Biomarkers for Tobacco Exposures, Toxicology, Regulation, and Cessation

This month’s issue of Nicotine & Tobacco Research provides the reader with a dozen original research papers evaluating the effects of acute and chronic tobacco exposures on a wide variety of behavioral, developmental and metabolic responses, and two linked editor’s choice articles on smoking cessation that review “omic” studies and encourage collaborative efforts in future genomic studies of smoking cessation. The original research articles include animal model, human laboratory, and population-based studies ranging widely over the acute or chronic effects of nicotine or tobacco product exposures.

One animal model study demonstrated reduction of the inflammatory response pathway, activation of the dopaminergic neurotropic pathway and reduced postoperative cognitive dysfunction following nicotine administration immediately after anesthesia induction.¹ Two model studies focused on the effects of waterpipe smoke on embryonic development,² and adult learning and memory.³ The first study adds avian model evidence at the organismal, tissue and genic levels to the tobacco smoke developmental toxicology literature and novel evidence for the effects of waterpipe smoke, while the second provides evidence of the effects of prenatal exposure on learning and memory at the behavioral and molecular level. The contrast in effects observed on hippocampal brain derived neurotrophic factor, where the postoperative cognition study observed acute reduction attenuation,¹ and the waterpipe exposure study where chronic reduction was observed,³ adds to our understanding of the toxicity of tobacco smoke.

One human laboratory study focused on nicotine pharmacokinetics and subjective effects in a comparison of a novel nicotine delivery device combining nicotine and lactic acid, and a nicotine replacement therapy inhalator⁴; the novel device, which generates a nicotine aerosol, provided a more rapid maximum plasma nicotine level than the inhalator. The other human laboratory studies evaluated the acute effects of nicotine delivery via an electronic nicotine delivery system or a cigarette in terms of β²*-nAChR occupancy using a novel neuroimaging radiotracer,⁵ or chronic effects of cigarette smoking on anatomic and functional brain imaging measures.^6,7 The former identified dose–response effects by e-liquid nicotine concentration, whereas the cigarette resulted in greater maximal nicotine concentration, but similar nicotine exposure, to the highest nicotine concentration e-liquid; in general, subjective effects did not differ. The latter two studies compared different brain volume and functional measures in smokers and nonsmokers, where chronic smoking is associated with reduced cerebellum grey matter and functional connectivity with several systems,⁶ and reduced thalamus volume,⁷ with both findings inversely associated with a common measure of nicotine dependence, revealing a dose–response effect.

The population-based studies with hundreds to thousands of participants evaluated chronic environmental exposures to tobacco,^8–12 and in one case, genomic variation,¹³ in diverse settings by age, ancestry, country, and occupation. The adolescent studies^8,10 examined two large cohorts through questionnaire and urinary cotinine to investigate environmental tobacco smoke (ETS) exposures and associated effects. The US cohort found 18% of adolescents with the highest category of ETS (ie, suggesting active smoking), with significantly increased glycated hemoglobin observed in males with evidence of active smoking¹⁰; the Mexican cohort identified increased dependence (time to first cigarette) with increased ETS, independent of adolescent smoking intensity.⁸ Both studies point to ETS as a target for tobacco control and cessation programs in this critical developmental period.

Two studies evaluated tobacco exposures in waterpipe smokers and nonsmokers in social⁹ and occupational¹¹ settings. Social exposure to waterpipe smoking in lounges or in residential settings resulted in significant increases in a biomarker for the toxin acrolein for both smokers and nonsmokers, with implications for health communication and waterpipe tobacco additive regulation.⁹ Exhaustive sampling and analysis of biospecimens, indoor air and occupational roles in a study of waterpipe lounge employees in three countries revealed multiple risk factors (smoking status, customer-centric role, hours at work, and increased indoor air nicotine) for increased exposures of nicotine metabolites, a tobacco-specific nitrosamine, and polyaromatic hydrocarbons,¹¹ with implications for waterpipe lounge regulation to reduce employee exposures.

Two studies evaluated questionnaire-assessed smoking behaviors in cohorts defined by ancestral origin: two Native American populations that included biospecimen analysis of cotinine,¹² and four Hispanic populations that included genomic variation analysis.¹³ Both represent tobacco exposure risk investigations into ancestries infrequently studied using these approaches. A majority of smokers and substantial fractions of nonsmokers exhibited cotinine levels suggestive of active smoking across the two populations with significant effects of self-reported second-hand smoke exposure observed¹²; enhancement of tobacco control policies would reduce risk. Genomic analysis of Hispanic American populations demonstrated that this ancestry shares the single largest genomic predictor of smoking heaviness (the chromosome 15q25.1CHRNA5 cholinergic locus) at genome-wide significance with European and African American ancestries; evidence at other cholinergic loci was concordant with prior results.¹³

The two reviews focused on smoking cessation omic analyses resulted from the efforts of the Genetics and Treatment Networks of the Society for Research on Nicotine and Tobacco: review of past omic biomarker findings, including associations with smoking cessation,¹⁴ and outline of the collaborative consortial efforts necessary to obtain adequate sample sizes for identifying and translating genomic predictors of response to therapy.¹⁵ The omic review focuses on a genomic biomarker of smoking heaviness, biomarkers of nicotine metabolism, and emerging epigenomic markers of exposure and cessation; the cessation consortial review focuses on trial design, biospecimens, ethics, outcomes, and analysis approaches to foster biomarker discovery and translation.

This issue provide abundant evidence that biomarker-based tobacco research extends from exposure assessment to tobacco attributable disease studies, uses animal and human models at multiple levels to evaluate effects of tobacco toxicants, and informs cessation therapy. In other areas of research and translation (eg, drug development), increasingly formal approaches to defining context of use and utility of biomarkers for further development have arisen through a multiple stakeholder framework,¹⁶ with strong support from the FDA.¹⁷ Tobacco biomarker development is a priority for tobacco control¹⁸ and for cessation therapy.^19,20 A continued focus on tobacco biomarkers taking advantage of efforts to formalize biomarker development should help translation to tobacco control, tobacco product regulation and cessation therapy.

Funding

AWB was supported by a consulting agreement with Westat, Inc. when working on this editorial. AWB acknowledges past support from R21DA033813 and R43DA041211.

Declaration of Interests

None declared.