Stacy Fiebelkorn

Assessment of novel tobacco heating product THP1.0. Part 3: Comprehensive chemical characterisation of harmful and potentially harmful aerosol emissions

ABSTRACT For a tobacco heating product (THP), which heats rather than burns tobacco, the emissions of toxicants in the aerosol were compared with those in cigarette smoke under a machine‐puffing regimen of puff volume 55 ml, puff duration 2 s and puff interval 30 s. The list of toxicants included those proposed by Health Canada, the World Health Organization Study Group on Tobacco Product Regulation (TobReg), the US Food and Drug Administration and possible thermal breakdown products. In comparison to the University of Kentucky 3R4F reference cigarette the toxicant levels in the THP1.0 emissions were significantly reduced across all chemical classes. For the nine toxicants proposed by TobReg for mandated reduction in cigarette emissions, the mean reductions in THP1.0 aerosol were 90.6–99.9% per consumable with an overall average reduction of 97.1%. For the abbreviated list of harmful and potentially harmful constituents of smoke specified by the US Food and Drug Administration Tobacco Products Scientific Advisory Committee for reporting in cigarette smoke (excluding nicotine), reductions in the aerosol of THP1.0 were 84.6–99.9% per consumable with an overall average reduction of 97.5%. HighlightsTHP1.0, which heats rather than burns tobacco, was compared with 3R4F cigarette.Harmful and potentially harmful constituents were measured in the aerosols and compared.Toxicants in the aerosol of THP1.0 were substantially lower than in 3R4F smoke.Reduction averaged 96.1 per cent for nine substances prioritised for lowering in cigarettes.Reduction averaged 96.8 per cent for 18 substances prioritised by the US FDA.

A preliminary regional PBPK model of lung metabolism for improving species dependent descriptions of 1,3-butadiene and its metabolites

1,3-Butadiene (BD), a volatile organic chemical (VOC), is used in synthetic rubber production and other industrial processes. It is detectable at low levels in ambient air as well as in tobacco smoke and gasoline vapors. Inhalation exposures to high concentrations of BD have been associated with lung cancer in both humans and experimental animals, although differences in species sensitivity have been observed. Metabolically active lung cells such as Pulmonary Type I and Type II epithelial cells and club cells (Clara cells)(1) are potential targets of BD metabolite-induced toxicity. Metabolic capacities of these cells, their regional densities, and distributions vary throughout the respiratory tract as well as between species and cell types. Here we present a physiologically based pharmacokinetic (PBPK) model for BD that includes a regional model of lung metabolism, based on a previous model for styrene, to provide species-dependent descriptions of BD metabolism in the mouse, rat, and human. Since there are no in vivo data on BD pharmacokinetics in the human, the rat and mouse models were parameterized to the extent possible on the basis of in vitro metabolic data. Where it was necessary to use in vivo data, extrapolation from rat to mouse was performed to evaluate the level of uncertainty in the human model. A kidney compartment and description of downstream metabolism were also included in the model to allow for eventual use of available urinary and blood biomarker data in animals and humans to calibrate the model for estimation of BD exposures and internal metabolite levels. Results from simulated inhalation exposures to BD indicate that incorporation of differential lung region metabolism is important in describing species differences in pulmonary response and that these differences may have implications for risk assessments of human exposures to BD.

Estimation of the Leukemia Risk in Human Populations Exposed to Benzene from Tobacco Smoke Using Epidemiological Data

Several epidemiological studies have demonstrated an association between occupational benzene exposure and increased leukemia risk, in particular acute myeloid leukemia (AML). However, there is still uncertainty as to the risk to the general population from exposure to lower environmental levels of benzene. To estimate the excess risk of leukemia from low-dose benzene exposure, various methods for incorporating epidemiological data in quantitative risk assessment were utilized. Tobacco smoke was identified as one of the main potential sources of benzene exposure and was the focus of this exposure assessment, allowing further investigation of the role of benzene in smoking-induced leukemia. Potency estimates for benzene were generated from individual occupational studies and meta-analysis data, and an exposure assessment for two smoking subgroups (light and heavy smokers) carried out. Subsequently, various techniques, including life-table analysis, were then used to evaluate both the excess lifetime risk and the contribution of benzene to smoking-induced leukemia and AML. The excess lifetime risk for smokers was estimated at between two and six additional leukemia deaths in 10,000 and one to three additional AML deaths in 10,000. The contribution of benzene to smoking-induced leukemia was estimated at between 9% and 24% (Upper CL 14-31%). For AML this contribution was estimated as 11-30% (Upper CL 22-60%). From the assessments carried out here, it appears there is an increased risk of leukemia from low-level exposure to benzene and that benzene may contribute up to a third of smoking-induced leukemia. Comparable results from using methods with varying degrees of complexity were generated.

Generation of in vitro margin of exposure (MOE) values to support the postulated mode of action (MOA) for selected tobacco smoke toxicants

Where the in vivo MOEs generated for individual toxicants do not provide a conclusive evaluation and are split across the critical value of 10,000 (e.g. NNK and arsenic) or where the available in vivo data is unsuitable for MOE generation (e.g. hydroquinone and catechol), the use of in vitro data can provide an alternative source of information. This can then be used to focus future research direction for each individual toxicant assessed. In the cases where in vivo and in vitro MOEs are conflicting this may indicate that a further understanding of the pathways and metabolism involved is required, in addition to potential refinement of the in vitro method.

Assessment of benzo[a]pyrene (a tobacco smoke toxicant), as a driver of genotoxicity

BaP is a known human carcinogen (IARC 2012) and one of several polycyclic aromatic hydrocarbons (PAHs) present in tobacco smoke (4). Levels of BaP in smoke have been measured as 16.2 ng per 3R4F reference cigarette smoked under Health Canada Intense conditions (5). ASSESSMENT OF BENZO[a]PYRENE (A TOBACCO SMOKE TOXICANT), AS A DRIVER OF GENOTOXICITY S. A. Fiebelkorn, E. L. Bishop, D. Breheny, F.H. Cunningham, D. M. Dillon and C. Meredith. British American Tobacco, Group Research and Development, Southampton, SO15 8TL, UK Correspondence: Clive_Meredith@bat.com