We report that under the conditions of this study, when presented with the option of using Discs, many adult smokers replace their cigarettes, ~ 78% of the study participants reducing their cigarette consumption, and ~ 10% of the study participants reduced their cigarette consumption by 50% or more. These observations are of relevance since the adult smokers in this study had no intentions to quit smoking in the next 30 days. Further, as illustrated by the BOE measurements, adult tobacco consumers replacing cigarettes with the candidate products have lower exposure to the HPHCs found in tobacco smoke.
While the maximum health benefit can best be achieved by smoking cessation, smoking reduction is a potential pathway to smoking cessation [9–14]. No scientific consensus exists among public health regarding the impact of smoking reduction and relationship to disease risks. Favorable changes in cardiovascular risk markers and quality of life assessments have been reported from long-term smoking reduction of at least 50% of daily cigarettes . Rennard et al.  report that smoking reduction with the help of nicotine gum was associated with decreased respiratory tract inflammation as assessed by bronchoalveolar lavage. While smoking reductions may have favorable health outcomes, smoking cessation is the desirable outcome to achieve proven reductions in smoking-related disease risks. Nevertheless, the reductions in BOE (nicotine, NNK, benzene, and carbon monoxide) among participants replacing their cigarettes with Discs indicates lower exposure to HPHCs, which is encouraging, and indeed a small number of participants switch completely from cigarettes to Discs. The average reduction in blood COHb corresponded to the CPD reduction for the overall study population (~ 20% CPD reduction), in the 50–99% CPD reduction group as well as for the participants reducing their CPD by 100%, thus providing biochemical confirmation of CPD reduction.
Further assessment revealed that one participant completely switched to the Discs and the other participant stopped using all tobacco products. The reductions in the BOE for HPHCs including NNK, benzene and carbon monoxide exposure confirmed the changes in product use behavior in these two participants. For the participant who reported complete tobacco product cessation, we did not detect nicotine levels and the reductions in urinary NNAL were comparable to the estimated levels expected upon smoking cessation. These results further verified the self-report status of no cigarette consumption for both study participants. While these numbers are small, such changes in cigarette consumption were not observed in the Control Group.
Although all the urinary BOEs tended to be lower in the Test Group compared with the Control Group, they did not correspond to the extent of CPD reduction which could be due to three likely reasons. First, as reported by Hatsukami et al  reduction in cigarette consumption may be accompanied with compensatory cigarette smoking behavior. However, the proportionate reduction in the blood COHb levels does not support likely occurrence of this phenomenon. Second, the dose-response relationship between CPD and BOEs differs among BOEs and the elimination kinetics may influence the biomarkers’ ability to reflect changes in cigarette consumption. In particular, NNAL has a half-life of 10- to 18-days and can be detected in urine for 6 to 12 weeks after smoking cessation , thus requiring similar time to reach a new steady state level after switching between tobacco products. Third, variability in spot urine is often observed, even after adjusting for creatinine [18, 19]. Circadian rhythm in glomerular filtration rate (GFR) and renal plasma flow has been reported in healthy individuals . Day-time GFR was found to be higher compared with overnight, and urine flow was found to have the same circadian rhythm as GFR. Within individual variability in biomarkers (e.g. cadmium excretion ranging from 4-10-fold) has been attributed to circadian rhythm. Similarly significantly high variability has been observed in cigarette smoke related BOE during day-time urine measurements than early morning voids . We collected spot urine samples during afternoon visits to the study site, perhaps the large variability in spot urine samples may be minimized in first morning void samples.
The study results should be interpreted with the limitations of the study. The participants received the test products free. Thus, only limiting inferences can be drawn regarding actual product use behavior under “real-world” conditions since the study does not consider all the factors that may influence purchase decisions of adult smokers. Such limitations may be offset by conducting in-market observational studies. The number of participants switching to Discs and reducing cigarette consumption by > 50% was relatively small (~ 12%). However, given that none of the AS in the Control Group exhibited this behavior and that the participants did not intend to quit, this phenomenon suggests that the impact of Discs might alter smoking behavior in a favorable direction. Recall bias from tracking test product use under ambulatory conditions is another limitation, however likely similar recall bias in the control group and daily IVRS calls may counterbalance this limitation. Another potential limitation is that this study was not designed as a complete switching study and concomitant use of other tobacco products was allowed. Although these products were reportedly used only sporadically by a small number of participants, their impact on BOEs has not been specifically analyzed and cannot be ruled out. The participants enrolled in the study were only those that expressed an interest in using the product upon a single use trial, thus likely incorporating self-selection bias. Nevertheless, this might reflect a realistic situation where an adult smoker may try a new product before making a decision to become a regular user. The clinical model of presenting adult smokers with the open access and choice of using a new tobacco product is a useful paradigm to assess the impact on product use behavior and exposure to select HPHCs.