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Determination of age and gender differences in biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice and rats to improve PBPK modeling.
Toxicol Lett. 2005 Mar 28; 156(1):127-61.TL

Abstract

2-Butoxyethanol (BE) is the most widely used glycol ether solvent. BEs major metabolite, butoxyacetic acid (BAA), causes hemolysis with significant species differences in sensitivity. Several PBPK models have been developed over the past two decades to describe the disposition of BE and BAA in male rats and humans to refine health risk assessments. More recent efforts by Lee et al. [Lee, K.M., Dill, J.A., Chou, B.J., Roycroft, J.H., 1998. Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. Toxicol. Appl. Pharmacol. 153, 211-226] to describe the kinetics of BE and BAA in the National Toxicology Program (NTP) chronic inhalation studies required the use of several assumptions to extrapolate model parameters from earlier PBPK models developed for young male rats to include female F344 and both sexes of B6C3F1 mice and the effects of aging. To replace these assumptions, studies were conducted to determine the impact of age, gender and species on the metabolism of BE, and the tissue partitioning, renal acid transport and plasma protein binding of BAA. In the current study, the Lee et al. PBPK model was updated and expanded to include the further metabolism of BAA and the salivary excretion of BE and BAA which may contribute to the forestomach irritation observed in mice in the NTP study. The revised model predicted that peak blood concentrations of BAA achieved following 6 h inhalation exposures are greatest in young adult female rats at concentrations up to 300 ppm. This is not the case predicted for old (> or =18 months) animals, where peak blood concentrations of BAA in male and female mice were similar to or greater than female rats. The revised model serves as a quantitative tool for integrating an extensive pharmacokinetic and mechanistic database into a format that can readily be used to compare internal dosimetry across dose, route of exposure and species.

Authors+Show Affiliations

Biological Monitoring and Modeling Group, Battelle Pacific Northwest Division, 902 Battelle Blvd., P.O. Box 999, MSIN P7-59, Richland, WA 99352, USA. rick.corley@pnl.govNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15705493

Citation

Corley, R A., et al. "Determination of Age and Gender Differences in Biochemical Processes Affecting the Disposition of 2-butoxyethanol and Its Metabolites in Mice and Rats to Improve PBPK Modeling." Toxicology Letters, vol. 156, no. 1, 2005, pp. 127-61.
Corley RA, Grant DM, Farris E, et al. Determination of age and gender differences in biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice and rats to improve PBPK modeling. Toxicol Lett. 2005;156(1):127-61.
Corley, R. A., Grant, D. M., Farris, E., Weitz, K. K., Soelberg, J. J., Thrall, K. D., & Poet, T. S. (2005). Determination of age and gender differences in biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice and rats to improve PBPK modeling. Toxicology Letters, 156(1), 127-61.
Corley RA, et al. Determination of Age and Gender Differences in Biochemical Processes Affecting the Disposition of 2-butoxyethanol and Its Metabolites in Mice and Rats to Improve PBPK Modeling. Toxicol Lett. 2005 Mar 28;156(1):127-61. PubMed PMID: 15705493.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Determination of age and gender differences in biochemical processes affecting the disposition of 2-butoxyethanol and its metabolites in mice and rats to improve PBPK modeling. AU - Corley,R A, AU - Grant,D M, AU - Farris,E, AU - Weitz,K K, AU - Soelberg,J J, AU - Thrall,K D, AU - Poet,T S, PY - 2005/2/12/pubmed PY - 2005/3/25/medline PY - 2005/2/12/entrez SP - 127 EP - 61 JF - Toxicology letters JO - Toxicol Lett VL - 156 IS - 1 N2 - 2-Butoxyethanol (BE) is the most widely used glycol ether solvent. BEs major metabolite, butoxyacetic acid (BAA), causes hemolysis with significant species differences in sensitivity. Several PBPK models have been developed over the past two decades to describe the disposition of BE and BAA in male rats and humans to refine health risk assessments. More recent efforts by Lee et al. [Lee, K.M., Dill, J.A., Chou, B.J., Roycroft, J.H., 1998. Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. Toxicol. Appl. Pharmacol. 153, 211-226] to describe the kinetics of BE and BAA in the National Toxicology Program (NTP) chronic inhalation studies required the use of several assumptions to extrapolate model parameters from earlier PBPK models developed for young male rats to include female F344 and both sexes of B6C3F1 mice and the effects of aging. To replace these assumptions, studies were conducted to determine the impact of age, gender and species on the metabolism of BE, and the tissue partitioning, renal acid transport and plasma protein binding of BAA. In the current study, the Lee et al. PBPK model was updated and expanded to include the further metabolism of BAA and the salivary excretion of BE and BAA which may contribute to the forestomach irritation observed in mice in the NTP study. The revised model predicted that peak blood concentrations of BAA achieved following 6 h inhalation exposures are greatest in young adult female rats at concentrations up to 300 ppm. This is not the case predicted for old (> or =18 months) animals, where peak blood concentrations of BAA in male and female mice were similar to or greater than female rats. The revised model serves as a quantitative tool for integrating an extensive pharmacokinetic and mechanistic database into a format that can readily be used to compare internal dosimetry across dose, route of exposure and species. SN - 0378-4274 UR - https://www.unboundmedicine.com/medline/citation/15705493/Determination_of_age_and_gender_differences_in_biochemical_processes_affecting_the_disposition_of_2_butoxyethanol_and_its_metabolites_in_mice_and_rats_to_improve_PBPK_modeling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0378-4274(04)00464-3 DB - PRIME DP - Unbound Medicine ER -