses and internal concentrations of active metabolite for benchmark dose modeling. Similar adaptation of the available rat model will allow interspecies comparisons of dose response for a variety of developmental endpoints.
We will produce an exemplary study using Monte Carlo probabilistic approaches applied to interpretation of biomarker measurements for PBPK-based dose response modeling for various endpoints for a developmental toxicants. This will pave the way for applications by a variety of regulatory and advisory agencies (including the U.S. Food and Drug Administration, the U.S. Department of Energy, the World Health Organization and Others) and private parties involved in health regulatory decision-making, including development of Reference Doses (RfDs), Acceptable Daily Intakes (ADIs) and similar values for agents where there is concern for reproductive/developmental risks. The model and assessed benchmark dose levels will also be used to interpret NHANES general population urinary biomarker measurements in terms of chlorpyrifos doses and possible developmental risks. The study team will also draw inferences for improved design of biomarker measurements for future studies and general population monitoring.