Morphology of neoplastic lesions induced by 1,3-butadiene in B6C3F1 mice

1,3-Butadiene (CAS No. 106-99-0) was studied for potential carcinogenicity and chronic toxicity by inhalation in B6C3F1 mice. Groups of 50 mice of each sex were exposed to 0, 625, or 1250 ppm 1,3-butadiene for 6 hr/day, 5 days/week for 60 weeks (male) or 61 weeks (female). The study was scheduled for 104 weeks of exposure but was terminated early because of reduced survival related to induction of a variety of tumors in 1,3-butadiene-exposed mice. A second chronic inhalation study was conducted in which male and female mice were exposed to 0, 6.25, 20, 62.5, 200, or 625 ppm for up to 2 years. Additional groups of 50 male mice were exposed to 625 ppm for 13 or 26 weeks, 312 ppm for 52 weeks, or 200 ppm for 40 weeks, then held without exposure until scheduled sacrifice 104 weeks after initial exposure. 1,3-Butadiene-exposed mice from both studies had increased incidences of malignant lymphomas that were observed as early as week 20 in the first study and week 23 in the second study. The lymphomas were primarily lymphocytic and originated in the thymus, although generalized lymphoma was often present. Exposed mice in both studies developed cardiac hemangiosarcomas that were observed as early as week 32 in the first study and week 41 in the second study. Also present were foci of endothelial hyperplasia in the myocardium that were regarded as early evidence of developing hemangiosarcoma. Alveolar epithelial hyperplasia, alveolar/bronchiolar adenomas and alveolar/bronchiolar carcinomas represented the spectrum of proliferative lung lesions induced by exposure to 1,3-butadiene in both studies. Exposure-related proliferative forestomach lesions observed in both studies included epithelial hyperplasia, squamous cell papillomas, and squamous cell carcinomas. 1,3-Butadiene-exposed female mice in both studies developed mammary gland neoplasms at increased incidences. Most of the mammary tumors were pleomorphic adenocarcinomas, but several adenoacanthomas were also seen. Granulosa cell tumors of the ovary were exposure-related neoplasms in both studies. Occasionally the granulosa cell tumors were malignant as evidenced by vascular invasion or pulmonary metastasis. Although there was an increased incidence of hepatocellular neoplasms in exposed females in the first study, by week 65 of the second study there was not evidence of a clear response of liver neoplasms. The preliminary results of the second study indicate there was induction of tumors similar to those seen in the first study but occurring in response to lower concentrations of 1,3-butadiene.