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Evaluation of a Rapid, Multi-Chemical Human Gestational Dose Model
Citation:
Sfeir, Mark A., D. Kapraun, A. Lumen, R. Judson, L. Aylward, D. Abrahamsson, T. Woodruff, C. Carignan, J. Rager, R. Sayre, R. Pearce, AND J. Wambaugh. Evaluation of a Rapid, Multi-Chemical Human Gestational Dose Model. SOT, Anaheim, CA, March 15 - 19, 2020. https://doi.org/10.23645/epacomptox.22572913
Impact/Purpose:
This is an abstract for a presentation to the Society of Toxicology annual meeting. This abstract describes ORD efforts to develop a human gestational expansion to the high throughput toxicokinetics (HTTK) software tool.
Description:
Human health chemical risk assessment involves consideration of potentially susceptible subpopulations, including pregnant women and developing fetuses. It is estimated that humans and other organisms encounter thousands of artificial chemicals in their environments, few of which have been characterized in terms of health risk. To assess the risk posed by a chemical, toxicokinetic (TK) information is needed to relate chemical exposure to potentially toxic tissue concentrations. Human-specific gestational exposure data are unavailable for most chemicals, however, making physiologically-based TK (PBTK) models needed to extrapolate knowledge from existing toxicological studies and/or in vitro bioactivity data to human pregnancy. Though development of chemical-specific PBTK models is possible, it is resource-intensive, and therefore a generic PBTK approach—where an underlying ordinary differential equation (ODE) system incorporates chemical-specific information but remains chemical-independent in structure—enables expedited, high-throughput model parameterization and preliminary analysis. Here we report the systematic evaluation of a generic PBTK model for a human mother and a developing fetus. Building upon a statistically plausible set of parameters with which to simulate the major physiological changes that accompany pregnancy, as well as upon the existing High-Throughput Toxicokinetics (httk) software package in R, we present a generic tool for estimating the dispositions of many chemicals throughout a maternofetal system. As derived from model equations, we compare an analytic determination of the equilibrium concentrations of chemicals in maternal and fetal plasma resulting from regular exposure to existing data on maternal to umbilical plasma concentration ratios at delivery for 25 chemicals. The analysis stands to be extended to the over 944 already parameterized for this model in httk. Chemical membership spans classes from organochlorine pesticides to perfluorinated compounds. As a result of its built-in, generic assumption of equality between maternal and fetal plasma concentrations, we find our model to be descriptive on average, though better fitting of certain classes of chemicals than others. This gestational model may be used to efficiently generate insights into exposure and risk, as well as to prioritize the regulatory efforts geared toward a given potential toxicant.
URLs/Downloads:
DOI: Evaluation of a Rapid, Multi-Chemical Human Gestational Dose Model
GESTATIONAL_MODEL_SOT_POSTER_2020_FINAL.A.PDF (PDF, NA pp, 1223.598 KB, about PDF)