3.2.2 Environmental factors

The hypothalamus–pituitary–thyroid–periphery (HPTP) axis has been known to be a vulnerable target for environmental factors and nutritional agents for centuries. Goitrogenesis, hypo- and hyperthyroidism, tumorigenesis, and autoimmune diseases of this gland have been linked to single or combined deficiencies of several essential trace elements. Normal thyroid function depends on adequate and balanced availability of the essential trace elements iodine, selenium, iron, and the mineral zinc in the daily diet. It has been suggested that the evolution of humankind and Eve’s route of migration out of Africa, to displace the Neanderthal people and to populate the other continents, closely followed coastlines and regions with high availability of iodine, the key element required for thyroid hormone synthesis (1, 2). Involuntary or voluntary environmental or nutritional exposure to adverse factors and agents impairing thyroid hormone synthesis, secretion, binding, transport, metabolism, and action (‘goitrogens’) contributes to the development and persistence of thyroid disorders (3). Iodine deficiency, still prevalent in many regions of our world, and iodine excess (4), both of which might occur during embryonal and fetal development as well as in newborns, adolescents, and adults, provide the platform for action of adverse agents, which might be well tolerated by a normally functioning ‘quiescent’ thyroid gland with adequate iodine supply (see Chapters 3.2.3, 3.2.4). Compounds adversely affecting the HPTP axis belong to several chemical classes of food ingredients and environmental contaminants, but might also represent pharmaceutical drugs acting either directly on biomolecules comprising the HPTP axis or after modification by phase I and/or II drug metabolism (see Table 3.2.2.1). Apart from by ingestion, several agents reach their targets after inhalation (e.g. occupational exposure or smoking) or by dermal application (e.g. UV screens).

Environmental factors such as temperature, light, altitude, and latitude of living, as well as physical, emotional, and acute mental stress, diseases, and adverse life events impinge on normal HPTP function (Box 3.2.2.1) (40). Very recently it has been suggested that the worldwide pandemic of diseases associated with changes in industrialized and developing countries, such as obesity, diabetes, and metabolic syndromes, is linked to inadequate iodine supply and altered thyroid hormone homeostasis by epigenetic mechanisms during development (15, 41). Current conditions in industrialized western-style countries are characterized by the permanent availability and overconsumption of energy-rich, fibre-poor, semiprocessed, manufactured, enhanced, fortified, or even ‘novel’ foods, a sedentary life style, and a lack of sufficient mobility and physical activity, all of which impinge on hormonal homeostasis that is mainly integrated at the hypothalamic level involving thyrotropin-releasing hormone-producing neurons. It is becoming apparent that not only starvation, fasting, and protein–calorie malnutrition in developing countries but also overfeeding with hypercaloric energy-dense food and obesity in western-style regions can lead to inadequate intake of micronutrients (minerals, vitamins, and secondary metabolites of plants). In addition, active and passive smoking, wellness-, life style-, fashion- and psychodrugs, and narcotics have a major impact on thyroid hormone synthesis, secretion, and action.

Impaired thyroid function has also been observed after consumption of protein-restricted diets, as recommended for patients with phenylketonuria or milder hyperphenylalaninaemias, where adequate iodide supply is essential to compensate for possible adverse effects on thyroid hormone synthesis and metabolism (51). Various staple foods, if inadequately processed or preserved, contain efficient goitrogens (e.g. linamarin, goitrin), which release (iso-)thiocyanate, potent inhibitors of NIS-mediated iodide uptake by thyrocytes and–at higher concentrations–also act as effective blockers of thyroperoxidase (TPO), if iodide supply is inadequate.

This chapter will summarize established data for humans, discuss recent findings and possible risk factors identified from exposure data of human subgroups, epidemiology, and findings in experimental animal models accepted as relevant for human risk analysis. Figure 3.2.2.1 illustrates currently identified targets of the HPTP axes for environmental agents. Issues of iodine deficiency and excess, pharmaceutical drugs, and radioactive isotopes interfering with the thyroid axis will be discussed elsewhere in this volume.

Various mechanisms for interference with the HPTP axis by environmental factors have been identified:

Many of these disturbances may be initially compensated by the complex regulatory network of the axis, which is characterized by multiply redundant and fail-safe feedback mechanisms and a high degree of plasticity and adaptation to the environment. However, long-term exposure to low-dose or acute challenge by adverse agents may overstrain the HPTP axis, especially under conditions of inadequate iodine supply or during vulnerable phases of the individual’s life (development, pregnancy and lactation, nonthyroidal disease), and thus create harm or disease.

Perchlorate, similar to pertechnetate, perrhenate, astatinate, and (iso-)thiocyanate, is a voluminous anion and a relevant (electroneutral transport) substrate for the sodium-iodide symporter (NIS) (5), which is located not only in the basolateral membrane of thyrocytes but also in the lactating mammary gland, the salivary gland, and several internal epithelial structures (gastric mucosa, lung epithelium, etc.). These anions effectively compete for the essential iodide uptake (Table 3.2.2.2), but are not organified in thyroglobulin by the haemoprotein thyroid peroxidase (TPO). Thus, perchlorate has been used as an efficient pharmaceutical to treat hyperthyroidism and to block unwanted (radio-)iodide uptake into the gland or for the diagnostic perchlorate discharge test, performed to identify iodide organification defects. Hypothyroidism can be achieved by regular administration of perchlorate doses of 0.4 mg/kg body weight per day, while reference doses, where no appreciable risk can be observed for human populations, are in the order of 0.7 μg/kg per day. Thiocyanate or nitrate are less potent by a factor of 15 or 240, respectively (6). Recently, reports have been emerging on increasing contamination of surface land and water by potassium or ammonium perchlorate around areas close to civil or military plants as well as installations producing and handling rockets, missiles, ammunitions, and fireworks. Potassium and ammonium perchlorate are increasingly used and widely distributed over our planet as rocket and missile fuel waste; it is extremely stable and poorly degraded in the environment. Other perchlorate salts are used as oxidizers, electrolytes, and in various technical processes (7). Concerns have been raised and published whether this increasing contamination of surface soil and drinking water might negatively impact on thyroid function of exposed populations, especially babies, children, and adolescents who still have limited capacity and reserve to synthesize and store iodinated thyroglobulin. In contrast, adults, whose follicular colloid thyroglobulin stores might last for up to 3 months if adequately supplied with iodide before interference, might be less vulnerable, except during pregnancy or lactation where iodine demands are increased. This controversial issue is the subject of several ongoing surveys by environmental and regulatory authorities, but for the moment no clear evidence for risk assessment is available. However, concentr ations in drinking water of exposed areas have been determined which are in the range or even exceed recommendations by regulatory authorities. Observations in workers regularly exposed to airborne perchlorate provided no evidence for adverse effects, but individuals with inadequate iodide intake, exposed to other environmental NIS inhibitors, or belonging to other susceptible risk groups might experience negative consequences of long-term perchlorate exposure by drinking water with perchlorate concentrations in the range of the discussed US reference doses (US Environmental Protection Agency reference dose 0.7 μg/kg body weight per day) (6).

Perchlorate exposure leads to increased urinary iodine excretion due to the blocking of thyroidal uptake (8) and perchlorate has been found in mothers’ and cows’ milk, generating a risk for babies and children with inadequate iodide supply. A longitudinal study in pregnant women exposed to different perchlorate concentrations in drinking water during pregnancy and lactation revealed no changes in thyroid status and function or adverse effects in mothers and newborns (9).

Exposure of tadpoles and adult African clawed frogs Xenopus laevis to perchlorate impairs amphibian metamorphosis and the thyroid function of these model organisms, which might serve as a very sensitive biomarker for monitoring purposes of several compensatory and also adverse effects caused by environmental exposure to goitrogens such as perchlorate and others; interspecies differences for adverse effects in amphibians, rodents, and humans have not been ruled out (10, 42). These studies indicate that aquatic life forms might already be affected by environmental agents, while humans and terrestrial animals might still be able to compensate or adapt to some extent as long as the concentrations of goitrogens are not excessive. Issues related to extrapolations of rodent studies with perchlorate to human iodide and thyroid hormone kinetics and possible risk assessments have been extensively studied and discussed (43).

While another chloride compound, ClO₂, used for chlorination of drinking, sanitary, or swimming pool water, appears nontoxic, its by-product NaClO₃ is harmful to humans and might occur in water in concentrations of up to 2 mg/l (44). Bromate, BrO₃⁻, the most prevalent water disinfection by-product generated during ozonation, is a carcinogen for the thyroid. For most of these adverse effects, which have been studied in the rat model, a dose-dependent increase in incidence and severity of follicular cell hyperplasia in a gender-specific manner has been observed, with male rats been more sensitive. The bromide anion cannot be efficiently utilized by the iodide-selective organification system of the thyroid follicle, but exposure to elevated bromide concentrations markedly impairs thyroid hormone synthesis and thyroid function (45) (for the effects of brominated organic compounds, see below).

A continuously increasing world population requires enhanced efforts for the production of sufficient food and this is achieved by a greater use of nitrogen-containing fertilizers in agricultural production. Nitrate and nitrite contamination of ground, surface, and drinking water as well as many food products, especially vegetables, is the downside of this development. Nitrite and nitrate are also widely used as preservatives for fish and meat. Nitrate efficiently interferes with NIS catalysed iodide uptake and represents a relevant goitrogen especially in children exposed to drinking water containing 100 mg/l or more nitrate (46). In highly contaminated or nutritionally exposed areas, the goitrogenic effects of nitrate/nitrite cannot be neglected, but adequate iodide supply might prevent this adverse effect and subchronic exposure (15 μg/kg body weight for 28 days in volunteers) appears to be tolerable in humans with respect to thyroid function (24). Whether nitrate also directly interferes with TPO or thyroid oxidase (DUOX) is unclear.

Nitric oxide, NO, identified as prostacyclin- and endothelium-derived hyperpolarizing factor, is a powerful signalling molecule activating guanylate cyclase and cGMP production in the vascular system and thyrocytes and acts as a potent inhibitor of thyroid hormone synthesis and function (47). Whether pharmaceuticals generating NO, which is also endogenously produced in the thyroid by NO synthase isoenzymes, have adverse or therapeutic effects on thyroid function in hyperthyroidism remains to be analysed (47).

This voluminous anion and its related structural isomer isothiocyanate are both potent iodide competitors for NIS, and at higher concentrations thiocyanate also inhibits TPO by acting as a pseudosubstrate. Thiocyanate and isothiocyanate are formed by metabolic pathways from cyanogenic glucosides or thioglucosides of plant origin, respectively. Plant and (bacterial) glucosidases in the gut cleave these glucosides and release cyanide, which is converted to thiocyanate or isothiocyanate. ‘Goitrin’ (l-5-vinyl-2-thio-oxazolidone), isolated from yellow turnips and from Brassica seeds, is a potent antithyroid compound and thiocyanate is also endogenously released from linamarin, a cyanogenic glucoside present particularly in the tuberous roots of the staple food cassava (31). Goitrin, a goitrogen as potent as 6-propyl-2-thiouracil, is not degraded like thioglycosides. Relevant sources for such goitrogens are the Brassicaceae (e.g. cabbage, broccoli, cauliflower, Brussels sprouts), Cruciferaceae, Compositae, and Umbelliferae, but the food content of these adverse metabolites largely depends on adequate processing by cooking, hydrolysis, and preservation. Exposure to these goitrogens, monitored by urinary excretion of (iso-)thiocyanate, is a major problem in developing countries, where inadequate economic and social life conditions or energy resources prevent correct processing of these staple foods such as cassava, sweet potatoes, lima beans, sorghum, pearl millet, and corn, which are the main source for carbohydrates. In addition, concomitant iodide deficiency and protein malnutrition leading to inadequate iron supply can exaggerate this problem for risk groups such as pregnant and lactating women, infants, children, and adolescents. In the thyroid, thiocyanate is metabolized to sulfate and thus does not accumulate.

Thiocyanate and isothiocyanate exposure is also of relevance in western countries, as recently documented (32) for nutritional sources; it is especially relevant for tobacco smokers, who inhale significant amounts of these goitrogens together with other adverse agents. Up to fourfold increases in thiocyanate concentrations were found in breast milk of breastfeeding mothers who smoked and this was associated with up to a twofold decrease in iodide content, the combination of which amplified the goitrogenic risk for the baby (48). Further adverse combinations might be observed if nutritional and environmental exposures to several of these goitrogens add to or amplify the risk and potential damage to thyroid hormone homeostasis. Altered maternal and fetal thyroid function has been reported for mothers who smoke (26) and smoking is one of the main risk factors for progress and severity of Graves’ disease. Conversely, smoking reduces anti-TPO and antithyroglobulin antibodies and might reduce the incidence of Hashimoto’s thyroiditis by mechanisms not understood so far (27, 28). Smoking is a also risk factor for goitrogenesis, even with an improved iodide supply (29).

Tolerable exposure limits recommended by environmental and health authorities and goitrogen contents of nutrients and foods vary greatly in different regions, countries, and continents of our globe. As several of these environmental or nutritional exposures cannot be modified by exposed individuals, it is more than necessary to ensure adequate iodide intake for the whole population, and especially for risk groups (6, 49).

Gaitan et al. have reported on the occurrence of small aliphatic disulphides (R-S-S-R; R = methyl-, ethyl-, n-propyl, phenyl-), which are goitrogens inhibiting iodide organification catalysed by TPO. These compounds occur in some vegetables (onion and garlic), well water, sedimentary rocks, and as water contaminants in aqueous effluents from coal-conversion processes (14). Humic acids, another coal or plant origin contaminant of well and drinking water, have also been identified as goitrogens, but again their effect is only observed when there is inadequate iodide supply, at least in animal experimental models (50).

Impaired thyroid function has also been observed after consumption of protein-restricted diets, as recommended for patients with phenylketonuria or milder hyperphenylalaninaemias, where adequate iodide supply is essential to compensate for possible adverse effects on thyroid hormone synthesis and metabolism (51).Various staple foods, if inadequately processed or preserved, contain efficient goitrogens (e.g. linamarin, goitrin), which release (iso-)thiocyanate, potent inhibitors of NIS-mediated iodide uptake by thyrocytes and–at higher concentrations–also act as effective blockers of TPO, if iodide supply is inadequate.

The remarkable progress of worldwide industrialization, expanded and intensified agricultural, (semi-)industrial production of nutrients and food, and the tremendous increase in quality of life associated with longevity, has had and continues to have a major impact on our environment, which raises several concerns. In particular, the synthesis, use, and dissemination of tens of thousands of new chemicals and compounds, some of which are produced at high tonnage worldwide, have introduced new agents into our environment, some of which interfere with the hormonal systems including the thyroid. Several candidate agents with relevance to the HPTP axis have been identified from effects in wildlife, including aquatic life forms, and for some compounds the adverse effects on thyroid morphology, structure, function, and thyroid hormone status have already been described. Among these are polychlorinated (polychlorinated biphenyls (PCBs), hexachlorobenzene (HCB), organochlorines) and polybrominated (polybrominated diphenyl ethers (PBDE)) aromatic and phenolic (resorcinol, bisphenol A (BPA)) compounds, chlorinated furans such as dioxin derivatives, polyphenolic hydrocarbons, phthalates, pyridines, and others (see Table 3.2.2.3 for selected compounds and their main characteristics).

The Seveso accident in 1976 releasing highly persistent 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) created a first indication, shortly followed by Bhopal, India in 1984, Basel 1986, and several other accidents, which raised awareness of the issue of endocrine disrupters which have not only immediate toxic effects but also might act in a transgenerational way including epigenetic mechanisms of action (Box 3.2.2.2).

Maternal exposure to TCDD and related compounds in the Seveso area has been linked to markedly elevated neonatal thyroid-stimulating hormone (TSH) blood levels in the inner versus the marginally affected and the control area (18) in the affected offspring after the accident. This still controversial data, although correlated with current plasma TCDD and coplanar dioxin-like compounds, suggests long-lasting impact of such contamination both for the immediately exposed population and for the subsequent generation. Elevated neonatal TSH is a well-accepted biomarker for fetal hypothyroidism and is used in the highly successful worldwide screening programmes for congenital hypothyroidism. Increased thyroid volume and elevated prevalence of antibodies against TPO and the TSH receptor associated with impaired fasting glucose were also reported for the young adult offspring of mothers exposed and living in a highly polluted area in eastern Slovakia, where a mix of organochlorines (PCBs, dichlorodiphenyldichloroethylene (DDE), HCB) can still be detected in the exposed inhabitants, albeit at lower levels in the young adults compared to their parents, but still higher than in a control region (16, 17). Again these data were discussed in the context of a transgenerational adverse effect on the HPTP and other endocrine axes, and convincing evidence for an altered HPTP axis seems obvious for the total exposed population of that region.

A major human biomonitoring programme was initiated in 2002 in a heavily industrialized and populated area in Flanders, Belgium. Results from this carefully conceived analysis, including internal exposure to various endocrine disrupters and agents, revealed, among other alterations of hormonal parameters, effects on the serum thyroid hormone levels (e.g. lowered TSH, and elevated free triiodothyronine (T₃) (52). Thyroid hormone serum profiles were also found to be altered in adolescents from the Akwesasne Mohawk Nation living in a PCB-exposed area (15). Different relationships were observed for different PCB congeners, HCB, and DDE versus TSH and free thyroxine (T₄) levels, with breastfeeding modulating these interactions. Although only a small group of adolescents had been analysed, the authors interpreted their findings as evidence for prenatal impact of exposure to these endocrine disrupters on long-lasting alterations of the set points of the HPTP axis, in agreement with several other recent studies in exposed regions. Apparently small amounts of selected persisting endocrine disrupters already present during fetal, postnatal, and pubertal development might lead to adverse effects on the HPTP axis via epigenetic mechanisms. Whether these mechanisms manifest only in certain subpopulations, susceptible or genetically predisposed subgroups or individuals, remains to be studied in more detail. Nevertheless, even subtle alterations of the HPTP axis will have a major impact on brain development, IQ, and long-term metabolic and age-related disease risks due to the pleiotropic nature of thyroid hormone action and feedback regulation (Box 3.2.2.3).

As there are trends for direct relationships between blood, tissue, adipose tissue, whole body, or breast milk contents for TCDD, polychlorinated dibenzofurans (PCDFs), PCB congeners, and other related endocrine disrupters to impaired thyroid function, especially in babies, children, and young adults (11), there is not only a need for monitoring and further research of potential long-term damage, but also the urgent necessity to implement adequate iodide intake in these areas. This precaution might reduce the risk of endocrine disrupter exposure and contamination of the HPTP axis. Even under such conditions breastfeeding should be considered, provided the mother adapts her iodine intake not only to pregnancy and lactation but also to her elevated endocrine disrupter contamination, transferred into the breast milk.

PCBs are environmentally persistent, and some of their more than 200 congeners show bioaccumulation in adipose tissue and exhibit high structural similarity to thyroid hormone. This is reflected by their significant competition of thyroid hormone binding to serum transthyretin but also significant competition for T₃ binding to T₃ receptor as demonstrated by in vitro, cellular, and intact animal experimental models. Whether these mechanistically plausible effects, which are however associated with divergent findings on serum thyroid hormone status of affected humans, will also have impact on functionally relevant readouts and biomarkers, remains to be analysed in long-term studies in larger cohorts.

Recently several highly sensitive, powerful, and sophisticated high-throughput in vitro screening systems have been established, validated, and are currently used in research. They are also used for biomonitoring by environmental authorities and allow for detailed analysis of terrestrial and aquatic environment, food components, nutrition, and occupational exposure with respect to endpoints of interference of endocrine disrupters with thyroid hormone synthesis, metabolism, and action (12, 42, 53–55).

The ‘xenoestrogen’ BPA, recently receiving much scientific and public attention among the most controversial compounds, is a relevant antagonistic ligand for T₃ receptor and might affect modulation of T₃-responsive genes. BPA, an agent used as a plasticizer in daily life articles from polycarbonate baby bottles and food can inner linings to cosmetic and dental products, is currently intensively analysed as a potent endocrine disrupter not only for the thyroid but also the hypothalamus–pituitary–gonadal (HPG) axis (20–22). Some companies have already stopped using the compound in baby products. Animal experimental studies suggest immediate and also transgenerational BPA effects including alterations of sex differentiation. As long as only few accepted data exist on critical BPA leakage and human exposure levels during various life phases, caution should be taken in further expanding the use of this compound in human daily life. BPA has clear adverse effects on several components of the HPTP axis in experimental in vitro and in vivo models and is a powerful endocrine disrupter inhibiting several T₃-regulated pathways in vertebrate development, as analysed in the excellent premetamorphic Xenopus laevis model (23). These observations add complexity to the analysis of adverse effects and necessary risk assessment because BPA in scientific and public discussions has been mainly considered to be a ‘xenoestrogenic’ compound with impact on development, differentiation, and function of the HPG axis. Findings like this and related observations of endocrine disrupter agents affecting more than one endocrine axis with rather distinct developmental windows of susceptibility to even very low doses of the compounds led to new initiatives, paradigms, and approaches as to how to analyse such endocrine disrupter effects that will probably rarely be detected using the classic approaches of toxicology focusing on serum parameters, morphology, linear dose-response relationships, and toxicological endpoints (20). It should not be forgotten, that relevant species differences for the HPTP axis require careful analysis of potential human impact of finings in nonhuman in vitro and animal experimental models.

Similar considerations apply for the various phthalates in use, which have already created a worldwide significant exposure level in humans. Here only very few data have been collected related to their interference with the HPTP axis, but most studies indicate relevant interference with thyroid hormone levels in children, pregnant women, and adult individuals (13). The detailed mode of action remains unclear as the wide number of phthalate congeners and their metabolites poses major analytical problems for clear cause–effect analysis.

Also for another group of persistent organohalogen pollutants, the perfluorinated compounds, which are markedly enriched in the aquatic food chain, interference with the HPTP axis has been shown in environmental, nutritional, and occupational exposure analyses. Perfluorinated compounds are structurally related to free fatty acids and thus bind to albumin in the blood, thereby competing with thyroid hormone and interfering with thyroid hormone bioavailability to target tissues. While at high occupational exposures altered thyroid hormone serum parameters were reported, so far no clinical evidence for disturbed thyroid hormone status in humans is evident. However, as exposure to perfluorinated agents increases globally this issue will remain on the agenda.

Many drugs are known to interact with the thyroid gland or with components involved in the function and regulation of the HPTP axis. In toxicology departments of the pharmaceutical industry the thyroid gland is a well-known problematic target for adverse or toxic side effects of new pharmaceuticals. It is estimated that up to one-third of newly developed compounds, especially aromatic and polycyclic compounds, fail the acute or chronic toxicity screening test batteries due to their side effects leading to alterations of thyroid morphology, goitrogenesis, development of thyroid tumours, or merely changes of serum TSH and/or thyroid hormone levels. The reason for this is not completely understood, but the permanent lifelong H₂O₂ production by thyroid follicles catalysed by the NADPH-dependent DUOX and peroxide consumption by TPO for iodide oxidation, organification, and thyroid hormone synthesis on the thyroglobulin scaffold might be the major cause. Compounds accumulating in the thyroid and its luminal colloid might be exposed to H₂O₂, be chemically modified by oxidative processes, and be deposited there or damage the follicles. One illustrative example might be the rare observation of ‘black thyroid’ syndrome, which is a tetracycline (especially minocycline)-induced discolouration of the thyroid gland probably related to TPO-induced oxidation of the tetracycline (13).

The powerful benzofuran drugs amiodarone and dronedarone are widely used for treating resistant tachyarrhythmia. Apart from their target molecules in the heart, these drugs, the active metabolite desethylamiodarone, and other derivatives are potent antagonistic ligands for the T₃ receptor and inhibitors for the Dio enzymes (Fig. 3.2.2.2). However, debutyl dronedarone acts as a selective T₃ receptor α1 antagonist (see Chapter 3.3. 12). Therefore, chronic administration leads to impaired thyroid function with a clear cumulative dose-associated increase in risk. The drugs are substantially accumulated in the thyroid, which in addition to the high iodine content of amiodarone (between 3 and 20 mg iodide are released per day into the blood) explains their prominent disturbance of thyroid function (39). Not only the iodide contamination associated with the administration of the drug but also the thyroid accumulation of the drug might lead to the severe structural defects of the gland and follicles seen in some patients treated with amiodarone (56). Therefore, the new iodine-free alternative dronedarone is of great interest as no comparable thyroid-related effects are reported, such as inhibition of deiodinase, binding to T₃ receptor, or thyroid accumulation. The adverse effects with respect to iodide contamination of other iodinated drugs, such as the iodinated oral bile radiographic contrast agent iopanoic acid and its congeners, will be discussed elsewhere in this volume.

A further representative example of a group of endocrine disrupters with relevance for the HPTP axis are widely used UV screens or absorbers. These are ubiquitous components of various plastic materials used in daily life which have to be protect from UV damage; also they are contained in sun screens and various cosmetics such as lip sticks or body lotions. UV screens may contain up to 10% (w/w) of typical compounds such as benzophenone 2 or 3, 4-methylbenzylidene camphor (4-MBC), and related products. Typical administration of the UV filters leads to measurable serum levels in the submicromolar to micromolar range (25). At these concentrations clear adverse effects have been observed in thyroid-related in vitro and in vivo animal models, such as rapid and dose-dependent goitrogenesis in rats after 4-MBC administration or efficient inhibition of TPO by benzophenone 2 (3). Some of these effects might be prevented or at least attenuated by adequate iodide supply which still is not warranted globally. Considering the increased application of these UV screens, not only for product protection but also for prevention of human skin cancer due to higher exposure to UV irradiation associated with ozone loss in the atmosphere, some of these UV filters might impose marked risks for the adequate function of the HPTP axis. This might apply especially to babies and children, whose skin is more sensitive to UV light and less protected by endogenous melanocytes, and therefore more frequently treated with these dermal UV lotions. Also these products might be even more easily absorbed by young skin. So far no clear evidence for a goitrogenic action of UV filter ingredients has been described in humans. Therefore, the advice might be to guarantee an adequate iodide supply and to protect skin from UV irradiation by avoiding too much sun and applying UV screens that have less risk for interference with the HPTP axis, especially in babies, children, and individuals with sensitive skin.

Environmental contamination by heavy metals and their ions has raised public concern based on their direct effects on several tissues and organs. Both accidentally and occupationally exposed subgroups are affected, and significant adverse effects might result in the CNS during development and with respect to the pathogenesis of neurodegenerative ageing-associated diseases. Whether the thyroid hormone system, known to have a major impact on proper brain development and function in children and adults, is directly involved in these processes remains unclear. As thyrocytes exhibit a highly active redox-regulated cellular metabolism (57), impairment of reactive redox centres of enzymes and other thyrocyte proteins such as metallothioneins by heavy metals will create problems for thyroid hormone synthesis and secretion. Therefore, environmental or occupational exposure to high mercury, lead, and cadmium concentrations has been associated with altered thyroid homeostasis. For example, a gender-specific effect on increased serum TSH, correlated with increased hair and blood mercury concentrations in males, has been reported in lakeside communities of Quebec and is associated with consumption of contaminated lake fish from the exposed environment (58, 59). Divergent reports have been published on the relationship between cadmium exposure and TSH, positively associated in several studies, but inversely related in a pilot study in cord blood of Japanese newborns (60). Animal experimental data clearly suggest adverse effects of cadmium exposure, which interferes with both thyroid hormone synthesis and peripheral Dio1 activity.

Adverse effects of lead on the thyroid axis have been reported. Previous environmental lead sources were lead-enhanced gasoline and lead-based paints, but both of these sources are of decreasing relevance due to bans that have been enforced in most countries, while contaminations by cadmium, mercury, and, recently, platinum leaking into environment from car exhaust catalytic converters are tending to further increase. Soldin and Aschner (61) reviewed the evidence that manganese, an essential constituent of several redox-relevant enzymes, such as manganese superoxide dismutase, may directly or indirectly affect thyroid function by injuring the thyroid gland or dysregulating dopaminergic modulation of thyroid hormone synthesis and thus contributing to altered thyroid hormone homeostasis and neurodegenerative diseases.

On the other hand, adequate selenium supply can efficiently counteract the adverse effects of several heavy metal cations such as cadmium, mercury, lead, and vanadium and thus avoid their age-related neurotoxicity (62, 63). Apparently selenium leads to their accumulation or deposition in a presumably nontoxic complex in the brain, kidney, and several other tissues.

Many nutritional and environmental contaminants exhibit their goitrogenic potential only under conditions of inadequate maternal, fetal, or neonatal iodide supply. Therefore, comprehensive nutritional iodide supplementation is one of the most efficient preventive measures to avoid impaired and delayed development of humans and other higher life forms.

Temperature, light, circadian and circannual rhythms, altitude, latitude, and extreme environmental life conditions are well known to influence thyroid hormone, energy, and thermoregulatory and metabolic homeostasis not only in free-living animals (homeotherms, hibernators, or aestivators such as bears) but also in humans and livestock adapted to modern housing conditions. Nevertheless, there exist clear circadian and circannual rhythms of TSH and, delayed in phase, of free T₃ in human serum, while T₄, tightly bound to its four serum distributor proteins (thyroxine-binding globulin (TBG), transthyretin, albumin, and lipoproteins) shows no significant circadian or circannual variation (64, 65).

Lowest TSH values are observed in spring and summer and increases of 25% are seen in autumn not reflected by T₄ variations and not related to iodine intake. It has to be kept in mind that the TSH response curve is exponentially related to linear changes in thyroid hormone serum concentration. Whether alterations in food intake, enhanced sympathetic tone and adrenergic stimulation of thermogenesis, altered contribution of thermogenesis by uncoupling protein 3 activation in skeletal muscles mediated by fatty acids and bile acid metabolites, or neuroendocrine hypothalamic adaptations are contributing to these changes remains to be studied. During a prolonged stay in arctic environments, enhanced thyroid hormone secretion by the thyroid has been documented, indicated by increased serum thyroglobulin and elevated T₃ production and turnover, reflected by decreased total and free T₃, but accompanied by unchanged total and free T₄ and TBG. This combination has been termed ‘polar T₃ syndrome’ and related combinations can be found under extreme physical exercise, endurance training, etc. Some of the changes might be prevented by increased calorie intake, sleep adaptation, or thyroid hormone treatment (66). As well as thyroid hormone changes, the melatonin system is altered under these unusual conditions, but direct relationships between these two hormones remain to be established for humans, although studies in pre- and postpubertal blind people (67) suggest an association, similar to clear evidence in various animal models.

Whether adaptations to altered ambient temperature reflect the situation of newborns after birth, characterized by a marked TSH elevation and enhanced synthesis and release of thyroid hormone, all of which can be blunted by elevated ambient temperature for the newborn, remains unclear until the mechanisms of hypothermia-induced activation of the HPTP axis have been elucidated. Recently, novel thyroid hormone metabolites, 3-T₁-thyronamine and related analogues, were shown to reversibly decrease body temperature in experimental animal models, but it is unclear whether they are involved in central hypothalamic and/or peripheral regulation of body temperature and activity of the thyroid hormone axis (68). Increased environmental temperature during summer time and also elevated body temperature during febrile conditions are associated with lower TSH and serum T₃ levels (69, 70).

Various short- and long-term adaptations of thyroid hormone secretion, turnover, serum levels, and feedback set points have been observed in studies examining the HPTP axis in people at high altitude, but results were controversial and might be confounded by other altered factors such as nutritional profiles, physical activity, light, sleep rhythm, and altered time zone adaptations. Animal experimental simulations could dissociate between distinct effects of high altitude and hypoxia and suggest powerful adaptations of the thyroid hormone axis, characterized by decreased thyroid hormone synthesis and secretion but elevated serum free thyroid hormone (40).

This work has been supported by grants of the Deutsche Forschungsgemeinschaft (DFG) to J. Köhrle (DFG GRK 1208 and DFG Ko 922/12–2).