Epidemiology studies show increased
leukemia mortality among
styrene butadiene rubber (SBR) workers but not among
butadiene monomer production employees. A detailed review of the SBR manufacturing process indicates that
sodium dimethyldithiocarbamate (DMDTC) introduced into the SBR manufacturing process for a period in the 1950s coincides with increased
leukemia mortality. Using the Computer-Optimized Molecular Parametric Analysis of Chemical Toxicity (COMPACT), we assessed the
enzyme (
cytochrome P450) substrate specificity of an
olefin series including
1,3-butadiene (BD) and also modeled its interaction with DMDTC. These analyses showed correlation of a structural/electronic parameter--the COMPACT radius--with the presence or absence of cytogenetic activity and also found that DMDTC would inhibit the oxidative metabolism of BD at least at high concentrations. Both DMDTC and its diethyl analog (DEDTC) bind with
CYP 2E1 and CYP 2A6. Both of these
isoforms are important in the initial oxidative metabolism of
butadiene and other
olefins. In co-exposure studies in mice of DMDTC with BD or with epoxybutene (EB), we found that there was a reduced increase in genotoxic activity based on micronuclei induction compared with BD or EB exposure alone. Treatment with DMDTC significantly increased the
protein carbonyl contents of hepatic microsomes compared with that of controls, a finding that may be related to DMDTC's activity as a prooxidant. Co-exposure with DMDTC and EB increased hepatic microsomal carbonyls to levels significantly greater than those of DMDTC-treated mice, while EB administration in the absence of DMDTC did not change
protein carbonyls relative to those of controls. The increase in hepatic microsomal
protein carbonyls suggests that DMDTC may modulate EB metabolism towards the formation of reactive intermediates that react with
proteins. The present molecular modeling and mechanistic studies suggest that co-exposure of BD and DMDTC is a plausible
biological hypothesis regarding increased
leukemia risk among SBR workers.