Elsevier

Toxicology Letters

Volume 175, Issues 1–3, 10 December 2007, Pages 64-70
Toxicology Letters

Effects of sub-chronic nitrate exposure on the thyroidal function in humans

https://doi.org/10.1016/j.toxlet.2007.09.010Get rights and content

Abstract

No experimental data exist on the thyroid toxicity of nitrate among humans. We aimed to show that no significant antithyroid effect could be observed after exposure to a three times the acceptable daily intake of nitrate in humans. In a randomized controlled non-inferiority trial, 10 volunteers received 15 mg/kg sodium nitrate during 28 days whereas 10 control participants received distilled water. We performed 5- and 24-h measurements of thyroidal 131I uptake (RAIU) before and at the end of the exposure period. Thyroid hormone plasma concentrations of T3, rT3, T4, TSH were also measured prior to and after exposure. Differences in RAIU between the intervention and the control groups at 4 weeks were 3.4% (95% confidence interval −0.5 to 7.3, and 4.8% (95% confidence interval −1.4 to 11.0, respectively, for the 5- and 24-h RAIU measurement. Plasma concentrations of thyroid hormones stayed normal. In conclusion, no significant effects on thyroidal 131I uptake and thyroid hormones plasma concentrations were observed after sub-chronic exposition to 15 mg/kg sodium nitrate among humans.

Introduction

Health risks associated with nitrate intake are still the subject of an ongoing debate (van Grinsven et al., 2006). Nitrate intake occurs through drinking water contaminated by organic sources (e.g. human sewage and livestock manure) and/or inorganic sources (mainly fertilizers like potassium nitrate and ammonium nitrate). When nitrate levels in drinking water are below the current regulatory standards of 50 mg/l (WHO, 2006), the large majority of individual's nitrate intake comes from vegetables, in particular from spinach, lettuce and beetroot in European countries (Sušin et al., 2006, Tamme et al., 2006). Consumption of cured meats is another potential route of human exposure to nitrate (Gangolli et al., 1994).

The main risk of nitrate is due to its reduction to nitrite, and subsequently to the possible occurrence of methaemoglobinaemia among bottle-fed infants below the age of 6 months. In this situation, normal haemoglobin is oxidated and converted to methaemoglobin, which is incapable of binding and carrying oxygen. Other possible outcomes of nitrate exposure are cancers, via the bacterial production of N-nitroso compounds, hypertension, increased infant mortality, central nervous system birth defects, diabetes, spontaneous abortion, respiratory tract infections, and changes to the immune system, but these outcomes are currently inconclusive (Fewtrell, 2004).

Possible relationships between nitrate intake and effects on the thyroid have also been reported. In animals, experimental studies have shown that inorganic nitrate is a goitrogenic agent at short term (Lee et al., 1970, Gatseva et al., 1999). Among humans, only epidemiological studies have been conducted, to study chronic exposure to nitrate, in particular through drinking water from wells. They have revealed indications for a possible antithyroid effect of nitrate (Höring and Schiller, 1987, Van der Heide and Schröder-van der Elst, 1992). A dose–response has been found between the level of nitrate in drinking water and the thyroid volume (van Maanen et al., 1994). However, these data are difficult to interpret since well water can also be contaminated by other compounds and because, apart from drinking water nitrate intake, vegetable nitrate intake varies a lot between individuals. Also, other agents not considered could have affected thyroid metabolism in these studies. No experimental data exist on the sub-chronic thyroid toxicity of nitrate among humans.

We conducted a study to show that no significant antithyroid effect could be observed after an exposure to nitrate. We hypothesized that thyroidal function will be similar with or without exposure to a three times the acceptable daily intake (ADI) of nitrate during 28 days. Our premise was that the thyroid functioning would be comparable after nitrate exposure and placebo exposure; therefore, we chose a non-inferiority trial approach. Our aim was to compare the thyroid functioning after nitrate exposure and placebo exposure.

Section snippets

Participants and randomization

We recruited participants through advertisements on the bulletin boards in buildings of the Utrecht University and through direct mailing to former participants or individuals that had notified us to be willing to participate in studies with healthy volunteers. All participants underwent a screening visit including a medical examination, blood and urine samples, and electrocardiogram measurement. Inclusion criteria were age 18–35, body mass index (BMI) 20–24, weight <85 kg, normal functioning

Flow of participants, follow-up, and sample characteristics

Thirty-two persons were assessed for eligibility. Among them, four were excluded because of abnormalities of the plasma bilirubin concentration (one person), of the erythrocite sedimentation rate (two persons), or of the plasma calcium concentration (one person), and four persons declined to participate. Twenty-four participants were included and randomly assigned to either the nitrate or the control group. Four persons did not complete the intervention (two in each group). These four persons

Discussion

This study is the first experimental trial among humans about the effect of sub-chronic exposure to nitrate on the thyroidal function. We have shown that thyroidal function was equivalent between the control group who received distilled water and the nitrate group who received daily three times the acceptable ADI of nitrate, for 28 days.

Until now, experimental studies about the effect of nitrate have been conducted only among animals. Extrapolation from these experimental animal studies to

References (23)

  • P. Gatseva et al.

    Pathomorphological study of rats submitted to a drinking water regime with high nitrate content

    Fresenius Environ. Bull.

    (1999)
  • Cited by (28)

    • Benefit-risk analysis for foods (BRAFO): Evaluation of exposure to dietary nitrates

      2018, Food and Chemical Toxicology
      Citation Excerpt :

      The strongest data for this endpoint are from a randomized controlled trial in which volunteers consumed 15 mg/kg-bw/day sodium nitrate (∼11 mg nitrate/kg-bw/d) for a 28-day period (Hunault et al., 2007). No treatment-associated effects on thyroidal 131iodine uptake or plasma thyroid hormone levels (i.e., T3, rT3, T4, and TSH) were identified (Hunault et al., 2007). Data from observational studies are inconsistent; some have reported suggestive evidence related to exposure in the drinking water and development of an enlarged thyroid and goiter (Gatseva and Argirova, 2008; Tajtakova et al., 2006; van Maanen et al., 1994), though others have not found an association (Below et al., 2008; Hunault et al., 2007).

    • Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid

      2016, Toxicology Letters
      Citation Excerpt :

      Measurement of the uptake of radioactive iodine as a diagnostic tool for thyroid function testing (RAIU test) was introduced in the fifties of the previous century (Astwood and Stanley, 1947; Goodwin et al., 1951; Greer, 1951). As reliable methods for measuring thyroid hormones became available the diagnostic use of the RAIU test declined, but in recent years the test has been employed for examining the potential adverse effects of chemical substances on the human thyroid (Braverman et al., 2005, 2006; Greer et al., 2002; Hunault et al., 2007; Kunii et al., 2016; Lawrence et al., 2001, 2000). In the RAIU test, a quantity of radioactive iodide, usually sodium 131I-, 132I- or 123I-iodide, is administered orally.

    • Is dietary nitrate/nitrite exposure a risk factor for development of thyroid abnormality? A systematic review and meta-analysis

      2015, Nitric Oxide - Biology and Chemistry
      Citation Excerpt :

      A short-term intervention with high and low nitrate diets in female rats, at three dietary iodine levels (0.68, 0.23 and 0.08 ppm, as high, medium and low), indicated that only in the combined high-nitrate and the low-iodine diets, hyperplasia, hypertrophy, and follicular colloid depletion, plus decreased iodide uptake, and increased weight of the thyroid gland were observed [51]. A randomized controlled non-inferiority trial has shown no significant anti-thyroid effect following exposure to a relatively high dose of nitrate; in this study, 4-week consumption of 15 mg/kg sodium nitrate (~3 times the ADI) in 20 healthy volunteers had no significant effect on thyroidal 131I uptake or plasma concentrations of T3, rT3, T4, or TSH [76]. The nitrate dose used in this study was lower than doses mostly used in clinical investigations on its potential therapeutic benefits [76]; the authors have mentioned some limitations, including small sample size, a relatively short intervention period, considerable variation and a high standard deviation of 24-h thyroidal 131I uptake before nitrate exposure, and suggested larger sample sizes, a longer exposure period and/or higher doses of nitrate for future studies.

    View all citing articles on Scopus
    1

    Present address: IrisZorg addiction care centre, Postbus 351, 6800 AJ Arnhem, The Netherlands.

    2

    Present address: Clinic for treatment of drug addiction in northern, Vondellaan 71-73, 9721 LB Groningen, The Netherlands.

    View full text