Open Access

Research Article

Materials and Methods Top

Study population

The Nurses’ Health Study (NHS) is a long-term prospective cohort study of U.S. female nurses. The NHS was initiated in 1976 when 121,700 U.S. registered female nurses, 30–55 years of age, completed a mailed questionnaire and provided informed consent. At the study inception they resided in 11 states throughout the United States (California, Connecticut, Florida, Massachusetts, Maryland, Michigan, New Jersey, New York, Ohio, Pennsylvania, and Texas). Although most of the nurses have not moved, they now reside in all 50 states. Follow-up questionnaires, with response rates > 90%, are mailed every 2 years to update information on risk factors and the occurrence of major illnesses. We included women in the present study if their 2000 residential address was successfully geocoded to the street segment level in the continental United States and they had no history of RA or cancer (other than nonmelanoma skin cancer) at baseline in 1976. A total of 90,297 members were available for analysis.

Assessment of outcome

We used a two-stage procedure to identify nurses with RA. All nurses reporting RA or other connective tissue disease on a biennial questionnaire (n = 11,674) received a follow-up screening questionnaire for connective tissue symptoms (Karlson et al. 1995). If the screening questionnaire was positive, we requested medical records, which underwent detailed examination for American College of Rheumatology diagnostic criteria for RA. Subjects who self-reported but later denied RA diagnosis, denied permission to obtain medical records, or who had a negative screening questionnaire were excluded (n = 8,877) (Karlson et al. 2004). In this analysis, we included a total of 687 incident cases (1976–2004), 390 (57%) of whom had rheumatoid factor (RF)-positive RA as determined by medical record review.

Exposure assessment

We studied distance to road in the year 2000 as a proxy for traffic pollution exposure. Distance to road (in meters) for all available nurses’ addresses was determined using geographic information system software (ArcGIS, version 9.2; ESRI, Redlands, CA). Road segments in the 2000 U.S. Census Topologically Integrated Geographic Encoding and Referencing system (TIGER) files (http://www.census.gov/geo/www/tiger/) were selected by U.S. Census feature class code to include A1 (primary roads, typically interstates, with limited access), A2 (primary major, noninterstate roads), or A3 (smaller, secondary roads, usually with more than two lanes) road segments. We calculated the shortest distance between each address and the closest road segment. We conducted analyses using the distance to the closest of all three road types, and the distance to the nearest primary road (A1, A2 only). For the main analyses, we used the distance to A1–A3 roads at the 2000 mailing address. In sensitivity analyses, we also assessed the associations with distance to road for all other available address years and to primary roads only. Based on the distribution of distance to road in this cohort and previous exposure studies showing exponential decay in exposures with increasing distance to road, we divided distance to road into the following categories (0–50, 50–200, ≥ 200 m) (Adar and Kaufman 2007; Lipfert et al. 2006; Lipfert and Wyzga 2008; Sahlodin et al. 2007; Zhu et al. 2002).

Additional covariates

Information on potential confounders and effect modifiers is updated every 2 years in the NHS, so we assigned each woman updated covariate values for each individual questionnaire cycle where appropriate. We examined possible confounding by age (in months), non-Caucasian race, age at menarche, parity, total months of lactation, current menopausal status, menopausal hormone use, oral contraceptive use, physical activity, and body mass index (BMI), many of which have been shown to be risk factors for RA (Costenbader et al. 2008; Karlson et al. 2004). To control for smoking, we used data from lifetime smoking history to calculate pack-years (number of packs/day multiplied by number of years of cigarette smoking) and current smoking status (current/former/never). Because smoking is a major risk factor for RA and residual confounding by smoking may obscure any traffic pollution effect, we also restricted models to never-smokers. To control for individual level socioeconomic status, we included several variables, including nurses’ educational level, occupation of both parents, marital status, and, if applicable, husband’s education. To control for area-level socioeconomic status, we included area-level information from the 2000 Census on tract level median income and house value.

Tables

Table 1.

Age-standardized characteristics of the study population (n = 90,297) at baseline (1976) by distance to road category.

Table 2.

HRs (95% CIs) from Cox proportional hazard models for incident RA (1976–2004) with distance to the closest A1–A3 road measured in 2000.

Table 3.

HRs (95% CIs) from Cox proportional hazard models for incident RA (1976–2004) with distance to the closest A1–A3 road measured in 2000 by RF status.

Table 4.

HRs (95% CIs) from Cox proportional hazard models for incident RA (1976–2004) with distance to the closest A1–A2 road measured in 2000.

Statistical analysis

Time-varying Cox proportional hazards models were used to assess the relationship of incident RA (1976–2004) with distance to road. These models were based on a biennial time scale and were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Person-time accrued from 1 January 1976 until diagnosis of RA, date of death, or the end of follow-up (31 May 2004), whichever was first. All Cox models were stratified by age in months and calendar year. We also ran sensitivity analyses restricted to women who were nonsmokers at baseline and by RF status (positive/negative). All statistical analyses used SAS (version 9.1; SAS Institute Inc. 2006).

Results Top

Table 1 presents the characteristics of the cohort at baseline (1976) by distance to road category. The average (± SD) age at baseline of women in NHS was 42.4 ± 7.1, and the average BMI was 23.7 ± 4.0. Only 31.4% of the women were current smokers, and 44.4% had never smoked cigarettes. Most of the cohort was premenopausal, and more than half of the postmenopausal women had never used postmenopausal hormones. Twenty percent of the women had < 3 metabolic equivalent hours per week of physical activity, and only 11.2% had more than 27. Most of the women had Registered Nurse degrees, were married, and had husbands with a high school education or greater. There was little difference in the distribution of RA risk factors by exposure level. As expected, members of the cohort living closer to roads did live in census tracts with lower median family income and home values than did those living farther away from roads.

In models adjusted for age and calendar year, individuals living within 50 m of an A1–A3 road had a 33% (95% CI, 0–77%) higher risk of incident RA compared with those living 200 m or farther away (Table 2). Women living 50–200 m from these roads had a non-statistically significant decreased risk (HR = 0.85; 95% CI, 0.66–1.09). Additional adjustment for race, cigarette smoking, parity/lactation, menopausal status and hormone use, oral contraceptive use, BMI, physical activity, and census-tract-level median income and house value did not change the results (0–50 m: HR = 1.31; 95% CI, 0.98–1.74; 50–200 m: HR = 0.84; 95% CI, 0.65–1.08). Among never-smokers, the association of living within 50 m and incident RA was slightly elevated compared with that in the full cohort, with an HR = 1.62 (95% CI, 1.04–2.52) in fully adjusted models. The results were similar in sensitivity analyses using a subsample of women who did not move between 1988–2004 [Supplemental Material, Table 1 (available online at http://www.ehpon-line.org/members/2009/0​800503/suppl.pdf )], as well as analyses using distance to road in all other available address years (data not shown). This is reasonable given the residential stability in this cohort (58% of the cohort had only one address between 1988–2004, and among the participants who did move, the median number of moves was 1).

We also observed associations with distance to road with RF-positive RA (Table 3). In fully adjusted models, women living within 50 m of a road had a 44% higher risk (95% CI, 0–107%) of RF-positive RA than did those living 200 m or farther away. The association among never-smokers was similar but did not achieve statistical significance. Among RF-negative RA cases, women living within 50 m of a road had a non-statistically significant 15% increased risk (95% CI, –17% to 83%) in fully adjusted models. The association between distance to road and RF-negative RA among never-smokers was also elevated (HR = 1.77; 95% CI, 0.93–3.38).

In multivariable analyses restricted to primary (A1 and A2) roads (Table 4), women living within 50 m of a primary road had an HR of 1.63 (95% CI, 1.06–2.51), whereas those living 50–200 m away had an HR of 0.86 (95% CI, 0.60–1.23). Unlike models including A1–A3 roads, the HRs were not higher when the cohort was limited to nonsmokers. There were too few cases living within 50 m of a primary road to conduct analyses stratified by RF status.

Discussion Top

In a prospective assessment of incident RA and distance to road, we found that women living within 50 m of an A1–A3 road are at a 31% increased risk of RA compared with women living more than 200 m away. This association was also observed in analyses among nonsmokers (especially among RF-negative cases) and in women with RF-positive RA. We found higher risks for those women living closer to primary roads (A1, A2). These results suggest that higher exposure to traffic pollution may be associated with RA risk. To the best of our knowledge, this is the first time an association had been demonstrated between RA incidence and residential distance to the closest road.

A large body of health effects literature has developed using distance to road as an indicator of traffic exposures (Adar and Kaufman 2007; Beelen et al. 2008; Brunekreef et al. 1997; Ciccone et al. 1998; Duhme et al. 1996; English et al. 1999; Finkelstein et al. 2004; Garshick et al. 2003; Guo et al. 1999; Hoek et al. 2002; Jerrett et al. 2005a, 2005b; Lipfert et al. 2006; Maheswaran and Elliott 2003; Nitta et al. 1993; Oosterlee et al. 1996; Tonne et al. 2007; Venn et al. 2000, 2001, 2005; Weiland et al. 1994; Wjst et al. 1993). Adverse health effects have been demonstrated with respiratory symptoms, asthma, lung function, and all cause and cardiopulmonary mortality in populations living near roads around the world. Because traffic is a major source of air pollution, these results are also consistent with the general air pollution health effect literature. Many studies have demonstrated the adverse effects of air pollution on mortality and morbidity (Downs et al. 2007; Pope and Dockery 2006; Schikowski et al. 2005; Sunyer et al. 2006), and specifically air pollution from traffic sources (Beelen et al. 2008; Laden et al. 2000; Schwartz et al. 2005). Our observed higher risks in nonsmokers are also consistent with results from the general air pollution literature. In an analysis of particulate matter exposures with all-cause mortality and coronary heart disease events in the NHS cohort, we found higher risks among women who were never-smokers, with no associations seen in current smokers (Puett et al. 2008). This suggests that the overall detrimental effects of smoking may mask the effects of traffic or air pollution. In these multivariable models, compared with never-smokers, the HR for being a current smoker was 2.12 (95% CI, 1.29–3.48) and for former smokers was 2.57 (95% CI, 1.62–4.09). Therefore, the 31% higher risk we observed for living within 50 m of an A1–A3 road, and the 63% higher risk for those near A1–A2 roads are much smaller than the risks from former/current smoking in this cohort.

Epidemiologic evidence has provided strong evidence that cigarette smoke is a risk factor for RA (Costenbader et al. 2006; Criswell et al. 2002; Hazes et al. 1990; Heliovaara et al. 1993; Hernandez Avila et al. 1990; Karlson et al. 1999; Krishnan et al. 2003; Padyukov et al. 2004; Stolt et al. 2003, 2005; Sverdrup et al. 2005; Symmons et al. 1997; Uhlig et al. 1999; Vessey et al. 1987; Voigt et al. 1994). Stronger effects have been seen in individuals with seropositive RA, similar to our findings with distance to road. Cigarette smoke contains hundreds of compounds, many of which have been shown to lead to elevated levels of inflammation (Bermudez and Ridker 2002; Tracy et al. 1997). Traffic exposures and cigarette smoking may act to increase risk of RA through similar mechanisms. Respiratory exposure to particulate matter (of which traffic is a major source) has similarly been associated with increased systemic inflammation (Jimenez et al. 2002; Peters et al. 1997; Seaton et al. 1995; van Eeden et al. 2005). Human exposure to high levels of ambient particles stimulates the production of inflammatory cytokines in the lung, which may stimulate the bone marrow to release neutrophils and monocytes into the circulation (Tan et al. 2000). In animals, respiratory exposure to particulate matter accelerates transit of neutrophils and monocytes in bone marrow and expands the leukocyte pool size (Mukae et al. 2001; Terashima et al. 1997). Studies in cellular and animal models suggest that reactive oxygen species are generated by respiratory exposure to particulate matter (Gonzalez-Flecha 2004). Reactive oxygen species and oxidative stress are generated indirectly by proinflammatory mediators released from stimulated macrophages, but there is also evidence of direct effects of particles on intracellular sources of reactive oxygen species. Many proinflammatory genes induced upon exposure to particulate matter are regulated by redox-sensitive transcription factors, such as nuclear factor κ B (NFκB) (Shukla et al. 2000). In vivo models of inhalation exposure to particulate matter demonstrate that NFκB- regulated genes, including interleukin-6, tumor necrosis factor-α, and γ-interferon, are up-regulated by exposure to particulate matter (Jimenez et al. 2000; Kennedy et al. 1998; Shukla et al. 2000). Oxidative stress, in turn, may be involved in the mechanism of RA initiation after respiratory exposure.

This analysis has several important limitations. We used distance to A1–A3 road as a proxy for exposure, so we did not have information on actual pollutant levels at the residential addresses over time. Additionally, we do not have information on the intensity of traffic, which could be used as an additional proxy for the exposures experienced at these residential locations. However, the results were slightly stronger when we considered only primary roads, presumably with higher traffic volume. We did not have power to break out the road categories individually. In our primary analyses, we focused on the distance to road in 2000, because that was the year the Census TIGER file of roads was created (U.S. Census Bureau 1992). In our sensitivity analyses using other available address years (1986–2004), the results were similar, suggesting that this is not likely to be an important limitation, potentially because most of the cohort had only one address during this time period and results in nonmovers were also similar. By using only one point in time, however, we are unable to determine potentially important time windows of exposure. All of these issues likely lead to exposure misclassification, which would bias our results toward the null and make associations harder to detect. Our conclusions are also weakened by the lack of a dose response. It is also possible that access to rheumatology specialists and differences in RA diagnostic proclivity may be an unmeasured confounder in this study. We examined differences in the RA cases at diagnosis according to distance to road category, and although the mean age at diagnosis did not vary with distance to road, the percentage of RF-positive cases increased at greater distances.

Conclusions Top

The observed association between exposure to traffic pollution and RA suggests that pollution from traffic in adulthood may be a newly identified environmental risk factor for RA. This association study should be followed by further research into whether fine particles or chemicals are associated with RA risk and to discern whether there are time windows of exposure that may be particularly important.

References Top

1. Adar SD, Kaufman JD 2007. Cardiovascular disease and air pollutants: evaluating and improving epidemiological data implicating traffic exposure Inhal Toxicol 19(suppl 1): 135–149. Find this article online
2. Beelen R, Hoek G, van den Brandt PA, Goldbohm RA, Fischer P, Schouten LJ, et al. 2008. Long-term effects of traffic-related air pollution on mortality in a Dutch cohort (NLCS-AIR study) Environ Health Perspect 116: 196–202. Find this article online
3. Begovich AB, Carlton VE, Honigberg LA, Schrodi SJ, Chokkalingam AP, Alexander HC, et al. 2004. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis Am J Hum Genet 75(2): 330–337. Find this article online
4. Bermudez EA, Ridker PM 2002. C-reactive protein, statins, and the primary prevention of atherosclerotic cardiovascular disease Prev Cardiol 5(1): 42–46. Find this article online
5. Brunekreef B, Janssen NA, de Hartog J, Harssema H, Knape M, van Vliet P 1997. Air pollution from truck traffic and lung function in children living near motorways Epidemiology 8(3): 298–303. Find this article online
6. Ciccone G, Forastiere F, Agabiti N, Biggeri A, Bisanti L, Chellini E, et al. 1998. Road traffic and adverse respiratory effects in children. SIDRIA Collaborative Group Occup Environ Med 55(11): 771–778. Find this article online
7. Costenbader KH, Chang SC, Laden F, Puett R, Karlson EW 2008. Geographic variation in rheumatoid arthritis incidence among women in the United States Arch Intern Med 168(15): 1664–1670. Find this article online
8. Costenbader KH, Feskanich D, Mandl LA, Karlson EW 2006. Smoking intensity, duration, and cessation, and the risk of rheumatoid arthritis in women. Am J Med. 119(6): pp. 503–509.
9. Criswell LA, Merlino LA, Cerhan JR, Mikuls TR, Mudano AS, Burma M, et al. 2002. Cigarette smoking and the risk of rheumatoid arthritis among postmenopausal women: results from the Iowa Women’s Health Study Am J Med 112(6): 465–471. Find this article online
10. Dockery DW, Pope AC 3rd, Xu X, Spengler JD, Ware JH, Fay ME, et al. 1993. An association between air pollution and mortality in six U.S. cities N Engl J Med 329(24): 1753–1759. Find this article online
11. Doran MF, Pond GR, Crowson CS, O’Fallon WM, Gabriel SE 2002. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period Arthritis Rheum 46(3): 625–631. Find this article online
12. Downs SH, Schindler C, Liu LJ, Keidel D, Bayer-Oglesby L, Brutsche MH, et al. 2007. Reduced exposure to PM10 and attenuated age-related decline in lung function N Engl J Med 357(23): 2338–2347. Find this article online
13. Drosos AA, Alamanos I, Voulgari PV, Psychos DN, Katsaraki A, Papadopoulos I, et al. 1997. Epidemiology of adult rheumatoid arthritis in northwest Greece 1987–1995 J Rheumatol 24(11): 2129–2133. Find this article online
14. Duhme H, Weiland SK, Keil U, Kraemer B, Schmid M, Stender M, et al. 1996. The association between self-reported symptoms of asthma and allergic rhinitis and self-reported traffic density on street of residence in adolescents Epidemiology 7(6): 578–582. Find this article online
15. English P, Neutra R, Scalf R, Sullivan M, Waller L, Zhu L 1999. Examining associations between childhood asthma and traffic flow using a geographic information system Environ Health Perspect 107: 761–767. Find this article online
16. Finkelstein MM, Jerrett M, Sears MR 2004. Traffic air pollution and mortality rate advancement periods Am J Epidemiol 160(2): 173–177. Find this article online
17. Gabriel SE, Crowson CS, O’Fallon WM 1999. The epidemiology of rheumatoid arthritis in Rochester, Minnesota, 1955–1985 Arthritis Rheum 42(3): 415–420. Find this article online
18. Garshick E, Laden F, Hart JE, Caron A 2003. Residence near a major road and respiratory symptoms in U.S. Veterans Epidemiology 14(6): 728–736. Find this article online
19. Gonzalez-Flecha B 2004. Oxidant mechanisms in response to ambient air particles Mol Aspects Med 25(1–2): 169–182. Find this article online
20. Gregersen PK, Silver J, Winchester RJ 1987. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis Arthritis Rheum 30(11): 1205–1213. Find this article online
21. Guo YL, Lin YC, Sung FC, Huang SL, Ko YC, Lai JS, et al. 1999. Climate, traffic-related air pollutants, and asthma prevalence in middle-school children in Taiwan Environ Health Perspect 107: 1001–1006. Find this article online
22. Hazes JM, Dijkmans BA, Vandenbroucke JP, de Vries RR, Cats A 1990. Lifestyle and the risk of rheumatoid arthritis: cigarette smoking and alcohol consumption Ann Rheum Dis 49(12): 980–982. Find this article online
23. Heliovaara M, Aho K, Aromaa A, Knekt P, Reunanen A 1993. Smoking and risk of rheumatoid arthritis J Rheumatol 20(11): 1830–1835. Find this article online
24. Hernandez Avila M, Liang MH, Willett WC, Stampfer MJ, Colditz GA, Rosner B, et al. 1990. Reproductive factors, smoking, and the risk for rheumatoid arthritis Epidemiology 1(4): 285–291. Find this article online
25. Hoek G, Brunekreef B, Goldbohm S, Fischer P, van den Brandt PA 2002. Association between mortality and indicators of traffic-related air pollution in the Netherlands: a cohort study Lancet 360(9341): 1203–1209. Find this article online
26. Jerrett M, Arain A, Kanaroglou P, Beckerman B, Potoglou D, Sahsuvaroglu T, et al. 2005a. A review and evaluation of intraurban air pollution exposure models J Expo Anal Environ Epidemiol 15(2): 185–204. Find this article online
27. Jerrett M, Burnett RT, Ma R, Pope CA 3rd, Krewski D, Newbold KB, et al. 2005b. Spatial analysis of air pollution and mortality in Los Angeles Epidemiology 16(6): 727–736. Find this article online
28. Jimenez LA, Drost EM, Gilmour PS, Rahman I, Antonicelli F, Ritchie H, et al. 2002. PM(10)-exposed macrophages stimulate a proinflammatory response in lung epithelial cells via TNF-alpha Am J Physiol Lung Cell Mol Physiol 282(2): L237–L248. Find this article online
29. Jimenez LA, Thompson J, Brown DA, Rahman I, Antonicelli F, Duffin R, et al. 2000. Activation of NF-kappaB by PM(10) occurs via an iron-mediated mechanism in the absence of IkappaB degradation Toxicol Appl Pharmacol 166(2): 101–110. Find this article online
30. Karakatsani A, Andreadaki S, Katsouyanni K, Dimitroulis I, Trichopoulos D, Benetou V, et al. 2003. Air pollution in relation to manifestations of chronic pulmonary disease: a nested case-control study in Athens, Greece Eur J Epidemiol 18(1): 45–53. Find this article online
31. Karlson EW, Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH 1999. A retrospective cohort study of cigarette smoking and risk of rheumatoid arthritis in female health professionals Arthritis Rheum 42(5): 910–917. Find this article online
32. Karlson EW, Mandl LA, Hankinson SE, Grodstein F 2004. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses’ Health Study Arthritis Rheum 50(11): 3458–3467. Find this article online
33. Karlson EW, Sanchez-Guerrero J, Wright EA, Lew RA, Daltroy LH, Katz JN, et al. 1995. A connective tissue disease screening questionnaire for population studies Ann Epidemiol 5(4): 297–302. Find this article online
34. Kennedy T, Ghio AJ, Reed W, Samet J, Zagorski J, Quay J, et al. 1998. Copper-dependent inflammation and nuclear factor-kappaB activation by particulate air pollution Am J Respir Cell Mol Biol 19(3): 366–378. Find this article online
35. Kobayashi M, Thomassen MJ, Rambasek T, Bonfield TL, Raychaudhuri B, Malur A, et al. 2005. An inverse relationship between peroxisome proliferator-activated receptor gamma and allergic airway inflammation in an allergen challenge model Ann Allergy Asthma Immunol 95(5): 468–473. Find this article online
36. Krishnan E, Sokka T, Hannonen P 2003. Smoking-gender interaction and risk for rheumatoid arthritis Arthritis Res Ther 5(3): R158–R162. Find this article online
37. Künzli N, Jerrett M, Mack WJ, Beckerman B, LaBree L, Gilliland F, et al. 2005. Ambient air pollution and atherosclerosis in Los Angeles Environ Health Perspect 113: 201–206. Find this article online
38. Laden F, Neas LM, Dockery DW, Schwartz J 2000. Association of fine particulate matter from different sources with daily mortality in six U.S. cities Environ Health Perspect 108: 941–947. Find this article online
39. Laden F, Schwartz J, Speizer FE, Dockery DW 2006. Reduction in fine particulate air pollution and mortality: extended follow-up of the Harvard Six Cities study Am J Respir Crit Care Med 173(6): 667–672. Find this article online
40. Lipfert FW, Baty JD, Miller JP, Wyzga RE 2006. PM2.5 constituents and related air quality variables as predictors of survival in a cohort of U.S. military veterans Inhal Toxicol 18(9): 645–657. Find this article online
41. Lipfert FW, Wyzga RE 2008. On exposure and response relationships for health effects associated with exposure to vehicular traffic J Expo Sci Environ Epidemiol 18(6): 588–599. Find this article online
42. Maheswaran R, Elliott P 2003. Stroke mortality associated with living near main roads in England and Wales: a geographical study Stroke 34(12): 2776–2780. Find this article online
43. Mukae H, Vincent R, Quinlan K, English D, Hards J, Hogg JC, et al. 2001. The effect of repeated exposure to particulate air pollution (PM10) on the bone marrow Am J Respir Crit Care Med 163(1): 201–209. Find this article online
44. Nafstad P, Haheim LL, Oftedal B, Gram F, Holme I, Hjermann I, et al. 2003. Lung cancer and air pollution: a 27 year follow up of 16,209 Norwegian men Thorax 58(12): 1071–1076. Find this article online
45. Nitta H, Sato T, Nakai S, Maeda K, Aoki S, Ono M 1993. Respiratory health associated with exposure to automobile exhaust. I. Results of cross-sectional studies in 1979, 1982, and 1983 Arch Environ Health 48(1): 53–58. Find this article online
46. Oosterlee A, Drijver M, Lebret E, Brunekreef B 1996. Chronic respiratory symptoms in children and adults living along streets with high traffic density Occup Environ Med 53(4): 241–247. Find this article online
47. Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L 2004. A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis Arthritis Rheum 50(10): 3085–3092. Find this article online
48. Penard-Morand C, Charpin D, Raherison C, Kopferschmitt C, Caillaud D, Lavaud F, et al. 2005. Long-term exposure to background air pollution related to respiratory and allergic health in schoolchildren Clin Exp Allergy 35(10): 1279–1287. Find this article online
49. Pereira FA, de Assuncao JV, Saldiva PH, Pereira LA, Mirra AP, Braga AL 2005. Influence of air pollution on the incidence of respiratory tract neoplasm J Air Waste Manag Assoc 55(1): 83–87. Find this article online
50. Peters A, Doring A, Wichmann HE, Koenig W 1997. Increased plasma viscosity during an air pollution episode: a link to mortality? Lancet 349(9065): 1582–1587. Find this article online
51. Pope CA III, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, et al. 2002. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution JAMA 287(9): 1132–1141. Find this article online
52. Pope CA III, Dockery DW 2006. Health effects of fine particulate air pollution: lines that connect J Air Waste Manage Assoc 56: 709–742. Find this article online
53. Puett RC, Schwartz J, Hart JE, Yanosky JD, Speizer FE, Suh H, et al. 2008. Chronic particulate exposure, mortality, and coronary heart disease in the Nurses’ Health Study Am J Epidemiol 168: 1161–1168. Find this article online
54. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP, et al. 2008. Common variants at CD40 and other loci confer risk of rheumatoid arthritis Nat Genet 40(10): 1216–1223. Find this article online
55. Sahlodin AM, Sotudeh-Gharebagh R, Zhu Y 2007. Modeling of dispersion near roadways based on the vehicle-induced turbulence concept Atmos Environ 41(1): 92–102. Find this article online
56. SAS Institute Inc 2006. SAS Statistical Software 9. Cary, NC: SAS Institute, Inc.
57. Schikowski T, Sugiri D, Ranft U, Gehring U, Heinrich J, Wichmann HE, et al. 2005. Long-term air pollution exposure and living close to busy roads are associated with COPD in women Respir Res 6: 152.10.1186/1465-9921-6-152 [Online 22 December 2005]. Find this article online
58. Schwartz J, Laden F, Zanobetti A 2002. The concentration-response relation between PM(2.5) and daily deaths Environ Health Perspect 110(10): 1025–1029. Find this article online
59. Schwartz J, Litonjua A, Suh H, Verrier M, Zanobetti A, Syring M, et al. 2005. Traffic related pollution and heart rate variability in a panel of elderly subjects Thorax 60(6): 455–461. Find this article online
60. Seaton A, MacNee W, Donaldson K, Godden D 1995. Particulate air pollution and acute health effects Lancet 345(8943): 176–178. Find this article online
61. Shukla A, Timblin C, BeruBe K, Gordon T, McKinney W, Driscoll K, et al. 2000. Inhaled particulate matter causes expression of nuclear factor (NF)-kappaB-related genes and oxidant-dependent NF-kappaB activation in vitro Am J Respir Cell Mol Biol 23(2): 182–187. Find this article online
62. Stolt P, Bengtsson C, Nordmark B, Lindblad S, Lundberg I, Klareskog L, et al. 2003. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases Ann Rheum Dis 62(9): 835–841. Find this article online
63. Stolt P, Kallberg H, Lundberg I, Sjogren B, Klareskog L, Alfredsson L 2005. Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study Ann Rheum Dis 64(4): 582–586. Find this article online
64. Sunyer J 2001. Urban air pollution and chronic obstructive pulmonary disease: a review Eur Respir J 17(5): 1024–1033. Find this article online
65. Sunyer J, Jarvis D, Gotschi T, Garcia-Esteban R, Jacquemin B, Aguilera I, et al. 2006. Chronic bronchitis and urban air pollution in an international study Occup Environ Med 63(12): 836–843. Find this article online
66. Sverdrup B, Kallberg H, Bengtsson C, Lundberg I, Padyukov L, Alfredsson L, et al. 2005. Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case-control study Arthritis Res Ther 7(6): R1296–R1303. Find this article online
67. Symmons DP, Bankhead CR, Harrison BJ, Brennan P, Barrett EM, Scott DG, et al. 1997. Blood transfusion, smoking, and obesity as risk factors for the development of rheumatoid arthritis: results from a primary care-based incident case-control study in Norfolk, England Arthritis Rheum 40(11): 1955–1961. Find this article online
68. Tan WC, Qiu D, Liam BL, Ng TP, Lee SH, van Eeden SF, et al. 2000. The human bone marrow response to acute air pollution caused by forest fires Am J Respir Crit Care Med 161(4 pt 1): 1213–1217. Find this article online
69. Terashima T, Wiggs B, English D, Hogg JC, van Eeden SF 1997. The effect of cigarette smoking on the bone marrow Am J Respir Crit Care Med 155(3): 1021–1026. Find this article online
70. Tonne C, Melly S, Mittleman M, Coull B, Goldberg R, Schwartz J 2007. A case-control analysis of exposure to traffic and acute myocardial infarction Environ Health Perspect 115: 53–57. Find this article online
71. Tracy RP, Psaty BM, Macy E, Bovill EG, Cushman M, Cornell ES, et al. 1997. Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects Arterioscler Thromb Vasc Biol 17(10): 2167–2176. Find this article online
72. Uhlig T, Hagen KB, Kvien TK 1999. Current tobacco smoking, formal education, and the risk of rheumatoid arthritis J Rheumatol 26(1): 47–54. Find this article online
73. U.S. Census Bureau1992 [[accessed 12 June 2005]]. Tiger/Line Files Appendix E: Census Feature Class Codes (CFCC).
74. van Eeden SF, Yeung A, Quinlam K, Hogg JC 2005. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease Proc Am Thorac Soc 2(1): 61–67. Find this article online
75. Venn AJ, Lewis SA, Cooper M, Hubbard R, Britton J 2001. Living near a main road and the risk of wheezing illness in children Am J Respir Crit Care Med 164(12): 2177–2180. Find this article online
76. Venn A, Lewis S, Cooper M, Hubbard R, Hill I, Boddy R, et al. 2000. Local road traffic activity and the prevalence, severity, and persistence of wheeze in school children: combined cross sectional and longitudinal study Occup Environ Med 57(3): 152–158. Find this article online
77. Venn A, Yemaneberhan H, Lewis S, Parry E, Britton J 2005. Proximity of the home to roads and the risk of wheeze in an Ethiopian population Occup Environ Med 62(6): 376–380. Find this article online
78. Vessey MP, Villard-Mackintosh L, Yeates D 1987. Oral contraceptives, cigarette smoking and other factors in relation to arthritis Contraception 35(5): 457–464. Find this article online
79. Voigt LF, Koepsell TD, Nelson JL, Dugowson CE, Daling JR 1994. Smoking, obesity, alcohol consumption, and the risk of rheumatoid arthritis Epidemiology 5(5): 525–532. Find this article online
80. Weiland SK, Mundt KA, Ruckmann A, Keil U 1994. Self-reported wheezing and allergic rhinitis in children and traffic density on street of residence Ann Epidemiol 4(3): 243–247. Find this article online
81. Wjst M, Reitmeir P, Dold S, Wulff A, Nicolai T, von Loeffelholz-Colberg EF, et al. 1993. Road traffic and adverse effects on respiratory health in children BMJ 307(6904): 596–600. Find this article online
82. Zhu Y, Hinds WC, Kim S, Sioutas C 2002. Concentration and size distribution of ultrafine particles near a major highway J Air Waste Manag Assoc 52(9): 1032–1042. Find this article online