Relative effect potency estimates of dioxin-like activity for dioxins, furans, and dioxin-like PCBs in adults based on two thyroid outcomes.

BACKGROUND: Toxic equivalency factors (TEFs) are an important component in the risk assessment of dioxin-like human exposures. At present, this concept is based mainly on in vivo animal experiments using oral dosage. Consequently, the current human TEFs derived from mammalian experiments are applicable only for exposure situations in which oral ingestion occurs. Nevertheless, these "intake" TEFs are commonly-but incorrectly-used by regulatory authorities to calculate "systemic" toxic equivalents (TEQs) based on human blood and tissue concentrations, which are used as biomarkers for either exposure or effect. OBJECTIVES: We sought to determine relative effect potencies (REPs) for systemic human concentrations of dioxin-like mixture components using thyroid volume or serum free thyroxine (FT4) concentration as the outcomes of interest. METHODS: We used a benchmark concentration and a regression-based approach to compare the strength of association between each dioxin-like compound and the thyroid end points in 320 adults residing in an organochlorine-polluted area of eastern Slovakia. RESULTS: REPs calculated from thyroid volume and FT4 were similar. The regression coefficient (ß)-derived REP data from thyroid volume and FT4 level were correlated with the World Health Organization (WHO) TEF values (Spearman r = 0.69, p = 0.01 and r = 0.62, p = 0.03, respectively). The calculated REPs were mostly within the minimum and maximum values for in vivo REPs derived by other investigators. CONCLUSIONS: Our REPs calculated from thyroid end points realistically reflect human exposure scenarios because they are based on chronic, low-dose human exposures and on biomarkers reflecting body burden. Compared with previous results, our REPs suggest higher sensitivity to the effects of dioxin-like compounds.

Hashimoto encephalopathy: a rare intricate syndrome.

Recently, several patients have been reported with various signs of encephalopathy and high thyroid antibody levels together with good responsiveness to glucocorticoid therapy. Despite the various clinical presentations, these cases have been termed "Hashimoto encephalopathy" (HE). Although all of the pathogenic components have not yet been clearly elucidated, it is believed that brain vasculitis and autoimmunity directed against common brain-thyroid antigens represent the most likely etiologic pathway. The most common clinical signs include unexplained or epilepsy-like seizures resistant to anti-convulsive treatment, confusion, headaches, hallucinations, stroke-like episodes, coma, impairment of cognitive function, behavioral and mood disturbance, focal neurological deficits, disturbance of consciousness, ataxia, and presenile dementia, together with the presence of high thyroid antibody levels, especially against thyroperoxidase (TPOab). In most cases, the thyroid function is normal or decreased; the thyroid function is rarely increased. The examination of the cerebrospinal fluid, EEG, MRI, SPECT, and neuropsychological examinations are primarily used as diagnostic tools. Most cases showed neural symptoms for months before the acute onset; in some cases, a dramatic acute onset was described. Once the diagnosis is made, corticosteroid treatment usually provides a dramatic recovery. The authors also present a short review of literary cases reported in last decade.

The impacts of organochlorines and other persistent pollutants on thyroid and metabolic health.

High prevalence of thyroid and metabolic disorders has been repeatedly observed in the population living in the area of eastern Slovakia highly polluted by a mixture of PCBs, DDE and HCB since about 50 years ago. Among thyroid disorders, increase of thyroid volume as measured by ultrasound volumetry may be suggested as one of notable findings which appeared possibly related to increased OCs levels and to autoimmunity signs (e.g. positive thyroperoxidase antibodies in blood and/or hypoechogenicity image obtained by ultrasound), while some participation of individual susceptibility and also of immunogenic effect of OCs and iodine in this iodine replete country cannot be excluded. Another notable finding has been the increase of blood FT4 and TT3 positively related to high PCBs level. Such increased FT4 level has been found associated with TSH level in hyperthyroid range in about 2% of examined population from polluted area. High prevalence of thyroid autoimmune disorders strongly supported the assumption on impaired immune system and thus also on presumably increased prevalence of other autoimmune disorders in highly exposed population. In addition, markedly increased prevalence of prediabetes and diabetes significantly related to major OCs (PCBs, DDE and HCB) levels and accompanied by increasing level of cholesterol and triglycerides has been observed. The observations also suggested a role of prenatal exposure to OCs in the development of several adverse health signs (e.g. increased prevalence of thyroid antibodies, impaired fasting glucose level, increased thyroid volume, decreased thymus volume, decreased neurobehavioral performance, increased hearing and dental disorders) in young generation born to highly exposed mothers in polluted area.

Multiple adverse thyroid and metabolic health signs in the population from the area heavily polluted by organochlorine cocktail (PCB, DDE, HCB, dioxin).

BACKGROUND: Several our previous studies showed associations of increasing blood level of persistent organochlorinated pollutants (POPs) with individual thyroid and metabolic adverse health signs in subjects from heavily polluted area (POLL) compared to these from the area of background pollution (BCGR). In this study we present increasing number of subjects with multiple adverse signs positively associated with blood level of polychlorinated biphenyls (PCBs) which is used as a marker of other POPs cocktail. METHODS: In a total of 2046 adults (834 males and 1212 females; age range 21-75) from POLL and BCGR the serum level of major POPs such as of 15 most abundant PCBs congeners, dichlorodiphenyl-dichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) was estimated by high resolution gas chromatography. In addition, the data on thyroid volume by ultrasound and body mass index were obtained and serum level of thyroperoxidase and thyrotropin receptor antibodies as well as that of free thyroxine, total triiodothyronine, thyrotropin, thyroglobulin, fasting glucose and insulin, cholesterol and triglycerides was measured. Thus, a total of 13 adverse signs were defined and the interrelations between PCBs level and increasing number of subjects with increasing number of adverse signs were evaluated. RESULTS: Because of high correlation between major POPs (PCB, DDE and HCB), for this purpose the level of PCBs was considered as a marker also for the presence of DDE and HCB. Thus, if all data obtained from 2046 subjects were stratified according to quintiles of PCBs level, highly significant increase was found (p < 0.02 to 0.0000 by chi-sqauare) for the frequency of 8 among 13 signs, while the increase of one additional sign was slightly above significance limit and that in 4 other was not significant. Also the number of subjects with multiple adverse signs was significantly higher in POLL than in BCGR. For instance, in BCGR area (1038 subjects; median PCB level of 744 ng/g and 5%-95% range of 423 - 1329 ng/g serum lipids) there were 84 (8.1%) cases with 6 or 7 adverse health signs, while in POLL area (1008 subjects; median PCB level of 1892 ng/g; 5%-95% range of 685 - 9016 ng/g) the prevalence of respective cases was twice as high (195 cases = 19.3%; p < 0.001 by chi-square). For the subjects with the same PCB levels, but with 8 or 9 adverse signs the respective values were 22/1038 (2.1%) vs. 54/1008 (5.3%; p < 0.001). CONCLUSION: Significantly higher accumulation of adverse signs in subjects with high POPs level was found in POLL thus supporting the conclusion that POPs appear to increase the prevalence of several subclinical and overt thyroid and metabolic disorders.

Increased thyroid volume, prevalence of thyroid antibodies and impaired fasting glucose in young adults from organochlorine cocktail polluted area: outcome of transgenerational transmission?

In 137 females (F) and 94 males (M) aged 21-35 years from organochlorines (OCs) polluted area (POLL) increased thyroid volume (ThV), prevalence of antibodies to thyroperoxidase (TPOab), thyrotropin receptor (TRab) and of impaired fasting glucose (IFG) was found compared to 116 F and 107 M from background pollution area (BCGR). In F and M from POLL also strikingly increased level of PCBs, DDE and HCB was found. Such findings were compared to the generation of their parents aged 41-55 years consisting of 320F/213M from POLL and 406F/231M from BCGR. However, in spite of strikingly lower level of those OCs in young adults from POLL, they showed about the same prevalence of adverse health signs as the old generation. From such reason 44 young F and 40 young M with lowest PCBs level from POLL were selected to obtain nearly the same PCB level as found in all young F and M from BCGR. In such PCB adjusted groups the prevalence of TPOab, TRab, IFG and increased ThV was still significantly higher than that in all young subjects from BCGR. At the same time, also the level of DDE and HCB in such PCBs adjusted groups was considerably lower. It was concluded that such adverse effects in young adults from POLL possibly did not result from their actual OCs levels, but very likely from their exposure to high OCs levels of their mothers during their prenatal and perinatal life. Thus, the data may be compatible with present views on transgenerational transmission of endocrine disruptors action.

Possible effects of environmental nitrates and toxic organochlorines on human thyroid in highly polluted areas in Slovakia.

Heavy environmental pollution resulting from uncontrolled industrial and agricultural activities has occurred in several areas of Slovakia. So far, field surveys focused mainly on the thyroid have been conducted in one area polluted by nitrates and in a large area polluted mainly by organochlorinated toxicants. In children from the high nitrate area (HNA, n = 324) significantly higher thyroid volume (ThV) by ultrasound was found compared with age-matched children from surrounding areas with low nitrate (LNA, n = 764). In blood samples of 324 children from the HNA and of 100 children from the LNA no difference between areas was found in the level of total thyroxine (T4) and free triiodothyronine (T3). However, positive thyroid peroxidase antibodies (TPOAb) were found in 7/324 (2.2%) and thyrotropin (TSH) levels > 4.0 mIU/L in 13/324 (4.0%) of children from the HNA area, while no positive values were obtained in the LNA. In the area heavily polluted by an organochlorine (OC) cocktail consisting of polychlorinated biphenyls (PCBs), 2,2'-bis(4-chlorophenyl)-1,1-dichloroethylene (p,p'-DDE), hexachlorobenzene (HCB), and dioxins and furans (polluted area) and in the background pollution area (background area) a total of 2046 adults were examined. In polluted area very high blood levels of OCs were found as well as increased ThV and prevalence of thyroid hypoechogenicity by ultrasound. For the evaluation of data the level of PCBs was used as a marker of all OCs. Increasing PCB levels were significantly associated with the increase of free T4 (p < 0.001) and total T3 (p < 0.05) in blood, while slight but not significant negative association of PCBs was observed with the level of TSH. In both women and men the prevalence of TPOAb was significantly higher in polluted area. Although the absolute TPOAb prevalence in both areas was higher in women than that in men, the increase in polluted vs. background area was more striking in men. From these data it appears that the effects of environmental pollution on the thyroid cannot be neglected.

Exposure to polychlorinated biphenyls and hearing impairment in children.

The objective of this cross-sectional epidemiological study was to assess if long-term exposure to polychlorinated biphenyls (PCBs) is associated with hearing impairment. Four hundred and thirty-three children aged 8-9 years residing in an area polluted by PCBs in Eastern Slovakia were examined otoscopically, tympanometrically and by pure tone audiometry. PCB levels in their serum were determined by gas chromatography. Transient otoacoustic emissions (TEOAE) were measured in a subgroup of 161 children. The mean of the sum of PCB concentrations in serum was 528.2ng/g serum lipids (median 321ng/g serum lipids). Serum PCB concentrations were associated with an increase of hearing threshold at low frequencies and a negative correlation between serum PCBs and the amplitude of TEOAE response was observed in the uppermost tertile of children grouped with regard to serum PCBs, not related to thyroid hormone levels. It was concluded that long-term environmental exposure to PCBs is associated with subclinical but diagnosable hearing deficits.

Possible effects of persistent organochlorinated pollutants cocktail on thyroid hormone levels and pituitary-thyroid interrelations.

In polluted district of Michalovce in East Slovakia (POLL) and two districts with background pollution (BCGR) 2046 adults (834 males and 1212 females aged 20-75 years) were examined. Serum levels of thyrotropin (TSH), free thyroxine (FT4), total triiodothyronine (TT3) and antithyroperoxidase antibodies (TPOab) were estimated by electrochemiluminiscent assay and also these of 15 polychlorinated biphenyl congeners (PCBs), p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane were measured by high resolution gas chromatography/mass spectrometry. In addition, also dioxins, furans, coplanar- and mono-ortho-PCBs as well as selected hydroxylated and methylsulphonated PCBs and DDE metabolites were measured by appropriate methods based on gas chromatography/mass spectrometry principle. In POLL significantly higher levels of all organochlorines were found than these in BCGR. When pooled values from both areas were stratified in terms of PCBs level and treated as continuous variables, positive association of PCBs with FT4 and TT3 was found, the latter two being also mutually associated. However, within the category of PCBs level <530 ng/glipid (n=232) the association between PCBs and both the FT4 (p<0.09) and TT3 (p<0.03) was negative and any association of these was not found within the category of PCBs level of 531-1000 ng/g (n=691). In contrast, in the category of 531-2000 ng/g (n=1307) positive association appeared between PCBs and FT4 (p<0.001) as well as TT3 (p<0.05). Highly significant association of PCBs with FT4 (p<0.001) was further found in the categories with PCBs level of 1001-101414 ng/g (n=1307) and 2001-101414 (n=1123), while significant association with TT3 was observed only in the category of 531-2000 ng/g. Such findings suggest possible threshold level in positive effect of PCBs on FT4 and TT3 level which seems to be individual and located somewhere around the PCBs level of 1000 ng/g. However, highly significant negative association of both FT4 and TT3 with TSH was found in each of above indicated PCBs categories. Considerable difference in FT4 and TT3 level between large groups of subjects with the same range of PCBs level was also found suggesting different individual susceptibility to the effects of organochlorines. Among a total of 26 cases from POLL with very low TSH level (<0.5 mU l(-1)) 13 cases showed very high level of PCBs, FT4 and TT3, thus supporting a hypothesis on a novel sporadic form of high PCBs related peripheral subclinical hyperthyroidism possibly resulting from the long-term disruption of equilibrium between bound and free thyroxine in plasma by high PCBs level followed by a striking inhibition of TSH release from the pituitary.

Thyroid ultrasound volume, structure and function after long-term high exposure of large population to polychlorinated biphenyls, pesticides and dioxin.

We examined 2,046 adults (834 males and 1,212 females aged 20-75 years) from polluted district in East Slovakia (POLL) and two neighboring upstream and upwind located districts of background pollution (BCGR). By ultrasound we estimated the thyroid volume (ThV), hypoechogenicity (HYE), nodules and cysts. Serum levels of thyrotropin (TSH), thyroperoxidase antibodies (TPOab) and thyroglobulin were estimated by electrochemiluminiscent assay and these of 15 PCB congeners, p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane by high-resolution gas chromatography. In 320 subjects also selected hydroxylated and methylsulfonated PCB metabolites, polychlorinated dibenzo-dioxins (PCDDs), -furans (PCDFs), five dioxin-like coplanar and eight mono-ortho PCB congeners were estimated. Urinary iodine was measured by automatic microplate method. Reciprocal positive association was found between three major POPs (PCBs, DDE and HCB), the levels of these and also PCDDs plus PCDFs in polluted area being considerably higher than in background pollution area. ThV in groups of males and females from POLL with high PCBs level was significantly higher (p<0.001 by t-test) then in age and sex matched groups from BCGR with low PCBs level. In 1,048 males and females aged <60 years with serum PCBs level >1,000 ng g(-1) lipid (median=1,756 ng g(-1)) a significant effect of age on ThV was found (p<0.01 by ANOVA), while in 921 respective subjects with PCBs level <1,000 ng g(-1) (median=661 ng g(-1)) it was not. These findings supported the view on the additional effect of PCBs on ThV other than that of age. Since the urinary iodine in both districts showed optimal range, any interfering effect of unsatisfactory iodine intake on ThV may be excluded. The frequency of autoimmune thyroiditis signs such as HYE, increased serum level of TPOab and TSH resulting in subclinical or overt thyroid hypofunction was positively associated with sex, age and organochlorine levels. The increase of such frequency in males with POPs levels was much more abrupt than that in females. No considerable differences in the frequency of thyroid nodules as related to PCBs level were found.

Fish from industrially polluted freshwater as the main source of organochlorinated pollutants and increased frequency of thyroid disorders and dysglycemia.

In a certain area of Michalovce district in East Slovakia, heavy industrial pollution by polychlorinated biphenyls (PCBs) developed in 1955-1984 and very high PCB levels in environmental and human samples are still persisting. Recently, a total of 2045 adults from this and the surrounding background pollution area have been examined using questionnaire data, thyroid volume by ultrasound (ThV), urinary iodine and serum levels of 15 PCB congeners, hexachlorobenzene (HCB), 2,2'-2-bis(4-chlorobiphenyl)-1,1-dichloroethylene (DDE), 2,2'-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), alpha-, beta- and gamma-hexachlorocyclohexane (HCH), thyrotropin (TSH), free thyroxine (FT4), anti-thyroperoxidase antibodies (TPOab) and fasting glucose. As based on our previous findings of strikingly high level of PCBs in fish from high pollution area (e.g. mean level of 375430 ng/g lipid) and considerably lower, but still relatively high level in background pollution area (e.g. mean PCB level of 5150 ng/g), the information on the frequency of fish meals and approximate annual consumption of fish from local waters was obtained by questionnaires. The association of contaminated fish consumption with very high blood levels of PCBs, DDE and HCB and increased ThV as well as with increased frequency of positive TPOab, high values of FT4 and impaired fasting glucose (IFG) was found. These associations were also confirmed in 16 marital pairs from high pollution area with very high PCB level in both members associated with high fish consumption. It was concluded that, due to persistent heavy pollution of waters, soil and food chain namely by PCBs, but also by pesticides (e.g. DDE and HCB) resulting from their previous extensive use in agriculture, the fish from local waters still remains the most important source of these toxic pollutants which results in considerable adverse health effects.

Increased thyroid volume and frequency of thyroid disorders signs in schoolchildren from nitrate polluted area.

Thyroid volume (ThV) and echogenicity by ultrasound were estimated in 324 schoolchildren (aged between 10 and 13-years) from high nitrate area (HNA) located in agricultural lowland with high nitrate drinking water supply (51-274 mg/l) from shallow wells. The data were compared to children of the same age from low nitrate area (LNA) consisting of 168 children from the neighboring area with very low nitrate (< 2 mg/l) drinking water and of 596 children from the city of Kosice located in a vicinity of LNA and also supplied by low nitrate water. Blood samples were obtained from 315 willing children from HNA and 109 children from LNA and the levels of thyrotropin (TSH), total thyroxine (TT4), free triiodothyronine (FT3) and thyroperoxidase antibodies (anti-TPO) in serum were determined. ThV (mean +/- SE) in 10-year (5.10 +/- 0.14 ml) and 13-year (5.97 +/- 0.11 ml) old children from HNA was significantly higher than that in two groups of respective age from LNA, 4.58 +/- 0.17 (p < 0.02) and 5.23 +/- 0.15 ml (p < 0.05), and from the city of Kosice, 4.77 +/- 0.10 ml (p < 0.05) and 4.87 +/- 0.1 0ml (p < 0.0001). The frequency of hypoechogenicity in HNA was also significantly higher than that in pooled LNA plus Kosice, 13.7% vs. 4.7% (p < 0.01) in 10-year and 10.6% vs. 5.7% (p < 0.03) in 13-year, respectively. The frequency of TSH level in the range of subclinical hypothyroidism (> 4.0 mU/l) in pooled age groups from HNA was 13/324 (4.0%) and that of positive anti-TPO was 8/324 (2.5%), while no case of either increased TSH or positive anti-TPO was found in 109 children from LNA. Finally, no differences in the levels of TT4 and FT3 were found between HNA and LNA. It was concluded that long-term exposure to high nitrate intake by drinking water and home made meals from local products results in increased thyroid volume and increased frequency of signs of subclinical thyroid disorders (thyroid hypoechogenicity by ultrasound, increased TSH level and positive anti-TPO).

Genome-wide linkage analysis reveals evidence for four new susceptibility loci for familial euthyroid goiter.

Euthyroid goiter is characterized by diffuse or nodular enlargement of the thyroid gland. Iodine deficiency and cigarette smoking have been identified as important environmental factors. However, family and twin pair studies suggest a strong genetic predisposition. Therefore, we performed the first extended genome-wide scan to identify susceptibility loci that predispose for euthyroid goiter using 450 microsatellite markers in 18 extended Danish, German, and Slovakian families. Parametric and nonparametric multipoint linkage analyses were performed. The highest nonparametric LOD scores were obtained for chromosomes 2q and 3p with values of 2.54 at D2S1363 and 2.25 at D3S3038, respectively. Assuming heterogeneity and dominant inheritance, heterogeneity LOD scores (HLOD) of 2.71 and 1.94 were calculated for 2q and 3p, respectively. Furthermore, nonparametric LOD scores of 1.87 (HLOD 1.39) at D7S1808 on 7q and 1.79 (HLOD 1.80) at D8S264 on 8p were obtained. Haplotyping of families contributing to the linkage signals revealed four families compatible with a putative locus on 3p and one family each showing strict cosegregation with the loci on 2q, 7q, and 8p. The four novel candidate loci corroborate the assumed heterogeneity in the etiology of euthyroid familial goiter. For the first time, a more prevalent putative locus, present in 20% of the families investigated, was identified.

Further indications for genetic heterogeneity of euthyroid familial goiter.

Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also strongly indicate a genetic prediposition. In euthyroid goiters molecular defects in the thyroglobulin (TG), and Na+/I- symporter (NIS) gene have been identified. Numerous mutations in the Pendrin (PDS) gene have been found in families with PDS characterized by deafness and euthyroid goiter. Moreover, family studies indicated two major candidate loci MNG-1 on chromosome 14q31 and Xp22. However, all previous linkage studies investigated only one family. To clarify the general relevance of these previously identified two major candidate loci for the etiology of euthyroid goiter we investigated four families with a total number of 74 family members by linkage analysis with microsatellite markers. Moreover, we analyzed the thyroid candidate genes TG, thyroperoxidase (TPO), NIS, TSH receptor, and PDS. In a further family with 12 members in whom we have previously demonstrated linkage to the MNG-1 locus we investigated the Xp22 locus and the PDS gene in addition to our initial study. Linkage analysis results of our study are not significant enough to definitely exclude or confirm linkage to the investigated candidate genes and loci. Nevertheless, we obtained very weak indications for possible linkage to Xp22 in one family by a maximal multipoint LOD score of 1.15, and cosegregation of haplotypes among affected family members. Moreover, in another family linkage to PDS was indicated by a maximal multipoint LOD score of 1.87 as well as cosegregation of haplotypes. However, sequencing of the PDS gene did not reveal germline mutations. A significant total NPL score of 6.5 for PDS over all families most likely indicated linkage to a genomic region close to PDS. Furthermore, the likelihood of linkage to MNG-1 and Xp22 is reduced, because multipoint LOD scores were below 1 or negative. In all families there was no significant evidence for linkage for the thyroid candidate genes TG, TPO, NIS, or the TSH receptor. In conclusion, a general role of MNG-1 and Xp22 for the etiology of euthyroid goiter is unlikely but cannot clearly excluded. The multipoint parametric and nonparametric LOD scores further suggest genetic heterogeneity in the etiology of familial euthyroid goiter. To identify other susceptibility loci it is necessary to perform genome-wide linkage analysis studies with more families.

Multimodal distribution versus logarithmic transformation of thyroid volumes in adolescents: detection of subgroup with subclinical thyroid disorders and its impact on the assessment of the upper limit of normal thyroid volumes.

Our objective was to evaluate whether there is a multimodal distribution of thyroid volume (ThV) in iodine-replete adolescents and to examine the relation between excessive ThV and the presence of thyroid hypoechogenicity (HE), serum thyroperoxidase antibodies (anti-TPO) and TSH levels >4.5 mU/l. ThV was measured by ultrasound in adolescents aged 13 yr (N = 1083) and 17 yr (N = 1089) from 22 schools in 6 districts of eastern Slovakia and expressed as ml and ml/m2 body surface area. For each age group the multimodal distribution of ThV values was tested by computing their frequency at intervals of 0.5 m/m2 and plotting the cumulative frequency on a probability scale in which each segment with normal distribution should give a straight line. In all examined subjects the HE was evaluated by ultrasound; in 924 (42.5%) of those anti-TPO was estimated by radioimmunoassay and TSH by immuno-electrochemiluminiscent assay. The medians of urinary iodine found in 55-164 spot urine samples from each of 6 districts (total number = 1003) were 126-142 microg/l, indicating an iodine-replete status. There was a trimodal distribution of ThV in each group, 80-85% in the lowest, 10-15% in the middle, and 5-7% in the upper segments. In the 10th ThV decile of the 17-yr group the frequency of HE (33/109 = 30.3%), anti-TPO (13/62 = 21.0%) and TSH (6/62 = 9.7%) was significantly higher than that in the 1st-9th decile (71/980 = 7.2%, P<0.001; 23/482 = 4.8%, P<0.001 and 5/482 = 1.0%, P<0.001, resp.). Similar differences were found in the 13-yr group (21/109 = 19.2% vs. 58/974 = 5.9%, P<0.001 for HE, 5/60 = 8.3% vs. 3/320 = 0.9%, P<0.001 for anti-TPO and 2/64 = 3.1% vs. 4/317 = 1.3% (not significant) for TSH >4.5 mU/l. Thus in the 10% of subjects with the highest ThV, the frequency of HE and anti-TPO was 4-5 times higher than in the remaining 90%. Our data indicate that an epidemiological evaluation of a large population of adolescents can detect a group with early signs of thyroid dysfunction (e.g. excessive ThV, increased frequency of HE, anti-TPO and TSH >4.5% mU/l), although such dysfunction may not be clinically apparent. This contrasts with numerous earlier reports which used a logarithmic transformation of the data in similar ThV sets, thus making the data appear homogeneous (unimodal) and with a normal distribution and obscuring the true multimodal distribution. This further prevents recognition of subjects with evidence of disordered thyroid status which thus become falsely included into a normal range.

Possible effects of polychlorinated biphenyls and organochlorinated pesticides on the thyroid after long-term exposure to heavy environmental pollution.

The purpose of this work was to study the effects of high environmental exposure to polychlorinated biphenyls (PCBs) and other organochlorines on the thyroid. Thyroid volume, hypoechogenicity and nodules (by ultrasound), presence of antithyroid peroxidase (anti-TPO) antibodies, and abnormal thyroid-stimulating hormone (TSH) levels in serum (by radioimmunoassay) were examined in 101 adults from the PCB-polluted area in 360 controls. Serum levels of PCBs, hexachlorobenzene, gamma-hexachlorocyclohexane (HCH), p,p'-DDT(1,1,1-trichloro-2,2'-bis(p-chlorophenyl)ethane), and p,p'-DDE(1,1-dichloro-2,2'-bis(p-chlorophenyl)ethene) were measured by high-resolution gas chromatography. Very high levels of PCBs were found in the polluted area (7300 +/- 871 ng/g lipids) compared with controls (2045 +/- 147 ng/g). Positive correlations (P < 0.001) were found between the levels of all organochlorines and their total except for hexachlorocyclohexane (HCH). In the polluted area, the highest thyroid volumes (18.7 +/- 2.32 mL; mean +/- SE) were clustered among 23 subjects (17 males and six females) with PCB levels above 10,000 ng/g (range 10,000-58,667 ng/g). In the remaining 438 subjects the thyroid volume was 14.2 +/- 0.29 mL. These data suggest that there might be a threshold serum PCB level of approximately 10,000 ng/g that may influence the thyroid volume. A two-way ANOVA showed that all thyroid volumes in the polluted area were significantly higher (P < 0.001) than in the control area. In males from the polluted area, the frequencies of thyroid hypoechogenicity, thyroid nodules, positive anti-TPO, and abnormal TSH level were higher than in males from the control area, whereas such differences were not observed in females. Increased thyroid volume and indicators of potential thyroid dysfunction were associated with long-term environmental exposure to PCBs. These effects on the thyroid were confined to subjects with PCB levels above 10,000 ng/g of lipid (thyroid volume) and to males from the polluted area (thyroid hypoechogenicity, thyroid nodules, positive anti-TPO, and abnormal TSH).

High prevalence of anti-glutamic acid decarboxylase (anti-GAD) antibodies in employees at a polychlorinated biphenyl production factory.

An increased prevalence of thyroid antibodies was seen in employees of a factory that formerly produced polychlorinated biphenyls (PCBs). In this study, the authors expand the evaluation of possible long-term PCB effects by comparing the prevalence of glutamic acid decarboxylase (anti-GAD) antibodies with the development of diabetes mellitus. The sera of 240 factory employees and 704 control subjects were analyzed. Anti-GAD antibody values exceeded 1.20 U/ml in all employees (40.4%), was 4 times higher (p < .001) than in all controls (10.5%), and were 5 times higher in employees aged 51-60 yr (53.2%) than in age-matched controls (10.5%) (p < .001). Although the prevalence of diabetes could not be determined from this retrospective study, this is the first report of a possible relationship between xenobiotics and the prevalence of anti-GAD antibodies, and it supports the concept of an immunomodulatory effect of PCBs. However, such antibodies may be present decades before the development of clinical diabetes, and not all anti-GAD antibody-positive individuals become diabetic. Presently, it is unknown whether there is an increased prevalence of diabetes among the former factory employees.