Use of biomarker data and metabolite relative potencies to support derivation of noncancer reference values based on the reproductive and developmental toxicity effects of 1,3-butadiene

• Published in: Regulatory toxicology and pharmacology 2022-10, Vol.134, p.105239-105239, Article 105239
• Main Authors: Kirman, C.R., North, C.M., Tretyakova, N.Y., Erraguntla, N., Shen, H., Hays, S.M.
• Format: Article
• Language: English
• Subjects: 1,3-Butadiene; Benchmark dose; Biomarkers; Data derived extrapolation factors; Hemoglobin adducts; Internal dose; Metabolism; Mixtures assessment; Noncancer reference concentration; Pooled analysis; Species differences
• ISSN: 0273-2300; 1096-0295
• DOI: 10.1016/j.yrtph.2022.105239

Subchronic and chronic reference values (RfVs) were derived for 1,3-butadiene (BD) based upon its ability to cause reproductive and developmental effects observed in laboratory mice and rats. Metabolism has been well-established as an important determinant of the toxicity of BD. A major challenge to human health risk assessment is presented by large quantitative species differences in the metabolism of BD, differences that should be accounted for when the rodent toxicity responses are extrapolated to humans. The methods of Fred et al. (2008)/Motwani and Törnqvist (2014) were extended and applied here to the noncancer risk assessment of using data-derived extrapolation factors to account for species differences in metabolism, as well as differences in cytotoxic potency of three BD metabolites. This approach made use of biomarker data (hemoglobin adducts) to quantify species differences in the internal doses of BD metabolites experienced in mice, rats and humans. Using these methods, the dose-response relationships in mice and rats exhibit improved concordance, and result in subchronic and chronic inhalation reference values of 29 and 10 ppm, respectively, for BD. Confidence in these reference values is considered high, based on high confidence in the key studies, medium-to-high confidence in the toxicity database, high confidence in the estimates of internal dose, and high confidence in the dose-response modeling. •Subchronic and chronic reference values for 1,3-butadiene were derived.•Reproductive and developmental endpoints serve as the basis for the reference values.•Biomarker data were used to quantify large species differences in metabolism.•Benchmark dose methods were used to estimate points of departure.•Confidence in the resulting subchronic (29 ppm) and chronic (10 ppm) reference values is high.