Background: Nicotine products have been the subject of considerable innovation over the past few decades.  While the health risks of combustible cigarettes and most tobacco-based products are well characterized, there is less clarity regarding newer nicotine products, and how they compare with the traditional forms. Methods: In this study, we have developed a relative risk hierarchy (RRH) of 13 nicotine products based on systematic review of the scientific literature and analysis of the best available evidence. In total, 3980 publications were identified and screened, with 320 studies being carried through to the final analysis. The health risk data for each product was extracted and the level assessed.  The products were analyzed in terms of their toxin emissions and epidemiological data, which were combined on an arbitrary scale from 0 to 100 (low to high risk) to derive a combined risk score for each nicotine product. Results: Combustible tobacco products dominate the top of the RRH, with combined risk scores ranging from 40 to 100. The most frequently consumed products generally score highest. Dipping and chewing tobacco place considerably lower on the hierarchy than the combustible products with scores of 10 to 15, but significantly above heat-not-burn devices and snus, which score between 3 and 4. The lowest risk products have scores of less than 0.25 and include electronic cigarettes, non-tobacco pouches and nicotine replacement therapy. Conclusions: The RRH provides a framework for the assessment of relative risk across all categories of nicotine products based on the best available evidence regarding their toxin emissions and the observed risk of disease development in product users. As nicotine products continue to evolve, and more data comes to light, the analyses can be updated to represent the best available scientific evidence.

Background: The nicotine products relative risk assessment estimates the relative risk of tobacco-related diseases due to use of 15 nicotine products. This update adds new data to the original analysis and creates separate categories for United States and rest of world varieties of smokeless tobacco, as well as bidi cigarettes. Methods: The PubMed®, MEDLINE and Clinicaltrials.gov databases were searched systematically. The study lists were exported, screened at the title, abstract and full-text level according to pre-defined inclusion/exclusion criteria. The study quality was assessed, and risk of bias was accounted for in the screening criteria. The extracted data was synthesized into a toxin emissions/content analysis for 12 Group 1 carcinogens, used to estimate lifetime cancer risk, and epidemiological meta-analysis of over 40 tobacco-related diseases. The two analyses were integrated into a combined risk score for each nicotine product, weighted by the risk of bias due to missing data, and incorporated into the relative risk spectrum. Results: In this update, 70 new studies were added to the synthesis, making a total of 123 studies included. All combustible tobacco products score between 40 and 100, with bidis and smokeless (rest of world) also in this range. All other products have a combined risk score of 10 or less, including U.S. chewing tobacco, U.S. dipping tobacco, snus, heat-not-burn tobacco, electronic cigarettes, non-tobacco pouches and nicotine replacement therapy. Discussion: Consistent with previous studies, we define a group of high-risk nicotine products, scoring between 40 and 100 on the spectrum, and reduced risk nicotine products, scoring less than 10. Limitations of this study include the potential for bias due to missing data, the heterogeneity of the data included in the relative risk hierarchy synthesis, and the assumed consumption levels.