The most frequently induced tumors in the lungs were alveolar/bronchiolar (A/B) adenoma and/or carcinoma in rats and mice. Of the sixty-six reports that showed evidence of site-specific carcinogenicity in the lung, sixty reports indicated A/B adenoma, A/B carcinoma, or both as the primary tumors induced. The six exceptions were PCBs, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), or dioxin mixtures studies in female SD rats, in which primary cystic keratinizing epitheliomas of the lung were induced (National Toxicology Program 2006a
). Cystic keratinizing epitheliomas are often observed in the lungs of rats following exposure to particles such as diesel exhaust, black carbon, quartz, talc, and nickel oxide (Boorman et al. 1996
; Mohr et al. 2006
; Rittinghausen and Kaspareit 1998
). Other compounds such as nickel (subsulfide and oxide), cobalt sulfate heptahydrate, dimethyl hydrogen phosphite, indium phosphide and tetranitromethane all induced squamous cell carcinoma in the lungs of rats in addition to A/B tumors. Sarcomas and mixed malignant tumors were observed in rats exposed to tetranitromethane. Induced bronchial adenoma and carcinoma and mesotheliomas were rarely observed in the lungs of rats and mice exposed to NTP chemicals.
In NTP studies, mesenchymal tumors of the lung were also less often diagnosed in chemically treated rats and mice. When present, these included hemangioma, hemangiosarcoma, fibroma, fibrosarcoma, leiomyosarcoma, and sarcoma. Among the spontaneous systemic tumors affecting the lung, mononuclear cell leukemia was the most common systemic tumor found in F344/N rats (male = 41.6%; female = 26.8%). Spontaneous malignant lymphoma was often observed systemically in female B6C3F1 mice (19.2%; male = 4.1%), with an incidence of less than 1% in male and female F344/N rats. Spontaneous histiocytic sarcoma was less often observed in male and female B6C3F1 and F344/N rats, with the incidence being less than 2.0%.
The liver was the most common primary site of origin for metastatic lung tumors in mice, whereas in rats, skin was most often the primary site of origin. Metastatic hepatocellular carcinoma, hepatoblastoma, histiocytic sarcoma, hepatocholangiocarcinoma, cholangiocarcinoma, hemangiosarcoma, and malignant fibrous histiocytoma were observed in the lungs of mice from NTP studies. Metastatic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, and squamous cell carcinoma originating from the skin were often reported in the lungs of rats. Similar metastatic lesions were also found in mice, because the skin was the second most common site of origin. Bone was the second most common primary site of origin of metastatic lesions to the lungs of rats.
The most common nonneoplastic lesions in the lungs of rats and mice were hyperplasia of the alveolar epithelium and inflammation. Most inflammatory lesions were categorized as acute, acute/chronic, or chronic; suppurative, granulomatous, and other types were less frequently observed in the lungs of rats and mice from NTP studies. Cellular infiltrates of primarily histiocytes were commonly observed in the alveoli of both rats and mice. Hemorrhage and congestion were common changes observed in both species. Squamous metaplasia of the alveoli, mineralization, and fibrosis occurred more often in rats than in mice. Thrombosis was observed in mice but was uncommon in rats. It should be noted that it is often difficult to differentiate nonneoplatic lesions such as A/B hyperplasia and histiocytic infiltrates induced in some of the inhalation studies from similar but spontaneous lesions related to aging, especially in rats.
In conclusion, A/B adenomas and carcinomas are the most frequently diagnosed chemically induced tumors in the lungs of rats and mice in NTP studies, with hyperplasia and inflammation being the most common nonneoplastic changes in both species. The lung is the second most common target site of tumor induction of chemicals tested in the NTP two-year rodent bioassay. Of the 545 peer-reviewed NTP studies to date, sixty-six produced significant site-specific neoplasia in the lung of rats and mice. Primary lung tumor diagnoses are most often associated with chemicals administered by the inhalation, gavage, or dosed-feed routes, with all other routes of administration composing a total of 11%.