Advancing In Vitro-In Vivo Extrapolations of Mechanism-Specific Toxicity Data Through Toxicokinetic Modeling.
International legislation, such as the European REACH regulation (registration, evaluation, authorization, and restriction of chemicals), mandates the assessment of potential risks of an ever-growing number of chemicals to the environment and human health. Although this legislation is considered one of the most important investments in consumer safety ever, the downside is that the current testing strategies within REACH rely on extensive animal testing. To address the ethical conflicts arising from these increased testing requirements, decision-makers, such as the European Chemicals Agency (ECHA), are committed to Russel and Burch's 3R principle (i.e., reduction, replacement, refinement) by demanding that animal experiments should be substituted with appropriate alternatives whenever possible. A potential solution of this dilemma might be the application of in vitro bioassays to estimate toxic effects using cells or cellular components instead of whole organisms. Although such assays are particularly useful to assess potential mechanisms of toxic action, scientists require appropriate methods to extrapolate results from the in vitro level to the situation in vivo. Toxicokinetic models are a straightforward means of bridging this gap. The present chapter describes different available options for in vitro-in vivo extrapolation (IVIVE) of mechanism-specific effects focused on fish species and also reviews the implications of confounding factors during the conduction of in vitro bioassays and their influence on the optimal choice of different dose metrics.
Department of Ecosystem Analysis, Institute for Environmental Research, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany. markus.brinkmann@bio5.rwth-aachen.de.
Markus
M
Brinkmann
Bayer CropScience AG, Monheim am Rhein, Germany.
Thomas G
TG
Preuss
Department of Ecosystem Analysis, Institute for Environmental Research, Aachen Biology and Biotechnology - ABBt, RWTH Aachen University, Worringerweg 1, 52074, Aachen, Germany. henner.hollert@bio5.rwth-aachen.de.|College of Resources and Environmental Science, Chongqing University, 1 Tiansheng Road Beibei, Chongqing, 400715, China. henner.hollert@bio5.rwth-aachen.de.|College of Environmental Science and Engineering and State Key Laboratory of Pollution Control and Resource Reuse, Tongji University, 1239 Siping Road, Shanghai, China. henner.hollert@bio5.rwth-aachen.de.|State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing, China. henner.hollert@bio5.rwth-aachen.de.
Henner
H
Hollert
D000818:Animals; D001681:Biological Assay / Q000592:standards*; D003198:Computer Simulation; D004785:Environmental Pollutants / Q000493:pharmacokinetics* / Q000633:toxicity*; D005060:Europe; D017408:Guidelines as Topic; D023421:Models, Animal; D008954:Models, Biological; D018408:Patch-Clamp Techniques / Q000592:standards*; D018675:Toxicity Tests / Q000592:standards*; D066007:Toxicokinetics
D004785:Environmental Pollutants
Bioassay; IVIVE; PBPK; PBTK; Predictive toxicology; Toxicokinetics