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To study the genotoxic effects of subchronic exposure to environmental tobacco smoke, Sprague-Dawley rats were exposed to 0, 0.1, 1.0, and 10 mg total particulate matter (TPM)/m3 of aged and diluted sidestream smoke (ADSS) from 1R4F reference cigarettes 6 hr per day, 5 days a week for 13 weeks. DNA from lung, heart, larynx, bladder, and liver was tested for adduct formation by the 32P-postlabeling assay after 28 (except bladder) and 90 days of exposure and 90 days after cessation of exposure. In addition, alveolar macrophages from animals exposed for 28 or 90 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any tissue in any of the animals exposed to 0.1 or 1.0 mg TPM/m3. However, increased levels of DNA adducts with diagonal radioactive zones were observed in lung, heart, and larynx DNA of animals exposed to the highest concentration of ADSS (10 mg TPM/m3). Adduct analyses with varying amounts of DNA from lungs of mid- and high-exposure animals clearly indicate that the dose-response for DNA adduct formation is nonlinear. The adduct levels were highest after 90 days of exposure and were significantly reduced in all target tissues 90 days after cessation of exposure. Chromosomal aberrations in alveolar macrophages were not elevated in any group after 28 or 90 days of exposure. These results indicate a no-observed-effect-level (NOEL) of at least 1.0 mg/m3 for DNA adduct formation in lung, heart, and larynx, and a NOEL of at least 10 mg/m3 for the induction of chromosome aberrations in alveolar macrophages, under the conditions of this study.

The chemical constituents of cigarette smoke are greatly diluted in environmental tobacco smoke (ETS). In the typical indoor environment where cigarettes are smoked, the mean value of respirable suspended particles is approximately 0.1 mg/m3. In this study, we used aged and diluted sidestream smoke (ADSS) of 1R4F University of Kentucky research cigarettes as a surrogate for ETS and exposed Sprague-Dawley rats nose-only to 0, 0.1, 1.0, and 10 mg wet total particulate matter (WTPM)/m3 for 6 hr per day for 14 consecutive days. DNA from lung, heart, larynx, and liver was tested for adduct formation after 7 and 14 days of exposure and after 14 days of recovery. In addition, alveolar macrophages from animals exposed for 7 days were examined for chromosomal aberrations. Exposure-related DNA adducts were not observed in any of the animals at 0.1 or 1.0 mg WTPM/m3, which represent ambient and 10-fold exaggerated ETS concentrations, respectively. Slight diagonal radioactive zones, characteristic of adducts observed in human smokers and in animals exposed to mainstream smoke, were observed, but only in lung and heart DNA of animals exposed to the highest concentration of ADSS (10 mg WTPM/m3), a 100-fold exaggeration of typical field measurements of ETS. The mean relative adduct labeling values (+/- SE) were 8.7 (+/- 0.2) adducts per 10(9) nucleotides for lung DNA and 5.7 (+/- 0.7) adducts per 10(9) nucleotides for heart DNA after 14 days of exposure. No elevation in chromosomal aberrations was observed in alveolar macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Sprague-Dawley rats were exposed 6 hr per day for 14 consecutive days 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 per cubic meter. 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 only pathological response observed was slight to mild epithelial hyperplasia and inflammation in the most rostral part of the nasal cavity, in the high-exposure group only. No effects were noted at medium or low exposures. The minimal changes noted were reversible, using a subgroup of animals kept without further treatment for an additional 14 days. Overall, the end-points used in the study demonstrated that there was no detectable biological activity of ADSS at typical or even 10-fold ETS concentrations and that the activity was only minimal at very exaggerated concentrations (particle concentrations 100 times higher than typical real-world concentrations).

Toxicologists and pathologists are often faced with the dilemma of categorizing changes observed in the respiratory tract of laboratory animals as either "adaptive" or "toxic." However, it is often difficult to interpret the nature of a given change as either "adaptive" or "toxic." Certain lesions or changes in the respiratory tract are to be expected from the concentration of materials given or the experimental design of a study. Careful analysis suggests that some of these changes may be more properly described as adaptive rather than toxic within the context of a given study or situation. Tissue changes discussed in this paper include squamous metaplasia of laryngeal epithelium, goblet cell change in respiratory epithelium, macrophage accumulation within alveoli, and bronchiolization of alveolar epithelium. Examples provided show that some of these changes observed in inhalation studies are similar in severity but slightly increased in frequency over sham control animals. The introduction of exogenous material into the respiratory tract of laboratory animals in an experimental setting should be expected to result in certain changes. The challenge scientists must accept is to interpret these changes so that toxic events may be separated from adaptive changes. In order to meet this challenge, studies incorporating several species and novel technologies may have to be utilized.

Eight groups of 30 male and 30 female rats were exposed 1 hr per day, 5 days per week for 13 weeks, to smoke from reference (tobacco burned) or test (tobacco only heated) cigarettes, at nicotine concentrations of 5, 15, or 30 micrograms/liter of air. Similar smoke concentrations of wet total particulate matter and carbon monoxide were produced in each of the test/reference comparisons. There was a pronounced depression of minute ventilation of animals in the reference groups, but not in the test animals. Blood carboxyhemoglobin concentrations were similar in animals exposed to smoke from test and reference cigarettes. Plasma concentrations of nicotine and cotinine in the test groups were higher than in the reference groups. There were no differences between the smoke-exposed groups in terms of body weight or feed consumption. At necropsy, an increase in heart weight was noted in both high exposure groups. There were notable differences in histopathology, with fewer and less-pronounced changes in the test groups than in the reference groups. Many of the histopathological responses induced in the reference groups were absent in the test groups. Overall, the study demonstrated a substantial reduction in the biological activity of smoke from the test cigarette when compared with the reference.