FDA-Funded Abstracts of Menthol-Related Studies
The FDA is committed to a science-based approach that addresses the public health issues raised by menthol cigarettes. As such, the agency is funding the following three menthol-related studies. The abstracts, written by the authors of the study, are provided below:
- Genetic Factors in Taste Perception and Tobacco Usage
- Real-Time Measurement and Uptake of Carcinogens by Menthol Cigarette Smokers
- Counter-Irritation by Menthol: Molecular Targets and Role in Airway Disease
This project is a collaborative investigation into the role of inherited differences in taste perception in tobacco use, taking advantage of our substantial experience in the genetics of human taste perception and the role of taste variation in tobacco use.
We will catalog and quantify the variation in genes that encode the taste perception system and use these to measure association between taste- specific genetic variants and tobacco use in a large multi-ethnic U.S. population sample. This will include studies of the genes encoding receptors for menthol (TRPM8), bitter (TAS2R gene family), sweet and savory (TAS1R gene family), sour (PKDL gene family), and burning (TRPV1 gene) tastes. It also includes genes encoding the downstream signaling components in taste cells, including the GNAT3, GNB3, GNG13, and PLCB2 genes. These variants will be assayed in the Dallas Heart Study (DHS) population, a group of 4,700 subjects, including 2,500 African Americans, that has been well characterized for cardiovascular risk factors including tobacco use. Existing genotypes typed at 20,000 loci across the genome in the DHS population will be evaluated directly to generate measures of linkage disequilibrium and haplotypes that can impute genotypes at taste perception gene loci, as well as at coding and non-coding loci across the genome. This medium-resolution data will allow association studies with tobacco use phenotypes to begin immediately, and can identify associations with tobacco usage that reside outside known taste perception gene loci.
To gain additional power in this sample, we will make a more global analysis of genetic differences in the subset of DHS subjects who display extreme phenotypes. This will consist of whole-exome sequencing in a total of 1700 subjects, half representing the lowest 12.5 percentile and half representing the highest 12.5 percentile of the distribution of scores on measures of daily tobacco use frequency and use of mentholated cigarettes. Whole exome sequencing is expected to enumerate all of the sequence variants that exist in the expressed portion of the genome, including known taste perception genes and perhaps other genes not yet known to be involved in taste perception.
Correlations between genetic variants and tobacco use behaviors, including the use of mentholated tobacco products, will be determined. These analyses will involve genotype-phenotype association tests using linear regression, as well as a novel approach for testing associations in aggregate.
The overall goal of this project will be to disentangle the relative roles of genetic sensory factors present in specific populations, including African Americans, from environmental and other non-genetic factors in tobacco use.
Real-Time Measurement and Uptake of Carcinogens by Menthol Cigarette Smokers [Sydney Michael Gordon]
Menthol, the only cigarette additive that is actively marketed by manufacturers, is particularly favored by youth and ethnic/racial minorities. There is growing evidence that menthol cigarettes are starter products for youth, impede cessation, increase relapse following cessation and undermine social justice by the incessant targeted marketing of these products to communities of color.
Tying menthol cigarette use to increased risk of tobacco-related diseases has been difficult. Generally, epidemiologic studies that have been used to try to make that connection have been inconclusive, whereas laboratory-based studies have been hampered by the inability to get established menthol or non-menthol smokers to use the opposite cigarette style for the extended periods necessary to compare classic measures of toxicity, and results obtained have been mixed. A major reason for this may lie with the commercial cigarettes that were used in these tests. Because cigarettes are so highly engineered, there are likely many differences between menthol and non-menthol cigarettes other than menthol levels.
The investigators' previous work has resulted in some intriguing contrasts in menthol and non-menthol cigarettes, but it cannot be known if the differences were the result of the effects of mentholation alone, or the many other possible differences in the properties of commercial cigarettes. To adequately study the effect of mentholation of cigarettes, we need to test cigarettes that differ only in menthol content. The specific aims of this research are to determine the acute effects of smoking cigarettes that are equivalent except for levels of menthol.
The over-all goal is to establish methods for testing which are valid without requiring prolonged periods of exposure and compliance with long-duration protocols. We will therefore characterize a set of cigarettes that are the same except for variation in menthol levels. The cigarettes are a commercial non-menthol cigarette that is mentholated at a low level and a high level, and Camel Crush, a non-menthol cigarette with a small menthol pellet in the filter which, when crushed, releases menthol into the filter. Chemical characterization of the cigarettes will be followed by real-time human toxicity measurements in a within-subjects design, to assess human exposure to select smoke-related toxins/carcinogens.
Finally, to generate subject-specific smoke emissions and estimate uptake of smoke- related toxins/carcinogens, a smoking machine will be programmed to smoke the test cigarettes, and smoke emissions of each of the test cigarettes will be compared.
Electronic cigarettes have become popular tobacco cigarette substitutes, with a rapidly growing consumer population in the United States. While marketed as non-toxic nicotine delivery devices, the acute and long-term health effects of electronic cigarettes are largely unknown. Similar to mentholated tobacco cigarettes, the most popular electronic cigarette products contain large amounts of menthol and other mint-like chemical additives such as carvone, the natural product of spearmint. Electronic cigarettes also contain many of the chemical flavors and sensory additives outlawed for use in tobacco cigarettes by the Family Smoking Prevention and Tobacco Control Act (FSPTCA).
The goal of our FDA-funded research is to investigate whether menthol and the other flavor additives in electronic cigarettes were selected by the manufacturers to mask the unpleasant taste and irritant effects of nicotine and whether they cause respiratory irritation and inflammation. We will use the mouse as a model system to study whether flavor additives increase nicotine levels, lead to alterations in breathing, and if they cause lung inflammation and exaggeration of asthma. These studies aim to provide data for the FDA to support potential regulatory actions towards the marketing of electronic cigarette products.