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Oral Presentation at FutureToxIV Meeting
Citation:
Wetmore, B. Oral Presentation at FutureToxIV Meeting. SOT - FutureTox IV, Arlington, VA, November 14 - 16, 2018.
Impact/Purpose:
This talk, given to an national audience with a specific interest in new approach methodologies (NAMs), discussed recent and future efforts to characterize chemical toxicokinetics and strategies to understand better the range of toxicokinetic variability that may exist across different populations and life stages. The talk covered current knowledge of contributors to toxicokinetic variability, availability of experimental and modeling tools to measure the extent of this variability, and additional research and information needs that will support further efforts to refine and advance these approaches.
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. The case study also identified specific hepatic enzymes that predominated in those situations where the greatest variability was identified across different lifestages or other populations. The presentation will go on to discuss available knowledge, databases, tools and approaches that can be utilized to further inform assessments regarding population variability and needs to advance the field further.
