Authors: Zhengyi Deng (1Department of Urology, Stanford University School of Medicine, Stanford, California; 2Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, California), Jinhui Li (1Department of Urology, Stanford University School of Medicine, Stanford, California), Renyue Ji (3School of Public Health, Lee Ka Shin Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR), Juan Ramon Delgado (1Department of Urology, Stanford University School of Medicine, Stanford, California; 4School of Public Health, University of California, Los Angeles), Steve H. L. Yim (5Centre for Climate Change and Environmental Health, Nanyang Technological University, Singapore; 6Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore; 7Asia School of Environment, Nanyang Technological University, Singapore), Linda Kachuri (2Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, California; 8Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California), Andres Cardenas (2Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, California), Rebecca E. Graff (9Department of Epidemiology and Biostatistics, University of California, San Francisco), John T. Leppert (1Department of Urology, Stanford University School of Medicine, Stanford, California; 10Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, California; 11Division of Urology, Veterans Affairs Palo Alto Health Care System, Palo Alto, California), Leslie K. Dennis (12Department of Epidemiology & Biostatistics, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson), Benjamin I. Chung (1Department of Urology, Stanford University School of Medicine, Stanford, California), Marvin E. Langston (2Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, California)
Categories: Original Investigation
Source: JAMA Network Open
Environmental Nonessential Element Exposure and Urologic Cancer
Authors: Zhengyi Deng, Jinhui Li, Renyue Ji, Juan Ramon Delgado, Steve H. L. Yim, Linda Kachuri, Andres Cardenas, Rebecca E. Graff, John T. Leppert, Leslie K. Dennis, Benjamin I. Chung, Marvin E. Langston
Abstract
This systematic review and meta-analysis explores whether environmental exposure to nonessential elements with no known beneficial role in the body, including arsenic, cadmium, and vanadium, is associated with risk of urologic cancers.
Introduction
Urologic cancers, comprising malignant neoplasms affecting the urinary system and male reproductive organs, are among the most prevalent cancers worldwide.^1^ They account for 13.1% of new cancer cases and 7.9% of cancer deaths globally.^1^ The most common urologic cancers are prostate, kidney, and bladder, with the number of new cases projected to increase substantially by 2045.^2^ While inherited genetic predisposition explains 30% to 60% of urologic cancer cases,^3,4,5^ a large proportion of risk is likely attributed to exogenous factors, such as environmental exposures, lifestyle behaviors, and other unknown risk factors.^6,7,8,9,10,11,12^ Identifying additional modifiable risk factors is pivotal for prevention.
Various urologic cancers have been linked to nonessential elements, which are chemical elements with no known beneficial role in the body.^13,14,15^ The International Agency for Research on Cancer classified arsenic, cadmium, chromium, and nickel as group 1 carcinogens.^16^ Arsenic and cadmium are potential carcinogens for kidney and prostate cancer, whereas arsenic is a carcinogen for bladder cancer, with sufficient evidence in humans.^13^ Most of the evidence, however, stems from studies of high-level environmental or occupational exposure.^17^ The effects of low-level environmental exposure on urologic cancer risk remain poorly understood.
Nonessential elements are ubiquitous in food, water, air, and soil and can enter the body through inhalation or ingestion. Due to their long biological half-lives, these elements accumulate over time in multiple organs. The urinary system is particularly vulnerable to their toxic effects, given its ability to filter, reabsorb, concentrate, store, and excrete these elements. Nonessential elements can have direct contact with multiple urinary organs simultaneously and may promote urologic cancers through shared biological mechanisms.^18,19,20^ Therefore, combining evidence across urologic cancers can help generate shared hypotheses and inspire new research, which is especially needed given the limited current data on the association of these cancers with exposure to nonessential elements.
Several meta-analyses have examined specific nonessential elements and the individual urologic cancers.^21,22,23,24,25,26^ These meta-analyses, however, often focused on a single exposure source, such as arsenic in drinking water, despite exposure occurring through multiple pathways. Many of these meta-analyses included studies on occupational exposures, which are often high point-source exposures and do not reflect chronic exposures in the general population. The studies also included ecological or cross-sectional studies, which are limited in their implications for cancer etiology.^17,27,28^ To address these limitations, we conducted a comprehensive systematic literature review and meta-analysis to evaluate associations between exposure to multiple environmental nonessential elements and the risk of individual and overall urologic cancers.
Methods
Literature Search and Selection Criteria
The protocol for this systematic review and meta-analysis was registered in PROSPERO.^29^ We searched multiple English- and Chinese-language databases (PubMed, Embase, Scopus, Web of Science, Cumulated Index in Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, China National Knowledge Infrastructure, and Wanfang Data) from inception to January 27, 2026, using mapped and MeSH terms related to nonessential elements and urologic cancers without language or date restrictions; the full strategy is provided in eAppendix 1 and eFigure 1 in Supplement 1. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline.
The PRISMA flow diagram (eFigure 1 in Supplement 1) summarizes the steps of study selection from the literature search. Detailed inclusion and exclusion criteria are presented in eAppendix 2 in Supplement 1. In brief, we included cohort and case-control studies evaluating at least 1 nonessential element in relation to urologic cancer incidence or mortality and reporting effect estimates for the associations. We excluded nonhuman studies, occupational studies with high-level exposure, nonoriginal reports, cross-sectional or ecological studies, and studies that did not evaluate cancer incidence or mortality. For overlapping populations, the most recent publication was retained. Studies without suitable data for quantitative synthesis were included only in the systematic review.
Data Extraction and Quality Assessment
Four reviewers (Z.D., J.L, R.J., J.R.D.) participated in study screening, with each study independently reviewed by 2 of the 4 reviewers. Citation details, study design, exposure and outcome information, covariates, and association estimates with 95% CIs were extracted. Study quality was assessed using a modified version of the Newcastle-Ottawa Quality Control Assessment Scale.^30^ Studies with a score of 6 or higher on the 9-point scale were considered high quality. Details are presented in eAppendix 3 in Supplement 1.
Data Synthesis and Analysis
Because urologic cancers are rare, odds ratios from case-control studies were considered a reasonable approximation of risk ratios. These estimates, along with hazard ratios and risk ratios, were combined in the meta-analyses and are reported as pooled relative risks (RRs). Meta-analyses were conducted for the element-cancer associations with at least 3 RR estimates from at least 2 studies, yielding analyzable associations for arsenic, cadmium, vanadium, nickel, lead, and chromium. Cancer outcomes included prostate, kidney, bladder, and urothelial carcinoma. Because some studies reported urothelial carcinoma across multiple urinary sites (renal pelvis, ureter, urethra, and bladder) without site-specific estimates, urothelial carcinoma was analyzed as a separate group. All urologic cancer types were also pooled to estimate overall urologic cancer risk. For cadmium exposure, bladder cancer and urothelial carcinoma were combined because of the limited number of studies. We used 2 complementary approaches for exposure a comparison of the top vs bottom tertile of the exposure level and dose-response meta-analyses according to measurement sources.
Statistical Analysis
For the meta-analysis comparing top vs bottom tertiles of exposure, we transformed RR estimates to compare the top vs bottom tertiles in each study, ensuring consistent interpretation using a prior method (eAppendix 4 in Supplement 1).^31,32^ Pooled RRs were estimated using random-effects models, with heterogeneity assessed across studies. Robust variance estimation was applied to account for correlated effect sizes from the same or overlapping study populations.^33^ For arsenic and cadmium, subgroup analyses and meta-regressions were performed to examine potential sources of heterogeneity (eAppendix 4 in Supplement 1). Publication bias was examined using the Egger test and funnel plots.^34^ These methods were interpreted cautiously, as funnel plot asymmetry and significant Egger test results may indicate publication bias and/or small-study effects. Trim-and-fill analysis was used as an approximate and exploratory sensitivity analysis to assess the potential influence of publication bias or small-study effect, and the Rosenthal fail-safe N was used to evaluate the potential influence of unpublished null studies.^35^ Leave-1-out meta-analyses and additional sensitivity analyses were performed to examine the robustness of the findings (eAppendix 4 in Supplement 1).
We also performed a dose-response meta-analysis using summarized data from the identified studies. Specifically, we extracted RRs with 95% CIs and corresponding nonessential-element levels for each exposure category. Using these category-specific estimates, we applied 2-stage random-effects models with the Hamling method^36^ to approximate the covariance matrix of the log RRs. Associations were modeled using random-effects methods, allowing for nonlinear associations; when no evidence of nonlinearity was observed, linear models were used. Dose-response analyses were conducted for overall urologic cancer incidence and mortality by exposure source. For arsenic in drinking water, studies were further grouped by mean concentrations at or below 10 μg/L (the US Food and Drug Administration and World Health Organization standard) vs more than 10 μg/L to compare associations at low and high exposure levels (eAppendix 4 in Supplement 1).
We also assessed the urologic cancer burden that would be attributable to arsenic in drinking water for countries or areas where mean levels exceeded 10 µg/L, assuming a causal relationship. Arsenic levels and cancer statistics were obtained from previous publications or public resources.^37,38,39^ Using results from our dose-response analyses, we calculated the population attributable fraction (PAF) as (RR − 1)/(1 + [RR − 1]) and applied it to estimate annual reductions in the age-standardized rate (ASR) and number of urologic cancer cases for a reduction of arsenic level to 10 µg/L.
All analyses were performed with R, version 4.3.1 (R Project for Statistical Computing), and Stata, version 12.0 (StataCorp LCC). Two-sided P < .05 was considered significant. We conducted a certainty assessment using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.^40^
Results
Characteristics of Included Studies
We identified 23 160 records and included 68 studies in the systematic review,^7,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107^ of which 62^7,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,103,104,105,106,107^ were included in the meta-analysis (eFigure 1 in Supplement 1). The 68 studies included 26 cohort studies (38.2%)^41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66^ and 42 case-control studies (61.8%)^7,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107^ conducted across Asia, North America, Europe, South America, and Africa. Arsenic and cadmium were the most frequently studied exposures, and bladder, prostate, kidney, and urothelial carcinoma were the most commonly evaluated outcomes. Other exposures included nickel, lead, vanadium, chromium, cobalt, manganese, mercury, uranium, and antimony. Detailed study characteristics are described in eAppendix 5 and eTables 1 to 3 in Supplement 1. Most studies were rated as high quality (57 of 68 [83.8%]) (eTable 4 in Supplement 1).^7,41,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,70,71,72,73,74,75,76,78,80,81,82,84,85,86,87,88,90,91,93,94,95,99,100,101,102,103,104,105,106^
Associations Between Nonessential Elements and Risk of Urologic Cancer
Arsenic
From 46 risk estimates reported for the association between arsenic exposure and 1 or more urologic cancers, the top vs bottom tertile of arsenic level was significantly associated with an increased risk of overall urologic cancer (RR, 1.72; 95% CI, 1.33-2.22; I^2^ = 82.77; P < .001 for heterogeneity) (Table 1). When restricted to studies using biosamples, which can reflect exposure from various external sources, a similar association was observed (RR, 1.73; 95% CI, 1.12-2.68; I^2^ = 78.87; P < .001 for heterogeneity). Arsenic level was also associated with an increased risk of bladder cancer (RR, 1.60; 95% CI, 1.13-2.27; I^2^ = 76.0%; P < .001 for heterogeneity), prostate cancer (RR, 1.19; 95% CI, 1.01-1.40; I^2^ = 35.7%; P = .10 for heterogeneity), and urothelial carcinoma (RR, 3.37; 95% CI, 1.71-6.66; I^2^ = 81.1%; P < .001 for heterogeneity) (Figure 1). We did not observe an association with kidney cancer (RR, 1.38; 95% CI, 0.76-2.52; I^2^ = 72.9%; P < .001 for heterogeneity). Dose-response analyses revealed a nonlinear association between urologic cancer risk and arsenic concentration greater than 10 µg/L in drinking water, where the RR steadily increased from concentrations of 10 to 429 µg/L and reduced thereafter (eFigure 2 in Supplement 1). No association was found for drinking-water arsenic concentration of 10 µg/L or less. We observed a significant positive linear association between an arsenic level within 100 µg/L in urine samples (the range of exposure across included studies) and increased urologic cancer risk (eFigure 3 in Supplement 1). No significant dose-response association was found for arsenic in toenail samples or from the diet.
From 8 risk estimates that reported associations between percentage of monomethylarsonic acid (MMA) and urologic cancer risk (eTable 5 in Supplement 1), we observed a significant positive association for the top vs bottom exposure tertile (RR, 1.67; 95% CI, 1.51-1.85; I^2^ = 0%; P = .61 for heterogeneity).^51,70,72,78,83,84,90^ From 6 estimates (5 from Taiwan^51,70,72,83,84^ and 1 from Chile^78^) that reported results for percentages of inorganic arsenic and dimethylarsinic acid (DMA), we did not find significant associations. Keeping only the Taiwan studies yielded a significant positive association for the top vs bottom tertile of percentage of inorganic arsenic (RR, 2.09; 95% CI, 1.17-3.74; I^2^ = 58.88%; P = .06 for heterogeneity) and an inverse association for percentage of DMA (RR, 0.54; 95% CI, 0.35-0.81; I^2^ = 78.20%; P = .002 for heterogeneity).
Of studies included in the systematic review only,^97,98,99,100,101,102^ 1 reported a significant positive association between arsenic in blood samples and bladder cancer risk.^101^ One reported a significant positive association between arsenic in drinking water and bladder cancer risk.^102^ Another observed a significant positive association between serum arsenic concentration and prostate cancer risk in its unadjusted model, which became null after adjusting for confounders and other nonessential elements.^100^
Cadmium
Combining 24 risk estimates, the top vs bottom tertile of cadmium level was associated with a significant increase in risk of overall urologic cancer (RR, 1.38; 95% CI, 1.04-1.82; I^2^ = 92.67%; P < .001 for heterogeneity) (Table 1). When restricting to 14 studies using biosamples, there was no longer an association (RR, 1.55; 95% CI, 0.91-2.66; I^2^ = 82.33%; P < .001 for heterogeneity). We observed no significant increase in the risk of bladder cancer and urothelial carcinoma combined (RR, 2.08; 95% CI, 0.37-11.80; I^2^ = 92.0%; P < .001 for heterogeneity) or of kidney cancer (RR, 2.01; 95% CI, 0.67-6.08; I^2^ = 62.4%; P = .02 for heterogeneity) with top-tertile cadmium exposure. We also did not find a significant association with increased risk of prostate cancer (RR, 1.07; 95% CI, 0.97-1.18; I^2^ = 28.5%; P = .007 for heterogeneity) (Figure 2). The dose-response analysis showed a positive linear association between cadmium concentration within 2 µg/L in blood samples and overall urologic cancer risk (eFigure 3 in Supplement 1). No dose-response association was found for cadmium in urine or toenail samples or in diet.
Of the studies included only in the systematic literature review, 1 reported a positive association of serum cadmium level with the risk of testicular cancer.^97^ Another found higher serum cadmium levels in patients with bladder cancer than in control individuals, albeit the between-group difference in cadmium levels was not significant.^99^ A third study did not identify an association between cadmium levels in blood samples and prostate cancer risk.^100^
Other Nonessential Elements
We performed meta-analyses for nonessential elements with 3 or more estimates, which included nickel (9 estimates), vanadium (8 estimates), lead (7 estimates), and chromium (3 estimates) (eTable 6 in Supplement 1). We observed a significant association between exposure to the top vs bottom tertile of vanadium level and increased overall urologic cancer risk (RR, 1.15; 95% CI, 1.05-1.26; I^2^ = 50.62%; P = .13 for heterogeneity). All studies on vanadium assessed exposure to air pollutants, including fine particulate matter with an aerodynamic diameter of 2.5 μm or less (PM2.5) and particulate matter with an aerodynamic diameter of 10 μm or less (PM10). We did not observe significant associations of nickel, lead, and chromium exposure with overall urologic cancer risk. The dose-response analysis found a positive linear association between lead concentration within 2 µg/L in blood samples and urologic cancer risk (eFigure 3 in Supplement 1).
One study found no association between bladder cancer and uranium in drinking water or in toenail samples.^103^ Another study found no association between prostate cancer and mercury in blood samples.^104^ One study reported significant positive associations of kidney, bladder, and prostate cancer with manganese in PM2.5.^66^ Meta-analyses could not be conducted for these elements, because for each element, all estimates came from a single study.
In 2 studies included in the systematic review only, 1 reported no association between testicular cancer risk and lead level in blood samples^97^ and 1 reported no association between prostate cancer risk and lead level in blood samples.^98^ One study found no association between prostate cancer risk and cobalt level in blood samples.^98^ One study reported no association of blood-sample manganese or antimony levels with prostate cancer risk after adjusting for other nonessential elements.^100^
Subgroup Analyses
In subgroup analyses (Table 2), exposure source and water-sampling approach significantly contributed to heterogeneity for arsenic. Significant increases in risk of overall urologic cancer were observed for studies that measured arsenic in drinking water (RR, 2.07; 95% CI, 1.41-3.02) or urine samples (RR, 1.93; 95% CI, 1.06-3.51) but not for studies using estimates from other sources (diet, toenail samples, and ambient PM2.5). We found a larger RR and I^2^ for studies of arsenic exposure in Asia (RR, 2.36; 95% CI, 1.26-4.41; I^2^ = 83.53%) compared with studies in North America (RR, 1.22; 95% CI, 1.04-1.43; I^2^ = 0.01%) and Europe (RR, 1.18; 95% CI, 1.03-1.35; I^2^ = 35.39%); no significant increase in RR was found for studies of arsenic exposure in South America (RR, 2.36; 95% CI, 0.66-8.51; I^2^ = 89.02%). When stratifying by arsenic level in drinking water, we observed an increased risk of urologic cancer for studies with a drinking-water arsenic level of greater than 10 µg/L (RR, 2.39; 95% CI, 1.32-4.31), while no increase in RR was observed for studies with a drinking-water arsenic level of 10 µg/L or less (the estimated mean arsenic level in drinking water ranged from 0 µg/L in Iceland to 229 µg/L in Taiwan [eTable 8 in Supplement 1]).^37^ No clear subgroup differences were observed for cadmium exposure.
Publication Bias, Sensitivity Analyses, and Certainty Assessment
Funnel plots and the Egger test indicated possible publication bias and/or small-study effects for the association between arsenic exposure and urologic cancer risk (P = .006 from Egger test) (eFigures 4 and 5 in Supplement 1), with similar results observed for lead (Egger P = .03) and chromium (Egger P < .001) exposure. No clear evidence of funnel plot asymmetry was found for associations of cadmium (Egger P = .69), nickel (Egger P = .06), or vanadium (Egger P = .17) with overall urologic cancer risk (eFigures 4 and 6 in Supplement 1). The fail-safe N analysis indicated that 1918 additional null studies would be required to nullify the observed association between arsenic and urologic cancer risk. Trim-and-fill analyses, leave-1-out, and other sensitivity analyses were consistent with the primary findings (Table 1 and eFigures 7 and 8 in Supplement 1). Certainty of evidence ranged from very low to moderate (eTable 7 in Supplement 1).
PAF and Public Health Burden
Among 17 areas where the mean arsenic concentration in drinking water exceeded 10 µg/L, the PAF for a reduction in arsenic levels to 10 µg/L for overall urologic cancer risk was estimated to range from 3.44% in Ethiopia to 76.30% in Taiwan (eTables 8 and 9 in Supplement 1). Accordingly, it was estimated that the annual ASRs of prostate cancer (in males) and bladder or kidney cancer (in males and females) would reduce by ranges of 0.2 to 31.8 and 0.1 to 8.4 cases per 100 000 population, respectively, across these areas if arsenic levels in drinking water were reduced to 10 µg/L (Figure 3).
Discussion
In this systematic review and meta-analysis, arsenic exposure was associated with increased risk of overall urologic cancer, bladder cancer, prostate cancer, and urothelial carcinoma. Cadmium exposure was associated with increased risk of overall urologic cancer, although evidence for individual cancer types remained limited. Vanadium exposure from air pollutants was associated with increased risk of overall urologic cancer. However, there was large heterogeneity across included studies, which persisted even in subgroup analyses.
Previous meta-analyses have examined associations between arsenic exposure and urologic cancers, with most focusing on drinking water and bladder cancer risk and consistently suggesting a positive association.^108^ We also found that the top vs bottom tertile of arsenic exposure from various sources was significantly associated with an increased bladder cancer risk, suggesting potential carcinogenicity. However, findings for low-dose arsenic exposure remained inconsistent. In our subgroup and dose-response analyses evaluating drinking-water arsenic levels of greater than 10 µg/L and 10 µg/L or less separately, we found a significantly increased risk of overall urologic cancer at levels of greater than 10 µg/L but no significant association below that threshold. We also identified a significant linear association between higher urinary arsenic levels (within 100 µg/L) and an increased risk of urologic cancer. Boffetta et al^21^ and Tsuji et al^109^ found no significant association between low-dose arsenic in drinking water (below 150 µg/L and 100 µg/L, respectively) and bladder cancer risk. In contrast, Issanov et al^110^ found an increased risk of bladder cancer at drinking-water arsenic concentrations below 150 µg/L.
Few studies have examined associations between arsenic exposure and urologic cancers beyond bladder cancer. We found more than a 3-fold increase in urothelial carcinoma risk among individuals in the top tertile of arsenic exposure, although, to our knowledge, no published meta-analysis exists for comparison. Arsenic may have a particular influence on urothelial carcinoma, potentially driving its association with bladder cancer, given urothelial carcinoma is the predominant histologic subtype of bladder cancer. We also observed a significant association between arsenic exposure and prostate cancer risk, consistent with Yang et al,^23^ although their meta-analysis included ecological and cross-sectional studies. A major strength of our study is the inclusion of only case-control and cohort studies, which have the potential to provide stronger evidence implicating nonessential elements in cancer etiology than do ecological and cross-sectional studies. In contrast, a meta-analysis conducted by Devi et al^111^ observed no difference in serum levels of arsenic between patients with prostate cancer and controls. Issanov et al^110^ found a positive association between arsenic exposure and kidney cancer, whereas we did not observe such an association. However, their analyses also included ecological studies. Large cohort studies are needed to confirm our findings.
We observed considerable heterogeneity in the associations between arsenic exposure and urologic cancer risk. Subgroup analyses by region revealed that the pooled associations had smaller RRs and were less heterogenous in European and North American countries compared with Asian countries, likely due to regional arsenic level differences; no association of arsenic exposure with urologic cancer risk in South American countries was found. Europe and North America typically reported lower drinking-water arsenic levels than Asia and South America. The estimated mean arsenic level in drinking water ranged from 0 µg/L in Iceland to 229 µg/L in Taiwan. This pattern was supported by our dose-response analyses, which showed an association with greater urologic cancer risk at higher arsenic exposure levels. We identified a nonlinear dose-response association for drinking-water arsenic levels above 10 µg/L, with urologic cancer risk increasing as arsenic levels in drinking water rose from 10 to 429 µg/L and reducing thereafter. Assuming causality, our data suggested reducing drinking-water arsenic levels to 10 µg/L in 17 countries or areas where mean levels exceed this standard could lower the ASR of urologic cancers by 0.1 to 31.8 cases per 100 000 population, suggesting substantial public health benefits. Many other countries had an arsenic level less than 10 µg/L in drinking water, where we did not observe an association of arsenic exposure with urologic cancer.
We observed a significant association of cadmium exposure with overall urologic cancer risk but not with individual cancer types. Associations were observed for blood but not urinary cadmium concentrations, although urinary cadmium is often considered a marker of long-term exposure.^112^ Urinary cadmium level may be influenced by kidney function, dilution variability, and creatinine adjustment, potentially attenuating the association.^113^ This discrepancy may also reflect differences in the exposure window captured by these biomarkers, timing of sample collection, study population, and measurement error across studies. Previous meta-analyses of cadmium exposure have focused primarily on prostate and kidney cancers.^24,25,114,115^ Consistent with our findings, studies of prostate cancer have not reported significant associations with cadmium exposure.^24,25,114^ Our meta-analysis specifically examined environmental cadmium exposure, whereas previous meta-analyses included studies on occupational exposure to high cadmium levels.^114,115^ Firmani et al^114^ conducted a meta-analysis by environmental and occupational exposure separately and found no significant association in either group. Although Song et al^115^ reported a 47% (95% CI, 27%-71%) increased risk of kidney cancer for the highest vs lowest category of cadmium exposure, this finding was driven largely by occupational studies. Our imprecise risk estimates for kidney cancer and for bladder cancer and urothelial carcinoma combined suggest a lack of epidemiologic evidence.
Nonessential elements beyond arsenic and cadmium have been studied little. We found that urologic cancer risk was significantly positively associated with air-pollutant vanadium. For nickel, lead, and chromium exposure, the broad 95% CIs showed no association with urologic cancer, and heterogeneity was high. Epidemiologic studies are needed to assess these elements’ carcinogenic potential.
Nonessential elements are associated with carcinogenic mechanisms such as oxidative stress, DNA damage, genotoxic and epigenetic alteration, and microRNA dysregulation.^16,116,117,118^ Arsenic has been shown to promote bladder and kidney tumorigenesis in experimental models and to induce lipid oxidation, mitochondrial dysfunction, DNA damage, altered DNA methylation, and reduced tumor-suppressing miR-200 microRNAs in urothelial cells.^45,119,120,121,122,123,124^ Arsenic metabolites also differ in toxicity, with MMA considered more carcinogenic and DMA reflecting more efficient methylation of inorganic arsenic.^125,126,127^ Consistent with this, we observed an inverse association of DMA proportion and a positive association of MMA proportion with urologic cancer risk. Cadmium promotes carcinogenesis by displacing redox-active metals, inhibiting antioxidant enzymes, and impairing DNA repair.^128^ Vanadium compounds have been associated with oxidative stress, DNA damage, and proinflammatory signaling, and inhaled vanadium was shown to cause kidney injury in a mouse model.^129,130^ Other metals (lead, nickel, and chromium) can disrupt cell cycles and signaling pathways.^131,132^
Limitations
We acknowledge several limitations of this study. First, the associations of arsenic and cadmium exposure with overall urologic cancer risk were highly heterogenous. Subgroup analyses revealed that large variations in nonessential element levels across countries, urologic cancer types, and exposure sources might be significant contributors. However, other potential factors, such as dietary patterns or population-specific characteristics (eg, genetic background), may also contribute to the observed heterogeneity. Studies have reported that human exposure to metals and metalloids may vary through dietary intake across populations worldwide.^133^ Additionally, genetic polymorphisms, such as variants in arsenic (+III) methyltransferase and metallothionein 2A genes, have been considered internal contributors to individual susceptibility to heavy metal–related toxicity.^134,135^ Second, the small number of studies made pooled estimates for associations of cadmium with kidney cancer, bladder cancer, and urothelial carcinoma statistically uncertain, underscoring the need for more future research. Third, the scarcity of studies in areas where arsenic levels were below the current standard of 10 µg/L hindered evaluation of low-level arsenic exposure. Fourth, our meta-analyses that synthesized data across multiple exposure sources should be considered as hypothesis-generating. The source-specific dose-response analyses were limited by sparse data. Future research should use biomarkers that better capture cumulative exposure and active internal constituents. In addition, concurrent exposure to multiple nonessential elements or mixtures is common in typical environmental settings. More studies are warranted to examine the potential synergistic or antagonistic effects of such mixed exposures in urologic cancer risk assessment.
Conclusions
In this systematic review and meta-analysis, environmental exposure to nonessential elements, including arsenic, cadmium, and vanadium, was associated with increased urologic cancer risk, even at relatively low levels of exposure. Our results reinforce the well-established link between arsenic and bladder cancer^13^ while also pointing to possible associations with other elements, such as cadmium and vanadium. Given the limitations of the current evidence base, these latter findings should be interpreted cautiously but highlight important knowledge gaps. Further prospective studies using biosamples that reflect cumulative exposure are needed to clarify the effects of individual and coexposures from multiple sources.