A Toxicokinetic Study of Inhaled Ethylene Glycol Ethyl Ether Acetate and Validation of a Physiologically Based Pharmacokinetic Model for Rat and Human

Gargas, Michael L.; Tyler, T. R.; Sweeney, Lisa; Corley, Richard A.; Weitz, Karl K.; Mast, T.J.; Paustenbach, Dennis J.; Hays, Sean M.

doi:10.1006/taap.2000.8927

Cited by 37 publications

(8 citation statements)

References 49 publications

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“…( 10 , 15 , 16 , 35 ) Some models employ hybrid CFD-PBPK structures ( 36 ) to best capture behavior of gas uptake due to the combined influences of tissue metabolism and airway architecture. PBPK models have been used to improve dosimetry for risk analysis of numerous chemicals, e.g., PBPK models of trichloroethylene, ( 37 ) glycol ethers, ( 38 – 41 ) or methyl iodide. ( 42 , 43 ) These PBPK models were used to estimate internal dose and to estimate safe exposure levels or OELs based on, respectively: the sum of the parent compound (trichloroethylene) and metabolite concentration in blood; the average daily area under the blood concentration of metabolites and time curve (AUC) (glycol ethers); and separate dose estimates based on MOA for different endpoints extrapolated from animal data, including maximum concentration of methyl iodide in the brain for neurotoxic effects and fetal blood iodide AUC for developmental effects.…”

Section: Hierarchical Model Selection Criteriamentioning

confidence: 99%

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Kuempel

Sweeney

Morris

et al. 2015

Journal of Occupational and Environmental Hygiene

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The purpose of this article is to provide an overview and practical guide to occupational health professionals concerning the derivation and use of dose estimates in risk assessment for development of occupational exposure limits (OELs) for inhaled substances. Dosimetry is the study and practice of measuring or estimating the internal dose of a substance in individuals or a population. Dosimetry thus provides an essential link to understanding the relationship between an external exposure and a biological response. Use of dosimetry principles and tools can improve the accuracy of risk assessment, and reduce the uncertainty, by providing reliable estimates of the internal dose at the target tissue. This is accomplished through specific measurement data or predictive models, when available, or the use of basic dosimetry principles for broad classes of materials. Accurate dose estimation is essential not only for dose-response assessment, but also for interspecies extrapolation and for risk characterization at given exposures. Inhalation dosimetry is the focus of this paper since it is a major route of exposure in the workplace. Practical examples of dose estimation and OEL derivation are provided for inhaled gases and particulates.

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Section: Hierarchical Model Selection Criteriamentioning

confidence: 99%

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Kuempel

Sweeney

Morris

et al. 2015

Journal of Occupational and Environmental Hygiene

Self Cite

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“…Thus, the differences between model predictions and measured values are likely to involve factors other than blood/air partitioning. Because PBPK models are typically validated on the basis of blood concentrations rather than exhaled air 35 and the model reported here adequately predicted human blood levels as well as rat brain and blood levels, it was concluded that the present model was adequate for its intended use in cross-species extrapolation.…”

Section: Discussionmentioning

confidence: 86%

Physiologically Based Pharmacokinetic Modeling of Cyclohexane as a Tool for Integrating Animal and Human Test Data

et al. 2009

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This report describes a physiologically based pharmacokinetic model for cyclohexane and its use in comparing internal doses in rats and volunteers following inhalation exposures. Parameters describing saturable metabolism of cyclohexane are measured in rats and used along with experimentally determined partition coefficients. The model is evaluated by comparing predicted blood and brain concentrations to data from studies in rats and then allometrically scaling the results to humans. Levels of cyclohexane in blood and exhaled air are measured in human volunteers and compared with model values. The model predicts that exposure of volunteers to cyclohexane at levels of 4100 mg/m(3) ( approximately 1200 ppm) will result in brain levels similar to those in rats exposed to 8000 mg/m(3) (the no-effect level for acute central nervous system effects). There are no acute central nervous system effects in humans exposed to 860 mg/m(3), consistent with model predictions that current occupational exposure levels for cyclohexane protect against acute central nervous system effects.

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“…PBPK models of EGEE acetate (Gargas et al 2000;Hays et al 1999), data of a study on the developmental toxicity of EGEE in rats (Doe 1984; NOAEC: 50 ml/m 3 ) and data from a volunteer study with 4-hour exposure to EGEE or EGEE acetate (Groeseneken et al a, b, 1987 were used for this purpose. The models considered five compartments, rapid hydrolysis of EGEE acetate to EGEE, metabolization of EGEE to ethoxyacetic acid and urinary excretion of ethoxyacetic acid.…”

Section: Pbpk Modelsmentioning

confidence: 99%

Ethylene glycol monoethyl ether [MAK Value Documentation, 2008]

2015

The MAK‐Collection for Occupational Health and Safety

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A Toxicokinetic Study of Inhaled Ethylene Glycol Ethyl Ether Acetate and Validation of a Physiologically Based Pharmacokinetic Model for Rat and Human

Cited by 37 publications

References 49 publications

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Advances in Inhalation Dosimetry Models and Methods for Occupational Risk Assessment and Exposure Limit Derivation

Physiologically Based Pharmacokinetic Modeling of Cyclohexane as a Tool for Integrating Animal and Human Test Data

Ethylene glycol monoethyl ether [MAK Value Documentation, 2008]

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