Clinical: Exposure

Scientist handling medication
17 September 2024
CHAPTER 4 . OUR SMOKELESS SCIENCE

Clinical: Exposure

What individuals are exposed to when using the products

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Our lab-based emission and toxicological studies have proven that our Smokeless Products deliver significantly lower levels of harmful chemicals than cigarette smoke. To understand the potential impact of these reductions on adult smokers who completely switch to our Smokeless Products, we conduct clinical studies for both exposure and potential risk.

Portrait of Dr Kristen Jordan Head of Clinical Research, Global Life Sciences, RAI Services Company
"Adult smokers who completely switch to our Smokeless Products can greatly reduce their exposure† to a number of harmful chemicals as compared to continued smoking."

 

Dr Kristen Jordan

Head of Clinical Research, Global Life Sciences, RAI Services Company

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In our clinical exposure studies, we measure up to 15 biomarkers in adult smokers that indicate exposure to certain harmful chemicals. These ‘Biomarkers of Exposure’ (BoE) can be measured in urine, blood and/or exhaled breath, at levels that can demonstrate exposure differences between adult smokers, former adult smokers, and non-adult smokers.[1]

 

Associated with tobacco product use, our 15 BoE are linked to the harmful and potentially harmful constituents (HPHC) the World Health Organization has recommended lowering in smoke (Table 1).[2]

BoE Associated HPHC Carcinogen Respiratory Toxicant Cardiovascular Toxicant
4-Aminobiphenyl (4-ABP) 4-Aminobiphenyl +    
2-Aminonaphthalene (2-AN) 2-Aminonaphthalene +    
3-Hydroxybenzo(a)pyrene (3-OH B[a]P) Benzo[a]pyrene (B[a]P) +    
2-Cyanoethylmercapturic acid (CEMA) Acrylonitrile +    
Carbon monoxide (CO) Carbon Monoxide     +
2-Hydroxyeythylmercapturic acid (HEMA) Ethylene Oxide + +  
3-Hydroxy-1-methylpropylmercapturic
acid (HMPMA)		 Crotonaldehyde +    
3-Hydroxypropylmercapturic acid (HPMA) Acrolein   + +
Monohydroxybutenylmercapturic acid (MHBMA)Tneq 1,3-Butadiene + +  
Total nicotine equivalents (TNeq) Nicotine      
Total 4-(methylnitrosamino)-1-(3-pyridyl)
-1-butanol (NNAL)		 4-(methylnitrosamino) -1-(3-pyridyl)-1-butanone (NNK) +    
Total N-nitrosonornicotine (NNN) NNN +    
1-Hydroxypyrene (1-OHP^) Pyrene +    
o-Toluidine (o-Tol) o-Toluidine +    
s-Phenylmercapturic acid (S-PMA) Benzene +    

Table 1: Our 15 BoEs and their associated HPHCs

Our core principles for conducting clinical research:

  • Ethics committee or independent review board assessment of our study objectives, as per the 1964 Declaration of Helsinki
  • Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) for clinical conduct and bioanalysis
  • All studies conducted in independent clinics under supervision of a principal investigator


As part of our clinical exposure studies, we look to measure the BoE of up to four different participant groups to represent different 'smoker' status.

As part of our clinical exposure studies, we look to measure the BoE of up to four different participant groups to represent different 'smoker' status.

In our clinical exposure studies, our primary objective is to statistically compare the BoE levels of those who smoke to those who have completely switched to our Smokeless Products. This comparison allows us to determine if our significant reductions in lab-measured emissions is also achieved when adult consumers switch to our Smokeless Products.

 

We also compare the BoE levels of those who have completely switched to our Smokeless Products to Former and Never Smokers. We make this comparison as “the closer the risks and exposures […] are to cessation products, the more confident a regulator can be in the chances for net public health benefit.” (U.S. Institute of Medicine).[3]

 

Compliance = CEVal

Cyanoethylvaline (or CEVal) is a blood biomarker that can determine if someone has been smoking cigarettes.

 

It is formed through exposure to a chemical found in cigarette smoke, acrylonitrile, and can last in the body for up to 120 days. We use CEVal as a biomarker of compliance in our clinical studies.

 

It allows us to confirm whether participants in our studies have stopped using cigarettes as requested. It provides us with evidence that our non-smoking groups’ biomarker data is truly reflective of a complete switch to Smokeless Products or cessation. 

We have two different clinical study designs to evaluate exposure: Longitudinal and Cross-Sectional. Both study types have their benefits when evaluating exposure.

 

Our cross-sectional clinical exposure studies have proven that adult consumers of our Vuse[4] and Velo[5] products have lower levels of exposure to a number of harmful chemicals compared to adult smokers.

snapshot icon

Cross-Sectional (Snapshot)

real world icon

Ambulatory (Real world)

Point in time 
One-off clinic visit

Participants are asked to declare what products they use (Smokeless Product or cigarettes). 

 

Cross-sectional studies enable a comparison of realistic use between those who smoke and those who use our Smokeless Products at a specific point in time. The resulting data can be presented as a ‘%difference’ in BoE levels between study groups.

Vuse Users: BoE %Difference vs. Smokers
Longitudinal (Journey) icon

Longitudinal (Journey)

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Ambulatory (Real world)

Point in time 
One-off clinic visit

real world icon

Ambulatory (Real world)

Point in time 
One-off clinic visit

Participants are asked to either switch completely to our Smokeless Product or continue to smoke cigarettes.

 

Longitudinal studies allow for a baseline measurement of all participants at Day 0. Subsequent clinic measurements then show changes in effects over time. The resulting data can be presented as a ‘%change from baseline’ (Day 0), which can be compared between study groups.

Vuse Users: BoE %Difference vs. Smokers

Our longitudinal exposure study tracked and measured a range of BoEs when smokers switched to glo for one year. The results showed that smokers who completely switched to glo had significant reductions in BoEs compared to participants who continued to smoke. These reductions were comparable to those who quit smoking.*†[6]

Standard deviations have been omitted from charts for ease of reading, Full figures are available in references: [4], [5] and [6]

Footnotes

* Based on the weight of evidence and assuming a complete switch from cigarette smoking. These products are not risk free and are addictive.

† Our products as sold in the U.S., including Vuse, Velo, Grizzly, Kodiak, and Camel Snus, are subject to FDA regulation and no reduced-risk claims will be made as to these products without agency clearance.

 

References

[1] Lowe, F.J., et al., Evaluation of biomarkers of exposure and potential harm in smokers, former smokers and never-smokers. Clin Chem Lab Med, 2009. 47(3): p.311-320. DOI: 10.1515/CCLM.2009.069

[2] Burns, D.M., et al., Mandated lowering of toxicants in cigarette smoke: a description of the World Health Organization TobReg proposal. Tob Control, 2008. 17(2): p. 132-141. DOI: 10.1136/tc.2007.024158

[3] Institute of Medicine (US), Board on Population Health and Public Health Practice and Committee on Scientific Standards for Studies on Modified Risk Tobacco Products, Scientific Standards for Studies on Modified Risk Tobacco Products. National Academies Press, 2012. Available at: https://nap.nationalacademies.org/catalog/13294/scientific-standards-for-studies-on-modified-risk-tobacco-products

[4] Haswell, L.E., et al., Biomarkers of exposure and potential harm in exclusive users of electronic cigarettes and current, former, and never smokers. Intern Emerg Med, 2023. 18(5): p. 1359-1371. DOI: 10.1007/s11739-023-03294-9

[5] Azzopardi, D., et al., Assessment of biomarkers of exposure and potential harm, and physiological and subjective health measures in exclusive users of nicotine pouches and current, former and never smokers. Biomark, 2023. 28(1): p. 118-129. DOI: 10.1080/1354750X.2022.2148747

[6] Gale, N., et al., Changes in biomarkers of exposure and biomarkers of potential harm after 360 days in smokers who either continue to smoke, switch to a tobacco heating product or quit smoking. Intern Emerg Med, 2022. 17: p. 2017-2030. DOI: 10.1007/s11739-022-03062-1

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