Two-Year Inhalation Exposure of Female and Male B6C3F1 Mice and F344 Rats to Chlorine Gas Induces Lesions Confined to the Nose

Chlorine gas is a respiratory irritant in both animals and humansthat produces concentration-dependent responses ranging fromminor irritation to death. Female and male B6C3F1 mice and F344rats were exposed to chlorine gas for up to 2 years to determinechronic toxicity and carcinogenicity. Groups of approximately70 each of female and male mice and rats were exposed to 0,0.4, 1.0, or 2.5 ppm chlorine gas for 6 hr/day, 5 days/week(mice and male rats), or 3 alternate days/week (female rats)for 2 years, with an interim necropsy of rats at 12 months (10rats/sex/concentration group). A complete necropsy was performedon all animals. Histological examination was performed on allorgans from high-concentration and control animals and selectedtarget organs from mid-and low-concentration groups. Exposure-dependentlesions were confined to the nasal passages in all sex and speciesgroups. Chlorine-induced lesions, which were most severe inthe anterior nasal cavity, included respiratory and olfactoryepithelial degeneration, septal fenestration, mucosal inflammation,respiratory epithelial hyperplasia, squamous metaplasia andgoblet cell hypertrophy and hyperplasia, and secretory metaplasiaof the transitional epithelium of the lateral meatus. Intracellularaccumulation of eosinophilic proteinaceous material was alsoa prominent response involving the respiratory, transitional,and olfactory epithelia, and in some cases the squamous epitheliumof the nasal vestibule. Many of these nasal lesions exhibitedan increase in incidence and/or severity that was related tochlorine exposure concentration and were statistically significantlyincreased at all chlorine concentrations studied. Male miceand female rats appeared more sensitive to chlorine than femalemice and male rats, respectively. The reasons for the sex differenceswithin a species were not determined. Interspecies differencesin regional dosimetry and site-specific tissue susceptibilityto chlorine exposure should be taken into account when usingthese data for accurate assessment of potential human healthrisks. The incidence of neoplasia was not increased by exposure,indicating that inhaled chlorine in rats and mice is an upperrespiratory tract toxicant but not a carcinogen.