Perchlorate is a persistent ubiquitous chemical used worldwide in nitrate fertilizers, fireworks, road flare, matches, airbag inflation systems, and as oxidizers in solid propellants for rockets and missiles. Perchlorate appears in drinking water, milk, wine, beer, and lettuce, but also a natural perchlorate background of atmospheric origin exists [²⁸]. Perchlorate has previously been used in the treatment of hyperthyroidism [²⁹] due to its potent competitive inhibition of thyroid iodine uptake through the sodium-iodine symporter (NIS) [³⁰]. However, the thyroid disrupting effect of perchlorate is dose dependent. Thus, occupational or environmental exposures of perchlorate have been associated with a reduction in thyroid iodine uptake [³¹–³³] but without direct effects on thyroid function or volume except in a study of women with urinary iodine excretion below 100 μg/L in whom TSH was increased and TT4 was found reduced [³⁴], and these findings are further supported by findings of an interaction of perchlorate and thiocyanate on thyroid status in smoking women with low iodine intake [³⁵] (Table 1). A study of euthyroid and hypothyroid pregnant women from Cardiff in Wales and Turin in Italy found perchlorate in all urine samples and low iodine excretion from all the pregnant women, but no correlation was found between perchlorate levels and thyroid function parameters [³⁶]. Likewise, in pregnant women and their neonates, perchlorate in drinking water did not influence thyroid hormone levels [³⁷, ³⁸], and no correlations were found between urinary perchlorate concentrations and fT4 or thyroid stimulating hormone (TSH), respectively, during first trimester in mildly hypothyroid women. Iodine is secreted into breast milk through NIS, and one study found that the highest concentrations of perchlorate in breast milk were associated with lower iodine concentrations [³⁹], while others found no obvious correlations [⁴⁰].

Thiocyanate and nitrate are less potent inhibitors of NIS than perchlorate [³⁰] but, nitrate may decrease iodine absorption from the intestine [⁴⁷].

Thiocyanate is present in a number of vegetables such as cabbage, broccoli, Brussels sprouts, rapeseed and mustard seed, cassava, radishes, spinach and tomatoes but also in milk. In many tropical countries, cassava as staple food is a major ingredient in the daily food supply. In iodine-deficient regions, food with high concentrations of thiocyanate contributes significantly to goitre development [⁴⁸, ⁴⁹]. However, in industrialized societies, the main source of thiocyanate is cigarette smoke [⁴⁸]. Although this has well-known detrimental effects on the thyroid function of neonates and breastfed babies, it is beyond the scope of this paper.

Nitrate is found in several food items either occurring naturally, as in green leafy vegetables, or added as a preservative in cubed meats and other food and is also generated from the decomposition of organic materials. Inorganic nitrates are used as fertilizers, which may contaminate drinking water supplies, groundwater, and soil. Finally, the intestinal flora causes an endogenous formation of nitrate. Population studies on nitrate exposure through drinking water have found increased thyroid volume and slightly reduced thyroid function [⁵⁰], but the isolated effect of nitrate has been difficult to assess due to concomitant iodine deficiency [⁵¹, ⁵²]. But low levels of nitrate intake did not influence thyroid volume in adults despite of previous iodine deficiency [⁵³].

PCBs are still in use though several of them have been banned for decades in many countries. PCBs and their hydroxylated metabolites are biologically active, highly persistent compounds accumulating in lipid tissues, and structurally very close to T4 [⁵⁴]. Many studies have been performed on the thyroid disturbing effects of PCBs, but results are conflicting (Table 2). PCBs may interfere with thyroid hormone homeostasis in several ways (Figure 1): by binding to transthyretin (TTR) [⁵⁵], by affecting the expression of thyroid hormone-responsive genes, and by antagonizing the complexes from the thyroid hormone responsive elements (TRE) [⁵⁶, ⁵⁷]. Perinatal exposure may be most important in humans. Negative correlations have been demonstrated between PCBs in maternal blood during pregnancy and maternal thyroid hormones, and positive correlations have been described between PCBs and TSH [⁵⁸]. As thyroid hormones in humans are mainly bound to thyroid hormone-binding globulin (TBG), the reduction in total T4 (TT4) and total T3 (TT3) could be explained by a reduced TBG level, whereas this would not necessarily affect free hormone levels [⁵⁹]. In cord blood, a positive correlation of PCB and TSH of the child and a negative correlation with maternal TT3 and TT4 were found [⁶⁰]. PCBs in cord blood have generally not demonstrated associations to T3 and T4 levels of the child [⁵⁸, ⁶¹–⁶⁵], except in a recent study finding higher TSH and lower T4 in infants of mothers with high levels of PCB in breast milk [⁶⁶, ⁶⁷]. Yet, not all studies found associations between infant thyroid hormone levels and PCB exposure [⁶³–⁶⁵, ⁶⁸], and in a study of a prenatal boys exposed to high PCB levels, the thyroid function was comparable to that of the control group [⁶⁹].

In several studies of humans of all ages from high PCB-exposed areas, blood PCB concentrations correlated negatively to circulating thyroid hormone levels [⁷⁶, ⁷⁹, ⁸⁰, ⁸³] and positively to TSH [⁷⁴], while others could not find such associations [⁷⁸, ⁸¹]. Increased thyroid volume has also been found more often in a PCB-polluted area with the largest volumes among subjects with the highest levels of PCB [⁸²].

Dioxins are highly toxic, lipophilic, widely used, and persistent environmental pollutants from industrial burning processes or production of herbicides, detectable in samples from humans and wildlife populations though banned for years in many countries. The most toxic prototype is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and the toxic equivalent of all other dioxins is measured against this. In particular, the metabolites show a high degree of structural similarity to T4 and are the most biologically active. Dioxins have been found to decrease the level of circulating thyroid hormones in rats [⁸⁵–⁸⁷], and mixtures of dioxin-like compounds were even found to reduce levels of T4 in an additive manner [⁸⁸]. Given to pregnant rats, a single dose of TCDD was transferred to the pups via placenta and during lactation [⁸⁹] and resulted in a dose-dependent decrease of T4 and fT4 with a concomitant increase in TSH [⁸⁶, ⁸⁷]. High exposure with TCDD of US war veterans of the Vietnam war resulted in significantly increased TSH [⁹⁰]. In children, no associations between placental dioxins and thyroid hormones were found at the age of 2 years, but after 5 years, T3 was significantly higher in the highly exposed individuals in utero [⁹¹]. But as recently reviewed, so far, no clear and significant correlation between background exposure to dioxins and thyroid function during development has been found [⁹²].

Phthalates are widely used chemicals mainly to improve the flexibility of materials such as plastic and have been widely used in medical products, food handling and storage products, electrical devices, toys, and in non-polyvinylchloride applications such as paints, lacquers, and cosmetics. Phthalates can leach, migrate, or evaporate into indoor air and atmosphere, foods, and liquids and have become ubiquitous. Consequently, humans are constantly exposed by oral, inhalation, and dermal routes [⁹³]. Unfortunately, certain vulnerable groups may be massively exposed to phthalates, such as hospitalized neonates in whom urinary excretion of phthalates was shown to correlate with exposure to medical devices [⁹⁴]. However, a followup of adolescents exposed to high concentrations of phthalates in the neonatal period showed normal thyroid hormones [⁹⁵]. On the other hand, men recruited from a fertility clinic [⁹⁶] and pregnant women [⁹⁷] demonstrated a negative association between phthalates and fT4 and T3, respectively.

We studied 845 children aged 4–9 years with determination of urinary concentrations of 12 phthalate metabolites and serum levels of TSH, thyroid hormones, and insulin-like growth factor-I (IGF-I) [⁹⁸]. Our study showed a negative association between urinary phthalate concentrations and thyroid hormones, IGF-I and growth of the children, respectively. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations may suggest causative negative roles of phthalate exposures for child health.

The exact thyroid disturbing mechanisms of these chemicals are not known, but triclosan, and bisphenol A (BPA) share structural similarities with thyroid hormones and may bind to and interact with the thyroid hormone receptor (TR). Phenols bind competitively to TTR, [⁹⁹, ¹⁰⁰] and act as a T3 antagonist [¹⁰¹, ¹⁰²].

BPA is used to manufacture polycarbonate and several hard plastic products such as compact discs, food can linings, adhesives, powder paints, dental sealants, and clear plastic bottles which means that humans are ubiquitously exposed to BPA [¹⁰³, ¹⁰⁴]. BPA is rapidly glucuronidated in humans and rodents.

Phenols were found to bind competitively to TTR, possibly with a very strong binding affinity [⁹⁹, ¹⁰⁰], but a recent study found that the concentrations of BPA usually found in humans is probably not high enough to interfere with T4 transport [¹⁰⁵]. Finally, T3-mediated gene activation through TRα1 and TRβ was dose-dependently suppressed by, BPA and the expression of T3- suppressed genes was up-regulated by BPA [¹⁰¹, ¹⁰²]. In pregnant rats, BPA was associated with a significant increase of TT4 in the pups 15 days postpartum [¹⁰⁶].

Triclosan in an antibacterial and antifungal agent used in products for personal hygiene and household cleaning agents but also in plastics and fabrics. Though found in human urine [¹⁰⁷] and breast milk [¹⁰⁸], so far, no epidemiological studies have been published on the influence of triclosan on thyroid hormone homeostasis. A small intervention study [¹⁰⁹] could not demonstrate changes in CYP3A4-activity or peripheral thyroid hormone levels after triclosan exposure through toothpaste. However, in vitro studies suggest that higher exposure levels may activate human pregnane x receptor, which upregulates the activity of CYP3A4 [¹¹⁰]. In rats, gestational exposure to triclosan lowered T4 in the pregnant animal and transitorily in the pups at postnatal day 4 [¹¹¹, ¹¹²].

Isoflavones, naturally occurring phytoestrogens, are mainly found in soy and grain products [¹¹³]. Isoflavones inhibit thyroid peroxidase (TPO) function and thereby thyroid hormone production [¹¹⁴]. Iodine insufficient children fed on soy products risk development of goitre and hypothyroidism [¹¹⁵]. As reviewed by Messina and Redmond several studies have been performed in humans to explore the thyroid disrupting effect of isoflavones, but only one study from Japan of healthy volunteers fed for 1–3 months with soy beans reported increased TSH though within the normal reference interval and increased thyroid volume. But other studies could not reveal such relationships [¹¹⁶].

Flame retardants constitute a group of chemicals such as tetrabromobisphenol A (TBBPA), a halogenated derivative of BPA and polybrominated biphenyls. These chemicals are found in different products such as plastic paints and synthetic textiles and are often used in electrical devices such as televisions, computers, copying machines, video displays, and laser printers. These chemicals are structurally more similar to T4 than PCBs and bind competitively to TTR [⁹⁹]. In general, flame retardants are found to reduce thyroid hormone levels. A recently published study of pregnant women showed a negative association between serum levels of brominated flame retardants and TSH [¹¹⁷]. A newer study of recreational fish consumers reported a negative association between concentrations of some congeners in serum and serum levels of T3 and TSH and a positive relationship with T4 [¹¹⁸]. This was confirmed by others [⁷⁸] but not all [¹¹⁹], and in a smaller study of 12 mother-infant pairs, maternal brominated flame retardants levels were not significantly correlated to thyroid hormone levels in cord blood [¹²⁰].

Pesticides constitute a large and very inhomogeneous group of chemicals, which differ significantly in their chemical and physical properties and, thus, their ability to be either detoxified in vivo or to bioaccumulate in lipid-rich tissue. It is beyond the scope of the paper to give a comprehensive overview about potential thyroid disrupting effects. Many of the organochlorine pesticides are persistent with long environmental half-lives, and therefore, humans are continuously exposed though many pesticides have been banned for years in many countries while still in use in others. Dichlorodiphenyltrichloroethane (DDT), hexachlorobenzene (HCB), and nonylphenol (NP) are among the most examined. Metabolites of HCB are used as a biocide and wood preservative in the timber industry and as antifungal agent in the leather industry. NP is an industrial additive used in detergents, plastics, and pesticides. In humans, an enlarged thyroid was found after accidental exposure to HCB [¹²¹], and studies have found negative associations between HCB and T4 [⁷⁷, ⁸¹] or T3 [⁵⁸] but not TSH or free thyroid hormone levels [⁷⁷]. In newborns, pentachlorphenol (PCP) in cord blood but not HCB [⁵⁸] was negatively correlated to T3, fT4 and TBG [¹²²], and thus may potentially impair neurodevelopment. Also, other pesticides seem to posses thyroid disrupting properties [¹²³–¹²⁷].

Ultraviolet (UV) filters also called sunscreens, that is, benzophenone, 4-methylbenzylidene camphor and 3-benzylidene camphor, comprise a group of chemicals used to absorb and dissipate UV irradiation in cosmetic products, not only sun lotions, to enhance product longevity and quality. So far, only animal and in vitro studies have indicated that UV filters may disrupt thyroid hormone homeostasis.

Parabens are commonly used as preservatives in food, cosmetics and pharmaceutical products. In vitro methyl-paraben dose-dependently inhibited iodine organification and thus seemed to have a weak intrinsic antithyroid effect [¹²⁸], but human studies are lacking.

The industrial use of perfluorinated chemicals (PFC) is increasing in products such as stain- and oil-resistant coatings for example, food packaging for fast food, as well as in floor polishes and insecticide formulations. PFCs are extremely persistent in the environment. Women with high levels of PFCs were treated more often for thyroid disease than controls [¹²⁹], and in employees from a PFC factory, PFCs displayed a negative association to fT4 [¹³⁰].

Styrene is an industrial chemical widely used in the production of plastics, resins, and polyesters. Humans are exposed by low-level contamination in food items, but the exposure is most abundant through inhalation of tobacco smoke, automobile exhaust, and vapors from building materials [¹³¹]. Occupational styrene exposure resulted in thyroid disrupting effects: there was a positive correlation between exposure time and thyroid volume and a positive correlation between urinary concentrations of styrene metabolites and f T4 or fT4/fT3 ratios without a correlation to TSH. This indicated an inhibition of the conversion of T4 to T3 [¹³²].

Exposure to lead is typically from cigarette smoke or gasoline, but also workers in the mining, smelting, refining, battery manufacturing, soldering, electrical wiring, and ceramic glazing industries are at risk of occupational exposure. Lead may cause a toxic effect on the central part of the hypothalamic-pituitary-thyroid axis [¹³³, ¹³⁴], but the mechanism is not yet known and effects on the selenium metabolism is also possible. In lead-exposed children, an impaired release of TSH has been reported [¹³⁵], but another study found unchanged T4 levels after lead exposure [¹³⁶].

Studies in occupational lead exposed workers indicates induction of secondary hypothyroidism; one study found low T4 and fT4 and inappropriately normal TSH [¹³⁷] and in auto repair workers, a negative correlation between blood lead levels and fT4 was found, but TSH, T3, and thyroid volume were comparable to unexposed controls [¹³³]. In another group of petrol pump workers or mechanics, TSH was increased compared to the unexposed controls, and T3 declined by longer exposure, but T4 levels were unchanged [¹³⁴]. These findings are in contrast to the evaluation of subacute and cumulative effects in lead smelter workers, where no thyroidal effects were shown [¹³⁸].

Lithium is widely used in the treatment of bipolar mental disorders and has known influences on thyroid function [¹³⁹], and lithium is used in the manufacturing of button and rechargeable batteries, ceramics, and glass. Recently, lithium has been found in ground and drinking water in Argentina, where the urine lithium concentration corresponded to a daily lithium intake of 2–30 mg [¹⁴⁰]. Exposure to lithium in drinking water and other sources seem to suppress thyroid function as urinary lithium was found to correlate negatively with T4 and positively with TSH [¹⁴¹].