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Derivation of an occupational exposure limit for diacetyl using dose‐response data from a chronic animal inhalation exposure study
Author(s) -
Beckett Evan M.,
Cyrs William D.,
Abelmann Anders,
Monnot Andrew D.,
Gaffney Shan H.,
Finley Brent L.
Publication year - 2019
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.3757
Subject(s) - occupational exposure limit , inhalation , physiologically based pharmacokinetic modelling , inhalation exposure , medicine , confidence interval , confounding , no observed adverse effect level , pharmacokinetics , toxicology , toxicity , occupational exposure , pharmacology , anesthesia , biology , emergency medicine
Occupational exposure limits (OELs) have been previously proposed for diacetyl; however, most of these values are based on worker cohort studies that are known to have several limitations and confounders. In this analysis, an 8 hour time‐weighted average (TWA) OEL for diacetyl was derived based on data from a chronic, 2 year animal inhalation study recently released by the US National Toxicology Program. In that study, complete histopathology was conducted on male and female mice and rats exposed to 0, 12.5, 25 or 50 ppm diacetyl. Several responses in the lower respiratory tract of rats (the more sensitive species) were chosen as the critical endpoints of interest. Benchmark concentration (BMC) modeling of these endpoints was used to estimate BMC values associated with a 10% extra risk (BMC 10 ) and the associated 95% lower confidence bound (BMCL 10 ), which were subsequently converted to human equivalent concentrations (HECs) using a computational fluid dynamics‐physiologically based pharmacokinetic (CFD‐PBPK) model to account for interspecies dosimetry differences. A composite uncertainty factor of 8.0 was applied to the human equivalent concentration values to yield 8 hour TWA OEL values with a range of 0.16‐0.70 ppm. The recommended 8 hour TWA OEL for diacetyl vapor of 0.2 ppm, based on minimal severity of bronchiolar epithelial hyperplasia in the rat, is practical and health‐protective.