Intraperitoneal mesotheliomas induced in mice by a polycyclic aromatic hydrocarbon

Female mice of 6 strains (C3H/HeN, BALB/c, C57BL/6N, DBA/2, NIH Swiss, and AKR/N) were given the polycyclic aromatic hydrocarbon carcinogen 3-methylcholanthrene (MC) intragastrically in olive oil at a dose of 20 mg/kg, weekly for 12 wk. Half were pretreated 24 h before each MC administration with intraperitoneal beta-naphthoflavone (beta-NF, 150 mg/kg in olive oil), a noncarcinogenic inducer of certain cytochrome P-450 isozymes. Remaining mice were given olive oil prior to MC in the same fashion, or beta-NF in olive oil or olive oil alone without subsequent exposure to MC. All mice were killed when moribund or 13 mo after the start of treatment. Most of the mice, irrespective of treatment, exhibited signs of peritoneal injury, including inflammation, necrosis, granuloma formation, and mineralization. Mice of some of the strains also presented peritoneal mesotheliomas, in addition to a variety of other tumors. The incidence of unequivocal mesothelioma-bearing mice was 12/31 C3H/He and 9/32 BALB/c mice given only MC. Incidence was low in C57BL/6 (1/31) and DBA/2 (1/26), and no definite mesotheliomas were found in Swiss or AKR mice. There were in addition a number of cases of sarcoma (nine total in all strains) and of peritonitis (four total) that resembled mesothelioma to some degree and were initially diagnosed as much. beta-NF pretreatment reduced the frequency of mesotheliomas: there was only one definite mesothelioma in any of the beta-NF-MC groups, in a C3H/He mouse. Most of the mesotheliomas were mixed fibro-mesothelial type, sometimes with papillary epithelial excrescences. They typically grew in a botryoid pattern within the peritoneal cavity, coating the abdominal organs and sometimes actively invading these organs and the diaphragm. Some lesions exhibited pleomorphism, prominent giant cells, and frequent mitoses. In addition, several lesions consisting of severe mesothelial hyperplasia associated with tissue necrosis and inflammation were considered as possible early stages of mesothelioma development. It was postulated that peritoneal injury imposed by repeated intraperitoneal injection of oil acted as an enhancing factor for mesothelioma induction by MC. The pertinence of such a relationship to mechanisms in the etiology of human mesotheliomas is discussed.