Background:

Despite the success of smoking cessation campaigns, lung cancer remains the leading cause of cancer death in the U.S. Variations in smoking behavior and lung cancer mortality are evident by sex and region.

Methods:

Applying geospatial methods to lung cancer mortality data from the National Vital Statistics System and county-level estimates of smoking prevalences from the NCI's Small Area Estimates of Cancer-Related Measures, we evaluated patterns in lung cancer mortality rates (2005–2018) in relation to patterns in ever cigarette smoking prevalences (1997–2003).

Results:

Overall, ever smoking spatial patterns were generally associated with lung cancer mortality rates, which were elevated in the Appalachian region and lower in the West for both sexes. However, we also observed geographic variation in mortality rates that is not explained by smoking. Using Lee's L statistic for assessing bivariate spatial association, we identified counties where the ever smoking prevalence was low and lung cancer rates were high. We observed a significant cluster of counties (n = 25; P values ranging from 0.001 to 0.04) with low ever smoking prevalence and high mortality rates among females around the Mississippi River region south of St. Louis, Missouri and a similar and smaller cluster among males in Western Mississippi (n = 12; P values ranging from 0.002 to 0.03) that has not been previously described.

Conclusions:

Our analyses identified U.S. counties where factors other than smoking may be driving lung cancer mortality.

Impact:

These novel findings highlight areas where investigation of environmental and other risk factors for lung cancer is needed.

This article is featured in Highlights of This Issue, p. 155

Lung cancer is the leading cause of cancer death among both males and females in the U.S. (1). Nearly a quarter of all cancer deaths are due to lung cancer, an estimated 82% of which are caused by cigarette smoking (2). Historical trends in cigarette consumption, with per capita consumption rising between the 1930s and the 1950s, largely influence today's mortality trends. In the U.S., cigarette smoking was primarily a male behavior until the 1930s, when tobacco advertisements began to specifically target females (3, 4). The prevalence of current smoking had reached more than 50% among males and about 34% among females in 1965 (5) but has been declining steadily since the 1964 Surgeon General's Report that clearly linked cigarette smoking with lung cancer risk (6). Some smokers have been able to quit; the proportion of the general population that are former smokers has varied around 30% among men and 20% among women (5). The resulting estimates of ever smokers, the sum of the current and former smokers, have declined from more than 70% and 40% among males and females, respectively, in 1965 to less than 50% and 35% in 2007 (5).

Lung cancer mortality rates have also changed over time, following trends in smoking prevalence but lagging by 20 to 30 years (2, 7, 8). Mortality rates rose exponentially among males from about 4 per 100,000 in 1930 to 24 in 1950 to 68 in 1970 before peaking at around 92 in 1990 (9, 10). The rates among females were lower but also rose rapidly from about 3 in 1930 to 6 in 1950, 13 in 1970, and 37 in 1990 before peaking around 42 during the early 2000s. In addition to the substantial variation in lung cancer rates by sex, the geographic patterns have changed over time (7). Lung cancer rates in the U.S. reflect historical differences in the prevalence of smoking as well as more recent differences in state and county/city smoking laws and societal influences that have helped to modify smoking prevalence (11, 12). The prevalence of cigarette smoking has remained high in Southern states and states in the Appalachian region, while decreasing over the last few decades in most other states, particularly those in the West (13). Smoking prevalence also varies both between and within states on the county level (14).

As national smoking prevalence has declined, lung cancer among nonsmokers is of increasing public health interest, with secondhand smoke, hormones, and genetic predisposition as noted risk factors (15–17). To investigate other risk factors, cancer mapping and hot spot analyses have been used for decades to inform epidemiologic studies of associations between lung cancer and putative exposures (18–20), including environmental and occupational hazards that vary geographically. Early cancer mortality atlases (21) and subsequent case–control studies (22–24) revealed that shipyard work was associated with increased risk of lung cancer along southern coastal regions in the 1970s and early 1980s. This excess risk was later primarily attributed to asbestos exposure, and shipyards began phasing out asbestos-containing materials, leading to decreases in the relative rate of lung cancer across many coastal areas (25). As another example, long-term exposure to radon, a gas released from decaying radioactive materials, is associated with an increased risk of lung cancer, especially among nonsmokers (16, 26). Similarly, exposures to diesel exhaust fumes and ambient particulate matter less than 2.5 μm in diameter are also associated with increased risk (16, 27). Exposures to these hazards vary across the U.S., including between nonmetropolitan and metropolitan areas.

The objective of this study was to describe recent patterns of lung cancer mortality and prior smoking behavior by sex using publicly available data and geospatial methods. By identifying counties where cigarette smoking prevalence has been low, but lung cancer mortality rates are high, we sought to identify regions where future studies of potential lung carcinogens may be fruitful.

Data for the county-level and state-level smoking prevalence estimates (ever smoking and current smoking) were obtained using the NCI's Model-based Small Area Estimates of Cancer-Related Measures. These estimates are based on self-reported data from the Behavioral Risk Factor Surveillance System (BRFSS) and the National Health Interview Survey (NHIS). Established in 1984, the BRFSS is an annual nationally representative telephone survey collecting data on health risk behaviors among adults from the 50 U.S. states, the District of Columbia, Puerto Rico, the U.S. Virgin Islands, and Guam (28). Similarly, the NHIS was established in 1957 and is an annual cross-sectional household survey that collects health information via interviews of adults (29). For ever smoking, a person must have reported smoking at least 100 cigarettes in their lifetime by the interview date. For current smoking, a person must have reported smoking at least 100 cigarettes in their lifetime and smoked cigarettes some days or every day by the interview date. Separate county-level and state-level models were used to produce the respective county- and state-level estimates of prevalence with adjustments to make aggregated county-level estimates agree with state-level estimates. Historical smoking data prior to the mid-1990s was only available at the state level. We used the small-area estimates for 1997–1999 and 2000–2003, available for persons aged 18 years and older, to calculate the combined prevalence percent for persons aged 18+ years during 1997–2003 by sex and county, and by sex and state, where the state-level prevalences were further combined to obtain prevalence percent by sex and the nine statistical divisions specified by the U.S. Census Bureau: New England, Middle Atlantic, East North Central, West North Central, South Atlantic, East South Central, West South Central, Mountain, and Pacific.

National (conterminous U.S.), county-level, and census division-level lung and bronchus cancer (ICD-10 code C34: malignant neoplasm of lung and bronchus, hereafter referred to as lung cancer) mortality rates from 2005 to 2018 (the most recent year available) were calculated using National Vital Statistics System data from the National Center for Health Statistics (NCHS) (30). Deaths were available by 5-year age groups and we selected deaths among adults ages 20 years and older. Sex-specific rates were expressed per 100,000 person-years and age-adjusted with the 2000 U.S. standard population using SEER*Stat version 8.3.9 (31). Due to NCHS reporting guidelines, mortality count data were suppressed for counties with fewer than 10 deaths, which excluded 89 counties for males and 161 counties for females (32).

We calculated spatial autocorrelation among counties using Lee's L statistic for bivariate spatial association, identifying clusters with significant correlation between the two variables [i.e., smoking prevalence (X) and lung cancer mortality rate (Y)] in all four combinations (high-high, low-high, high-low, and low-low; refs. 33, 34). Lee's L statistic integrates Pearson's r and Moran's I to reflect the association between two spatially defined variables by accounting for (i) their correlation within the same county and (ii) the correlation of their spatially lagged values, allowing us to prepare maps with county-specific bivariate clustering results for each sex. Spatial neighbors were identified using a Queen's case adjacency matrix, which defines neighbors (and assigns a corresponding spatial weight) as counties that share a border. We calculated empirical P values from 100,000 random permutations of the bivariate values for the given spatial weighting. We used the FDR procedure to correct each bivariate analysis for multiple comparisons (35). All statistical analyses were calculated using SEER*Stat version 8.3.9 and the “spdep” package in R version 4.1.0 (36). R code used to calculate the Lee's L statistic and generate maps is available on GitHub (https://github.com/idblr/geo_US_lung_cancer_and_smoking). All spatial analyses excluded Alaska and Hawaii because of their spatial non-adjacency to the conterminous U.S.

Data availability

The data analyzed in this study included all counties in the conterminous U.S. and were obtained from the NCI's Model-based Small Area Estimates of Cancer-Related Measures and the National Vital Statistics System data from the NCHS (30, 37). Subject consent was not required for this aggregate-level analysis.

Lung cancer mortality

During 2005–2018, 1,188,445 males ages 20 years and older died of lung cancer in the U.S. (Table 1). The overall age-adjusted mortality rate was 78.1 per 100,000 person-years [95% confidence interval (CI), 77.9–78.2], and the rates ranged from a low of 56.8 (95% CI, 56.4–57.3) in the Mountain Division to a high of 113.2 (95% CI, 112.5–133.9) in the East South Central Division. Across males, lung cancer mortality rates varied substantially by county with rates in the highest decile exceeding 126.9 per 100,000 person-years, more than twice those in the lowest decile with rates of 58.8 or lower (Fig. 1A). The mortality rates were notably elevated across many areas of the southeast (e.g., East South Central and South Atlantic Divisions) and parts of the Midwest while relatively low in the upper plains, mountain, and western states.

Table 1.

Lung and bronchus cancer mortality rates ages 20+ for 2005–2018 and ever smoking percent ages 18+ for 1997–2003 in the conterminous U.S. by sex and by U.S. Census Division.

Lung and Bronchus MortalityEver Smoking
DeathsRatea (95% CI)Prevalencea (95% CI)
Males 
 Conterminous U.S. 1,188,445 78.1 (77.9–78.2) 52.6 (52.0–53.2) 
 New England 55,670 73.3 (72.7–73.9) 54.3 (52.8–55.9) 
 Middle Atlantic 151,656 72.5 (72.1–72.9) 52.4 (51.0–53.8) 
 East North Central 202,667 86.8 (86.4–87.2) 55.1 (54.0–56.1) 
 West North Central 85,753 80.9 (80.4–81.5) 55.0 (53.7–56.2) 
 South Atlantic 263,674 82.9 (82.6–83.2) 54.2 (53.2–55.3) 
 East South Central 104,958 113.2 (112.5–113.9) 57.4 (56.0–58.8) 
 West South Central 133,583 83.7 (83.2–84.2) 52.3 (50.8–53.7) 
 Mountain 60,940 56.8 (56.4–57.3) 48.9 (47.5–50.3) 
 Pacific 129,544 59.6 (59.3–59.9) 48.4 (47.0–49.9) 
Females 
 Conterminous U.S. 984,645 50.3 (50.2–50.4) 40.2 (39.6–40.8) 
 New England 52,737 53.2 (52.7–53.7) 46.6 (44.8–48.3) 
 Middle Atlantic 134,374 48.2 (48.0–48.5) 41.9 (40.5–43.2) 
 East North Central 166,990 56.3 (56.1–56.6) 41.8 (40.7–43.0) 
 West North Central 85,753 50.8 (50.1–51.6) 42.5 (41.0–43.9) 
 South Atlantic 203,306 50.9 (50.7–51.1) 39.2 (38.2–40.2) 
 East South Central 72,909 61.6 (61.1–62.0) 42.6 (41.0–44.2) 
 West South Central 98,700 49.4 (49.1–49.7) 35.6 (34.3–36.8) 
 Mountain 52,702 41.7 (41.3–42.0) 38.2 (36.6–39.9) 
 Pacific 117,174 42.8 (42.5–43.0) 34.0 (32.7–35.3) 
Lung and Bronchus MortalityEver Smoking
DeathsRatea (95% CI)Prevalencea (95% CI)
Males 
 Conterminous U.S. 1,188,445 78.1 (77.9–78.2) 52.6 (52.0–53.2) 
 New England 55,670 73.3 (72.7–73.9) 54.3 (52.8–55.9) 
 Middle Atlantic 151,656 72.5 (72.1–72.9) 52.4 (51.0–53.8) 
 East North Central 202,667 86.8 (86.4–87.2) 55.1 (54.0–56.1) 
 West North Central 85,753 80.9 (80.4–81.5) 55.0 (53.7–56.2) 
 South Atlantic 263,674 82.9 (82.6–83.2) 54.2 (53.2–55.3) 
 East South Central 104,958 113.2 (112.5–113.9) 57.4 (56.0–58.8) 
 West South Central 133,583 83.7 (83.2–84.2) 52.3 (50.8–53.7) 
 Mountain 60,940 56.8 (56.4–57.3) 48.9 (47.5–50.3) 
 Pacific 129,544 59.6 (59.3–59.9) 48.4 (47.0–49.9) 
Females 
 Conterminous U.S. 984,645 50.3 (50.2–50.4) 40.2 (39.6–40.8) 
 New England 52,737 53.2 (52.7–53.7) 46.6 (44.8–48.3) 
 Middle Atlantic 134,374 48.2 (48.0–48.5) 41.9 (40.5–43.2) 
 East North Central 166,990 56.3 (56.1–56.6) 41.8 (40.7–43.0) 
 West North Central 85,753 50.8 (50.1–51.6) 42.5 (41.0–43.9) 
 South Atlantic 203,306 50.9 (50.7–51.1) 39.2 (38.2–40.2) 
 East South Central 72,909 61.6 (61.1–62.0) 42.6 (41.0–44.2) 
 West South Central 98,700 49.4 (49.1–49.7) 35.6 (34.3–36.8) 
 Mountain 52,702 41.7 (41.3–42.0) 38.2 (36.6–39.9) 
 Pacific 117,174 42.8 (42.5–43.0) 34.0 (32.7–35.3) 

aMortality rates are per 100,000 person-years and are age-adjusted to the 2000 U.S. standard population. Ever smoking prevalence estimates are percents. The nine U.S. Census Divisions include the following states: New England (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont), Mid-Atlantic (New Jersey, New York, and Pennsylvania), East North Central (Illinois, Indiana, Michigan, Ohio, and Wisconsin), West North Central (Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, and South Dakota), South Atlantic (Delaware, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia, District of Columbia, and West Virginia), East South Central (Alabama, Kentucky, Mississippi, and Tennessee), West South Central (Arkansas, Louisiana, Oklahoma, and Texas), Mountain (Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, and Wyoming), and Pacific (California, Oregon, and Washington).

Figure 1.

Geographic patterns in the conterminous U.S. by county among males. A, lung and bronchus cancer mortality rates per 100,000 person-years during 2005–2018, ages 20+ years. B, ever smoking prevalence percents during 1997–2003, ages 18+ years. C, Lee's L analysis findings with colors indicating statistically significant counties.

Figure 1.

Geographic patterns in the conterminous U.S. by county among males. A, lung and bronchus cancer mortality rates per 100,000 person-years during 2005–2018, ages 20+ years. B, ever smoking prevalence percents during 1997–2003, ages 18+ years. C, Lee's L analysis findings with colors indicating statistically significant counties.

Close modal

During 2005–2018, 984,645 females aged 20 years and older died of lung cancer in the U.S. (Table 1). The lung cancer mortality rates for females were lower than males overall and for all Divisions, but the relative ranking across Divisions was similar. The overall age-standardized mortality rate was 50.3 per 100,000 person-years (95% CI, 50.2–50.4), and rates ranged from a low of 41.7 (95% CI, 41.3–42.0) in the Mountain Division to a high of 61.6 (95% CI, 61.1–62.0) in the East South Central Division. The county-level mortality rates ranged from 38.7 or less in the lowest decile to 72.6 or more in the highest decile (Fig. 2A). Counties with elevated rates stretched from West Virginia through Kentucky and across to northeastern Texas but not across the Deep South. There were also several counties with high (top decile) mortality rates in the west, including in Oregon (n = 2 counties), Nevada (n = 3), and Arizona (n = 1).

Figure 2.

Geographic patterns in the conterminous U.S. by county among females. A, lung and bronchus cancer mortality rates per 100,000 person-years during 2005–2018, ages 20+ years. B, ever smoking prevalence percents during 1997–2003, ages 18+ years. C, Lee's L analysis findings with colors indicating statistically significant counties.

Figure 2.

Geographic patterns in the conterminous U.S. by county among females. A, lung and bronchus cancer mortality rates per 100,000 person-years during 2005–2018, ages 20+ years. B, ever smoking prevalence percents during 1997–2003, ages 18+ years. C, Lee's L analysis findings with colors indicating statistically significant counties.

Close modal

Ever smoking prevalence

The national prevalence of ever smoking from 1997 to 2003 was 52.6% (95% CI, 52.0–53.2) among males, ranging from 48.4% (95% CI, 47.0–49.9) in the Pacific Division to 57.4% (95% CI, 56.0–58.8) in the East South Central Division (Table 1). The prevalence of ever smoking among males also varied across counties, from 65.3% or more in the highest decile to 50.7% or less in the lowest decile (Fig. 1B). Elevated ever smoking prevalence stretched across many areas in the Appalachian region and several areas in the North Central states. Ever smoking was lowest across the states in the middle of the country, namely parts of Texas, Oklahoma, and Kansas, and throughout most of the Southwest.

Among females, the 1997–2003 national ever smoking prevalence was 40.2% (95% CI, 39.6–40.8), ranging from 34.0% (95% CI, 32.7–35.3) in the Pacific Division to 46.6% (95% CI, 44.8–48.3) in the New England Division (Table 1). As shown in Fig. 2B, the prevalence of ever smoking ranged from 49.1% or more in the highest decile to 33.4% or less in the lowest decile. Counties in the highest decile of ever smoking prevalence were concentrated in the northeast and stretched through the Appalachian region (New England, Middle Atlantic, and parts of the East North Central Division). There were also several counties with high prevalence around the Great Lakes and in the Pacific Northwest. The lowest rates were in the Mid- and South Atlantic states and across the south-central and western areas of the U.S. (West South-Central Division and the southernmost part of the Pacific Division).

Bivariate analysis for ever smoking prevalence and lung cancer mortality

Among males, results from the Lee's L statistic of bivariate spatial association revealed that although most counties did not have significant associations, there were several counties with statistically significant high ever smoking prevalence and high mortality rates stretching across mid-Appalachia from West Virginia to Arkansas (Fig. 1C). A few counties with low ever smoking prevalence and high mortality rates were scattered throughout the southeast, with a cluster on the western border of Mississippi (n = 12 counties; P values from 0.002 to 0.03). Several counties with high ever smoking prevalence and low mortality rates were in the South Atlantic, the upper Midwest, and across the Pacific and Mountain West divisions. Counties with low ever smoking prevalence and low mortality rates appeared throughout the West and clustered in eastern coastal cities.

Among females, counties with high ever smoking prevalence and high mortality rates stretched across the mid-Appalachia region and from Wisconsin to Michigan and parts of Maine (Fig. 2C). A few counties with low ever smoking prevalence and high mortality rates were scattered throughout Kentucky, with a line of counties running down the Mississippi River (n = 25 counties; P values from 0.01 to 0.04). There were a few counties with high ever smoking prevalence and low mortality rates, including in the Middle Atlantic and the West, spread mostly throughout the Mountain Division. Counties with low ever smoking prevalence and low mortality rates were located across the southeast, with some clusters on the Mississippi and Alabama border, in Georgia, around the District of Columbia, and across the southwest.

Current smoking prevalence and lung cancer mortality

Among males, the 1997–2003 national current smoking prevalence was 25.6% (95% CI, 25.4–26.5), less than half the 52.6% prevalence of ever smoking, and ranged from 20.4% in the Pacific Division to 29.8% in the East South Central Division (Supplementary Table S1). Similar patterns were apparent for the prevalence of current smoking as for ever smoking, although not as prominent in the north central states, and they were more widely spread across the southeast (Supplementary Fig. S1B). For females, the national prevalence of current smoking was 21.3% (95% CI, 20.7–21.6), ranging from 14.6% in the Pacific Division to 25.6% in the East South Central Division. It was highest in the Appalachian region and central portions of the country (Supplementary Fig. S2B). The Lee's L analysis yielded fewer statistically significant clusters of counties with both high current smoking prevalence and high mortality rates compared with ever smoking analyses, but patterns of association were similar (Supplementary Figs. S1A and S2A, S1C and S2C).

In this analysis of U.S. cancer surveillance data, we observed that lung cancer mortality rates and smoking prevalence, both ever and current, vary substantially across the nine statistical divisions and the counties within states. Generally, patterns of cigarette smoking were positively associated with lung cancer mortality. Furthermore, we identified areas where smoking prevalence was low and lung cancer mortality rates were high, findings that reveal the potential value of further exploration of possible environmental, occupational, behavioral, and sociodemographic risk factors for lung cancer.

Findings from our lung cancer mortality analyses at the county level are consistent with results from a previous study that reported patterns on the county level for 2014 (38). For both sexes, the lowest mortality rates were in the Mountain Division and throughout the West, and the highest rates were in the East South Central Division and across the Appalachian region. There were substantial geographic variations in the trends in lung cancer mortality rates between 1980 and 2014, with declines in the northeast and west and increases in the mid-Appalachian and Midwest regions (38). These trends reflected the dramatic changes in the geographic patterns of lung cancer mortality by decade over the 1950–1994 period (7).

We also observed patterns in both ever and current cigarette smoking similar to those from other studies that have reported county-level differences and variation in smoking prevalence between sexes. Both sexes had high ever smoking prevalence across the Appalachian region, but patterns of elevation among females were more diffuse than those for males. Like previous studies, we found a higher prevalence of smoking in rural areas, including counties in and around Appalachia and the southwest. One investigation found that this rural–urban divide persisted through an additional 10 years of current smoking data beyond those included in our analysis (14). We found that the lowest ever and current smoking prevalences occurred for both sexes within the Pacific Division, but the pattern of elevated rates differed between sexes by division, which is consistent with maps for current smoking for 1992–2007 using data from another source, the Tobacco Use Supplement to the Current Population Survey (39).

Our Lee's L analysis identified counties with significantly high ever smoking prevalence and high lung cancer mortality rates primarily through Appalachia, and clusters of counties with low ever smoking and low mortality rates mostly in the west and around cities along the Atlantic coast for both males and females. These patterns were expected given the well-established link between smoking and lung cancer mortality risk. Counties with high ever smoking and low mortality rates were dispersed throughout the west for both sexes. These counties may experience an increase in lung cancer mortality rates in the future after the latency period for lung cancer following smoking has elapsed, estimated to be 20 to 30 years (2, 8, 16). Our Lee's L evaluation of ever smoking patterns also allowed for the detection of areas with high mortality in the absence of current smoking (i.e., arguably the strongest lung cancer risk factor), thus potentially revealing the role of other risk factors. For instance, counties with concordant high mortality rates and low smoking prevalence across sexes may suggest community-specific environmental exposures. We observed several counties with this pattern, which has not been previously reported. Among males, the analysis yielded several significant clusters throughout the southeast and on the western border of Mississippi. Additional groupings of counties with low smoking prevalence but high mortality rates were observed among both sexes throughout Kentucky and a prominent line of counties running down the Mississippi River south of St. Louis, Missouri, the latter of which had clearer clustering among females than males. Just south of this cluster is the lower Mississippi River region, a 100-mile industrial corridor in southeastern Louisiana colloquially referred to as “Cancer Alley” after multiple studies related the high number of petrochemical plants and other industrial sources in this region with elevated rates of lung, stomach, and kidney cancers (40). The cluster of counties we identified is north of Cancer Alley, on the border between Mississippi and Arkansas.

We postulate several potential explanations for this cluster along the Mississippi River and the difference between sexes. These differences could be driven by occupational exposures; most occupational studies of lung cancer have focused on males because females entered these occupations later than men (41–43), whereas the risks associated with common female-centric jobs or industries are less well understood. These findings may also suggest some important drivers of risk among women, such as exposure to secondhand smoke (44). Given the historical differences in smoking patterns by sex, i.e., with higher smoking prevalence among males, secondhand smoke exposure may contribute to the elevated lung cancer mortality rates among females with low levels of active smoking. Like the industrial exposures connected to Cancer Alley, the general pattern of high lung cancer rates with low smoking prevalence could reflect localized environmental hazards (45, 46). While such hazards would theoretically exist for both sexes, the lower smoking prevalence among females versus males in the region could make the risk pattern more discernable in females. The federally designated Mississippi Delta Region is a poor and largely rural region with documented elevated rates of all-cancer and lung cancer mortality (47). Several of the counties where smoking prevalence was low but mortality rates among women were high were in eastern Kentucky, an area known for intense coal production and where clusters of lung cancer cases have been previously observed (48). Like some of the spatial patterns we observed, a prior analysis identified significant clustering of lung cancer cases in eastern areas of the state with high levels of coal production as well as in western areas where coal mining was less common. These findings were robust to analyses among women only, indicating they may not just reflect risk from occupational coal exposures (48, 49). Arsenic is another candidate environmental exposure of interest, given its known association with lung cancer (16). A map of the probability that arsenic levels in private well drinking water is greater than 5ppb (1/2 the regulatory limit) across the U.S. included several of the 9 states with significant findings in our Lee's L analysis among women (50). However, the proportion of the population on domestic wells in these states ranges from about 10 to 22% (51), and arsenic levels tend to be lower in public drinking water supplies, so it seems unlikely that arsenic would exclusively drive the patterns observed in our data. Radon is also an environmental risk factor for lung cancer and naturally exhibits clear geographic patterns (52). Local policies and mitigation practices greatly influence indoor radon levels, so evaluating this exposure on an individual level will be important for future studies.

Our Lee's L analysis also identified a smaller and more geographically dispersed set of counties with high prevalence of ever smoking and low lung cancer rates. More than 80% of lung cancer deaths in the U.S. are attributed to smoking (17), but smoking is also associated with risk of several other chronic health conditions, including chronic obstructive pulmonary disease, cardiovascular disease (17), and stroke (53), all of which are leading causes of death in the U.S. Therefore, it is possible that smoking-related deaths from other health conditions might mask the association between smoking and lung cancer mortality in these counties. Socioeconomic status (SES) and related behaviors may also contribute to this pattern, as SES is inversely associated with lung cancer risk (54). Several counties where we observed this discordant pattern are in states like Colorado, where poverty rates are relatively low, compared with states where we observed many counties with both high smoking prevalence and high lung cancer mortality rates, like Kentucky, West Virginia, and Louisiana (55).

We also analyzed data for current smoking and found similarities with the ever smoking maps, including both sexes having the highest rates in the East South Central and South Atlantic Divisions and lowest rates in the west (Mountain and Pacific Divisions). Overall, the maps of current smoking during 1997–2003 resemble the mortality maps for 2005–2018 more closely than the maps of ever smoking across both sexes. This concordance between current smoking prevalence and lung cancer mortality patterns emphasizes the public health significance of smoking cessation programs that have been shown to be highly effective at reducing smoking prevalence (56–58). Further, while many modern anti-smoking policies have been enacted on the state-level, evidence from our analysis and prior studies suggest that smoking behaviors continue to differ within states on the county level. We note however, that our analyses of ever smokers captured data from both current and former smokers, increasing the statistical power of our investigation. Lung cancer mortality is lower in former smokers than current smokers, but former smokers continue to have elevated risk relative to never smokers (59, 60). The most widely used state-level anti-smoking policy is an excise tax on tobacco products, which decreases smoking initiation, particularly among vulnerable groups like young individuals and those of lower SES (61). On the other hand, evidence that taxing and other economic anti-smoking policies promote smoking cessation is lacking (62). On the neighborhood level, tobacco industry marketing is a major driver of smoking behavior (63). Individual-level factors also drive smoking behaviors, including family smoking history, social pressure, stress, and other environmental and genetic factors (61). As the prevalence of these influences varies within states and across communities, our study can offer insight into geographic regions where smoking cessation programs or policies have been implemented or have been most successful and highlight counties where further public health measures may be warranted.

The primary limitation of this study is the inability to control for confounding, particularly at the individual-level, by lung cancer risk factors such as occupational and environmental exposures, body mass index, and nonmalignant respiratory disease. However, because none of these have been identified as particularly strong risk factors for lung cancer mortality when compared with smoking, our analysis is still informative for describing spatial patterns that may direct next steps in this area of research (16, 27). Although it would have been preferable to have several decades between our smoking measures and the lung cancer rates, we used the earliest smoking data available at the level of detail necessary and the most recent subsequent mortality data. In addition, it would have been advantageous to describe patterns by race and ethnicity because there are documented variations in both smoking and lung cancer rates across racial/ethnic groups (64, 65). Socioeconomic factors are also of interest, especially in areas where lung cancer rates and smoking prevalences were discordant and environmental exposures are postulated, as previous studies have demonstrated disproportionally high percentages of low-income residents living near petrochemical plants, refineries, landfills, and factories (66–68). However, the small-area race/ethnicity-specific smoking prevalence estimates were not available, the existing mortality data were sparse at the county level except for White non-Hispanics, and the Lee's L method can accommodate only one comparison at a time. Another limitation of Lee's L is that the results should not be directly compared between sexes because the significance tests are conducted within each sex rather than between groups (and sensitive to their respective mean values; ref. 33). However, the Lee's L analysis allowed us to better describe and formally identify statistically significant spatial patterns in associations between two variables on the county level. We note that mortality data for a small proportion of counties were suppressed by NCHS and these counties were not included in the computations of the Lee's L statistic.

Our study had several strengths, including an attempt to account for the latency between smoking and lung cancer mortality by incorporating smoking data for the decade preceding the mortality data. We used the earliest smoking data available by sex at the county level, combining the estimates for 1997–1999 with those for 2000–2003 to reduce the variance of the estimates. It would be interesting to compare the mortality patterns with earlier smoking data, but they do not exist at the geographic level needed to extend our analysis farther back in time. While other studies have used the same data sources to describe trends in smoking and mortality separately, we believe this is one of the first to integrate publicly available data sources for a county-level epidemiologic analysis. As such, our study identified some geographic patterns that are not apparent in studies using national or state-level estimates. The results have several implications and can be used to generate hypotheses about determinants of lung cancer mortality and identify areas where analytic studies may clarify factors driving these patterns. These findings can also be used to identify regions where smoking cessation programs and policies could be particularly effective in reducing lung cancer mortality. Further, studies in counties where smoking prevalence was high but mortality rates are low could reveal factors that potentially mitigate or interfere with the mortality risk attributable to smoking. Trends in the rates of the three main histologic types of lung cancer (adenocarcinoma, squamous cell, and small cell carcinoma) have differed over time (69, 70) and the association with cigarette smoking is much stronger for the latter two types (17). Histology information was not available for the mortality dataset, as it is generally not recorded on death certificates. However, histologic type is collected and coded by cancer registries. In future analyses, it will be useful to explore the geographic patterns of lung cancer incidence across by histologic type to further our understanding of the roles of smoking and other exposures in their etiology.

We described geographic variation in lung cancer mortality and smoking prevalence by county and sex across the U.S., accounting for some latency between smoking and mortality. We found that most areas with high smoking prevalence had elevated mortality rates in the following decade, which is consistent with the established risk due to cigarette smoking. We also identified several counties with discordant mortality and smoking patterns that have not been previously described. Among these, a stretch of counties with elevated mortality rates but low previous smoking prevalence among females and, to a lesser extent among males, along the Mississippi River warrants future investigation of the factors driving this observation.

E. Chase reports grants from National Science Foundation and grants from NCI during the conduct of the study. No disclosures were reported by the other authors.

A.H. Shreves: Formal analysis, investigation, writing–original draft, writing–review and editing. I.D. Buller: Formal analysis, visualization, writing–original draft, writing–review and editing. E. Chase: Data curation, formal analysis, writing–review and editing. H. Creutzfeldt: Data curation, formal analysis, writing–review and editing. J.A. Fisher: Supervision, investigation, methodology, writing–original draft, writing–review and editing. B.I. Graubard: Data curation, supervision, writing–original draft, writing–review and editing. R.N. Hoover: Conceptualization, supervision, writing–review and editing. D.T. Silverman: Conceptualization, supervision, investigation, writing–review and editing. S.S. Devesa: Conceptualization, resources, supervision, investigation, writing–original draft, project administration, writing–review and editing. R.R. Jones: Conceptualization, resources, supervision, investigation, methodology, writing–original draft, project administration, writing–review and editing.

This research was supported by the Intramural Research Program of the NCI.

The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC Section 1734.

Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).

1.
Siegel
RL
,
Miller
KD
,
Fuchs
HE
,
Jemal
A
.
Cancer statistics
,
2021
.
CA Cancer J Clin
2021
;
71
:
7
33
.
2.
Islami
F
,
Goding Sauer
A
,
Miller
KD
,
Siegel
RL
,
Fedewa
SA
,
Jacobs
EJ
, et al
.
Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States
.
CA Cancer J Clin
2018
;
68
:
31
54
.
3.
Amos
A
,
Haglund
M
.
From social taboo to "torch of freedom": the marketing of cigarettes to women
.
Tob Control
2000
;
9
:
3
8
.
4.
Burns
DM
,
Lee
L
,
Shen
LZ
,
Gilpin
E
,
Tolley
HD
,
Vaughn
J
, et al
.
Cigarette smoking behavior in the United States
.
Bethesda, Maryland
:
Department of Health and Human Services, National Cancer Institute
;
1997.
Report no.: Monograph 8 Vol 2
.
5.
National Center for Health Statistics
.
Health, United States, 2009: With Special Feature on Medical Technology
.
Washington, D.C.
;
2009
.
6.
The Surgeon General's Advisory Committee on Smoking and Health
.
Smoking and Health: Report of the Advisory Committee to the Surgeon General of the Public Health Service
.
U.S. Department of Health, Education, and Welfare, Public Health Service
;
1964
.
Report no.: 1103
.
7.
Devesa
SS
,
Grauman
DJ
,
Blot
WJ
,
Fraumeni
JF
.
Cancer surveillance series: changing geographic patterns of lung cancer mortality in the United States, 1950 through 1994
.
J Natl Cancer Inst
1999
;
91
:
1040
50
.
8.
Teng
A
,
Atkinson
J
,
Disney
G
,
Wilson
N
,
Blakely
T
.
Changing smoking-mortality association over time and across social groups: national census-mortality cohort studies from 1981 to
2011
.
Sci Rep
2017
;
7
:
11465
.
9.
Jemal
A
,
Thun
MJ
,
Ries
LAG
,
Howe
HL
,
Weir
HK
,
Center
MM
, et al
.
Annual report to the nation on the status of cancer, 1975–2005, featuring trends in lung cancer, tobacco use, and tobacco control
.
J Natl Cancer Inst
2008
;
100
:
1672
94
.
10.
Wingo
PA
,
Cardinez
CJ
,
Landis
SH
,
Greenlee
RT
,
Ries
LAG
,
Anderson
RN
, et al
.
Long-term trends in cancer mortality in the United States, 1930–1998
.
2003
;
97
:
3133
275
.
11.
American Cancer Society
.
Cancer Facts & Figures 2021
.
Atlanta
:
American Cancer Society
;
2021.
12.
National Cancer Institute
.
Evaluating ASSIST – A Blueprint for Understanding State-level Tobacco Control | Division of Cancer Control and Population Sciences (DCCPS)
.
Bethesda
:
National Cancer Institute
.
Report no.: 17
.
13.
Centers for Disease Control and Prevention
.
State-Specific Smoking-Attributable Mortality and Years of Potential Life Lost — United States, 2000–2004
.
Department of Health and Human Services
;
2009
.
14.
Dwyer-Lindgren
L
,
Mokdad
AH
,
Srebotnjak
T
,
Flaxman
AD
,
Hansen
GM
,
Murray
CJL
.
Cigarette smoking prevalence in US counties: 1996–2012
.
Population Health Metrics
2014
;
12
:
5
.
15.
Kirsch-Volders
M
,
Bonassi
S
,
Herceg
Z
,
Hirvonen
A
,
Möller
L
,
Phillips
DH
.
Gender-related differences in response to mutagens and carcinogens
.
Mutagenesis
2010
;
25
:
213
21
.
16.
Thun
MJ
,
Henley
SJ
,
Travis
WD
.
Chapter 28: Lung Cancer. Schottenfeld and Fraumeni Cancer Epidemiology and Prevention
. 4th ed.
New York
:
Oxford University Press
;
2018
.
17.
United States Department of Health and Human Services Office of the Surgeon General
.
The Health Consequences of Smoking - 50 Years of Progress
.
2014
.
18.
National Cancer Institute
.
NCI Cancer Atlas
2022
.
19.
Devesa
SSGD
,
Blot
WJ
,
Pennello
GA
,
Rn
H
,
Fraumeni
JE
.
Atlas of Cancer Mortality in the United States, 1950–94
.
Bethesda, MD
:
NIH Publication No. 99–4564, National Cancer Institute
;
1999
.
20.
Hoover
R
,
Mason
TJ
,
McKay
FW
,
Fraumeni
JF
Jr
.
Cancer by county: new resource for etiologic clues
.
Science
1975
;
189
:
1005
7
.
21.
Mason
TJMF
,
Hoover
R
,
Blot
WJ
,
Fraumeni
JF
Jr
.
Atlas of cancer mortality for U.S. counties: 1950–1969
.
Washington, D.C.
;
1975
.
22.
Blot
WJ
,
Morris
LE
,
Stroube
R
,
Tagnon
I
,
Fraumeni
JF
Jr
.
Lung and laryngeal cancers in relation to shipyard employment in coastal Virginia
.
J Natl Cancer Inst
1980
;
65
:
571
5
.
23.
Blot
WJ
,
Harrington
JM
,
Toledo
A
,
Hoover
R
,
Heath
CW
Jr
,
Fraumeni
JF
Jr
.
Lung cancer after employment in shipyards during World War II
.
N Engl J Med
1978
;
299
:
620
4
.
24.
Tagnon
I
,
Blot
WJ
,
Stroube
RB
,
Day
NE
,
Morris
LE
,
Peace
BB
, et al
.
Mesothelioma associated with the shipbuilding industry in coastal Virginia
.
Cancer Res
1980
;
40
:
3875
9
.
25.
Blot
WJFJJ
.
Cancers of the lung and pleura
.
In:
Schottenfeld
D FJJ
, editor.
Cancer Epidemiology and Prevention
, 2nd edition.
New York
:
Oxford University Press
;
1996
.
26.
Berrington de González
A
,
Bouville
A
,
Rajaraman
P
,
Schubauer-Berigan
M
.
Chapter 13: Ionizing Radiation. Schottenfeld and Fraumeni Cancer Epidemiology and Prevention
. 4th ed.
New York, NY
:
Oxford University Press
;
2018
.
27.
Samet
JM
,
Cohen
AJ
.
Chapter 17: Air Pollution. Schottenfeld and Fraumeni Cancer Epidemiology and Prevention
. 4th ed.
New York
:
Oxford University Press
;
2018
.
28.
Centers for Disease Control and Prevention
.
Behavioral Risk Factor Surveillance System
.
Centers for Disease Control and Prevention
.
2020
.
29.
Centers for Disease Control and Prevention
.
National Health Interview Survey.
2021
.
30.
Centers for Disease Control and Prevention
.
National Vital Statistics System Homepage
.
National Center for Health Statistics
.
2021
.
31.
National Cancer Institute
.
SEER*Stat Software
,
2021
.
Available from
: https://seer.cancer.gov/seerstat/.
32.
National Cancer Institute
.
U.S. Mortality Data
.
Surveillance, Epidemiology, and End Results Program
.
33.
Lee
S-I
.
Developing a bivariate spatial association measure: an integration of Pearson's r and Moran's I
.
J Geograph Syst
2001
;
3
:
369
85
.
34.
Yang
Y
,
Li
J
,
Zhu
G
,
Yuan
Q
.
Spatio–Temporal relationship and evolvement of socioeconomic factors and PM2.5 in China during 1998–2016
.
Int J Environ Res Public Health
2019
;
16
:
1149
.
35.
Benjamini
Y
,
Hochberg
Y
.
Controlling the false discovery rate: a practical and powerful approach to multiple testing
.
J R Stat Soc Series B Stat Methodol
1995
;
57
:
289
300
.
36.
Bivand
RS
,
Pebesma
EJ
,
Gómez-Rubio
V
.
Applied Spatial Data Analysis with R
. 2nd ed.
New York
:
Springer
;
2013
.
37.
National Cancer Institute
.
Model-based Small Area Estimates of Cancer Risk Factors and Screening Behaviors - Small Area Estimates | SRP/DCCPS/NCI/NIH
.
Small Area Estimates for Cancer-Related Measures
.
38.
Mokdad
AH
,
Dwyer-Lindgren
L
,
Fitzmaurice
C
,
Stubbs
RW
,
Bertozzi-Villa
A
,
Morozoff
C
, et al
.
Trends and patterns of disparities in cancer mortality among US counties, 1980–2014
.
JAMA
2017
;
317
:
388
.
39.
Jemal
A
,
Thun
M
,
Yu
XQ
,
Hartman
AM
,
Cokkinides
V
,
Center
MM
, et al
.
Changes in smoking prevalence among U.S. adults by state and region: estimates from the tobacco use supplement to the current population survey, 1992–2007
.
BMC Public Health
2011
;
11
:
512
.
40.
Tsai
SP
,
Cardarelli
KM
,
Wendt
JK
,
Fraser
AE
.
Mortality patterns among residents in Louisiana's industrial corridor, USA, 1970–99
.
Occup Environ Med
2004
;
61
:
295
304
.
41.
Artazcoz
L
,
Borrell
C
,
Cortès
I
,
Escribà-Agüir
V
,
Cascant
L
.
Occupational epidemiology and work related inequalities in health: a gender perspective for two complementary approaches to work and health research
.
J Epidemiol Community Health
2007
;
61
:
ii39
45
.
42.
Messing
K
,
Dumais
L
,
Romito
P
.
Prostitutes and chimney sweeps both have problems: towards full integration of both sexes in the study of occupational health
.
Soc Sci Med
1993
;
36
:
47
55
.
43.
Messing
K
,
Mager Stellman
J
.
Sex, gender, and women's occupational health: the importance of considering mechanism
.
Environ Res
2006
;
101
:
149
62
.
44.
Asomaning
K
,
Miller
DP
,
Liu
G
,
Wain
JC
,
Lynch
TJ
,
Su
L
, et al
.
Second hand smoke, age of exposure, and lung cancer risk
.
Lung Cancer
2008
;
61
:
13
20
.
45.
Bonner
MR
,
Freeman
LEB
,
Hoppin
JA
,
Koutros
S
,
Sandler
DP
,
Lynch
CF
, et al
.
Occupational exposure to pesticides and the incidence of lung cancer in the Agricultural Health Study
.
Environ Health Perspect
2017
;
125
:
544
51
.
46.
Moore
JX
,
Akinyemiju
T
,
Wang
HE
.
Pollution and regional variations of lung cancer mortality in the United States
.
Cancer Epidemiol
2017
;
49
:
118
27
.
47.
Zahnd
WE
,
Jenkins
WD
,
Mueller-Luckey
GS
.
Cancer mortality in the Mississippi Delta region: descriptive epidemiology and needed future research and interventions
.
J Health Care Poor Underserved
2017
;
28
:
315
28
.
48.
Christian
WJ
,
Huang
B
,
Rinehart
J
,
Hopenhayn
C
.
Exploring geographic variation in lung cancer incidence in kentucky using a spatial scan statistic: elevated risk in the Appalachian coal-mining region
.
Public Health Rep
2011
;
126
:
789
96
.
49.
Graber
JM
,
Stayner
LT
,
Cohen
RA
,
Conroy
LM
,
Attfield
MD
.
Respiratory disease mortality among US coal miners; results after 37 years of follow-up
.
Occup Environ Med
2014
;
71
:
30
9
.
50.
Lombard
MA
,
Bryan
MS
,
Jones
DK
,
Bulka
C
,
Bradley
PM
,
Backer
LC
, et al
.
Machine learning models of arsenic in private wells throughout the conterminous united states as a tool for exposure assessment in human health studies
.
Environ Sci Technol
2021
;
55
:
5012
23
.
51.
Johnson
TDBK
,
Lombard
MA
.
Domestic wells in the United States: Where are domestic wells located and how many people use them?
2020.
Available from
: https://ca.water.usgs.gov/projects/USGS-US-domestic-wells.html.
52.
United States Environmental Protection Agency
.
EPA map of radon zones by U.S. county
.
United States Environmental Protection Agency
;
2019
.
53.
Pan
B
,
Jin
X
,
Jun
L
,
Qiu
S
,
Zheng
Q
,
Pan
M
.
The relationship between smoking and stroke: a meta-analysis
.
Medicine
2019
;
98
:
e14872
.
54.
Sidorchuk
A
,
Agardh
EE
,
Aremu
O
,
Hallqvist
J
,
Allebeck
P
,
Moradi
T
.
Socioeconomic differences in lung cancer incidence: a systematic review and meta-analysis
.
Cancer Causes Control
2009
;
20
:
459
71
.
55.
Shrider
EA
,
Kollar
M
,
Chen
F
,
Semega
J
.
United States Census Bureau. Income and poverty in the United States: 2020
.
Washington, D.C
.;
2021
.
Report No.: P60–273.
56.
Davis
KC
,
Farrelly
MC
,
Duke
J
,
Kelly
L
,
Willett
J
.
Antismoking media campaign and smoking cessation outcomes, New York State, 2003–2009
.
Prev Chronic Dis
2012
;
9
:
E40
.
57.
Frieden
TR
,
Mostashari
F
,
Kerker
BD
,
Miller
N
,
Hajat
A
,
Frankel
M
.
Adult tobacco use levels after intensive tobacco control measures: New York City, 2002–2003
.
Am J Public Health
2005
;
95
:
1016
23
.
58.
Pierce
JP
,
Shi
Y
,
McMenamin
SB
,
Benmarhnia
T
,
Trinidad
DR
,
Strong
DR
, et al
.
Trends in lung cancer and cigarette smoking: California compared to the rest of the United States
.
2019
;
12
:
3
12
.
59.
Jha
P
,
Ramasundarahettige
C
,
Landsman
V
,
Rostron
B
,
Thun
M
,
Anderson
RN
, et al
.
21st century hazards of smoking and benefits of cessation in the United States
.
N Engl J Med
2013
;
368
:
341
50
.
60.
Tindle
HA
,
Stevenson Duncan
M
,
Greevy
RA
,
Vasan
RS
,
Kundu
S
,
Massion
PP
, et al
.
Lifetime smoking history and risk of lung cancer: results from the Framingham Heart Study
.
J Natl Cancer Inst
2018
;
110
:
1201
7
.
61.
United States Public Health Service Office of the Surgeon G, National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health
.
Smoking cessation: a report of the Surgeon General
.
Washington, DC
:
US Department of Health and Human Services
;
2020
.
62.
Bafunno
D
,
Catino
A
,
Lamorgese
V
,
Del Bene
G
,
Longo
V
,
Montrone
M
, et al
.
Impact of tobacco control interventions on smoking initiation, cessation, and prevalence: a systematic review
.
J Thorac Dis
2020
;
12
:
3844
56
.
63.
Lee
JG
,
Henriksen
L
,
Rose
SW
,
Moreland-Russell
S
,
Ribisl
KM
.
A systematic review of neighborhood disparities in point-of-sale tobacco marketing
.
Am J Public Health
2015
;
105
:
e8
18
.
64.
American Cancer Society
.
Key Statistics for Lung Cancer
.
About Lung Cancer
.
2021
.
65.
Gadgeel
SM
,
Kalemkerian
GP
.
Racial differences in lung cancer
.
Cancer Metastasis Rev
2003
;
22
:
39
46
.
66.
James
W
,
Jia
C
,
Kedia
S
.
Uneven magnitude of disparities in cancer risks from air toxics
.
Int J Environ Res Public Health
2012
;
9
:
4365
85
.
67.
Simonsen
N
,
Scribner
R
,
Su
LJ
,
Williams
D
,
Luckett
B
,
Yang
T
, et al
.
Environmental exposure to emissions from petrochemical sites and lung cancer: the Lower Mississippi Interagency Cancer Study
.
J Environ Public Health
2010
;
2010
:
759645
.
68.
Singer
M
.
Down cancer alley: the lived experience of health and environmental suffering in Louisiana's chemical corridor
.
Med Anthropol Q
2011
;
25
:
141
63
.
69.
Devesa
SS
,
Bray
F
,
Vizcaino
AP
,
Parkin
DM
.
International lung cancer trends by histologic type—male:female differences diminishing and adenocarcinoma rates rising
.
Int J Cancer
2005
;
117
:
294
9
.
70.
Lewis
DR
,
Check
DP
,
Caporaso
NE
,
Travis
WD
,
Devesa
SS
.
US lung cancer trends by histologic type
.
Cancer
2014
;
120
:
2883
92
.