Comprehensive review of epidemiological and animal studies on the potential carcinogenic effects of nicotineper se

Abstract

The effects of long-term use of nicotine per se on cancer risk, in the absence of tobacco extract or smoke, are not clearly understood. This review evaluates the strength of published scientific evidence, in both epidemiological and animal studies, for the potential carcinogenic effects of nicotine per se; that is to act as a complete carcinogen or as a modulator of carcinogenesis. For human studies, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a carcinogenic effect due to the limited information available. In animal studies, limited evidence suggests an association between long-term nicotine exposure and a lack of a complete carcinogenic effect. Conclusive studies using current bioassay guidelines, however, are missing. In studies using chemical/physical carcinogens or transgenic models, there appears to be inadequate evidence for an association between nicotine exposure and the presence of or lack of a modulating (stimulating) effect on carcinogenesis. This is primarily due to the large number of conflicting studies. In contrast, a majority of studies provides sufficient evidence for an association between nicotine exposure and enhanced carcinogenesis of cancer cells inoculated in mice. This modulating effect was especially prominent in immunocompromized mice. Overall, taking the human and animal studies into consideration, there appears to be inadequate evidence to conclude that nicotine per se does or does not cause or modulate carcinogenesis in humans. This conclusion is in agreement with the recent US Surgeon General’s 2014 report on the health consequences of nicotine exposure.

A systematic review of possible serious adverse health effects of nicotine replacement therapy

“…Based on findings from animal and mechanistic studies, a case for biological plausibility has been proposed for a potential role of nicotine in carcinogenesis (Cardinale et al 2012; Grando 2014; Haussmann and Fariss 2016; Improgo et al 2011). Carcinogenesis is a multistage process that involves three stages: initiation, promotion and progression (Klaunig 2013).…”

“…Carcinogenesis is a multistage process that involves three stages: initiation, promotion and progression (Klaunig 2013). For initiation, a substance must exhibit genotoxic properties which have been reported for nicotine at concentrations relevant to NRT use (Haussmann and Fariss 2016). Similarly, nicotine has been reported to stimulate cell proliferation, inhibit apoptosis, induce angiogenesis and inhibit immune function (Cardinale et al 2012; Grando 2014).…”

“…A major modification to the IARC strength of evidence assessment is the separation of their classification “evidence suggesting lack of carcinogenicity” into “limited evidence suggesting a lack of effect” and “sufficient evidence of a lack of effect”. With this revised classification in place, the strength of evidence conclusions can be neutral (inadequate evidence) or can be deemed limited or sufficient in both directions, for an adverse effect or a lack of an adverse effect (Haussmann and Fariss 2016). The criteria used were as follows.…”

“…Pharmaceutical NRT products have been available, for over three decades, with current forms such as chewing gum, lozenge, oral tablet, skin patch, nasal spray and inhaler (Ferguson et al 2011; Royal College of Physicians 2016). Because daily exposure to these products depends on individual preferences and needs, a broad range of maximum plasma nicotine levels from 6 to 43 ng/ml has been reported (Haussmann and Fariss 2016; Schneider et al 2001; Shiffman et al 2005). In the USA, the recommended duration of use for NRT products is 8–12 weeks depending on the product form (US Food and Drug Administration 2013).…”

“…Evidence from experimental animal models clearly demonstrate nicotine’s ability to enhance existing tissue injury and diseases such as cancer, cardiovascular disease, stroke, pancreatitis, peptic ulcer, renal injury and developmental (e.g. pulmonary, reproductive and central nervous system) abnormalities (Arany et al 2011; Bruin et al 2010; Chowdhury et al 1995; Hall et al 2016; Haussmann and Fariss 2016; Lau et al 2006; Qiu et al 1991; Rehan et al 2012; Wang et al 1997). These reported adverse health effects were observed following short-term exposure to nicotine per se (<12 weeks) and appear to be dependent on nicotine activation of nACh receptors in the affected tissue.…”