Us For-Never

LUNG CANCER IN NEVER SMOKERS: CLINICAL EPIDEMIOLOGY AND ENVIRONMENTAL RISK FACTORS

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In several studies, the frequency of adenocarcinoma has surpassed that of squamous cell carcinoma. For example, a study of , Korean men in whom new lung cancer cases were indentified found that adenocarcinoma was the most frequent histological type among never smokers, former smokers, and current smokers A study in Malaysia similarly showed that squamous cell carcinoma was the most frequent histological subtype among both male and female smokers from —, but by — adenocarcinoma became the most frequent histological subtype for both sexes However, among never smokers adenocarcinoma was the most frequent histological subtype in — and — The available evidence demonstrates a bias toward adenocarcinoma among never smokers relative to smokers.

There appear to be gender differences as well, with female never smokers and smokers tending to have adenocarcinomas more commonly than parallel male cohorts. Although adenocarcinoma is the most common histologic type among male never smokers, male smokers tend to have more squamous cell carcinomas. Hypotheses concerning the shift in histopathology among smokers have focused on the potential role of the substantial changes in the characteristics of cigarettes and the associated changes in the dosages of carcinogens inhaled and the pattern of deposition in the lung Puff volume has likely increased in the past few decades with the possibility that patterns of deposition in the lung have changed, tending toward enhanced deposition of tobacco smoke in the peripheral airways and alveoli Nitrate levels in tobacco smoke have also increased, which enhances the combustion of tobacco smoke.

Although more complete combustion decreases the concentrations of polycyclic aromatic hydrocarbons, the increased production of nitrogen oxides contributes to increased formation of tobacco specific nitrosamines TSNAs. An increase in dosage of the potent TSNA 4- methylnitrosamino 3-pyridyl butanone NNAL has been postulated as one factor leading to the increase in adenocarcinomas 61 , NNAL induces lung carcinomas, predominantly adenomas and adenocarcinomas, in mice, regardless of route of administration 62 , These hypotheses about the shift in histopathology among smokers are also relevant for never smokers.

Non-smokers inhale a mixture of sidestream smoke and exhaled mainstream smoke that is generally referred to as secondhand smoke SHS. Never smokers exposed to SHS have experienced changes in the SHS mixture in the past few decades since increases in puff volume and enhancement of the combustion of tobacco smoke have increased the formation of TSNAs These diverse changes in the inhaled doses of carcinogens delivered to smokers and nonsmokers are likely to have contributed to the time trend of changing histopathology.

To date there has been limited research on differences in lung cancer histology subtypes among never smokers, pointing to a need to develop evidence in this area. In published reports from Japan 64 and Greece 65 indicated increased lung cancer risk in never smoking women married to cigarette smokers. Subsequently this association has been examined in over 50 investigations conducted in the United States and other countries. Over the past 20 years, review groups have repeatedly and consistently concluded that exposure to SHS causes lung cancer in never smokers.

A causal association of involuntary smoking with lung cancer derives biological plausibility from the presence of carcinogens in sidestream smoke and the lack of a documented threshold dose for respiratory carcinogens in active smokers 66 — Genotoxic activity had been demonstrated for many components of SHS 70 — Experimental and real-world exposures of non-smokers to SHS lead to excretion of NNAL, a tobacco-specific carcinogen, in the urine 74 , Non-smokers exposed to SHS also have increased concentrations of adducts of tobacco-related carcinogens 76 , Additionally, Mauderly and colleagues, using an animal model, found that whole-body exposure in rats to cigarette smoke increases the risk of neoplastic proliferative lung lesions and induces lung cancer In an autopsy study in Greece, Trichopoulos and colleagues 79 examined lung specimens from persons 35 years of age and older and found that airway epithelial lesions were more common in nonsmokers married to smokers than in nonsmokers married to nonsmokers.

Epidemiologists have tested the association between lung cancer and involuntary smoking using case-control and cohort designs have consistently found that SHS exposure is associated with lung cancer risk in never smokers. For decades, the tobacco industry and its consultants attributed the association to bias The potential for bias and the related methodologic issues are addressed at length in the Report of the U. Surgeon General 81 and elsewhere. Specific methodologic concerns have been misclassification of ever smokers as never smokers and inaccuracy in the classification of SHS exposure status in the different places where exposure occurs, particularly the home and workplaces.

Quantitative and qualitative assessments of these sources of misclassification have led to the conclusion that bias from misclassification does not account for the observed association 81 — Use of spouse smoking alone to represent exposure to SHS does not cover exposures outside of the home 86 or necessarily all exposure inside the home, particularly during the time period relevant to the epidemiological studies.

Klepeis and colleagues used data from the National Human Activity Pattern Survey to assess the contribution of the home and other indoor environments to SHS exposures In considering alternatives to a causal association, confounding has also been proposed as contributing to the association of SHS with lung cancer. Critics of these findings on SHS and lung cancer have argued that uncontrolled confounding by lifestyle, occupation, or other factors may explain the association 90 , In some countries, including the United States, smoking prevalence varies markedly with indicators of income and education, more recently tending to rise sharply with decreasing educational level and income 66 , In general, exposure to SHS follows a similar trend, and critics of the findings on SHS and lung cancer have argued that uncontrolled confounding by lifestyle, occupation, or other factors may explain the association.

In fact, current data for the United States do indicate a generally less healthy lifestyle in those with greater SHS exposure However, other than a few occupational exposures at high levels, as well as indoor radon, risk factors for lung cancer in never smokers that might confound the SHS association cannot be proffered and the relevance to past studies of these current associations of potential confounders with SHS exposure is uncertain. By , the evidence had mounted and three reports published in that year concluded that SHS was a cause of lung cancer.

The National Research Council 94 and the U. Surgeon General 68 also concluded that involuntary smoking increases the incidence of lung cancer in never smokers. In reaching this conclusion, the National Research Council 94 cited the biological plausibility of the association between exposure to SHS and lung cancer and the supporting epidemiological evidence. The report of the Surgeon General 68 characterized involuntary smoking as a cause of lung cancer in never smokers.

This conclusion was based on the extensive information already available on the carcinogenicity of active smoking, on the qualitative similarities between SHS and mainstream smoke, and on the epidemiological data on involuntary smoking. In the U. A meta-analysis of the 31 studies published to that time was central in the decision to classify SHS as a Group A carcinogen - namely a known human carcinogen. The meta-analysis considered the data from the epidemiologic studies by tiers of study quality and location and used an adjustment method for misclassification of smokers as never smokers.

Overall, the analysis found a significantly increased risk of lung cancer in never smoking women married to smoking men; for the studies conducted in the United States, the estimated relative risk was 1. Subsequent to the risk assessment, over 20 additional studies and several major reports have been published that further contribute to the evidence supporting a causal association between SHS and the risk of lung cancer 81 , 95 , Among the additional studies, the multicenter study of Fontham and colleagues is the largest published to date 97 , with cases and 1, controls.

Adjustment for potential bias and confounding by diet did not alter the estimate. A subsequent IARC meta-analysis 96 including 46 studies and 6, cases yielded similar results: Results of studies on exposure to secondhand smoke and risk of lung cancer among never smokers. The extent of the lung cancer hazard associated with involuntary smoking in the United States and in other countries remains subject to some uncertainty, however, although estimates have been made that are useful indications of the magnitude of the disease risk 68 , In Repace and Lowrey reviewed the risk assessments of lung cancer and exposure to SHS and estimated the numbers of lung cancer cases in U.

Similarly the estimate of the Environmental Protection Agency, based on the epidemiologic data, was about 3, cases annually Of those 3, deaths, were attributed to non-spousal exposures to SHS and 2, to spousal exposure In summary, most comprehensive analyses suggest that in the US, SHS exposure is responsible for approximately — lung cancer deaths annually.

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These calculations illustrate that exposure to SHS must be considered an important cause of lung cancer death from a public health perspective; exposure is involuntary and not subject to control. The specific risk assessments require assumptions concerning the extent and degree of exposure to SHS, exposure-response relationships, and the lifetime expression of the excess risk associated with exposure to SHS at different ages. Moreover the calculations do not consider the potential contributions of other exposures, such as occupational agents and indoor radon.

The current decline in the prevalence of active smoking and the implementation of strong clean indoor air policies will reduce the relevance of estimates based on past patterns of smoking behavior. Radon, long established as a respiratory carcinogen, is not only of concern for underground miners but for the population generally, as a ubiquitous contaminant of indoor air.

Radon is an inert gas, produced naturally from radium in the decay series of uranium. Radon decays with a half-life of 3. As the biologic basis of respiratory carcinogenesis was analyzed and the lung dosimetry of radon and its short-lived progeny was described, it was recognized that alpha-particle emissions from inhaled radon progeny, not from radon itself, cause lung cancer Two of those decay products, polonium and polonium, emit alpha particles, which are high-energy and high-mass particles consisting of two protons and two neutrons that cause DNA base mutations and chromosomal strand breaks.

The energy of these particles is invariant with concentration of radon progeny so that the potential for passage of alpha particles to damage target cells is the same at high and low concentrations. When the alpha emissions take place within the lung as inhaled and deposited radon progeny decay, the DNA of cells lining the airways is damaged and lung cancer may ultimately result. Animal studies have demonstrated that radon alone through its progeny can induce cancer in the respiratory tract Elegant experimental studies have documented the occurrence of permanent damage to a cell from just one hit by an alpha particle This experimental finding suggests that assuming a linear non-threshold relationship between exposure and risk at the levels found not only in mines but indoors is biologically appropriate, supporting concern that indoor radon represents a significant public health problem.

In this same type of experimental system, a bystander mutagenic effect has been demonstrated; a hit to a cell affects cells adjacent to the cell damaged by a single alpha particle This effect may amplify the risks of radon exposure beyond those anticipated based on the construct that passage of an alpha particle through a cell affects only that cell. Radon was the first identified environmental cause of lung cancer. As early as the s, the elevated risk of lung cancer in miners in Eastern Europe working in mines with high levels of radon had led to the hypothesis that radon was the causal agent Numerous subsequent epidemiological studies of miners showed a strong association of radon exposure with lung cancer risk These worker groups included several comprised largely of never smokers.

In fact, the original case report of respiratory malignancy in underground miners in Schneeberg was published in , long before manufactured cigarettes were available In the United States, Navajo uranium miners, almost all never smokers, experienced a clear excess of lung cancer — In a cohort study of members of this group 34 deaths from lung cancer were identified when only In a population-based case-control study of lung cancer in Navajo males from —, the majority of the cases were attributable to radon exposure in uranium mines. A cohort study of white miners who have never smoked cigarettes, pipes, or cigars from the Colorado Plateau cohort showed 14 lung cancer deaths with only 1.

The risk of lung cancer in never smoking uranium miners has been quantified in a pooled analysis of data from 11 cohort studies, all having estimates of the exposures of individual miners to radon progeny. A pooled analysis of the 2, never smoking miners in the cohorts quantified the risk per working-level month WLM as almost three times as high in never smokers as in smokers, consistent with the sub-multiplicative interaction between smoking and radon found with analysis of the full data set Beginning in the s, there was widespread recognition that radon is present in indoor environments, including homes where people spend the majority of their time At the time, given the already recognized carcinogenicity of radon, concern was raised as to the risk of indoor radon and consideration was given to the most appropriate risk management strategies.

Case-control studies of radon and lung cancer risk in the general population were carried out to quantify the risk as a basis for risk management; numerous studies, most involving measurement of radon in the current and previous residences, were initiated. These studies have now been completed, the findings of individual studies reported, and two pooled analyses completed, one of studies in North America and the other of studies in Europe. The results show a significantly increased risk that is comparable in the two analyses Table 2.

The estimated number of lung cancer cases in the United States in never smokers attributable to radon alone is approximately 2, to 2, annually Results of pooled analyses of case-control studies evaluating risks of radon for lung cancer among never smokers. In summary, radon is a well established cause of lung cancer in never smokers.

Radon progeny act through a mechanism that predicts risk at any level of exposure, regardless of smoking. Epidemiological studies of miners and of the general population provide strong evidence for a causal association and the risk has been quantified for both groups. Estimates of the burden of lung cancer attributable to radon place indoor radon among the leading causes of lung cancer in never smokers.

Products of incomplete combustion contain respirable particles and many organic compounds, including carcinogens such as benzo[a]pyrene, formaldehyde, and benzene. Occupational exposure to the combustion products of coal by inhalation is known to cause lung cancer , and many studies, mostly from China, now show similar effects from household use of coal. These studies have been recently reviewed by an IARC Working Group that concluded that there is sufficient evidence in humans for the carcinogenicity of indoor emissions from household combustion of coal This evaluation is supported by the results of studies in experimental animals and by mechanistic evidence from humans and animals.

Although the IARC evaluation was not specific to never smokers, one important feature of the studies of indoor air pollution from coal burning in China and to a less extent other countries is that they included a large number of and often were restricted to never smoking women. Results of epidemiological studies of indoor combustion of coal and lung cancer risk in never smokers are summarized in Supplemental Table 2.

Use of coal for cooking and heating was associated with increased lung cancer risk among never smokers in two of the earliest studies , A population-based case-control study found that the risk of lung cancer among women is China is strongly dependent on the type of coal used for home heating and cooking Using coal for cooking throughout life compared to using modern cooking fuels gas, electricity or kerosene increased the risk of lung cancer OR: Worldwide, biomass is much more widely used as fuel than coal but the adverse health effects have been studied less Supplemental Table 2.

In five studies, researchers investigated indoor exposure to smoke from wood, straw, and other solid fuel and lung cancer risk among never smoking women. Three studies, conducted in Japan, China, and Mexico, found an increased risk in lung cancer among never smoking women exposed to smoke produced while cooking with various biomass fuels. However, in two studies conducted in India, ever use of biomass fuels was not associated with an increased risk of lung cancer among never smoking women, nor was long-term use of solid cooking fuel in comparison to modern cooking fuel gas, electricity, or kerosene.

These studies suggest that exposure to smoke from wood combustion is associated with an increased risk of lung cancer, but the results on exposure duration and intensity are difficult to interpret. Furthermore, a study from Central and Eastern Europe provided no supporting evidence that use of solid fuels, including coal and wood, increases the risk of lung cancer among non-smokers The epidemiological evidence of an increased risk of lung cancer for exposure to biomass mainly wood combustion emissions was classified by the IARC working group as limited Stir-frying, deep-frying, and pan-frying, which involve heating oil to high temperatures, are practiced worldwide, especially in China.

The epidemiological evidence on cancer from exposure to emissions from high-temperature frying was classified as limited by the IARC Working Group Results from ten case-control studies have investigated the relationship between exposure to cooking fumes and the risk for lung cancer among never smokers Supplemental Table 3.

The majority of the studies found a positive association between lung cancer in never smoking women and various methods of cooking with oil at high temperatures. A study of Chinese women from Singapore, however, did not detect an increased risk for stir-frying In summary, an increased risk of lung cancer has been consistently shown among never smoking women exposed to indoor biomass smoke and cooking fumes.

Less consistent results were found for different types of oils used for cooking and exposure to smoke from coal and risk of lung cancer among never smokers. The effect of asbestos exposure on risk of lung cancer among never smokers has been investigated in several cohort and case-control studies Supplemental Table 4. With a few exceptions, these studies found an increased risk of lung cancer among never smokers who were occupationally exposed to asbestos relative to comparison groups of unexposed never smokers.

The relative risks for exposure to asbestos varied between the studies, likely reflecting both the heterogeneity of exposure circumstances level of exposure, type of fibers and differences in the definition of asbestos exposure and never smokers. The relative risks of lung cancer for asbestos exposure tended to be higher in never smokers than in smokers relative asbestos effect [RAE] ranging from 1. Although the precise nature of the interaction between asbestos and tobacco smoking in lung carcinogenesis remains subject to debate 96 , the evidence of a carcinogenic effect of asbestos independent from smoking is very strong.

In a case-control study nested in a cohort of copper smelter workers from Sweden, Pershagen and colleagues reported an OR of 2. An expanded analysis of this population confirmed the increased risk of lung cancer OR 1. Similar results were reported in a study of Chinese tin mines Additional cohort studies from United States and Japan also reported an increased risk of lung cancer among never and non- smoking , miners or smelters, with risk estimates ranging from 2.

Occupational exposure to arsenic was self-reported in a community-based case-control study from Missouri OR 1. In a study from Sweden, residence near a non-ferrous smelter emitting arsenic together with other metals was not associated with increased risk of lung cancer Several industry-based studies of workers exposed to silica and of silicotic patients reported an increased risk of lung cancer among never smokers Supplemental Table 6. In a multicenter case-control study from 7 European countries, in which exposure to 70 agents was assessed by industrial hygienists on the basis of detailed occupational questionnaires, the RR for ever exposure to silica was 1.

Two additional studies reported an increased risk of lung cancer among never and non-smoking workers exposed to silica , At least ten studies analyzed lung cancer risk among never smoking silicosis patients, defined either on the basis of compensation or medical including necropsy records. All but three showed an increased RR, in the range 1. Although a formal meta-analysis is made difficult by the lack of confidence interval of several of the risk estimates, the overall evidence points towards an increased risk of cancer among persons with silicosis in the absence of tobacco smoking.

In the case-control study of lifetime non-smoking women from Missouri, an increased risk of lung cancer was detected for exposure to pesticides OR 3. In the multicentric European study , results were reported for 11 agents, in addition to silica: For these two agents, a duration-response relationship was suggested. Three European case-control studies reported results according to employment in job and industries entailing exposure to known list A or suspected list B occupational lung carcinogens, based on a simplified job exposure matrix developed by Ahrens and Merletti Supplemental Table 7.

In a pooled analysis of 12 European case-control studies of never smoking women, the OR for employment and jobs entailing exposure to suspected carcinogens was 1. In a few studies, risk estimates of lung cancer among never smokers were reported according to employment in specific occupational or industry categories Supplemental Table 8. A systematic analysis of jobs and industries of employment and lung cancer risk among non-smoking US Veterans revealed an increased risk for employment as a baker, agent, farm and home management advisor, therapist or healer, building manager, bookbinder, decorator or window dresser, and painter.

The large number of job and industries included in this analysis, however, has likely generated false positive results. In summary, an increased risk of lung cancer has been consistently shown among workers exposed to asbestos, arsenic and silica. Results on exposure to other known or suspected occupational lung carcinogens among never smokers are sparse. In general, the findings on occupational risk factors in never smokers parallel those in smokers, although the measure of the magnitude of the smoking interaction is complicated by the small number of cases of lung cancer among never smokers included in most studies.

An increased risk of lung cancer has been reported in populations exposed to high levels of outdoor air pollution. This association, however, might result from confounding by other factors, notably tobacco smoking, rather than from air pollution. Cohort and case-control studies are limited by difficulties in assessing past exposure to the relevant air pollutants. In several studies, exposure to air pollution has been assessed either on the basis of proxy indicators, such as the number of inhabitants in the community, or residence near a major pollution source: In a small number of studies, exposure to outdoor air pollution has been assessed on the basis of data on pollutant level matched to the residence of the study subjects.

Two of these studies have reported results for never smokers Supplemental Table 9: In a third study, which included an equal number of never smokers and long-term quitters, no association was found between exposure to PM 10 and lung cancer risk On the one hand, results on lung cancer risk from outdoor air pollution exposure among never smokers can be biased by residual confounding from occupational exposure to lung carcinogens and other social class-related factors. On the other hand, retrospective exposure to outdoor air pollution may be particularly vulnerable to misclassification, which in prospective studies would likely result in underestimation of the effect.

While an increased risk of lung cancer among never smokers exposed to high levels of outdoor air pollution is plausible, the available evidence does not allow an accurate estimate of risk. Dietary factors have been noted to be leading preventable causes of cancer The second expert report from the World Cancer Research Fund and the American Institute for Cancer Research comprehensively reviewed the evidence for the association between diet and cancer for both smokers and non-smokers.

For lung cancer, the expert panel concluded that fruits and foods containing carotenoids likely protect against lung cancer Similarly, for consumption of foods containing selenium, selenium supplements, and foods containing quercetin, they also concluded that the limited evidence was suggestive of protection against lung cancer.

The potential protective effect of selenium is the basis of an ongoing randomized clinical study of selenium supplementation vs. The panel concluded that there is convincing evidence that arsenic in drinking water is a cause of lung cancer, and that there is limited, inconsistent evidence suggesting that high-dose retinol supplements in smokers , consumption of red meat, processed meats, total fat, and butter are causes of lung cancer In 14 studies, researchers investigated fruit consumption and lung cancer among never smokers.

Among these studies, three were cohort studies — including one multicenter study involving follow-up of 16 cohorts from seven countries over 25 years and one multicenter case-control study with participants from six European countries None of the cohort studies found a significant association between total fruit consumption and lung cancer risk. Of 11 case-control studies — , three found that never smokers who consumed the highest amount of fruit were less likely to have lung cancer when compared to those who consumed the lowest amount , , Dose-response relationships were identified in two case-control studies.

A multi-center case-control study, the study with the largest number of cases found in this literature review, did not find a relationship between total fruit consumption and lung cancer risk Two cohort studies , and eight case-control studies , , , , — investigated consumption of total vegetables and lung cancer among never smokers. The Japan Public Health cohort study followed 56, participants for seven to ten years; a total of cases of lung cancer developed among never smokers.

Of the eight case-control studies that examined total consumption of vegetables, most found a decreased risk for lung cancer among those in the highest category of consumption Supplemental Table Most of the studies that considered total vegetable consumption also investigated specific vegetables. Additionally, four studies one cohort and three case-control studies were found on the association between specific grouping of vegetables and lung cancer.

Results of the few studies in each category are presented in Supplemental Table One cohort study and five case-control studies investigated meat consumption and risk of lung cancer among never smokers, mostly women. SHS exposure was not a confounder in this study High fish consumption was found to decrease the risk of lung cancer among never smokers in China. The majority of studies looking at other aspects of diet, including fat consumption, food preparation, and dairy, egg, and soy product consumption Supplemental Table 10 , found no significant association with lung cancer in never smokers.

One nested case-control study and eight case-control studies investigated dietary carotenoid consumption. A case-control study conducted in Stockholm reported a protective effect and a dose-response with increasing intake of total carotenoids, with adjustment for SHS exposure A few studies also investigated other micronutrients Supplemental Table In a case-control study from Chile, the risk ratios of lung cancer were 5.

In a similar study from Taiwan, risk ratios were 1. The relevance of these data to never smokers specifically has not been addressed. There is relatively little research in the area of hormone replacement therapy HRT and lung cancer risk, although some studies indicate a reduction of lung cancer risk associated with HRT use Supplemental Table However, although this inverse association has been present in case-control studies that have adjusted for smoking, stratification by smoking status reveals this inverse association exists for current smokers only , For example, one study that examined risk among smokers and never smokers who had taken HRT showed that only the current smokers had a significant decrease in lung cancer risk When examining lung cancer risk and hormone replacement therapy among never smokers, there does not appear to be a statistically significant association , although very few studies have been conducted that stratified by smoking status.

Furthermore, the studies that have examined never smokers include a very small number of patients, so that their results are imprecise. In conclusion, although several studies have demonstrated an inverse association between HRT use and lung cancer risk, it is unclear whether such an association is present among never smokers. Several studies have examined whether chronic infections can increase lung cancer risk. Human papillomavirus HPV infection has been observed in association with lung cancer cases in many studies, particularly in China Supplemental Table HPV 6, which was examined in only one of these studies, appeared to be associated with smoking status, with male smokers having higher odds of having HPV 6 than male never smokers OR 7.

Although these studies suggest an association of HPV infection with lung cancer risk, it is still unclear if HPV infection is associated with lung cancer risk among never smokers. These studies were limited to China and it is unknown if similar associations are present in other countries.

Human immunodeficiency virus HIV has been studied in association with lung cancer risk, although this has not been a large area of study. Results from a retrospective cohort study conducted at a HIV specialty clinic showed that people infected with HIV had approximately a 2-fold significant increase in lung cancer risk, after adjustment for smoking status Although it has been shown that people infected with HIV have an increased lung cancer risk, this has not been stratified by smoking status, so it is unclear of whether the risk is the same or different among never smokers.

Chlamydia pneumonia has also been investigated in relation to lung cancer risk under the hypothesis that chronic infections may increase risk , It has been reported that former smokers that are infected have a larger risk of lung cancer than current smokers, but there were no never smokers included in this study History of lung disease has been examined in association with lung cancer risk, including tuberculosis, asthma, emphysema, and chronic obstructive pulmonary disease COPD.

Interestingly, one study that examined lung cancer risk among smokers and never smokers with tuberculosis found that female never smokers with tuberculosis had approximately an 8-fold increase in lung cancer risk, while there was no association among female smokers This study is limited by the small number of never smoking lung cancer patients.

Asthma has also been frequently studied in terms of lung cancer risk. Several studies have examined this potential risk factor, including a meta-analysis consisting of 8 case-control and 10 cohort studies Most of these studies demonstrated an increased risk of lung cancer in never smokers with asthma Table 3.

Several studies have suggested that patients with idiopathic pulmonary fibrosis or other fibrotic disorders are at increased risk for lung cancer — , but these risk factors have not been clearly defined in never smokers. There has been little research on COPD and lung cancer risk specific to never smokers, as never smokers rarely develop this disease.

In a Chinese province in which exposure indoor smoky coal combustion is common, COPD chronic bronchitis in never-smoking women has been associated with increased lung cancer risk Many studies have examined the risk of lung cancer due to ionizing radiation among never smokers. However, most of these studies show that this increased risk is higher among smokers, possibly due to the multiplicative effects of cigarette smoking and radiotherapy — For atomic bomb survivors, the effect of radiation exposure and smoking on lung cancer has been found to be additive Results of studies on exposure to radiation and risk of lung cancer among never smokers.

The large numbers of current and former smokers dying of lung cancer have obscured the important problem of lung cancer in never-smokers.

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Lung cancer in never smokers accounts for 16, — 24, deaths annually in the US, among the top 10 causes of cancer mortality as a separate entity from smoking-related cancer. Incidence of lung cancer in never smokers increases with age. Current epidemiologic data does not indicate a significant change in risk over time, or a clear gender bias in the risk of lung cancer in never smokers.

However, among female never-smokers, large differences in lung cancer risk exist between populations, with strikingly higher risk in several East Asian countries, and in particular China. Factors contributing to these population differences may include both underlying genetic susceptibility as well as exposure to carcinogens including coal smoke, aerosolized cooking oils, and second hand smoke. Studies evaluating gene—environment interactions may provide important insights into carcinogenesis pathways of lung cancer in never smokers.

Such studs require not only adequate sample sizes, but also detailed exposure assessments in relevant populations. Strong evidence from multiple sources supports the causal association of second hand smoke exposure in lung cancer in never smokers. Similarly, exposure to radon, common in indoor environments, is a well established cause of lung cancer in never smokers. In the US, these two factors may account for the majority of cases of lung cancer in never smokers.

Indoor air pollution, including combustion of coal or solid fuels for cooking or heating in poorly ventilated spaces, has been clearly associated with increased risk of lung cancer in never smokers, and may be a particularly important factor contributing to the high incidence of lung cancer in never smokers in the East Asia. In addition to radon, other exogenous ionizing radiation exposures have been clearly linked to lung cancer risk.

Additional exposures associated with lung cancer in never smokers in multiple studies include asbestos, which has known carcinogenic synergy with tobacco smoke, arsenic, and silica.

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Studies of dietary factors contributing to lung cancer have been less consistent, and data specific to never smokers has not been extensively explored. Diets containing relatively high levels of carotenoids, selenium, or quercetin appear to be associated with decreased risk of lung cancer; conversely consumption of meat, fat, and butter may be associated with increased risk of lung cancer.

Viral infections including HPV and HIV have been implicated in lung cancer risk in studies that included both never smokers and ever smokers.

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It is unclear whether these viruses act synergistically with tobacco, or constitute independent risk factors for lung cancer in never smokers. Finally, chronic lung diseases including tuberculosis, COPD, and asthma have been associated with increased lung cancer risk. Of these, asthma appears to be significantly associated with lung cancer risk in never smokers. The death rate due to lung cancer in never smokers over several decades has remained relatively constant in the US, and represents a significant ongoing public health problem.

Common limitations found in many of the epidemiologic studies reviewed included a failure to clearly stratify analyses by smoking status never vs. Given the significant impact of lung cancer in never smokers, focused research on genetic and environmental factors associated with this disease, in carefully defined and extensively characterized populations, is warranted.

National Center for Biotechnology Information , U. Author manuscript; available in PMC Sep Thun , 3 and Charles M. Author information Copyright and License information Disclaimer. The publisher's final edited version of this article is available free at Clin Cancer Res. See other articles in PMC that cite the published article. Associated Data Supplementary Materials 1. Abstract More than , lung cancer deaths are projected to occur in the U. Open in a separate window. Gender Clinicians have observed that women outnumber men among lung cancer patients who report never having smoked regularly.

Geographic variability The incidence of lung cancer in women varies by as much as fold, even among countries reported to have low prevalence of female smoking 34 , and even in the age range 40—69 years where ascertainment is most comparable. Temporal trends Several researchers have suggested that lung cancer risk is increasing in the general population due to factors other than tobacco smoking 46 — Putting risks into perspective It is not surprising that lung cancer risk is substantially lower among lifelong nonsmokers than cigarette smokers.

Research Needs Better data are needed to answer several basic questions about the descriptive epidemiology of lung cancer in lifelong nonsmokers. Table 1 Results of studies on exposure to secondhand smoke and risk of lung cancer among never smokers. Age only, when possible Women 37 studies, cases: Husband currently smoked vs.

Husband never smoked 1. Wife currently smoked vs. Wife never smoked 1. Spouse currently smoked vs. Spouse never smoked 1. Age and demographic characteristics, when possible Women 40 studies, No. Husband ever smoked vs.

Wife ever smoked vs. Women 14 studies, cases: Workplace SHS exposure vs. No workplace SHS exposure 1.

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Women 18 studies, cases: Ever exposed to SHS during childhood vs. Never exposed to SHS during childhood 0. North America, Europe, Asia Publication dates: Women 25 studies, No. Mother smoked during childhood vs. Mother did not smoke during childhood 1. Father did not smoke during childhood 1. Neither parent smoked during childhood 1.

Radon Radon, long established as a respiratory carcinogen, is not only of concern for underground miners but for the population generally, as a ubiquitous contaminant of indoor air. Table 2 Results of pooled analyses of case-control studies evaluating risks of radon for lung cancer among never smokers.

North America Publication dates: Coal Although the IARC evaluation was not specific to never smokers, one important feature of the studies of indoor air pollution from coal burning in China and to a less extent other countries is that they included a large number of and often were restricted to never smoking women. Biomass Worldwide, biomass is much more widely used as fuel than coal but the adverse health effects have been studied less Supplemental Table 2.

Cooking fumes Stir-frying, deep-frying, and pan-frying, which involve heating oil to high temperatures, are practiced worldwide, especially in China. Occupational agents Asbestos The effect of asbestos exposure on risk of lung cancer among never smokers has been investigated in several cohort and case-control studies Supplemental Table 4.

Arsenic In a case-control study nested in a cohort of copper smelter workers from Sweden, Pershagen and colleagues reported an OR of 2. Silica Several industry-based studies of workers exposed to silica and of silicotic patients reported an increased risk of lung cancer among never smokers Supplemental Table 6. Exposure to other agents In the case-control study of lifetime non-smoking women from Missouri, an increased risk of lung cancer was detected for exposure to pesticides OR 3. Exposure to any known or suspected occupational lung carcinogens Three European case-control studies reported results according to employment in job and industries entailing exposure to known list A or suspected list B occupational lung carcinogens, based on a simplified job exposure matrix developed by Ahrens and Merletti Supplemental Table 7.

Employment in specific occupations and industries In a few studies, risk estimates of lung cancer among never smokers were reported according to employment in specific occupational or industry categories Supplemental Table 8. Outdoor air pollution An increased risk of lung cancer has been reported in populations exposed to high levels of outdoor air pollution. Diet Dietary factors have been noted to be leading preventable causes of cancer Fruit In 14 studies, researchers investigated fruit consumption and lung cancer among never smokers.

Vegetables Two cohort studies , and eight case-control studies , , , , — investigated consumption of total vegetables and lung cancer among never smokers. Meat and fish One cohort study and five case-control studies investigated meat consumption and risk of lung cancer among never smokers, mostly women. Miscellaneous The majority of studies looking at other aspects of diet, including fat consumption, food preparation, and dairy, egg, and soy product consumption Supplemental Table 10 , found no significant association with lung cancer in never smokers.

Micronutrients One nested case-control study and eight case-control studies investigated dietary carotenoid consumption. Arsenic in drinking water In a case-control study from Chile, the risk ratios of lung cancer were 5. Other risk factors Hormone replacement therapy There is relatively little research in the area of hormone replacement therapy HRT and lung cancer risk, although some studies indicate a reduction of lung cancer risk associated with HRT use Supplemental Table Infections Human papillomavirus HPV Several studies have examined whether chronic infections can increase lung cancer risk.

Human immunodeficiency virus HIV Human immunodeficiency virus HIV has been studied in association with lung cancer risk, although this has not been a large area of study. Chlamydia pneumoniae Chlamydia pneumonia has also been investigated in relation to lung cancer risk under the hypothesis that chronic infections may increase risk , History of lung disease prior to lung cancer diagnosis History of lung disease has been examined in association with lung cancer risk, including tuberculosis, asthma, emphysema, and chronic obstructive pulmonary disease COPD. Table 3 Risk of lung cancer associated with previous lung disease among never smokers.

No history of pulmonary tuberculosis infection 8. China Shanghai Study years: Never diagnosed with tuberculosis 3. Never diagnosed with tuberculosis 1. No history of lung disease 1. No history of asthma 2. No history of pneumonia 1. China Xuanwei Study years: No history of chronic bronchitis 7. No history of pulmonary tuberculosis infection 5. China Nanjing Study year: No history of pulmonary tuberculosis or chronic bronchitis 3.

USA, China Publication dates: No history of asthma 1. No previous lung disease 2. No history of asthma, allergic rhinitis, or atopic dermatitis all histological types 1. No history of asthma, allergic rhinitis, or atopic dermatitis adenocarcinomas 1. Ionizing radiation Many studies have examined the risk of lung cancer due to ionizing radiation among never smokers. Table 4 Results of studies on exposure to radiation and risk of lung cancer among never smokers. Did not receive radiation therapy for breast cancer 3.

The Netherlands Study years: No occupational exposure to radiation sources 2. Did not receive radiation therapy for breast cancer 0. No occupational x-ray examinations 1. No occupational x-ray examinations 2. SUMMARY The large numbers of current and former smokers dying of lung cancer have obscured the important problem of lung cancer in never-smokers. Supplementary Material 1 Click here to view. US Center for Disease Control.

Annual smoking-attributable mortality, years of potential life lost, and productivity losses -- United States, — Lung cancer death rates in lifelong nonsmokers. Russia understands that the US wants to project its power and create a worldwide network of frontier forts to maintain global dominance. That explains why the US dropped more bombs on Afghanistan in September than in any other month since He has also increased the number of US troops on the ground from to The increase is mainly to adequately protect US bases that the Taliban had started to attack.

But the US strategy in Afghanistan will backfire in the end. The bombing runs are largely indiscriminate, killing countless civilians and fanning hatred of what is seen as the American occupying forces. The notion that the US is merely using Afghan soil to test its military hardware is not lost on Afghans. The growing enmity between them and US forces explains why the Taliban have managed to reclaim significant territory.

The idea that the US can make the Afghan security forces stronger so they can succeed is unrealistic. He argues that the US should prioritise an initiative to achieve a negotiated settlement between the government and the Taliban. However, an end to the conflict could result in the US being forced to close its bases, as happened in Iraq, which makes simmering conflict in Afghanistan the preferred option for US strategists.

The military has no strategy for victory, merely a plan to avoid defeat. What the US is going for is war without end in one of the poorest nations in the world. Read Part 1 here. Man nabbed after dropping hundreds of bank notes from Hong Kong building.

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