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Citation
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HERO ID
3223200
Reference Type
Journal Article
Title
Using physiologically based pharmacokinetic modeling and benchmark dose methods to derive an occupational exposure limit for N-methylpyrrolidone
Author(s)
Poet, TS; Schlosser, PM; Rodriguez, CE; Parod, RJ; Rodwell, DE; Kirman, CR
Year
2016
Is Peer Reviewed?
1
Journal
Regulatory Toxicology and Pharmacology
ISSN:
0273-2300
EISSN:
1096-0295
Volume
76
Page Numbers
102-112
Language
English
PMID
26776754
DOI
10.1016/j.yrtph.2015.12.020
Web of Science Id
WOS:000375514200013
Abstract
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.
Keywords
Occupational exposure limit; Benchmark dose; PBPK modeling; Developmental toxicity; Window of susceptibility
Tags
IRIS
•
Phthalates – Targeted Search for Epidemiological Studies
Source – all searches
WOS
Excluded
Source - Jun 2016 Update (Private)
WOS
Source - Dec 2016 Update (Private)
WOS
OPPT REs
•
OPPT_N-methylpyrrolidone (NMP)_F. Human Health
Total – title/abstract screening
On topic
Peer review
Primary source
On topic - additional tags for titles/abstracts
Animal hazard ID
ADME
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