Mohammad Javad

Zare Sakhvidi

Emeline Lequy

Marcel Goldberg

Bénédicte Jacquemin
email: benedicte.jacquemin@inserm.fr

Keywords: Air pollution, Cancer, Mortality, Incidence, Systematic review

Background: Exposure to outdoor air pollution has been linked to lung cancer, and suspicion arose regarding bladder, kidney, and urinary tract cancer (urological cancers). However, most of evidence comes from occupational studies; therefore, little is known about the effect of exposure to air pollution on the risk of urological cancers in the general population.

Method:

We systematically searched Medline, Scopus, and Web of Science for articles investigating the associations between long-term exposure to air pollution and the risk of urological cancer (incidence or mortality). We included articles using a specific air pollutant (PM 10 , PM 2.5 , …) or proxies (traffic, proximity index…). We assessed each study's quality with the Newcastle-Ottawa scale and rated the quality of the body of evidence for each pollutant-outcome with the GRADE approach. The different study methodologies regarding exposure or outcome prevented us to perform a meta-analysis.

Results: twenty articles (four case-control, nine cohort, and seven ecologic) met our inclusion criteria and were included in this review: eighteen reported bladder, six kidney, and two urinary tract. Modeling air pollutants was the most common exposure assessment method. Most of the included studies reported positive associations between air pollution and urological cancer risk. However, only a few reached statistical significance (e.g. for bladder cancer mortality, adjusted oddsratio of 1.13 (1.03-1.23) for an increase of 4.4 µg.m-3 of PM 2.5 ). Most studies inadequately addressed confounding, and cohort studies had an insufficient followup.

Discussion: Overall, studies suggested positive (even though mostly nonsignificant) associations between air pollution exposure and bladder cancer mortality and kidney cancer incidence. We need more studies with better confounding control and longer follow-ups.

Introduction

Sixteen percent of the deaths from non-communicable diseases are attributed to air pollution [START_REF]Ambient air pollution: A global assessment of exposure and burden of disease[END_REF]. Exposure to ambient air pollution has been linked to several health outcomes, including incidence and mortality from cardiovascular, respiratory, and cancerous diseases [START_REF] Guo | The association between lung cancer incidence and ambient air pollution in China: a spatiotemporal analysis[END_REF][START_REF] Turner | Ambient air pollution and cancer mortality in the cancer prevention study II[END_REF][START_REF] Tie | Lung cancer mortality and exposure to atmospheric aerosol particles in Guangzhou, China[END_REF][START_REF] Pope | Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution[END_REF][START_REF] Pope | Relationships between fine particulate air pollution, cardiometabolic disorders, and cardiovascular mortality[END_REF]. Respiratory and cardiovascular effects of air pollution exposure are well demonstrated in both occupational and the general population [START_REF] Cohen | Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015[END_REF].

Most of the available literature on the relationships between air pollution exposure and cancer focused on lung [START_REF] Santibáñez-Andrade | Air pollution and genomic instability: the role of particulate matter in lung carcinogenesis[END_REF][START_REF] Raaschou-Nielsen | Particulate matter air pollution components and risk for lung cancer[END_REF] and child cancers [START_REF] Shmuel | Residential exposure to vehicular traffic-related air pollution during childhood and breast cancer risk[END_REF][START_REF] Pacitto | Particle-related exposure, dose and lung cancer risk of primary school children in two European countries[END_REF], and relied on occupational air pollution exposures [START_REF] Antoni | Bladder cancer incidence and mortality: a global overview and recent trends[END_REF][START_REF] Brown | Occupational cancer in Britain: Urinary tract cancers: bladder and kidney[END_REF]. In 2013, the International Agency for Research on Cancer (IARC) classified outdoor air pollution as a human carcinogen, based on sufficient evidence especially on lung cancer. The IARC also suggested a positive association for bladder cancer [START_REF]Internation Agency for Research on Cancer[END_REF]. The link between outdoor air pollution exposure and bladder cancer was first reported at the end of the 19 th century, based on the findings in a group of workers in the dye industry [START_REF] Dietrich | Ludwig Rehn (1849-1930)-pioneering findings on the aetiology of bladder tumours[END_REF]. Later occupational studies revealed that exposure to several air pollutants (such as polycyclic aromatic hydrocarbon (PAHs) and diesel engine exhausts) are linked with an increased risk for bladder cancer [START_REF] Boffetta | A meta-analysis of bladder cancer and diesel exhaust exposure[END_REF][START_REF] Latifovic | Bladder cancer and occupational exposure to diesel and gasoline engine emissions among Canadian men[END_REF]. However, up to date, new evidence keeps coming out for the general population and other cancer sites including bladder [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF], kidney [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF], and urinary tract [START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF].

The likely shared mechanisms between air pollution and tobacco smoking -an established risk factor for bladder cancer-support the rationale for a link between bladder cancer and air pollution. Excretion of mutagenic metabolites of inhaled air pollutants through the urinary system could also increase the urological system J o u r n a l P r e -p r o o f cells' exposure to carcinogens [START_REF] Hansen | Urinary 1hydroxypyrene and mutagenicity in bus drivers and mail carriers exposed to urban air pollution in Denmark. Mutation research/genetic toxicology and environmental mutagenesis[END_REF]. However, the concentration of air pollutants in the general environment is considerably lower than in occupational settings, and little is known about the effect of general population exposure to air pollution on the risk of urological cancers.

In this review, we aimed to systematically review the available evidence on longterm exposure to air pollution, and surrogate indices of vehicle emissions, with the risk of bladder, kidney, and urinary tract cancers incidence and mortality.

Materials and Methods

Search strategy

This review was conducted according to the Meta-analyses Of Observational Studies in Epidemiology (MOOSE) guidelines [START_REF] Stroup | Metaanalysis of observational studies in epidemiology: a proposal for reporting[END_REF]. We used three databases including Medline, Scopus, and Web of Science (without language restriction) to systematically search for the available literature on the association between longterm exposure to outdoor air pollution (and surrogate indices such as traffic proximity) and bladder, kidney or urinary tract cancer incidence and mortality published until the June 15 th , 2019. Combination of MeSH and non-MeSH keywords related to outdoor air pollution as the exposure of interest: as exposure, particulate matters with an aerodynamic diameter smaller than 2.5 and 10 micrometers (PM 2.5 and PM 10 ), sulfur oxides and dioxide (SO x and SO 2 ), nitrogen oxides and dioxide (NO x and NO 2 ), ozone (O 3 ), carbon monoxide (CO), distance to road, traffic density, and, as the outcome, selected urological cancer incidence and mortality (kidney, bladder, urinary tract and "urinary cancer" in general) were used to search the selected databases (Table S1). We also conducted a manual search J o u r n a l P r e -p r o o f from the reference lists of relevant original studies or reviews to identify any additional documents relevant for this review.

Study selection

After duplicates removal, titles and abstracts were evaluated according to the study inclusion and exclusion criteria by two independent reviewers (M.Z and E.L) (Table S2). The reviewers included all the studies that met these inclusion criteria and reported at least one association between the exposure to one of the air pollutants of interest (PM 10 , PM 2.5 , NO 2 , NO x , SO 2 , O 3 ), or proxies of air pollution exposure, and one of the cancers of interest. In the case of inconsistency between reviewers, the third reviewer (B.J) assessed the eligibility criteria of the study, and then a consensual decision was taken by the three reviewers. Editorials, case reports, reviews, in-vitro, animal studies, as well as studies that reported exclusively the effects of occupational exposure, and indoor air pollutants were excluded. Due to the only recent development of exposure assessment models allowing estimating air pollution at the individual level, we also included studies that used proxies of air pollution exposure such as distance to major roads, traffic, or petrol station densities.

Data extraction

All relevant data including first author name (as the study ID), publication date, study title, location of study, study design, number of participants and cases, follow-up time (for cohort studies), population of interest, age group and sex of participants, exposure assessment method, type of air pollutant or proxy, type of outcome (mortality or incidence), type of cancer, outcome measurement method, J o u r n a l P r e -p r o o f statistical method, type of observed exposure-response relationship (if reported), level of adjustment, the point estimate and 95% confidence intervals (CIs) of crude and adjusted effect size(s) were extracted in a Microsoft Excel sheet.

Quality assessment

Newcastle-Ottawa Scale (NOS):

The quality of each selected case-control and cohort study was assessed by the NOS, which was not applicable for ecologic studies [START_REF] Hartling | Validity and inter-rater reliability testing of quality assessment instruments[END_REF][START_REF] Ajejoe | Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[END_REF]. The NOS is based on eight items distributed in three domains: (i) the selection of study groups, (ii) the comparability of cases and controls (or of exposed and non-exposed participants), and (iii) the ascertainment of exposure/outcome. Using a starring system, all items can earn one star, except the comparability item that can earn up to two stars (first, the studies were checked for adjustment for the minimal required set of a priori defined covariates (here we chose age, sex, occupation, and smoking) and second, they were checked for any further adjustment). The final NOS score of each study sums up the earned stars. We considered studies with exposure assessment via land-use regression or dispersion models linked to residential addresses as a gold standard and highest exposure assessment quality. For cohort studies, a minimum of 10 years was considered a sufficient follow-up time. As we found no universally accepted criterion for the definition of good-quality based on the NOS score, we considered a cut-off score of 6 out of 9 to define good-quality articles. We finally reported the mean NOS score according to the study design and cancer site.

Grading of Recommendations Assessment, Development, and Evaluation system (GRADE):

J o u r n a l P r e -p r o o f

We evaluated the overall quality of the evidence using the GRADE system for each pair of exposure-outcome [START_REF] Swiglo | A case for clarity, consistency, and helpfulness: state-of-the-art clinical practice guidelines in endocrinology using the grading of recommendations, assessment, development, and evaluation system[END_REF]. GRADE is a subjective framework yielding a score between "high", "moderate", "low", and "very low". GRADE starts the evaluation by attributing a score from the study design and then uses eight domains to modify this score. GRADE was initially developed for clinical practice recommendations, for which observational studies were considered low-quality.

Yet in air pollution epidemiology, nearly all studies are observational; therefore, we adapted the original methodology as follows. As a starting point, we considered the cohort and case-control studies as the sources with high-quality evidence, and cross-sectional and ecologic design studies as sources with low-quality evidence.

The original score can upgrade/downgrade according to five downgrading (risk of bias, inconsistency, imprecision, indirectness, and publication bias) and three upgrading domains (dose-response trend, the magnitude of associations, and residual confounding). For the risk of bias, representativeness of population, the origin of controls, inadequate control of confounders, and inadequate follow-up (ten years) were considered. More specifically for the control of confounders, adjustment for major known risk factors of the urinary system cancers such as sex, occupation, age, and smoking was considered necessary to study the possible effect of air pollution. Indeed bladder and kidney cancers are known smoking-related [START_REF] Freedman | Association between smoking and risk of bladder cancer among men and women[END_REF][START_REF] Kiriluk | Bladder cancer risk from occupational and environmental exposures[END_REF][START_REF] Sasco | Tobacco smoking and cancer: a brief review of recent epidemiological evidence[END_REF], and an important proportion of bladder cancer is attributed to occupational exposures [START_REF] Antoni | Bladder cancer incidence and mortality: a global overview and recent trends[END_REF]. Heterogeneity in the effect sizes and non-overlapping of reported confidence intervals were considered as the measures of inconsistency.

Imprecision was considered as a small number of studies (less than three) or studies showing associations in the opposite direction for the same pair of exposure/outcome. The accordance of the population, exposure, and outcome of the studies to the targeted population, exposure, and outcome of this review was considered as a measure of indirectness. In this review, deciding about publication J o u r n a l P r e -p r o o f bias was hard due to the impossibility to perform a meta-analysis and lack of funnel plot or relevant statistical tests. Therefore, we could just consider the omission of reporting certain results in the included papers as possible publication bias. Reporting of an effect size above 1.4 (based on the estimates reported in studies on air pollution and cancer) or of a dose-response relationship, as well as the role of residual confounding, were also considered for upgrading. We considered only one type of residual confounding: cases where the exposure misclassification could shift the association towards the null.

Statistical methods used in the included papers

Studies reported results of associations (crude and/or adjusted) by odds ratio (OR), relative risk (RR), the hazard ratio (HR), incidence rate ratio (IRR), or standardized incidence ratio (SIR), and their corresponding CIs. Because of the diversity of outcomes, air pollutants, and study designs, each exposure-outcome pair included at most four articles, and often with different statistical models and measures of association; therefore, we were unable to perform a meta-analysis. Instead, we reported the quantitative outcomes for those exposure-outcome associations that were available in more than one study in a separate table for each site of cancer.

Results

General characteristics of studies

A total of 2773 items were identified through databases searches (we did not find any non-English paper). We did not find any other articles using other sources.

After duplicate removal, we screened titles and abstracts and selected 70 articles J o u r n a l P r e -p r o o f for full-text evaluation; we excluded 50 articles because they did not meet the inclusion criteria. We found four case-control studies [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF], nine cohort studies [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF][START_REF] Wong | Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle[END_REF], and seven ecologic studies [START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Al-Ahmadi | NO(2) and cancer incidence in Saudi Arabia[END_REF][START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF][START_REF] Eitan | Spatial analysis of air pollution and cancer incidence rates in Haifa Bay, Israel[END_REF][START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF][START_REF] Yeh | Spatial Analysis of Ambient PM2.5 Exposure and Bladder Cancer Mortality in Taiwan[END_REF][START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF], totalizing 20 articles included into this review (Figure 1, Table 1 andTable 2). All of these studies were conducted since 2004, and since 2010 for 85% (n=17) of them (19, 20, 22-25, 34, 35, 37-45). Nine studies took place in Asia (20, 21, 24, 39-42, 44, 45), nine in Europe [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF] and two in North America [START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF][START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF]. Five of the Asian studies were ecologic (40-42, 44, 45), with two case-control studies [START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF] and two cohort studies [START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Wong | Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle[END_REF]. European studies included one ecologic study [START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF], two case-control studies [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF], and six cohort studies [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF]. In the casecontrol studies, the number of cases ranged between 680 [START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF] and 1641(20) (sum of cases across all case-control studies: 4478). In the cohort studies, the number of outcomes ranged between 73 [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF] and 1324 [START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF], with total of 5438 cases across all cohorts.

Quality assessment

Tables 3 and4 and Figure 2 report quality scores of the selected cohort and casecontrol studies respectively (as stated in the methods section, the NOS was not applicable for ecologic studies). Pooling all relevant articles, we estimated an average NOS score of 6.58, which is higher than our cut-off of six which defines good-quality.

The seven cohort studies on bladder cancer earned between 3 and 9 stars and five of them earned a NOS score of six or higher. Exposure and outcome assessment domain was the strongest domain across studies, whereas the adequacy of followup and comparability (in terms of the adequacy of adjustment for confounders) was the weakest domain. The four case-control studies on bladder cancer earned J o u r n a l P r e -p r o o f between four and six stars (only one study earned six stars). The strongest items in the case-control studies were using the same method of exposure assessment and ascertainment for both cases and controls across studies and also control selection.

None of the case-control studies reported a response rate.

The four cohort studies on kidney cancer all earned at least 6 stars (mean NOS score: 7.75), and the two cohort studies on urinary tract cancers earned 7 and 9 stars: they were considered of good-quality with the same weak points as the cohort studies on bladder cancer (follow-up inadequacy and lack of comparability).

GRADE assessment

The GRADE approach was used to assess the overall quality of the evidence of the nine exposure-outcome pairs that were investigated by two or more studies (all were on bladder cancer risk) (Table S3-S11). In most cases, the level of evidence was very low, except for "PM 10 and bladder cancer mortality" and "NO 2 and bladder cancer mortality" (Figure 2). The most frequent limitation concerned "indirectness" due to the few numbers of studies for each pair, especially PM 2.5 and bladder cancer mortality. The risk of bias was quite high, due to insufficient follow-up time, unclear case definition, imprecise exposure assessment, lack of representativeness, and residual confounding, decreasing the score on the quality of evidence for all exposure-outcome pairs except for bladder cancer incidence and PM 2.5 . The available evidence for bladder cancer mortality and exposure to NO 2 or PM 10 was consistent. However, for the other exposure-outcome pairs, we downgraded the evidence quality because of inconsistency. The magnitude of the reported effect size was generally lower than 1.4 (except for NO 2 and PM 10 with bladder cancer mortality). The lack of sufficient evidence of a dose-response relationship prevented us from upgrading the score in this domain. Potential J o u r n a l P r e -p r o o f exposure misclassification (as a measure of residual confounding in this review) was observed for all reported exposure-outcome pairs, except NOx exposure and bladder cancer incidence.

Exposure assessment

Different air pollutants or proxies of air pollution with different quantification approaches were used across the studies (Table 1 and2; Figure 2). Among classic air pollutants, studies reported results for PM 10 (21-23, 25, 34, 35, 42), PM 2.5 [START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF][START_REF] Wong | Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle[END_REF][START_REF] Yeh | Spatial Analysis of Ambient PM2.5 Exposure and Bladder Cancer Mortality in Taiwan[END_REF][START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF], PM 2.5 absorbance [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF], organic carbon in PMs [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF], and elemental composition of PMs [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF]; and for gases NO x [START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF], NO 2 [START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF][START_REF] Al-Ahmadi | NO(2) and cancer incidence in Saudi Arabia[END_REF], SO x [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF], SO 2 [START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Eitan | Spatial analysis of air pollution and cancer incidence rates in Haifa Bay, Israel[END_REF], hydrogen sulfide [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF], O 3 [START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF], CO [START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF], and benzene [START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF]. NO 2 , PM 2.5, and PM 10 were the most used air pollutants across studies (each one reported in seven studies).

Air pollution modeling was the most common method of exposure assessment in the selected studies, whether by dispersion modeling [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF], land-use regression [START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF][START_REF] Wong | Cancer Mortality Risks from Long-term Exposure to Ambient Fine Particle[END_REF], remote sensing [START_REF] Al-Ahmadi | NO(2) and cancer incidence in Saudi Arabia[END_REF][START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF], interpolation [START_REF] Eitan | Spatial analysis of air pollution and cancer incidence rates in Haifa Bay, Israel[END_REF] and kriging [START_REF] Yeh | Spatial Analysis of Ambient PM2.5 Exposure and Bladder Cancer Mortality in Taiwan[END_REF]. One study used stationary stations measurements of criteria air pollutants at the municipality level [START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF]. Seven studies also reported results for proxies of air pollution such as traffic density, presence of major roads near residential addresses [START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF], window facing traffic [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF], type and quantity of traffic, petrol station density near the residential area [START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF], and annual total waste gas emission at the state level [START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF]. The exposure assessment method was unclear in one study [START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF].

Reported outcomes

J o u r n a l P r e -p r o o f

We considered cancer incidence or mortality separately. Different approaches were used across studies to assess the outcome. Most of the studies used data from national or regional cancer registries (23-25, 34-37, 40-45), however, two casecontrol studies used data from hospital registries [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF], and five others used death certificates (20-22, 38, 39). Hereafter, we will summarize the evidence on each cancer site (bladder, kidney, and urinary tract), first regarding incidence and then mortality.

Bladder cancer

Eighteen studies reported bladder cancer incidence and/or mortality data (Table 1), including seven cohort studies [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF] with total cancer cases of 3219, four case-control studies with a total of 4478 cases [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF][START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF], and seven ecologic studies [START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Al-Ahmadi | NO(2) and cancer incidence in Saudi Arabia[END_REF][START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF][START_REF] Eitan | Spatial analysis of air pollution and cancer incidence rates in Haifa Bay, Israel[END_REF][START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF][START_REF] Yeh | Spatial Analysis of Ambient PM2.5 Exposure and Bladder Cancer Mortality in Taiwan[END_REF][START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF]. Five of the cohort studies [START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF][START_REF] Collarile | Residence in Proximity of a Coal-Oil-Fired Thermal Power Plant and Risk of Lung and Bladder Cancer in North-Eastern Italy. A Population-Based Study: 1995-2009[END_REF][START_REF] Pedersen | Is There an Association Between Ambient Air Pollution and Bladder Cancer Incidence? Analysis of 15 European Cohorts[END_REF][START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF], two of the case-control studies [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF], and five of the ecologic studies [START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Al-Ahmadi | NO(2) and cancer incidence in Saudi Arabia[END_REF][START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF][START_REF] Eitan | Spatial analysis of air pollution and cancer incidence rates in Haifa Bay, Israel[END_REF][START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF] dealt with bladder cancer incidence; six (20-22, 38, 43, 44) (including two cohorts [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF], two casecontrols [START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF] and two ecologic studies [START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF][START_REF] Yeh | Spatial Analysis of Ambient PM2.5 Exposure and Bladder Cancer Mortality in Taiwan[END_REF]) dealt with bladder cancer mortality.

Bladder cancer incidence

Among 26 associations (excluding correlation coefficients) on five air pollutants (excluding proxies), we found one null and six point-estimates below one, and all the other ones were above one (Table 5). But only three associations reached the statistical significance, for NO 2 (34) and PM 2.5 [START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF]. Unexpectedly, one of the cohort studies found a higher SIR in the areas with lower traffic intensity score compared to the areas with higher traffic intensity (SIR: 1.16 vs. 0.87) [START_REF] Visser | Residential traffic density and cancer incidence in Amsterdam, 1989-1997[END_REF]. The J o u r n a l P r e -p r o o f two case-control studies [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF][START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF] -using the same epidemiologic data but different exposure measures (PM 2.5 and NO 2 [START_REF] Turner | Ambient air pollution and incident bladder cancer risk: Updated analysis of the Spanish Bladder Cancer Study[END_REF]; and windows facing traffic and type and quantity of traffic( 18))-found positive but not significant associations between exposures and bladder cancer incidence, and larger point estimates for nonsmokers and women (but still statistically non-significant). In contrast to these cohorts and case-control studies, four ecologic studies [START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Al-Ahmadi | NO(2) and cancer incidence in Saudi Arabia[END_REF][START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF][START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF] found significant positive associations between at least one air pollution measure and bladder cancer incidence. However, the pollutants of interest in all these studies were different and it was impossible to compare the results.

Bladder cancer mortality

Among 17 associations on five air pollutants and bladder cancer mortality from non-ecological studies, only one point-estimate was below one, the others were positive (with generally higher point-estimates than for bladder cancer incidence) and actually, six reached statistical significance [START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF][START_REF] Radespiel-Troger | Cancer incidence in urban, rural, and densely populated districts close to core cities in Bavaria, Germany[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF]. Further, Liu et al.

(2009) found significant p for trends across tertiles of exposure for NO 2 , SO 2 , and PM 10 -although in unadjusted models. When using a pollution index (combining NO 2 and SO 2 ), they also found a significant p for trend. When analyzing associations in subgroups of the population, Ancona et al. [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF] found a positive and significant association between bladder cancer mortality and hydrogen sulfide exposure in women (HR=1.35; 95% CI: 1.00-1.82); Turner et al [START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF] reported a significant association with PM 2.5 only for men, never smokers and those with at least high school education. In Taiwan [START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF][START_REF] Liu | Ambient exposure to criteria air pollutants and risk of death from bladder cancer in Taiwan[END_REF], the case-control studies found a significant positive association between the days with ozone pollution (as a measure of short-term exposure to air pollution) and bladder cancer mortality(21), J o u r n a l P r e -p r o o f but no association with the density of petrol stations near the residential addresses [START_REF] Ho | Traffic air pollution and risk of death from bladder cancer in Taiwan using petrol station density as a pollutant indicator[END_REF].

Three ecologic studies reported inconsistent results for PM 2.5 : a non-significant association [START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF], a significantly positive association [START_REF] Yeh | Spatial Analysis of Ambient PM2.5 Exposure and Bladder Cancer Mortality in Taiwan[END_REF], and a significantly negative association [START_REF] Wang | An urban-rural and sex differences in cancer incidence and mortality and the relationship with PM2.5 exposure: An ecological study in the southeastern side of Hu line[END_REF]. Smith et al. also found a significant association between bladder cancer mortality and ozone days [START_REF] Smith | Bladder Cancer Mortality in the United States: A Geographic and Temporal Analysis of Socioeconomic and Environmental Factors[END_REF].

Kidney cancer

Five studies -including four cohorts [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF] and one ecologic study [START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF] reported associations between kidney cancer and air pollution (Table 2). Two studies [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF] dealt with kidney cancer mortality and three [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF][START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF] with kidney cancer incidence. The two cohort studies [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF][START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF] on kidney cancer incidence included 792 cases. For kidney cancer mortality, the largest study was from "the Cancer Prevention Study-II" with 927 cases [START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF]. Another study was based on the data from 14 European cohorts of the ESCAPE study with 697 kidney cancer incidence cases [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF].

Kidney cancer incidence

The five associations between kidney cancer incidence and three air pollutants were all positive but none reached statistical significance [START_REF] Raaschou-Nielsen | Air pollution from traffic and cancer incidence: a Danish cohort study[END_REF][START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF]. One of the two studies investigating NOx reported a point estimate larger than 1.4 (Table 6). The study pooling 14 European cohorts [START_REF] Raaschou-Nielsen | Outdoor air pollution and risk for kidney parenchyma cancer in 14 European cohorts[END_REF] reported heterogeneous findings across cohorts. The ecological study reported a significant positive correlation between waste gas emissions and kidney cancer incidence; the analyses by sex indicted J o u r n a l P r e -p r o o f significant correlations for both men and women with a coefficient of 0.8 for male -twice as high as for women [START_REF] Cong | Air pollution from industrial waste gas emissions is associated with cancer incidences in Shanghai, China[END_REF].

Kidney cancer mortality

The two cohort studies on air pollution and kidney cancer mortality [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF][START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF] did not investigate the same air pollutant. Turner et al. [START_REF] Turner | Ambient Air Pollution and Cancer Mortality in the Cancer Prevention Study II[END_REF] found a significant association with PM 2.5 (HR= 1.14; 95% CI:1.03-1.27), but not for NO 2 or O 3 . The analyses on subgroups showed that this association was only significant among men and current smokers. Ancona et al. [START_REF] Ancona | Mortality and morbidity in a population exposed to multiple sources of air pollution: A retrospective cohort study using air dispersion models[END_REF] found no significant association between kidney cancer mortality and NO 2 , PM 10 , hydrogen sulfide or SO X exposure.

Urinary tract cancer

Two cohort studies reported associations between air pollution exposure and urinary tract cancer incidence [START_REF] Cohen | Chronic exposure to trafficrelated air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study[END_REF] and mortality(39) (Table 2). Both studies found non-significant associations between these outcomes and exposure to selected air pollutants.

Discussion

In this study, we reviewed the available body of evidence on the association between the bladder, kidney, and urinary tract cancers incidence and mortality and J o u r n a l P r e -p r o o f air pollution exposure, concluding to a suggestive association between kidney and bladder cancer risk and air pollution.

Indeed, overall five cohorts found small to moderate positive associations especially for bladder and kidney cancer mortality (even mostly non-significant) with different air pollutants exposure. Five out of seven ecological studies found a significant increase in the risk of bladder and kidney cancer incidence and mortality. Evidence on the association between air pollution exposure and kidney cancer seems stronger compared to bladder cancer, as we found proportionally more papers with positive and significant associations even if based on only three studies. Additionally, for bladder cancer, the results on mortality were more suggestive than on incidence. Most of the studies included had an acceptable quality in terms of NOS score, and the weakest point was generally low quality in adjustment and insufficient follow-up time (in the case of cohort studies). In total, the quality of evidence on the associations between air pollutants and bladder cancer was very low or low. The use of different exposure indices, statistical approaches, effect sizes, outcomes, and study designs made it impossible to do a meta-analysis.

The currently available evidence on the association of bladder and kidney cancer incidence and mortality with air pollution exposure comes mostly from occupational environments concerning exposure to gasoline vapors [START_REF] Latifovic | Bladder cancer and occupational exposure to diesel and gasoline engine emissions among Canadian men[END_REF], chlorinated solvents [START_REF] Buhagen | Association between kidney cancer and occupational exposure to trichloroethylene[END_REF][START_REF] Purdue | Occupational exposure to chlorinated solvents and kidney cancer: a case-control study[END_REF], asbestos [START_REF] Peters | Workplace exposure to asbestos and the risk of kidney cancer in Canadian men[END_REF], pesticides [START_REF] Koutros | Occupational exposure to pesticides and bladder cancer risk[END_REF] and PAHs [START_REF] Boffetta | Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons[END_REF]. A review and meta-analysis found an increased risk of urinary bladder cancer in motor vehicle drivers, who were occupationally exposed to a considerable amount of traffic-related air pollution [START_REF] Manju | Urinary bladder cancer risk among motor vehicle drivers: a meta-analysis of the evidence, 1977-2008[END_REF]. However, even if the intensity of air pollution exposure in the general population is considerably lower than for the drivers and J o u r n a l P r e -p r o o f industrial workers, considering lifetime exposure in the general population, it is reasonable to suppose that the exposure to air pollution could be associated with an increased risk of urinary tract cancers. Several mechanisms could explain the relationship between exposure to air pollution and urological cancer. For instance, recent animal studies have shown that exposure to PM 2.5 can induce angiotensin/bradykinin system imbalance, subsequent early kidney damage and oxidative stress, and/or inflammation, which finally can cause cancer [START_REF] Aztatzi-Aguilar | Early kidney damage induced by subchronic exposure to PM 2.5 in rats[END_REF]. A glomerular filtration rate reduction was also associated to exposure to particulate matters in those living near a major roadway [START_REF] Lue | Residential proximity to major roadways and renal function[END_REF] and also in those exposed to particulate matter [START_REF] Mehta | Long-term exposure to ambient fine particulate matter and renal function in older men: the veterans administration normative aging study[END_REF]; this reduced glomerular filtration rate could be a predictor of kidney and bladder cancer recurrence and progression [START_REF] Rausch | Impaired estimated glomerular filtration rate is a significant predictor for non-muscleinvasive bladder cancer recurrence and progression-Introducing a novel prognostic model for bladder cancer recurrence[END_REF][START_REF] Iff | Reduced estimated GFR and cancer mortality[END_REF]. These physiological findings suggest that exposure to air pollutants could induce lesions on the urinary system ultimately leading to urological cancers.

One of the main weaknesses of the non-ecological included studies was an inadequate adjustment for confounders. In addition to the main confounding variables described above, several studies have reported an association between environmental tobacco smoke (passive smoking) and kidney [START_REF] Theis | Smoking, environmental tobacco smoke, and risk of renal cell cancer: a population-based case-control study[END_REF] and bladder cancer [START_REF] Yan | Secondhand smoking increases bladder cancer risk in nonsmoking population: a meta-analysis[END_REF][START_REF] Tao | Environmental tobacco smoke in relation to bladder cancer risk-the Shanghai bladder cancer study[END_REF]. Not only not all of the selected papers in our review adjusted their analyses for smoking status, but none of them considered passive smoking exposure. Additionally, ecological studies could not include these variables in their models because of their natural design limitations. The other main weakness of the non-ecological studies was that they did not consider an adequate follow-up time.

In addition, another major issue concerns the air pollution exposure assessment: since cancer occurrence is a chronic process, and since the spatial patterns of the environmental stressors may change over the years as well as studies' participants may move, taking a unique exposure value in the analyses may lead to exposure J o u r n a l P r e -p r o o f misclassification. Considering that for the long-term exposure there is more spatial than temporal variability, taking one value as an exposure poses a problem especially for people moving over time [START_REF] Shekarrizfard | An examination of population exposure to traffic related air pollution: Comparing spatially and temporally resolved estimates against long-term average exposures at the home location[END_REF]. Most of the selected studies do not include information on historic exposures at the individual level. Another important yet seldom addressed the question in the available literature is how long the latency period between air pollution exposure and cancer outcomes should be considered in the statistical analyses. Therefore, because the selected studies used air pollutant exposures that do not necessarily take into account the long latency period between exposure and occurrence of outcomes, the co-occurrence of several environmental exposures, and the historic exposures, their analyses may yield biased risk estimates.

Other limitations of the included studies are the following. Ambient air pollution and noise usually co-occur in the environment [START_REF] Davies | Correlation between co-exposures to noise and air pollution from traffic sources[END_REF]. Recent studies suggest a possible association between noise exposure and cancer [START_REF] Roswall | Modeled traffic noise at the residence and colorectal cancer incidence: a cohort study[END_REF][START_REF] Roswall | Residential road traffic noise exposure and colorectal cancer survival-A Danish cohort study[END_REF]. Considering noise exposure, the existence or type of insulation, and opening or closing pattern of windows or time-activity patterns of participants in future studies is advisable.

Additionally, the inclusion of the role of indoor air pollution is also worthwhile. Castaño et al. [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF] found that living more than 40 years in a city with a population of more than 100,000 was associated with an increased risk for bladder cancer.

Exposure to air pollution could be an underlying cause of the urban-rural difference in cancer incidence and mortality. However, other factors such as a different lifestyle and different environmental exposures in rural and urban areas (such as higher noise, or light at night exposures and lower green space access for urban-dwellers) should not be neglected. All of these factors are correlated and could be regarded as underlying factors in the etiology of the cancers.

J o u r n a l P r e -p r o o f

Different measures of air pollution exposure were reported in the studies selected in this review. Two studies based on the same epidemiologic data, but using either direct air pollution measures or proxies to assess exposure, found similar results: this indicates the comparability of this two exposure assessment approaches.

Traffic indicators seem to be a good alternative in the case of data paucity to predict long-term exposure to air pollutants [START_REF] Brauer | Estimating long-term average particulate air pollution concentrations: application of traffic indicators and geographic information systems[END_REF]. However, proximity models may lead to greater misclassification than models based on direct air pollution measurements, such as land use regression [START_REF] Ryan | A comparison of proximity and land use regression traffic exposure models and wheezing in infants[END_REF]. Both approaches are based on the residential addresses of the participants, and relying only on residential addresses can increase the risk of non-differential misclassification. Without knowing the activity pattern of the participants, such as commuting to the workplace, it is not possible to know their precise exposure. Additionally, relying on self-report, as noticed in some studies [START_REF] Castano-Vinyals | Air pollution and risk of urinary bladder cancer in a case-control study in Spain[END_REF], could introduce further bias. Given the availability of modeling data on air pollutants or traffic measures, the limiting step in the ecologic studies is the spatial resolution of outcome data instead of exposure. For example, in most studies, the exposure data are available in finer resolution (several kilometers'), compared to the outcomes (mostly reported in the level of the region or district).

Strengths and limitations

To our knowledge, this is the first systematic review on the association between air pollution exposure in the general population and bladder, kidney, and urinary tract cancer incidence and mortality. We found only one review on the associations between exposure to particulate matters and urological cancers in the general J o u r n a l P r e -p r o o f population [START_REF] Kim | Particulate matter (fine particle) and urologic diseases[END_REF]. However, it was not a systematic but narrative review, which focused only on PM. Moreover, more than half of the studies included in our review have been published between 2015 and 2019, whereas the previous one included articles up to 2017: therefore an updated review of the evidence seemed useful necessary. In this review, we collected evidence from all types of study design and using different direct and indirect air pollution exposure metrics.

Another strength of our review is that we encompassed both incidence and mortality evidence, which could give a broader insight into the possible associations between air pollution and urologic cancer. Using a strict quality assessment tool made it possible to compare the quality of the studies. However, our study suffers from several limitations. First of all, due to huge heterogeneity in the exposure metrics, study design, type of outcomes, and cancers and reported effect sizes, it was impossible to do a meta-analysis. We also were unable to detect publication bias in our study objectively. Additionally, nearly one-third of the selected studies were ecologic in design, and we were unaware of the standard and applicable instrument to measure and rank the quality across ecologic studies.

Conclusion

The results of this review showed a suggestive association between kidney and bladder cancer risk and air pollution. However, the diversity of outcomes, air pollutants, and study designs prevented us to conduct a meta-analysis, and furthermore, we identified several major shortcomings in many studies. Therefore, the results of our review could be used in the conduction and design of future studies for the assessment of the associations between ambient air pollution and cancer especially bladder and kidney cancer. Future studies should consider a J o u r n a l P r e -p r o o f more comprehensive adjustment, and more accurate exposure assessment and ascertainment methods.

Funding

This study was supported by the ARC Foundation which funded the OCAPOL study (A longitudinal observatory of the effects of chronic exposure to outdoor air pollution on cancer risk) within the framework of the CANC'AIR call (CANCAIR-201501234).

Role of the funding source

The study funder did not contribute to the study design, data collection, data analysis, data interpretation, or writing of this manuscript. The corresponding author had full access to all the data used in this study and had final responsibility for the decision to submit for publication.

Contributors

MZ, EL, and BJ contributed to the study design. MZ and EL did the evidence screening. BJ contributed to the selection of papers with no-consensus by MZ and EL. MZ took the lead in drafting the manuscript. All authors contributed to the interpretation of data, provided critical revisions to the manuscript, and approved the final draft.

Declaration of Competing Interest

J o u r n a l P r e -p r o o f

List of Figures

Figure 1. PRISMA flow diagram for the systematic review of the association between air pollution exposure and the risk of selected urological cancers. Figure 2. Evidence map of the association between urological cancer and air pollutants. The left panel shows the total number of studies (number of ecological studies between parentheses), color-coded based on the number of available studies (from light green for 1 to dark green for 4). The right panel shows, for bladder cancer, the strength of the evidence assessed for each studies using the NOS score as y-axis (here we present the average of the NOS score by pollutant and outcome, and the line depicts a NOS score of 6, our cut-off to define good-quality articles), and for each pair of outcome-pollutant using the GRADE approach. Table 1. Summary of finding for the association between exposure to air pollution and bladder cancer risk Table 2. Summary of finding for the association between exposure to air pollution and kidney and urinary system cancer risk Table 3. Newcastle-Ottawa Scale (NOS) score for the cohort studies on the association between air pollution exposure and bladder, kidney, and urinary cancer risk Table 4. Newcastle-Ottawa Scale (NOS) score for the case-control studies on the association between air pollution exposure and bladder, kidney, and urinary cancer risk Table 5. Reported associations between exposure to outdoor air pollution exposure and bladder cancer risk Table 6. Reported associations between exposure to outdoor air pollution exposure and kidney and urinary cancer risk Table S3: GRADE assessment for the association between exposure to PM 10 and risk of bladder cancer incidence Table S4: GRADE assessment for the association between exposure to PM 10 and bladder cancer mortality Table S5: GRADE assessment for the association between exposure to PM 2.5 and risk of bladder cancer incidence Table S6: GRADE assessment for the association between exposure to PM 2.5 and bladder cancer mortality Table S7: GRADE assessment for the association between exposure to NO 2 and risk of bladder cancer incidence Table S8: GRADE assessment for the association between exposure to NO 2 and risk of bladder cancer mortality Table S9: GRADE assessment for the association between exposure to NO x and risk of bladder cancer incidence Table S10: GRADE assessment for the association between exposure to SO 2 and risk of bladder cancer incidence Table S11: GRADE assessment for the association between exposure to O 3 and risk of bladder cancer mortality J o u r n a l P r e -p r o o f Most of the studies were ecologic and the source of outcome data was not clear in one of them. Due to the nature of ecologic studies, the risk of bias was high.

List of Tables

J o u r n a l P r e -p r o o f

Downgrade

Inconsistency Direction and the value of the effect sizes were different across studies.

Downgrade Indirectness

The methods of exposure assessment and allocation across the studies were different. However, the population and outcome were similar.

No change Imprecision

The point estimates and confidence intervals were not consistent.

Downgrade Publication bias

Given the comprehensive search, it seems little even no publication bias. However, we were not able to check it objectively. The risk of bias in the cohort study was high. Also considering the low quality of ecologic studies per se, the overall quality of methodological issues is not satisfactory.

Downgrade Inconsistency

The point estimate of the observed risk in studies was 1.02 to 1.39 however all of them reported an increase in the risk. The confidence intervals (especially in the ecologic study) are wide.

Downgrade

Indirectness

Given the ecologic allocation of exposure to the population in one of the studies, there is a heterogeneity in the exposure assessment methods.

Downgrade Imprecision

The number of studies is limited (n=2). The judgment will be changed according to the selection of each side of the confidence interval.

Downgrade

Publication bias Given the comprehensive search, it seems little even no publication bias. However, we were unable to objectively evaluate the possible publication bias.

Figure 1 .

 1 Figure 1. PRISMA flow diagram for the systematic review on the association between air pollution exposure and the risk of selected urological cancers.

Figure 2 .

 2 Figure 2. Evidence map of the association between urological cancer and air pollutants. The left panel shows the total number of studies (number of ecological studies between parentheses), color-coded based on the number of available studies (from light green for 1 to dark green for 4). The right panel shows, for bladder cancer, the strength of the evidence assessed for each studies using the NOS score as y-axis (here we present the average of the NOS score by pollutant and outcome, and the line depicts a NOS score of 6, our cut-off to define good-quality articles), and for each pair of outcome-pollutant using the GRADE approach.

5 [

 5 cancer incidence"[Title/Abstract]) OR "incidence of cancer"[Title/Abstract]) OR "cancer mortality"[Title/Abstract]Title/Abstract]) OR pm10[Title/Abstract]) OR o3[Title/Abstract]) OR ozone[Title/Abstract]) OR no2[Title/Abstract]) OR "nitrogen dioxide"[Title/Abstract]) OR "carbon monoxide"[Title/Abstract]) OR so2[Title/Abstract]) OR "Sulfur dioxide"[Title/Abstract]) OR "Sulphur dioxide"[Title/Abstract]) OR "air pollutants"[Title/Abstract]) OR "air pollution"[Title/Abstract]) OR "particulate matter"[Title/Abstract]) OR "Ambient air"[Title/Abstract]) OR "Air quality"[Title/Abstract])) OR ((((("Air Pollution"[Mesh]) OR "Particulate Matter"[Mesh]) OR "Air Pollutants" [Mesh]) OR "Vehicle Emissions"[Mesh]) OR "Traffic-Related Pollution"[Mesh])) r n a l P r e -p r o o f

  Unclear Dose-response trend None of the studies reported the dose-response trend. No change Magnitude of associations The magnitude of effect sizes was large enough to upgrade the level of evidence. No change Residual confounding Three studies used area-level measures of exposure. No change Overall judgment Very low 950 951 J o u r n a l P r e -p r o o f

  UnclearDose-response trendNo report.No change Magnitude of associationsIn all reported associations the magnitude of the effect sizes was below 1r n a l P r e -p r o o f

Table 1 . Summary of findings for the association between exposure to air pollution and bladder cancer risk 882

 1

	First			Design;	number	of	Case definition	Exposure	assessment	Adjustment	Findings
	author(year);		cases/outcomes				and metrics
	study location ‡
	Turner	et	al.	Case-control (case: 938)	Incidence		LUR	(PM 2.5 ;	NO 2 );	Age group, sex, region, smoking,	No clear association either for ambient PM 2.5 or
	(2019); Spain					(histologically	windows facing a street	high-risk occupations	NO 2 . No evidence for a trend.
							confirmed	hospital	with traffic (including
							cases)		number of traffic lanes
									and traffic intensity)
	Wang (2019); China et Cong et (2018); China Cohen et (2018); Israel	al. al. al.	Ecologic study Ecologic study Cohort (outcome: 74)		Incidence mortality registry and mortality and (cancer data) Incidence (cancer registry) Incidence (cancer registry) J o u r n a l P r e -p r o o f Remote sensing (PM 2.5 ) Unclear Annual waste gas emissions (total volume of waste gas, industrial waste gas, other waste gas, SO 2 , and soot) Sex, number of doctors per 10,000 population, education, Engel's coefficient LUR (NO X ) Sex, smoking, neighborhood socioeconomic status, ethnicity, hypertension, diabetes, chronic heart and renal failure, hemoglobin levels	A positive association between PM 2.5 exposure and bladder cancer incidence, but a negative association for bladder cancer mortality. A significant association for annual waste gas emission and bladder cancer incidence trend. The gender-specific analysis was only significant for men. A non-significant and small positive association was found. The effect size did not change after adjustment.
	Collarile et al.	Cohort (outcome: 650)		Incidence	(cancer	Dispersion model (C 6 H 6 ,	Unclear	Only in women aged 75 years or older the risk
	(2017); Italy					registry)		NO 2 , PM 10 , SO 2 )	increased by increasing exposure to benzene and
											NO 2 . The associations for PM 10 or SO 2 were not
											linear.
	Radespiel-Troger	Ecologic study		Incidence	(Cancer	Dispersion model (PM 10 )	Age, deprivation, age-adjusted	A significant positive association between PM 10
	et al.	(2017);				registry)				lung cancer and chronic liver	exposure and bladder cancer in both sexes. The
	Germany										disease mortality rate	relative risk in males was lower than females.
	Pedersen et al. 15 prospective cohort	Incidence	(cancer	LUR (PM 10 ; PM 2.5 ; PM 2.5	Age, sex, calendar time; smoking,	No association.
				(outcome: 943)		registry)		absorbance; NO 2 ; NO x ;	occupation,	employment,

Table 2 . Summary of finding for the association between exposure to air pollution and kidney and urinary system cancer risk 889 890

 2

	First	author	Design;	number	of	Case definition		Exposure	assessment	Adjustment	Findings
	(year);	study	case/outcome					and metrics
	location ‡
	Cong	(2018);	Ecologic study		Kidney	cancer	Annual	waste	gas	Sex, number of doctors per	A significant association for kidney cancer
	China					incidence	(cancer	emissions (total volume	10,000 population, education,	incidence. The effect size was higher for males.
						registry)			of waste gas, industrial	Engel's coefficient
	Raaschou-Nielsen (2017); Europe Raaschou-Nielsen (2011); Denmark	Cohort (outcome: 697) Cohort (outcome: 95)		Kidney incidence registry) Kidney incidence registry)	waste gas, other waste gas, SO 2 , and soot) LUR (PM 10 ; PM 2.5 ; PM 2.5 absorbance; NO 2 ; NO x ; traffic intensity; PM elements; organic carbon in PM) LUR (NO x ), presence of a major road within 50 m, Per 10 4 vehicle km/day within 200 m J o u r n a l P r e -p r o o f cancer (cancer Age, sex, calendar time; smoking, occupation, employment, and education; area-level socio-economic status cancer (cancer BMI, smoking, hypertension, education, occupation	Higher HR in association with higher PM 2.5 concentration and PM 2.5 absorbance. HR of NO x and traffic density on the nearest street were slightly above one. Effect estimates in non-movers were slightly stronger than movers. A significant increase in kidney cancer risk in crude models, but disappeared in the adjusted model.
	Turner	(2017);	Cohort (outcome: 927)		Kidney	cancer	LUR (PM 2.5 ; NO 2 ; O 3 )	Age, gender, race, education,	Significant positive associations of PM 2.5 in
	USA					mortality (Cause of			marital status; BMI; smoking,	minimally and fully adjusted models. PM 2.5
						death	from	the			dietary intake, consumption of	results were only significant for men, never
						questionnaire)				alcoholic beverages; occupational	smokers, and those with at least high school
											exposures	education.
	Ancona et al.	Cohort (outcome: 54)		Kidney	cancer	Dispersion	modeling	Sex, age, education, occupation,	No significant associations were found.
	(2015); Italy				mortality (registry of	(PM 10 ; H 2 S; SO X )	civil status, area-based SEP
						causes of death)				index, and outdoor NO 2

Table 4 . Newcastle-Ottawa Scale (NOS) score for the case-control studies on the association between air pollution exposure and bladder, kidney, and urinary cancer risk

 4

	Outcome	Study (first author and year)	Case	Representati	Control	Control	Compara	Exposure	Same	Response	NOS score
			definitio	veness	selection	definition	bility	assessment	exposure	rate
			n						method
	Bladder	Castano-Vinyals et al. (2008)	1	0	0	1	2	0	1	0	5
	cancer	Liu et al. (2009)	0	1	0	1	0	1	1	0	4
		Ho et al. (2010)	0	1	1	1	0	0	1	0	4
		Turner et al. (2019)	1	0	0	1	2	1	1	0	6

Table S1 . The sample search algorithm used for literature search on outdoor air pollution exposure (as an exposure) and selected urological cancer incidence and/or mortality (as an outcome) on PubMed (https://www.ncbi.nlm.nih.gov/pubmed/). Last updated on June 15, 2019.

 S1

	#	Search query							Numbers of items
									found
	1	(((((((((Urological[Title/Abstract]) OR Urologic[Title/Abstract]) OR Urinary Tract[Title/Abstract]) OR Kidney[Title/Abstract]) OR	1044802
		Renal[Title/Abstract])	OR	Ureteral[Title/Abstract])	OR	URETER[Title/Abstract])	OR	Urethral[Title/Abstract])	OR
		URETHRA[Title/Abstract]) OR Bladder[Title/Abstract]
	2	(((tumor[Title/Abstract]) OR neoplasm[Title/Abstract]) OR cancer[Title/Abstract]) OR malignancy[Title/Abstract]	2338139
	3	1 and 2							147101
	4	(((((

"Kidney Neoplasms"[Mesh]) OR "Pelvic Neoplasms"[Mesh]) OR "Ureteral Neoplasms"[Mesh]) OR "Urinary Bladder Neoplasms"[Mesh]) OR "Urologic Neoplasms"[Mesh]) OR "Urethral Neoplasms"

[Mesh]

Table S2 . Inclusion and exclusion criteria based on PECOS (population, exposure, comparison, outcome and study type) for a systematic review on the association between outdoor air pollution exposure and risk of selected urological cancers

 S2

	Decision	Population	Exposure	Comparison	Outcome		Type of study
	Inclusion Human; Adult	Ambient air pollution including	Not applicable Selected	urological	Prospective and
			a) specific pollutants (e.g. PM 10 ; PM 2.5 ;		cancers		retrospective
			SO 2 ; NO 2 ; O 3 ; CO; NO x )		incidence/mortality	cohort;
			b) proxies (traffic; proximity index; …)		(including	kidney;	case-control;
	Exclusion Children; Animal; Occupational cohorts	bladder; urinary tract) Not applicable Urinary cancer hospital admission; other urological cancers J o u r n a l P r e -p r o o f Occupational /Industrial air pollution exposure; geothermal and volcanic air pollution exposure; radioactive pollutants; radon; asbestos; pesticides; indoor air pollution; smoking-related products	ecologic studies Time series; case-report; reviews; in-vitro studies

Table S6 : GRADE assessment for the association between exposure to PM 2.5 and risk of bladder cancer mortality

 S6

	Domains	Assessment	Downgrading/ upgrading
	Start level	One cohort, three ecologic studies	Low
	Risk of bias

Table S10 : GRADE assessment for the association between exposure to SO 2 and risk of bladder cancer incidence

 S10

	Domains	Assessment	Downgrading/ upgrading
	Start level	One cohort and one ecologic study	High
	Risk of bias

We declare no competing interest. 566 J o u r n a l P r e -p r o o f

List of supplement Tables

 Table S1.The sample search algorithm used for literature search on outdoor air pollution exposure (as an exposure) and selected urological cancer incidence and/or mortality (as an outcome) on PubMed (https://www.ncbi.nlm.nih.gov/pubmed/). Last updated on June 15, 2019. Table S2. Inclusion and exclusion criteria based on PECOS (population, exposure, comparison, outcome and study type) for a systematic review on the association between outdoor air pollution exposure and risk of selected urological cancers J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f One of the cohorts suffering from different methodological issues such as insufficient follow-up period. In two ecologic studies, the adjustment is unclear.

Downgrade

Inconsistency

The values of effect sizes across the studies were inconsistent. The point estimates were in the range of 0.82 to 1.70, and confidence intervals were partially overlapped. However, in one of the estimates in the ecologic study, the upper confidence interval reached 5.11.

Downgrade

Indirectness

The exposure to air pollution allocated differently across different studies to the participants (LUR, dispersion modeling, and interpolation).

No change Imprecision Change in the direction of the decision at the two extremes of reported effect sizes.

Downgrade Publication bias

Given the comprehensive search, it seems little even no publication bias. Unclear Dose-response trend One out of four studies analyzed a trend, however, found no linear trend.

No increase Magnitude of associations

In all studies and reported associations, the magnitude of the effect sizes was below 1.4.

No increase Residual confounding

Two ecologic studies suffering from the risk of exposure misclassifications. The case-control study suffering from non-clear case and control definition, exposure assessment, and adjustment. The cohort study also suffering from low follow-up duration and is not clear about the absence of outcome at the beginning of the study.

No increase Overall judgment

Very

Downgrade

Inconsistency

The direction of the effect sizes are not opposite; however, the magnitudes are different.

No change Indirectness

All of the studies conducted on the general population and the outcomes drawn from death registries.

No change Imprecision

Change in the direction of the decision at the two extremes of reported effect sizes.

Downgrade Publication bias

Given the comprehensive search, it seems little even no publication bias. Unclear Dose-response trend One of the studies reported a dose-response association. Upgrade Magnitude of associations Two studies reported effect sizes with a magnitude below 1.4.

No increase

Residual confounding

One of the studies used readings from monitoring stations for exposure allocation. Also, one study just reported a crude association.

No increase

Overall judgment Low

947

J o u r n a l P r e -p r o o f The cohort study summarized the results of several other cohorts and has a good NOS score. However, the case-control suffering from representativeness and appropriate selection of controls.

No change

Inconsistency

The direction and magnitude of the effect sizes across the studies were inconsistent. The point estimates were varying and confidence intervals were partially overlapped.

Downgrade

Indirectness

Exposure to air pollution, population, and outcome were in accordance with the review aim.

No change

Imprecision

The point estimates and confidence intervals were not consistent. The number of studies is not sufficient.

Downgrade

Publication bias Given the comprehensive search, it seems little even no publication bias. However, we were not able to test it objectively.

Unclear Dose-response trend None of the studies reported the dose-response.

No increase Magnitude of associations

In all studies and reported association, the magnitude of the effect sizes was below 1.

Downgrade

Inconsistency

The point estimates were different and confidence intervals were partially overlapped. The confidence intervals were reasonable except in the case of the ecologic study.

Downgrade

Indirectness

Exposure to air pollution allocated differently across the studies (LUR, dispersion modeling, and ecologic approaches). However, in general, the population, exposure, and exposure were in accordance with the PECO.

No change Imprecision Decision based on each side of the confidence intervals was associated to a different judgment.

Downgrade

Publication bias Given the comprehensive search and size of the sample in the published studies we decided little even no publication bias.

Unclear

Dose-response trend

One out of four studies conducted the categorized analyses based on exposure intensity. However, the observed trend in the groups was not similar in males and females.

No change

Magnitude of associations

In all reported associations, the magnitude of the effect sizes was large enough to lead to an upgrade of evidence.

No change

Residual confounding

In two out of four studies the confounding adjustment was not clear. We think adjustment would decrease the observed strength of observed associations.

No change

Overall judgment

Very low 952 953 J o u r n a l P r e -p r o o f The case-control study suffering from different methodological issues including case definition, control selection, unclear response rate, and inadequate control of confounders. The cohort study suffering from the inadequacy of follow-up.

Downgrade

Inconsistency

The direction of effect sizes are similar for both studies, but the point estimates are different.

No change

Indirectness

Both studies conducted on the general population and the outcomes drawn from death registries. The exposure assessment in the case-control study was not as precise as the cohort (it was based on station reading in the case-control study).

No change Imprecision

The effect estimates in the case-control were precise. However, in the cohort study, there was impreciseness in the reported effect sizes.

Downgrade

Publication bias Given the comprehensive search, it seems little even no publication bias. However, we were not able to systematically assess the publication bias by statistical tests or visual plots.

Unclear Dose-response trend One of the studies reported dose-response data. Upgrade Magnitude of associations

In one case-control study, the magnitude of the effects was above 1.4.

No increase

Residual confounding Considering possible exposure misclassification in using monitoring stations readings for exposure allocation, effect estimates would shift to null. The risk of bias in the case-control study was high due to no exact definition of cases and controls. Follow-up time in the cohort was not sufficient.

No increase

Overall judgment

Downgrade

Inconsistency

The magnitude of observed risk in the studies was 0.88 to 1.07. The observed effect sizes in the case-control study were opposite at different doses of exposure.

Downgrade

Indirectness

The population and outcome were in accordance with the PECO. However, the exposure assessment methods in the studies were different.

No change

Imprecision The judgment will be changed according to the selection of each side of the confidence intervals.

Downgrade

Publication bias Given the comprehensive search, it seems little even no publication bias. However, we were unable to objectively evaluate the possible publication bias. Highlights:

Unclear

• Few studies -ecological, case-control and cohorts -were eligible.

• Limitation issues of the studies prevented the meta-analysis realization.

• Positive association between air pollution and bladder and kidney cancer risk were showed. • For bladder cancer, mortality evidences were stronger than the incidence.

• Future studies should be rigorous with adjustment, exposure assessment methods and follow-ups.

J o u r n a l P r e -p r o o f

Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: