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SUBACUTE MECHANISTIC STUDIES OF INHALED CHLORINE IN F344 RATS
Citation:
George, M. H., J. MCKEE, G. Wilson, R. H. JASKOT, D. G. ROSS, T. MOORE, T. Peay, AND A. M. JARABEK. SUBACUTE MECHANISTIC STUDIES OF INHALED CHLORINE IN F344 RATS. Presented at Society of Toxicology 49th Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
Our hypothesis for the mode of action (MOA) for CI2 is that its irritant effects are due to oxidative stress mediated by hypochlorous acid (HOCI).
Description:
Chlorine (C12) is very reactive in water and a respiratory tract irritant. Lesions in the respiratory tract show a proximal to distal distribution determined by concentration, but roles for airflow, mucus flow and tissue susceptibility have been indicated. Our hypothesis for the mode of action (MOA) for CI2 is that its irritant effects are due to oxidative stress mediated by hypochlorous acid (HOCI). HOCI is formed in tissues by hydrolysis of CI2, and to a lesser extent by downstream responses including inflammation. To better understand the pathogenesis of inhaled CI2 and provide an important link between new acute mechanistic studies (Peay et aI., SOT 2010) and the extant 2-yr bioassay (Wolf et aI., 1995), we performed a 5-day and 14-day study. Female F344 rats were exposed whole-body 6 hid, 5 dlw to inhaled CI2 for 5 days at 0, 0.1,0.5, 1.0 and 2.5 ppm; or 14-days to 0, 0.1 and 1.0 ppm. These concentrations· coincide with those of the 2-yr bioassay (1.0 and 2.5 ppm) and extend the exposure levels below the lowest in the 2-yr bioassay (0.4 ppm) as no no-observed-adverse-effect level (NOAEL) was identified. "C x til equivalent exposure levels are 0,0.6,3,6 and 15 ppm-hr. Tissue histopathology was performed immediately post exposure and biochemical or cellular evaluation of lavage fluids at 24-hr post exposure. Noses were sectioned transversely to provide six standard section levels. Biochemical analyses of nasal lavage and bronchoalveolar lavage fluids included lactate dehydrogenase, Nacetyl- 13-D-glucosaminidase, and total protein. Inflammation and hyperplasia, not observed in the acute studies, dominated the type of observed lesions for both studies. Also unlike the acute studies, no involvement of the olfactory epithelium was indicated. Goblet cell metaplasia emerged at 14-days in a concentration dependent manner. Nasopharyngeal hyperplasia only occurred at the 15 ppm-hr level of the5-day study. These findings suggest that refined approaches to duration adjustment for risk assessment of different exposure scenarios are necessary to map the dynamic pathogenesis of inhaled irritants. (This abstract does not reflect Agency policy).