Introduction. More than a decade ago, concerns were raised that menthol in cigarettes might enhance addiction to smoking. This article provides a comprehensive review of published studies examining cigarette dependence among menthol and nonmenthol smokers. The purpose of the review is to evaluate the scientific evidence to determine if menthol increases cigarette dependence. Materials and Methods. The published literature was searched in 2019 for studies that provide evidence on cigarette dependence among menthol compared to nonmenthol smokers. Included in this review are published studies that compare menthol and nonmenthol smokers based on widely accepted and validated measures of dependence, or other established predictors of dependence (age of smoking initiation [first cigarette]/age of progression [regular/daily smoking]) and indicators of dependence (smoking frequency, cigarettes smoked per day, time to first cigarette after waking, night waking to smoke, smoking duration). Results and Conclusion. Based on a review of the available studies, including those with adjusted results and large representative samples, reliable and consistent empirical evidence supports a conclusion that menthol smokers are not more dependent than nonmenthol smokers and thus menthol in cigarettes does not increase dependence.

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Cigarette smoking is established as a substantial contributor to risks for cancer, cardiovascular and respiratory diseases. Less is known about the potential of cigarette composition to affect smoking risks. The use of cigarette flavoring ingredients such as menthol is currently of worldwide public health and regulatory interest. The unique conditions of menthol inhalation exposure that occur coincident with that of the complex cigarette smoke aerosol require specialized studies to support an assessment of its safety in cigarette flavoring applications. The present state of knowledge is sufficient to support an assessment of the safety of the use of menthol in cigarettes. Scientific, smoking behavioral and epidemiological data available through mid-2009 is critically reviewed and a broad convergence of findings supports a judgment that menthol employed as a cigarette tobacco flavoring ingredient does not meaningfully affect the inherent toxicity of cigarette smoke or the human risks that attend smoking. There remains a need for well-designed studies of the potential of menthol to affect smoking initiation, cessation and addiction in order to differentiate any independent effects of menthol in cigarettes from those imposed by socioeconomic, environmental and peer influences on these complex human behaviors.

There has been speculation that the addition of menthol to cigarettes may affect the manner in which cigarettes are smoked, potentially influencing smokers' exposures to smoke constituents that have been associated with smoking-related diseases. One hundred twelve male and female smokers participated in a parallel-arm study to determine whether the ad libitum smoking of menthol cigarettes results in differences in smoke constituent exposure biomarkers in blood and urine relative to those smoking nonmenthol cigarettes having similar machine-measured (Federal Trade Commission) yields of approximately 9 to 10 mg "tar." The study subjects were provided cigarettes of their preferred menthol or nonmenthol types prior to two 24-hour study intervals spaced one week apart. Carboxyhemoglobin levels were measured in blood samples drawn at midafternoon following the two 24-hour urine collection periods. Six urinary nicotine metabolites (nicotine, cotinine, trans-3'-hydroxycotinine and respective glucuronides) were determined as measures of nicotine intake, and urinary 4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronide were determined to assess exposure to the tobacco-specific nitrosamine 4-(N-nitrosomethylamino)-1-(3-pyridinyl)-1-butanone. Subjects' median blood carboxyhemoglobin values did not differ significantly between the cigarette types. Neither total urinary NNAL nor urinary nicotine equivalents exhibited statistically significant differences between the menthol and nonmenthol cigarette smokers. The present findings indicate that moderately heavy smokers of menthol and nonmenthol cigarettes of similar machine-generated smoke yield exhibit essentially identical levels of biomarkers of smoke constituent exposure. These results are consistent with the substantial majority of epidemiology studies to date that suggest the risks attending the smoking of menthol and nonmenthol cigarettes are similar.

The previous Lorillard memorandum #6384 reviewed and discussed the scientific literature on the title subjects . However, several new papers relating to these subjects have recently been published . The present memorandum discusses these new papers and is submitted as an addendum to the previous memorandum #6384 . (1.) A newly reported epidemiology study found no statistically significant differences between lung cancer risks for menthol smokers and regular cigarette smokers . (2.) A new paper on the complexities of the binding of carbon monoxide to hemoglobin, the oxygen- carrying component of the blood, further documented the problems inherent in the use of carbon monoxide exhalation to investigate purported effects of menthol on smoking topography . (3.) A new study of smoke constituent exposure in black and white women smokers reported increased puff volumes for mentholated cigarette smoke, in contrast to the findings of several prior investigations . However, the data for the menthol variable was incompletely presented in the new report, and the study design was seriously compromised by uncontrolled smoking by the experimental subjects immediately prior to the laboratory smoking sessions . The conclusions of this author's previous memorandum that cigarette mentholation has no substantive effect on smoking topography or on risks for the development of cancers of the respiratory tract are reinforced and remain unchanged in light of the recent publications .

The effects of serum components and amino acids on the uptake and cytotoxicity of NiCl2 were examined in cultured Chinese hamster ovary (CHO) cells. CHO cells maintained in a minimal salts/glucose medium accumulated 10-fold more63Ni than did cells maintained in complete medium supplemented with 10% fetal bovine serum. Cell-surface binding of63Ni appeared to account for the majority of this increased accumulation of cell-associated nickel observed in the simple maintenance medium since such increases were reduced 70% by trypsin treatment. The addition of the Ni2+-binding amino acids cysteine or histidine to the salts/glucose medium markedly decreased63Ni accumulations, an effect not observed following addition of any of several amino acids that do not bind Ni2+. Supplementation of the salts/glucose medium with fetal bovine serum decreased in a concentration dependent fashion both the63Ni2+ uptake and cell detachment caused by Ni2+, while dialyzed (amino acid-free) serum was 3–5-fold less effective than undialyzed serum at reducing63Ni2+ uptake and similarly exhibited only a slight protective effect against nickel-induced cytotoxicity. Supplementation of dialyzed serum with cysteine at levels approximating those in whole serum partially restored its inhibitory activity toward nickel uptake by cells and restored completely its inhibition of nickel's cytotoxicity, indicating the predominant role of specific amino acids over serum proteins in regulating the uptake and subsequent cytotoxicity of Ni2+. Addition of cysteine to the salts/glucose medium during a 2 h exposure of cells to either 100 μM HgCl2 or 1 mM NiCl2 masked the cytotoxic effects of these metal ions. These results demonstrate the importance of extracellular small molecular weight metal ion chelators in altering the biological effects of metal ions at the level of metal uptake.

Overloading by selective phagocytosis of nickel sulfide particles results in DNA damage and transformation.

Overloading by selective phagocytosis of nickel sulfide particles results in DNA damage and transformation.

A review of in vitro mutagenesis assessment of metal compounds in mammalian and nonmammalian test systems has been compiled. Prokaryotic assays are ineffective or inconsistent in their detection of most metals as mutagens, with the notable exception of hexavalent chromium. Mammalian assay systems appear to be similarly inappropriate for the screening of metal compounds based upon the limited number of studies that have employed those compounds having known carcinogenic activity. Although of limited value as screening tests for the detection of potentially carcinogenic metal compounds, the well-characterized in vitro mutagenesis systems may prove to be of significant value as a means to elucidate mechanisms of metal genotoxicity.