Comparing the preclinical risk profile of inhalable candidate and potential candidate modified risk tobacco products: A bridging use case.

Cigarette smoking causes major preventable diseases, morbidity, and mortality worldwide. Smoking cessation and prevention of smoking initiation are the preferred means for reducing these risks. Less harmful tobacco products, termed modified-risk tobacco products (MRTP), are being developed as a potential alternative for current adult smokers who would otherwise continue smoking. According to a regulatory framework issued by the US Food and Drug Administration, a manufacturer must provide comprehensive scientific evidence that the product significantly reduces harm and the risk of tobacco-related diseases, in order to obtain marketing authorization for a new MRTP. For new tobacco products similar to an already approved predicate product, the FDA has foreseen a simplified procedure for assessing "substantial equivalence". In this article, we present a use case that bridges the nonclinical evidence from previous studies demonstrating the relatively reduced harm potential of two heat-not-burn products based on different tobacco heating principles. The nonclinical evidence was collected along a "causal chain of events leading to disease" (CELSD) to systematically follow the consequences of reduced exposure to toxicants (relative to cigarette smoke) through increasing levels of biological complexity up to disease manifestation in animal models of human disease. This approach leverages the principles of systems biology and toxicology as a basis for further extrapolation to human studies. The experimental results demonstrate a similarly reduced impact of both products on apical and molecular endpoints, no novel effects not seen with cigarette smoke exposure, and an effect of switching from cigarettes to either MRTP that is comparable to that of complete smoking cessation. Ideally, a subset of representative assays from the presented sequence along the CELSD could be sufficient for predicting similarity or substantial equivalence in the nonclinical impact of novel products; this would require further validation, for which the present use case could serve as a starting point.

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.

A scattering methodology for droplet sizing of e-cigarette aerosols.

CONTEXT: Knowledge of the droplet size distribution of inhalable aerosols is important to predict aerosol deposition yield at various respiratory tract locations in human. Optical methodologies are usually preferred over the multi-stage cascade impactor for high-throughput measurements of aerosol particle/droplet size distributions. OBJECTIVE: Evaluate the Laser Aerosol Spectrometer technology based on Polystyrene Sphere Latex (PSL) calibration curve applied for the experimental determination of droplet size distributions in the diameter range typical of commercial e-cigarette aerosols (147-1361 nm). MATERIALS AND METHODS: This calibration procedure was tested for a TSI Laser Aerosol Spectrometer (LAS) operating at a wavelength of 633 nm and assessed against model di-ethyl-hexyl-sebacat (DEHS) droplets and e-cigarette aerosols. The PSL size response was measured, and intra- and between-day standard deviations calculated. RESULTS: DEHS droplet sizes were underestimated by 15-20% by the LAS when the PSL calibration curve was used; however, the intra- and between-day relative standard deviations were < 3%. This bias is attributed to the fact that the index of refraction of PSL calibrated particles is different in comparison to test aerosols. This 15-20% does not include the droplet evaporation component, which may reduce droplet size prior a measurement is performed. Aerosol concentration was measured accurately with a maximum uncertainty of 20%. Count median diameters and mass median aerodynamic diameters of selected e-cigarette aerosols ranged from 130-191 nm to 225-293 nm, respectively, similar to published values. DISCUSSION AND CONCLUSION: The LAS instrument can be used to measure e-cigarette aerosol droplet size distributions with a bias underestimating the expected value by 15-20% when using a precise PSL calibration curve. Controlled variability of DEHS size measurements can be achieved with the LAS system; however, this method can only be applied to test aerosols having a refractive index close to that of PSL particles used for calibration.

The heterogeneous kinetics of HOBr and HOCl on acidified sea salt and model aerosol at 40-90% relative humidity and ambient temperature.

The HOBr and HOCl uptake coefficient gamma on H(2)SO(4)-acidified submicron salt aerosol of known size distribution was measured in an atmospheric pressure laminar flow reactor. The interaction time of the trace gas with the aerosol was in the range 15 to 90 s and led to gamma values in the range 10(-4) to 10(-2). The acidity of the aerosol is essential in order to enable heterogeneous reactions of HOBr on NaCl, recrystallized sea salt (RSS) and natural sea salt (NSS) aerosols. Specifically, HOCl only reacts on acidified NSS aerosol with a gamma ranging from 0.4 x 10(-3) to 1.8 x 10(-3) at a relative humidity (rh) at 40 and 85%, respectively. Uptake experiments of HOBr on aqueous H(2)SO(4) as well as on H(2)SO(4)-acidified NaCl, RSS or NSS aerosol were performed for rh ranging from 40 to 93%. The gamma value of HOBr on acidified NSS reaches a maximum gamma = 1.9 x 10(-2) at rh = 76 +/- 1% and significantly decreases with increasing rh in contrast to acidified NaCl and RSS aerosols whose gamma values remain high at gamma = (1.0 +/- 0.2) x 10(-2) at rh >/= 80%. An explanation based on the formation of an organic coating on NSS aerosol with increasing rh is proposed.

The kinetics of H2O vapor condensation and evaporation on different types of ice in the range 130-210 K.

The kinetics of condensation (kc) and the evaporation flux (J(ev)) of H2O on ice were studied in the range 130-210 K using pulsed-valve and steady-state techniques in a low-pressure flow reactor. The uptake coefficient gamma was measured for different types of ice, namely, condensed (C), bulk (B), single crystal (SC), snow (S), and cubic ice (K). The negative temperature dependence of gamma for C, B, SC, and S ice reveals a precursor-mediated adsorption/desorption process in agreement with the proposal of Davy and Somorjai.(1) The non-Arrhenius behavior of the rate of condensation, kc, manifests itself in a discontinuity in the range 170-190 K depending on the type of ice and is consistent with the precursor model. The average of the energy of sublimation DeltaH(S) degrees is (12.0 +/- 1.4) kcal/mol for C, B, S, and SC ice and is identical within experimental uncertainty between 136 and 210 K. The same is true for the entropy of sublimation DeltaS(S). In contrast, both gamma and the evaporative flux J(ev) are significantly different for different ices. In the range 130-210 K, J(ev) of H2O ice was significantly smaller than the maximum theoretically allowed value. This corroborates gamma values significantly smaller than unity in that T range. On the basis of the present kinetic parameters, the time to complete evaporation of a small ice particle of radius 1 mum is approximately a factor of 5 larger than that previously thought.