Reexamination of Respiratory Tract Responses in Rats, Mice, and Rhesus Monkeys Chronically Exposed to Inhaled Chlorine

Important data for human risk assessment of inhaled chlorine are provided by a recent rodent cancer bioassay (Wolf et al., 1995) and a chronic inhalation toxicity study in rhesus monkeys (Klonne et al., 1987). To improve interspecies comparisons based upon these data sets, the tissues from these studies were reexamined to (a) map the location of responses to assess the potential role of local chlorine dosimetry, (b) generate quantitative data on selected endpoints to compliment subjective scores, and (c) further characterize the responses in relation to interspecies differences and potential human health risks. Chlorine-induced lesions, which were confined to the respiratory tract, exhibited both similarities and differences among rodents and primates. At equivalent airborne concentrations (∼2.5 ppm), chlorine-induced responses were less severe in rhesus monkeys, but extended more distally in the respiratory tract to involve the trachea, while treatment-induced lesions were confined to the nose in rats and mice. Quantitation of septal fenestration, intraepithelial mucus, intraepithelial eosinophilic material, eosinophil infiltration (detected during the present study), and olfactory sensory cell loss generally supported previously reported subjective pathology scores and clarified concentration-response relationships. In both rodents and rhesus monkeys, airflow-driven regional dosimetry patterns were considered to play a major role in lesion distribution. The present work highlights the need for understanding regional respiratory-tract dosimetry and mechanisms of tissue response for inhaled chlorine in laboratory animals and humans.