Induction of Nasal Tumors in Rats Exposed to Hexamethylphosphoramide by Inhalation

Abstract

Charles River-CD Sprague-Dawley rats in 4 equal groups of 240 each were exposed to 4,000, 400, 50, and 0 ppb of hexamethylphosphoramide (HMPA) vapor for 9 to 24 months. In an additional study, 4 equal groups of 200 rats were similarly exposed to 100, 50, 10, and 0 ppb HMPA vapor. Nasal tumors were first detected after approximately 7 months exposure at 4,000 and 400 ppb, after 9 months at 100 ppb, and 12 months at 50 ppb. No HMPA-related lesions were found at 10 ppb. Tumor incidence was 83% at 4,000 ppb exposure, 82% at 400 ppb, 38% at 100 ppb, and 20% at 50 ppb after 24 months of exposure. Most tumors developed from the squamous, respiratory epithelium and nasal gland both of which showed squamous metaplasia or dysplasia in the anterior nasal cavity. Exposure concentrations correlated with tumor induction and latency but not with tumor types. Of a total of 473 nasal tumors, epidermoid carcinoma was predominant (71.9%) followed by adenoid squamous carcinoma (15%), papilloma (8.2%), transitional (respiratory epithelial) carcinoma (1.9%), adenocarcinoma (1.3%), and undifferentiated tumor (1.1%), (mixed) pleomorphic tumor (0.4%), and adenomatous polyp (0.2%). Most tumors developed in the anterior nasal cavity (59.1%), then progressed to the posterior nasal cavity (40.9%). Only 0.4% of the tumors involved the posterior nasal cavity alone. Tumors invaded the nasal bone (47.5%) and brain (1.1%), or metastasized to the lung (1.5%) and cervical lymph nodes (1.1%). Malignancy of the epidermoid carcinoma was correlated to the cellular differentiation and degree of keratinization.