Respiratory carcinogenesis of nitroaromatics

The carcinogenic potential of 1-nitropyrene, a major mutagenic constituent of diesel-exhaust particles, was investigated using a hamster respiratory-carcinogenesis model. The specific aims of the investigation were to assess the activity of 1-nitropyrene as a complete carcinogen (Study 1) and as a cocarcinogen (Study 2) when administered in combination with the known environmental carcinogen benzo[a]pyrene. Preparations of 1-nitropyrene and benzo[a]pyrene adsorbed onto an equal mass of carbon carrier particles (Stokes diameter 2 to 5 microns, greater than 70 percent) were used for the intratracheal administration. Evaluation of 1-nitropyrene as a complete carcinogen involved exposing male Syrian golden hamsters to 1 or 2 mg of 1-nitropyrene either once or twice each week. A once-per-week instillation of 2 mg of benzo[a]pyrene served as a positive control. Two groups of animals received sterile saline only (saline controls) or carbon particles suspended in saline (particle controls). In addition, a group of untreated hamsters served as shelf controls. Evaluation of 1-nitropyrene as a cocarcinogen involved treating animals once each week with either 1 or 2 mg of 1-nitropyrene with or without concomitant exposure to 0.25 mg of benzo[a]pyrene. The studies were terminated after 92 weeks of treatment. In both studies, hamsters receiving 1-nitropyrene showed a dose-related decrease in survival and body-weight gain. In general, animals in Study 2 showed better survival than those in Study 1. A high intercurrent mortality was observed in the control groups of Study 1. In order to adjust for intercurrent mortality, tumor incidences were analyzed after modeling (using Cox regression) the effect of treatment in all animals for the period they were alive. A broad spectrum of neoplastic and nonneoplastic lesions was observed in the lungs and tracheas of all hamsters except shelf controls. Because of the histologic complexity of these lesions, the slides were coded, and the tissues were evaluated by an unbiased pathologist. The tumor types included papillomas, adenomas, adenocarcinomas, and squamous cell carcinomas, the latter being the most prevalent type in benzo[a]pyrene-treated animals. In view of the low incidence of tumors in 1-nitropyrene-treated hamsters, the tumor incidences in various experimental groups were compared regardless of the tumor type, location, and multiplicity. A small, but significant, increase in tumor incidence, with a dose-response trend, was observed only in Study 2 hamsters receiving 1-nitropyrene once weekly. In contrast, treatment with benzo[a]pyrene adsorbed onto carbon particles induced benign and malignant tumors virtually in all animals that survived more than 50 weeks of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)