Exposure Profiling Of Potentially Genotoxic Constituents In Complex Mixtures | 17622
Occupational Medicine & Health Affairs
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Humans are constantly exposed to mixtures, such as vehicle exhaust or occupational exposures, containing several
thousand compounds, including many known human carcinogens. Covalent binding to DNA and formation of stable
adducts is believed to be the causal link between exposure and carcinogenesis. DNA and protein adducts are well established
biomarkers for the internal dose. Technical limitations, however, have prevented simultaneous and comprehensive detection
of a broad spectrum of adducts. To overcome this limitation, we present here our efforts for establishing methodology suitable
for comprehensive exposure assessment using the N-terminal valine adduct profile as biomarker. The method was evaluated
using alkylated peptide standards and globin reacted in vitro with known alkylating agents, including butadiene mono- and
di-epoxides (DEB), ethylene oxide, styrene oxide, ethylnitrosourea (ENU), propylene oxide and methyl methanesulfonate.
Interestingly, ENU formed a carbamoylated adduct but none of the expected ethyl adducts. Subsequently, the method was
applied to human globin samples. DEB-specific pyr-Val adducts, carbamoylated and methylated adducts were clearly detected
in patients with no known exposure and represent background derived from the environment. The intra-day CV was ≤39% and
inter-day CV was ≤50% for all detectable adducts. These patients were subsequently given tresulfan, a precursor to DEB, as an
immunosuppressant for liver transplantation. The drug treatment caused a 2-fold increase of pyr-val adducts, demonstrating
that the method can in fact determine chemical- (drug) induced adduct formation. The preliminary results suggest that the
new design is suitable for human bio-monitoring of exposures to mixtures. Global exposure profiling reveal adduct profile
that are distinctively different between various (I have to see which groups I will chose for that conference) exposure groups.
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