Well water contaminants and colorectal cancer in North Dakota

Abstract

This study aims to identify common contaminants in well water linked to an increase in colorectal cancer (CRC) incidence rates in North Dakota (ND) counties. County-specific incidence rates for CRC were obtained from the ND Statewide Cancer Registry. Corresponding demographic, agricultural, and geophysical data were obtained from population-based sources. Associations between well water contaminants and CRC incidence were examined for 16 counties in ND with complete well water profiles between 1997-2019. Data were analyzed by multiple linear regression. Iron in well water exhibited a significant positive association with CRC incidence (4.75, P = 0.001), and barium exhibited a small, but significant negative association (-0.06907, P = 0.01). Residents in counties in ND with prevalent well water usage contaminated with iron may be at higher risk for CRC.

Key Words: Colorectal cancer; Iron; Water quality; Well water; North Dakota

Core Tip: The goal of this study was to investigate the association between colorectal cancer (CRC) incidence and chemicals commonly found in well water. The most important finding from this ecologic study is that iron in well water is significantly associated with CRC incidence across 16 counties in the state of North Dakota. These findings are broadly consistent with epidemiologic and experimental studies on the effects of iron in CRC carcinogenesis. Exploration into the implications of excess iron exposure and colorectal carcinogenesis may facilitate preventive interventions in rural and agricultural areas that rely heavily on well water as a drinking water source.

TO THE EDITOR

We conducted an ecological study using publicly available data provided by North Dakota Statewide Cancer Registry (NDSCR), the United States Geological Survey’s (USGS) well water monitoring program, and the North Dakota (ND) Department of Environmental Quality chemical profiles of well water, to determine the relationship between well water contaminants and county-level incidence of colorectal cancer (CRC). Environmental data were obtained from the USGS groundwater monitoring program in ND that reported chemical and physical qualities of well water. Chemical profiles for approximately 1900 well water samples across ND counties between 1997-2017 were compared with CRC rates from this same time period. Trace elements were analyzed by USGS using inductively coupled plasma-atomic emission spectroscopy and inductively coupled plasma-mass spectrometry[1]. The relative error between the analytical values and the most probable values averaged less than 0.2 percent for both methods[2]. CRC cancer incidence rates by county were obtained from the NDSCR between 1997-2019. All rates were age-adjusted to the 2000 United States Census. Due to the small number of non-whites in sparsely populated counties, the analyses were restricted to white, non-Hispanic populations.

Multiple linear regression was used to identify associations between the independent variables with age-adjusted CRC incidence rates provided by NDSCR (Table 1). This analysis allowed us to investigate the strength of the relationship between multiple common well-water contaminants and CRC outcomes. The well water contaminants, barium and iron, were the only statistically significant predictors of CRC. Iron showed a statistically significant positive correlation (4.75, P = 0.014)). The relationship between iron and CRC was visualized by scatter plot (Figure 1). Conversely, barium appeared to be a significant negative predictor (-0.07, P = 0.01)). Consistent with Schwartz et al[3], in 2019, race, sex, age, income, and poverty level were not significant predictors of CRC rates. Cadmium, chromium, and dichlorodiphenyltrichloroethane were excluded from the full model multiple regression analysis as observed levels were far below the Environmental Protection Agency’s maximum contaminant level.

Figure 1 Colorectal cancer incidence rate per 100000 population. CRC: Colorectal cancer.

Table 1 Multiple linear regression results in full-model.

Variable	Degree of freedom	Estimate	Error	T value	P value > |t| value
Intercept	1	40.95586	6.38254	6.42	0.0002
Arsenic	1	-0.2069	0.32602	-0.63	0.5434
Barium	1	-0.06907	0.02115	-3.27	0.0114
Chlorine	1	0.02976	0.02203	1.35	0.2137
Iron	1	4.75042	0.992	4.79	0.0014
Nitrogen	1	0.48432	0.52651	0.92	0.3845
Well water	1	1.01243	0.42954	2.36	0.0462
Population density	1	0.01519	0.11723	0.13	0.9001

CURRENT SITUATION AND CHALLENGES WITH CRC

CRC is a major cause of cancer incidence and mortality worldwide. In ND, CRC incidence is 40.2 per 100000 people (95%CI: 38.2-42.2) with a total of 1709 new cases of CRC reported between 2015-2019[4]. This is substantially higher than the overall United States incidence rate of 37.7 per 100000 people between 2015-2019. Recent studies have suggested an association between well water and increased cancer incidence in the United States. This is of particular concern in ND, as more than 26500 wells provide drinking water for more than 60% of the state’s population[5,6]. Numerous contaminants that are found in well water, e.g., coliform bacteria, disinfection by-products, iron, and nitrates have previously been implicated in CRC[3]. We found a significant positive connection between CRC rates and iron. Although barium was weakly, negatively associated with CRC rates, this is likely an artefactual finding as barium is a naturally occurring trace element found in drinking water[7] along other known carcinogenic contaminants such as nitrates and iron[7,8].

IRON AS AN IMPORTANT PREDICTOR IN CRC

Iron as an environmental modifier of CRC has been examined in population-based studies with evidence that excess iron increases the risk of CRC[9]. Although dietary iron (heme and non-heme) is an essential nutrient, iron in excess is toxic, as it leads to transferrin saturation[10]. A large cohort study by Knekt et al[11] observed an association between excess iron exposure and CRC risk through the production of free oxygen radicals reporting a relative risk of 3.04, adjusted for age, sex and smoking. In addition, the majority (75%, n = 33) of the cohort studies evaluated by Torti et al[12] in 2020, examining CRC outcomes, support an association between excess iron and an increased risk of CRC. Similarly, case-control studies have found an increase in serum ferritin levels associated with the formation of pre-cancerous CRC adenomatous polyps[6,7].

Mechanistic studies indicate that iron contributes to CRC initiation and promotion via iron-induced oxidative stress and inflammation[9,12-14]. For example, Charlebois et al[10] (2023) reported that iron transport and metabolism play a role in the promotion of CRC growth. In vitro studies demonstrate that excess dietary iron promotes colon tumors in mice[12,15,16]. Intestinal tumor development increased in mice fed a high iron diet and decreased in mice fed an iron-restricted diet[12,17]. Excess iron in intestinal tumors may lead to an increase in tumor-elicited inflammation and tumor growth leading to the progression of CRC[18]. Iron-regulatory mechanisms play a significant role in CRC due to iron-mediated pro-tumorigenic pathways, including hyperproliferation[19]. For example, dysregulation of intestinal iron transporters has been observed in CRC and leads to iron accumulation in tumors and increased cell proliferation[18]. Iron is involved in numerous biological and cellular processes such as oxygen transport, oxidative phosphorylation, and DNA synthesis, as well as cell cycle progression and growth[13,20]. Studies have also shown that iron exposure at the cellular level leads to iron dependent cell death (ferroptosis) in CRC cells[14].

Limitations of this study include a small sample size; only 16/53, or 30% of counties had matching data on contaminants and CRC incidence rates. Additionally, incidence rates and contaminant levels were measured during approximately the same time interval. For these associations to be causal, the contaminant levels we studied must be a valid surrogate of previous contaminant levels. The most important limitation is that these are ecologic, and not individual level data; thus, they indicate that counties with higher iron levels in water are associated with higher CRC incidence rates, and not that individuals exposed to higher iron in water do so.

CONCLUSION

We found that ND counties with elevated levels of iron in well water are positively associated with CRC incidence. Confirmation of these results in other states, e.g., those with large agricultural activities, would be valuable. Finally, a case-control study of iron in water among cases with CRC and controls without CRC would be an essential next step. Further exploration into the implications of iron exposure on CRC carcinogenesis offers the possibility of preventive interventions and early screenings for high risk groups.

ACKNOWLEDGEMENTS

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We thank Oancea C of the NDSCR for assistance with the county-specific CRC incidence rates.