对甲状腺健康饮用水的高氯酸盐污染的可能影响

Abstract

背景。Perchlorate is an anion that occurs as a contaminant in groundwater. It originates from the improper disposal of ammonium perchlorate, a component of rocket fuel. The objective of this study was to explore whether the exposure to perchlorate in drinking water had an impact on the thyroid function of the population residing near an ammonium perchlorate plant in Kerala.Methodology。üsing an ecological study design, we compared the serum levels of thyroid-stimulating hormone, thyroxine, and thyroid peroxidase antibodies among a representative sample of 289 study subjects from the area surrounding the ammonium perchlorate enrichment plant to 281 study subjects in a control area.Results。The perchlorate concentration in the groundwater varied from 1600 ppb to 57,000 ppb in the 10 samples from the contaminated area and was below 24 ppb in all locations in the control area. No significant differences were found in the mean serum TSH concentration and mean T4 levels between the subjects from the contaminated area and the control area. On regression analysis, perchlorate contamination was not found to be a significant predictor of TSH.Conclusion。这项研究没有发现高氯酸盐之间的任何显著的关联饮用水和变化，甲状腺激素水平。我们的研究结果表明，使用尿高氯酸盐作为个体暴露的测量这一假设的进一步调查的必要性。

1.背景

高氯酸铵是广泛地用作固体燃料火箭推进剂的氧化剂成分的无机化合物。[1]It has been used therapeutically for clinical indications like hyperthyroidism associated with amiodarone toxicity [2]。In pharmacologic doses, perchlorate ions concentrate in the thyroid tissue and are competitive inhibitors of the sodium/iodine symporter (NIS). NIS is a membrane protein located on the basolateral side of the follicular cells of the thyroid gland. Perchlorate anions will decrease the active transport of iodine into the follicular cells, inhibiting organification of iodide and consequently decreasing thyroid hormone synthesis [3，4]。This in turn increases the TSH levels causing thyroid hypertrophy or hyperplasia possibly followed by clinical hypothyroidism. [3，4]In vitro在NIS-表达由Tonacchera等细胞的研究。表明，高氯酸盐具有用于碘化物为NIS 30倍更大的效力比[五]。

现有证据不支持甲状腺激素水平的变化和高氯酸盐暴露的环境水平之间存在因果关系。[6]However, human activities have led to the widespread presence of perchlorate in the environment and drinking water. One major source of contamination is the manufacture and improper disposal of ammonium perchlorate that is used for rocket fuel [7]。胎儿和婴儿是最脆弱的se effects because they need thyroid hormone for normal neurodevelopment [3]。

In the year 2014, a medical officer of a Primary Health Centre in Keezhmad in the Ernakulam district of Kerala noticed an unusually high incidence of hypothyroidism and subclinical hypothyroidism among the residents of the Kulakkad colony in the Keezhmad panchayath. As the Kulakkad colony shares a compound wall with the central government’s Ammonium Perchlorate Experimental Plant (APEP) facility, exposure to perchlorate was suspected to be the cause of hypothyroidism. A study conducted by the National institute of Interdisciplinary Science and Technology, Thiruvananthapuram, revealed high levels of perchlorate contamination in ground and surface water around the Ammonium Perchlorate Experimental Plant (APEP) at Aluva in the Ernakulam district of Kerala, India. The contamination was found to be severe in groundwater as compared to surface water (7270 μg/L vs 355 μg/L) at this location. [8]Following press reports on the contamination of drinking water and the incidence of hypothyroidism, the district authorities initiated administrative action to control the situation and constituted a technical expert committee to assess the risk from these exposures. The present study aimed to examine whether exposure to perchlorate in drinking water has an impact on the thyroid function of the population residing near the ammonium perchlorate plant.

2。Materials and Methods

2。1。Study Design and Study Setting

This study used an ecologic design, integrating environmental measurement data of perchlorate levels in the groundwater and data on the thyroid function of the subjects. The study population encompasses residents from two contaminated areas that surround the Ammonium Perchlorate Experimental Plant (APEP) facility and two control areas located 20 kilometers north of the contaminated area. The areas considered as “contaminated areas” were Edathala and Keezhmad panchayaths with perchlorate levels exceeding 24 ppb in the groundwater used for drinking purpose. The areas designated as “control areas” were Pallissery and Karukutty panchayaths with perchlorate levels below 24 ppb. The authors compared the thyroid function of the subjects living in the contaminated areas to the control areas. Both areas are similar in size and other sociodemographic characteristics.

2。2。Sample Size, Sampling Technique, and Eligibility

我们通过分层随机取样，招募570具有代表性的样本。其中，289个居民生活中的“污染区”和281个居民居住在控制区。为了确保两种性别和所有年龄组的充分代表性，分层是由性别和10岁年龄组进行。从每个参与者获得书面知情同意书。低碘水平有潜力充当高氯酸盐与游离T4和TSH，参与者尿碘<100关联一个混杂因素 μ克/升被排除在外。研究参与者谁是怀孕，参与者称为自身免疫性甲状腺疾病，并已知会影响甲状腺像左甲状腺素，丙硫氧嘧啶，或β受体阻滞剂功能那些服用药物也被排除在外。排除后，共有542名受试者被认为是合格的。

2。3。Study Procedure and Environmental Exposure Assessment

All subjects included in this analysis received a standardized clinical examination, and a fasting blood sample was collected from which serum TSH levels, serum-free T4 levels, and TPO antibody levels were measured. The analysis of thyroid function parameters was done using the ARCHITECT i2000SR immunoassay analyser based on the chemiluminescence assay, and their normal reference ranges are as follows: serum TSH (0.35 to 4.9 uIU/ml), serum-free T4 (0.7 to 1.48 ng/dl), and TPO antibody (0.0 to 5.61 U/ml). The urinary iodine levels of the participants were also measured in the morning urine samples. As thiocyanate, which is elevated in smokers, and nitrate in drinking water have the potential to interact with iodine uptake, we ascertained the smoking status of the subjects and the nitrate levels in the groundwater samples [五]。The groundwater samples were collected from eight open wells and two borewells from Edathala and Keezhmad, the contaminated areas, and from four open wells and one borewell of Pallissery and Karukutty, the control areas. The analysis for perchlorate was performed using the ion chromatography system (IC-1100, Dionex) at NIIST, Thiruvananthapuram. General physical and chemical water quality parameters including nitrate levels were analysed at the Department of Oceanography, CUSAT.

2。4。Statistical Analysis

对于正态分布的变量，使用卡方检验单因素分析，独立样本的Ť- 测试和Pearson相关被完成。曼 - 惠特尼ü测试非正态分布变量来完成。所述T4的值呈正态分布和TSH值近似正态分布，但TPO抗体值在分配非正常。TSH是数转换和分析。回归分析使用广义线性模型以测定甲状腺功能的独立关联与饮用水高氯酸盐存在。以下变量包括在回归模型用TSH水平作为因变量：高氯酸盐污染，年龄，性别的存在，和BMI（对于受试者18岁以上）。

3.结果

The total number of subjects after exclusion was 542 with 272 subjects from the contaminated area and 270 subjects from the control area. The demographic characteristics of the study population are presented in Table1。The mean age of the study participants in the contaminated area was 34.76 ± 21.60 and 34.20 ± 19.57 in the control area. The primary source of drinking water, as participants reported, was water from the well and borewell water. The data indicate that the study subjects from the contaminated area and the control area are comparable with respect to their demographic characteristics.

We determined the perchlorate concentrations in the groundwater of ten locations from the contaminated areas and five locations from the control areas. The perchlorate concentration in the groundwater varied from 1600 ppb to 57,000 ppb in the 10 samples from the contaminated areas. These values were about 70 to 480 times higher than the permitted drinking water equivalent level of 24 ppb established by the USEPA. [7]The highest perchlorate levels were detected in the samples taken from areas adjacent to the APEP plant. The concentrations of perchlorate in the control area were largely comparable to levels in the groundwater as previously reported from other parts of Kerala [8]。The concentrations there varied from below detectable levels (BDL) to 20 ppb, all of which were less than the regulatory standard [7]。The details of the perchlorate levels in the contaminated and the control areas are summarized in Table2。

The urinary levels of iodine in this population were also evaluated, and all the subjects included had urinary iodine >100 µ克/升，这表明足够的碘营养水平。[9]硝酸盐和硫氰酸盐是天然存在的goitrogens。硝酸盐在这项研究中的地下水样品中发现的水平相媲美的水平以前发现从类似的人群样本[7]。吸烟者的比例，这是硫氰酸曝光的一个指标，而这两个地区被验者中也类似。

The mean serum TSH concentrations were 2.049 mIU/L among the subjects from the contaminated area and 1.90 mIU/L among the subjects residing in the control area. This difference was not statistically significant (value 0.657). Expressing the data as proportions, there was no significant difference in the prevalence of hypothyroidism, which was 4% in the contaminated area and 3.3% in the control area (值0.841）。我们剔除异常TPO水平的受试者经过反复的分析。The mean serum TSH concentrations after exclusion were 1.827 mIU/L among the subjects from the contaminated area and 1.780 mIU/L among subjects residing in the control area. This difference was also not statistically significant (value 0.671). The results were consistent when stratified by age, gender, and BMI. The details of the thyroid function parameters with respect to the area are given in Tables3和4。

Adjusting for age, gender, and BMI (for subjects above 18 years) and modeling TSH concentration as the outcome, we observed no significant relationship with perchlorate levels in the generalized linear regression model. The乙coefficient for perchlorate contamination was −0.022 (value = 0.62). However, age of the participants was found to be a significant predictor of thyroid function. The results of the regression analysis are shown in Table五。

4。Discussion

我们的研究没有发现甲状腺功能异常的研究对象谁与高氯酸盐污染的地下水居住的社区中发病率增加的任何证据。The results of our univariate analysis revealed a slightly increased prevalence of hypothyroidism with exposure to perchlorate levels above 24 ppb in drinking water, but this was not statistically significant. The geometric mean of primary thyroidal parameters TSH and T4 showed no significant differences between the subjects from the perchlorate-contaminated area and the control area. These findings were consistent with the majority of available epidemiological evidence from chronic occupational exposure studies and ecologic investigations [2]。

The majority of the available published scientific literature does not demonstrate a causal association between perchlorate exposure and hypothyroidism. A study by Li et al. on the prevalence of thyroid diseases in Nevada counties did not observe an increased rate of any specific thyroid disease associated with perchlorate exposure in drinking water [10]。A similar study on thyroid function in the pediatric population of a perchlorate-contaminated area showed that there was no variation in the TSH levels and free thyroxine (T4) levels as compared to children of other regions with no perchlorate in drinking water. [11]The possible explanation why long-term exposure to high levels of perchlorate did not affect plasma TSH levels or T4 levels, as suggested by De Groef et al., is that the inhibition of iodine uptake is duration dependent and the existence of compensatory mechanisms which counteract the perchlorate-induced NIS inhibition [12]。Similar observations were made in an experimental setting which observed no effect on the inhibition of iodide uptake by the thyroid at 0.007 mg/kg of perchlorate per day. [4]An observational study carried out at an ammonium perchlorate production factory in China found no effect on thyroid function from long-term exposure to ammonium perchlorate. [13]。

However, it must be pointed out that some investigators have identified a relationship between perchlorate contamination of water supplies and thyroid dysfunction. The results of the present study is in contrast with the findings of a cross-sectional study based on the NHANES data by Blount et al. which conclude that perchlorate exposure is associated with increased TSH and decreased T4 among women who had iodine deficiency (urinary iodine values < 100 μg/L) [14]。Similar observations were made by Greer et al. in the TSH levels of subjects whose iodine nutrition was insufficient [4]。The observations found that intake of 150 μg iodine daily would protect against goiter in a person whose perchlorate ingestion is 4 mg/day (dose that would inhibit iodide uptake) [4]。However, the present study excluded individuals who had urinary iodine values < 100 μ克/升，因为这可能对结果的混杂影响被评估[9]。This can be one reason why the authors of the present study did not observe any significant effect for perchlorate. The findings of another study which looked at the relation between perchlorate and serum-free thyroxine (FT4) indicate that adolescent boys and girls are vulnerable to the thyroid-blocking effects of perchlorate [15]。

Pregnancy is considered to be a vulnerable period for perchlorate exposure, and it may have an adverse effect on the offsprings’ cognitive development. A study conducted among Arizona newborns by Brechner et al. reported an association between perchlorate in drinking water and incidence of hypothyroidism [16]。泰勒等人的研究。在2014年846名妇女孕龄在16个两周报告的尿高氯酸盐和后代智商之间的关联在3岁。[17]The transport of iodine into breast milk is through the same sodium/iodine symporter which is inhibited by the perchlorate ion [18]。孕妇被排除在本研究中。

目前研究的结果与那些先前的研究相对于人口因素的混杂影响协议。在我们的回归模型分析了人口学特征，只有年龄被认为是在预测高TSH一个显著的因素。在健康成人，平均TSH随着年龄的增大[19]。虽然许多研究报告在正常范围和BMI内血清TSH之间存在正相关关系，我们没有发现在回归模型中的任何显著的关联[20，21]。

One possible explanation for the findings of the present study is that the exposure ascertainment procedure did not account for variation due to individual consumption patterns of water. Even though all residents in the contaminated area reported consuming groundwater from the area, the possibility of them relying on several water sources cannot be ruled out. This was a major limitation of the study, and this can be rectified only by individual measurement of perchlorate exposure using urinary perchlorate estimation.

4.1。建议

（1）乙iomonitoring of perchlorate exposure in this population by measuring urinary perchlorate levels.（2）地下水高氯酸盐水平的日常环境监测。（3）Small amount of iodine supplementation can modify the goitrogenic effects of perchlorate in drinking water [22]。（4）Analytical research studies which measure individual exposures such as urinary perchlorate with the additional use of indirect biomarkers for perchlorate.(5)Measures to educate the residents on proper storage of iodised salt at home so as to maintain the iodine content at 15 ppm.

五。Conclusion

作者认为，从目前的生态研究的数据是不是甲状腺功能和暴露之间的因果联系高氯酸盐在用于饮用目的地下水一致。然而，目前的研究是受到生态谬论。我们假设地理上划定暴露于高氯酸盐有效地代表了受污染区域的人口下进行研究。假设的进一步调查使用的分析研究，用高氯酸尿估计纳入高氯酸盐曝光的个别测量污染区保证。

缩略语

NIS:	钠/碘转运体
TSH:	甲状腺-stimulating hormone
APEP：	高氯酸铵实验厂
PPB：	十亿分之
T4：	甲状腺素4
TPO:	甲状腺过氧化物酶
NIIST：	国家研究所e for Interdisciplinary Science and Technology
CUSAT:	Cochin University of Science and Technology
乙MI:	身体质量指数
美国环保局：	üñited States Environmental Protection Agency
BDL:	低于可检测水平
NHANES：	National Health and Nutrition Examination Survey
智商：	Intelligence quotient
ppm:	百万分之一。

Data Availability

用来支持这项研究的结果的数据可应要求提供。

Ethical Approval

The authors of this publication had research funding from the Indian Space Research Organisation (ISRO). The terms of this arrangement have been reviewed and approved by a specially constituted ethics committee headed by the district collector.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

Thanks are due to the Indian Space Research Organisation for funding and the National Institute for Interdisciplinary Science and Technology (NIIST) and CUSAT (Cochin University of Science and Technology) for technical assistance.

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Copyright © 2020 Sunny P Orathel et al. This is an open access article distributed under the知识共享署名许可，which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.