Mg. Bird et al., Application of process chemistry and SAR modelling to the evaluation of health findings of lower olefins, CHEM-BIO IN, 135, 2001, pp. 571-584
Epidemiology studies show increased leukemia mortality among styrene butadi
ene rubber (SBR) workers but not among butadiene monomer production employe
es. A detailed review of the SBR manufacturing process indicates that sodiu
m dime thyldithiocarbamate (DMDTC) introduced into the SBR manufacturing pr
ocess for a period in the 1950s coincides with increased leukemia mortality
. Using the Computer-Optimized Molecular Parametric Analysis of Chemical To
xicity (COMPACT), we assessed the enzyme (cytochrome P450) substrate specif
icity 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 dieth
yl analog (DEDTC) bind with CYP 2E1 and CYP 2A6. Both of these isoforms are
important in the initial oxidative metabolism of butadiene and other olefi
ns. 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 o
n micronuclei induction compared with BD or EB exposure alone. Treatment wi
th DMDTC significantly increased the protein carbonyl contents of hepatic m
icrosomes 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 h
epatic microsomal carbonyls to levels significantly greater than those of D
MDTC-treated mice, while EB administration in the absence of DMDTC did not
change protein carbonyls relative to those of controls. The increase in hep
atic microsomal protein carbonyls suggests that DMDTC may modulate EB metab
olism towards the formation of reactive intermediates that react with prote
ins. The present molecular modeling and mechanistic studies suggest that co
-exposure of BD and DMDTC is a plausible biological hypothesis regarding in
creased leukemia risk among SBR workers. (C) 2001 Elsevier Science Ireland
Ltd. All rights reserved.