Table 2.
Case-control and cohort studies of drinking water nitrate and cancer (January 2004–March 2018) by cancer site.
| First Author (Year) Country |
Study Design, Years Regional Description |
Exposure Description | Cancer Sites Included | Summary of Drinking-Water Findings a,b | Evaluation of Effect Modification c |
|---|---|---|---|---|---|
| Zeegers, 2006 Netherlands [131] |
Cohort Incidence, 1986–1995 204 municipal registries across the Netherlands |
1986 nitrate level in 364 pumping stations, exposure data available for 871 cases, 4359 members of the subcohort | Bladder | Highest vs. lowest quintile intake from water (≥1.7 mg/day NO3-N [median 2.4 mg/day] vs. <0.20) RR = 1.11 (CI: 0.87–1.41; p-trend = 0.14) | No interaction with vitamin C, E, smoking |
| Espejo-Herrera, 2015 Spain [33] |
Hospital-based multi-center case-control Incidence, 1998–2001 Asturias, Alicante, Barcelona, Vallès-Bages, Tenerife provinces |
Nitrate levels in PWS (1979–2010) and bottled water (measurements of brands with highest consumption based on a Spanish survey); analyses limited to those with ≥70% of residential history with nitrate estimate (531 cases, 556 controls) | Bladder | Highest vs. lowest quartile average level (age 18-interview) (≥2.26 vs. 1.13 mg/L NO3-N) OR = 1.04 (CI: 0.60–1.81) Years >2.15 mg/L NO3-N (75th percentile) (>20 vs. 0 years) OR = 1.41 (CI: 0.89–2.24) |
No interaction with vitamin C, E, red meat, processed meat, average THM level |
| Jones, 2016 USA [31] |
Population-based cohort of postmenopausal women ages 55–69 Incidence, 1986–2010 Iowa |
Nitrate levels in PWS (1955–1988) and private well use among women >10 years at enrollment residence with nitrate and trihalomethane estimates (20,945 women; 170 bladder cases); no measurements for private wells Adjusted for total trihalomethanes (TTHM) |
Bladder | Highest vs. lowest quartile PWS average (≥2.98 vs. <0.47 mg/L NO3-N) HR = 1.47 (CI: 0.91–2.38; p-trend = 0.11) Years >5 mg/L (≥4 years vs. 0) HR = 1.61 (CI: 1.05–2.47; p-trend = 0.03) Private well users (vs. <0.47 mg/L NO3-N on PWS) HR = 1.53 (CI: 0.93–2.54) |
Interaction with smoking (p-interaction = 0.03); HR = 3.67 (CI: 1.43–9.38) among current smokers/≥2.98 mg/L vs. non-smokers/<0.47 mg/L NO3-N); No interaction with vitamin C, TTHM levels |
| Mueller, 2004 USA, Canada, France, Italy, Spain [139] |
Pooled case-control studies Incidence among children <15 years (USA <20 years) 7 regions of 5 countries |
Water source during pregnancy and first year of child’s life (836 cases, 1485 controls); nitrate test strip measurements of nitrate and nitrite for pregnancy home (except Italy) (283 cases, 537 controls; excluding bottled water users: 207 cases, 400 controls) | Brain, childhood | Private well use versus PWS associated with increased risk in 2 regions and decreased risk in one; No association with nitrate levels in water supplies Astrocytomas (excludes bottled water users): ≥1.5 vs. <0.3 mg/L NO2-N OR = 5.7 (CI: 1.2–27.2) |
Not described |
| Brody, 2006 USA [137] |
Case-control Incidence, 1988–1995 Cape Cod, Massachusetts |
Nitrate levels in public water supplies (PWS) since 1972 was used as an indicator of wastewater contamination and potential mammary carcinogens and endocrine disrupting compounds; excluded women on private wells | Breast | Average ≥1.2 mg/L NO3-N vs. <0.3 OR = 1.8, (CI: 0.6–5.0); summed annual NO3-N ≥ 10 vs. 1–< 10 mg/L OR = 0.9, CI: 0.6–1.5); number of years >1 mg/L NO3-N ≥8 vs. 0 years OR = 0.9 (CI: 0.5–1.5) | Not described |
| Inoue-Choi, 2012 USA [128] |
Population-based cohort of postmenopausal women ages 55–69 Incidence, 1986–2008 Iowa |
Nitrate levels in PWS (1955–1988) and private well use among women >10 years at enrollment residence (20,147 women; 1751 breast cases); no measurements for private wells | Breast | Highest vs. lowest quintile PWS average (≥3.8 vs. ≤0.32 mg/L NO3-N) HR = 1.14 (CI: 0.95–1.36; p-trend = 0.11); Private well (vs. ≤ 0.32 mg/L NO3-N) HR = 1.14 (CI: 0.97–1.34); Private well (vs. ≤0.32 mg/L NO3-N on PWS) HR = 1.38 (CI: 1.05–1.82); No association among those with low folate <400 µg/day |
Interaction with folate for PWS (p-interaction = 0.06). Folate ≥400 µg/d: (≥3.8 vs. ≤0.32 mg/L NO3-N) HR = 1.40 (CI: 1.05–1.87; p-trend = 0.04) |
| Espejo-Herrera, 2016 Spain [138] |
Hospital-based multi-center case-control Incidence, 2008–2013 Spain (8 provinces) |
Nitrate levels in PWS (2004–2010), bottled water measurements and private wells and springs (2013 measurements in 21 municipalities in León, Spain, the area with highest non-PWS use) Analyses include women with ≥70% of period from age 18 to 2 years before interview (1245 cases, 1520 controls) |
Breast | Water nitrate intake based on average nitrate levels (age 18 to 2 years prior to interview) and water intake (L/day). Post-menopausal women: >2.0 vs. 0.5 mg/day NO3-N OR = 1.32 (0.93–1.86); Premenopausal women: >1.4 vs. 0.4 mg/day NO3-N OR = 1.14 (0.67–1.94) | No interaction with red meat, processed meat, vitamin C, E, smoking for pre- and post-menopausal women |
| McElroy, 2008 USA [134] |
Population-based case-control, women Incidence, 1990–1992 and 1999–2001 Wisconsin |
Limited to women in rural areas with no public water system (475 cases, 1447 controls); nitrate levels at residence (presumed to be private wells) estimated by kriging using data from a 1994 representative sample of 289 private wells | Colorectal | All colon cancers: Private wells ≥10.0 mg/L NO3-N vs. <0.5 OR = 1.52 (CI: 0.95–2.44); Proximal colon cancer: OR = 2.91 (CI: 1.52–5.56) | Not described |
| Espejo-Herrera, 2016 Spain, Italy [135] |
Multi-center case-control study Incidence, 2008–2013 Spain (9 provinces) and population-based controls; Italy (two provinces) and hospital-based controls |
Nitrate levels in PWS (2004–2010) for 349 water supply zones, bottled water (measured brands with highest consumption), and private wells and springs (measurements in 2013 in 21 municipalities in León, Spain, the area with highest non-PWS use) Analyses include those with nitrate estimates for ≥70% of period 30 years before interview (1869 cases, 3530 controls) |
Colorectal | Water nitrate intake based on average nitrate levels (estimated 30 to 2 years prior to interview) and water intake (L/day) Highest vs. lowest exposure quintiles (≥2.3 vs. <1.1 mg /day NO3-N) OR = 1.49 (CI:1.24–1.78); Colon OR = 1.52 (CI: 1.24–1.86), Rectum OR = 1.62 (CI: 1.23–2.14) |
Interaction with fiber for rectum (p-interaction = 0.07); >20 g/day fiber + >1.0 mg/L NO3-N vs. <20 g/day + ≤1.0 mg/L HR = 0.72 (CI: 0.52–1.00). No interaction with red meat, vitamin C, E |
| Fathmawati, 2017 Indonesia [136] |
Hospital-based case-control Incidence, 2014–2016 Indonesia (3 provinces) |
Nitrate levels in well water collected during the raining season (Feb-March 2016) and classified based on >11.3 or ≤11.3 mg/L as NO3-N and duration of exposure >10 and ≤10 years Analyses included participants who reported drinking well water (75 cases, 75 controls) |
Colorectal | Water nitrate > WHO standard vs. below (> 11.3 vs. ≤11.3 mg/L NO3-N) OR = 2.82 (CI: 1.08–7.40); > 10 years: 4.31 (CI: 11.32–14.10); ≤10 years: 1.41 (CI: 0.14–13.68) | Not described |
| Schullehner, 2018 Denmark [32] |
Population-based record-linkage cohort of men and women ages 35 and older, 1978–2011 Denmark |
Nitrate levels in PWS and private wells among 1,742,321 who met exposure assessment criteria (5944 colorectal cancer cases, including 3700 with colon and 2308 with rectal cancer) | Colorectal | Annual average nitrate exposure between ages 20–35 among those who lived ≥75% of study period at homes with a water sample within 1 year (61% of Danish population). Highest vs. lowest exposure quintile (≥2.1 vs. 0.16 mg/L NO3-N); Colorectal: HR = 1.16 (CI: 1.08–1.25); colon: 1.15 (CI: 1.05–1.26); rectum: 1.17 (CI: 1.04–1.32) |
No information on dietary intakes or smoking |
| Ward, 2007 USA [34] |
Population-based case control Incidence, 1986–1989 Iowa |
Nitrate levels in PWS among those with nitrate estimates for ≥70% of person-years ≥1960 (201 cases, 1244 controls) | Kidney (renal cell carcinomas) | Highest vs. lowest quartile PWS average (≥2.8 mg/L NO3-N vs. <0.62) OR = 0.89 (CI 0.57–1.39); Years >5mg/L NO3-N 11+ vs. 0 OR = 1.03 (CI: 0.66–1.60) | Interaction with red meat intake (p-interaction = 0.01); OR = 1.91 (CI 1.04–3.51) among 11+ years >5 mg/L NO3-N and red meat ≥1.2 servings/day. Interaction with vitamin C showed similar pattern (p-interaction = 0.13) |
| Jones, 2017 USA [127] |
Population-based cohort of postmenopausal women ages 55–69 Incidence, 1986–2010 Iowa |
Nitrate levels in PWS (1955–1988) and private well use among women >10 years at enrollment residence. PWS measurements for nitrate and TTHM; no measurements for private wells (20,945 women; 163 kidney cases) | Kidney | Nitrate and TTHM metrics computed for duration at water source (11+ years) 95th percentile vs. lowest quartile PWS average (≥5.00 vs. <0.47 mg/L NO3-N) HR = 2.23 (CI: 1.19–4.17; p-trend = 0.35) Years >5 mg/L (≥4 years vs. 0) HR = 1.54 (CI: 0.97–2.44; p-trend = 0.09) Private well users (vs. <0.47 mg/L NO3-N in PWS) HR = 0.96 (CI: 0.59–1.58) |
No interaction with smoking, vitamin C |
| Ward, 2006 USA [35] |
Population-based case-control Incidence, 1998–2000 Iowa |
Nitrate levels in PWS among those with nitrate estimates for ≥70% of person-years ≥1960 (181 case, 142 controls); nitrate measurements for private well users at time of interviews (1998–2000; 54 cases, 44 controls) | Non-Hodgkin lymphoma | Private wells: >5.0 mg/L NO3-N vs. ND OR = 0.8 (CI 0.2–2.5) PWS average: ≥2.9 mg/L NO3-N vs. <0.63 OR = 1.2 (CI 0.6–2.2) Years ≥5mg/L NO3-N: 10+ vs. 0 OR = 1.4 (CI: 0.7–2.9) |
No interaction with vitamin C, smoking |
| Inoue-Choi, 2015 USA [129] |
Population-based cohort of postmenopausal women ages 55–69 Incidence, 1986–2010 Iowa |
Nitrate levels in PWS (1955–1988) and private well use among women >10 years at enrollment residence; PWS measurements for nitrate and TTHM; no measurements for private wells (17,216 women; 190 ovarian cases) | Ovary | Nitrate and TTHM metrics computed for reported duration at water source (11+ years) Highest vs. lowest quartile PWS average (≥2.98 mg/L vs. <0.47 mg/L NO3-N) HR = 2.03 (CI = 1.22–3.38; p-trend = 0.003) Years >5 mg/L (≥4 years vs. 0) HR = 1.52 (CI: 1.00–2.31; p-trend = 0.05) Private well users (vs. <0.47 mg/L NO3-N in PWS) HR = 1.53 (CI: 0.93–2.54) |
No interaction with vitamin C, red meat intake, smoking for PWS nitrate Interaction with private well use and vitamin C intake (p-interaction = 0.01) |
| Quist, 2018 USA [126] |
Population-based cohort of postmenopausal women ages 55–69 Incidence, 1986–2011 Iowa |
Nitrate levels in PWS (1955–1988) and private well use among women >10 years at enrollment residence; nitrate and TTHM estimates for PWS (20,945 women; 189 pancreas cases); no measurements for private wells Adjusted for TTHM (1955–1988), measured levels in 1980s, prior year levels estimated by expert) |
Pancreas | Nitrate and TTHM metrics computed for reported duration at water source (11+ years) 95th percentile vs. lowest quartile PWS average (≥5.69 vs. <0.47 mg/L NO3-N) HR = 1.16 (CI: 0.51–2.64; p-trend = 0.97) Years >5 mg/L (≥4 years vs. 0) HR = 0.90 (CI: 0.55–1.48; p-trend = 0.62) Private well users (vs. <0.47 mg/L NO3-N) HR = 0.92 (CI: 0.55–1.52) |
No interaction with smoking, vitamin C |
| Ward, 2008 USA [133] |
Population-based case control Incidence, 1988–1993 Nebraska |
Controls from prior study of lymphohematopoetic cases and controls interviewed in 1992–1994; Proxy interviews for 80%, 76%, 61% of stomach, esophagus, controls, respectively. Nitrate levels (1965–1985) in PWS for ≥70% of person-years (79 distal stomach, 84, esophagus, 321 controls); Private well users sampling at interview (15 stomach, 22 esophagus, 44 controls) |
Stomach and esophagus (adenocarcinomas) | Highest vs. lowest quartile PWS average (>4.32 vs. <2.45 mg/L NO3-N): stomach OR = 1.2 (CI 0.5–2.7); esophagus OR = 1.3 (CI: 0.6–3.1); Years >10 mg/L NO3-N (9+ vs. 0): stomach OR = 1.1 (CI: 0.5–2.3); esophagus OR = 1.2 (CI: 0.6–2.7) Private well users (>4.5 mg/L NO3-N vs. <0.5) stomach OR = 5.1 (CI: 0.5–52; 4 cases, 13 controls); esophagus OR = 0.5 (CI: 0.1–2.9; 8 cases; 13 controls) |
No interaction with vitamin C, processed meat, or red meat for either cancer |
| Ward, 2010 USA [37] |
Population-based cohort of postmenopausal women ages 55–69 Incidence, 1986–2004 Iowa |
Nitrate levels in PWS (1955–1988) and private well use among women >10 years at enrollment residence (21,977 women; 40 thyroid cases); no measurements for private wells | Thyroid | Highest vs. lowest quartile PWS average (>2.46 vs. <0.36 mg/L NO3-N) HR = 2.18 (CI: 0.83–5.76; p-trend = 0.02) Years >5 mg/L (≥5 years vs. 0) HR = 2.59 (CI: 1.09–6.19; p-trend = 0.04); Private well (vs. <0.36 mg/L NO3-N on PWS) HR = 1.13 (CI: 0.83–3.66) Dietary nitrate intake quartiles positively associated with risk (p-trend = 0.05) |
No interaction with smoking, vitamin C, body mass index, education, residence location (farm/rural vs. urban) |
ND = not detected; PWS = public water supplies; a nitrate or nitrite levels presented in the publications as mg/L of the ion were converted to mg/L as NO3-N or NO2-N; b Odds ratios (OR) for case-control studies, incidence rate ratios (RR) and hazard ratios (HR) for cohort studies, and 95% confidence intervals (CI); c Factors evaluated are noted. Interaction refers to reported p ≤ 0.10 from test of heterogeneity.