Reference change values to assess changes in concentrations of biomarkers of exposure in individuals participating in a cigarette-switching study

Abstract

Background: In a previous clinical study, levels of biomarkers of exposure (BoEs) for specific toxicants were significantly reduced in smokers who switched from conventional cigarettes to reduced toxicant prototype (RTP) cigarettes. Very little is known about the biological variability of tobacco smoke BoEs within individuals and sub-groups, and the descriptive group-comparison statistics might not be sufficient to understand such changes. Therefore, we assessed how different statistical methods could be used to interpret changes in urine BoE levels at the individual level. Methods: We used non-parametric statistical reference limits, the empirical rule and reference change values (RCVs) to assess changes in levels of BoEs related to four toxicants in cigarettes smoke. Current smokers [of 6 mg and 1 mg International Organization for Standardization (ISO) tar yields] were allocated to switching to RTP groups or non-switching control groups within their respective tar bands. There were two 6 mg tar study groups, with a non-switching group (CC6, n = 46) and a group switching to an RTP containing tobacco-substitute sheet and modified filter (TSS6, n = 49); and three 1 mg tar smoker groups, with one non-switching (CC1, n = 42), a group switching to an RTP containing tobacco-substitute sheet and modified filter (TSS1, n = 44) and one switching to an RTP containing an enzyme-treated tobacco and modified filter (BT1, n = 47). Results: Assessment of the direction of change showed that up to the 100% of subjects experienced a decrease in levels of some BoEs. Between 49% and 64% of subjects in the switching groups were classified as having decreased levels of 3-hydroxy-1-methylpropylmercapturic acid (HMPMA) by the non-parametric criterion, whereas only 2%-6% had reduced levels of N-nitrosoanatabine (NAT). Of non-switchers, in 7%-14% of those smoking 1 mg ISO tar yield cigarettes increases were classified across

Reference change values in concentrations of urinary and salivary biomarkers of exposure and mouth level exposure in individuals participating in an ambulatory smoking study

“…NNAL levels were also comparable with previously published data on a per cigarette basis, with an overall geometric mean of 16.5 ng/cig. [21] Nicotine equivalents adjusted for creatinine, produced a mean value of 10167.7 ng/mg and a median of 9311.3 ng/mg, which are also comparable with data published previously. [39] In saliva, mean cotinine ranged from 218 to 338 ng/mL, which is in line with the range reported in the literature for smokers of 15–20 cigarettes per day.…”

“…With respect to the two approaches used for calculating the RCVs, the classical approach [16] yields decreasing references over 100%, which is counterintuitive and therefore the alternative approach estimates [18] seem more reasonable. However, upper reference values reached over 200% using Fokkema’s approach [18] , which seems high in practical terms compared with previous clinical data [21] , but it may just reflect the intrinsic variability of an ambulatory study.…”

“…In this non-confined and unrestricted setting, RCVs were calculated to aid evaluation of biomarker levels between consecutive observations that may be undertaken during potential MRTP monitoring. Increased variability was observed compared with a confined clinical study that reported a symmetric RCV of 68% for NNAL (ng/cig) [21] . This previous estimate was similar to the RCVs for decreases (RCV DOWN ) that we observed here, with values between 65% and 70%, but clearly underestimated the significant increases observed in ambulatory studies (up to 229%).…”

“…RCVs have been applied in a wide range of clinical settings and endpoints [19] , [20] . RCVs for biomarkers of smoke exposure were calculated in a clinical confinement setting to assess metabolic and behavioural variation in subjects who switched between their conventional cigarette and an MRTP [21] . In this study, RCVs for biomarkers were calculated based on the variability observed in an ambulatory setting in which subjects were free to switch between cigarette products.…”

Magnitudes of biomarker reductions in response to controlled reductions in cigarettes smoked per day: A one-week clinical confinement study

“…Such exposure scenarios would include concomitant smoking and NRT use, or concomitant smoking and low-exposure tobacco products use (e.g., smokeless tobacco, e-cigarettes) that are anticipated to approximate to cessation in terms of their effect on different combustion-related toxicants/biomarkers (but probably not on their effect on biomarkers relating to nicotine exposures, if the alternate products contain nicotine). This is important because there is also the possibility of using biomarkers as proxies for characterizing the risk of tobacco-related disease (Boffetta et al, 2006;Camacho et al, 2014;Hatsukami et al, 2009;Institute of Medicine, 2001Shields, 2002).…”