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DOI10.1016/j.yrtph.2015.12.020
Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone
Poet, T. S.1; Schlosser, P. M.2; Rodriguez, C. E.3,4; Parod, R. J.5; Rodwell, D. E.6; Kirman, C. R.7
发表日期2016-04-01
ISSN0273-2300
卷号76页码:102-112
英文摘要

The developmental effects of NMP are well studied in Sprague Dawley rats following oral, inhalation, and dermal routes of exposure. Short-term and chronic occupational exposure limit (OEL) values were derived using an updated physiologically based pharmacokinetic (PBPK) model for NMP, along with benchmark dose modeling. Two suitable developmental endpoints were evaluated for human health risk assessment: (1) for acute exposures, the increased incidence of skeletal malformations, an effect noted only at oral doses that were toxic to the dam and fetus; and (2) for repeated exposures to NMP, changes in fetal/pup body weight. Where possible, data from multiple studies were pooled to increase the predictive power of the dose response data sets. For the purposes of internal dose estimation, the window of susceptibility was estimated for each endpoint, and was used in the dose response modeling. A point of departure value of 390 mg/L (in terms of peak NMP in blood) was calculated for skeletal malformations based on pooled data from oral and inhalation studies. Acceptable dose response model fits were not obtained using the pooled data for fetal/pup body weight changes. These data sets were also assessed individually, from which the geometric mean value obtained from the inhalation studies (470 mg*hr/L), was used to derive the chronic OEL. A PBPK model for NMP in humans was used to calculate human equivalent concentrations corresponding to the internal dose point of departure values. Application of a net uncertainty factor of 20-21, which incorporates data-derived extrapolation factors, to the point of departure values yields short-term and chronic occupational exposure limit values of 86 and 24 ppm, respectively. (C) 2016 The Authors. Published by Elsevier Inc.


英文关键词Occupational exposure limit;Benchmark dose;PBPK modeling;Developmental toxicity;Window of susceptibility
语种英语
WOS记录号WOS:000375514200013
来源期刊REGULATORY TOXICOLOGY AND PHARMACOLOGY
来源机构美国环保署
文献类型期刊论文
条目标识符http://gcip.llas.ac.cn/handle/2XKMVOVA/60259
作者单位1.Summit Toxicol, Richland, WA USA;
2.US EPA, Res Triangle Pk, NC 27711 USA;
3.US EPA, Washington, DC 20460 USA;
4.Coca Cola Co, Atlanta, GA USA;
5.BASF Corp, Wyandotte, MI USA;
6.Rodwell & Associates, Houston, TX USA;
7.Summit Toxicol, Orange Village, OH USA
推荐引用方式
GB/T 7714
Poet, T. S.,Schlosser, P. M.,Rodriguez, C. E.,et al. Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone[J]. 美国环保署,2016,76:102-112.
APA Poet, T. S.,Schlosser, P. M.,Rodriguez, C. E.,Parod, R. J.,Rodwell, D. E.,&Kirman, C. R..(2016).Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone.REGULATORY TOXICOLOGY AND PHARMACOLOGY,76,102-112.
MLA Poet, T. S.,et al."Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone".REGULATORY TOXICOLOGY AND PHARMACOLOGY 76(2016):102-112.
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