QUANTITATIVE AND TEMPORAL RELATIONSHIPS BETWEEN DNA ADDUCT FORMATION IN TARGET AND SURROGATE TISSUES - IMPLICATIONS FOR BIOMONITORING

DNA-carcinogen adducts offer a potential dosimeter for environmental genotoxicants reaching the exposed individual. Because the target tissues for many chemical carcinogens are not readily accessible for monitoring adducts in humans, peripheral blood lymphocytes (PBLs) have served as surrogate sources of exposed DNA. Both benzo[a]pyrene (BaP) and benzo[b]fluoranthene (BbF) are widely distributed in the environment as components of complex mixtures, such as automobile exhaust, cigarette smoke, foods, water, and urban air. Thus, human exposure to these chemicals is widespread, and they probably contribute to overall human lung cancer risk. The interpretation of the results of such studies would be enhanced by an understanding of the pharmacokinetics of specific DNA adduct formation and persistence in both target and surrogate tissues. Polycyclic aromatic hydrocarbons (PAHs) were administered to male Sprague-Dawley rats IP at 100 mg PAH/kg body weight. Lung, liver, and PBL tissues were harvested 1, 3,7,14,28, and 56 days after treatment. DNA was extracted from each tissue and P-32-postlabeling analysis of DNA adducts with nuclease P1 enhancement was conducted. In all three tissues, BaP-DNA adducts exhibit a similar pattern, reaching a maximum at 3-4 days, followed by a decrease to 56 days. For BbF, the maximum DNA adduct levels in each tissue were between 5 and 14 days after injection. By 56 days after administration, the total adducts remaining in all tissues were measurable. Correlation analyses of the amount of DNA adducts in lung or liver compared to those found in the PBL of the same animals suggest a range of correlations (R2 = 0.67-0.83). For BaP, DNA adducts in both liver and lung may be predicted by PBL DNA adduct levels. For BbF, adduct levels in PBLs directly reflect adduct levels in the liver and are less predictive of lung adduct levels. The collateral pharmacokinetics for DNA adduct persistence in lung, liver, and PBLs suggest that PBL adduct-based dosimetry may reflect patterns of adduction in other less accessible tissues. Thus, PBL DNA adducts may prove to be useful dosimeters for the delivered dose of DNA.