We found significant associations and exposure-response patterns between traffic-related air pollution at the residence and risks for cervical and brain cancer.
The strengths of this study include a 10-year prospective follow-up of a relatively large cohort and adjustment for potential confounders. Individual assessment of the exposure of all cohort members allowed us to link air pollution to all major types of cancer. Virtually complete follow-up for incident cancers was possible through nationwide population-based registries, and complete follow-up for vital status was available from the Central Population Registry. Another strength of the study is the availability of residential address histories dating back to 1971, so that exposure could be assessed over several decades. A limitation of this study is the relatively few cases of some types of cancer, although more than 100 cases were identified for 11 of the 20 cancers included. The inclusion of cancers at 20 different sites means that the results should be interpreted with caution. The positive findings for cancers at sites for which there is no or little previous epidemiological evidence of an association with air pollution should be considered as the basis for hypothesis-generating.
Exposure assessment is a major challenge in studies of the health effects of long-term exposure to air pollution. We used three markers of air pollution from traffic at residences, which were moderately correlated (r, 0.43-0.53). The outdoor NOx level at all addresses was calculated over decades from a validated model that requires comprehensive input data; the two other markers are simple, intuitively understandable measures of traffic at the residence at the time of enrolment. The dispersion models we used to assess NOx levels at the addresses of study participants have been successfully validated [34–36] and applied [12, 13, 38]. Although markers of air pollution concentrations are inevitably somewhat uncertain, the resulting non-differential misclassification would create artificial associations only in rare situations . If the geocoding, and therefore also the exposure assessment, failed at an address, we imputed the air pollution concentration from the previous or next address. Since the imputation strategy was identical for all cohort members and the ability of geocoding an address is unlikely to be associated with later development of cancer, we would expect the resulting misclassification of exposure to be non-differential. We minimized the degree of misclassification by including only cohort members for whom air pollution was successfully assessed for at least 80% of the time from 1971 until diagnosis/censoring/end-of-follow up.
This study shows an exposure-response association between concentration of NOx at residence and risk for cervical cancer, and associations were also seen for indicators of traffic at the residence. Occupational exposure to diesel engine exhaust was previously associated with risk for cervical cancer in a study with no adjustment for tobacco smoking , but to our knowledge no study has been conducted of the exposure of the general population to ambient air pollution. We adjusted our analyses for smoking, education, and oral contraceptive use but had no information on human papillomavirus (HPV) infection, which is a major cause of cervical cancer . It is possible that HPV infection is more prevalent among women living in areas with heavy traffic and air pollution. Early findings of associations between smoking and cervical cancer were similarly suspected of confounding by HPV infection, although today smoking is an established risk factor for this cancer. Further, we cannot exclude the possibility that compliance with the nation-wide cervical cancer screening program differs in areas with high and low levels of air pollution due to differences in educational level. However, the educational level differed only little between cohort members living at addresses with high and low air pollution levels  and the results in the present study was adjusted for educational level minimizing the potential for confounding. The hypothesis of an association between air pollution and risk for cervical cancer should be further investigated in a study with control for HPV infection (in addition to other risk factors), preferably with more power than the current study.
We found an exposure-response association between NOx at the residence and risk for brain cancer, which was almost doubled for people living close to a street with high traffic density. In general, the causes of brain cancer remain unknown, although high-dose ionizing radiation and certain genetic syndromes are established risk factors . These, however, seem unlikely to be associated with air pollution at the residential address. A previous study in Denmark indicated a higher risk for brain cancer in association with agricultural class and higher income . These factors are probably inversely associated with air pollution from traffic in Denmark, and, if they were risk factors for brain tumors, we would expect any confounding to have decreased the IRR for brain cancer in association with air pollution. There is growing experimental evidence that ultrafine particles can reach the brain both via the systemic circulation through the blood-brain barrier and via the olfactory neuronal pathway [3, 5], causing an inflammatory response [43, 44]. Further, a recent study showed that exposure to diesel engine exhaust causes functional changes in the human brain indicating cortical stress response . Boeglin et al.  showed an ecological association between emissions of volatile organic compounds and brain cancer incidence rates at county level in the USA; but a large cohort study with individual adjustment for potential confounders showed that people who lived in metropolitan areas with higher air pollution levels measured at routine monitoring network stations did not have a higher risk for death from brain cancer . Although our study is smaller, it has several advantages, including individual exposure assessment, thus accounting for within-city variations in air pollution concentrations, which might explain the difference in results. Furthermore, we studied brain cancer incidence, whereas the US study measured mortality. If survival after brain cancer differs in different metropolitan areas and survival correlates with air pollution levels, the results of a mortality study would differ from those of a study of incidence. We recommend that studies be conducted to replicate our finding of an increased incidence of brain cancer in association with individual-level exposure to air pollution.
We found a borderline significantly increased risk for liver cancer associated with traffic within 200 m of the residence, after adjustment for relevant confounders, although there was no significant association with NOx levels. There is consistent evidence that liver cancer is associated with tobacco smoking . One of the few previous epidemiological studies on ambient air pollution and liver cancer was a retrospective cohort study, which showed an increased risk in urban bus drivers and tramway employees . Mucociliary clearance of particles deposited in the airways usually leads to gastrointestinal exposure due to swallowing, and, in experimental studies, intragastric exposure of animals to diesel exhaust particles induced oxidative stress and DNA damage in the liver . In addition, particles translocated to the circulation accumulated in Kupfer cells in the liver, with very slow elimination and further potential oxidative stress .
Our study also showed that the risk for kidney cancer increased with NOx concentration at the residence. Several studies of occupational groups, such as transport workers, drivers, policemen, metal foundry workers, and gasoline service station workers exposed to gasoline vapors, engine exhaust, PAHs, and other air pollutants, have indicated weakly increased risks for kidney cancer [15, 16, 26], although the literature is neither consistent  nor conclusive . The indication in the present study of an association between ambient air pollution at the residence and risk for kidney cancer in a general population should be confirmed before conclusions can be drawn.
Our study showed a weak, insignificant association between traffic-related air pollution and risk for breast cancer. A recent study in Montreal, Canada, showed that the risk for breast cancer was associated with NO2 concentrations at the residence , and a study in New York, USA, indicated an association between early-life exposure to air pollution at the residence and risk for this cancer . PAH-induced breast tumor mutations might explain any link between air pollution and risk for breast cancer .
Previous studies have shown associations between risks for upper aerodigestive tract cancers and indoor fuel combustion  and occupational exposure to engine exhaust [15–18], and our study also indicated a possible association between ambient traffic-related air pollution and cancers of the buccal cavity and pharynx, although the result was insignificant.
Our results showed a weak, insignificant association between traffic-related air pollution and bladder cancer. The evidence of an association between ambient air pollution and bladder cancer in the general population is not conclusive [19, 20, 30].
Benzene at relatively high occupational concentrations is a known leukemogen, and a few studies have suggested that ambient concentrations near point sources  and near traffic  might be associated with risks for hematological cancers, whereas other studies found no such association [53, 54]. The exposure of the general population to benzene is much lower than the lowest effect level seen in studies of occupational exposure, so that any related risk for leukemia in the general population would probably not be detectable with current methods . Our results are in accordance with this notion.
Although we found associations between NOx concentration and the risks for some cancers, NOx is an indicator of vehicle engine exhaust, which is a complex mixture of many carcinogenic and mutagenic chemicals . The NOx concentration correlates closely with that of particulate matter, especially the ultrafine fraction emitted from diesel engines in Danish streets . Although it is difficult to disentangle the effects of single air pollutants in epidemiological designs, particulate matter from traffic emissions appears to be the most important determinant of cancer risk. Ultrafine particles have a large surface area and contain absorbed PAHs, transition metals and other substances, which cause oxidative stress, inflammation and direct and indirect genotoxicity [56, 57]. Further, there is evidence that ultrafine particles can translocate from the airways to other organs , which might explain our finding of higher risks for cervical and brain cancer in cohort members living at residences with high levels of traffic-related air pollution.