Arsenic exposure and prostate cancer risk: analysis of recent epidemiological evidence from Chile

Arsenic is widespread in nature and is the 20th most abundant element in Earth’s crust (1). More than 200 minerals, especially sulfide-rich minerals such as arsenopyrite (FeAsS), serve as natural arsenic reservoirs (2), which enter the environment through natural processes, including volcanic eruptions or weathering, or man-made processes linked to industrial activities (3-5). Globally, millions of people are affected by arsenic pollution of drinking water, which constitutes a significant public health concern, especially in Asia and Latin America (6). Similarly, a major environmental risk linked to several illnesses, including lung cancer, is air pollution, such as arsenic-bearing particulate matter from industrial smoke. Although arsenic exposure is clearly linked to lung and bladder cancers, its relationship with prostate cancer remains insufficiently understood. Schwalb et al. (7) examined the association between arsenic levels in drinking water and prostate cancer in Northern Chile, a region with a well-documented history of exposure. This commentary reviews the key findings and evaluates whether the study’s inferences adequately address the potential link between arsenic exposure and prostate cancer risk.

Arsenic metabolism, exposure, and carcinogenesis

In humans, inorganic arsenic enters the body mainly through ingestion or inhalation and is rapidly absorbed in the gastrointestinal tract and lungs (8-11). With an absorption rate of about 70–95%, arsenic quickly circulates to various organs. Its initial delivery to the liver via portal circulation leads to its first-pass metabolism (12). Similarly, inhaled arsenic is deposited in the lungs, some absorbed through the alveolar membrane, while the remainder is transported and subsequently swallowed. In the liver, arsenic is sequentially methylated by arsenic methyltransferase (AS3MT), producing monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), which are subsequently excreted in urine (13). As illustrated in Figure 1, MMA and other reactive intermediates can induce DNA damage and broader genetic and epigenetic alterations that contribute to arsenic-related carcinogenesis, including skin lesions, bladder, lung, and vascular disease (14).

Figure 1 iAs is metabolized in the liver to MMA and DMA, both of which can induce genetic and epigenetic alterations associated with bladder and lung cancer. The potential role of iAs exposure in prostate cancer development remains uncertain, as current epidemiological evidence is inconclusive. As; DMA, dimethylarsinic acid; MMA, monomethylarsonic acid; iAs, inorganic arsenic.

Strong epidemiological evidence links arsenic-contaminated drinking water to increased lung and bladder cancer incidence and mortality. The urinary bladder’s continuous exposure to arsenic and its metabolites during excretion may explain the higher incidence of bladder carcinogenicity observed in northern Chile and other highly exposed regions. Apart from continuous exposure, early-life exposure to arsenic has also been shown to be significantly associated with higher cancer mortality rates more than 30 to 40 years after peak contamination. Moreover, a strong dose-response relationship has been noted while comparing individuals with high and low lifetime arsenic exposure in several population-based case-control studies for lung as well as bladder cancer. Wherein, the odds ratios in the highest exposure categories exceed 4 or 5 compared with the lowest categories, even after adjustment for smoking, age, and other known risk factors (6). These elevated risks are shown in both men and women, highlighting the widespread carcinogenic effects of arsenic on the lungs and bladder and showing that the effect is not limited to particular occupational or behavioral categories.

Bladder and lung cancers are strongly linked to direct arsenic-induced genotoxic and epigenetic effects (15). Although exposure to arsenic may increase prostate cancer risk through epigenetic mechanisms that promote cellular growth and survival, prostate cancer development is largely shaped by endocrine regulation and cellular stress adaptation and is highly age dependent (16). Epidemiologic evidence from multiple countries indicates that even relatively low levels of inorganic arsenic exposure are associated with increased prostate cancer mortality, as demonstrated in a U.S.-based prospective cohort where low to moderate arsenic exposure correlated with elevated prostate cancer death rates (17). Furthermore, recent data indicate an increased risk of more advanced or aggressive prostate tumors among individuals with higher arsenic exposure, with stronger associations observed for International Society of Urological Pathology (ISUP) grade 3–5 and American Joint Committee on Cancer (AJCC) stage IIB–IV prostate cancers (18). These characteristics introduce a unique possibility that arsenic may influence prostate cancer progression or aggressiveness rather than incidence, different from other cancers, such as bladder, lung, or skin cancers. This underscores the importance of well-characterized, long-term exposure data that capture temporal changes in arsenic exposure. Toenail arsenic concentrations have been identified as a reliable biomarker for assessing long-term internal arsenic exposure. Evidence indicates that a single toenail sample can represent exposure over several months to years, including at low to moderate levels (19).

Unfortunately, most epidemiologic studies examining arsenic and cancer are limited by modest exposure differences, incomplete monitoring, heterogeneous water sources, and population mobility (6), undermining the efforts to reconstruct lifetime exposure and are unable to isolate arsenic’s specific effects from other co-exposures (6). However, the availability of arsenic measurements for over 97% of drinking water sources has enabled Schwalb et al. to ascertain an unusually high level of exposure with measurement of substantial temporal variation in arsenic concentrations, including the periods of extremely high exposure and subsequent mitigation and exposure reduction, allowing for assessment of cumulative and average exposures.

This is a major strength of the study, however, as discussed above, an important point to note here is that prostate carcinogenesis is shaped by hormonally (primarily androgen, testosterone) regulated developmental and aging-related processes that occur over the lifetime of an individual, such as the fetal stage or early childhood [prostate bud formation (20)] or puberty [androgen-driven prostate growth and differentiation (21) or midlife] and aging [characterized by hormonal decline, inflammation, senescence (22)]. Hence, lifetime averaging of arsenic exposure may dilute effects arising from exposure during certain life stages, such as early development, puberty, or later-life disease progression.

While several countries implemented strict regulatory measures, northern Chile stands out as an exception. Northern Chilean water sources have high average arsenic concentrations of approximately 860 µg/L, which is 80 to 90 times higher than the widely accepted 10 µg/L drinking water standard in the United States and many other countries (6). Arsenic concentrations can be accurately allocated at the city or town level because drinking water in northern Chile is supplied by centralized municipal systems. This allows for systematic monitoring of exposure and human health issues in this population (6) and has enabled researchers to assess or reconstruct lifetime arsenic exposure. Additionally, the near-identical numbers of common numbers and reported residences between cases and controls (3.2 vs. 3.3) reduce concern about exposure misclassification, thereby strengthening causal inference. Moreover, the selection of population-based controls from the voter registry provided Schwalb et al. a robust and unbiased comparison group, minimizing selection bias as the controls were from the same underlying source population that gave rise to the cancer cases and were cleanly linked to centralized municipal water arsenic records. Choosing control subjects from the same population is a clear advantage over hospital-based or convenience-control groups commonly used in earlier arsenic studies.

Despite elevated arsenic levels and prolonged exposure, the authors did not identify a correlation between arsenic exposure and prostate cancer risk. While some ecological and smaller studies from other regions have suggested possible associations, raising concerns about prostate tissue as a potential target (14), many of these studies were limited by imprecise exposure assessment and by confounding factors difficult to control (14). This makes the study by Schwalb et al. a reliable reference point, as it does not share these limitations. Notably, although a 5-year lag is a standard assumption for many solid tumors in environmental epidemiology, extensive research indicates that prostate cancer often exhibits a substantially longer latency, sometimes exceeding 20 years, due to its slow-growing, indolent nature, particularly when associated with metal exposures (23). Consequently, recent environmental association studies for prostate cancer have adopted longer lag periods of 10–18 years to better account for its development.

The long latency of many environmentally induced cancers underscores the importance of capturing temporal changes in arsenic exposure when evaluating the impact of regulatory interventions. Although the study did not identify a clear association with prostate cancer incidence, this does not diminish the public health significance of its findings. In this context, the study by Schwalb et al. underscores the importance of water safety policy and environmental health governance, demonstrating that regular monitoring can mitigate cancer risks and reduce the burden of chronic disease (6). Furthermore, the study highlights the necessity of detailed documentation and continuous monitoring. The comprehensive arsenic measurements and archival records enabled recognition of the full extent and persistence of health impacts from arsenic exposure, and the opportunity to learn from this natural experiment would otherwise have been missed (6).

Conclusions

In summary, the investigation by Schwalb et al. exemplifies rigorous environmental epidemiology by using detailed exposure data to assess the health effects of arsenic. Although no direct association with prostate cancer was identified, the study highlights the urgent need for aggressive mitigation strategies in regions where drinking water concentrations exceed health-based guidelines, given that arsenic is a potent carcinogen for specific organs, particularly the lung and bladder. In contrast to the strong associations observed with lung, bladder, and other cancers, this study demonstrates that prostate cancer is not equally affected, providing a valuable case for evaluating organ specificity in arsenic carcinogenesis. However, evidence from diverse populations shows that even low to moderate arsenic exposure can increase prostate cancer mortality and progression to advanced disease, underscoring the need for continued etiologic research.

Recognizing this organ specificity can improve risk estimates, inform screening and prevention strategies, and foster trust in mitigation efforts by avoiding exaggerated or overly broad claims (7). Northern Chile thus continues to contribute to a more accurate, evidence-based understanding of how a single environmental contaminant can be both highly potent and selectively targeted in its health effects.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Cancer Epidemiology. The article has undergone external peer review.

Peer Review File: Available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0006/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://ace.amegroups.com/article/view/10.21037/ace-2026-1-0006/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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