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QIVIVE Approaches to Evaluate Inter-individual Toxicokinetic Variability
Citation:
Wetmore, B. QIVIVE Approaches to Evaluate Inter-individual Toxicokinetic Variability. 2017 SOT Annual Meeting, MD, Baltimore, March 12 - 16, 2017.
Impact/Purpose:
This oral presentation, to be given during a symposium session at the Society of Toxicology's annual meeting, will discuss the current knowledge base regarding what is known to contribute to differences in how different people and populations (ie, life stages, ethnic groups, etc.) metabolize chemicals to which they are exposed - known as toxicokinetic variability. These variations impact how different populations may be affected following chemical exposures. Given recent progress in computational modeling and experimental techniques, a research approach is presented that integrates in vitro and in silico tools to quantitate this toxicokinetic variability. This approach is poised to be incorporated into future chemical safety assessment strategies. Also future steps that will facilitate its adoption into high-throughput toxicokinetic approaches are also discussed.
Description:
Manifestation of inter-individual variability in toxicokinetics (TK) will result in identical external exposure concentrations yielding differing blood or tissue concentrations. As efforts to incorporate in vitro testing strategies into human health assessment continue to grow, a greater understanding of TK variability will aid in refining interpretation and application of these in vitro bioactivity datasets to consider sensitive populations and lifestages. The availability of in vitro, in silico, and in vitro-in vivo extrapolation (IVIVE) modeling tools developed for use on pharmaceutical compounds provides key opportunities to toxicologists to quantitatively estimate TK variability following exposure to chemicals and environmental pollutants through incorporating differences in physiology, ontogeny, and genetics. This presentation will describe a case study that incorporates in vitro isozyme-specific clearance measurements for ToxCast chemicals with physiologic parameters in an IVIVE approach that predicts population and lifestage specific plasma steady-state concentrations (Css). In addition to incorporating variabilities in physiology, the Css values are adjusted for the known differing abundances in cytochrome P450 (CYP) and uridine diphospho-glucuronosyltransferase isozymes due to developmental, ethnic, and health-based differences. TK variability, measured by dividing the upper 95th percentile Css for the relevant population by the median general adult population Css ranged from approximately 3-11-fold for the most sensitive group, the lifestage representing children from birth to 6 months of age. Chemicals exhibiting the largest variability in this case study were primarily metabolized by CYP1A2, while those exhibiting minimal variability were metabolized by 3 or more CYP isozymes. These Css values were incorporated with ToxCast in vitro data using reverse dosimetry to estimate the external dose equivalent required to achieve in vitro testing concentrations in the blood. These values can then be compared against an external exposure estimate to aid in prioritizing those chemicals for which population or lifestage variability may trigger a response at a realistic exposure level. Although the available toolset provides promising information to estimate TK variability, further efforts are needed to ensure sufficient information on ontogenetic and genetic differences exist for additional isozymes known to be substrate s for environmental chemicals. This abstract does not necessarily reflect the views of the US EPA.
