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High-Ambient Air Pollution Exposure Among Never Smokers Versus Ever Smokers With Lung Cancer

Open AccessPublished:July 10, 2021DOI:https://doi.org/10.1016/j.jtho.2021.06.015

      Abstract

      Introduction

      Air pollution may play an important role in the development of lung cancer in people who have never smoked, especially among East Asian women. The aim of this study was to compare cumulative ambient air pollution exposure between ever and never smokers with lung cancer.

      Methods

      A consecutive case series of never and ever smokers with newly diagnosed lung cancer were compared regarding their sex, race, and outdoor and household air pollution exposure. Using individual residential history, cumulative exposure to outdoor particulate matter (PM2.5) in a period of 20 years was quantified with a high-spatial resolution global exposure model.

      Results

      Of the 1005 patients with lung cancer, 56% were females and 33% were never smokers. Compared with ever smokers with lung cancer, never smokers with lung cancer were significantly younger, more frequently Asian, less likely to have chronic obstructive pulmonary disease or a family history of lung cancer, and had higher exposure to outdoor PM2.5 but lower exposure to secondhand smoke. Multivariable logistic regression analysis revealed a significant association with never-smoking patients with lung cancer and being female (OR = 4.01, 95% confidence interval [CI]: 2.76–5.82, p < 0.001), being Asian (ORAsian versus non-Asian = 6.48, 95% CI: 4.42–9.50, p < 0.001), and having greater exposure to air pollution (ORln_PM2.5 = 1.79, 95% CI: 1.10–7.2.90, p = 0.019).

      Conclusions

      Compared with ever-smoking patients with lung cancer, never-smoking patients had strong associations with being female, being Asian, and having air pollution exposures. Our results suggest that incorporation of cumulative exposure to ambient air pollutants be considered when assessing lung cancer risk in combination with traditional risk factors.

      Keywords

      Introduction

      Globally, lung cancer is the leading cause of cancer mortality in both men and women.
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      The worldwide burden of lung cancer is substantial and projected to rise during the coming years, especially in East Asian countries, such as, the People’s Republic of China, Japan, South Korea, and Taiwan, because of the large population size, high incidence rates in males, and marked upward trend in incidence in females.
      • Bray F.
      • Ferlay J.
      • Soerjomataram I.
      • Siegel R.L.
      • Torre L.A.
      • Jemal A.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      ,
      • Chen W.
      • Zheng R.
      • Baade P.D.
      • et al.
      Cancer statistics in China, 2015.
      The proportion of lung cancer in people who have never smoked has been increasing steadily in these countries.
      • Yano T.
      • Miura N.
      • Takenaka T.
      • et al.
      Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival.
      In some Asian countries, the incidence of lung adenocarcinoma has also been increasing over time, despite a steady decline in male smoking since the 1990s and a constant low smoking rate among females.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      As a separate entity, lung cancer in never smokers is the seventh leading cause of cancer deaths in both sexes worldwide.
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      Traditionally, exposure to secondhand smoke (SHS), workplace carcinogens, residential radon, air pollution, diesel exhaust, cooking and heating fumes, arsenic in drinking water, or genetic susceptibility is thought to increase the risk of lung cancer in never smokers.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      ,
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      SHS is a relatively weak carcinogen and can only account for a few of lung cancers arising in never smokers.
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      ,
      • Song K.
      • Bi J.H.
      • Qiu Z.W.
      • et al.
      A quantitative method for assessing smoke associated molecular damage in lung cancers.
      In 2013, the International Agency for Research on Cancer revealed that outdoor air pollution and one of its major components, particulate matter (PM), specifically PM2.5, are important causes of lung cancer.
      ,
      • Loomis D.
      • Grosse Y.
      • Lauby-Secretan B.
      • et al.
      The carcinogenicity of outdoor air pollution.
      The most recent Global Burden of Disease report estimated that 265,000 lung cancer deaths were attributed to outdoor air pollution in 2017 (14% of all lung cancer deaths).
      GBD 2017 Risk factor collaborators
      Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017.
      Despite the importance of ambient air pollution exposure as a lung cancer risk factor, cumulative exposure to particulate matter at the individual level in relation to sex and race or ethnicity has not been studied in patients with lung cancer. The purpose of this study was to compare the air pollution exposure in never smokers with lung cancer versus ever smokers with lung cancer, adjusting for sex, race/ethnicity, and additional factors.

      Materials and Methods

      Study Design and Participants

      A sequential, representative case series of lung cancers was studied comparing outdoor air pollution exposures in never smokers with lung cancer versus ever smokers with lung cancer. We compared sex, race, and outdoor or household air pollution between lung cancer cases with no smoking exposure histories and lung cancer cases with smoking exposure histories. In an attempt to provide a representative sample, patients newly diagnosed with having lung cancer who were seen at the Thoracic Surgery Department of the Vancouver General Hospital or the BC Cancer Vancouver Cancer Center between November 15, 2017, and May 31, 2019, were prospectively invited to take part in the study. The Vancouver General Hospital Thoracic Surgery Unit is the primary regional thoracic surgery center for surgical treatment of patients with early lung cancer, whereas those with advanced inoperable lung cancer were seen at the adjacent BC Cancer Vancouver Center. The participation rate was 76%. After providing an informed consent, a lung cancer risk assessment questionnaire (Supplementary Materials) was completed, which included a detailed smoking history, family history of lung cancer, personal history of cancer, chronic obstructive pulmonary disease (COPD), occupation, symptoms, medications, and SHS exposure. Detailed residential histories from birth to cancer diagnosis for residences within Canada and previous residences outside of Canada (for foreign-born immigrants) were recorded. Street and city address or postal codes allow accurate linking of residential locations to satellite-derived PM2.5 exposure data that were available from 1996 onward.
      • Shaddick G.
      • Thomas M.L.
      • Amini H.
      • et al.
      Data integration for the assessment of population exposure to ambient air pollution for global burden of disease assessment.
      In Canada, six-digit postal codes typically represent one side of a city block in urban areas, whereas rural area postal codes are larger. Household exposures from cooking (yes or no by 20 y periods from birth) and heating with solid fuels (yes/no for each residence) were also obtained by the questionnaire (Supplementary Materials). Never smokers were defined as those who had smoked less than 100 cigarettes in their lifetime.

      Procedures

      Exposure to PM2.5 was quantified from 1996 to the date of lung cancer diagnosis by applying high-resolution (~10 × 10 km) concentration estimates of a particle matter with aerodynamic diameter less than 2.5 μm (PM2.5) from satellite observations, chemical transport models, and ground measurements to each individual’s residential history.
      • Shaddick G.
      • Thomas M.L.
      • Amini H.
      • et al.
      Data integration for the assessment of population exposure to ambient air pollution for global burden of disease assessment.
      • Brauer M.
      • Freedman G.
      • Frostad J.
      • et al.
      Ambient air pollution exposure estimation for the global burden of disease 2013.
      • Crouse D.L.
      • Peters P.A.
      • Hystad P.
      • et al.
      Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the Canadian Census Health and Environment Cohort (CanCHEC).
      • van Donkelaar A.
      • Martin R.V.
      • Brauer M.
      • Boys B.L.
      Use of satellite observations for long-term exposure assessment of global concentrations of fine particulate matter.
      Using the addresses, a coordinate value was obtained from Google Maps (www.maps.google.ca) for each place of residence. The coordinates were used for mapping of the mean ambient concentrations of PM2.5. Cumulative exposure was estimated by taking into account the intensity and duration of exposure and summing over all residences each participant resided at. No extrapolation was made between birth and 1996 as accurate exposure data were not available.
      SHS exposure was estimated with a score (SHS score) that was composed by adding together SHS exposure in four levels (0 = minimal or zero, 1 = mild, 2 = moderate, 3 = heavy) in five locations or circumstances ([1] exposure <18 years of age, [2] adult exposure at home, [3] adult exposure at work, [4] adult exposure in private functions, and [5] adult exposure in public places).
      • Tammemagi C.M.
      • Davis R.M.
      • Benninger M.S.
      • Holm A.L.
      • Krajenta R.
      Secondhand smoke as a potential cause of chronic rhinosinusitis: a case-control study.
      The SHS score ranged in value from 0 to 15.
      Race or ethnicity was self-reported and was placed into the following three categories: White or Caucasian; East Asian, including Chinese, Taiwanese, Filipino, and Japanese; and Other, including South Asian, Aboriginal, African, Caribbean, Arab, Hispanic, Jewish, Middle Easterner, and others.
      Ventilation with indoor cooking was scored by adding together one point for each of the following: open window, chimney, exhaust fan, or partial opening to outside.

      Statistical Methods

      Descriptive statistics were prepared using contingency table analyses for categorical data and Fisher’s exact test. The 95% confidence intervals (CIs) for proportions were estimated using the binomial exact method. Comparisons of skewed continuous data used nonparametric test of trend
      • Cuzick J.
      A Wilcoxon-type test for trend.
      and for approximately normally distributed continuous data used Student’s t test not assuming equivalence of variance. Air pollution data were skewed and were natural log transformed before entry into the models.
      Some variables had missing data (SHS = 22.7%, Canadian or foreign born 6.0%, and air pollution exposure 4.9%). Missing values were handled with multiple imputations using 20 data sets, and the rule of Rubin was used to produce model coefficient estimates.
      • Rubin D.B.
      • Schenker N.
      Multiple imputation in health-care databases: an overview and some applications.
      Multivariable logistic regression models were prepared with lung cancer in never smokers versus lung cancer in ever smokers as the outcome. A potential confounder was considered for inclusion in the model when it led to a change in effect estimate between study outcome and air pollution of greater than 15% compared with the model excluding the covariate.
      • Greenland S.
      • Morgenstern H.
      Confounding in health research.
      The existence of nonlinear associations between continuous variables and the study outcome was evaluated using locally weighted scatterplot smoothing plots and multivariable fractional polynomial analysis.
      • Royston P.
      • Sauerbrei W.
      Multivariable Model-Building: a Pragmatic Approach to Regression Analysis Based on Fractional Polynomials for Modelling Continuous Variables.
      Interactions between important predictors in final models were evaluated by including interaction terms along with main effect terms.
      Stata MP16.1 (StataCorp, College Station, TX) software was used to prepare statistics and figures. Interpretations of estimates were based on Cis,
      • Rubin D.B.
      • Schenker N.
      Multiple imputation in health-care databases: an overview and some applications.
      and hypothesis testing applied a two-sided p value less than 0.05.
      This study was approved by the UBC_BC Cancer Research Ethics Board.

      Results

      A total of 1005 patients with newly diagnosed lung cancer were interviewed. Of these, 670 (67%) were ever smokers and 335 (33%) were never smokers (Table 1 and Supplementary Table 1). Compared with ever smokers, the never smokers with lung cancer were significantly younger (66.5 ± 10.2 y versus 69.2 ± 8.3 y, p = 0.0001), more often female (70.5% versus 48.2%, p < 0.001), of Asian race (67.8% versus 16.7%, p < 0.001), and with more than high-school education level (61.8% versus 50.3%, p = 0.001) (Supplementary Table 1). A total of 80% of the never smokers with lung cancer were foreign-born Canadians who had lived outside of Canada longer than ever smokers with lung cancer who were foreign born (37.7 ± 14.1 y versus 29.9 ± 15.7 y, p < 0.001). The average pack-years smoked in ever smokers was 33.0 (interquartile range = 12.5–48.0). In addition, the never smokers were less likely to have COPD (4.5% versus 35.5%, p < 0.001) or a family history of lung cancer (19.4% versus 26.6%, p = 0.01) compared with ever smokers. SHS exposure, as measured by the SHS score, was significantly lower in the never smokers (3.9 ± 3.4 versus 8.3 ± 3.8, p < 0.001). Outdoor air pollution exposure, specifically PM2.5 levels, were significantly higher in the never smokers compared with the ever smokers (p < 0.001). In relation to household exposure to potential air pollutants, the proportion of never smokers using biomass fuel cooking was slightly higher (14.9% versus 11.6%, p = 0.160) but the proportion of never smokers using a rangehood with cooking was higher (86.9% versus 81.5%, p = 0.097). A smaller proportion of never smokers heated their homes with biomass than ever smokers (17.9% versus 41.8%, p < 0.001). Lung cancers in female never smokers are more likely to be adenocarcinoma compared with ever smokers (92.8% versus 85.1%, p = 0.010) and were more likely to be stage III or IV lung cancer (Table 1).
      Table 1Sociodemographic, Medical, and Exposure Characteristics of the Study Participants, Stratified by Sex and Smoking Status
      Sex and Smoking StatusFemaleFemalep ValueMaleMalep ValueTotal (N = 1005)
      Never Smoker (n = 236)Ever Smoker (n = 323)Never Smoker (n = 99)Ever Smoker (n = 347)
      Sociodemographic
       Age66.1 (SD 10.4)69.0 (SD 7.72)pttest = 0.000467.6 (SD 9.7)69.3 (SD 8.8)pttest = 0.11768.3 (SD 9.1)
       Race,
      Asian includes East Asian, South Asian, Southeast Asian, and West Asian. Caucasian includes Caucasian and White. Other includes Aboriginal, African Caribbean, Arab, Filipino, Hispanic, Jewish, Middle Easterner, North African, and others.
      n (%)
      White4 (18.6)276 (85.5)pFET <0.00132 (32.3)225 (64.8)pFET <0.001577 (57.4)
      Asian168 (71.2)24 (7.4)59 (59.6)88 (25.4)339 (33.7)
      Other24 (10.2)23 (7.1)8 (8.1)34 (9.8)89 (8.9)
       Education, n (%)
      High school or less98 (41.5)162 (50.1)pFET = 0.04830 (30.3)171 (49.3)pFET = 0.001461 (45.9)
      Post high school138 (58.5)161 (49.9)69 (69.7)176 (50.7)544 (54.1)
       Place of birth, n (%)
      Foreign190 (83.3)72 (23.6)pFET <0.00169 (73.4)161 (50.6)pFET <0.001492 (52.1)
      Canada38 (16.7)233 (76.4)25 (26.6)157 (49.4)453 (47.9)
       Mean years lived in foreign country if not born in Canada37.3 (SD 13.7) (n = 183)25.5 (SD 15.4) (n = 66)pttest <0.000138.8 (SD 15.2) (n = 67)31.9 (SD 15.5) (n = 152)pttest = 0.00334.1 (SD 15.3) (n = 468)
      Medical
       COPD, n (%)
      No224 (94.9)192 (59.4)pFET <0.00196 (97.0)240 (69.2)pFET <0.001752 (74.8)
      Yes12 (5.1)131 (40.6)3 (3.0)107 (30.8)253 (25.2)
       Family history of lung cancer, n (%)
      No184 (78.0)222 (68.7)pFET = 0.01686 (86.9)270 (77.8)pFET = 0.048762 (75.8)
      Yes52 (22.0)101 (31.3)13 (13.1)77 (22.2)243 (24.2)
      Exposures
       Smoking status, n (%)
      Never236 (100)99 (100)335 (33.3)
      Current265 (82.0)276 (79.5)541 (53.8)
      Former58 (18.0)71 (20.5)129 (12.8)
       Pack-years smoked31.1 (SD 23.2) n = 32334.8 (SD 26.6) n = 34733.0 (SD 25.1) N = 670
       Secondhand smoke
      SHS score is a summary score adding together self-reported exposure at four levels (0 = none or minimal, 1 = light, 2 = moderate, or 3 = heavy) in five sites (youth <20 y, home, work, public, and social functions).
      3.9 (SD 3.5) n = 18387 (SD 3.7) n = 266pttest <0.00013.9 (SD 3.1) n = 757.8 (SD 3.9) n = 253pttest <0.0016.8 (SD 4.2) N = 777
       Outdoor air pollution,
      Outdoor air pollution estimates were obtained from satellite geolocation estimates made for each residential address obtained dating back to 1996 (20 y).
      PM2.5 in 20 y
      Range4.5–65.84.2–85.5pnptrend <0.0014.5–43.54.3–155.9pnptrend <0.0014.21–155.9
      25th, 50th, 75th percentiles6.9, 7.1, 7.46.4, 6.9, 7.16.9, 7.1, 7.36.6, 6.9, 7.26.7, 7.0, 7.2
      Numbern = 321n = 635N = 956
       Cooking with biomass, n (%)
      No192 (81.4)279 (86.4)pFET = 0.12693 (90.2)313 (90.2)pFET = 0.320877 (87.3)
      Yes44 (18.6)44 (13.6)6 (6.1)34 (9.8)128 (12.7)
       Residence heating with biomass, n (%)
      No195 (82.6)164 (50.8)pFET <0.00180 (80.8)226 (65.1)pFET = 0.003665 (66.2)
      Yes41 (17.4)159 (40.2)19 (19.2)121 (34.9)340 (33.8)
       Using a rangehood with cooking, n (%)
      No19 (10.7)47 (18.5)pFET = 0.03010 (23.3)34 (18.6)pFET = 0.522110 (16.7)
      Yes159 (89.3)207 (81.5)33 (76.7)149 (81.4)548 (83.3)
       Ventilation with indoor cooking,
      The inside cooking ventilation score was obtained by adding one for each of the following conditions when they usually applied during inside cooking: open window, chimney, exhaust fan, or partial opening to outside.
      n (%)
      197 (46.6)121 (43.1)pFET = 0.46342 (46.1)112 (38.9)pFET = 0.423372 (42.9)
      2103 (49.5)141 (50.2)42 (46.1)152 (52.8)438 (50.5)
      37 (3.4)14 (5.0)7 (7.7)19 (6.6)47 (5.4)
      41 (0.5)5 (1.8)0 (0.0)5 (1.7)11 (1.3)
       Cumulative months with truck traffic passing regularly nearby residence, n (%)
      099 (41.9)149 (46.1)pFET = 0.08945 (45.5)177 (51.0)pFET = 0.040470 (46.8)
      1–31261 (25.9)97 (30.0)20 (20.2)94 (27.1)272 (27.1)
      >312 (max 960)76 (32.2)77 (23.8)34 (30.9)76 (21.9)263 (26.2)
       Ever lived where primary water source was a well, n (%)
      No215 (91.1)260 (80.5)pFET <0.00189 (89.9)292 (84.1)pFET = 0.196856 (85.2)
      Yes21 (8.9)63 (19.5)10 (10.1)55 (15.9)149 (14.8)
      Tumor characteristics
       Stage, n (%)
      I64 (27.1)109 (33.7)pFET <0.00115 (15.1)95 (27.4)pFET <0.016283 (28.2)
      II19 (8.1)43 (13.3)14 (14.1)46 (13.3)122 (12.1)
      III35 (14.8)70 (21.7)20 (20.2)88 (25.4)213 (21.2)
      IV97 (41.1)66 (20.4)36 (36.4)70 (28.2)269 (268)
      Limited SCLC0 (0.0)1 (0.3)0 (0.0)1 (0.3)2 (0.2)
      Extensive SCLC0 (0.0)1 (0.3)0 (0.0)1 (0.3)2 (0.2)
      Unknown21 (8.9)33 (10.2)14 (14.1)46 (13.3)114 (11.3)
       Cell Type, n (%)
      Adenocarcinoma219 (92.8)275 (85.1)pFET = 0.0105 (85.9)284 (81.8)pFET = 0.415863 (85.9)
      Squamous cell1 (0.4)9 (2.8)3 (3.%)24 (6.9)37 (3.7)
      Other16 (6.8)39 (12.1)11 (11.1)39 (11.2)105 (10.5)
      COPD, chronic obstructive pulmonary disease; pFET, probability by Fisher’s exact test; PM, particulate matter; pnptrend, probability by nonparametric test of trend; pttest, probability by Student’s t test with no assumption of equal variances; SHS, secondhand smoke.
      a Asian includes East Asian, South Asian, Southeast Asian, and West Asian. Caucasian includes Caucasian and White. Other includes Aboriginal, African Caribbean, Arab, Filipino, Hispanic, Jewish, Middle Easterner, North African, and others.
      b SHS score is a summary score adding together self-reported exposure at four levels (0 = none or minimal, 1 = light, 2 = moderate, or 3 = heavy) in five sites (youth <20 y, home, work, public, and social functions).
      c Outdoor air pollution estimates were obtained from satellite geolocation estimates made for each residential address obtained dating back to 1996 (20 y).
      d The inside cooking ventilation score was obtained by adding one for each of the following conditions when they usually applied during inside cooking: open window, chimney, exhaust fan, or partial opening to outside.
      Multivariable logistic regression analysis revealed a significant association with never-smoker lung cancer and being female (OR = 4.01, 95% CI: 2.76–5.82, p < 0.001), Asian (ORAsian versus non-Asian = 6.48, 95% CI: 4.42–9.50, p < 0.001), and greater exposure to air pollution (ORln_PM2.5 = 1.79, 95% CI: 1.10–7.2.90, p = 0.019) (Table 2). The relationship between sex, Asian status, and air pollution and probability of being a never-smoker patient with lung cancer is depicted in Figure 1. In addition, lower education level, history of COPD, and greater SHS exposure were significantly associated with lung cancer in ever smokers versus lung cancer in never smokers (Table 2).
      Table 2Multivariable Logistic Regression Model ORs (95% CI, p Value) for Predictors of Never-Smoker Lung Cancer Versus Ever-Smoker Lung Cancer, N = 1005
      PredictorsORs (95% CI, p Value)
      Sex (female vs. male)4.01 (2.76–5.82, <0.001)
      Asian vs. other race/ethnic group
      Asian included individuals reporting to be East Asian, Filipino, or Southeast Asian and Other included individuals reporting to be Aboriginal, African Caribbean, Arab, White/Caucasian, Hispanic, Jewish, African, Middle Easterner, South Asian, or Western Asian.
      6.48 (4.42–9.50, <0.001)
      Education, greater than high school1.73 (1.21–2.49, 0.003)
      COPD0.19 (0.10–0.34, <0.001)
      Air pollution
      Outdoor air pollution estimates were obtained from satellite geolocation estimates made for each residential address obtained dating back to 1996.
      (LN transformed)
      1.79 (1.10–7.2.90, 0.019)
      SHS
      SHS exposure was estimated with a score (SHS score) that was composed by adding together SHS exposure in four levels (0 = minimal or zero, 1 = mild, 2 = moderate, 3 = heavy) in five locations or circumstances ([1] exposure <18 y of age, [2] adult exposure at home, [3] adult exposure at work, [4] adult exposure in private functions, and [5] adult exposure in public places). The SHS score ranged in value from 0 to 15.14
      (per 1 of 16 possible levels)
      0.83 (0.79–0.88, <0.001)
      CI, confidence interval; COPD, chronic obstructive pulmonary disease; LN, lymph node; SHS, secondhand smoke.
      a Asian included individuals reporting to be East Asian, Filipino, or Southeast Asian and Other included individuals reporting to be Aboriginal, African Caribbean, Arab, White/Caucasian, Hispanic, Jewish, African, Middle Easterner, South Asian, or Western Asian.
      b Outdoor air pollution estimates were obtained from satellite geolocation estimates made for each residential address obtained dating back to 1996.
      c SHS exposure was estimated with a score (SHS score) that was composed by adding together SHS exposure in four levels (0 = minimal or zero, 1 = mild, 2 = moderate, 3 = heavy) in five locations or circumstances ([1] exposure <18 y of age, [2] adult exposure at home, [3] adult exposure at work, [4] adult exposure in private functions, and [5] adult exposure in public places). The SHS score ranged in value from 0 to 15.
      • Tammemagi C.M.
      • Davis R.M.
      • Benninger M.S.
      • Holm A.L.
      • Krajenta R.
      Secondhand smoke as a potential cause of chronic rhinosinusitis: a case-control study.
      Figure thumbnail gr1
      Figure 1Probability of lung cancer being in persons who never smoked versus ever smoked by levels of PM2.5 exposure, stratified by sex and Asian status. Other predictors are kept constant: Individuals have greater than high-school education, have no COPD, and have a secondhand smoking score of 7 (the median) of 16 possible levels. Vertical line indicates the WHO PM2.5 limit of 10 μg/m3. COPD, chronic obstructive pulmonary disease; PM, particulate matter.

      Discussion

      In this study, we took a pragmatic approach by asking the question from a clinical perspective: what factor(s) other than secondhand tobacco smoking is (are) associated with never smokers with lung cancer? We observed a significantly higher outdoor particulate matter PM2.5 exposure among never smokers compared with ever smokers with lung cancer. Compared with ever smokers with lung cancer, never smokers with lung cancer were more likely females who were significantly younger with adenocarcinoma, more frequently East Asian, better educated, less likely to have COPD or a family history of lung cancer, and had higher exposure to outdoor PM2.5 but lower exposure to SHS.
      Lung cancer in never smokers affects more women than men, irrespective of geography.
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      In East and South Asia, 60% to 90% of lung cancers in never smokers are in women.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      ,
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      In Taiwan, 55% of the lung cancers are in never smokers and 90% of the females with lung cancer are never smokers.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      The finding in our study that female sex and Asian race or ethnicity are significantly higher in never versus ever smokers with lung cancer are consistent with those in previous studies.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      ,
      GBD 2019 Risk Factors Collaborators
      Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019.
      The Global Burden of Disease 2019 study revealed that the percent of the global lung cancers attributable to each risk factor is 62.4% for smoking, 5.8% for SHS, 15.3% for PM2.5, and 4% for household air pollution from use of solid fuels for cooking.
      GBD 2019 Risk Factors Collaborators
      Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019.
      The increasing incidence of lung adenocarcinoma in never smokers over time in East Asian countries, despite a steady decline in male smokers since the 1990s and a constant low smoking rate among females, has not been adequately explained.
      • Chen W.
      • Zheng R.
      • Baade P.D.
      • et al.
      Cancer statistics in China, 2015.
      • Yano T.
      • Miura N.
      • Takenaka T.
      • et al.
      Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      Traditionally, risk factors for lung cancer in never smokers are thought to be exposure to secondhand tobacco smoke, workplace carcinogens, residential radon, air pollution, diesel exhaust, cooking and heating fumes, arsenic in drinking water, hormonal factors (in female), or genetic susceptibility.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      ,
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      ,
      GBD 2019 Risk Factors Collaborators
      Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019.
      • Couraud S.
      • Zalcman G.
      • Milleron B.
      • Morin F.
      • Souquet P.J.
      Lung cancer in never smokers--a review.
      World Health Organization
      WHO handbook on indoor radon: a public health perspective.
      • Krewski D.
      • Lubin J.H.
      • Zielinski J.M.
      • et al.
      Residential radon and risk of lung cancer: a combined analysis of 7 North American case-control studies.
      • Brunekreef B.
      • Beelen R.
      • Hoek G.
      • et al.
      Effects of long-term exposure to traffic-related air pollution on respiratory and cardiovascular mortality in the Netherlands: the NLCS-AIR study.
      • Silverman D.T.
      • Samanic C.M.
      • Lubin J.H.
      • et al.
      The Diesel Exhaust in Miners Study: a nested case–control study of lung cancer and diesel exhaust.
      • Raaschou-Nielsen O.
      • Andersen Z.J.
      • Beelen R.
      • et al.
      Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE).
      • Minatel B.C.
      • Sage A.P.
      • Anderson C.
      • et al.
      Environmental arsenic exposure: from genetic susceptibility to pathogenesis.
      The driver mutation profiles and frequency of the mutations in lung adenocarcinoma are different between never and ever smokers and between East Asians and Caucasians suggesting a different cause.
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      ,
      • Mitsudomi T.
      Molecular epidemiology of lung cancer and geographic variations with special reference to EGFR mutations.
      ,
      • Chen Y.J.
      • Roumeliotis T.I.
      • Chang Y.H.
      • et al.
      Proteogenomics of non-smoking lung cancer in East Asia delineates molecular signatures of pathogenesis and progression.
      In keeping with previous observations that SHS is a relatively weak carcinogen and can only account for a few of lung cancers arising in never smokers,
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      ,
      • Song K.
      • Bi J.H.
      • Qiu Z.W.
      • et al.
      A quantitative method for assessing smoke associated molecular damage in lung cancers.
      SHS exposure was low among never smokers in our study cohort and significantly lower than in ever smokers with lung cancer. Workplace exposure to known occupational carcinogens, such as asbestos, chromium, nickel, arsenic, or polycyclic hydrocarbons, was infrequent (questionnaire data not found). Residential exposure to radon is known to be associated with lung cancer.
      World Health Organization
      WHO handbook on indoor radon: a public health perspective.
      ,
      • Krewski D.
      • Lubin J.H.
      • Zielinski J.M.
      • et al.
      Residential radon and risk of lung cancer: a combined analysis of 7 North American case-control studies.
      Radon concentrations vary substantially from individual residence to residence, even in the same general location, with the season, from day to day and even from hour to hour precluding any global estimation or modeling in the absence of direct measurements.
      World Health Organization
      WHO handbook on indoor radon: a public health perspective.
      Reliable measurements of radon concentrations over years for individuals at all residences were not available. A previous study that estimated risks of radon-induced lung cancer for different exposure profiles on the basis of the Environmental Protection Agency model for the United States did not find a sex difference in lung cancer risk; furthermore, females arrived at the half value of total excess risk 5 years after than males.
      • Chen J.
      Estimated risks of radon-induced lung cancer for different exposure profiles based on the new EPA model.
      Similar to previous reports,
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      ,
      • Sun S.
      • Schiller J.H.
      • Gazdar A.F.
      Lung cancer in never smokers - a different disease.
      ,
      • Radkiewicz C.
      • Dickman P.W.
      • Johansson A.L.V.
      • Wagenius G.
      • Edgren G.
      • Lambe M.
      Sex and survival in non-small cell lung cancer: a nationwide cohort study.
      the never smokers with lung cancer in our study were predominantly females and younger than the ever smokers with lung cancer. The never smokers with lung cancer in our study were more likely to live near truck routes where diesel fumes were concentrated, another source of outdoor air pollutant that has been associated with lung cancer.
      • Brunekreef B.
      • Beelen R.
      • Hoek G.
      • et al.
      Effects of long-term exposure to traffic-related air pollution on respiratory and cardiovascular mortality in the Netherlands: the NLCS-AIR study.
      ,
      • Raaschou-Nielsen O.
      • Andersen Z.J.
      • Beelen R.
      • et al.
      Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE).
      ,
      • Groen H.J.M.
      • Hiltermann T.J.N.
      Air pollution and adenocarcinoma in never-smokers.
      Household exposure to biomass fuel for heating and drinking of water from wells that may be contaminated with arsenic that can cause lung cancer
      GBD 2017 Risk factor collaborators
      Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017.
      ,
      • Minatel B.C.
      • Sage A.P.
      • Anderson C.
      • et al.
      Environmental arsenic exposure: from genetic susceptibility to pathogenesis.
      ,
      • Groen H.J.M.
      • Hiltermann T.J.N.
      Air pollution and adenocarcinoma in never-smokers.
      was significantly less frequent in our never smokers. A higher proportion of our never smokers used biomass fuel for cooking than the ever smokers, but this association was not significant. The use of ventilator with cooking was similar between never and ever smokers. The reason why never smokers with lung cancer are predominantly females especially in Asian countries is not clear. Hormonal factors may play a role.
      • Siegfried J.M.
      • Stabile L.P.
      Estrogenic steroid hormones in lung cancer.
      Lung cancer susceptibility gene-environment associations have been difficult to validate owing to limited number of people with accurate exposure measurements.
      • Bossé Y.
      • Amos C.I.
      A decade of GWAS results in lung cancer.
      ,
      • Chien L.H.
      • Chen C.H.
      • Chen T.Y.
      • et al.
      Predicting lung cancer occurrence in never-smoking females in Asia: TNSF-SQ, a prediction model.
      Genes involved in xenobiotic detoxification pathway that have been found to make a difference in toxicity and response to chemotherapy treatment between Asians and Caucasians may play a role.
      • Gandara D.R.
      • Kawaguchi T.
      • Crowley J.
      • et al.
      Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics.
      Most previous studies on the effect of outdoor air pollution and lung cancer in never smokers typically had shorter term measurements (2–4 y), were at the metropolitan or district level with less spatial precision compared with individual address level, or had less precise methods for measurement of air pollutants, such as using atmospheric visibility instead of direct measurement of PM2.5.
      • Tseng C.H.
      • Tsuang B.J.
      • Chiang C.J.
      • et al.
      The relationship between air pollution and lung cancer in non-smokers in Taiwan.
      ,
      • Chien L.H.
      • Chen C.H.
      • Chen T.Y.
      • et al.
      Predicting lung cancer occurrence in never-smoking females in Asia: TNSF-SQ, a prediction model.
      ,
      • Turner M.C.
      • Krewski D.
      • Pope 3rd, C.A.
      • Chen Y.
      • Gapstur S.M.
      • Thun M.J.
      Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers.
      A significant strength of this study is the comparison of never versus ever smokers with cancer of different race or ethnicity and sex using individual assessment of exposure to ambient particulate matter (PM2.5) for the past 20 years of their lives before their cancer diagnosis.
      • Shaddick G.
      • Thomas M.L.
      • Amini H.
      • et al.
      Data integration for the assessment of population exposure to ambient air pollution for global burden of disease assessment.
      • Brauer M.
      • Freedman G.
      • Frostad J.
      • et al.
      Ambient air pollution exposure estimation for the global burden of disease 2013.
      • Crouse D.L.
      • Peters P.A.
      • Hystad P.
      • et al.
      Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the Canadian Census Health and Environment Cohort (CanCHEC).
      • van Donkelaar A.
      • Martin R.V.
      • Brauer M.
      • Boys B.L.
      Use of satellite observations for long-term exposure assessment of global concentrations of fine particulate matter.
      The etiologically relevant period for PM2.5 exposure is not known. Our study is guided by what is known for tobacco smoking. The change in demographics of the Canadian population, including migration, in the past 30 years allowed us to evaluate the relationships between race, sex, smoking status, outdoor or household air pollution, and lung cancer. Our study does, however, have limitations. In contrast to a classic epidemiologic study that includes nonlung cancer cases from the start, the case series design does not allow us to calculate the true incidence or risk of disease occurrence. Such a study would require a large longitudinal cohort or cohorts of never and ever smokers in men and women starting without lung cancer, known country of birth, different race or ethnicity, long-term residential history to derive the cumulative PM2.5 exposure, other outdoor exposures, indoor exposures, occupational exposures, etc. Longitudinal studies of this kind with detailed information on known lung cancer risk factors are limited.
      • Thun M.J.
      • Hannan L.M.
      • Adams-Campbell L.L.
      • et al.
      Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
      ,
      • Bowe B.
      • Xie Y.
      • Yan Y.
      • Al-Aly Z.
      Burden of cause-specific mortality associated with PM2.5 air pollution in the United States.
      They generally lack detailed information on smoking, and none that that we are aware of have residential history from birth or can account for a contrast in historical exposure (e.g., owing to moving from Asia to Canada). The difference in the median PM2.5 exposure between the never and ever smokers with lung cancer may seem to be small (7.0 μg/m3 versus 6.9 μg/m3, respectively). Nevertheless, the interquartile ranges of 6.9 to 7.4 versus 6.5 to 7.1, respectively, indicate a more sizable difference along the continuum of values. A study in Australia revealed that the percent increase in respiratory mortality increases exponentially above an annual average PM2.5 exposure of 4.5 μg/m3.
      • Yu W.
      • Guo Y.
      • Shi L.
      • Li S.
      The association between long-term exposure to low-level PM2.5 and mortality in the state of Queensland, Australia: a modelling study with the difference-in-differences approach.
      The study by Bowie et al.
      • Bowe B.
      • Xie Y.
      • Yan Y.
      • Al-Aly Z.
      Burden of cause-specific mortality associated with PM2.5 air pollution in the United States.
      in the United States also revealed an association between the age-standardized lung cancer death rates with PM2.5 exposure even within the standard of the Environmental Protection Agency.
      With a growing, aging, and urbanizing world population, it will become increasingly more important to evaluate air pollution as a determinant for lung cancer development in people who have never smoked, especially in the context of declines in some traditional risk factors, such as exposure to secondhand tobacco smoke, workplace carcinogens, cooking fumes, and biomass fuel, which may change over time with socioeconomic development, implementation of stricter tobacco smoking control, and workplace safety measures.
      The findings in our study of the significantly higher cumulative exposure to PM2.5 at the individual level in never- versus ever-smoking patients with lung cancer may have important implications for clinical and public health practice.
      In conclusion, although data from non-lung cancer cases are lacking, never-smoking patients with lung cancer had strong associations with being female, being Asian, and having ambient air pollution exposures, as compared with ever-smoking patients with lung cancer. Incorporation of cumulative exposure to ambient air pollutants in combination with sex and race/ethnicity and accurate quantification of traditional risk factors, such as smoking, should be considered when evaluating risk for developing lung cancer.

      CRediT Authorship Contribution Statement

      Renelle Myers: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Writing—original draft, Writing—review and editing.
      Michael Brauer: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing.
      Trevor Dummer: Conceptualization, Methodology, Writing—original draft, Writing—review and editing.
      Sukhinder Atkar-Khattra: Data curation, Formal analysis, Project administration, Writing—review.
      John Yee: Data curation, Funding acquisition, Investigation, Project administration, Writing—review.
      Barbara Melosky, Anna L. McGuire, Sophie Sun, Kyle Grant, Alexander Lee: Investigation, Writing—reviewing.
      Cheryl Ho: Data curation, Investigation, Writing—reviewing and editing.
      Martha Lee, Weiran Yuchi: Data curation, Methodology, Reviewing.
      Martin Tammemagi: Conceptualization, Data curation, Formal analysis, Methodology, Funding acquisition, Writing—original draft, Writing—review and editing.
      Stephen Lam: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Funding acquisition, Writing—original draft, Writing—review and editing.

      Acknowledgments

      This study acknowledges the following support sources: The Terry Fox Research Institute , British Columbia Cancer Foundation, and Vancouver General Hospital-UBC Hospital Foundation. The authors also acknowledge the assistance of Sim Ladhar and Kelly Cho in data collection.

      Supplementary Data

      References

        • Bray F.
        • Ferlay J.
        • Soerjomataram I.
        • Siegel R.L.
        • Torre L.A.
        • Jemal A.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clin. 2018; 68: 394-424
        • Chen W.
        • Zheng R.
        • Baade P.D.
        • et al.
        Cancer statistics in China, 2015.
        CA Cancer J Clin. 2016; 66: 115-132
        • Yano T.
        • Miura N.
        • Takenaka T.
        • et al.
        Never-smoking nonsmall cell lung cancer as a separate entity: clinicopathologic features and survival.
        Cancer. 2008; 113: 1012-1018
        • Tseng C.H.
        • Tsuang B.J.
        • Chiang C.J.
        • et al.
        The relationship between air pollution and lung cancer in non-smokers in Taiwan.
        J Thorac Oncol. 2019; 14: 784-792
        • Sun S.
        • Schiller J.H.
        • Gazdar A.F.
        Lung cancer in never smokers - a different disease.
        Nat Rev Cancer. 2007; 7: 778-790
        • Song K.
        • Bi J.H.
        • Qiu Z.W.
        • et al.
        A quantitative method for assessing smoke associated molecular damage in lung cancers.
        Transl Lung Cancer Res. 2018; 7: 439-449
      1. Straif K. Cohen A. Samet J. Air pollution and cancer. IARC Press, Lyon, France2013
        • Loomis D.
        • Grosse Y.
        • Lauby-Secretan B.
        • et al.
        The carcinogenicity of outdoor air pollution.
        Lancet Oncol. 2013; 14: 1262-1263
        • GBD 2017 Risk factor collaborators
        Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017: a systematic analysis for the global burden of disease study 2017.
        Lancet. 2018; 392: 1923-1994
        • Shaddick G.
        • Thomas M.L.
        • Amini H.
        • et al.
        Data integration for the assessment of population exposure to ambient air pollution for global burden of disease assessment.
        Environ Sci Technol. 2018; 52: 9069-9078
        • Brauer M.
        • Freedman G.
        • Frostad J.
        • et al.
        Ambient air pollution exposure estimation for the global burden of disease 2013.
        Environ Sci Technol. 2016; 50: 79-88
        • Crouse D.L.
        • Peters P.A.
        • Hystad P.
        • et al.
        Ambient PM2.5, O3, and NO2 exposures and associations with mortality over 16 years of follow-up in the Canadian Census Health and Environment Cohort (CanCHEC).
        Environ Health Perspect. 2015; 123: 1180-1186
        • van Donkelaar A.
        • Martin R.V.
        • Brauer M.
        • Boys B.L.
        Use of satellite observations for long-term exposure assessment of global concentrations of fine particulate matter.
        Environ Health Perspect. 2015; 123: 135-143
        • Tammemagi C.M.
        • Davis R.M.
        • Benninger M.S.
        • Holm A.L.
        • Krajenta R.
        Secondhand smoke as a potential cause of chronic rhinosinusitis: a case-control study.
        Arch Otolaryngol Head Neck Surg. 2010; 136: 327-334
        • Cuzick J.
        A Wilcoxon-type test for trend.
        Stat Med. 1985; 4: 87-90
        • Rubin D.B.
        • Schenker N.
        Multiple imputation in health-care databases: an overview and some applications.
        Stat Med. 1991; 10: 585-598
        • Greenland S.
        • Morgenstern H.
        Confounding in health research.
        Annu Rev Public Health. 2001; 22: 189-212
        • Royston P.
        • Sauerbrei W.
        Multivariable Model-Building: a Pragmatic Approach to Regression Analysis Based on Fractional Polynomials for Modelling Continuous Variables.
        John Wiley & Sons, Hoboken, NJ2008
        • GBD 2019 Risk Factors Collaborators
        Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019.
        Lancet. 2020; 396: 1223-1249
        • Couraud S.
        • Zalcman G.
        • Milleron B.
        • Morin F.
        • Souquet P.J.
        Lung cancer in never smokers--a review.
        Eur J Cancer. 2012; 48: 1299-1311
        • World Health Organization
        WHO handbook on indoor radon: a public health perspective.
        • Krewski D.
        • Lubin J.H.
        • Zielinski J.M.
        • et al.
        Residential radon and risk of lung cancer: a combined analysis of 7 North American case-control studies.
        Epidemiology. 2005; 16: 137-145
        • Brunekreef B.
        • Beelen R.
        • Hoek G.
        • et al.
        Effects of long-term exposure to traffic-related air pollution on respiratory and cardiovascular mortality in the Netherlands: the NLCS-AIR study.
        Res Rep Health Eff Inst. 2009; 139: 5-89
        • Silverman D.T.
        • Samanic C.M.
        • Lubin J.H.
        • et al.
        The Diesel Exhaust in Miners Study: a nested case–control study of lung cancer and diesel exhaust.
        J Natl Cancer Inst. 2012; 104: 855-868
        • Raaschou-Nielsen O.
        • Andersen Z.J.
        • Beelen R.
        • et al.
        Air pollution and lung cancer incidence in 17 European cohorts: prospective analyses from the European Study of Cohorts for Air Pollution Effects (ESCAPE).
        Lancet Oncol. 2013; 14: 813-822
        • Minatel B.C.
        • Sage A.P.
        • Anderson C.
        • et al.
        Environmental arsenic exposure: from genetic susceptibility to pathogenesis.
        Environ Int. 2018; 112: 183-197
        • Mitsudomi T.
        Molecular epidemiology of lung cancer and geographic variations with special reference to EGFR mutations.
        Transl Lung Cancer Res. 2014; 3: 205-211
        • Chen Y.J.
        • Roumeliotis T.I.
        • Chang Y.H.
        • et al.
        Proteogenomics of non-smoking lung cancer in East Asia delineates molecular signatures of pathogenesis and progression.
        Cell. 2020; 182: 226-244.e17
        • Chen J.
        Estimated risks of radon-induced lung cancer for different exposure profiles based on the new EPA model.
        Health Phys. 2005; 88: 323-333
        • Radkiewicz C.
        • Dickman P.W.
        • Johansson A.L.V.
        • Wagenius G.
        • Edgren G.
        • Lambe M.
        Sex and survival in non-small cell lung cancer: a nationwide cohort study.
        PLoS One. 2019; 14e0219206
        • Groen H.J.M.
        • Hiltermann T.J.N.
        Air pollution and adenocarcinoma in never-smokers.
        J Thorac Oncol. 2019; 14: 761-763
        • Siegfried J.M.
        • Stabile L.P.
        Estrogenic steroid hormones in lung cancer.
        Semin Oncol. 2014; 41: 5-16
        • Bossé Y.
        • Amos C.I.
        A decade of GWAS results in lung cancer.
        Cancer Epidemiol Biomarkers Prev. 2018; 27: 363-379
        • Chien L.H.
        • Chen C.H.
        • Chen T.Y.
        • et al.
        Predicting lung cancer occurrence in never-smoking females in Asia: TNSF-SQ, a prediction model.
        Cancer Epidemiol Biomarkers Prev. 2020; 29: 452-459
        • Gandara D.R.
        • Kawaguchi T.
        • Crowley J.
        • et al.
        Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics.
        J Clin Oncol. 2009; 27: 3540-3546
        • Turner M.C.
        • Krewski D.
        • Pope 3rd, C.A.
        • Chen Y.
        • Gapstur S.M.
        • Thun M.J.
        Long-term ambient fine particulate matter air pollution and lung cancer in a large cohort of never-smokers.
        Am J Respir Crit Care Med. 2011; 184: 1374-1381
        • Thun M.J.
        • Hannan L.M.
        • Adams-Campbell L.L.
        • et al.
        Lung cancer occurrence in never-smokers: an analysis of 13 cohorts and 22 cancer registry studies.
        PLoS Med. 2008; 5: e185
        • Bowe B.
        • Xie Y.
        • Yan Y.
        • Al-Aly Z.
        Burden of cause-specific mortality associated with PM2.5 air pollution in the United States.
        JAMA Netw Open. 2019; 2e1915834
        • Yu W.
        • Guo Y.
        • Shi L.
        • Li S.
        The association between long-term exposure to low-level PM2.5 and mortality in the state of Queensland, Australia: a modelling study with the difference-in-differences approach.
        PLoS Med. 2020; 17e1003141