Association between prostate cancer and long-term exposure to nitrate and THMs in drinking water


This study explore the relationship between exposure to nitrate and THMs through drinking water and prostate cancer at the individual level.

During the period 2008–2013, 697 hospital-based incident prostate cancer cases (97 aggressive tumors) and 927 population-based controls were recruited in Spain, providing information on residential histories and type of water consumed.

Average nitrate and THMs levels in drinking water were linked with lifetime water consumption to calculate waterborne ingestion. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using mixed models with recruitment area as random effect. Effect modification by tumor grade (Gleason score), age, education, lifestyle, and dietary factors was explored.

The study findings were published in the peer reviewed journal: Environmental Health Perspectives.

Prostate cancer has become widespread worldwide,1,2 with 1,414,259 estimated new cases in 2020 (7.3% of all cancer sites),2 and the prostrate is the leading incident cancer site in Spanish men (22% of all cancers sites).3 However, the etiology of prostate cancer remains largely unknown, and it is one of the few types of cancer for which the International Agency for Research on Cancer (IARC) has not identified a clear carcinogenic agent.4

Currently recognized risk factors are nonmodifiable, including age, ethnicity, and family history of cancer (including genetic heritage).1,5,6 Aggressive and fatal prostate cancers have been suggested to have different underlying causes in comparison with slow-growing tumors with an indolent course. 7–9

Other suggested risk factors, particularly for advanced-stage and aggressive prostate cancer, are lifestyle/behaviors such as smoking, unhealthy diet, overweight status, and lack of exercise,9–11 as well as exposure to endocrine-disrupting chemicals 12,13 such as Agent Orange (i.e., dioxins)8 and pesticides.14

An association between nitrite and nitrate from food additives and prostate cancer has also been recently reported.15

Cancer mortality maps reporting spatial and temporal distribution within countries and globally suggest that environmental exposures may contribute to prostate cancer development and could partly explain increasing incidence rates.16–18

Nitrate occurrence in the water cycle is rising worldwide because of growing use of nitrogen fertilizers and intensive farming.19 Human exposure to nitrate mainly occurs through ingestion of food and drinking water.20

Ingested nitrate is reduced to nitrite, which can react with amines and amides under acidic conditions in the stomach to form N-nitroso compounds. Ingested nitrate or nitrite under conditions that result in endogenous nitrosation is probably carcinogenic to humans.21,22

There are limited epidemiological studies seeking to disclose the relationship between nitrate exposure from drinking water and cancer, and, to date, consistent evidence has only been established with colorectal cancer.19

Disinfectants added to raw water to inactivate microbial pathogens result in the formation of several disinfection by-products (DBPs). DBPs constitute a complex mixture of chemicals formed as by-products of the reactions of the disinfectants applied to drinking-water.23

Chlorine is the most widespread disinfectant used worldwide, and trihalomethanes (THMs) and haloacetic acids are the DBPs formed at the highest concentrations after chlorination.

When water containing ammonia is chlorinated, chloramines are formed, which, in turn, lead to the formation of nitrogenated by-products such as the carcinogenic N-nitrosamines.24

Several DBPs are genotoxic in vitro and carcinogenic in animal experiments,25,26 and the IARC has classified some DBPs as possible human carcinogens.27–29

This study was designed to evaluate the association between prostate cancer and long-term exposure to nitrate and THMs in drinking water. Because risk factors for advanced-stage and aggressive prostate cancer may differ from slow-growing tumors 7,18 we also evaluated the associations by Gleason score (less than 8<8 vs. greater than or equal to 8≥8 as aggressive prostate cancer). We further investigated the effect modification by age, dietary factors, education, and adherence to a healthy lifestyle.

Findings suggest long-term waterborne ingested nitrate could be a risk factor of prostate cancer, particularly for aggressive tumors and in men less than 66<66 y old.

A high dietary intake of fiber, fruits and vegetables, or vitamin C may reduce this negative effect of drinking-water nitrate.

Association with residential levels but not ingested chloroform/Br-THM may suggest inhalation and dermal routes could be relevant for prostate cancer. Further studies are warranted to draw firm conclusions.

The trihalomethanes (THM) present in drinking water are by-products formed from the disinfection process of surface water. The THMs detected most often in drinking water are chloroform (CHCl3), dichlorobromomethane (CHBrCl2), dibromochloromethane (CHClBr2), and bromoform (CHBr3). The formation of these compounds occurs through the chlorination reaction with organic matter, which may be abundant in the surface water before being served to the public [1].

In this sense, factors such as pH and T, chlorine, and humic substance concentration favor the formation of THMs. Thus, during the warmer seasons of the year, there is a substantial increase in the concentration of THMs [2].

Since the presence of THMs in drinking water is related to the increase in cases of bladder cancer, rectal cancer, and spontaneous abortion, the maximum contaminant level [MCL] of THMs were set by the environmental agencies. Nowadays, the maximum concentration of THMs is established at 100 µg L−1 both in the USA and Europe [3,4].

In this way, the determination of THMs has become an even bigger challenge given the low concentration of the analytes and the increasingly efficient analytical methods. Currently, the determination of THMs is performed by efficient techniques. However, they are expensive and uncompromising with the principles of green chemistry. These include the techniques recommended by the US EPA 501.2 analytical protocol: liquid-liquid extraction, purge and trap preconcentration and GC-ECD detection [5].

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In this large prospective cohort study, food additive nitrates intakes, in particular potassium nitrate (e252), were associated with increased breast cancer risk, specifically pre-menopausal breast cancer, and nitrite additives intakes, especially sodium nitrite (e250), were positively associated with prostate cancer risk.

Although similar HRs were observed for colorectal cancer, no association was detected in this study. No association was detected for nitrites or nitrates from natural sources.


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