Environmental Goitrogens - Eduardo Gaitan

[Amazoniac]

Eduardo Gaitan MD
(FACP)
University of Mississipi Medical School Endocrinology Section VA Medical Center Jackson, Mississippi, USA
Error encountered - PubMed - NCBI

He has a book named "Environmental Goitrogenesis", I haven't read but it's probably a synthesis of his work, should be good.
Apparently he's constantly invited to write chapters for books addressing environmental goitrogens.

I merged two chapters from different books because they are quite similar. Here are some selected parts, but for explanations and details I suggest reading them:

Diseases of the Thyroid
ESPN: 978-1-4757-2594-0
Pharmacotherapeutics of the thyroid gland
ESPN-13: 978-3-642-64519-8

"At present, no less than 200 million of the world's population have goiters and associated disorders, resulting in a public health and socioeconomic problem of major proportions (1,2). Seventy-five percent of people with goiter live in less developed countries where iodine deficiency (ID) is prevalent. Twenty-five percent of people with goiter live in more developed countries where goiter occurs in certain areas despite iodine prophylaxis."
"However, observations indicate the existence of other factors in the etiopathogenesis of endemic goiter. First, ID does not always result in endemic goiter (3). Even in the presence of extreme iodine deficiency there is unequal geographical distribution of goiter. Second, exposure to other naturally occurring agents, such as a cyanogenic glucoside from Cassava (4-6), and to flavonoids from millet (7-12), magnifies the severity of the goiter endemia. Third, iodine supplementation does not always result in complete eradication and prevention of goiter (1,3,13-18)."

"Besides iodine deficiency and environmental goitrogens, protein-calorie malnutrition (PCM) also results in various alterations of thyroid gland morphology and function (2,20). PCM and endemic goiter frequently coexist, and poor nutrition appears to increase the risk of goiter development in susceptible groups of the population (infants, children, and pregnant women). Studies demonstrate that malnourished individuals have the same thyroid gland abnormalities that have been shown in experimental animals to favor enlargement of the thyroid gland. A low-protein diet in rats impairs the thyroidal transport of iodine, decreases iodine concentration in the thyroid, and is accompanied by an enlargement of the thyroid. Under these circumstances, the goitrogenic effect of antithyroid agents is enhanced. The administration of protein reverses these alterations and decreases the action of such goitrogenic agents."

"A large number of agents in the environment, both naturally occurring and man-made, are known to interfere with thyroid gland morphology and function, posing the danger of thyroid disease (Table 1). Thyroid enlargement or goitre is the most prominent effect of these agents. They may cause the goitrous condition by acting directly on the thyroid gland (Fig. 1), but also indirectly by altering the regulatory mechanisms of the thyroid gland and the peripheral metabolism and excretion of thyroid hormones (GAITAN 1988, 1989a, 1990)."
"These agents may enter into the food, water, and air exposure pathways, becoming important environmental antithyroid and/or goitrogenic factors in man (GAITAN 1988, 1989a, 1990)."
"In iodine-sufficient areas, these compounds may be responsible for the development of some "sporadic" goitres or the persistence of the goitre endemia with its associated disorders, namely, autoimmune thyroiditis, hypothyroidism, hyperthyroidism, and, probably, thyroid carcinoma (GAITAN et al. 1991; GAITAN and DUNN 1992; MORENO-REYES et al. 1993)."

They are:
- Sulfurated organics

"Thiocyanates and isothiocyanates have been demonstrated as goitrogenic principles in plants of the Cruciferae family."
"Cyanogenic glycosides (thiocyanate precursors) have also been found in several staple foods (cassava, maize, bamboo shoots, sweet potatoes, lima beans) from the Third World. After ingestion these glycosides can be readily converted to thiocyanate by widespread glycosidases and the sulphur transferase enzyme. Isothiocyanates not only use the thiocyanate metabolic pathway but react with amino groups, forming derivatives with thiourea-like antithyroid effects. Thus, the actual concentration of thiocyanates or isothiocyanates in a given foodstuff may not represent its true goitrogenic potential, nor does the absence of these compounds negate a possible antithyroid effect, because inactive precursors can be converted into goitrogenic agents both in the plant itself and in the animal after its ingestion."
"Ingestion of progoitrin, a naturally occurring thioglycoside, elicits antithyroid activity in rats and humans because of its partial conversion by intestinal microorganisms into the more potent antithyroid compound "goitrin". This ability of plants and animals readily to convert inactive precursors into goitrogenic agents must be considered when the possible aetiological role of dietary elements in endemic goitre is being investigated (GAITAN 1988, 1990; DELANGE 1989; ERMANS and BOURDOUX 1989)."
"Several goitre endemias have been attributed to the presence of these sulphurated organic compounds in foodstuffs (ERMANS et al. 1980; DELANGE and AHLUWALIA 1983; GAITAN 1988, 1990; DELANGE 1989; ERMANS and BOURDOUX 1989; GAITAN and DUNN 1992)."
"Cassava [..] has definite antithyroid effects in humans and experimental animals. Thus, daily consumption of cassava, in the presence of severe iodine deficiency, is thought to be the cause of endemic goitre and cretinism in [..] areas of Zaire."
"Studies in Sweden indicate that cigarette smoking may produce goitre."
"Several observations suggest that thiocyanate crosses the human placenta and may cause both goitre and neonatal hypothyroidism (ROTI et al. 1983; WALFISH 1983; CHANOINE et al. 1991)."
"Thiocyanate or thiocyanate-like compounds primarily inhibit the iodine-concentrating mechanism of the thyroid, and their goitrogenic activity can be overcome by iodine administration[.]"
​

- Flavonoids (polyphenols)

"Flavonoids are important stable organic constituents of a wide variety of plants. Flavonoids are universally present in vascular plants and in a large number of food plants. Because of their widespread occurrence in edible plants such as fruits, vegetables, and grains, flavonoids are an integral part of the human diet (HULSE 1980; CODY et al. 1986, 1988; GAITAN 1989a). They are present in high concentrations in polymeric (tannins) and oligomeric (pigments) forms in various staple foods of the Third World, such as millet, sorghum, beans, and groundnuts."
"They have high chemical reactivity with multiple important biological implications (CODY et al. 1986, 1988). Flavonoids are quickly metabolized in higher organisms and that is the reason why they are not found in normal tissue constituents (LINDSAY et al. 1989)."
"Each metabolic step [occuring in the intestines by the action of microbial enzymes] is characterized by a marked increase in antithyroid effects (LINDSAY et ai. 1989)." "As a result, the antithyroid effects of flavonoid glycosides in foodstuffs may be greatly enhanced by metabolic alterations after ingestion by mammals, as in the case of the flavonoids present in the pearl millet grain."
"Flavonoids not only inhibit TPO [thyroid pboyxidase] but, acting on iodothyronine deiodinase enzymes, also inhibit the peripheral metabolism of thyroid hormones. Flavonoids in addition affect serum thyroid hormone binding and TSH regulation."
"At this point, there is substantial epidemiological and experimental evidence indicating, first, that various millet species used as staple food by populations in the semiarid tropics are rich in flavonoids. Second, that flavonoids have potent and diverse antithyroid properties and, third, that under the appropriate environmental-dietary conditions of low iodine and protein-calorie intakes, which are prevalent in most countries of the Third World, flavonoids become an important aetiological determinant of endemic goitre and hypothyroidism (OSMAN and FATAH 1981; ELTOM et al. 1985; GAITAN 1989a; GAITAN et al. 1989; GAITAN and DUNN 1992; MORENO-REYES et al. 1993; KONDE et al. 1994)."
​

- Polyhydroxyphenols and phenol derivatives

"Coal is a source of a large variety of antithyroid and goitrogenic compounds, such as phenol, dihydroxyphenols (resorcinol), substituted dihydroxybenzenes, thiocyanate, disulphides, phthalic acids, pyridines, and halogenated and polycyclic aromatic hydrocarbons (PAHs) (PITT et al. 1979; KUBANOF et al. 1983; MOSKOWITZ et al. 1985; GAITAN 1986, 1988, 1989a, 1990) (Table 1). Most of these compounds have been identified in drinking water from the iodine-sufficient goitrous areas of Kentucky in the United States and Colombia (GAITAN 1986, 1989a)."
"Recent demonstration in vivo and in vitro of antithyroid and goitrogenic activities of coal-water extracts from iodine-sufficient goitre areas (GAITAN et al. 1993) indicate that shale- and coal-derived organic pollutants appear to be a major factor contributing to the high goitre prevalence and associated disorders observed in certain areas with aquifers and watersheds rich in these organic rocks (GAITAN 1986, 1988, 1989a, 1990)."
"Cigarette smoke, besides thiocyanate, contains a variety of goitrogenic resorcinol derivatives, flavonoids, and hydroxypyridines (GAITAN 1988)."
"The presence of halogenated organic compounds with known or potential harmful effects has awakened public health and environmental concerns. These compounds are produced by the chlorination of water supplies, sewage, and power plant cooling waters."
"Derivatives of 2,4-dinitrophenol (DNP) are widely used in agriculture and industry. An insecticide, herbicide, and fungicide, DNP is also used in the manufacture of dyes, to preserve timber, and as an indicator; it is also a byproduct of ozonization of parathion. DNP is readily absorbed through intact skin and respiratory tract. DNP causes toxicity by the uncoupling of oxidative phosphorylation in the mitochondria of cells throughout the body. Administration of 2,4-DNP to human volunteers resulted in rapid and pronounced decline of circulating thyroid hormones."
​

- Pyridines

"Hydroxypyridines also occur in aqueous effluents from coal conversion processes, as well as in cigarette smoke (PITT et al. 1979; KUBANOF et al. 1983; MOSKOWITZ et al. 1985; GAITAN 1986, 1988, 1990; LINDSAY 1989; LINDSAY et al. 1992). Dihydroxypyridines and 3-hydroxypyridine are potent inhibitors of TPO, producing effects comparable to or greater than those of propylthiouracil (LINDSAY et al. 1992). After ingestion, mimosine, a naturally occurring amino acid in the seeds and foliage of the tropical legume Leucaena leucocephala, is metabolized to 3,4-dihydroxypyridine (3,4-DHP), a potent antithyroid agent that produces goitre in mice, rats, sheep, and cattle (GAITAN 1988,1990; LINDSAY 1989)."
​

- Phthalate esters and metabolites

"Phthalic acid esters, or phthalates, are ubiquitous in their distribution and have been frequently identified as water pollutants (PEAKALL 1975; PROCEEDINGS 1982; GAITAN 1988, 1989b, 1990). Dibutyl (DBP) and dioctyl phthalates (DOP) have been isolated from water-supplying areas of endemic goitre in western Colombia and eastern Kentucky in the United States (GAITAN 1986, 1988, 1989a, 1990). Although phthalate esters are most commonly the result of industrial pollution, they also appear naturally in shale, crude oil, petroleum, plants, and fungal metabolites, and as emission pollutants from coal liquefaction plants (PITT et al. 1979; KUBAN OF et al. 1983; MOSKOWITZ et al. 1985; GAITAN 1986, 1988, 1989b, 1990)."
"Phthalate esters are well absorbed from the gastrointestinal tract."
"Phthalate esters are commonly used as plasticizers to impart flexibility to plastics, particularly polyvinylchloride polymers (PVC), which have a wide variety of biomedical and others uses: building and construction, home furnishings, cars, clothing, food wrappings, etc. A small fraction of phthalate esters are used as non-plasticizers for pesticide carriers, oils, and insect repellents. Phthalates may be present in concentrations of up to 40% of the weight of the plastic (PEAKALL 1975; PROCEEDINGS 1982)."
"Phthalate esters are known to leach out from finished PVC products into blood and physiological solutions. The entry of these plasticizers into a patient's bloodstream during blood transfusion, intravenous fluid administration, or haemodialysis has become a matter of concern among public health officials and the medical community (PEAKALL 1975; PROCEEDINGS 1982; GAITAN 1988, 1989b). A high incidence of goitre in patients receiving maintenance haemodialysis has been reported."
"Although phthalate esters and phthalic acids do not possess intrinsic antithyroid activity (Table 1), they undergo degradation by gram-negative bacteria to form DHBA (GAITAN 1988, 1989b, 1990). DHBAs are known to possess antithyroid properties (COOKSEY et al. 1985; GAITAN 1988, 1989b)[.]"
"The proven effective role of gram-negative bacteria in phthalate biodegradation may explain in part the relationship established between frequency of goitre and bacterial contamination of water supplies (GAITAN et al.1980; GAITAN 1988, 1989a, 1990). Furthermore, marked ultrastructural changes of the thyroid gland, similar to those seen after administration of TSH, and decreased serum T4 concentration, have been observed in rats treated with phthalic acid esters (HINTON et al. 1986)."
"Whether these widely distributed pollutants exert deleterious effects on the thyroids of humans has not been investigated."
​

- Polychlorinated (PCB) and polybrominated (PBB) biphenyls

"Polychlorinated (PCB) and polybrominated (PBB) biphenyls are aromatic compounds containing two benzene nuclei with two or more substituent chlorine or bromine atoms. They have a wide variety of industrial applications, including electric transformers, capacitors, and heat transformers (BUCKLEY 1982; GAITAN 1988; BARSANO 1989)."
"Perhaps the most significant human exposures are limited to individuals consuming freshwater fish from contaminated streams and lakes, and to occupational exposure of industrial workers. PCBs can also be found in the milk of nursing mothers who have eaten large amounts of sport fish or who have been occupationally exposed (SAFE DRINKING WATER COMMITTEE 1980; GAITAN 1988; BARSANO 1989)."
"They are slowly metabolized, and their excretion is limited. Longterm low-level exposure to the organohalides results in their gradual accumulation in fat, including the fat of breast milk. PCBs have been found in the adipose tissue of 30%-45% of the general population (SAFE DRINKING WATER COMMITTEE 1980; BARSANO 1989; GAITAN 1992)."
"Despite the lack of evidence that dietary PCBs and PBBs have any deleterious effects on health, there is a growing concern and uncertainty about the long-range effects of bioaccumulation and contamination of our ecosystem with these chemicals. The uncertainty extends to the potential harmful effect of these pollutants on the thyroid. For instance, an increased prevalence of primary hypothyroidism (11 %) was documented among workers from a plant that manufactured PBBs and PBB oxides (BAHN et al. 1980)."
​

- Other organochlorines

"DDT has been used extensively, both in malaria control and in agriculture, all over the world. Because of biomagnification and persistence, DDT and its breakdown products, DDE and DDD (dichlorodiphenyldichloroethane), are ubiquitous contaminants of water and of virtually every food product. For example, most of the fish from Lake Michigan in North America contain DDT residues. The substance is also present in milk; man is at the top of the food pyramid, so human milk is especially contaminated. The situation is basically similar for dieldrin, which is found in surface waters virtually everywhere. Dieldrin is heavily bioconcentrated in the lipids of terrestrial and aquatic wildlife, humans, and foods, especially animal fats and milk."
"DDT is known to cause marked alterations in thyroid gland structure, such as thyroid enlargement, follicular epithelial cell hyperplasia, and progressive loss of colloid in birds, and DDD causes goitre and increased hepatobiliary excretion of thyroid hormones in rats (BARSANO 1989). All these compounds (DDT, DDE, DDD, and dieldrin) induce microsomal enzyme activity that may affect thyroid hormone metabolism in a similar way to that of the polyhalogenated biphenyls and PAH (ROGAN et al. 1980; GAITAN 1988). The impact of these pollutants on the human thyroid is unknown."
"Dioxin (tetrachlorodibenzodioxin - TCDD), one of the most toxic small organic molecules, is a contaminant in the manufacturing process of several pesticides and herbicides, including Agent Orange."
"Rats treated with TCDD concomitantly develop hypothyroxinaemia, increased serum TSH concentrations, and goitre, probably as a result of T4loss in the bile (GAITAN 1988)."
​

- Polycyclic aromatic hydrocarbons (PAH)

"Polycyclic aromatic hydrocarbons (P AHs) have been found repeatedly in food and domestic water supplies, and in industrial and municipal waste effluents (SAFE DRINKING WATER COMMITTEE 1977; GAITAN 1988, 1990; BARSANO 1989). They also occur naturally in coal, soils, ground water and surface water, and in their sediments and biota. One of the most potent of the carcinogenic PAR compounds, 3,4-benzpyrene (BaP), is widely distributed and, as in the case of other PARs, is not efficiently removed by conventional water treatment processes."
"The PAR carcinogens, BaP and 3-methylcolanthrene (MeA), accelerate T4 metabolism and excretion of T4-glucuronide by enhancement of hepatic UDP-glucuronyltransferase and glucuronidation, resulting in decreased serum T4 concentrations, activation of the pituitary-thyroid axis, and eventually goitre formation (GAITAN 1988, 1990; BARSANO 1989). There is also indication that MeA interferes directly with the process of hormonal synthesis in the thyroid gland."
​

- Inorganics (excess pboyodine and lithium)

Amino acids that inhibit T3 uptake in mammalian cells:
- Leucine
- Phenylalanine
- Tryptophan
Those and other chemicals are discussed here: "BLONDEAU et al. 1988, 1993; KRAGIE and DOYLE 1992; LAKSHMANAN et al. 1990; MOVIUS et al. 1989; PRASAD et al. 1994; TOPLISS et al. 1989, 1993; ZHOU et al. 1992"

--
Now a review of flavonoids and their impact on thyroid function (other authors):
Impact of flavonoids on thyroid function

"Dietary flavonoids are plant pigments that can be found in our daily food, including fruits, grains, nuts, wine, and tea. Normal human diet contains up to two grams of flavonoids a day (Divi and Doerge, 1996; van der Heide et al., 2003)."

"Despite the apparently beneficial health effects of flavonoids, several studies indicate that they can interfere in many enzymatic systems, including those involved in thyroid hormone status (Middleton et al., 2000)."

"In vegetables, flavonoids function as pigments and are important for plant defense and development (Peterson and Dwyer, 1998). The first observation regarding their biological activities was made in the 1930s, when a compound obtained from lemon peel was shown to reduce capillary permeability by Rusznyak and Szent-Györgi. These authors named the compound ‘‘vitamin P’’ (P for permeability) and showed that patients with vitamin C therapy resistant purpura could improve by consuming this substance."

"There are several proposed mechanisms of action to explain anti-inflammatory activity of flavonoids, including (1) antioxidative and radical scavenging activities, (2) modulation of inflammation-related cells activity (mast cells, macrophages, lymphocytes, and neutrophils), (3) regulation of the enzymes involved in the metabolism of arachidonic acid (phospholipase A2, cyclooxygenases, lipoxygenases) and nitric oxide synthase, (4) modulation of other proinflammatory molecules production and (5) proinflammatory gene expression regulation (García-Lafuente et al., 2009; Kim et al., 2004).
The antioxidant capacity of flavonoids is related to the presence of structural characteristics that allow them to chelate ions of transition metals such as Fe2+, Cu2+ or Zn2+; to transport electrons; to scavenge reactive oxygen species (ROS), like the superoxide anion, singlet oxygen and lipid peroxyl radicals; and to stabilize free ROS by hydrogenation or formation of complexes (Van Acker et al., 1996)."

"Flavonoids, potent natural plant-derived compounds, are capable to interfere with thyroid hormone economy (Gaitan, 1996)."

"[..]pearl millet contains high amount of apigenin and luteolin, flavonoids capable to reduce both organification and secretion of thyroid hormones."

"Divi and Doerge (1996) evaluated the effects of flavonoids baicalein, biochanin A, catechin, fisetin, flavanone, flavone, kaempferol, morin, myricetin, naringenin, naringin, quercetin and rutin on inhibition of TPO. All of the flavonoids tested except flavanone and favone inhibited tyrosine iodination by TPO, but with markedly different potencies[.]"

"Goiter was observed in infants fed soy formula and this was usually reversed by changing to cow milk or iodine-supplemented diets[*] (Hydovitz, 1960; Shepard et al., 1960; Ripp, 1961)."

"[..]our studies reinforce the idea that the high consumption of flavonoid-rich plant products allied to the nutritional deficiency of iodine might contribute to the development of hypothyroidism and goiter (Fig. 3B). Moreover, the anti-oxidant effect of flavonoids could contribute to the thyroid hormone synthesis inhibition, since they could scavenge H2O2, which is the cofactor of thyroperoxidase."

"Although excessive intake of flavonoids may be associated with goiter, flavonoids may have beneficial effects in thyroid cancer. Yin et al. (1999) showed that the flavonoids kaempferol, biochanin A, chrysin, genistein, apigenin and luteolin inhibit proliferation of thyroid follicular, papillary and anaplastic carcinoma cell lines, suggesting that they might be used as therapeutic agents in the management of thyroid cancer."
"Schröder-van der Elst et al. (2004) [..] showed that even though many flavonoids were able to decrease the proliferation of thyroid cancer cells, most of them also decreased thyroid cell iodide uptake."

"[..]flavonoids may affect thyroid hormone economy at diverse levels, not only inhibiting iodide uptake and thyroid hormone biosynthesis but also interfering with T4 to T3 conversion and with the binding of T4 to plasma protein."

Conclusions

"Flavonoids show important antithyroid effects, affecting biosynthesis, metabolism and transport of thyroid hormones in vivo and in vitro. However, important adverse effects, such as goiter, are not very often observed among humans consuming vegetables containing flavonoids."

"Even though the ingestion of flavonoids present in plant food does not seem to produce relevant effects to the human thyroid, it is important to underline that medicinal herbs that are rich in flavonoids can be consumed in high doses, possibly leading to a greater risk of thyroid disease. Moreover, predisposing factors, such as deficiency of iodine, subclinical hypothyroidism or antibodies against thyroid proteins, might contribute to a possible deleterious effect of flavonoids on thyroid function."

--
Natural Estrogens
"Flavonoids and polyphenols, like our own estrogens, suppress the detoxifying systems of the body."

Estriol, DES, DDT.
"The effects of the phytoestrogens are very complex, because they modify the sensitivity of cells to natural estrogens, and also modify the metabolism of estrogens, with the result that the effects on a given tissue can be either pro-estrogenic and anti-estrogenic. For example, the flavonoids, naringenin, quercetin and kaempherol (kaempherol is an antioxidant, a phytoestrogen, and a mutagen) modify the metabolism of estradiol, causing increased bioavailability of both estrone and estradiol. (W. Schubert, et al., "Inhibition of 17-beta-estradiol metabolism by grapefruit juice in ovariectomized women," Maturitas (Ireland) 30(2-3), 155-163, 1994.)

Why do plants make phytoestrogens? There is some information indicating that these compounds evolved to regulate the plants' interactions with other organisms--to attract bacteria, or to repel insects, for example, rather than just as pigment-forming materials. (Baker, 1995.) The fact that some of them bind to our "estrogen receptors" is probably misleading, because of their many other effects, including inhibiting enzyme functions involved in the regulation of steroids and prostaglandins. Their biochemistry in animals is much more complicated than that of natural estrogens, which is itself so complicated that we can only guess what the consequences might be when we change the concentration and the ratio of substances in that complex system."

--
What got me into this was a long consideration as to why purple sweet potato affects me negatively whereas the traditional white-fleshed sweet potato that we have where I live never bothered me. Traditionally, the purple variety is consumed mostly by those who ingest plenty of iodine, Westside has a related Youtube video. But since I don't ingest plenty of iodine, I'm more susceptible right now to those changes so it's easier for me to perceive.
Hopefully I'm not painting flavonoids as negative compounds because they're certainly not, some of them are more potent than others depending on their purpose (protection from light, microbes, incests, etc), and it's just their excess or *not being counteracted (robust metabolism, more of what they antagonize, etc) that seems to cause problems. It also supports the idea of diversifying plant foods, which is something that people should already know if they have studied the work of FullyRawKristina carefully.

Since I mentioned potatoes and the thread is about compounds that can suppress the thyroid, here's an interesting quote:
Eluv: Effects Of Stress And Trauma On The Body
"Some white potatoes, so-called, contain enough carotene that could provide the requirement for vitamin A, but sweet potatoes often contain so much carotene that it interferes with digestion and too much carotene has anti-hormonal effects it can slow down your production of thyroid hormones."

--
An interesting link mentioning this guy's research:
http://www.thyroidmanager.org/chapter/the-iodine-deficiency-disorders/

--
But the moral of the thread is: drink Sprite.

 

[gabys225]

This is a treasure chest. Thank you Amazoniac.

 

[Amazoniac]

Endocrine disruptors in bottled mineral water: Estrogenic activity in the E-Screen

 

[Amazoniac]

Dudu is often mentioned when the topic is goitrogens.

- Thiocyanate: a review and evaluation of the kinetics and the modes of action for thyroid hormone perturbations

Spoiler

"The most common route of exposure to thiocyanate is ingestion through the diet. Thiocyanate is one of the breakdown products of glycosinolates, which are thioglucosides. These chemicals are present in cruciferous vegetables, such as cabbage, kale, sprout, broccoli, turnips, swedes, and mustard, which belong to the Brassicaceae, Cruciferae, Capparidaceae, and Resedaceae families. Glycosinolates are usually stable and inactive in plants, but are released from the vacuoles once the plant is crushed. During food processing (i.e. mastication and digestion), glycosinolates are enzymatically hydrolyzed by myrosinases (b-thioglucosidases), generating metabolites such as organic isothiocyanates, organic nitriles, and thiocyanate ions (Choi et al. 2014)."

"Real-life exposure scenarios often include co-exposure to multiple thyroid stressors, such as perchlorate and nitrate, in addition to thiocyanate. These chemicals share common mode of action by inhibiting thyroidal uptake of iodide via the sodium iodide symporter (NIS). The descending rank order of these chemicals based on their NIS inhibition potency is perchlorate > thiocyanate > iodide > nitrate (Tonacchera et al. 2004). Although the difference in potency between thiocyanate and perchlorate is 15-fold, environmental exposure levels of a nonsmoking pregnant women to thiocyanate is 300–500-fold higher than that of perchlorate (Gibbs 2006)."

"Unlike perchlorate, thiocyanate interacts with multiple intra-thyroidal mechanisms in addition to the inhibition of NIS-mediated uptake of iodide."

"Due to its chemical properties (i.e. hydrophilic and low molecular weight), thiocyanate can be assumed to have a high affinity for hydrophilic matrices. Thiocyanate is also known to be a substrate of the NIS (Eskandari et al. 1997) and can therefore be potentially concentrated in organs expressing NIS on their membranes. NIS is expressed mainly in the thyroid and to a lesser extent in salivary and mammary glands, gastric mucosa, kidneys, lung airway epithelia, and placenta (Riedel et al. 2001; Dohan et al. 2003; Fragoso et al. 2004)."

"Thiocyanate and iodide have two mechanisms in common: they are both transported by NIS into the thyroid and oxidized by the enzyme TPO, either for metabolic activity (thiocyanate) or organification reaction (iodide)."

"Thiocyanate is sensitive to the metabolic activity TPO, lactoperoxidase, eosinophil peroxidase, and myeloperoxidase (Barrett & Hawkins 2012; Chandler & Day 2012; Bafort et al. 2014). Thiocyanate is, therefore, assumed to be metabolized in the matrices in which these peroxidases are located, such as some the extracellular fluids (saliva, airway epithelial lining, nasal lining fluid, gastric juice, tears, milk), or thyroid."

"All these enzymes are heme-peroxidases and belong to the cyclooxygenase superfamily. This superfamily is also referred to as haloperoxidase, since the enzymes mediate the oxidation of halides, such as iodide, in the presence of H2O2 (Zamocky et al. 2015)."

"The different mechanisms involved in the synthesis of the thyroid hormones in the context of the various modes of action for its disruption due to thiocyanate exposure are represented in Figure 1."

Spoiler

"The affinity of thiocyanate for NIS [38 ± 11 uM] is [..] in the same range as that of iodide (33 ± 6 uM); however, the Vmax [rate] of uptake of thiocyanate by NIS [16 uM/s] is approximately half the value for iodide (28 uM/s)."

"A low-iodine diet is known to enhance the expression of thyroidal NIS, consequently the thyroidal uptake of thiocyanate could be increased (Sanchez-Martin & Mitchell 1960; Bobek 1972)."

"Since thiocyanate is known to be a thyroid disruptor, its kinetics in the thyroid is of special interest. After the injection of 35SCN−, total 35S is known to accumulate in the thyroid whereas the free thiocyanate thyroid-to-serum ratio remains predominantly under 1." "[..]free thiocyanate once taken up by the thyroid does not seem to accumulate. Consequently, the distinction between total sulfur and thiocyanate when the S is radiolabeled is crucial. Studying only the kinetics of free thiocyanate can lead to a misrepresentation of the real distribution of 35S in the thyroid."

"The effect of thiocyanate on the iodide accumulation in the thyroid depends on the effective thiocyanate concentration in the circulating blood, and consequently on the residence time of thiocyanate in the whole body. This is important for a compound such as thiocyanate that has rapid elimination rate from the body."

"The relationship between the thiocyanate dose and the inhibition of the accumulation of iodide into the thyroid was quantified mostly using in vitro systems. The studies determined the in vitro concentration values leading to half maximal inhibition of the uptake of iodide in thyroid (i.e. IC50), by measuring the radioactive iodide uptake across several doses of thiocyanate (Fletcher et al. 1956; Bourke et al. 1973; O’Neill et al. 1987; Ajjan et al. 1998; Tonacchera et al. 2001; Van Sande et al. 2003; Tonacchera et al. 2004; Lecat-Guillet et al. 2007)." "The in vitro IC50 values for thiocyanate ranged from 10 to 34 uM, and up to 82 uM in vivo. IC50 values of thiocyanate for thyroidal iodide uptake inhibition were also measured when TPO enzyme was active, both in in vitro supports and in vivo (Wollman 1962; Greer et al. 1966; Fukayama et al. 1992; Jones et al. 1996; Waltz et al. 2010). In general, IC50 values seemed to be higher compared to when TPO was inactive, ranging from 60 to 230 uM, except in the study of Waltz et al. (2010), where the IC50 of 14 ± 0.4 uM remained the same."

"[..]it has to be noted that [..] these studies correspond to a single dose of exposure of thiocyanate in the system. The behavior of the iodide uptake in the presence of ascending doses of thiocyanate seems different in a chronic exposure context. Ermans et al. (1980) observed that rats receiving 0.25mg (4.3 * 10^−3 mmol) of thiocyanate per day during 3–11 weeks presented the same percentage of dose of iodide taken up into the thyroid than the controls; in another experiment, rats were exposed from 0.1 mg to 10 mg of thiocyanate, both acutely and chronically. After an acute exposure, the serum concentrations of thiocyanate increased by eight-fold, and the thyroid uptake of iodide decreased by 14-fold. After a chronic exposure, the serum concentrations of thiocyanate increased only by 1.5-fold, and the thyroid uptake of iodide, as a percentage of the dose, remained relatively stable, ranging from 10 to 13."

"As opposed to the transport mechanism, the intra-thyroidal enzymatic reactions are less well documented for both anions separately and when co-exposed (Pommier et al. 1973; Deme et al. 1976; Michot et al. 1980; Schweizer et al. 2008). The nature of the intra-thyroidal enzymatic reactions is different for iodide and thiocyanate. Once trapped into the thyroid cells, the iodide ion is oxidized to its reactive species of elemental iodine, followed by the iodination of thyroglobulin proteins and coupling to form a bound pool of iodide and the subsequent formation of thyroid hormones (Coval & Taurog 1967; Lamas et al. 1972; Taurog et al. 1996) (Figure 1). In contrast, thiocyanate is directly metabolized within the thyroid."

"Thiocyanate is [..] oxidized in the thyroid by peroxidases in the presence of H2O2 to yield HOSCN as its direct metabolite (Barrett & Hawkins 2012; Chandler & Day 2012) which is a transient intermediate for the formation of sulfate, the final metabolite (Wood & Williams 1949; Logothetopoulos & Myant 1956c; Maloof & Soodak 1959). The main pathway of excretion of thiocyanate is through urine (Okoh & Pitt 1982)."

"The measurement of sulfate is a good approach to quantify the degree of metabolism of thiocyanate in the thyroid because sulfate is the major sulfur-containing metabolite of thiocyanate (Maloof & Soodak 1959). Thiocyanate is rapidly metabolized to sulfate in the first 5 h. The percentage of radioactivity corresponding to thiocyanate fell from 92 to 26% in the thyroid from 5 min to 5 h. Meanwhile, the amount of sulfate increased, from 5 to 69% (Maloof & Soodak 1959)."

"Thiocyanate acts on the different steps of the iodide organification and hormone synthesis. A hierarchical view of the different steps of hormone synthesis has been published. Virion et al. (1980) simultaneously evaluated the effects of thiocyanate on iodination, organification, and coupling reaction steps using thyroid homogenates. Thiocyanate inhibited both the iodination and the organification reactions but stimulated the coupling reaction. IC50 values were at 60 and 10 uM for oxidation and iodination, and the concentration leading to half maximal stimulation of coupling reaction was 1 uM. Therefore, the coupling step seems more sensitive than the other reactions to thiocyanate concentrations."

"In 1966, Greer et al. concluded that thiocyanate was a potent inhibitor of the organification based upon in vitro experiments using thyroid lobes. With an increasing dose of thiocyanate, the proportion of recovered MIT/DIT decreased to a greater extent than free iodide. Consequently, the decrease of iodotyrosine content was assumed to be due to the inhibition of the binding reaction and not from the inhibition of the uptake. IC50 values of thiocyanate for the inhibition of iodide concentration in the thyroid and the inhibition of MIT and DIT synthesis were estimated at 4.8 ⨯ 10^2 uM, 2.9 ⨯ 10^3 uM, and 7.3 ⨯ 10^2 uM, respectively (Table 7). Greer et al. (1966) observed that thiocyanate inhibits half of the accumulation of iodide in the thyroid at lower concentrations (IC50 = 4.8 ⨯ 10^2 uM) and half of the organification reaction at higher concentrations (IC50 close to 8 ⨯ 10^3 uM). Consequently, when half of the iodide uptake is inhibited, the organification activity seems to remain unchanged, i.e. continued to be completely active. They assumed that at lower concentrations, the inhibition of the iodide uptake would be more pronounced and mask the inhibition effect of thiocyanate on the iodide organification."

"Iodide has an impact on the thiocyanate kinetics in the thyroid. Maloof and Soodak (1966) observed a four-fold accumulation of thiocyanate in iodide-deficient rats compared to healthy rats, and that thiocyanate metabolism was enhanced. In contrast, the metabolism of thiocyanate by TPO was inhibited by an increasing dose of iodide (Maloof & Soodak 1959). Maloof and Soodak (1959) exposed rats to increasing doses of iodide from 0.1 to 100 umol and a constant amount of thiocyanate (0.02 mmol). The intra-thyroidal thiocyanate concentrations remained relatively similar to the controls with the increasing dose of iodide (the maximum decrease was only 0.6-fold); however, the concentration of metabolized thiocyanate was decreased two-fold at 0.1 umol iodide to 40- fold at higher doses (5–100 umol iodide) (Maloof & Soodak 1959). Iodide thus seems to be a potent inhibitor of the metabolism of thiocyanate by TPO. The inhibitory potential of iodide decreased only partially with an increase of thiocyanate dose."

"The mode of action of thiocyanate on the kinetics of iodide and the synthesis of thyroid hormones within the thyroid is [therefore] complex because at least three processes are disrupted: the active transporter NIS, the efflux of iodide from thyroid by diffusion, and the oxidative activities involving TPO. Consequently, the alterations in the production of thyroid hormones following exposure to thiocyanate are the result of the interplay of these different processes."

"Furthermore, additional studies pointed out likely extra-thyroidal effects by thiocyanate, such as the decrease of the binding of T4 to proteins in blood, which results in the increase of free T4 concentrations; percentage of free T4 degraded or excreted could thus be potentially increased (Yamada & Jones 1968; Langer 1971; Michajlovskij & Langer 1974)."

- Concentrations of thiocyanate and goitrin in human plasma, their precursor concentrations in brassica vegetables, and associated potential risk for hypothyroidism
- Broccoli sprout beverage is safe for thyroid hormonal and autoimmune status: results of a 12-week randomized trial.
- Relationship between conversion rate of glucosinolates to isothiocyanates/indoles and genotoxicity of individual parts of Brassica vegetables
- Preliminary Observations on the Effect of Dietary Brussels Sprouts on Thyroid Function
- Plant constituents and thyroid: A revision of the main phytochemicals that interfere with thyroid function