1,3-Butadiene (BD) is an important industrial chemical used to produce plastics, rubbers, and polymers. High-exposure rodent studies show noncancer effects, most notably ovarian atrophy and reduced fetal weight, but translating those findings into human health risk depends on understanding how the effects arise and how species differ in processing the chemical. Mice, rats, and humans metabolize BD into reactive epoxide metabolites at very different rates, so the internal dose reaching target tissues can differ across species by up to three orders of magnitude. Those differences have a large influence on any resulting risk assessment.
To evaluate these questions, SciPinion convened an independent panel of six experts in reproductive and developmental toxicology, mode of action (MOA) evaluation, and dose-metric decisions for risk assessment. The panel was charged with weighing the evidence for the proposed noncancer MOAs and its confidence in them, assessing whether the effects are relevant to humans, identifying data gaps, and advising on the most appropriate dose metric for extrapolating from animals to people. The candidate MOAs were developed using the International Programme on Chemical Safety (IPCS) framework and modified Bradford-Hill considerations.
The review followed SciPinion’s triple-blinded, multi-round modified Delphi process. The sponsor and the panelists were blinded to one another, the panelists were blinded to each other (identified during deliberations only as “Expert 1,” “Expert 2,” and so on), and every response and comment was recorded and reported in full to support transparency and reduce the risk of groupthink.
For ovarian atrophy, or premature ovarian failure, the proposed MOA centers on BD’s metabolism to its diepoxide metabolite (DEB). The panel expressed high confidence in this MOA, with a mean confidence score of 8.2 out of 10, and was unanimous (6 of 6) in concluding that the relevance of these effects to human health cannot be excluded on qualitative grounds, since BD’s metabolic pathways are qualitatively similar across species.
For reduced fetal weight and related general toxicity, the proposed MOA involves metabolism to multiple epoxide metabolites, depletion of glutathione, and subsequent toxicity. The panel expressed medium confidence in this MOA, with a mean confidence score of 5.2 out of 10, noting that much of the supporting evidence comes from non-pregnant animals and that mechanistic data in pregnant animals would strengthen confidence.
To quantify species differences in internal dose, the team relied on hemoglobin adduct data from mice, rats, and humans, including newly published measurements from female workers, as a direct empirical measure of the reactive epoxide dose each species receives. From these data, the preferred mouse-to-human data-derived extrapolation factors (DDEFs) were 0.00064 for ovarian atrophy, based on DEB, and 0.0070 for fetal body weight, based on all three epoxide metabolites. The panel assigned its highest confidence to adjustments grounded in these internal-dose measures and its lowest confidence to using external air concentration with no species adjustment at all.
These choices have substantial practical consequences. Using the U.S. Environmental Protection Agency’s proposed occupational exposure value calculation as an example, incorporating species differences in BD metabolism yields protective values of roughly 24 to 260 ppm, compared with 0.17 ppm when no pharmacokinetic adjustment is made. Both adjusted values sit well above the current Occupational Safety and Health Administration permissible exposure limit of 1 ppm, whereas the unadjusted approach, to which the panel attributed low confidence, produces a value below that limit. In other words, existing occupational standards appear protective for BD’s noncancer endpoints once the best available toxicokinetic science is applied.
The evaluation illustrates why mode-of-action evidence and quantitative dosimetry matter in risk assessment: without accounting for how differently mice, rats, and humans metabolize BD, noncancer risks can be overestimated. The authors conclude that hemoglobin adduct data represent the best available science for quantifying these species differences, while identifying the additional studies, particularly in pregnant animals, that would further strengthen confidence in the underlying modes of action.
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Figure 10. Occupational exposure values for 1,3-butadiene based on lower fetal body weight in mice under different interspecies extrapolation approaches (triangles = human equivalent concentration for the point of departure; dashed lines = application of a 30-fold uncertainty factor; circles = occupational exposure values).