Christopher R. E. Coggins

A Review of Chronic Inhalation Studies with Mainstream Cigarette Smoke in Rats and Mice

In this paper, I review the results of a representative selection of chronic inhalation studies with rats and mice exposed to mainstream cigarette smoke and describe the inhalation exposures and the histopathological changes reported by various authors. Many of the studies used nose-only exposure systems, whereas others simply used large whole-body chambers. Smoke-induced epithelial hypertrophy, hyperplasia, and squamous metaplasia were reported in the conducting airways in most of the studies, along with increased numbers of intra-alveolar macrophages that were occasionally associated with alveolar metaplasia. Lung adenomas and adenocarcinomas were reported in only a few of the studies. No statistically significant increase in the incidence of malignant lung tumors was seen in either species as a result of smoke exposure, a finding that does not agree with the results of epidemiological studies in humans. Possible reasons for this lack of correlation are given.

Light and intermittent cigarette smokers: a review (1989–2009)

RationaleGrowing proportions of smokers in the USA do not smoke everyday and can be referred to as light and intermittent smokers (LITS). Despite a current prevalence of LITS in the USA estimated at 25–33% of all smokers, a systematic review of the literature on this group of smokers has yet to be written.ObjectivesThe aim of this paper is to review and evaluate research on LITS and to identify, describe and discuss commonalities and differences between LITS and daily smokers.MethodsThe primary databases used to search for publications were Pub Med (National Library of Medicine) and SCOPUS (Elsevier).ResultsLITS inhale smoke and have post-smoking blood nicotine concentrations that are broadly equivalent to those found in daily smokers. However, LITS differ from daily smokers with regard to cigarette consumption and frequency of cigarette use, sociodemographic and socioeconomic characteristics, motives, personality traits, dependence, withdrawal and craving, response to smoking-related cues, quitting perception, past-smoking status, and initiation.ConclusionsIn contrast to daily smokers, LITS show few or no signs of dependence as currently defined by DSM-IV criteria, appear to exercise more self-control, seem to be less impulsive, and their smoking experience is primarily associated with positive rather than negative reinforcement. Conclusions drawn from the reviewed literature highlight the multivariate factors that must be taken into account when defining LITS and emphasize the importance of further research on this increasing fraction of smokers. The potential implications of increased LITS prevalence on smoking-related disease risks remain to be thoroughly investigated.

Histological sectioning of the rodent larynx for inhalation toxicity testing

In rodents, the larynx is a major site of histopathologic alteration following inhalation exposure to particulates, vapors, and aerosols. Specifically, the epithelial lining of a narrowly delineated region on the ventral floor of the larynges of rats and mice appears to be especially vulnerable to inhaled materials, and is recognized as a preferred site for histopathological evaluation in inhalation studies. This site is located at the base of the epiglottis, cranial to the ventral laryngeal diverticulum (ventral pouch). The presence of underlying seromucinous glands is critical for histologic identification of this site. We report a histologic sectioning technique, using the ventral laryngeal diverticulum as the anatomical landmark, to obtain tissue sections from this area of predilection in rats and in mice.

Ninety-day inhalation study in rats, comparing smoke from cigarettes that heat tobacco with those that burn tobacco

Abstract 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 μg/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.

SUBCHRONIC INHALATION STUDY IN RATS USING AGED AND DILUTED SIDESTREAM SMOKE FROM A REFERENCE CIGARETTE

AbstractMale 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 we...

Review Article: A Review of Chronic Inhalation Studies with Mainstream Cigarette Smoke, in Hamsters, Dogs, and Nonhuman Primates:

This paper is the continuation of previously published work, a review limited to studies on rats and mice. This paper makes an identical evaluation as before, but, restricting the species being evaluated to representative studies of smoke-exposed hamsters, dogs (both by tracheostomy and by direct inhalation), and nonhuma n primates. As was seen previously, no statistically significant increase in the incidence of malignant tumors of the respiratory tract was found in any of the 3 species, even though very long exposures and high doses of smoke were used. All 5 of the species of laboratory animals commonly used to evaluate carcinogenic potential produce results with mainstream cigarette smoke that are at variance with the epidemiological evidence in smokers.

An evaluation of the toxicity of 95 ingredients added individually to experimental cigarettes: approach and methods

Context: Ingredients have been used in modern cigarette manufacturing to facilitate tobacco processing, provide flavor, and preserve tobacco. Concern has been raised regarding the use of ingredients in cigarette manufacturing due to the possible generation of toxic chemicals resulting from their combustion when added to tobacco. Objective: Investigate the impact of individual ingredients on cigarette smoke toxicity. Materials and methods: A total of 95 ingredients were tested individually through addition at different concentrations to the tobacco of experimental cigarettes. Mainstream cigarette smoke chemistry analysis, bacterial mutagenicity testing, and cytotoxicity testing were conducted. Additionally, 31 of the ingredients were tested in 90-day nose-only rat inhalation studies using mainstream cigarette smoke. Studies were designed following conventional toxicity testing methods employed for food additives and other consumer products. Results: The studies reported here demonstrate that high levels of some ingredients can change the quantity of some smoke constituents, altering the smoke chemistry profile. From the panel of biological endpoints monitored, these added ingredients produced minimal changes in the overall toxicity profile of mainstream cigarette smoke. In some cases, the addition of high levels of an ingredient caused a small reduction in toxicity findings, probably due to displacement of burning tobacco. Conclusion: The battery of testing results presented here is a useful addition to the available scientific information for cigarette ingredients and extends the dataset which can be used for evaluating their appropriate use.

Ninety-day inhalation study in rats, using aged and diluted sidestream smoke from a reference cigarette : DNA adducts and alveolar macrophage cytogenetics

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)

Comparative Inhalation Study in Rats, Using a Second Prototype of a Cigarette that Heats Rather than Burns Tobacco

AbstractSprague-Dawley rats were exposed nose-only for 1 h/day on weekdays for 13 weeks to the smoke from test and reference cigarettes. The test cigarette was a new prototype: the tobacco is heated rather than burned. The University of Kentucky 1R4F cigarette was used as a reference. The exposures used were around 25% higher than those used in earlier studies, and for the test cigarette the resulting blood carboxy-hemoglobin concentrations approached those associated with death (62+%). The smoke from the reference cigarette produced substantial reductions in breathing frequency, whereas the smoke from the test cigarette did not. The availability of nicotine from test and reference cigarettes was very similar. The histopathology seen (mucus-secreting cells; nasal, laryngeal, and bronchial hyperplasia and squa-mous metaplasia, pulmonary macrophages) indicated that most of the changes observed in the reference animals were absent in the test animals. When changes were seen in the test groups (primarily in t...

Mechanisms Involved in A/J Mouse Lung Tumorigenesis Induced by Inhalation of an Environmental Tobacco Smoke Surrogate

Abstract Lung tumors have been reproducibly induced in A/J mice exposed to a surrogate for experimental environmental tobacco smoke (ETSS) in a 5-mo inhalation period followed by 4 mo without further exposure. In order to increase our mechanistic understanding of this model, male mice were whole-body exposed for 6 h/d, 5 d/wk to ETSS with a particulate matter concentration of 100 mg/m3. Food restriction regimens were included to model or exceed the ETSS-related impairment of body weight development. Half of the mice were pretreated with a single ip injection of urethane to study the effect of the above treatments on lung tumor development induced by this substance. At 5 mo, the tumor response was statistically the same for all groups of non-pretreated mice; however, the expected urethane-induced lung tumorigenesis was significantly inhibited by approximately 25% by ETSS and food restriction. This inhibition was accompanied by a threefold increase in blood corticosterone as a common stress marker for both ETSS and food restriction. At 9 mo, in mice not pretreated, the lung tumor incidence and multiplicity were significantly increased by twofold in the ETSS group; in the urethane-treated groups, the same high tumor multiplicity was reached regardless of previous treatment. The predominant tumor type in all groups was bronchiolo-alveolar adenoma. There was no induction of a specific K-ras mutation pattern by ETSS exposure. These data suggest a stress-induced inhibition of lung tumorigenesis in this model, explaining the need for the posttreatment period.