GLOSSARY

GLOSSARYAEROSOLAn aerosol is a suspension of fine solid particles and/or liquid droplets in a gas (usually air). Cigarettes generate a smoke aerosol that is the result of the combustion (burning) of tobacco and contains carbon- based solid particles. While smoke is an aerosol, not all aerosols are smoke.PMI’s smoke-free products do not produce smoke because they do not burn tobacco. Instead, they generate a nicotine-containing aerosol, either by heating tobacco or through other technologies that do not involve combustion.Consumers typically use the term “vapor” to refer to the aerosol generated from heated tobacco products or other nicotine-containing products.BIOMARKERSBiomarkers can be classified into biomarkers of exposure and clinical risk markers.

Biomarkers of exposure: indicate exposure to a potentially hazardous substance.
In our case, the biomarker may be a cigarette smoke constituent or metabolite that is measured in a biological fluid or tissue. Biomarkers of exposure can provide a measure of internal dose, which is the amount of the constituent taken up into the body.

Clinical risk markers: a measurable change in biochemical, physiological (organs, tissues, cells), or behavioral function within an organism that is known to be associated with a health impairment or disease. These biomarkers indicate the body’s response to exposure to harmful chemicals. While clinical risk markers do not necessarily cause these health concerns, their presence and magnitude help identify whether a person already has or is in danger of developing a health impairment or disease.

CLINICAL RISK MARKERSSee Biomarkers.

COMBUSTIONCombustion is the process of burning a substance in oxygen. When a cigarette is lit, the combination of tobacco (fuel) and oxygen in the air generates a self-sustaining combustion process that consumes the tobacco. The combustion of tobacco results in the formation of smoke (which contains a range of chemical constituents), heat and ash. The high heat associated with combustion leads to the thermal breakdown of the tobacco when it is burned, resulting in the production of many of the toxicants found in cigarette smoke.EXPOSURE RESPONSE STUDYDesigned to assess whether switching to a smoke-free product leads to favorable changes in clinical risk markers that are benchmarked to smoking cessation. This is a longer-term study conducted with adult smokers.MODIFIED RISK TOBACCO PRODUCT (MRTP)The term used to classify a potentially less harmful product by the US Family Smoking Prevention and Tobacco Control Act (2009), which granted to the FDA authority to regulate tobacco products and to authorize claims of reduced risk or exposure. MRTP is defined as “any tobacco product that is sold or distributed for use to reduce harm or risk of tobacco-related diseases associated with commercially marketed tobacco products.”PHARMACOKINETIC STUDIESMeasure how a substance, such as nicotine, is absorbed by the body. This helps in determining the extent to which adult smokers would find the alternative product an acceptable substitute for cigarettes, although other factors, such as taste and product design, are important elements
in determining consumer acceptability. In addition to the kinetic profile of nicotine, we also monitor the safety of the users of the product under investigation (e.g., data on vital signs, clinical biochemistry, and adverse events).REDUCED-RISK PRODUCT (RRP)The term PMI uses to refer to products that present, are likely to present, or have the potential to present less risk of harm to smokers who switch to these products versus continued smoking. We have a range of RRPs in various stages of development, scientific assessment and commercialization. Because our RRPs do not burn tobacco, they produce far lower quantities of harmful and potentially harmful compounds than found in cigarette smoke.REFERENCE CIGARETTE (3R4F)A standard cigarette for laboratory testing provided by the University of Kentucky. The current version is known as 3R4F and is used for non-clinical investigations by tobacco manufacturers, contract and government laboratories, and academic institutions.SYSTEMS TOXICOLOGYTo compare whether the reduction in the levels of harmful and potentially harmful chemicals generated by our smoke-free products reduces the toxicity of their aerosol, we perform a range of standard toxicological assays.For example, we have conducted a number of widely used in vitro assays comparing the toxicity of our smoke-free products’ aerosol to cigarette smoke. These include, but are not limited to:

The Neutral Red Uptake cytotoxicity assay (measuring mammalian cell toxicity)

The Ames bacterial mutagenicity assay (measuring bacteria cell mutations)

The Mouse Lymphoma mammalian mutagenicity assay (measuring mutations in mammalian cells)

We have also conducted in vivo assays of different durations, including acute and repeated dose inhalation studies in accordance with Organization for Economic Co-operation and Development (OECD) Test Guidelines.TOXICOLOGYSystems toxicology integrates standard toxicology with advanced experimental and computational methods (including large-scale molecular measurements, imaging technologies, mathematical modeling and computational biology) to identify the biological mechanisms triggered by exposure to toxic substances and quantify their biological impact.One example of a systems toxicology approach is to use organotypic tissues: tissue samples which behave as if they were in the body. These tissues can make the results more complex and difficult to interpretbut also more relevant to effects on the human body compared to standard toxicology methods.TOBACCO PRODUCTS SCIENTIFIC ADVISORY COMMITTEE (TPSAC)As part of the FDA review process for MRTP applications, TPSAC reviews the evidence associated with MRTP applications and provides the FDA with recommendations on specific key questions the FDA poses to the committee.TPSAC’s recommendation is non-binding, and the FDA considers the recommendations of TPSAC along with other relevant information, including public comments, to make a final decision regarding an MRTP application.