I summarize the causative role of smoking for the most common causes of death among adults in high-income countries, drawing on data from Canada, the United States (US) and the United Kingdom (UK). The main objective of this analysis is to review the hazards of smoking and the benefits of cessation. I do so by examining the cause, nature and extent of tobacco-related diseases in high-income countries between 1960 and 2020. The review has seven main conclusions.

First, in much of Europe and North America, the biggest cause of premature death, defined as death before 70 years, is smoking of manufactured cigarettes. Smoking as an important cause of many diseases in many populations has been recognized widely in the scientific literature for the last five decades. However, three surprising features of health hazards of smoking have been established reliably only since about 2012. The first feature is that risk of developing disease among smokers is big. The second feature is that for smokers to develop these big risks, they need to start smoking early in adult life and to continue smoking. If smokers don’t start early in life, their risks are substantially smaller. Third, if smokers stop smoking before they develop some serious disease, then their risks are substantially reduced.

However, most smokers whom start early in adult life and who continue to smoke are eventually killed by their tobacco use. This is because in every year during middle age (defined here as ages 30–69 years), the death rates among smokers are about three-fold higher than that of similar non-smokers (considering differences between smokers and non-smokers in heavy alcohol use, obesity patterns or different educational or economic status). So two-thirds of the mortality among smokers would not be happening if they had the non-smoker death rates. Most of this excess risk arises from diseases that are caused by smoking. This includes disease such as lung cancer, emphysema, heart attack, stroke, cancer of the upper aerodigestive areas, bladder cancer and various other conditions. Thus this excess risk of disease and death is a cause and effect relationship.

Second, despite substantial declines in the proportion of adults who smoke in most high-income countries, cigarette smoking remains a common exposure in many countries. There were approximately 34 million smokers in the US, 7 million in the UK and 5 million in Canada in 2017 and the number of cigarettes sold in recent years has remained mostly unchanged for the past decade in Canada, while it has declined in the US and the UK. In recent years, electronic cigarettes appear to have accelerated the decline in smoking among younger adults. E-cigarettes are far less hazardous than cigarettes, but do carry some risks, most notably the risk of addiction to nicotine among youths.

Third, a proper understanding of the hazards of smoking requires due consideration of the lag of decades between onset of smoking and the development of disease(s). For both individuals and populations to experience increases in the risk of death, prolonged smoking from early adulthood without cessation is required. The increases in the risk of death can be gauged reliably by studying trends in national lung cancer mortality of different generations. The age-specific health hazards can also be documented in large prospective studies, which monitor groups of smokers and non-smokers for the development of disease(s) over time. Conservatively, smoking-related disease was responsible for about 41 million deaths in the US, UK and Canada, cumulatively, from 1960 to 2020. Every million cigarettes smoked causes approximately one death in the US and Canada, but about 1.3 deaths in the UK.

Fourth, the hazards of smoking are much bigger than was documented just two decades ago. Differences in death rates among smokers and non-smokers imply that smokers lose on average at least a decade of life. About half of all smoking-attributable deaths occur in middle age. The specific conditions caused by smoking include vascular, respiratory and neoplastic (cancer) disease (which account for approximately 75% of all causes of death in most high-income countries). Smoking is increasingly linked to conditions such as diabetes, rheumatoid arthritis, age-related macular degeneration of the eye, orofacial clefts and ectopic pregnancy. Indeed, the list of smoking-attributable diseases continues to expand with additional studies and monitoring. Hence, total mortality differences between otherwise similar smokers and non-smokers are a robust yet simple way to estimate the effects of smoking.

Fifth, cessation is effective in reducing the increased risks of developing smoking-related disease. Smokers who successfully quit before age 40 avoid nearly all increased mortality risks of continued smoking. Smoking cessation yields specific benefits of reducing fatal and non-fatal vascular, respiratory and neoplastic disease. Former smokers have about only a quarter of the excess risk of death than do current smokers. Studying cessation provides further evidence about the causal nature of smoking and disease development.

Sixth, the biological evidence about particular carcinogens and other toxins found in manufactured cigarettes and the possible mechanisms that trigger heart attacks and strokes are consistent with the epidemiological evidence. Genetics is an important factor in disease susceptibility but does not negate the substantial importance of smoking in explaining the marked changes in cause-specific mortality and total mortality attributable to smoking over the last few decades.

Finally, there continues to be gross underestimation of the health hazards of smoking by the public, non-experts and even some experts. The large health risks inherent in smoking are often wrongly equated with the far smaller risks of other health exposures. For example, smoking remains far more hazardous to the individual adult in high-income countries versus moderate obesity, heavy alcohol use and other factors. Most adults surveyed in the US remained surprisingly unaware of the high levels of disease risk that occur today from smoking.

Tobacco use is well established as a major cause of death worldwide, accounting for about five to six million deaths per year worldwide (Jha and Peto, 2014). On current smoking patterns, about one billion deaths may occur from smoking during the 21^st century, in contrast to ‘only’ 100 million deaths in the 20^th century (Peto et al., 1994). Already about 100 million tobacco deaths have occurred this century and there will be another 250 million tobacco deaths before 2050. The vast majority of the deaths before 2050 will occur among current smokers. Hence, the major public health priority is to increase the proportions of adults who quit smoking as well as to reduce the uptake of smoking by young adults and children.

In order for individuals to properly understand their risks of smoking, an understanding of the risks of smoking and benefits of cessation is required. This in turn requires a detailed understanding of the cause, nature, and extent of tobacco-related disease, including an understanding of the evolution of cigarette smoking in populations. Relationships between smoking and disease depend on changes in consumption patterns of smokers and ingredients of commonly manufactured cigarettes. This review is intended to inform governments, researchers, health care providers and individuals about the contemporary hazards of smoking. To do so, I outline the contemporary evidence that defines the causal relationship between smoking and the development of major causes of premature death. I focus mostly on evidence relevant from the US, UK and Canada, as typical of most high-income countries.

As most of the evidence regarding the relationship between smoking and disease has been on mortality, I focus on mortality by cause. Mortality has less misclassification than non-fatal outcomes, such as a first or recurrent non-fatal heart attack (Jha, 2014; Menon et al., 2019). However, I assess to some extent the evidence on the development of new diseases in previously non-diseased (or healthy) populations (or incidence).

This review is in eight sections. This first section covers key sources of data and methods. Section two reviews the current number of smokers in the US, UK and Canada. It also looks at historical trends in smoking, specifically trends from 1920 to 2010, with an emphasis on trends over the last five decades. It describes changes in the manufactured cigarette which have influenced the addictive properties of cigarettes, and thus, the risks of disease development. A brief review of electronic cigarettes follows.

Section three focuses on smoking as a cause of disease. It reviews, briefly, the history of studies linking smoking to disease, with particular attention to the importance of prolonged smoking to the development of disease. Because lung cancer is a highly-studied disease, this section draws upon national rates of lung cancer mortality and prospective studies of individuals who were smokers or non-smokers and who were observed for the development of the disease. This section also provides estimates of total mortality from smoking from 1960 to 2020 in the three countries (totalling about 41 million deaths), including the relationship of number of cigarettes smoked with mortality.

Section four reviews the epidemiological evidence that relates smoking to both total mortality and cause-specific death rates from the most established conditions linked to smoking. It provides estimates of the avoidable proportion of deaths had the smokers had death rates of comparable non-smokers. Section five outlines the recent evidence on the reduction in total mortality and cause-specific mortality from smoking cessation. Cessation is a powerful way to establish the causal relationships between smoking, total mortality and specific diseases. This section also quantifies the reduction in excess risk among former smokers compared to continued smoking.

Section six briefly summarizes the biological evidence regarding the link between nicotine addiction and smoking, and between smoking and disease. It outlines how biological data can help dispel some commonly held myths about the ‘genetic basis’ of smoking-attributable disease. This summary reemphasizes the central point that reliable quantification of smoking hazards is best done at the level of populations, using epidemiological studies to determine both health risks in individual humans and death rates in populations. Section seven reviews and contrasts the commonly perceived risks of alcohol use and pollution or environmental exposures that influence human health to epidemiological findings on hazards of smoking. Section eight discusses implications for future research and provides a brief conclusion.

This review focuses on the consequences of smoking, and not on the causes of smoking (including the key biological, social, economic and marketing influences that lead to variable rates of smoking initiation and cessation across different populations). However, I do examine the engineering of addictive nicotine to the modern manufactured cigarette, which plays a central role in explaining smoking patterns. For a careful review of the causes of smoking, I refer the reader to various US Surgeon General Reports (USSGR), most notably those of 1989 and 2014 (U.S. Department of Health and Human Services, 1989; U.S. Department of Health and Human Services, 2014). Similarly, the emphasis is on high-income countries and not low and middle-income countries, where the evolution of the tobacco epidemic is not yet mature, and which has much lower rates of cessation (Jha and Peto, 2014). The issues related to disease patterns in low and middle-income countries are also quite distinct (Jha and Peto, 2014; International Agency for Research on Cancer (IARC), 2004; Jha et al., 2008; Liu et al., 1998). The review of the consequences of smoking does not include second-hand smoking. Rigorous assessments on the relationship of second-hand smoking to cancer and other diseases have been completed by the International Agency for Research on Cancer (IARC Working Group on the Evaluation of Carcinogenic Risk to Humans, 2004; International Agency for Research on Cancer (IARC), 2012), and the US Surgeon General (USSGR; U.S. Department of Health and Human Services, 2004; U.S. Department of Health and Human Services, 2014). Finally, this does not focus on control of smoking, including the most important role of higher exicse taxes to raise cigarette prices, for which there are several reviews and WHO reports (Jha and Chaloupka, 1999; Jha et al., 2015; World Health Organization, 2017; Jha and Peto, 2014).

Despite substantial declines in smoking, a large proportion of Americans, Canadians and UK citizens continue to smoke. Largely attributable to the addictive nature of cigarettes, the declines in smoking prevalence have not been matched by declines in the number of cigarettes smoked daily by continuing smokers.

Historical smoking trends and changes in prevalence in the last four decades

Prior to 1900, most tobacco consumed was in the form of chewed tobacco, snuff, pipes and cigars. Some of the first reports of smoked tobacco came from Spain, where beggars in the 16^th century collected discarded cigar butts, shredded them and rolled them in scraps of paper for smoking. These ‘poor man’s cigars’ were known as cigarillos (which translates, from Spanish, to ‘little cigars’). Late in the 18th century, cigarillos acquired respectability. Their use spread throughout Europe, aided by their popularity among troops in the Napoleonic Wars. The French named them cigarettes. British tastes switched to cigarettes filled with unmixed Virginia tobacco, while the US market preferred blended tobacco (Encyclopaedia Britannica, 2018).

Prior to the early 20th century, cigarettes were made by hand, either by the smoker or in factories. The factory process consisted of hand-rolling on a table, pasting and hand-packaging. In 1880, American James A. Bonsack was granted a US patent for a cigarette machine. Automated machines could produce 120,000 cigarettes in ten hours (approximately 200 per minute). This machine revolutionized the industry and supported a substantial expansion of the major cigarette companies in the US, as well as exports to the UK and European countries. By 1920, there was a marked increase in the use of cigarettes in much of Europe and North America and accelerated further during World War II (WWII), when cigarettes were part of soldier rations. This dissemination contributed to a major expansion in cigarette smoking during the first-half of the 20th century, displacing pipe smoking, chewed tobacco, snuff, cigars and other types of tobacco product (Encyclopaedia Britannica, 2018; Thun et al., 2002).

Figure 1 provides the per capita cigarette consumption in the US, Canada, and the UK from 1920 to 2010, based on a global compilation of sales data that includes tobacco industry sources (Forey et al., 2016). Sales data provide a useful indicator of overall consumption trends over prolonged periods. These data are obviously crude and subject to various reporting errors, such as illegal or undocumented sales, which in recent years has paralleled the increase in smuggling; given the tobacco industry’s active role in smuggling their own products (Merriman, 2012). Furthermore, sales data do not capture changes in the length of manufactured cigarettes, the amount of tobacco within various lengths, and mostly do not capture gender-specific smoking patterns, including the notable time lag between increased male smoking and female smoking in the three countries. Importantly, peak consumption among American males, as reported from prevalence surveys, was the year 1963, when overall US cigarette sales also peaked. In contrast, in the UK and in Canada, peak sales occurred around 1975 to 1980.

Figure 1

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Figure 2 shows trends in overall smoking prevalence in both sexes over the last five decades in the three countries, during which better-quality surveys of smoking prevalence in the adult population became available. These surveys document the steady decline in smoking prevalence that began around the same time as the publishing of the 1962 Royal College Report in the UK and the 1964 Surgeon General’s report in the US, both which provided expert opinion linking smoking to lung cancer (Royal College of Physicians, 1962; U.S. Department of Health, Education, and Welfare, 1964).

Figure 2

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In most high-income countries, there has been a notable reduction in heavy smoking (over 20 cigarettes/day). For example, in the UK, in 1974, 26% of men and 13% of women were heavy smokers compared to 5% of men and 3% of women in 2012.

The average number of cigarettes smoked per day by men and women has decreased across all age groups, consistent with the declines of per capita consumption as shown in Figure 2 (Action on Smoking and Health, 2016). Nevertheless, significant amounts of smoking defined as at least half a pack (ten cigarettes) a day persists in many populations.

From 2000 to 2015, smoking prevalence fell steadily by well over a third in the US, UK and Canada (Table 1). By contrast, the reduction in smoking amount among daily smokers has been more modest, at about one-fifth.

Table 1

Year	2000	2015	Change in %
Prevalence*
US	23.1	15.2	−34.2%
UK	27.0	17.8	−34.1%
Canada	24.4	13.0	−46.7%
Amount per day (among daily smokers)
US	18.1	14.2	−21.5%
UK*	13.8	11.3	−18.1%
Canada	16.8	13.8	−17.9%

1. ^*Daily and non-daily smokers.

   Note. Data from National Centre for Health Statistics, NHIS; Office of National Statistics, Adult Smoking habits in Great Britain; Statistics Canada and Reid et al., 2017, Tobacco Use in Canada: Patterns and Trends, 2017 Edition –Defined as having smoked in the past 30 days and having smoked 100 cigarettes in a lifetime. Adult ages are 15+ in Canada and the UK and 18+ in the US.

The main conclusion remains that in these three countries, about one in six to one in seven of adults, were smokers in 2017. In absolute terms, this represents about 45 million cigarette smokers in the three countries.

In contrast to the long delay between smoking onset and the development of disease, the main effects of widespread cessation are seen much more rapidly. Worldwide, cessation is the only practicable way to avoid a substantial proportion of tobacco deaths before 2050 (Jha and Chaloupka, 1999), as a substantial reduction in uptake by adolescents will have its main effect on mortality rates after 2050.

Cessation trends in US, UK and Canada

The prevalence of former smoking in middle-age is a useful measure of the success of tobacco control. Currently in Canada, the US and the UK, there are as many former as current smokers between the ages of 45 to 64 years (Figure 10) The short-term relapse rates among smokers considering cessation is very high. However, among those who persist in cessation, few re-start smoking.

Figure 10

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There is a large gap in high-income countries between the intent to quit smoking and actual success rates. This is mostly a consequence of the strongly addictive nature of cigarettes. Two-thirds of smokers wish to quit, while only about half of that actually try, while far fewer succeed (U.S. Department of Health and Human Services, 2020). In 2015, nearly two-thirds (65.8%) of Canadian smokers were seriously considering quitting in the next six months. Of those, about half (48.2%) were considering quitting within the next thirty days, which was equivalent to 31.1% of all current smokers. Between 1999 and 2015, the percentage of Canadian smokers seriously considering quitting in the next six months appears to have increased slightly (Reid et al., 2017). In 2015, over half (52.3%) of Canadian smokers and recent quitters reported having made at least one attempt at successful cessation in the past year, while more than one-third had made multiple attempts. From 1999 to 2015, the percentage of smokers and recent quitters who had attempted to quit in the past 12 months appears to have remained fairly stable, at around half (Reid et al., 2017). The US and the UK reports similar patterns of attempted cessation (Babb, 2017; Office for National Statistics, 2018b).

Reduction in overall mortality from cessation

Smokers who stop smoking before age 40 (preferably well before age 40), avoid more than 90% of the excess risk for overall mortality among those who continue to smoke. Those who stop before age 30 avoid 97% of the risk of death. Those who have smoked cigarettes since early adult life but stop at 30, 40, or 50 years of age gain, respectively, about 10, 9, and 6 years of life expectancy, compared to those who continue smoking (Jha et al., 2013; Pirie et al., 2013).

The reductions in smoking risk for all deaths and for lung cancer mortality among women in the UK are shown in Figure 11. Very similar results were seen in the US for these same age groups among men and women (Jha et al., 2013). The smoker/non-smoker risks quickly converge for vascular disease, for some cancers other than lung, though less quickly for lung cancers, with intermediate convergence for respiratory disease. The overall persisting hazard for death from any cause is reduced but not eliminated. For those who smoke until age 40 years and then stop, the remaining excess risk of about 20% (relative risk, 1.2, hence 120% risk less 100% baseline risk = 20% excess risk) is substantial and implies that about one in six of these former smokers who dies before the age of 80 years would not have died if their death rates had been the same as otherwise similar non-smokers. However, this 20% excess has to be compared to an excess risk of 200% if they continued to smoke (RR = 3, hence 300% risk less 100% baseline risk = 200% excess risk). Similarly, for lung cancer, quitters by age 40 retain a substantial excess risk of 230%, but this is dwarfed by the 2000% excess risk from continued smoking. In both cases, the relative reduction in excess risk among former versus current smokers exceeds 90%.

Figure 11

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Similar results on reductions in lung cancer risk in former smokers are seen in other settings. The excess lung cancer mortality avoided in men who stopped smoking by age 40 was 91% in Germany and 80% in Italy (Crispo et al., 2004). In countries such as Canada, the UK, US or Poland, where high mortality rates from smoking were followed by widespread cessation, mortality from smoking has greatly decreased, for example by 25% per decade in Canada (Peto et al., 2018; Jha, 2009).

Earlier reviews note that the relationships of excess-risk for overall mortality with halving smoking amount reduces mortality risk far less than cessation (U.S. Department of Health and Human Services, 2014). This would imply that the mean reduction in daily amount smoked in the three countries from 1999 to 2013 (about three cigarettes fewer, per day, per smoker; Table 1) has had only a minimal impact on the risk of death. Cessation remains far more important than reduced smoking amount.

Thus far, I have focused on the epidemiological evidence of the causal links of smoking to specific diseases and to overall mortality. Here, I turn briefly to the biological evidence. A common criticism of the epidemiological studies is that the exact ‘mechanism’ that causes smoking to induce lung cancer has not yet been identified. This is mostly irrelevant. As Thun et al. (2002) point out, the epidemiological evidence of association is so strong between smoking and various diseases, that further biological evidence on mechanisms is not required to establish causality. Moreover, as smoking causes a wide range of diseases, it is likely different biological mechanisms apply (for example, there may be different mechanisms at the cellular level in cancers than in cardiovascular diseases).

Doll and Peto (1981) illustrate that human population trends have distinct advantages in studying smoking as an exposure. In Canada, the US and the UK, there have been substantial earlier increases and more recent decreases in smoking-attributable mortality and from specific conditions from about 1970. During that time period, the genetic susceptibility of the relevant populations has not likely changed; say, towards reduced expression of the genetic factors that predict lung cancer or genetic factors that decrease addictiveness to nicotine. Increases and the more recent decreases in smoking account for most of the dramatic changes in smoking-attributable diseases in recent decades; genetics has likely played only a minor or no role in explaining the marked changes in tobacco-attributable mortality in recent decades.

Despite about 40,000 studies since about 1950 on the relationship between smoking and disease, there continues to be widespread ignorance about the hazards of smoking by the public, non-experts and even some experts. For example, adults do not know that smoking is a cause of stroke based on numerous surveys, particularly in low-income countries or among less educated adults in high-income countries (Jha and Chaloupka, 1999; Jha and Chaloupka, 2000). What is surprising however, is the extent to which even informed professionals can be unaware of the hazards of smoking.

This confusion about smoking hazards in part reflects definitions of causality. Consider lung cancer, which is among the most widely-studied of the tobacco-attributable diseases. Despite the common myth, smoking is not the only cause of lung cancer. Smoking is a cause of about 90% of lung cancer deaths in high-income countries. However lung cancer occurs (albeit rarely) in non-smokers. These rare occurrences may be related to factors such as radon exposure, though it is useful to note the rate of lung cancer among non-smokers has changed little over time (Thun et al., 2008). Hence, smoking is not a necessary cause of disease. Some smokers do not die a premature death from their smoking, and not every smoker will develop lung cancer (or heart disease or other tobacco-attributable conditions). Hence, smoking is not a sufficient cause of disease. With that said, smoking is an important cause of lung cancer and other diseases. In epidemiological terms, when we state that smoking is an important cause of lung cancer, we are stating that, among people of the same age, smokers have a (statistically significant) increased probability of developing lung cancer in the near future than do otherwise similar non-smokers. Similarly, smoking is an important cause of vascular and respiratory disease and other diseases (U.S. Department of Health and Human Services, 1989).

Once causality is established for a particular condition, it is important to then consider the implications for public health. Here, we have to understand the relevant concept of the combination of two risks, together, as a cause of disease. For example, asbestos was used widely among shipyards in the UK that were built during WWI and WWII, prior to awareness of the hazards of asbestos on lung cancer and respiratory disease. Similar Canadian workers faced lower risks in part as the type of asbestos exposure was less carcinogenic than in the UK (Peto, 1985). Thus, large numbers of male UK shipyard workers were exposed to asbestos dust during each working day for many years. In these men, lung cancer developed at about ten times the rate of its development in otherwise similar men not exposed to asbestos dust (Barlow et al., 2017). Among these male shipyard workers, many smoked, and smoking made new lung cancer ten times more likely. Thus, shipyard workers who smoked and were exposed to asbestos dust were, by age 60 years, 100 times as likely to get lung cancer as men who had never smoked and who had not been exposed to asbestos dust (Markowitz et al., 2013).

If around 1950, we took 100 smokers who were exposed to asbestos and died of lung cancer, 90 of those 100 lung cancer deaths would not have happened if the individual had not smoked. Similarly, 90 of those 100 lung cancer deaths would not have happened if the individual had not been exposed to the particular types of asbestos dust. Thus, smoking and asbestos are each a cause of 90 of these 100 lung cancer deaths. The attributed fractions obviously add up to over 100%. Naturally, it follows that avoidance of both smoking and asbestos exposure would not avoid much more than the 90 deaths that each caused. Moreover, using the same analogy as above for asbestos, the fractions caused by genetic factors and caused by environmental factors are not mutually exclusive (Doll and Peto, 1981). A specific disease has both genetic and environmental causes.

In addition to misunderstanding of causality, two additional aspects of the divergence between the scientific evidence and popular understanding: underestimation of smoking hazards and confusion with other risks.

Confusion of the large hazards of smoking with the smaller hazards of most other exposures

Let’s consider one of the statements made by the British American Tobacco, a global multi-national cigarette manufacturing, in response to requests made by the US Congress in 2003 (Waxman, 2003) about their belief of the causal role of cigarette smoking:

“…that causes of lung cancer, chronic obstructive pulmonary disease, and cardiovascular diseases are complex, and the mechanism of causation, as well as the possible role of any cigarette smoke constituent in causation, have not been scientifically established” (Waxman, 2003).

Over the last decade, many tobacco companies have admitted that smoking causes disease, but most continue to fudge their belief in causality. Indeed many politicians have made similar arguments that minize the hazards of smoking. For argument’s sake, let’s extend the tobacco industry concerns about causality to a widely held suggestion that other ‘complex’ factors are responsible for smoking harms at the population level or in particular individuals. These other factors, based on common sense, should be closely associated with being a smoker. These might include lack of exercise, poor nutrition, alcohol drinking, peer pressure to smoke, low social status, psychology influences, and stress. Additional factors that might also be more common in smokers could include poor in-utero environment, poorer access to medical treatment, food choices, and the emerging area of science on the gut microbiome environment (Finlay and the Microbiome, 2020).

A noted UK geneticist, Sir Ronald Fisher, attacked the Doll and Hill studies of the early 1950s, suggesting that the case-control study design could not establish causality, instead hypothesizing that there was an underlying gene that resulted both in smoking and in lung cancer. Fisher was later reported to have received funding from the tobacco industry and eventually recanted some of his criticisms of Doll and Hill (Christopher, 2016).

Careful epidemiological studies have been able to examine many, but certainly not all of the first list of factors that by common sense occur in smokers. These find, for the most part, that ‘adjustment’ for such differences between smokers and non-smokers makes little difference to the observed smoker: non-smoker relative risks. What then of unmeasured variables or as yet unknown variables, as these are, by definition, bound to exist in any study? It would be expected that even undetermined factors should, for the most part, also correlate with known factors. Thus a mystery factor, either behavioural, environmental or genetic, that I will call ‘Zulu’ likely correlates closely with poor nutrition, lack of exercise as well as to smoking. It follows that, were Zulu the main true explanation for the observed smoker: non-smoker risks, adjustment for a closely correlated surrogate like lack of exercise would reduce the observed smoking relative risks. Most careful studies find, in fact, little diminution of smoker: non-smoker risks with such adjustment. This suggests that ‘residual confounding’ with unknown or unexplained risk factors does not explain most of the large observed risks for smoking. It also suggests that smoking acts independently of the other factors, even though they may be correlated.

Indeed, adjustment for smoking explains many of these other factors. Consider low social status, which is well described as a risk factor for many diseases. The UK Million Women’s study examined the social differences in hospitalization or death from ischemic heart disease. Heart disease death or hospitalization was strongly associated with lower levels of education or greater (neighborhood) deprivation, with clear dose-responses. However, smoking, alcohol consumption, physical inactivity and body mass index accounted for most of the risk factors, and of these four factors, smoking accounted for the biggest share (Floud et al., 2016; Jha et al., 2019).

Any particular disease can have in fact two (or more) causes. Therefore, obesity and smoking may both contribute to heart disease and avoidance of either might have prevented a particular heart attack. However, from a population health perspective, what is useful is to understand the comparative risks for each and to what extent are these risks avoidable.

I now review some of these major identified ‘other factors’ beginning first with obesity (presumed to be both ‘physiological’ and ‘based on lifestyle choices’ in tobacco industry parlance), then turning to alcohol, and finally genetics and environment. I selected these factors as the WHO has identified these as major risk factors for adult health (World Health Organization, 2016) and because clinicians and the public often turn to genetic differences to explain disease occurrence. Moreover, smoking and drinking, and to a lesser extent obesity are strongly correlated in healthy as well as in diseased individuals (Thun et al., 1997).

Comparison with obesity

Smoking risks are substantially greater than those of obesity for adults in high-income countries. Obesity (at its most extreme called severe obesity) is defined as excess body fat, and measured by body-mass index (BMI; or weight divided by height squared). Higher BMI causes a loss of premature life (Finucane et al., 2011). The loss of a decade of life requires a BMI of around 43, which is well above the averages seen in any country including the most obese populations of the US. More moderate levels of obesity, meaning of BMI of around 32, contibute to an average of three years of life loss. Hence, at the population level, a 2 kg per meter extra BMI if overweight or a 10% higher smoking prevalence both reduce life expectancy by one year (Figure 12; Peto et al., 2010).

Figure 12

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These individual risks also translate to the overall life expectancy gaps at the population level. About 15% of American smoke cigarettes, and smoking accounts, on average, for 10 years of life lost. Thus, smoking is reducing American life expectancy by about 1.5 years of life (i.e. 15% X 10 years). The mean BMI in the US is 28 and about 30% of the American population is modestly obese. If modest obesity accounts for 3 years of life lost, then obesity is reducing American life expectancy by 0.9 years (i.e. 30% X 3 years). Hence, smoking causes more lost life than does obesity in the US. Moreover, the main mechanisms for increased mortality from higher BMI from vascular disease are due to hypertension, ‘bad’ lipids and development of diabetes. Most of these factors driven by higher BMI are very treatable even without reducing weight (Yusuf et al., 2004; Yusuf et al., 2020). By contrast, the only plausible way to reduce smoking risks is by quitting (Jha et al., 2013).

Comparison with alcohol

Heavy alcohol use increases the death rate from some conditions (most notably, road traffic and other injuries, suicide, poisoning, liver cirrhosis, certain cancers and perhaps haemorrhagic stroke) (Thun et al., 1997); and recent studies have documented hazards from drinking for ischemic stroke and no protective effect for ischemic heart disease (Millwood et al., 2019). Thus, the overall survival of otherwise comparable drinkers and non-drinkers in Canada, the US and the UK are similar (the slightly greater survival in drinkers shown in earlier studies is mostly likely due to ‘reverse causality’ whereby sicker people give up drinking). This balance of risks is distinct from the extreme binge-drinking patterns of vodka among Russian men, in whom loss of life from such binge-drinking exceeds that of smoking (Zaridze et al., 2009; Zaridze et al., 2014). However, the hazards of smoking are observed in both drinkers and non-drinkers (Table 6).

Table 6

Sex and alcohol drinking status	Smokers	Non-smokers
MEN
Drinkers	43	22
Non-drinkers	46	26
WOMEN
Drinkers	28	14
Non-drinkers	30	17

1. Adapted from Alcohol consumption and mortality among middle-aged and elderly US adults, by Thun et al. (1997), New England Journal of Medicine, 337(24), p. 1712.

Even epidemiologists often underestimate the extreme hazards of tobacco. Consider the following comparisons. Firstly, among 1,000 male smokers aged 20, at least 500 (and perhaps up to 670), will die from smoking throughout their lifetimes. Of these, at least 250 will die from smoking in middle-age (meaning before 70 years). By contrast, only 20 would die from road accidents or violence and 30 from all alcohol-related conditions (Jha and Chaloupka, 2000).

Comparison with genetics

To return to the idea of causation; a common statement made by people (including doctors) is that ‘genetics was responsible’ for a particular person’s heart attack or lung cancer, even though they may have also smoked. At the population level, both genetics and smoking could for example, play roles in causing either disease. The population-based evidence should also guide the magnitude of the risk. For example, no single genetic factor has been identified that explains a significant proportion of heart attacks, although the combination of all tested factors suggest just over a quarter of heritability of heart disease (McPherson and Tybjaerg-Hansen, 2016).

However, smoking alone accounts for at least a quarter of the deaths from heart attack in the US (U.S. Department of Health and Human Services, 2014). Moreover, the largest identified single genetic factor (the relative risk from a specific lipid factor (lipoprotein (a), Loci SLC22A3-LPAL2-LPA SNP, rs2048327) carries a relative risk of 1.4, which is comparable to smoking 3–4 cigarettes a day. Similarly, a range of genetic factors has recently been suggested to modestly predict lung cancer risk in smokers and non-smokers (Timofeeva et al., 2012). These genetic factors do not negate the importance of smoking in explaining lung cancer risks.

Comparison to environmental pollutants and other exposures

Doll and Peto (1981) conducted an exhaustive review of the possible causes of cancer in the US in the late 1970s. Their focus was on the widely held belief that ‘pollutants’ in the environment were a major cause of cancer. They documented the available epidemiological evidence on the environmental exposures most commonly believed to be linked to cancer, such as pesticides, food additives, industrial products, ultraviolet light, and pollution. (They did not specifically study ambient air pollution). They concluded that tobacco smoking accounted for more of the proportions of cancer deaths than did a reasonable summation of all of the known risk factors, including nearly every known pollutant. Table 7 shows their summary results.

Table 7

Factor or class of factors	Percent of all cancer deaths
	Best estimate	Range of acceptable estimates
Tobacco	30	25–40
Alcohol	3	2–4
Food additives	<1	−5–2
Reproductive and sexual behaviour	7	1–13
Occupation	4	2–8
Pollution	2	<1–5
Industrial products	<1	<1–2
Medicines and medical procedures	1	0.5–3
Geophysical factors (mostly Ultraviolet light)	3	2–4
Infection	10?	1-?
Diet	35	10–70
Unknown	?	?

1. Adapted from The causes of cancer: Quantitative estimates of avoidable risks of cancer in the United States today, Doll and Peto (1981), Journal of the National Cancer Institute, 66(6), p. 1192–1308.

Doll and Peto also pointed out that, excluding smoking-attributable cancers, there was no ‘epidemic’ of cancer, as was commonly believed at that time. In fact cancer death rates except those attributable to smoking were falling modestly. Finally, they pointed out that smoking causes more death from causes other than cancer than it does from cancer itself.

In this review, I have considered the cause, nature and extent of tobacco related diseases in high-income countries between 1960 and 2020. I have drawn on existing epidemiological evidence, with careful re-interpretation of risks in individuals and rates among populations. It follows naturally to ask what additional epidemiological or biological evidence is needed on the consequences of smoking in high-income countries. A full treatise on research priorities is beyond the scope of this review, but a few priorities should be considered. First, the rapidly changing prevalence of smoking, including increases in cigarette cessation require ongoing studies to document the benefits of quitting, particularly on various diseases and at different ages (U.S. Department of Health and Human Services, 2020). Second, the emergence of e-cigarettes demands further documentation of the long-term risks (and possible benefits) of their use among adults and by adolescents. The current state of evidence is mostly insufficient for conclusions on the net effects of e-cigarettes on population health. Third, research to better understand how risks are perceived and internalized by individuals and governments is needed to ensure that epidemiological studies on the consequences of smoking are incorporated into decision-making.

Based on the existing epidemiological and biological evidence, I provide four overall conclusions.

Firstly, in much of North America and Western Europe, the biggest cause of premature death, defined as death before 70 years, is the smoking of manufactured cigarettes. Smoking as an important cause of many diseases in many populations has been recognized widely in the scientific literature for the last five decades. However, three surprising features of health hazards of smoking have been established reliably only in the last decade. The first feature is that risk of developing disease among smokers is big. The second feature is that for smokers to develop these big risks, they need to start smoking early in adult life and to continue smoking. If smokers don’t start early in life, their risks are substantially smaller. Third, if smokers stop smoking before they develop some serious disease, then their risks are substantially reduced. However, most smokers whom start early in adult life and who continue to smoke are eventually killed by their tobacco use. This is because in every year during middle age, the death rates among smokers are about three-fold higher than that of similar non-smokers (taking into account differences between smokers and non-smokers in heavy alcohol use, obesity patterns or different social status). So up to two-thirds of the mortality among smokers would not be happening if they had the non-smoker death rates. Most of this excess risk arises from diseases that are caused by smoking. This includes disease such as lung cancer, emphysema, heart attack, stroke, cancer of the upper aerodigestive areas, bladder cancer and various other conditions. Thus this excess risk is a cause and effect relationship.

Secondly, from 1960 to 2020, smoking has likely killed 29.5 million Americans, 9.3 million UK residents, and 2.6 million Canadians, or a total of 41.3 million adults. This constitutes a crude ratio of one death per million cigarettes smoked in the US and Canada, but slightly more than one death per million cigarettes smoked in the UK.

Third, cessation, particularly before age 40 avoids nearly all the excess risk of continued smoking. Cessation at any age is effective, restoring substantial years of like lost versus continued smoking.

Finally, there continues to be widespread, serious underestimation of the hazards of smoking by the public, non-experts and even some experts.

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Author details

1. Prabhat Jha

   Centre for Global Health Research, Dalla Lana School of Public Health and Unity Health, Toronto, University of Toronto, Ontario, Canada

   For correspondence

   Prabhat.jha@utoronto.ca

   Competing interests

   Reviewing Editor at eLife.

   "This ORCID iD identifies the author of this article:" 0000-0001-7067-8341

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