The World Health Organization (WHO) estimates that 22.3% of the global population use tobacco, with Southeast Asia and India being the largest consumers.1 Between 1990 and 2021, smoking led to more than 175 million deaths.2 Each year, tobacco use causes 8 million deaths, 1.3 million among non-smokers exposed to second-hand smoke.3
Nicotine, the addictive chemical in tobacco, is among the most widely used stimulants worldwide. Compared to other stimulants, such as caffeine, it has significantly higher toxicity. It arouses the peripheral and central nervous system, increasing alertness, coronary blood flow, and myocardial oxygen intake. However, it also elevates heart rate and blood pressure, leading to vascular damage and compromised cardiac activity.4
Nicotine enters the body through various methods, including smoking cigarettes, chewing or sucking tobacco leaf, using water pipes, inhaling snuff, mucosal absorption through snus, or absorbing it through nicotine replacement products – such as gum, lozenges, sprays, and patches – and e-cigarettes (vapes). Once absorbed, it circulates through the bloodstream, reaching peak concentrations within 30 to 60 minutes. Absorption is slower from nicotine replacement products (NRPs) than traditional tobacco products.5
To curb nicotine addiction, the US Food and Drug Administration (FDA) recently proposed limiting nicotine levels to 0.7 milligrams per gram in cigarettes and other combusted tobacco products, excluding e-cigarettes. This policy could prevent an estimated 48 million US adolescents and young adults from taking up smoking by 2100, potentially saving 4.3 million lives.6
A smoker absorbs about half a milligram of nicotine per cigarette, which is then broken down into a metabolite called cotinine.7 Cotinine is oxidized in the liver and distributed through various bodily fluids such as blood, saliva, and urine; 10%-15% is excreted in urine.8
While nicotine serves as a biomarker for tobacco exposure, its sensitivity and specificity* are limited due to its short half-life of roughly two hours – the time it takes for the initial level to reduce by half. Cotinine, by contrast, has a much longer half-life of about 20 hours (ranging from 12 to 40 hours) and remains detectable in the body for up to 72 hours, and in some cases, up to one week from when a person was last exposed to nicotine (either directly or indirectly).9
Several factors influence nicotine metabolism and cotinine values, including distribution and elimination from the body. Additionally, cotinine values can vary based on gender, genetics, ethnicity, pregnancy status, hydration levels, and the type of nicotine product used. These variables complicate the distinction, particularly in underwriting, between smokers, non-smokers, and individuals exposed to second-hand smoke.10
Cotinine can be measured in urine, blood plasma, and saliva and has a high sensitivity and specificity. However, cotinine test cut-off values vary, and there is no standardized value to distinguish true smokers from true non-smokers or passive smokers. Cut-off values typically range from 10 to 20 nanograms per milliliter (ng/ml) for serum or salivary cotinine, and 50-200 ng/ml for urinary cotinine.8
In the US, the average salivary cotinine level for adult smokers exceeds 100 ng/ml.11 Mean saliva cotinine test results are reported at 9.53 ng/ml for non-smokers, 18.31 ng/ml for passive smokers, and 327.39 ng/ml for true smokers.12
Urinary cotinine levels correlate with daily nicotine intake absorbed and are typically four to six times higher than salivary cotinine levels, ranging from 20 to 550 ng/ml.13 Passive smokers exhibit elevated urinary cotinine levels, averaging approximately three times higher than that of non-smokers, reported at 13.6 ng/ml in non-smokers, 36.63 ng/ml in passive smokers, and 1043.7 ng/ml in smokers.12
Note: The scale measurements for the above two charts differ.
The sensitivity and specificity of cotinine tests vary based on the cut-off value used. Sensitivity can range between 69% and 99%, and specificity ranges between 74% and 99%. For example, with a cut-off value of 14.2 ng/ml, sensitivity is 99% and specificity is 96.4%.14 Lowering the cut-off value to 12 ng/ml slightly reduces sensitivity to 96.7% and specificity to 96.9%. Studies suggest that a cut-off value of 15 ng/ml for plasma or saliva cotinine provides the best distinction among current smokers, non-smokers, and passive smokers, while 20 ng/ml represents the upper limit typically associated with passive smoking.15
A lower cut-off value results in higher sensitivity but lower specificity, meaning more passive smokers may test positive. Conversely, a higher cut-off value increases specificity but reduces sensitivity, meaning some irregular light smokers could test negative.14
In simple terms, raising the cut-off value decreases the likelihood of detecting nicotine exposure, while lowering it increases the likelihood of a positive test result.
Studies show that light, passive smokers typically have cotinine levels below 5 ng/ml, whereas heavy, passive smokers may reach 10 ng/ml or slightly higher. Light, irregular smokers generally fall between 10 and 100 ng/ml, while regular smoker values are 100 ng/ml or more.14
Cotinine test cut-off values may also vary based on smoking prevalence in different countries. In regions where smoking rates are lower, more non-smokers have non-detectable levels due to reduced exposure to second-hand smoke. As a result, there is no universal cut-off value reliably distinguishing smokers from passive smokers.
Urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a tobacco-specific nitrosamine with a half-life of 10 to 40 days, making it a useful indicator of smoking status. NNAL is not detected in non-smokers unless they have been exposed to second-hand smoke. However, levels are significantly lower in passive smokers – 5.19 picograms per milligram** (pg/mg) of creatinine in urine – compared to active smokers (183 pg/mg) and may also be a useful indicator of non-smoker status in passive smokers who test positive on a cotinine test.10
Other testing methods can also distinguish smokers from non-smokers. Hair testing can accurately detect cotinine for up to three months after the last nicotine exposure. Epigenetic markers provide another means of differentiation. For example, DNA methylation status at cg05575921 is strongly associated with cigarette smoking, whereas e-cigarette use and smokeless tobacco use do not demethylate cg05575921. This makes it the most sensitive and specific epigenetic indicator of smoking. However, using epigenetic testing in the underwriting process is time-consuming and costly and presents a barrier to widespread implementation.16
Exposure to second-hand smoke can result in a positive cotinine test, which may create challenges during the underwriting process when true non-smoker applicants test positive.4 Passive smoke contains more than 50 carcinogens, and studies show that concentrations of carcinogenic chemicals are much higher than in directly inhaled smoke.
Research indicates that exposure to tobacco smoke increases all-cause mortality by 10%, cardiovascular disease (CVD)-related mortality by 12%, cancer-related mortality by 9%, and respiratory-related mortality by 14% compared to non-smokers.17
A growing problem is the use of nicotine replacement therapies (NRTs) – such as gum, patches, and other tobacco products, including snus in non-smokers. Snus, a smokeless tobacco product originating in Sweden, comes in a pouch that is placed between the upper lip and gums for approximately 30 minutes before being removed. Nicotine is rapidly absorbed across the mucosal membrane into the bloodstream. Each pouch contains approximately 15mg of nicotine, similar to a traditional cigarette, but prolonged exposure leads to higher nicotine concentrations in users.18
Nicotine products are often used to enhance aerobic performance, with many elite athletes using them to improve concentration and reaction times, control weight, and promote relaxation. When taken at higher doses, nicotine enhances the effect of serotonin and reduces feelings of anxiety and stress. However, studies do not support claims that nicotine improves athletic performance.19 Its use is associated with adverse effects, including nausea, vomiting, nicotine addiction, periodontal disease, heat intolerance, impaired cardiac function, and an increased risk of pancreatic cancer.18
An estimated 25%-50% of elite athletes on professional teams and in strength sports use nicotine products for performance enhancement. The rate is 28% among rugby players, while rates are even higher in other sports – up to 34% in major league baseball players, 50% in ice hockey, 56% in American football. These figures are substantially higher than the 25% nicotine detection rate in the general population.5,19 Reports suggest that the use of snus among elite athletes is rising.
The cotinine test does not determine smoker status; rather, it measures nicotine absorption from direct or indirect tobacco smoke, or nicotine-based products. It cannot differentiate between smoking from other nicotine sources, such as NRTs.
Furthermore, studies indicate a lack of standardization in optimal cotinine cut-off values, making it difficult to differentiate smokers, passive smokers, NRT users, and non-smokers. However, when cotinine values are assessed, they may provide insight into distinguishing true smokers from passive smokers, and passive smokers from individuals without second-hand smoke exposure.
* Sensitivity: the percentage of self-reported non-smokers classified as smokers (true positives); specificity: the percentage of self-reported non-smokers classified as non-smokers (true negatives)
** Picogram per milligram is equal to one trillionth of a milligram
RGA experts are eager to engage with clients to better understand and tackle the industry’s most pressing challenges together. Contact us to learn more about RGA's capabilities, resources, and solutions.
