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.