Chronic toxicity/oncogenicity study of styrene in CD-1 mice by inhalation exposure for 104 weeks

Groups of 70 male and 70 female Charles River CD-1 mice were exposed whole body to styrene vapor at 0, 20, 40, 80 or 160 ppm 6 h per day 5 days per we ek for 98 weeks (females) or 104 weeks (males), The mice were observed dail y; body weights, food and water consumption were measured periodically, a b attery of hematological and clinical pathology examinations were conducted at weeks 13, 26, 52, 78 and 98 (females)/104 (males), Ten mice of each gend er per group were pre-selected for necropsy after 52 and 78 weeks of exposu re and the survivors of the remaining 50 of each gender per group were necr opsied after 98 or 104 weeks. An extensive set of organs from the control a nd high-exposure mice were examined histopathologically, whereas target org ans, gross lesions and all masses were examined in all other groups. Styrene had no effect on survival in males, Two high-dose females died (acu te liver toxicity) during the first 2 weeks; the remaining exposed females had a slightly higher survival than control mice. Levels of styrene and sty rene oxide (SO) in the blood at the end of a 6h exposure during week 74 wer e proportional to exposure concentration, except that at 20 ppm the SO leve l was below the limit of detection, There were no changes of toxicological significance in hematology, clinical chemistry, urinalysis or organ weights . Mice exposed to 80 or 160 ppm gained slightly less weight than the contro ls. Styrene-related non-neoplastic histopathological changes were found onl y in the nasal passages and lungs, Tn the nasal passages of males and femal es at all exposure concentrations, the changes included respiratory metapla sia of the olfactory epithelium with changes in the underlying Bowman's gla nd; the severity increased with styrene concentration and duration of expos ure. Loss of olfactory nerve fibers was seen in mice exposed to 40, 80 or 1 60 ppm. In the lungs, there was decreased eosinophilia of Clara cells in th e terminal bronchioles and bronchiolar epithelial hyperplasia extending int o alveolar ducts, Increased tumor incidence occurred only in the lung. The incidence of bronchioloalveolar adenomas was significantly increased in mal es exposed to 40, 80 or 160 ppm and in females exposed to 20, 40 and 160 pp m. The increase was seen only after 24 months. In females exposed to 160 pp m, the incidence of bronchiolo-alveolar carcinomas after 24 months was sign ificantly greater than in the controls. No difference in lung tumors betwee n control and styrene-exposed mice was seen in the intensity or degree of i mmunostaining, the location of tumors relative to bronchioles or histologic al type (papillary, solid or mixed). It appears that styrene induces an inc rease in the number of lung tumors seen spontaneously in CD-1 mice. Copyrig ht (C) 2001 John Wiley & Sons, Ltd.