title: Improving in vitro to in vivo extrapolation by incorporating toxicokinetic measurements: a case study of lindane-induced neurotoxicity.
abstract: Approaches for extrapolating in vitro toxicity testing results for prediction of human in vivo outcomes are needed. The purpose of this case study was to employ in vitro toxicokinetics and PBPK modeling to perform in vitro to in vivo extrapolation (IVIVE) of lindane neurotoxicity. Lindane cell and media concentrations in vitro, together with in vitro concentration-response data for lindane effects on neuronal network firing rates, were compared to in vivo data and model simulations as an exercise in extrapolation for chemical-induced neurotoxicity in rodents and humans. Time- and concentration-dependent lindane dosimetry was determined in primary cultures of rat cortical neurons in vitro using "faux" (without electrodes) microelectrode arrays (MEAs). In vivo data were derived from literature values, and physiologically based pharmacokinetic (PBPK) modeling was used to extrapolate from rat to human. The previously determined EC50 for increased firing rates in primary cultures of cortical neurons was 0.6μg/ml. Media and cell lindane concentrations at the EC50 were 0.4μg/ml and 7.1μg/ml, respectively, and cellular lindane accumulation was time- and concentration-dependent. Rat blood and brain lindane levels during seizures were 1.7-1.9μg/ml and 5-11μg/ml, respectively. Brain lindane levels associated with seizures in rats and those predicted for humans (average=7μg/ml) by PBPK modeling were very similar to in vitro concentrations detected in cortical cells at the EC50 dose. PBPK model predictions matched literature data and timing. These findings indicate that in vitro MEA results are predictive of in vivo responses to lindane and demonstrate a successful modeling approach for IVIVE of rat and human neurotoxicity.
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Edward L
authors.initials: EL
authors.lastname: Croom
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Shafer
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Marina V
authors.initials: MV
authors.lastname: Evans
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Mundy
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Chris R
authors.initials: CR
authors.lastname: Eklund
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Andrew F M
authors.initials: AF
authors.lastname: Johnstone
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: Cina M
authors.initials: CM
authors.lastname: Mack
authors.affiliation: Integrated Systems Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address: pegram.rex@epa.gov.
authors.forename: Rex A
authors.initials: RA
authors.lastname: Pegram
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D001556:Hexachlorocyclohexane / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D008297:Male; D008839:Microelectrodes; D008954:Models, Biological; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D020318:Rats, Long-Evans; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D066007:Toxicokinetics
chemical_list: D009498:Neurotoxins; D001556:Hexachlorocyclohexane
keywords: Extrapolation; In vitro; In vivo; Lindane; Neurotoxicity; Toxicokinetics