Preliminary toxicological assessment of heated tobacco products: A review of the literature and proposed strategy.

Heated tobacco products (HTP) have become increasingly common in many countries worldwide. The principle of heating tobacco, without combustion, to produce a nicotine-containing aerosol with remarkably reduced levels of other known toxins, compared to combusted tobacco cigarettes, is now well established. As these products are intended as alternatives to traditional combusted products, during the early stages of their development, it is important for manufacturers to ensure that the design of the product does not lead to any unintentionally increased or new risk for the consumer, compared to the traditional products that consumers seek to replace.

Studies on the contributions of smoke constituents, individually and in mixtures, in a range of in vitro bioactivity assays.

Tobacco smoke is a complex mixture with over 8700 identified constituents. Smoking causes many diseases including lung cancer, cardiovascular disease, and chronic obstructive pulmonary disease. However, the mechanisms of how cigarette smoke impacts disease initiation or progression are not well understood and individual smoke constituents causing these effects are not generally agreed upon.

Evaluation of the Tobacco Heating System 2.2. Part 6: 90-day OECD 413 rat inhalation study with systems toxicology endpoints demonstrates reduced exposure effects of a mentholated version compared with mentholated and non-mentholated cigarette smoke.

The toxicity of a mentholated version of the Tobacco Heating System (THS2.2M), a candidate modified risk tobacco product (MRTP), was characterized in a 90-day OECD inhalation study. Differential gene and protein expression analysis of nasal epithelium and lung tissue was also performed to record exposure effects at the molecular level.

Automation of the in vitro micronucleus and chromosome aberration assay for the assessment of the genotoxicity of the particulate and gas-vapor phase of cigarette smoke.

Total particulate matter (TPM) and the gas-vapor phase (GVP) of mainstream smoke from the Reference Cigarette 3R4F were assayed in the cytokinesis-block in vitro micronucleus (MN) assay and the in vitro chromosome aberration (CA) assay, both using V79-4 Chinese hamster lung fibroblasts exposed for up to 24 h. The Metafer image analysis platform was adapted resulting in a fully automated evaluation system of the MN assay for the detection, identification and reporting of cells with micronuclei together with the determination of the cytokinesis-block proliferation index (CBPI) to quantify the treatment-related cytotoxicity. In the CA assay, the same platform was used to identify, map and retrieve metaphases for a subsequent CA evaluation by a trained evaluator.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 6: 6-Day randomized clinical trial of a menthol cigarette in Japan.

A randomized, controlled, open-label, parallel-group, single-center study to determine biomarkers of exposure to 12 selected harmful and potentially harmful constituents (HPHC) in cigarette smoke, excretion of mutagenic material in urine, and serum Clara cell 16-kDa protein (CC16) in 102 male and female Japanese subjects who smoked Marlboro Ultra Lights Menthol cigarettes (M4J(M); 4 mg tar and 0.3mg nicotine) at baseline. Subjects were randomized to continue smoking M4J(M), or switch to smoking either the Electrically Heated Cigarette Smoking System menthol cigarette (EHCSS-K6(M); 5mg tar and 0.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 4: Eight-day randomized clinical trial in Korea.

A randomized, controlled, open-label parallel-group, single-center study to determine biomarkers of exposure to 12 selected harmful and potentially harmful constituents (HPHC) in cigarette smoke and urinary excretion of mutagenic material in 72 male and female Korean subjects smoking Lark One cigarettes (1.0mg tar, 0.1mg nicotine, and 1.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 5: 8-Day randomized clinical trial in Japan.

A randomized, controlled, open-label, parallel-group, single-center study to determine biomarkers of exposure to twelve selected harmful and potentially harmful constituents (HPHCs) in cigarette smoke and urinary excretion of mutagenic material in 128 male and female Japanese subjects smoking Marlboro cigarettes (6 mg tar, 0.5mg nicotine, and 7.0mg CO) at baseline.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 3: Eight-day randomized clinical trial in the UK.

A randomized, controlled, open-label, parallel-group, single-center study to determine biomarkers of exposure to nine selected harmful and potentially harmful constituents (HPHC) in cigarette smoke and urinary excretion of mutagenic material in 160 male and female subjects smoking Marlboro cigarettes (6 mg tar, 0.5mg nicotine, and 7.0mg CO) at baseline.

Reduced exposure evaluation of an Electrically Heated Cigarette Smoking System. Part 1: Non-clinical and clinical insights.

The following series of papers presents an extensive assessment of the Electrically Heated Cigarette Smoking System EHCSS series-K cigarette vs. conventional lit-end cigarettes (CC) as an example for an extended testing strategy for evaluation of reduced exposure. The EHCSS produces smoke through electrical heating of tobacco.

Does the use of ingredients added to tobacco increase cigarette addictiveness?: a detailed analysis.

The possibility that ingredients added to tobacco contribute to the addictiveness of cigarette smoking was evaluated by comparing cessation rates of smokers of traditional blended cigarettes to those of smokers of flue-cured cigarettes. Such a comparison is a valid means of assessing cigarette ingredients as traditional blended cigarettes contain ingredients (>20), whereas flue-cured cigarettes contain no or very few ingredients. Separate analysis of 108 treatment groups and 108 control groups from randomized clinical trials of nicotine replacement therapy (NRT) were performed by multiple logistic regressions.

Toxicological assessment of cigarette ingredients.

Ingredients have been used in industrial manufacture of tobacco products since the early part of the 20th century. However, unlike other consumer goods, until now no regulatory authority has determined how tobacco ingredients should be assessed. Although there is currently no consensus on how added cigarette ingredients should be evaluated, this paper reviews some of the institutional guidance alongside published literature with a view to determining if there is a generally accepted approach in the absence of any strict regulation.