An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach

doi:10.1016/J.TAAP.2015.06.016

Title: An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach

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Abstract

Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastric juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in themore »« less

Authors:: Sasso, A.F., E-mail: sasso.alan@epa.gov; Schlosser, P.M., E-mail: schlosser.paul@epa.gov

Publication Date:: Tue Sep 15 00:00:00 EDT 2015

OSTI Identifier:: 22465831

Resource Type:: Journal Article

Journal Name:: Toxicology and Applied Pharmacology

Additional Journal Information:: Journal Volume: 287; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; BIOASSAY; CARCINOGENS; CHROMIUM; DOSES; DRINKING WATER; EVALUATION; EXTRAPOLATION; FEMALES; HUMAN POPULATIONS; IN VIVO; LINEAR ABSORPTION MODELS; MALES; MICE; RATS; SATURATION; STOMACH

Citation Formats


                    Sasso, A.F., E-mail: sasso.alan@epa.gov, and Schlosser, P.M., E-mail: schlosser.paul@epa.gov. An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach.  United States: N. p., 2015. 
        Web.  doi:10.1016/J.TAAP.2015.06.016.

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                    Sasso, A.F., E-mail: sasso.alan@epa.gov, & Schlosser, P.M., E-mail: schlosser.paul@epa.gov. An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach.  United States.  https://doi.org/10.1016/J.TAAP.2015.06.016

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                    Sasso, A.F., E-mail: sasso.alan@epa.gov, and Schlosser, P.M., E-mail: schlosser.paul@epa.gov. 2015.  
        "An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach".  United States.  https://doi.org/10.1016/J.TAAP.2015.06.016.

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@article{osti_22465831,

  title        = {An evaluation of in vivo models for toxicokinetics of hexavalent chromium in the stomach},

  author       = {Sasso, A.F., E-mail: sasso.alan@epa.gov and Schlosser, P.M., E-mail: schlosser.paul@epa.gov},

  abstractNote = {Hexavalent chromium (Cr6) is a drinking water contaminant that has been detected in most of the water systems throughout the United States. In 2-year drinking water bioassays, the National Toxicology Program (NTP) found clear evidence of carcinogenic activity in male and female rats and mice. Because reduction of Cr6 to trivalent chromium (Cr3) is an important detoxifying step in the gastrointestinal (GI) tract prior to systemic absorption, models have been developed to estimate the extent of reduction in humans and animals. The objective of this work was to use a revised model of ex vivo Cr6 reduction kinetics in gastric juice to analyze the potential reduction kinetics under in vivo conditions for mice, rats and humans. A published physiologically-based pharmacokinetic (PBPK) model was adapted to incorporate the new reduction model. This paper focuses on the toxicokinetics of Cr6 in the stomach compartment, where most of the extracellular Cr6 reduction is believed to occur in humans. Within the range of doses administered by the NTP bioassays, neither the original nor revised models predict saturation of stomach reducing capacity to occur in vivo if applying default parameters. However, both models still indicate that mice exhibit the lowest extent of reduction in the stomach, meaning that a higher percentage of the Cr6 dose may escape stomach reduction in that species. Similarly, both models predict that humans exhibit the highest extent of reduction at low doses. - Highlights: • We outline a new in vivo model for hexavalent chromium reduction in the stomach. • We examine in vivo reduction for mice, rats, and humans under varying conditions. • Species differences in toxicokinetics may explain susceptibility. • We show that a simplified stomach reduction model is adequate for extrapolation. • Internal dose uncertainties still exist.},

  doi          = {10.1016/J.TAAP.2015.06.016},

  url          = {https://www.osti.gov/biblio/22465831},
  journal      = {Toxicology and Applied Pharmacology},

  issn         = {0041-008X},

  number       = 3,

  volume       = 287,

  place        = {United States},

  year         = {Tue Sep 15 00:00:00 EDT 2015},

  month        = {Tue Sep 15 00:00:00 EDT 2015}

}

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