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Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation.
Toxicology. 2010 Sep 10; 275(1-3):79-91.T

Abstract

There are a number of cancer and toxicity studies that have been carried out to assess hazard from methyl tertiary-butyl ether (MTBE) exposure via inhalation and oral administration. MTBE has been detected in surface as well as ground water supplies which emphasized the need to assess the risk from exposure via drinking water contamination. This model can now be used to evaluate route-to-route extrapolation issues concerning MTBE exposures but also as a means of comparing potential dose metrics that may provide insight to differences in biological responses observed in rats following different routes of MTBE exposure. Recently an updated rat physiologically based pharmacokinetic (PBPK) model was published that relied on a description of MTBE and its metabolite tertiary-butyl alcohol (TBA) binding to alpha 2u-globulin, a male rat-specific protein. This model was used to predict concentrations of MTBE and TBA in the kidney, a target tissue in the male rat. The objective of this study was to use this model to evaluate the dosimetry of MTBE and TBA in rats following different exposure scenarios, used to evaluate the toxicity and carcinogenicity of MTBE, and compare various dose metrics under these different conditions. Model simulations suggested that although inhalation and drinking water exposures show a similar pattern of MTBE and TBA exposure in the blood and kidney (i.e. concentration-time profiles), the total blood and kidney levels following exposure of MTBE to 7.5mg/ml MTBE in the drinking water for 90 days is in the same range as administration of an oral dose of 1000 mg/kg MTBE. Evaluation of the dose metrics also supports that a high oral bolus dose (i.e. 1000 mg/kg MTBE) results in a greater percentage of the dose exhaled as MTBE with a lower percent metabolized to TBA as compared to dose of MTBE that is delivered over a longer period of time as in the case of drinking water.

Authors+Show Affiliations

Integrated Laboratory Systems Inc., 601 Keystone Park Drive, Suite 100, Durham, NC 27713, USA. sborghoff@ils-inc.comNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

20561556

Citation

Borghoff, Susan J., et al. "Physiologically Based Pharmacokinetic Rat Model for Methyl Tertiary-butyl Ether; Comparison of Selected Dose Metrics Following Various MTBE Exposure Scenarios Used for Toxicity and Carcinogenicity Evaluation." Toxicology, vol. 275, no. 1-3, 2010, pp. 79-91.
Borghoff SJ, Parkinson H, Leavens TL. Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation. Toxicology. 2010;275(1-3):79-91.
Borghoff, S. J., Parkinson, H., & Leavens, T. L. (2010). Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation. Toxicology, 275(1-3), 79-91. https://doi.org/10.1016/j.tox.2010.06.003
Borghoff SJ, Parkinson H, Leavens TL. Physiologically Based Pharmacokinetic Rat Model for Methyl Tertiary-butyl Ether; Comparison of Selected Dose Metrics Following Various MTBE Exposure Scenarios Used for Toxicity and Carcinogenicity Evaluation. Toxicology. 2010 Sep 10;275(1-3):79-91. PubMed PMID: 20561556.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Physiologically based pharmacokinetic rat model for methyl tertiary-butyl ether; comparison of selected dose metrics following various MTBE exposure scenarios used for toxicity and carcinogenicity evaluation. AU - Borghoff,Susan J, AU - Parkinson,Horace, AU - Leavens,Teresa L, Y1 - 2010/06/16/ PY - 2010/03/03/received PY - 2010/06/04/revised PY - 2010/06/08/accepted PY - 2010/6/22/entrez PY - 2010/6/22/pubmed PY - 2010/8/4/medline SP - 79 EP - 91 JF - Toxicology JO - Toxicology VL - 275 IS - 1-3 N2 - There are a number of cancer and toxicity studies that have been carried out to assess hazard from methyl tertiary-butyl ether (MTBE) exposure via inhalation and oral administration. MTBE has been detected in surface as well as ground water supplies which emphasized the need to assess the risk from exposure via drinking water contamination. This model can now be used to evaluate route-to-route extrapolation issues concerning MTBE exposures but also as a means of comparing potential dose metrics that may provide insight to differences in biological responses observed in rats following different routes of MTBE exposure. Recently an updated rat physiologically based pharmacokinetic (PBPK) model was published that relied on a description of MTBE and its metabolite tertiary-butyl alcohol (TBA) binding to alpha 2u-globulin, a male rat-specific protein. This model was used to predict concentrations of MTBE and TBA in the kidney, a target tissue in the male rat. The objective of this study was to use this model to evaluate the dosimetry of MTBE and TBA in rats following different exposure scenarios, used to evaluate the toxicity and carcinogenicity of MTBE, and compare various dose metrics under these different conditions. Model simulations suggested that although inhalation and drinking water exposures show a similar pattern of MTBE and TBA exposure in the blood and kidney (i.e. concentration-time profiles), the total blood and kidney levels following exposure of MTBE to 7.5mg/ml MTBE in the drinking water for 90 days is in the same range as administration of an oral dose of 1000 mg/kg MTBE. Evaluation of the dose metrics also supports that a high oral bolus dose (i.e. 1000 mg/kg MTBE) results in a greater percentage of the dose exhaled as MTBE with a lower percent metabolized to TBA as compared to dose of MTBE that is delivered over a longer period of time as in the case of drinking water. SN - 1879-3185 UR - https://www.unboundmedicine.com/medline/citation/20561556/Physiologically_based_pharmacokinetic_rat_model_for_methyl_tertiary_butyl_ether L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-483X(10)00248-9 DB - PRIME DP - Unbound Medicine ER -