1,3-Butadiene: Exposure Estimation, Hazard Characterization, and Exposure-Response Analysis

Abstract

1,3-Butadiene has been assessed as a Priority Substance under the Canadian Environmental Protection Act. The general population in Canada is exposed to 1,3-butadiene primarily through ambient air. Inhaled 1,3-butadiene is carcinogenic in both mice and rats, inducing tumors at multiple sites at all concentrations tested in all identified studies. In addition, 1,3-butadiene is genotoxic in both somatic and germ cells of rodents. It also induces adverse effects in the reproductive organs of female mice at relatively low concentrations. The greater sensitivity in mice than in rats to induction of these effects by 1,3-butadiene is likely related to species differences in metabolism to active epoxide metabolites. Exposure to 1,3-butadiene in the occupational environment has been associated with the induction of leukemia; there is also some limited evidence that 1,3-butadiene is genotoxic in exposed workers. Therefore, in view of the weight of evidence of available epidemiological and toxicological data, 1,3-butadiene is considered highly likely to be carcinogenic, and likely to be genotoxic, in humans. Estimates of the potency of butadiene to induce cancer have been derived on the basis of both epidemiological investigation and bioassays in mice and rats. Potencies to induce ovarian effects have been estimated on the basis of studies in mice. Uncertainties have been delineated, and, while there are clear species differences in metabolism, estimates of potency to induce effects are considered justifiably conservative in view of the likely variability in metabolism across the population related to genetic polymorphism for enzymes for the critical metabolic pathway.

Weight of Evidence: A Review of Concept and Methods

“…These 92 publications were further categorized in terms of how “weight of evidence” was defined. ( 4–95 ) Reference lists of these articles were reviewed to identify additional relevant documents (e.g., risk assessment guidelines from the Environmental Protection Agency ( 96–98 ) and other government agencies as well as classic methodologic articles (e.g., Austin Bradford Hill's classic 1965 article ( 99 ) on causation)). These were used throughout the text for illustrative purposes.…”

Reactions of Glyceraldehyde 3-Phosphate Dehydrogenase Sulfhydryl Groups with Bis-Electrophiles Produce DNA–Protein Cross-Links but Not Mutations

“…1,2-Dibromoethane and diepoxybutane are both carcinogens in laboratory animals (3)(4)(5)(6)(7) and induce mutagenicity and toxicity in in vitro systems (8)(9)(10).…”

Diepoxybutane-induced apoptosis is mediated through the ERK1/2 pathway

“…74,75 It is thus possible that ERK1/2-mediated apoptotic signaling may explain the bone marrow depletion observed in mice and humans exposed to high concentrations of BD. 76 –78 This report contributes towards the understanding of DEB-induced apoptotic signaling. Since apoptosis accounts for the cytotoxicity of low concentrations of DEB 17,23 this report also contributes towards the understanding of mechanisms involved in DEB-induced apoptosis and BD toxicity.…”