Subchronic Inhalation Study in Rats Using Aged and Diluted Sidestream Smoke from a Reference Cigarette

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Abstract
Male Sprague-Dawley rats were exposed 6 hr/day, 5 days/week for up to 13 weeks to aged and diluted sidestream smoke (ADSS), used as a surrogate for environmental tobacco smoke (ETS), at concentrations of 0.1 (“typical”), 1 (“extreme”), or 10 (“exaggerated”) mg of particulates/m3. Subgroups of animals were killed after 1 and 4 weeks of exposure. Animals were exposed nose-only, inside whole-body chambers, to ADSS from the 1R4F reference cigarette. End points included histopathology, CO oximetry, plasma nicotine and cotinine, clinical pathology, and organ and body weights. The target particulate concentrations were achieved; at the exaggerated exposure they resulted in CO concentrations in excess of 50 ppm. Particle size distributions showed that the aerosols were completely respirable: the mass median diameter values were less than 1 μm. The only pathological response observed was slight to mild epithelial hyperplasia in the rostral nasal cavity, in the exaggerated exposure group only. No effects were noted at low (typical of measured real-world ETS concentrations) or extreme exposures. The changes were similar in animals killed after 4, 28, or 90 days, and were also similar to those noted in an earlier experiment with only 14 days duration, indicating that the change does not progress with increased exposure duration from 4 to 90 days. The nasal change was absent in a subgroup of animals kept without further smoke exposure for an additional 90 days, indicating complete reversibility. Overall, the end points used in the study demonstrated that (1) there was no detectable biological activity of ADSS at typical or even 10-fold ETS concentrations, and (2) the activity was only minimal at exaggerated concentrations in one region of one organ only. Based on the nasal histopathology, the NOEL for the 90-day study is > 1 mg/m3.