Table 3.

Studies on the relationship between consumption of contaminated fish and thyroid disorders in humans. *

Reference	Methods and subjects studied	Main findings
Sarkar et al. 2015 (121)	The St. Lawrence River, its estuary, and the Gulf of St. Lawrence are heavily polluted with thyroid disrupting chemicals (TDC) from industries, their effluents, and urbanization in the Great Lakes Watershed and along the river. The west and south coasts are in contact with the Gulf of St. Lawrence (GSL). In studies on blubber samples from harbor porpoises collected in 1989-1991, samples from St. Lawrence were more contaminated by older varieties of persistent organic pollutants (POPs) than samples from the Avalon Peninsula (tip of east and south coasts of Newfoundland). Another study found polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane, and its metabolites (DDTs) infrequently consumed fish (capelin, halibut, tomcod, smelt, herring, flounder), shellfish (shrimp, crab) and mammals (beluga, seal) caught in the estuary and the GSL. Local marine products are a regular diet of the coastal communities of Newfoundland. [In contrast, Newfoundland depends mainly on food imported from the mainland because it has very few agricultural communities, a shorter growing season, and poor soil]. Data on hospitalizations with hypothyroidism (from 1998 to 2012) was obtained from the provincial hospital abstracts held at the Newfoundland and Labrador Centre for Health Information (NLCHI).	Mean ± SD hypothyroidism rates of the west [91.8 ± 36.7 persons hospitalized with hypothyroidism diagnosis per 100,000 population per year] and south coasts [96.3 ± 52.0/100,00/year] were significantly higher than in the east coast [51.3 ± 20.2/100,000/year], that is 1.8 and 1.9 times respectively. High levels of TDC were detected in marine animals. Hence, consumption of contaminated seafood might trigger hypothyroidism, the most common cause of which is autoimmune thyroiditis. The authors suspected that marine products caught from the GSL and consumed by communities from the west and south coasts were contaminated with TDCs. Such contamination, in turn, could contribute to the development of hypothyroidism in these areas.
Schell et al. (122)	The Akwesasne Mohawk Nation has long-lived, fished, planted, and hunted in the St. Lawrence River valley (both USA side and Canada side). Many industries had developed along the St. Lawrence River and its tributaries. The Mohawk Nation has relied heavily on locally caught fish and game. Some local species of fish, birds, amphibians, and mammals have polychlorinated biphenyls (PCB), p,p ´-DDE, hexachlorobenzene (HCB), and mirex levels that exceed the tolerance limits for human consumption established by the U.S. Food and Drug Administration. 115 youths (range 10–17 years) were sampled for PCB and their congeners, TSH, T4, FT4, T3, FT3, TPOAb. Breast-feeding history was taken into account, with 47 youths having been breastfed.	18 participants (15.6%) had increased TPOAb levels (23% of females, 9% of males). The rate of TPOAb positivity was similar in the breast-fed group and non-breast-fed group (17.0% vs. 14.7%). Among participants who were breastfed (n=47), those with elevated TPOAb levels had significantly higher levels of all PCB groupings, except levels of non-persistent PCBs which did not differ significantly. Levels of p,p’-DDE were also significantly elevated, while HCB and mirex were similar. Participants who were breastfed had significant, positive relationships between TPOAb levels and all PCB groupings, except groups comprised of non-persistent PCBs, and with p,p’-DDE, HCB, and mirex. No effects were evident among nonbreastfed young adults.
Turyk et al. (123)	To assess whether polybrominated diphenyl ethers (PBDE) body burdens are related to thyroid and steroid hormone levels, thyroid antibodies, and thyroid disease is frequent and infrequent adult male sport fish consumers. A cohort of 4,206 frequent and infrequent consumers of Great Lakes fish established during the early 1990s in a previous study, was invited to participate in a follow-up study. 405 adult males were tested for PBDE congeners, polychlorinated biphenyls (PCB) congeners, thyroglobulin antibodies (TgAb), TSH, T3, T4, and T4-binding globulin (TBG). Data were collected on demographics, fish consumption, medical diseases, and medication use.	Data are reported for the 308 men without exclusion criteria. Thus, excluded were also 21/405 men (5.2%) using thyroid hormones or having thyroid disease. PBDE were positively related to levels of T4 and inversely related to levels of T3 and TSH. PBDE were positively associated with the percentage of T4 bound to albumin, and inversely associated with the percentage of T4 bound to TBG. Participants with PBDE above the 95th percentile were more likely to have TgAb, although high PBDE exposure was not associated with thyroid disease. Indeed, TgAb were detected in 7.8% of the full cohort, but in 31.3% of those whose ∑PBDEs exceeded the 95th percentile [odds ratio (OR) = 6.1].
Bloom et al. (124)	Great Lakes sportfish anglers represent a population with potentially elevated dietary exposure to PBDEs. 36 licensed anglers who participated in the New York State Angler Cohort Study completed questionnaires regarding demographic, clinical, and sportfish consumption information. Archived blood samples were analyzed for T4, FT4, T3, TSH, and nine PBDE congeners.	There was a positive association between ΣPBDEs and FT4, which could have been significant with a sample size approximately 9 times greater.
Bloom et al. (125)	Study as above (124), except that the pollutants measured in sera of the 36 licensed anglers were polychlorinated dibenzo-p-dioxins (PCDDs), coplanar biphenyls (PCB), dibenzofurans (PCDFs), and PCB IUPAC #153.	There was a significant inverse linear association between the sum of dioxin-like congener concentrations (∑DIOXs) and FT4.
Hagmar et al. (126)	For the population living in the coastal areas around the Baltic Sea, consumption of locally caught fatty fish is the main source of exposure to persistent organohalogens (OHS), which are endocrine disruptors. Persons who consume great amounts of contaminated fatty fish from the Baltic Sea may constitute a risk population. The aim of this study was to assess whether high dietary exposure to OHSs affected hormone levels (among which FT3, T3, FT4, T4, and TSH) in adult men. Participants were 110 men who consumed varying amounts of fish (i.e., 0 to 32 meals per month).	In regard to thyroid function tests, the only significant association was negative, and consisted of the negative correlation between 2,2’,4,4’-tetrabromodiphenyl ether and TSH.
Langer et al. (127)	In an area of the Michalovce district in East Slovakia, heavy industrial pollution by polychlorinated biphenyls (PCBs) developed in 1955-1984 and very high PCB levels persist in the environment. Environmental pollution occurred because of activities of chemical factories manufacturing polychlorinated biphenyls (PCBs) and the entirely unlimited dumping of toxic waste to the nearby Laborec river. The average PCBs level found in the serum of 101 chemical factory employees and persons living nearby reached 7300 ng/g of lipids. In 1998, the average values of organochlorines found in predators (e.g., zander [Stizostedion lucioperca], pike [Esax lucius], sheatfish [Silurus glanis], perch [Perca fluviatilis], and asp [Aspius aspius], from the polluted Sirava lake and Laborec river, were 375430 ng/g lipids for a sum of 15 most abundant PCB congeners (upper range limit was 933 770 ng/g which is nearly 1 mg/g lipids) and 15620 ng/g for 2,20-2-bis(4-chlorobiphenyl)-1,1-dichloroethylene (DDE). In contrast, the same fish species from the neighboring Ondava river and Domasa lake with relatively background pollution had an average value of only 5150 ng/g for a sum of PCBs and 8420 ng/g for DDE, still considerably higher than the values of PCBs (1100 to 4600 ng/g) reported for the Baltic herring. 2045 adults from the said polluted area and the surrounding background pollution area were investigated using questionnaire data, thyroid volume by ultrasound (ThV), urinary iodine, and serum levels of 15 PCB congeners, hexachlorobenzene (HCB), α-, β- γ-hexachlorocyclohexane (HCH), 2,2’-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), 2,2’-2-bis(4-chlorobiphenyl)-1,1-dichloroethylene (DDE), and thyroid indices (TSH, FT4, anti-thyroperoxidase antibodies [TPOAb]). Information on the frequency of fish meals and approximate annual consumption of fish from local waters was obtained by questionnaires. Both within the high pollution area and the control background area, participants were divided into five groups based on the amount and frequency of fish consumption. Comparisons were made between different groups in the same area and between the same group in the two different areas.	In the whole cohort of 2045 participants, those with the highest fish consumption had levels of PCB, DDE, and HCB greater than the corresponding levels of those with no or low fish consumption, regardless of the area. However, the same group had greater levels if it belonged to a highly polluted area. For instance, in the group with the highest fish consumption from the polluted area, PCB levels were 4926 ± 971 ng/g lipid compared to 1063 ± 162 in the corresponding group of the background area. Upon continuing the comparison between these two groups, ThV was almost 2 mm greater (11.62 ± 0.58 vs 10.01 ± 0.05 ml), the rate of TPOAb positivity 3-fold greater (34% vs 10.6%) and the rate of FT4 levels above 20 pmol/L almost 50-fold greater (14.4% vs 0.3%). TSH levels were not presented, while they were presented in 16 marital pairs from the high pollution area [see below]. In contrast, in such 16 marital pairs, FT4 levels were not presented. The authors concluded for an association of contaminated fish consumption with very high blood levels of PCBs, HCB and DDE, increased ThV, increased frequency of positive TPOAb, and high levels of FT4. These relationships were confirmed in 16 marital pairs from the high pollution area with very high PCB levels in both members associated with high fish consumption. Actually, in these 32 persons, ThV was 12.60 ± 1.27 ml, the rate of TPOAb was 43.7%, and the rate of subclinical hypothyroidism was 10%.
Benvenga S et al. (17)	The Mediterranean Sea (MS) is a semi-closed basin considered to be the most polluted European sea. Top predators caught in the MS tend to accumulate high amounts of toxic metals and other pollutants. Swordfish caught in the main spawning area (Straits of Messina, southern Italy) were contaminated more than swordfish caught in the Atlantic Ocean (Azores islands). Fish consumption and serum thyroglobulin antibodies (TgAb) and thyroperoxidase antibodies (TPOAb) were measured during gestation (first and second trimester) and postpartum (day 4) in 236 thyroid disease-free, nonsmoker Caucasian women with stable dietary habits and stable residence in the Messina province. Women were divided into four groups (A-D) based on the type of fish consumed: groups A (n=48; selective or predominant swordfish consumption), B (n = 52; selective or predominant oily fish consumption), C (n= 68; swordfish plus other fish, with swordfish consumption accounting for <50% of the total monthly fish consumption; if eaten, oily fish also accounted for <50% of the total monthly fish consumption), D (n = 68; consumption of fish other than swordfish and oily fish).	Fish consumption was quantitatively similar in all groups, equivalent to 7.0 ± 2.6 through 7.8 ± 2.1 times monthly. The leading seafood in group A (swordfish) and group B (oily fish) were consumed with the same frequency (6.2 ± 2.2 vs. 6.1 ± 2.5 times monthly). Positivity rates and serum levels of the two thyroid Ab were the highest in group A and the lowest in group B. For instance, TPOAb positivity at 1st, 2nd trimester of pregnancy and day 4 postpartum was 25%, 17%, and 12% in group A, but always 0% in group B, with intermediate frequencies in groups C and D. Serum levels of both Ab were also the highest in group A and the lowest in group B. The content of mercury in the fish consumed monthly by the four groups was estimated to be the highest in group A and the lowest in group B (approximately 1000 and 25 μg), with values of approximately 250 and 35 μg in groups C and D, respectively.
Benvenga S et al. (18)	Study as in ref. 17, but on a larger cohort of pregnant women (n= 412) and with a longer follow-up (end of the 12th month postpartum) to permit evaluation of the primary outcome: frequency of postpartum thyroiditis (PPT) and its evolution into permanent hypothyroidism (PH). Secondary outcomes were serum levels of thyroid autoantibodies and, not done in the previous study, ultrasonography (US) signs of thyroiditis.	The four fish groups remained comparable in terms of frequency of fish consumption (7.5-8.0 times monthly or twice weekly). Frequencies of positivity of TgAb and TPOAb, and serum concentrations of either thyroid Ab confirmed those of the previous study (17). US signs of thyroiditis during gestation were detected more frequently in group A compared to group B (44.6% and 29.4%), with intermediate values in groups C and D. Overall, the frequency of PPT was 15.3%. However, the greatest frequency was recorded in group A (23.9%) and the lowest in group B (4.7%), with intermediate rates in the other groups. Overall, the frequency of PH was 54%, with no difference between the four fish groups (50 to 56.2%), particularly between fish groups A and B (54.5% and 50%).

*Keywords of relevance are highlighted by the bold-face print.