Diesel emissions are known to induce
tumors in experimental animals and are suspected of being carcinogenic in humans. Of the compounds associated with
diesel exhaust,
1,6-dinitropyrene is a particularly potent
mutagen and
carcinogen. In these experiments, we have investigated the use of
DNA adducts and T-lymphocyte mutations of
1,6-dinitropyrene as
biomarkers for exposure to diesel emissions.
1,6-Dinitropyrene (0-150 micrograms) was applied directly to the lungs of male F344 rats according to a protocol known to induce lung
tumors. In target (lung) and surrogate (liver, WBC, and spleen lymphocytes) tissues, one major
DNA adduct, N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene, was detected by HPLC and/or 32P-postlabeling analyses. The levels of this adduct reached a maximum 1-7 days following treatment and decreased to 13-50% of the peak values by 28 days after dosing. In the lung, a 2-fold increase in dose resulted in a 2-fold increase in
DNA binding up to the 30-micrograms dose; in the liver the same relationship was observed up to 10 micrograms
1,6-dinitropyrene. At higher doses, the extent of adduct formation still increased, but the rate was much lower than that occurring at lower doses. A limiting dilution clonal assay was used to measure mutation induction at the
hypoxanthine-
guanine phosphoribosyltranferase locus in spleen T lymphocytes. Following treatment, the mutant frequency increased until 21 weeks, remained constant until week 40, and then began to decrease. Mutant induction was dose related, with the increase in mutant frequency being significant at doses > or = 1 microgram
1,6-dinitropyrene. These data indicate that
1,6-dinitropyrene, a constituent of diesel emissions, is metabolically activated by nitroreduction to give
DNA adducts in target and surrogate tissues. They further suggest that T-lymphocyte mutations may be a more sensitive and longer-lived
biomarker than
DNA adducts for assessing previous exposures to nitropolycyclic
aromatic hydrocarbons.