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ACUTE STUDIES OF INHALED CHLORINE IN F344 RATS SUGGEST ALTERNATIVE TO HABER'S RULE FOR RISK EXTRAPOLATIONS
Citation:
Peay, T. S., J. MCKEE, G. A. Wilson, M. H. George, R. H. JASKOT, D. G. ROSS, T. MOORE, AND A. M. JARABEK. ACUTE STUDIES OF INHALED CHLORINE IN F344 RATS SUGGEST ALTERNATIVE TO HABER'S RULE FOR RISK EXTRAPOLATIONS. Presented at Society of Toxicology 49th Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
Chlorine (CI2), a high-production volume air pollutant, is an irritant of interest to homeland security. Risk assessment approaches to establish egress or re-entry levels typically use an assumption based on Haber's Rule and apply a concentration times duration ("C x t") adjustment to extrapolate across different exposure scenarios. We conducted a set of acute exposures to explicitly explore this assumption
Description:
Chlorine (CI2), a high-production volume air pollutant, is an irritant of interest to homeland security. Risk assessment approaches to establish egress or re-entry levels typically use an assumption based on Haber's Rule and apply a concentration times duration ("C x t") adjustment to extrapolate across different exposure scenarios. We conducted a set of acute exposures to explicitly explore this assumption. F344 female rats were exposed by whole-body inhalation to CI2 for 1 hour at 0, 6, 30 and 60 ppm; for 6 hours at 0,0.1, 1.0, 5.0 and 10 ppm, and for 24 hours at 0, 0.25, 1.25, and 2.5 ppm. The "C x t" equivalent exposure levels (pprrrhr) are 0, 0.6, 6, 30 and 60 ppm. Endpoints indicative of epithelial disruption in the respiratory tract were evaluated at various levels of observation, including tissue histopathology and biochemical and cellular evaluation of lavage fluids either immediately after the last exposure (histopathology) or 24-hr post exposure. Noses were sectioned transversely to provide six standard section levels. Both nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluids were sampled for biochemical analysis, including assays for lactate dehydrogenase (LDH), N-Acetyl-I3-D-Glucosaminidase (NAG) and total protein (TP). Generally, the expected proximal to distal distribution of epithelial lesions (inflammation, necrosis, degeneration and hyperplasia) was observed with increasing concentration levels, but the type, incidence and severity of each lesion did not follow a "C x t" pattern in this 24-hr range. Duration of exposure was a dominant determinant for the emergence of both inflammation and hyperplasia, but inflammation did not necessarily precede necrosis or degeneration. Both concentration and duration were determinants of olfactory degeneration. The dose-response, location, and severity scoring for each type of effect in the nose indicate a role for airflow and potentially mucus flow or tissue susceptibility. NAL TP was increased with concentration. Further analysis of tissue samples for 3-and 3,5-dichlorotyrosine as a dosimeter (Sochaski et aI., 2007), the above biochemical assays as well as total glutathione and anti-oxidant status (urate, ascorbate) may help interpret this pattern. It appears that updated algorithms for duration extrapolation are required to increase the accuracy of risk assessment approaches. (This abstract does not reflect Agency policy).