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Development of physiologically based toxicokinetic (PBTK) models for fish: Confessions of a former fish physiologist
Citation:
Nichols, J. Development of physiologically based toxicokinetic (PBTK) models for fish: Confessions of a former fish physiologist. SETAC North America, Minneapolis, MN, November 12 - 16, 2017.
Impact/Purpose:
Researchers working at the Duluth Water Quality Laboratory (US EPA/ORD/NHEERL/Mid-Continent Ecology Division) have pioneered methods and models for assessing risks associated with environmental contaminants. This platform presentation reviews the history of research leading to development of physiologically based toxicokinetic (PBTK) models for fish. Highlighted in the talk are important observations which contributed to our current understanding of mechanistic processes that control chemical uptake and accumulation in fish. The talk will address the critical issue of “fit for purpose” modeling and describe ongoing work designed to support application of PBTK models to hard-to-test chemicals and chemicals that exhibit complex kinetic behaviors (e.g., ionizable chemicals and substrates for membrane transporters). As such, this talk provides a comprehensive summary of past, present, and future research designed to support expanded use of fish PBTK models for assessment of both industrial chemicals and pesticides.
Description:
Abstract: In toxicology, as in pharmacology, the fundamental paradigm used to describe chemical interactions with biological systems is the dose-response relationship. Depending on the chemical mode of action, however, the relevant expression of dose may any one of several metrics related of the chemical concentration time-course (e.g., AUC or maximum achieved concentration). Moreover, a need exists to predict appropriate dose metrics for 1000s of untested chemicals and species in a manner that can be related to exposure conditions of interest. To address these challenges, researchers at the EPA laboratory in Duluth, working in collaboration with other scientists, adopted methods from fish physiology to develop a mechanistic understanding of processes that control chemical uptake and accumulation in fish. Early research demonstrated that temperature and dissolved O2 impact chemical uptake from water by influencing gill ventilation rate. Additional work showed that branchial uptake and elimination vary predictably with chemical log KOW, and that these relationships can be described using a mechanistic model for counter-current exchange at fish gills. Early PBTK models employed this gill sub-model to describe uptake and accumulation of chemicals that diffuse passively across cell membranes and partition non-specifically to tissue lipids. These models have since evolved to include descriptions of chemical flux across the skin and gut, and biotransformation in the liver. Subsequent work has shown that PBTK models may be used to extrapolate kinetic observations among species. Importantly, these advances have provided an improved understanding of conditions under which model complexity collapses and kinetic behavior can be adequately simulated using very simple descriptions. Ongoing work is focused on chemicals that exhibit more complex behaviors, including specific binding to plasma proteins and active secretion to urine. Descriptive compartmental and non-compartmental modeling approaches are being used with increasing frequency to quantify these behaviors and inform future development of PBTK models. The continuing goal of this effort is to develop mechanistic models of appropriate complexity to address the evolving needs of aquatic toxicologists and environmental risk assessors. The contents of this abstract neither constitute nor necessarily reflect US EPA policy.