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A comprehensive 2-year oral chronic toxicity/carcinogenicity study was conducted with smokeless tobacco using modern toxicological test methods and well-accepted standards. The study included a 1-year interim subgroup to assess toxicity at that intermediate time point. Test groups consisted of a tobacco blend (B) used in snus, and an aqueous tobacco extract of that tobacco blend (E) administered at 0.2, 2, or 5 mg nicotine/kg body weight/day via dosed feed to male and female Wistar Han rats. The dosages were selected to simulate potential exposure in humans ingesting smokeless tobacco or an aqueous extract of smokeless tobacco (the latter intended to simulate a snus extract, to enable bridging these data to snus epidemiology data). The following endpoints were evaluated: clinical observations, body weights, feed consumption (FC), ophthalmic exams, toxicokinetics, clinical pathology, gross pathology, and histopathology. During the 2-year study, clear treatment-related, dose-responsive effects included: (1) increases in plasma nicotine and cotinine (indicating that animals were appropriately exposed to levels relevant to human exposure) and (2) decreases in body weights with some alterations in FC. At the 2-year time point, two tumor types (in the highest B doses) displayed statistically significantly increased incidence trends vs. controls: (1) uterine carcinoma in females and (2) epididymal mesothelioma in males. Three tumor types displayed statistically significantly decreased incidence trends: (1) mammary gland adenomas in females, (2) skin basal cell carcinomas in females, and (3) thyroid follicular cell adenomas in males. These increases (and decreases) in tumor trends were interpreted as not being treatment-related because: (1) there were no preneoplastic or related non-neoplastic histopathological findings in the treated rats at the 1-year or 2-year time points to suggest that any of these neoplastic findings were treatment-related and (2) the tumor morphologies and incidences were generally within the expected range of historical controls for Wistar Han rats. Findings from this study indicate that chronic exposure of male and female Wistar Han rats to either a tobacco blend used in snus, or a tobacco extract of that blend does not lead to increased toxicity or carcinogenicity, based on the specified outcomes measured. [ABSTRACT FROM AUTHOR]

Abstract: This manuscript presents data from 90-day toxicology studies designed to characterize the subchronic effects of a smokeless tobacco blend and an aqueous extract of that blend when administered to rodents in NTP-2000 feed. Positive control (nicotine tartrate) and treatment groups were matched for a range of nicotine levels. The doses evaluated were 0.3, 3, and 6mgnicotine/kg body weight/day in Wistar Hannover rats and 6, 60, and 120mgnicotine/kg/day in CD-1 mice. Variables evaluated included plasma nicotine and cotinine, body weights, feed consumption, clinical observations, clinical and anatomic pathology (including organ weights), and histopathology. Plasma nicotine and cotinine levels were dose-responsive. Key effects such as body weight reductions and organ weight changes occurred in rats and mice predominantly at the highest doses of test articles and positive control in the absence of treatment-related gross or histopathological changes. Organ weight changes were attributed mainly to the lower body weights of treated vs. control groups. The blend- and extract-induced effects generally paralleled each other and the nicotine-induced effects. Based on these studies, the doses evaluated spanned the no observable adverse effect level, the lowest observable adverse effect level and the maximum tolerated dose. [Copyright &y& Elsevier]

Abstract: A tiered testing strategy based on a comparative chemical and biological testing program has been developed to evaluate the potential of tobacco processes, ingredients, or other technological developments to change the biological activity that results from burning tobacco. Cast sheet tobacco is a specific type of reconstituted tobacco sheet that can be used in the manufacture of cigarettes. The comparative chemical and biological testing program was used to compare the mainstream smoke and cigarette smoke condensate (CSC) from a Reference cigarette that did not contain cast sheet to that collected from Test cigarettes containing cast sheet at a final blend level of either 10% or 15%. Testing included mainstream cigarette smoke chemistry studies, in vitro studies (Ames assay, sister chromatid exchange assay, and neutral red cytotoxicity assay), and in vivo toxicology studies (13-week rat nose-only inhalation assay and 30-week mouse dermal tumor promotion assay). Certain statistically significant differences were observed in the chemical and biological studies when the Reference cigarette was compared to each of the Test cigarettes. However, when viewed collectively, the chemical and biological studies demonstrated that inclusion of cast sheet up to 15% in the final blend did not increase the inherent biological activity of mainstream cigarette smoke or CSC. [Copyright &y& Elsevier]

The current study tested the hypothesis that the pulmonary carcinogenic potential of cadmium (Cd) is related to its ability to inhibit the expression (mRNA and protein) and activity of 8-oxoguanine-DNA glycosylase (OGG1), a base excision repair (BER) enzyme that functions to preferentially excise pre-mutagenic 7,8-dihydro-8-oxoguanine (8-oxoG) from DNA. We demonstrate that a single Cd aerosol exposure of adult male Lewis rats causes time- and dose-dependent down-regulation in the pulmonary levels of rOGG1 mRNA and OGG1 protein, quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays and western analyses, respectively. Immunohistochemical studies confirmed that Cd inhalation reduces the relative amount of OGG1 in lungs of exposed animals without altering its over-all distribution within the lung, which appears to be more prominent within the alveolar epithelium. In agreement with our in vivo studies, we show that OGG1 expression is also attenuated in alveolar epithelial cell cultures exposed to CdCl2 either acutely or by repeated passaging in Cd-containing medium. The effects caused by Cd were observed in cells that show no loss in viability, as assessed by colony forming ability, the MTT assay, and propidium iodide membrane permeability studies. Nuclear extracts prepared from Cd-treated cells also exhibit a reduction in the ability to nick a synthetic oligonucleotide containing 8-oxoG. We conclude from these studies that Cd causes suppression of OGG1 in the lung and that this mechanism may, in part, play a role in the Cd carcinogenic process. [Copyright &y& Elsevier]