We found a positive association between nitrate intake from public drinking water supplies and incidence of thyroid cancer. However, we observed no increased risk of thyroid cancer among users of private wells, for whom we had no measurement data. Drinking-water nitrate concentrations and private well use were not associated with thyroid conditions. Greater dietary nitrate intake was associated with an increased risk of thyroid cancer and a greater prevalence of hypothyroidism but not hyperthyroidism. These positive findings are of interest in light of the increasing incidence of thyroid cancer over the past decades, and the ubiquitous exposure to nitrate from dietary and drinking water sources—the latter occurring mostly in agricultural regions.
Two epidemiologic studies14,15
among populations with sufficient iodine intake have provided some evidence that nitrate ingestion via drinking water is associated with subclinical hypothyroidism and hypertrophy of the thyroid. The hypothesized mechanism is inhibition of iodide uptake due to competitive binding to the sodium-iodide symporter on the surface of thyroid follicles. Nitrate levels in drinking water supplies have been associated with increased thyroid volume,14,15
increased TSH levels,14
and other signs of subclinical thyroid disorders.15
We did not observe an increased risk of hyperthyroidism or hypothyroidism in relation to nitrate exposure from public water supplies. However, dietary nitrate accounted for the majority of nitrate intake in this study population. The association between dietary nitrate intake and hypothyroidism was stronger among those with lower vitamin C intakes, suggesting that this dietary pattern (which is associated with endogenous formation of N
) rather than the nitrate level alone may be important. Still, this may be a chance finding. Our analysis of thyroid conditions was limited to self-reported medication use for these prevalent conditions; we did not have more objective or alternative measures of thyroid dysfunction such as thyroid hormone levels, thyroid weight, or ultrasonography data. We did not have information about iodine intake; however, the US National Health and Nutrition Examination Survey (NHANES I, 1971–1974) showed adequate to excessive dietary iodine intake in the US population.33
To our knowledge, these associations for thyroid cancer have not been reported in an epidemiologic study previously and suggest that nitrate intake may be an important area for future research. Although based on a small number of cases, our results are consistent with animal data showing that chronic TSH stimulation of the thyroid gland from nitrate exposure can lead to proliferative changes in follicular cells, including hypertrophy and hyperplasia. Alternatively, N
-nitroso compound formation may be a mechanism because about 5% of ingested nitrate is reduced to nitrite in vivo, thus serving as a precursor in the N
-nitroso formation. Specific N
-nitroso compounds cause thyroid and other cancers in animal studies.16
Strengths of this study include the prospective design and our historical database in which all samples were analyzed by the same laboratory. Additionally, we were able to reduce exposure misclassification by excluding communities with varying nitrate levels due to multiple sources. Other strengths include rapid and complete cancer ascertainment through the Iowa SEER registry, low population mobility, and information about several potential confounders.
There were several limitations to our exposure assessment. We ascertained the drinking water source only at the residence in 1989, and not for prior residences. An unknown proportion of women may have been consuming some portion of their drinking water from another source, particularly if they were employed in another town. Only 33% of women were employed outside the home in 1986.24
On the basis of the 1990 US census data for Iowa,34
68% of workers lived and worked in the same town and, therefore, would have been served by the same public supply. Use of other water sources with different nitrate levels would be expected to be nondifferential and, therefore, is most likely to attenuate associations.
Nitrate concentrations can be substantially higher in private wells than public supplies because private wells are not regulated. However, concentrations in private wells vary depending on depth, construction, aquifer characteristics, and other factors,18
making private well use a poor surrogate for nitrate exposure. We did not have information on the usual amount of tap water intake, which may also have resulted in nondifferential misclassification.
Finally, although the exposure of interest was nitrate in drinking water, we could not evaluate other potential contaminants in drinking water, such as pesticides and perchlorate; the latter is a known inhibitor of iodide uptake by the thyroid cells,11
which may be of etiologic importance. In a recent survey of private wells across the state35
perchlorate was detected in only 1 well, indicating that contamination is not common in Iowa.
Increased diagnosis has been suggested as an explanation for the rise in thyroid cancer incidence during the past decades.3,36
However, increases in papillary thyroid cancer, the major histologic type, occurred for all racial and ethnic groups and for local, regional, and distant diseases, suggesting that increases in diagnosis cannot explain all of the increase in incidence.4,5
Access to medical care can affect diagnosis rates, although all of the women were of age at least 65 years at the last follow-up and so were covered by Medicare. Women with higher dietary nitrate intake were less likely to be current or past smokers, were more educated, and engaged in more physical activity than women with lower nitrate intake. These factors, which are indicative of a healthy lifestyle, did not differ by level of nitrate in public water supplies.24
If a healthy lifestyle, including the consumption of high nitrate vegetables, was associated with increased use of health care screening for thyroid cancer, screening bias might partly explain the positive association with dietary nitrate intake, but not with drinking water nitrate concentrations. Due to the limited number of thyroid cancer cases, it was not possible to stratify by educational level, smoking status, or physical activity to evaluate the consistency of the association across subgroups of the population; however, education, smoking, and physical activity were not confounders.
In summary, we found that nitrate ingestion from dietary and drinking water sources was associated with an increased risk of thyroid cancer. Furthermore, our results suggest that higher intake of dietary nitrate is associated with hypothyroidism. Our findings for thyroid cancer were based on small numbers of cases; larger studies will be required to confirm or refute our observations and to evaluate the potential interactions between nitrate ingestion and factors that affect rates of endogenous nitrosation. Ascertainment of incident thyroid conditions to establish the timing of the association between nitrate ingestion and hypothyroidism would be preferable to self-reported information about these conditions. Our findings are novel and are biologically plausible. Given the increase in thyroid cancer incidence during the past decades, without an identifiable cause, a possible role for nitrate should be considered in future epidemiologic studies of thyroid cancer and thyroid conditions.