Carcinogenic Interactions between a Single Inhalation of ²³⁹PuO₂ and Chronic Exposure to Cigarette Smoke in Rats

Rats were exposed once by inhalation to plutonium-239 dioxide (²³⁹PuO₂), resulting in chronic α-particle irradiation of the lung, and exposed chronically to cigarette smoke to examine carcinogenic interactions between the two exposures. F344 rats were exposed to ²³⁹PuO₂ to achieve an initial lung burden of 0.5 kBq and then exposed 6 h/day, 5 days/week to cigarette smoke at 100 or 250 mg particulate matter/m³ for up to 30 months. Exposure to cigarette smoke increased the cumulative radiation dose to lung by slowing the clearance of ²³⁹PuO₂. ²³⁹PuO₂ alone did not affect survival, but the higher cigarette smoke exposure shortened survival in females. Combined exposure to ²³⁹PuO₂ and cigarette smoke acted synergistically to shorten survival in both genders. The combined effects of cigarette smoke and ²³⁹PuO₂ were approximately additive for lung hyperplasia and adenomas but were strongly synergistic for carcinomas. Differences between observed incidences and incidences predicted by survival-adjusted models accounting for increased radiation dose revealed a substantial component of synergy for carcinomas above that attributable to the radiation dose effect. The synergy for malignant lung tumors is consistent with findings from uranium miners and nuclear weapons production workers. These results bolster confidence in the epidemiological findings and have implications for risk assessment.