Evaluation of Cancer Tests of 1,3-Butadiene Using Internal Dose, Genotoxic Potency, and a Multiplicative Risk Model

Abstract

In cancer tests with 1,3-butadiene (BD), the mouse is much more sensitive than the rat. This is considered to be related to the metabolism of BD to the epoxide metabolites, 1,2-epoxy-3-butene (EB), 1,2:3,4-diepoxybutane, and 1,2-epoxy-3,4-butanediol. This study evaluates whether the large difference in outcome in cancer tests with BD could be predicted quantitatively on the basis of the concentration over time in blood (AUC) of the epoxide metabolites, their mutagenic potency, and a multiplicative cancer risk model, which has earlier been used for ionizing radiation. Published data on hemoglobin adduct levels from inhalation experiments with BD were used for the estimation of the AUC of the epoxide metabolites in the cancer tests. The estimated AUC of the epoxides were then weighed together to a total genotoxic dose, by using the relative genotoxic potency of the respective epoxide inferred from in vitro hprt mutation assays using EB as standard. The tumor incidences predicted with the risk model on the basis of the total genotoxic dose correlated well with the earlier observed tumor incidences in the cancer tests. The total genotoxic dose that leads to a doubling of the tumor incidences was estimated to be the same in both species, 9 to 10 mmol/LÂh EB-equivalents. The study validates the applicability of the multiplicative cancer risk model to genotoxic chemicals. Furthermore, according to this evaluation, different epoxide metabolites are predominating cancer-initiating agents in the cancer tests with BD, the diepoxide in the mouse, and the monoepoxides in the rat.

Hepatocellular carcinoma and the risk of occupational exposure

“…It has been shown in both human and animal models that VCM is able to induce liver angiosarcoma and HCC [98][99][100][101][102][103][104] . Maroni et al [105] reported the hepatotoxicity of VCM and other studies have shown the capacity of VCM to Group 1 [76] TCE 79-01-6 Dry cleaning; paint stripping; metal degreasing; production of chlorinated chemical compounds; shoe manufacturing; aircraft/aerospace, electronics and printing industry [125,127] Group 1 [129] PCE 127-18-4 Dry cleaning; textile processing; metal degreasing [138] Group 2A [129] DDT 50-29-3 Farming industry [141,145] Group 2B [148] N-nitrosamines 35576-91-1 Plastic, rubber and pharmacological manufacturing; farming industry; metalworking; electrical component production and use; gasoline and lubricant additives, production and use [159][160][161][162][163][164][165] Group [160,161] TCDD 1746-01-6 Waste management; paper mill; timber manufacturing; iron and steel manufacturing; electric power industry [175,179] Group 1 [76] PeCDF 57117-31-4 Cement and metalworking industry; chemical manufacturing [171,172,175] Group 1 [76] PCB 1336-36-3 Electrical industry, plastic and chemical industry; maintenance/repair technicians of PCB devices [175,[186][187][188][189][190] 1 Group …”

Mechanism of diepoxybutane‐induced p53 regulation in human cells

“…All three metabolites are genotoxic, carcinogenic, and mutagenic and induce chromosomal aberrations, micronucleus formation, sister chromatid exchanges, and mutations in various animal and human cells [7][8][9][10]. While these effects may explain or account for the toxicity and carcinogenicity of BD [8,11,12], detailed biochemical and molecular mechanisms for the toxicity of BD and its metabolites are not completely understood [13,14], and more studies are needed. DEB, the most potent of the three BD metabolites, is a bifunctional DNA alkylating agent that generates reactive oxygen species and exhibits cytotoxic properties [15].…”

In vivo doses of butadiene epoxides as estimated from in vitro enzyme kinetics by using cob(I)alamin and measured hemoglobin adducts: An inter-species extrapolation approach

“…The total genotoxic dose from the epoxide metabolites of BD can be obtained by converting the AUCs of the metabolites in relation to their respective relative mutagenic potency (Fred et al, 2008). With EB as a reference, we previously estimated the relative mutagenic potency per AUC of BD epoxides by using data from mutation studies in hprt loci; for EB, DEB and EBdiol, the relative mutagenic potency per μM · h was estimated to be 1, 32 and 0.21, respectively (Fred et al, 2008).…”

“…In the present work, the in vivo doses (or AUCs) of the BD epoxy-metabolites were calculated from Hb adduct levels as measured in BD-exposed mice and rats (which was somewhat refined in comparison with our earlier work (Fred et al, 2008)), and humans, as outlined below.…”

“…DEB is known to form DNA-DNA and DNA-protein cross-links, and it is a much more potent inducer of mutations than the monoepoxides (Cochrane and Skopek, 1994). We performed an earlier study (Fred et al, 2008) to evaluate the published BD cancer and exposure studies by using a multiplicative (relative) cancer risk model. The evaluation demonstrated that DEB was the primary contributor to genotoxicity/cancer induction from BD exposure in mice, but in rats, monoepoxides made the major contribution.…”