1,3-Butadiene (BD) is an important industrial chemical used in the production of plastics, rubbers, and polymers. This evaluation synthesizes mode of action (MOA) information to support interspecies extrapolations for key noncancer effects of BD (ovarian atrophy, lower fetal weight). Data-derived extrapolation factors (DDEFs) were calculated to account for substantial toxicokinetic differences between mice, rats, and humans. MOAs for the key noncancer effects were developed using the IPCS framework and modified Bradford-Hill considerations. An independent panel of six topic experts reviewed the weight of evidence, assessed human relevance, and provided recommendations on dosimetry approaches. DDEF values were calculated using newly published hemoglobin adduct data, including measurements from female workers, to quantify species differences in internal doses of BD's reactive epoxide metabolites. For ovarian atrophy, the MOA focuses on BD's metabolism to the diepoxide metabolite. The expert panel expressed high confidence (mean score: 8.2/10) in this MOA. For fetal weight effects, the proposed MOA involves metabolism to multiple epoxide metabolites, glutathione depletion, and subsequent toxicity. The panel expressed medium confidence (5.2/10) in this MOA, noting data gaps regarding mechanisms in pregnant animals. Based on hemoglobin adduct data from exposed workers and laboratory animals, preferred DDEFs for mouse-to-human extrapolation were 0.00064 for ovarian atrophy (based on BD's diepoxide metabolite) and 0.0070 for fetal body weight effects (based on all three epoxide metabolites of BD). Application of MOA-informed DDEFs has substantial impact on BD risk assessment. Using EPA's proposed occupational exposure value calculation as an example, incorporating species differences in BD metabolism and pharmacokinetics yields protective values of 24-260 ppm (compared to 0.17 ppm without quantitative pharmacokinetic adjustment), all well above the current OSHA permissible exposure limit of 1 ppm. These findings demonstrate that existing occupational standards are protective for BD's noncancer endpoints when best available science on species differences in toxicokinetics is appropriately considered. This work illustrates the critical importance of incorporating MOA evidence and quantitative dosimetry data to ensure risk assessments reflect scientific understanding and avoid potentially overestimating human health risks.
Kirman et al. (Tue,) studied this question.