Outdoor air pollution and lung cancer: recent epidemiologic evidence.

Abstract

International Journal of CancerVolume 111, Issue 5 p. 647-652 Mini ReviewFree Access Outdoor air pollution and lung cancer: Recent epidemiologic evidence Paolo Vineis, Corresponding Author Paolo Vineis paolo.vineis@unito.it Department of Biomedical Sciences and Human Oncology, University of Turin and CPO-Piemonte, Turin, Italy Fax: +39-011-670-6692Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Torino, via Santena 7, 10126 Torino, ItalySearch for more papers by this authorFrancesco Forastiere, Francesco Forastiere Local Health Unit 10, Rome, ItalySearch for more papers by this authorGerard Hoek, Gerard Hoek Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorMichael Lipsett, Michael Lipsett Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USASearch for more papers by this author Paolo Vineis, Corresponding Author Paolo Vineis paolo.vineis@unito.it Department of Biomedical Sciences and Human Oncology, University of Turin and CPO-Piemonte, Turin, Italy Fax: +39-011-670-6692Dipartimento di Scienze Biomediche e Oncologia Umana, Università di Torino, via Santena 7, 10126 Torino, ItalySearch for more papers by this authorFrancesco Forastiere, Francesco Forastiere Local Health Unit 10, Rome, ItalySearch for more papers by this authorGerard Hoek, Gerard Hoek Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorMichael Lipsett, Michael Lipsett Office of Environmental Health Hazard Assessment, California Environmental Protection Agency, Oakland, CA, USASearch for more papers by this author First published: 20 May 2004 https://doi.org/10.1002/ijc.20292Citations: 100 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Outdoor air pollution has long been suspected of increasing the risk of lung cancer.1 Although many pollutants have been linked with adverse health impacts, the component with the greatest public health impact is probably PM, a complex mixture of airborne solid and liquid particles including soot, organic material, sulfates, nitrates, other salts, metals and biologic material. Many carcinogens, including a multitude of PAHs, adsorb to particles and can be deposited throughout the respiratory tract. In most Western countries, motor vehicle exhaust represents the most widespread source of air pollution, including PM.2 For research purposes, PM is usually subdivided into PM10 (inhalable particles), PM2.5 (fine particles) and PM0.1 (ultrafine particles). These PM size cuts generally represent different sources and display different physical and chemical properties. The physicochemical characteristics responsible for PM-associated toxicity are incompletely understood. For example, the relative contributions of particle size, number, mass, surface area and chemical composition have not been determined. For a given mass concentration (in μg/m3), the particle size cut will determine both particle number and surface area (e.g., for a mass concentration of 10 μg/m,3 a particle diameter of 2 μ corresponds to 1.2 particles/ml air with a surface area of 24 μ,2 while a particle diameter of 0.02 μ corresponds to 2.4 million particles/ml with a surface area of 3,000 μ2).3 A larger surface area potentially means greater exposure to carcinogenic agents, such as PAHs adsorbed to the particles. Long-term average concentrations of PM pollution are quite variable in Western countries, from <10 μg/m3 of PM10 (e.g., in northern Sweden) to >50 μg/m3 in southern Europe, with intermediate levels in the United States (for U.S. levels, see the website http://www.epa.gov/oar/aqtrnd97/brochure/pm10.html). Gaseous constituents of outdoor air pollution include nitrogen compounds (e.g., NO2), sulfur compounds (e.g., SO2), CO, CO2, ozone and other chemicals. Unlike gaseous pollutants, such as ozone or SO2, the composition of PM varies considerably over space and time. In this minireview, we focus on the health impacts of particulate and gaseous emissions from diesel and gasoline exhaust. The contribution of other sources of outdoor air pollution, in particular industrial emissions, is beyond the scope of the present review. Abbreviations: ACS-II, American Cancer Society Study-II; AHSMOG, Adventist Health Study on SMOG; CI, confidence interval; PAH, polycyclic aromatic hydrocarbon; PM, particulate matter; RAL, relative adduct labeling; RR, relative risk; WBC, white blood cell. “PRE-COHORT” STUDIES Exposure to air pollution has been related to total mortality in scores of studies.4, 5 Overall respiratory mortality has also been linked with elevated levels of air pollution.5 Prior to the publication of 3 American cohort studies, the evidence for a relationship between air pollution and lung cancer was somewhat equivocal, having been based on geographic comparisons, case-control studies and occupational studies of workers exposed to PAHs or diesel exhaust. Estimation of the effects of air pollution on lung cancer incidence is difficult for several reasons: (i) clinically detectable lung cancer takes many years to develop, (ii) long-term records of air pollution are required, (iii) information on other risk factors (potential confounders) is needed and (iv) measurements of both air pollution and confounding factors are often difficult and subject to errors of classification and change over time. Among the “pre-cohort” studies, urban–rural comparisons have shown that an “urban factor” is associated with a 10–40% increase in lung cancer mortality. An obvious limitation of these cross-sectional studies, however, is the impossibility of disentangling air pollution from other factors associated with urban life.6 Some follow-up investigations conducted in urban populations have provided stronger evidence of an urban–rural difference when smoking was taken into account, with rate ratios in the range of 1.1–1.5.7, 8 Case-control studies incorporating data on smoking and occupational exposures have shown an association between living in more polluted areas and the occurrence of lung cancer.9 In a large case-control study in Trieste, Italy, residence in the polluted city center was associated with increased risks of small cell (RR = 2.0, 95% CI 1.2–3.4) and large cell (RR = 2.6, 95% CI 1.2–5.3) lung cancer relative to residence in a suburban area.10 These estimates included adjustment for smoking and for occupational exposures to carcinogens. No increase in risk was seen for either squamous cell carcinoma or adenocarcinoma. The authors indicated that during the preceding 20 years most of the air pollution in the city center was attributable to transportation. A Swedish case-control study, involving 1,196 male lung cancer cases and 2,364 controls, detected associations between traffic exposure and lung cancer.11 Exposures from traffic (using annual average NO2 at each subject's residence as an indicator pollutant) and residential heating (using annual average concentrations of SO2) were estimated from 1950 through 1989. An estimated RR of 1.44 (95% CI 1.05–1.99) was found in association with more than 29.3 μg/m3 of NO2 (representing the highest decile of estimated average exposures over the period 21–30 years prior to the end of follow-up) compared to exposures lower than 12.8 μg/m.3 There was no association with estimated SO2 levels.11 During the last 10 years, several well-conducted cohort studies have been published. The main advantage of the cohort studies is that exposure is ascertained independently of and prior to the onset of clinically apparent disease, reducing the likelihood of bias. COHORT STUDIES IN THE UNITED STATES Three U.S. cohort studies were published in the 1990s.12, 13, 14 Long-term exposure was estimated in 2 studies from metropolitan annual average ambient concentrations; air pollution exposure contrasts were based on intercity concentration differences, while no information was available at the individual level.13, 14 A third study12 was conducted in California, which historically has had one of the most extensive air pollution–monitoring networks in the world. In this investigation, monthly air pollution concentrations were refined by interpolating data from the monitoring sites to the zip codes corresponding to the individuals' residential and work addresses. In all 3 studies, individual-level information was available on potential confounders or effect modifiers, which were generally assessed at the start of follow-up. The AHSMOG12 was based on 6,338 California Seventh Day Adventists followed from 1977 through 1992. The investigators reported substantial increases in RRs of lung cancer mortality among men in relation to long-term ambient concentrations of PM10 (RR = 3.36, 95% CI 1.57–7.19 associated with an interquartile range of 24 μg/m3) and SO2 (RR = 1.99, 95% CI 1.24–3.20 associated with an interquartile range of 3.7 ppb); however, as suggested by the wide CIs, these results were based on very few cases (n = 18 lung cancer deaths in men). While the mean ozone concentration was not associated with lung cancer incidence in men or women, there was an association of ozone with lung cancer risk in males when the exposure metric was formulated as the number of hours per year with elevated ozone concentrations (RR = 4.19, 95% CI 1.81–9.69 for at least 551 hr/year > 100 ppb ozone, controlling for pack-years of cigarette smoking, educational level and current alcohol use). Although the RRs for lung cancer in women (n = 12) for various PM10 metrics were also >1.0, all CIs included the null value. PM10 was measured only during the last 5 years of follow-up in this study; during most of the study, PM10 concentrations were estimated from measurements of total suspended particles. The Harvard Six Cities Study13 was based on 8,111 residents of 6 U.S. cities, followed from 1974 through 1989. Exposure was estimated on the basis of average levels of pollution over the risk period, assuming residential stability. RR estimates were adjusted for age, gender, smoking habits, body mass index and education. The total number of lung cancer deaths was reported as 8.4% of 1,429 (or 120). The difference in the long-term average PM concentrations between the most and least polluted cities was approximately 20 μg/m,3 corresponding to an RR of 1.37, i.e., an approximately 19% increase in risk per 10 μg/m.3 The third and largest U.S. investigation is the ACS-II,14 based on the mortality experience of approximately 500,000 adult men and women who were followed from 1982 through 1998. Participants were assigned to metropolitan areas of residence, and mean PM2.5 concentrations were compiled for each metropolitan area from several data sources. Personal information on risk factors (confounders or effect modifiers) was collected by questionnaire at enrollment. The study indicated a significantly increased mortality risk ratio for lung cancer (RR = 1.14, 95% CI 1.04–1.23) for a difference of 10 μg/m3 of PM2.5, controlling for age, gender, race, smoking, education, marital status, body mass, alcohol consumption, occupational exposure and diet. Therefore, 2 of the U.S. cohort studies, which are not subject to some of the principal limitations of previous geographic comparisons or case-control studies, suggest an excess risk of lung cancer of about 19% per 10 μg/m3 increment in long-term average PM2.5, after adjustment for the most likely confounding factors.13, 14 (Although the point estimates from the AHSMOG were also elevated, these are less precise, having been based on relatively few events.) Therefore, inhabitants of some southern European cities, e.g., could be exposed to air pollution–associated lung cancer risks about 75% higher than those among urban residents in northern Europe. However, this would be true only if one assumes a linear relationship between exposure and risk and that local effect modifiers (e.g., environmental tobacco smoke, diet or social class–related exposures) have little relevance (see below). In a reanalysis of the ACS data, linear vs. log-linear models were used to estimate air pollution–attributable lung cancer burdens at higher concentrations than those observed in the ACS-II.15 On the basis of the available evidence, one cannot rule out a linear exposure–response relationship at this time. EUROPEAN COHORT STUDIES The first published European cohort study examining long-term exposure to air pollution was conducted in the Netherlands.16 Conducting studies in Europe is extremely valuable for at least 3 reasons: (i) the 2 largest U.S. studies assessed only between-community spatial variations of air pollution and not within-community exposures, (ii) ambient levels of several key pollutants are more variable in Europe than in the United States and usually higher and (iii) European populations have a wide range of different exposures and living habits (particularly diet and smoking prevalence), which could act as effect modifiers. Enrollment in the Netherlands Cohort Study on Diet and Cancer started in 1986. At baseline there were 120,852 55- to 59-year-old adults living in 204 small towns and large cities throughout the Netherlands. A baseline questionnaire requesting information on active and passive smoking, occupation, education, nutrition and up to 4 residential addresses was administered. For the air pollution study, a subcohort of 5,000 subjects was used to estimate person-time within a case-cohort design. Mortality between 1986 and 1994 was studied in the subcohort. Exposure assessment was based on estimation of long-term exposure at the baseline home address and included assessment of NO2 and black smoke. The strongest predictor of lung cancer risk was identified as residential distance from a heavily trafficked street (within 100 m of a freeway or 50 m of a major urban street). While the greatest effect estimate for cardiopulmonary mortality was living near a busy street, the report by Hoek et al.16 indicates that there were too few cases of lung cancer to estimate the risks associated with this exposure metric. Risk of lung cancer was slightly elevated, but the estimate was based on relatively few cases (n = 60; RR = 1.06, 95% CI 0.43–2.63 for a 10 μg/m3 increment in exposure to black smoke; RR = 1.25, 95% CI 0.42–3.72 for a 30 μg/m3 increment in exposure to NO2). A second European study comes from Norway. Nafstad et al.17 studied lung cancer incidence among 16,209 40- to 49-year-old men living in Oslo, who were recruited in 1972–1973. Exposure assessment was based on measured concentrations of 2 gaseous air pollutants (NO2 and SO2) available from 1974 to 1995. Exposures in different areas of Oslo were contrasted. The population was followed through the Cancer Registry. Information on several potential confounders (smoking, social class, occupation, physical exercise) was available. The authors found a risk ratio of 1.08 (95% CI 1.02–1.15) for an increment of 10 μg/m3 of NO2, with an exposure–response relationship (Table I). This investigation has several strengths: (i) large size and adequate statistical power (>400 lung cancer cases); (ii) prospective examination of cancer incidence; (iii) absence of between-city heterogeneity (study was conducted in only one city); (iv) only 40- to 49-year-old men were studied; (v) exposure assessment could be refined with data on emigration and changes of address, which were not available in earlier studies; (vi) confounding was addressed by including individual information on age, smoking, social class, occupation and physical exercise. Table I. Results of cohort studies A. AHSMOG (USA)—RR for lung cancer mortality in men (and 95% CI) per 3.7 ppb SO2 or 24 μg/m3 PM10 increase (interquartile range). Total number of lung cancer deaths 18. (Data from Abbey et al.12) SO2 1.99 (1.24–3.20) PM10 3.36 (1.57–7.19) B. Harvard Six Cities study (USA)—Mortality follow-up 1974–1989. RR (and 95% CI) for the most polluted city (29.6 μg/m3 PM2.5) vs. the least polluted (11.0 μg/m3 PM2.5). (From Dockery et al.13) All-cause mortality 1.26 (1.08–1.47) Cardiopulmonary 1.37 (1.11–1.68) Lung cancer 1.37 (0.81–2.31) Other causes 1.01 (0.79–1.30) C. ACS-II (USA)—Mortality follow-up 1982–1998 RR per 10 μg/m3 PM2.5 increase. (From Pope et al.14) All-cause mortality 1.06 (1.02–1.11) Cardiopulmonary 1.09 (1.03–1.16) Lung cancer 1.14 (1.04–1.23) Other causes 1.01 (0.95–1.06) D. NLCS study (the Netherlands)—RR (mortality) and 95% CI per 10 μg/m3 black smoke or 30 μg/m3 NO2 increase for living near a major road. (From Hoek et al.16) Causes of death Black smoke NO2 Major road Cardiopulmonary 1.34 (0.68–2.64) 1.54 (0.81–2.92) 1.95 (1.09–3.51) Lung cancer 1.06 (0.43–2.63) 1.25 (0.42–3.72) NA All causes 1.17 (0.76–1.78) 1.24 (0.83–1.86) 1.41 (0.94–2.11) E. Study in Oslo—Risk ratios for lung cancer (and 95% CI) per 10 μg/m3 increment of NO2 (μg/m3). (From Nafstad et al.17) NO2 (μg/m3) 0–9.99 10–19.99 20–29.99 30+ Lung cancer 1 (ref.) 0.90 (0.70–1.15) 1.06 (0.81–1.38) 1.36 (1.01–1.83) EFFECT MODIFIERS, SYNERGISM WITH SMOKING In a detailed reanalysis of both the Six Cities and the ACS-II cohort data, Krewski et al.18 found that level of education was inversely associated with RRs (Fig. 1). Degree of association with social class was important and could explain part of the observed geographic differences in risk estimates of the relationship between air pollution and lung cancer. Figure 1Open in figure viewerPowerPoint Education attained modifies the effects of sulfate or particles. HS, high school. (From Krewski et al.18) It has been suggested that a synergistic effect exists between tobacco smoking and environmental pollution with respect to lung cancer induction.19 In a small case-control study of lung cancer among women in Athens,20 an effect of air pollution exposure was observed only among smokers, suggesting biologic effect modification. Samet and Cohen,21 reviewing the evidence for such a joint effect, indicate that the few studies that have examined this issue suggest the existence of a synergistic relationship between exposure to ambient air pollution and cigarette smoking. However, the magnitude of the joint effect is difficult to estimate because of exposure measurement error (for both cigarette smoking and air pollution) and the imprecision due to the small numbers of lung cancer cases occurring in nonsmokers. EXPOSURE TO DIESEL-FUELED ENGINE EXHAUSTAND LUNG CANCER Despite numerous attempts, epidemiologic studies cannot disentangle the carcinogenic role played by single constituents of air pollution. The presence in ambient air of the myriad compounds recognized to be carcinogenic in animals supports the biologic plausibility of the nexus between air pollution and lung cancer. For instance, PAHs, which are carcinogenic in animals, are thought to play a role in occupational lung cancer and are emitted from a variety of sources of fossil fuel combustion.22 Although the specific role (if any) of these compounds in lung cancer induction in humans exposed to ambient air pollution remains uncertain, Cohen and Pope23 suggested that there is a gradient of relative risks of lung cancer associated with exposure to combustion products, ranging from 7.0–22.0 in cigarette smokers to 2.5–10.0 in coke oven workers to 1.0–1.6 in residents of areas exposed to high levels of air pollution and 1.0–1.5 in nonsmokers exposed to environmental tobacco smoke. These estimated risks integrate the carcinogenic potencies of the exposure mixtures but also roughly correspond to the intensity of exposure to combustion products. Another important component of air pollution is diesel exhaust, a complex mixture of thousands of gases and fine particles. The composition of diesel exhaust varies by engine type, operating conditions, fuel composition, lubricating oil and whether an emissions control system is present.24 The gaseous fraction is composed primarily of typical combustion gases (CO2, CO, oxides of nitrogen and sulfur), volatile hydrocarbons and PAHs/nitro-PAHs. Some of the gaseous components (benzene, formaldehyde, 1,3-butadiene) are suspected or known to cause cancer in humans. Diesel engines release particles at a rate about 20 times greater than gasoline-fueled vehicles. Approximately 92% of the mass of diesel exhaust particles is <1 μ in diameter, allowing them to reach the bronchial and alveolar regions of the lung upon inhalation.24 The inorganic fraction consists primarily of small solid (or elemental) carbon particles ranging 0.01–0.08 μ in diameter. As many as 18,000 different combustion products, including a variety of recognized genotoxicants, may adsorb to diesel exhaust particles, constituting 15–65% of the particulate mass.24 The organic fraction includes compounds such as aldehydes, alkanes, alkenes and high-m.w. PAH and PAH derivatives. Many of these PAH and PAH derivatives are powerful mutagens and carcinogens. Given the evidence that both diesel and gasoline engine exhausts are carcinogenic to experimental animals,2 exposure to these agents may also be carcinogenic to the respiratory tract of humans. In 1989, an IARC working group reviewed several studies of various occupational groups with potential exposure to diesel and gasoline exhausts, including railroad workers, bus company employees, professional drivers and miners. The working group concluded that the evidence for the carcinogenicity of exposure to diesel engine exhaust was “limited” and that of exposure to gasoline engine exhaust was “inadequate”.2 They concluded that diesel engine exhaust is probably carcinogenic to humans and classified it in group 2A (probable carcinogen, i.e., limited evidence in humans and sufficient in other animals); gasoline engine exhaust was classified in group 2B (possible carcinogen, i.e., limited evidence in humans and less than sufficient in other animals). After the IARC evaluation, additional industry-based cohort and case-control studies as well as population-based studies have addressed the issue of exposure to diesel exhaust fumes in relation to lung cancer. Both the Health Effects Institute and the WHO25, 26 found that the epidemiologic data were consistent in showing weak associations between exposure to diesel exhaust and lung cancer. Data from 23 and 30 studies, respectively, have been summarized in 2 independent meta-analyses.26, 27 These meta-analyses provide strong support for the hypothesis that occupational exposure to diesel exhaust is associated with increased risk of lung cancer. These studies, on average, found that long-term occupational exposure to diesel exhaust was associated with an approximately 30–50% increase in the RR of lung cancer. The association was present when the various studies were analyzed by occupational subgroup, study design and smoking habit. This association was supported when adjusting for the most important potential confounder, cigarette smoking, and when the issue of publication bias was considered. Several studies also provide evidence of exposure–response relationships.28, 29, 30, 31 Based on historical reconstruction of likely exposures in the trucking industry, Steenland et al.32 also reported evidence of a diesel exposure–response relationship. Animal experiments tend to support the epidemiologic observations. Chronic inhalation of high concentrations of whole diesel exhaust (particle concentrations > 2.2 mg/m3) has consistently resulted in increased incidence of lung tumors in rats; studies of mice have been somewhat less concordant, while those in hamsters have been negative.24 In contrast with the results of bioassays using whole diesel exhaust, exposure of rats in which the particulate fraction had been removed by filtration showed no evidence of carcinogenicity, even though the gaseous fraction is known to contain a variety of carcinogens.33, 34 Moreover, animal bioassays have demonstrated that chronic inhalation of carbon black (elemental carbon) particles results in a carcinogenic potency similar to that of diesel exhaust particles, which appears to corroborate the etiologic importance of the particulate fraction.35, 36 Based on both human and experimental animal evidence, the California Air Resources Board formally identified diesel exhaust particulate as a “toxic air contaminant”, which set in motion additional strategies to reduce such emissions.37 There were no direct measurements of historical diesel exposure of the study subjects in any of the occupational epidemiologic studies. Nevertheless, several attempts have been made to quantify the cancer risk for human populations posed by diesel vehicle emissions. In Austria, it has been estimated that at the mass concentrations of diesel particles in the Vienna atmosphere (5–23 μg/m3), between 1.0 and 2.6 additional lung cancers per 100,000 persons per year might be expected.38 In cancer risk assessment for air toxicants, a “unit risk” value represents an estimate of the carcinogenic potency of a chemical and here refers specifically to the modeled number of excess cancer cases per million population exposed for a 70-year lifetime to a specified concentration of that chemical. By convention, regulatory agencies in the United States have used the upper 95% CI limit on the maximum likelihood estimate of the risk for this purpose. The California Environmental Protection Agency23 estimated the 95% CI upper limit of the cancer unit risks to be in the range of 1.3 × 10−4 to 2.4 × 10−3 excess lung cancer cases per lifetime exposure to 1 μg/m,3 observing that the more scientifically valid estimates are likely to be at the lower end of this range. Applied to the Viennese data, the California unit risk estimate (1.3 × 10−4) would predict between 1 and 4 excess lung cancer cases per 100,000 population/year, consistent with the estimates by Horvath et al.38 Although there are large uncertainties associated with these estimates, they are compatible with prior estimates of the impact of air pollution generally on lung cancer.39 While estimating transportation-related cancer risks in the general population, it should not be forgotten that the greatest exposures to vehicular fuels and exhausts occur occupationally. In one of the diesel meta-analyses referred to above, the pooled risk estimate for 9 studies of truck drivers was consistently elevated, even after stratifying on whether the individual studies adjusted for the subjects' smoking (pooled RR = 1.47, 95% CI 1.33–1.63).24 Steenland et al.32 estimated that persons working in the trucking industry could have an excess lifetime risk of lung cancer attributable to diesel exhaust exposure on the order of 1–2%, which is about 2 orders of magnitude greater than the risks estimated for the general population (above). The epidemiologic and toxicologic evidence implicating diesel exhaust is more compelling than that for gasoline. Still, in some occupations in which there is exposure to both types of exhaust, there are indications of increased risk. For example, professional drivers as a group (including 6 studies of truck, bus and taxi drivers) had an increased pooled risk of 1.45 (95% CI 1.31–1.60); stratification by whether the studies had adjusted for cigarette smoking made little difference.24 BIOMARKER STUDIES: DNA ADDUCTS Biomarker studies have contributed to a nascent understanding of potential pathophysiologic mechanisms by which air pollution could initiate or exacerbate cardiovascular and pulmonary diseases. Several studies have considered DNA damage as an end point, in particular the detection of “bulky” DNA adducts in WBCs, which are related to exposure to aromatic compounds including PAHs.40, 41, 42, 43 To the extent that such adduct formation may also occur in bronchial epithelial cells, such studies may provide insight and biologic plausibility for a causal role of air pollution in the etiology of lung cancer. Several studies in Europe have shown that levels of WBC DNA adducts were higher among subjects heavily exposed to air pollutants. This observation has been made among police officers,40 newspaper vendors exposed to urban traffic,41 residents in a highly industrialized area in the United Kingdom42 and bus drivers in Denmark.43 In all these cases, the more exposed subjects had significant differences from those less exposed, with WBC DNA adducts of about 3 × 10−8 for the RAL in the former and 1 × 10−8 in the latter. A group of 114 workers exposed to traffic pollution and a random sample of 100 residents were studied in Florence. Bulky DNA adducts were analyzed in peripheral leukocytes donated at enrollment, using 32P-postlabeling. Adduct levels were significantly higher for traffic workers among never-smokers (p = 0.03) and light current smokers (p = 0.003). In both groups, urban residents tended to show higher levels than those living in suburban areas and a seasonal trend emerged, with adduct levels being highest in summer and lowest in winter.44 Lewtas et al.45 observed that human populations exposed to PAHs via air pollution show a nonlinear relationship between levels of exposure and WBC DNA adducts. Among highly exposed subjects, the DNA adduct level per unit of exposure was significantly lower than that measured among individuals exposed at common environmental exp