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Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods
Citation:
Martin, S., E. McLanahan, P. Bushnell, S. Hunter, AND H. El-Masri. Species Extrapolation of Life-Stage Physiologically-Based Pharmacokinetic (PBPK) Models to Investigate the Developmental Toxicology of Ethanol Using In vitro to In vivo (IVIVE) Methods. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 143(2):512-35, (2015).
Impact/Purpose:
Impact Statement: Kinetic modeling has the potential to reduce uncertainties associated with the extrapolation of chemical concentrations applied in in vitro assays to doses associated with induction of toxicity in vivo. Background: Incorporation of in vitro-derived data into risk assessments is complicated by difficulties associated with comparing concentrations used for in vitro assays to doses in the whole animal, as well as interpretation of effects observed in the in vitro setting but not in vivo. This is because in vitro assays often do not incorporate either metabolic clearance of the target chemical, or blood flow through the tissue of interest. Concentrations applied in vitro may also not be achievable in the whole animal under a realistic exposure scenario. Kinetic modeling offers the potential to address these issues in two ways. First, in vitro media concentrations that are known to induce toxicity can be converted into the externally administered doses that would be necessary to produce these concentrations in vivo. Second, the external doses applied during in vivo experiments where toxicity has been reported can be converted to internal concentrations at a specific target tissue. These internal concentrations from the in vivo experiment can then be compared to those used in the in vitro assays, facilitating interpretation of both types of toxicity data when both biological factors and realistic exposure scenarios are considered.
Description:
To provide useful alternatives to in vivo animal studies, in vitro assays for dose-response assessments of xenobiotic chemicals must use concentrations in media and target tissues that are within biologically-plausible limits. Determining these concentrations is a complex matter, which can be facilitated by applying physiologically-based pharmacokinetic (PBPK) models in an in vitro to in vivo extrapolation (IVIVE) paradigm. We used ethanol (EtOH), a ubiquitous chemical with defined metrics for in vivo and in vitro embryotoxicity, as a model chemical to evaluate this paradigm. A published series of life-stage PBPK models for rats was extended to mice, yielding simulations that adequately predicted in vivo blood EtOH concentrations (BECs) from oral, intraperitoneal, and intravenous routes in nonpregnant and pregnant adult mice. The models were then extrapolated to nonpregnant and pregnant humans, replicating SEC data within a factor of two. The rodent models were then used to conduct IVIVEs for rodent and whole embryo culture embryotoxicity data (neural tube closure defects, morphological changes). A second IVIVE was conducted for exposure scenarios in pregnant women during critical windows of susceptibility for developmental toxicity, such as the first 6-to-8 weeks (prerecognition period) or mid-to-late pregnancy period, when EtOH consumption is associated with fetal alcohol spectrum disorders. Incorporation of data from human embryonic stem cell studies led to a model-supported linkage of in vitro concentrations with plausible exposure ranges for pregnant women. This effort demonstrates benefits and challenges associated with use of multispecies PBPK models to estimate in vivo tissue concentrations associated with in vitro embryotoxicity studies.
