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Adenomas Induced by Polycyclic Aromatic Hydrocarbons in Strain A/J Mouse Lung Correlate with Time-integrated DNA Adduct Levels¹

Carcinogenesis and Metabolism Branch (MD-68), Health Effects Research Laboratory, U. S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711 [J. A. R., J. R. R., S. N., M. J. M]; Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina, 27709 [G. B. N.]; Environmental Health, Research, and Testing, Inc., Research Triangle Park, North Carolina 27709 [K. H. W.]; Department of Pathology, Medical College of Ohio, Toledo, Ohio 43699 [A. G.]; and Department of Preventive Medicine, Arthur James Cancer Hospital, Ohio State University, Columbus, Ohio 43210 [G. D. S.]

The induction of DNA adducts and adenomas in the lungs of strain A/J mice has been investigated following the single i.p. administration of each of the following polycyclic aromatic hydrocarbons (PAH): pyrene, dibenz[a,h]anthracene, benzo[a]pyrene, benzo[b]fluoranthene, 5-methyl-chrysene, and cyclopenta[c,d]pyrene. DNA adducts were measured by ³²P-postlabeling at times between 1 and 21 days following injection, while adenomas were counted at 240 days after treatment. Pyrene did not induce either DNA adducts or lung adenomas at any of the doses examined. Each of the remaining PAH induced both adenomas and DNA adducts in a dose-dependnent manner, with dibenz[a,h]anthracene > 5-methylchrysene > cyclopenta[c,d]pyrene > benzo[a]pyrene > benzo[b]fluoranthene. DNA adducts reached maximal levels between 3 and 9 days after injection, followed by a gradual decrease. The time-integrated DNA adduct level (TIDAL) was calculated by numerically integrating the areas under the adduct persistence curves extrapolated to 240 days for each PAH at each dose level. This value represents the effective total molecular dose of PAH that was delivered to the lung DNA over the entire course of tumorigenesis. A strong correlation of lung adenoma induction with the TIDAL values was observed for each PAH. The slopes of the tumors versus TIDAL value relationships were essentially identical for 5-methyl-chrysene, cyclopenta[cd]pyrene, benzo[a]pyrene, and benzo[b]fluoranthene. The slope of this relationship for dibenz[a,h]anthracene was markedly greater. The essentially identical induction of adenomas as a function of TIDAL values for these PAH suggests that the formation and persistence of DNA adducts determines their carcinogenic potency.

¹ Portions of this research were funded by United States Environmental Protection Agency Cooperative Agreement CR-816069 (to G. D. S.). The research described in this article has been reviewed by the Health Effects Research Laboratory, United States Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views of the Agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use.

² To whom requests for reprints should be addressed.

³ Present address: Duke University, Department of Anesthesiology, Durham, NC 27705.

Received 6/15/94. Accepted 12/30/94.

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