While the pollution mix in London during this fog was complex, it is likely that particulate air pollution was largely responsible for the excess deaths. These episodes demonstrate that exposure to urban air pollution can, in extreme cases, cause death. Epidemiological Studies Several studies have confirmed associations between increased PM concentrations and increased cardiopulmonary mortality. They found that for each 10 mg/m3 increase in PM10, mortality increased by a fraction of a percent (2, 3, 4, 5, 6, 7, 8, 9). In spite of the small effect of PM increases, the public health impact could be large if seen across broad populations. Thus, increasing ambient PM concentrations represent a fairly significant risk in terms of mortality. Similar studies have established other health dangers that are associated with increased PM, including increased for lung cancer and heart disease. The American Cancer Society Air Pollution Study was initiated by C. Arden Pope and colleagues based upon a cohort of 1.2 million individuals enrolled in the fall of 1982.1 A subgroup of 552,138 adults lived in 151 United States metropolitan areas that could be matched to air pollution data collected under the auspices of the Environmental Protection Agency (EPA).
At the same time the American Cancer Society cohort was being assembled, investigators at the Harvard School of Public Health established a longitudinal study on the health effects of air pollution in six cities. The Harvard Six Cities Study was a sixteen-year prospective cohort study of 8,111 adults living in the northeastern and midwestern United States beginning in the 1970s. The study reported that PM2.5 was positively associated with overall mortality, cardiopulmonary causes, and lung cancer.
Lung cancer is the most common cause of cancer death in the United States, with more than 200,000 new cases and 160,000 annual deaths. It is estimated that lung cancer causes about 1.2 million deaths annually worldwide. Approximately 90% of lung cancer cases are due to cigarette smoking in populations with prolonged cigarette use. The strongest determinant of lung cancer in smokers is duration of smoking; risk also increases with the number of cigarettes smoked. Smoking causes lung cancer in both men and women.
Cessation of smoking at any age avoids the further increase in risk of lung cancer caused by continued smoking. However, the risk of ex-smokers for lung cancer remains elevated for years after cessation, compared to the risk of never smokers. The impact of smoking on lung cancer in the twentieth century in the United States can be seen in Figure 5.5. Cigarette smoking was rare in the early part of the twentieth century, as was lung cancer. Smoking increased due to mass production of cigarettes, increased advertising, and pervasive use of cigarettes by military personnel during World War I. During the twentieth century, smoking rose first among males and then with a twenty- to thirty-year delay among females. Cigarette smoking peaked in the 1950s and 1960s and began to decline after the wave of studies documenting its risks appeared and the publication of the first Surgeon General’s report in 1964. Mortality due to lung cancer in men can be seen to follow the curve for smoking prevalence by about thirty years, beginning to decrease in the mid-1990s. Lung cancer became the most common cause of cancer death in U.S. women, surpassing breast cancer in 1988.
The range of total carcinogen exposure in smokers is approximately 1.4–2.2 mg/cigarette, which can be compared to the current sales-weighted average nicotine delivery of about 0.8 mg/cigarette. Some of the strongest carcinogens, such as polycyclic aromatic hydrocarbons (PAH), N-nitrosamines, and aromatic amines, occur in the lowest amounts, while some of the weaker carcinogens (such as acetaldehyde and isoprene) occur in the highest amounts. PAH are incomplete combustion products that were first identified as carcinogenic constituents of coal tar.49 They occur as mixtures in tars, soots, broiled foods, automobile engine exhaust and other materials generated by incomplete combustion. N-nitrosamines are a large class of carcinogens with demonstrated activity in at least thirty animal species. Considerable evidence favors PAH and N-nitrosamines as major etiological factors in lung cancer. PAH are strong, locally acting carcinogens, and tobacco smoke fractions enriched in these compounds are carcinogenic. PAH-DNA adducts have been detected in the human lung, and mutations in the TP53 tumor suppressor gene isolated from lung tumors are similar to those produced in vitro by PAH diol epoxide metabolites and in cell culture by Benzo(a)pyrene. Persistent DNA adducts can cause miscoding during replication when DNA polymerase enzymes process them incorrectly.52 There is considerable specificity in the relationship between specific DNA adducts caused by cigarette smoke carcinogens and the types of mutations which they cause. G to T and G to A mutations are frequently observed.53 Mutations have been frequently observed in the K-ras oncogene in smokers with lung cancer and in the TP53 tumor suppressor gene in a variety of cigarette smoke-induced cancers. The cancer-causing role of mutations in these genes has been firmly established in animal studies. The K-ras and TP53 mutations observed in lung cancer in smokers appear to reflect DNA damage by metabolically activated PAH, although acrolein can also cause p53 adducts in lung cancer hot spots, and there is far more acrolein in cigarette smoke than PAH. In addition, numerous cytogenetic changes have been observed in lung cancer, and chromosome damage throughout the aerodigestive tract is strongly linked with cigarette smoke exposure. Gene mutations can cause loss of normal cellular growth control functions via a complex process of signal transduction pathways, ultimately resulting in cellular proliferation and cancer. The most commonly mutated gene found in human cancers is the TP53 tumor suppresser gene.51 Among the tobacco related cancers, the most extensive database exists for lung cancer, in which mutations in the TP53 gene have been detected in approximately 70% of tumors. In smokers, the mutations are focused in the central part of the gene, which is the DNA binding region that is essential for its function. Smokers have mutations in hot spots of this region that are a characteristic signature, for example, codons 157, 176, 248, 249, 273. Exposure of lung fibroblasts or epithelial cells in vitro to activated PAH results in DNA adducts on the same codons.
Smoking Cessation
Mark Twain stated, ‘‘Giving up smoking is easy. I’ve done it a hundred times.’’ In 2008 it was noted that social networks amplify smoking cessation, with one’s spouse, sibling, friend, or coworker, in descending order, influencing a smoker’s possibility of smoking cessation, and that smokers over time are increasingly marginalized socially. The Lung Health Study was a randomized clinical trial of smoking cessation and inhaled bronchodilator (ipratropium) therapy in smokers 35 to 60 years of age who were in good health but had evidence of mild to moderate airway obstruction. They enrolled 5,887 smokers at ten clinical centers, with an intervention group of twelve smoking cessation sessions and nicotine gum; the intervention group had smaller declines in FEV1 than the control group. At five years, 21.7% of special intervention participants had stopped smoking since study entry, compared with 5.4% of usual care participants. At 14.5 years’ follow-up, there was a lower mortality in the intervention group, with the hazard ratio for usual care 1.18 (95% CI 1.02–1.37), and differences in death rates were greatest for lung cancer and cardiovascular disease. Tobacco cessation programs have difficulty exceeding sustained quit rates above 15%, which is the typical success rate of those attempting to stop ‘‘cold turkey.’’ Treatment of tobacco dependence with nicotine gum and patches may double this rate. Nicotine is the addictive substance in tobacco, and cigarette manufacturers are very sophisticated at mixing tobacco blends to achieve maximal nicotine delivery via the cigarette. Nicotine has a rather short half-life of about 20 minutes, requiring another cigarette to be smoked to keep blood levels of nicotine at sufficient levels to prevent withdrawal symptoms. Smoking provides an immediate delivery of nicotine to the blood and to the brain, where nicotinic acetylcholine receptors are critical for the development of dependence. The highest levels of these receptors, the a4b2, are in the reward center of the brain. A treatment strategy is to have a competitor for this receptor that doesn’t or only partially activates it; varenicline, a plant alkaloid cytisine, is such a drug. This drug had a higher sustained quit rate in comparative clinical trials with bupropion or nicotine-replacement therapy.
SO2 Health Effects
In several studies, SO2 exposure has been linked with increased mortality due to all causes and to lung cancer specifically. For example, the study of the American Cancer Society cohort that reported the link between mortality and criteria air pollutants, the relative risk (RR) of all-cause mortality from sulfate exposure was 1.25 (95% CI [confidence interval] 1.13–1.37) and was higher at the county level with an RR of 1.5.2 The National Mortality and Morbidity Air Pollution Study (NMMAPS) also analyzed SO2 and found no significant associations with total mortality.3 An international study of pulp and paper workers with 40,704 SO2-exposed workers found a reduced overall standardized mortality ratio of 0.89 (95% CI 0.87–0.96) but a marginally increased rate of 1.08 for lung cancer (95% CI 0.98–1.18).4 After adjustment for occupational co-exposures, the lung cancer risk was increased compared with unexposed workers (rate ratio ¼ 1.49; 95% CI 1.14–1.96). There was a suggestion of a positive relationship between weighted cumulative SO2 exposure and lung cancer mortality. These confirm that SO2 exposure increases mortality. SO2 is a respiratory irritant with exposures at 10 ppm, causing cough, dyspnea, irritation of the eyes and throat, and reflex bronchial constriction. In July 1990, Hong Kong introduced a requirement that all power plants and road vehicles had to use fuel oil with a sulfur content no greater than 0.5% by weight.5 In the ensuing twelve months, there was a reduction in seasonal deaths followed by a peak in the cool season death rate between thirteen and twenty-four months, returning to the expected pattern during years 3–5. There were declines in the average annual trend in deaths from all causes (2.1%, p ¼ 0.001), respiratory 3.9%, and cardiovascular 2.0%. The average gain in life expectancy per year of exposure to the lower pollutant concentration was twenty days for females and forty-one days for males. In the two years after the intervention, there was a reduction in chronic bronchitic symptoms and bronchial hyperresponsiveness in children. SO2 declined 45% over five years and respirable particulates declined for two years. In twelve Canadian cities, daily SO2 concentrations were significantly associated with daily mortality, with an average concentration of only 5 mg/ m3 . 6 In a district of Chongqing, China, daily mortality was analyzed from January through December 1995 for associations with daily ambient sulfur dioxide and fine particles.7 Particulate matter less than 2.5 mm in diameter (PM2.5) was monitored for seven months, while SO2 was monitored for the entire year. The investigators found positive associations between daily ambient SO2 concentrations and mortality from respiratory and cardiovascular disease. For example, the effect of a 100 mg/m3 (0.04 ppm) increase in daily SO2 concentrations was a relative risk of 1.20 (95% CI 1.11–1.30) for cardiovascular mortality, with up to a three-day lag. The SO2 association remained robust when controlled for PM2.5. No associations were observed between daily ambient PM2.5 concentration and any cause of mortality. A weakness of this study was the absence of measurements of carbon monoxide, ozone, or nitrogen dioxide. Chongqing is surrounded by mountains, is one of China’s largest cities at 30 million people, and uses high-sulfur coal for energy, with sulfur ranging from 4% to 12%.
