For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from...

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Hormones and endocrine-disrupting chemicals: Low-dose effects and nonmonotonic dose responses

Background: Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2...

https://www.thyca.org/download/document/486/PregnancyandPostpartum.pdf

2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum

Pregnancy has a profound impact on the thyroid gland and thyroid function. The gland increases 10% in size during pregnancy in iodine-replete countries and by 20%– 40% in areas of iodine deficiency. Production of thyroxine (T4) and triiodothyronine (T3) increases by 50%, along with a 50% increase in the daily iodine requirement. These physiological changes may result in hypothyroidism in the later stages of pregnancy in iodine-deficient women who were euthyroid in the first trimester. The range of thyrotropin (TSH), under the impact of placental human chorionic gonadotropin (hCG), is decreased throughout pregnancy with the lower normal TSH level in the first trimester being poorly defined and an upper limit of 2.5 mIU/L. Ten percent to 20% of all pregnant women in the first trimester of pregnancy are thyroid peroxidase (TPO) or thyroglobulin (Tg) antibody positive and euthyroid. Sixteen percent of the women who are euthyroid and positive for TPO or Tg antibody in the first trimester will develop a TSH that exceeds 4.0 mIU/L by the third trimester, and 33%–50% of women who are positive for TPO or Tg antibody in the first trimester will develop postpartum thyroiditis. In essence, pregnancy is a stress test for the thyroid, resulting in hypothyroidism in women with limited thyroidal reserve or iodine deficiency, and postpartum thyroiditis in women with underlying Hashimoto’s disease who were euthyroid prior to conception. Knowledge regarding the interaction between the thyroid and pregnancy/the postpartum period is advancing at a rapid pace. Only recently has a TSH of 2.5 mIU/L been accepted as the upper limit of normal for TSH in the first trimester. This has important implications in regards to interpretation of the literature as well as a critical impact for the clinical diagnosis of hypothyroidism. Although it is well accepted that overt hypothyroidism and overt hyperthyroidism have a deleterious impact on pregnancy, studies are now focusing on the potential impact of subclinical hypothyroidism and subclinical hyperthyroidism on maternal and

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Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and Postpartum The American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum

The Biomarkers of Nutrition for Development (BOND) project is designed to provide evidence-based advice to anyone with an interest in the role of nutrition in health. Specifically, the BOND program provides state-of-the-art information and service with regard to selection, use, and interpretation of biomarkers of nutrient exposure, status, function, and effect. To accomplish this objective, expert panels are recruited to evaluate the literature and to draft comprehensive reports on the current state of the art with regard to specific nutrient biology and available biomarkers for assessing nutrients in body tissues at the individual and population level. Phase I of the BOND project includes the evaluation of biomarkers for 6 nutrients: iodine, iron, zinc, folate, vitamin A, and vitamin B-12. This review represents the second in the series of reviews and covers all relevant aspects of folate biology and biomarkers. The article is organized to provide the reader with a full appreciation of folate's history as a public health issue, its biology, and an overview of available biomarkers (serum folate, RBC folate, and plasma homocysteine concentrations) and their interpretation across a range of clinical and population-based uses. The article also includes a list of priority research needs for advancing the area of folate biomarkers related to nutritional health status and development.

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Biomarkers of Nutrition for Development (BOND)-Iron Review.

Hofmeister phenomena: an update on ion specificity in biology.

Perchlorate inhibits iodide uptake and may impair thyroid and neurodevelopment in infants. Recently, we unambiguously identified the presence of perchlorate in all seven brands of dairy milk randomly purchased from grocery stores in Lubbock, TX. How widespread is perchlorate in milk? Perchlorate in 47 dairy milk samples from 11 states and in 36 human milk samples from 18 states were measured. Iodide was also measured in a number of the samples. Perchlorate was detectable in 81 of 82 samples. The dairy and breast milk means were, respectively, 2.0 and 10.5 microg/L with the corresponding maximum values of 11 and 92 microg/L. Perchlorate is present in virtually all milk samples, the average concentration in breast milk is five times higher than in dairy milk. Although the number of available measurements are few at this point, for breast milk samples with a perchlorate content greater than 10 microg/L, the iodide content is linearly correlated with the inverse of the perchlorate concentration with a r2 of >0.9 (n = 6). The presence of perchlorate in the milk lowers the iodide content and may impair thyroid development in infants. On the basis of limited available data, iodide levels in breast milk may be significantly lower than it was two decades ago. Recommended iodine intake by pregnant and lactating women may need to be revised upward.

Perchlorate and iodide in dairy and breast milk.

Perchlorate was unambiguously detected by ion chro matography-suppressed conductivity (IC-CD) and/or ion chromatography−electrospray mass spectrometry (IC-MS) in seven of seven supermarket milk samples bought randomly in Lubbock, TX. Quantitation by IC-MS and IC-suppressed conductivity detection in conjunction with a preconcentration-preelution method provided comparable results. With a sample cleanup procedure that involved protein removal by ethanol and sequential passage though activated alumina and C-18 silica, the limit of detection for perchlorate in milk was 0.5 μg/L. The levels found ranged from 1.7 to 6.4 μg/L. An evaporated milk sample contained perchlorate at 1.1 ± 0.6 μg/L level, while we did not find detectable levels in a reconstituted powdered milk sample.

https://www.waterboards.ca.gov/rwqcb4/water_issues/programs/remediation/articles/03_0925_es&tsept19,2003.pdf

Perchlorate in Milk

Breast milk is widely recognized as the best source of nourishment for infants (Gartner et al. 2005). Breast-feeding also fosters an infant’s emotional and social well-being (Else-Quest et al. 2003; Winberg 2005). The American Academy of Pediatrics (Gartner et al. 2005), World Health Organization (WHO 2001), and the International Council of Nurses (ICN 2006) all recommend that infants be exclusively breast-fed for the first 6 months of life. It is important that milk be as free of detrimental agents as possible (LaKind et al. 2004); it is also important that the maternal diet provides the nutrients needed for high milk quality (Dorea 2002). This is especially true for iodine. Iodine deficiency is widely recognized as the leading and most readily preventable cause of mental impairment in children (Delange et al. 2001). Unlike adults, neonates do not have significant thyroxine stores (van den Hove et al. 1999). Exclusively breast-fed infants depend on their mother’s milk iodine for thyroid hormone (TH) synthesis and establishment of TH stores from which they can draw TH if iodine availability falls.

Thyroid hormones and therefore iodine are essential to fetal and infant neurodevelopment. Infants born to hypothyroid- or iodine-deficient women exhibit intellectual and behavioral deficits as children (Rovet and Ehrlich 2000). Such deficits may be apparent in infants as young as 3 weeks even if the degree of early deficiency was small or transient or occurred during fetal development (Kooistra et al. 2006). The Institute of Medicine (IOM 2001) recommends an iodine intake of 110 μg/day for infants 0–6 months of age, and 130 μg/day for infants 7–12 months of age. Iodine needs of pre-term infants may be twice what is needed by full-term infants (Ares et al. 2005). Breast milk–iodine content is considered sufficient when levels are 150–180 μg/L (Delange 2004). Milk samples provided by most women in our previous study (Kirk et al. 2005) fell far short of this standard. The median iodide level in human milk from 23 donors residing in 15 different states (Kirk et al. 2005) was 33.5 μg/L, and only 4 samples fell within the recommended level. We have therefore been concerned that lactating women in the United States may not be consuming sufficient iodine to meet the needs of their breast-fed infants.

Exposure to perchlorate and other iodide transport inhibitors may increase the risk of iodine deficiency among infants. The sodium–iodide symporter (NIS) is 30-fold more selective for perchlorate than for iodide and is reportedly 9–100 times as potent as thiocyanate in inhibiting iodide uptake (Dohan et al. 2003; Tonacchera et al. 2004). Perchlorate and other iodide transport inhibitors such as thiocyanate thus likely reduce transfer of iodide to breast milk at the mammary NIS. Unless major dietary changes have occurred after the birth of her child, it is also likely that a woman with perchlorate and/or thiocyanate in her milk was similarly exposed during pregnancy, potentially reducing the pool of maternal TH needed for fetal development and reducing the ability of the fetal thyroid to produce its own hormones. For a nursing infant, the production of TH would be dually impaired: first by reduction of breast-milk iodide content and then by reduced iodide uptake by the infant thyroid. A discrimination factor of 30× at both stages amounts to 3 orders of magnitude of discrimination overall. Various aspects of brain development depend precisely on when TH deficiency occurs. An infant who had insufficient TH during fetal life might suffer delay or impairment in neurologic functions that develop in utero. This infant may suffer other impairments if TH deficiency occurs again, or continues, after parturition. Transient or mild hypothyroidism during fetal or infant development may result in long-standing, possibly permanent functional deficits that include learning disabilities and hyperactivity (Haddow et al. 1999; Morreale de Escobar et al. 2000; Rovet 2002, 2005; Pop et al. 1999). Some find strong links between iodine deficiency and attention deficit disorders (ADD; Vermiglio et al. 2004). In the United States, an estimated 3–5% of children (approximately 2 million) have ADD (National Institute of Mental Health 2003).

A lack of data on the variability of iodide excretion limits our ability to assess milk iodine levels. Most studies of human milk iodide, including our own, have been based on single samples (Ciardelli et al. 2002; Skeaff et al. 2005), although a few have examined iodide content in samples from two (Gushurst et al. 1984; Moon and Kim 1999) or three points in time (Chierici et al. 1999). These measures may not accurately portray infant intake, especially if samples were systematically collected at times when iodide content is low. The same holds for perchlorate in milk. Although perchlorate may be common in human milk, nothing is known about the temporal variation of perchlorate levels. Finally, thiocyanate, a by-product of cyanide metabolism, is also found in human milk. We describe the variation of iodide, perchlorate, and thiocyanate levels in series of human milk samples. The implications for infant development are discussed.

Temporal patterns in perchlorate, thiocyanate, and iodide excretion in human milk

Environmental perchlorate: Why it matters

Perchlorate, thiocyanate, and iodine excretion in urine and milk of 13 breastfeeding women was investigated and the results were interpreted by a model of parallel/competitive transport of these species by the sodium iodide symporter. For each species i, we assumed physiological homeostasis, where iT,in equals the corresponding total excretion in urine and milk (ie,u + ie,m). The fraction of the total excretion that appeared in milk fi,m was measured and ranged from 0.394−0.781, 0.018−0.144, and 0.086−0.464 for perchlorate, thiocyanate, and iodine, respectively. The corresponding median values were 0.541, 0.053, and 0.177, respectively. The selectivity factors of perchlorate over iodide transport, and thiocyanate over iodide transport, defined as fPC,m/fI,m, and fSCN,m/fI,m, respectively, were 3.14 ± 1.20 and 0.27 ± 0.26 while PCT,in, SCNT,in, and IT,in among individuals varied 4.9, 5.0, and 8.4×, respectively. These transport selectivities are an order of magnitude lower than those indicated by in vitro ...

Andrea B. Kirk

Papers

Perchlorate and iodide in dairy and breast milk.

Perchlorate in Milk

Temporal patterns in perchlorate, thiocyanate, and iodide excretion in human milk

Environmental perchlorate: Why it matters

Intake of Iodine and Perchlorate and Excretion in Human Milk