Critical Appraisal of Animal Studies Assessing Risk of Heated Tobacco Products—A Systematic Review

Introduction Heated tobacco products (HTPs) are marketed as reduced risk alternatives to conventional cigarettes by heating rather than burning tobacco. However, inconsistencies in animal study outcomes and variability in experimental design complicate the regulatory assessments. Methods A systematic review of animal studies on HTPs was conducted to assess their methodology and determine areas for future refinement. A search was performed in PubMed, Medline, Scopus, Web of Science, and Google Scholar, resulting in more than 3000 publications narrowed to 48 animal studies on HTPs being included in the review according to defined selection criteria. General study characteristics, experimental protocols, and reporting information were extracted for analysis. The risk of bias tool Systematic Review Center for Laboratory Animal Experimentation was used to assess the bias of methodology and outcomes. Each study was independently evaluated by two reviewers, and discrepancies were resolved through consensus. Results Of the included studies, 28 reported that the toxicological effects of HTPs were lower than those of cigarettes, while 20 studies did not support HTPs as safe or risk-reduced alternatives to cigarettes. Continuous HTPs exposure or switching from cigarette to HTPs significantly reduced exposure effects associated with cigarette smoking. Conclusions Many studies’ conclusions were positive with regard to reduced risk in comparison to tobacco smoking. However, HTPs cannot be considered definitively “safe” tobacco products, as current data remain insufficient for assurance of absolute reduced health risks in comparison to not smoking. Implications As HTPs become available globally, there is an urgent need for more high-quality animal studies, particularly from the nontobacco stake agents, to better assess the in vivo risk of HTPs and provide more robust evidence to support regulatory decision-making with regard to the category.