THS2.2 aerosol characterization: chemical composition, genotoxicity, cytotoxicity and physical properties (vs. 3R4F)

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The U.S. Family Smoking Prevention and Tobacco Control Act (FSPTCA) defines a Modified Risk Tobacco Product (MRTP) as “any tobacco product that is sold or distributed for use to reduce harm or the risk of tobacco related disease associated with commercially marketed tobacco products” (Family Smoking Prevention and Tobacco Control Act).

Philip Morris International is developing novel products, Modified Risk Tobacco Products (MRTPs), that may have the potential to reduce smoking-related diseases compared with cigarettes, and which deliver adult smoker satisfaction. To learn more about this topic, please consult the PMI science website.

The study reported in Schaller et al. and summarized in this page describes the assessment of a candidate MRTP, Tobacco Heating System 2.2 (THS2.2), using chemical analyses, physical characterization, and the in vitro genotoxicity and cytotoxicity assessments of the mainstream aerosol.

The low operating temperature of THS2.2 results in significantly lower concentrations of harmful and potentially harmful constituents (HPHCs) in the mainstream aerosol compared with the mainstream smoke of the 3R4F reference cigarette when expressed on either a per-Tobacco Stick/cigarette or a per-mg nicotine basis, while the mass median aerodynamic diameter (MMAD) of both aerosols remains similar. The reductions in the concentrations of most HPHCs in the THS2.2 aerosol were equal to or greater than 90% when compared with 3R4F, and were not affected by machine-smoking of THS2.2 under extreme climatic conditions.

No evidence of tobacco combustion was found when using the THS2.2 device with puffing regimens that were significantly more intense than the Health Canada Intense (HCI) conditions.

The mutagenic and cytotoxic potencies of the mainstream aerosol fractions from THS2.2, when evaluated by the Ames, mouse lymphoma, and neutral red uptake (NRU) assays were reduced by at least 85%–95% compared with the mainstream smoke aerosol of 3R4F.

Products

Candidate Modified Risk Tobacco Product (MRTP)

The candidate MRTP, Tobacco Heating System version 2.2 (THS2.2), is a new type of product which utilizes an electronically controlled heating system to heat tobacco. THS is a system comprising two main components:

  1. A Tobacco Stick which is a novel, patent pending tobacco product with unique processed tobacco made from tobacco powder, and which is designed to function with the Holder, producing an aerosol.
  2. The Tobacco Heating Device (THD) which is composed by a Holder and a Charger. The Holder, into which the Tobacco Stick is inserted, heats the tobacco material by means of an electronically controlled heater, and the Charger is used to recharge the Holder after each use.

The controlled heating of the tobacco generates an aerosol containing mainly water, glycerin, nicotine, and tobacco flavors.

Heat-not-burn concept to reduce tobacco smoking-related disease risk.
The functioning principle of the Tobacco Heating System, or THS, allows a careful control of the temperature and of the energy transferred to the tobacco plug. This design of the THS limits the formation of HPHCs and does not initiate combustion. The temperatures reported for the THS during use are far below those required for the combustion of tobacco to occur. The key characteristics of combustion (e.g., the formation of relevant amounts of nitrogen oxides and the generation of heat) are absent in the THS. The photographs of the Cambridge glass-fiber filter pads after the collection of  THS2.2 aerosol (left) and cigarette smoke (right) are also shown.

Reference Cigarette (3R4F)

3R4F cigarettes are standard reference cigarettes, used throughout the tobacco industry and in academic laboratories as a consistent and uniform test item for inhalation toxicology research. They have been in use since 2006. 3R4F cigarettes were purchased from the University of Kentucky (for specifications, see http://www.ca.uky.edu/refcig).

Harmful or Potentially Harmful Constituents

The FDA has determined that the phrase “harmful and potentially harmful constituents” (HPHCs) includes any chemical or chemical compound in a tobacco product or in tobacco smoke that i) is, or potentially is, inhaled, ingested, or absorbed into the body; and ii) causes, or has the potential to cause, direct or indirect harm to users or non-users of tobacco products1.

A list of HPHCs has been published in the Federal Register based on five broad criteria:

  • carcinogen (CA);
  • respiratory toxicant (RT);
  • cardiovascular toxicant (CT);
  • reproductive or developmental toxicant (RDT); or
  • addictive (AD).

The FDA has published the final list of 93 HPHCs in “Table 1—established list of the chemicals and chemical compounds identified as harmful and potentially harmful constituents in tobacco products and tobacco smoke” (2012). Among these, an abbreviated list of 18 constituents should be measured systematically when assessing HPHCs in cigarette smoke2.

In 2010, PMI established a list of 58 HPHCs (PMI-58 List) focusing on assessing candidate Modified Risk Tobacco Products (MRTPs) aerosols. This list was based on the following criteria:

  1. Smoke constituents determined by International Organization for Standardization (ISO) methods;
  2. Priority toxicants in tobacco smoke as listed by regulatory bodies, or proposed by cognizant authorities;
  3. Smoke constituents with established biomarkers of exposure;
  4. (Potentially) harmful aerosol constituents which are predominantly formed below 400°C, and which are NOT included in Criterion 2;
  5. (Potentially) harmful aerosol constituents which are predominantly formed above 400°C, and which are NOT included in Criterion 2;
  6. Aerosol characterization to identify aerosol constituents which have the potential to introduce novel hazards compared with lit-end cigarettes, and semi-quantitative analysis of ‘potentially harmful/harmful’ aerosol constituents; and
  7. Product-specific analytes, such as menthol (when used as a tobacco additive) or glycerin (added as an aerosol former in some candidate MRTPs).

References

  1. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Tobacco Products. Modified Risk Tobacco Product Applications. Guidance for Industry. (2012)
  2. U.S. Food and Drug Administration.Reporting Harmful and Potentially Harmful Constituents in Tobacco Products and Tobacco Smoke Under Section 904(a)(3) of the Federal Food, Drug, and Cosmetic Act (2012)
  3. Health Canada. Health Canada Test Method T-115, Determination of "Tar" and Nicotine in Sidestream Tobacco Smoke. (1999)

Aerosol characterization of THS2.2 (vs. 3R4F) Results

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Publications and Reports

Schaller, J. P. et al. Regulatory toxicology and pharmacology (2016)

Evaluation of the Tobacco Heating System 2.2. - Part 2: Chemical composition, genotoxicity, cytotoxicity, and physical properties of the aerosol.

The chemical composition, in vitro genotoxicity, and cytotoxicity of the mainstream aerosol from the Tobacco Heating System 2.2 (THS2.2) were compared with those of the mainstream smoke from the 3R4F reference cigarette. In contrast to the 3R4F, the tobacco plug in the THS2.2 is not burnt. The low operating temperature of THS2.2 caused distinct shifts in the aerosol composition compared with 3R4F. This resulted in a reduction of more than 90% for the majority of the analyzed harmful and potentially harmful constituents (HPHCs), while the mass median aerodynamic diameter of the aerosol remained similar. A reduction of about 90% was also observed when comparing the cytotoxicity determined by the neutral red uptake assay and the mutagenic potency in the mouse lymphoma assay. The THS2.2 aerosol was not mutagenic in the Ames assay. The chemical composition of the THS2.2 aerosol was also evaluated under extreme climatic and puffing conditions. When generating the THS2.2 aerosol under “desert” or “tropical” conditions, the generation of HPHCs was not significantly modified. When using puffing regimens that were more intense than the standard Health Canada Intense (HCI) machine-smoking conditions, the HPHC yields remained lower than when smoking the 3R4F reference cigarette with the HCI regimen.