Damaging Health Effects Of Nitrate In Drinking Water

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Note: Whole of house filtration  by Water Filter Corp is able to remove possible nitrate and other contamination from drinking and shower water

Cancer

NOC are potent animal carcinogens, inducing tumors at multiple organ sites including the esophagus, stomach, colon, bladder, lympatics, and hematopoietic system (Bogovski and Bogovski, 1981). NOC causes tumors in every animal species tested and it is unlikely that humans are unaffected (Lijinsky 1986). The number of well-designed epidemiologic studies with individual exposure data and information on nitrosation inhibitors and precursors are few for any single cancer site, limiting the ability to draw conclusions about cancer risk.

Most studies have been ecologic in design, linking incidence or mortality rates to drinking water nitrate levels at the town or county level. The early studies focused on stomach cancer mortality and most used drinking water nitrate measurements concurrent with the time period of cancer mortality. Results were mixed, with some studies showing positive associations, many showing no association and a few showing inverse associations (Cantor 1997). Recent ecologic studies of stomach cancer in Slovakia, Spain, and Hungary with historical measurements and exposure levels near or above the MCL have found positive correlations with stomach cancer incidence or mortality (Gulis et al. 2002; Sandor et al. 2001; Morales-Suarez-Varela et al. 1995).

 

Two studies included other cancer sites.

In Slovakia, incidence of NHL and colon cancer was significantly elevated among men and women exposed to public supply nitrate levels of 4.5-11.3 mg/L nitrate-N (Gulis et al.2002); there was no association with bladder and kidney cancer incidence. In Spain there was a positive correlation between nitrate levels in public supplies and prostate cancer mortality, but no relation with bladder and colon cancer (Morales-Suarez-Varela et al. 1995).

In the past decade, several case control and cohort studies have evaluated historical nitrate levels in public water supplies (largely below 10 mg/L nitrate-N) and risk of several cancers (Table 1). Some studies evaluated factors affecting nitrosation such as vitamin C intake.

A cohort study of older women in Iowa (USA) (Weyer et al. 2001) found a 2.8-fold and 1.8-fold risk of bladder and ovarian cancers, respectively, associated with the highest quartile (>2.46 mg/L nitrate-N) of the long-term average nitrate levels at the current residence. They observed significant inverse associations for uterine and rectal cancer and no significant associations for NHL, leukemia, colon, rectum, pancreas, kidney, lung, and melanoma. Case-control studies of bladder (Ward et al. 2003), brain (Ward et al.2004), colon and rectum (De Roos et al. 2003), and pancreas cancer (Coss et al. 2004) in Iowa found no association between cancer risk and average nitrate levels over almost 30 years.

Each study evaluated the interaction between nitrosation inhibitors or NOC precursors and nitrate intake from drinking water. For colon cancer, there was a significant positive interaction between 10 or more years of exposure above 5 mg/L nitrate-N and both low vitamin C and high meat intake, factors which are likely to increase endogenous NOC formation (De Roos et al. 2003).

A case-control study of NHL in Nebraska (Ward et al. 1996) found a significant positive association between the average nitrate level in public water supplies over about 40 years and risk among men and women. In the highest quartile of nitrate (4.0 mg/L nitrate-N), risk was elevated two-fold.

However, a recent study of NHL in Iowa with similar exposure levels, found no association (Ward et al. 2004). A case-control study of NHL in Minnesota (Freedman et al. 2000) with lower levels of nitrate found an inverse association among those with the highest level (>1.5 mg/L nitrate-N). Case-control studies in Nebraska (Ward et al. 2004) and Germany (Steindorf et al. 1994) found no association with long-term average nitrate levels in public water supplies and adult brain cancer. The Nebraska study found no evidence of an interaction with vitamin C intake. A case-cohort analysis of stomach cancer, within a cohort study in the Netherlands (van Loon et al. 1998) found no association with quintiles of water nitrate intake determined from public supply levels. Specific NOC are transplacental neurocarcinogens in animal studies.

A study of childhood brain cancer measured nitrate levels in water supplies using dipstick measurements, often many years after the pregnancy (Mueller et al. 2001). Measured levels of nitrate and nitrite were not associated with risk; however, women in western

Washington State, one of the three study centers, who used private wells as their drinking water source during the pregnancy had a significantly increased risk of brain cancer in their offspring.

Adverse Reproductive Outcomes

In 1961, Schmitz described a possible relationship between high maternal methemoglobin levels and spontaneous abortion. Since then, at least 10 studies have examined the association between drinking water nitrate and adverse reproductive outcomes. Table 2 summarizes these studies by location, study design, determination of water nitrate, and key findings.

Few studies have been published regarding water nitrate and the outcomes of spontaneous abortions, stillbirths, premature birth, or intrauterine growth retardation.

Results of these studies have been inconsistent possibly indicating that there is no true effect of water nitrate on reproductive outcomes at the levels evaluated in these studies.

Alternatively, the inconsistencies may be due to the differing time periods over which exposure was assessed, differing levels of water nitrate across studies, or differences in exposure to other co-factors.

Results of studies evaluating drinking water nitrate and congenital malformations in offspring are also mixed (Table 2). Four studies (Arbuckle et al. 1988; Brender et al. 2004a, Brender et al. 2004b, Croen et al. 2001, Dorsch et al. 1984) found positive  associations between drinking water nitrate and congenital malformations, particularly malformations of the central nervous system, and specifically neural tube defects. In each of these studies, water nitrate levels associated with increased risk of these defects were below the MCL, although the 95% confidence intervals for some of the risk estimates were  consistent with unity and varied by the source of water (groundwater, mixed, or surface).

Two of these studies (Croen et al. 2001; Brender et al. 2004a) also examined dietary intake of nitrates and nitrates and neural tube defects and found minimal or no effect on risk. In a study of nitrosatable drug exposure and risk of neural tube defects (Brender et al. 2004a), drinking water nitrates and dietary nitrites/total nitrites substantially modified the risk associated with this drug exposure during the periconceptional period; higher levels of nitrates in food or water significantly increased the risk of neural tube defects if women were exposed to such drugs.

Other health outcomes

Animal studies suggest that nitrate at high doses can competitively inhibit iodine uptake and induce hypertrophic changes in the thyroid (Bloomfield et al. 1960). In a human biomonitoring study in the Netherlands, consumption of water with nitrate levels at or above the MCL was associated with thyroid hypertrophy (van Maanen et al. 1994) and genotoxic effects (van Maanen et al. 1996). Animal studies provide evidence that NOC can damage the pancreatic beta-cells (Longnecker and Daniels 2001). Three epidemiologic studies (Kostraba et al. 1992; van Maanen et al. 2000; Parslow et al. 1997) that were ecologic in design found a positive correlation between drinking water nitrate levels below the MCL and the incidence of type I childhood diabetes, although the association observed by van Maanen was not statistically significant.

Other studies have found associations between water nitrate exposure and increased blood pressure (Poomeranz et al. 2000) and acute respiratory tract infections in children (Gupta et al.2000).

Recommendations for future research

Experimental/human biomonitoring studies

Endogenous nitrosation in humans has been demonstrated in relation to drinking water nitrate ingestion at levels above the MCL. However, further studies are needed to determine the extent of endogenous nitrosation at intermediate drinking water nitrate levels (5-10 mg/L as nitrate-N) and to clarify the role of nitrate from water as compared with food sources.

Furthermore, the role of precursors and modulators of NOC formation should be more fully investigated. These future studies should be conducted among healthy individuals as well as individuals with medical conditions that increase endogenous nitrosation.

In view of the complex kinetics of NOC formation and the organ specificity of several of these compounds (Hodgson et al. 1980; Suzuki et al. 1999), more studies are needed to evaluate the relationship between nitrate intake and formation, metabolism and excretion of NOC. Ideally, a physiologically based pharmacokinetic model should be developed as previously recommended (National Research Council 1995) in order to predict exposure to NOC from all sources of nitrate exposure (exogenous and endogenous), nitrite intake, the transformation of nitrate into nitrite, and anti-oxidant intake. However, this will require additional data on the formation of individual NOC as well as their respective toxicological characteristics.

The results of these investigations will reveal the value of different markers of NOC exposure in future epidemiological studies. Future studies linking NOC exposure to early makers of effect or to the actual disease will clarify the role of endogenous nitrosation and NOC-exposure as etiologic factors.

Because many NOC require α-hydroxylation by CYP2E1 for bioactivation and to form DNA adducts, it is important to investigate the influence of polymorphisms in the gene encoding for this enzyme. One study found that specific variants in this gene are linked to increased rectum cancer risk, particularly in subjects with high intake of red and processed meat, who are exposed to increased levels of NOC (Le Marchand et al. 2002). Moreover, gene expression levels of human CYP2E1 were found to be related to cytotoxicity and

DNA damage by nitrosamines in pancreatic beta-cell lines suggesting that such gene environment interactions are also relevant in type I diabetes (Lees Murdock et al. 2004).

These promising lines of research point to a possible interaction between drinking water nitrate exposure and gene expression of and/or genetic variation in CYP2E1 which may also influence the risk of several adverse health outcomes associated with nitrate exposure.

Epidemiologic studies

Methods need to be developed and validated to improve estimates of current and historical exposure to nitrate via foods and water, particularly for populations served by private wells which are less likely to be routinely monitored. Future epidemiologic studies should integrate i) exposure assessment for nitrate intake from drinking water, nitrate and nitrite intake from the diet, and amines and amides from dietary and drug sources, ii) endogenous exposure to NOC by analysis of relevant biological media (e.g. saliva, urine and/or feces) and iii) reliable health risk markers (e.g. biomarkers of genotoxicity) or diagnosis of actual disease.

Future studies should include populations with well-characterized long-term exposures including those who use private wells which can have higher nitrate levels than public supplies. With the increasing availability of public water supply monitoring data (many US states have almost 40 years of measurements) further detailed exposure assessment of populations using public supplies is also feasible.

Drinking water contaminants that mayco-occur with nitrate, such as agricultural pesticides, should also be evaluated.

Geographic-based modeling efforts to predict the probability of high nitrate concentration in groundwater using information on nitrogen inputs from agricultural and urban sources (Nolan et al. 2002) is a promising approach for estimating drinking water nitrate exposure for the population using private wells.

Additional studies of drinking water nitrate and cancer are needed to follow up on the suggestive positive findings to date and to evaluate other cancer sites for which human biomonitoring studies and/or animal studies suggest endogenously formed NOC may play a role.

Studies of reproductive outcomes should address the exposure period most relevant for the specific outcome of interest. Maternal residential mobility between conception and birth may lead to misclassification of exposure if the water source at birth is used in studies of spontaneous abortions and congenital malformations. Studies need to be of sufficient size to allow for examination of specific defects rather than groups of defects by system; “lumping” different defects together might mask associations. More research is needed on the relation between water nitrate and the reproductive outcomes of spontaneous abortion, fetal death, premature birth, and intrauterine growth retardation.

In the design and analysis stage, future epidemiological studies should take into account factors that modulate endogenous nitrosation, as discussed above, in order to be able to evaluate potential interactions of water nitrate intake with these factors, thus providing stronger evidence for or against an association. In particular, studies of susceptible populations may be fruitful and epidemiologic studies should be designed with sufficient power to evaluate risk among potentially susceptible subgroups. Such populations include patients with different forms of chronic inflammation (such as inflammatory bowel disease), patients infected with nitrate reducing bacteria (such as in periodontal disease), those with a systematic low intake of vitamins and other known nitrosation inhibitors, or those with a history of high incidence of potentially NOC-related diseases. An example of a population that fits the latter two categories are the people of Linxian County in China, known for their persistently low intake of several micronutrients and high risk of esophageal cancer (Blot et al.1993). Apart from the fact that such studies will provide better understanding of the risks associated with nitrate in drinking water and other NOC precursors, these are also the populations that are likely to benefit the most from preventive measurements that can be taken based on the results of these investigations.

Conclusions

Adverse health effects from drinking water nitrates are most likely the result of a comple interaction of the amount of nitrate ingested, the concomitant ingestion of nitrosating cofactor and precursors, and medical conditions of the host which may increase nitrosation.

Furthermore, these effects may be attenuated by inhibitors of endogenous nitrosation such as vitamin C and alpha-tocopherol. It is recommended that future studies take into account such complexities in understanding the relation between drinking water nitrates and cancer, adverse reproductive outcomes, and other health outcomes.

A number of authors (Avery 1999; L’hirondel and L’hirondel 2002) have questioned the importance of nitrate in drinking water as a risk factor for methemoglobinemia and have suggested that the current nitrate standard might be safely raised to 15-20 mg/L nitrate-N with no increase in methemoglobinemia cases. A better understanding of the conditions under which nitrate in drinking water poses a risk of methemoglobinemia is clearly needed, particularly in light of recent cases of methemoglobinemia associated with well water levels between 20-30 mg/L nitrate-N (Knobeloch et al. 2000).

Most importantly, the role of nitrate as a risk factor for cancer and adverse reproductive outcomes needs to be more thoroughly explored before changes to nitrate water quality standards are considered.

Note: Whole of house filtration  by Water Filter Corp is able to remove possible nitrate and other contamination from drinking and shower water

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