Excess iodine-induced lymphocytic impairment in adult rats.

Altered lymphocytic activity and its subset ratio found responsible for initiating abnormal autoimmune responses in men and animals after excess iodine exposure. Study objective is to reveal excess iodine-induced impairment of peripheral blood lymphocytes (PBL), its functional status, antioxidant balance, DNA damage, proliferation assay, and serum cytokine levels (IL6 and TNF α)in adult male rats to understand the onset of autoimmune alterations if any indirectly that is unexplored. Experimental animals were grouped depending on doses of iodine(KI) treatment with moderately excess-7 mg/kg bw (100EI) and excessively excess-35 mg/kg bw (500EI)for 30 days to analyze IL6 and TNF α, hematological indices, oxidative stress, lymphocytic DNA damage, and proliferation status. Significant impairment in superoxide dismutase, catalase, GPx activities including elevated NO, LPO in lymphocytes of treated group, with increased IL6 and TNF α level, lymphocyte proliferation and DNA damage depending on doses of iodine. Therefore, excess iodine consumption leads to lymphocytic impairment that may be the potential cause of autoimmune thyroid diseases in long run. Highlights Excess iodine triggers the oxidative stress in lymphocytes. Excess iodine promotes the activity of pro-inflammatory cytokines. Excess iodine causes impairment of functional status of lymphocytes leading to immune-cytotoxicity. Excess iodine exacerbates the autoimmunity.

Iodine in excess in the alterations of carbohydrate and lipid metabolic pattern as well as histomorphometric changes in associated organs.

Background Iodine is a nonpareil constituent of thyroid hormones (THs) and a prime regulator of thyroid gland functioning. Although essential at recommended levels for the prevention of iodine deficiency disorders (IDDs), exposure to excess iodine reportedly causes hypothyroidism, hyperthyroidism, and several other emerging deleterious impacts. The objective of the present study is to explore the influence of excess iodide exposure on carbohydrate and lipid metabolism along with the histoarchitecture of certain associated organs such as the pancreas, liver, kidney, and skeletal and cardiac muscle because information on those aspects was found to be scanty. Methods Twelve rats were taken, six were fed with iodine through gavage at a dose of 3.5 mg potassium iodide (KI)/100-g body weight, which corresponded to 500 times of the physiological daily dosage of iodide for a period of 60 days, while the other six formed the control group. Results KI-treated rats presented high body weight and urinary iodine with low TH levels, suggesting a primary thyroid dysfunction. There was an increase in blood glucose, cholesterol, triglycerides, low density lipoprotein (LDL), and very low density lipoprotein (VLDL), while high density lipoprotein (HDL) levels decreased. Tissue glycogen content in the liver and skeletal muscle was decreased and was increased in the heart and kidney. Histological sections of the pancreas showed a complete disruption with hardly recognizable histoarchistructure. Treated liver sections displayed the broadened central vein with degenerated hepatocytes, while skeletal muscle sections showed dissolution of muscle fibre cells linked with loss of glycogen from these organs. Histological changes in the heart include features similar to those of a fatty heart with cardiac muscles mutilation, while that of the kidney shows an increase in glomerular tuft size and Bowman's space expansion with general deterioration. Conclusions It may thus be concluded that excess iodine exposure for a long duration causes the development of a biochemical state of hypothyroidism. The developed hypothyroidism was found responsible for the hyperglycaemic and hypercholestromic status evident by high blood glucose and cholesterol levels and the depletion of glycogen at its storage sites in the liver and skeletal muscle but the extra deposition in the cardiac muscle and kidney; histomicrophotographs showed severe destruction of the pancreatic structure. All these alterations are conducive for the pathogenesis of cardiovascular and kidney diseases.

Toxicity of tetramethylammonium hydroxide to aquatic organisms and its synergistic action with potassium iodide.

The aquatic ecotoxicity of chemicals involved in the manufacturing process of thin film transistor liquid crystal displays was assessed with a battery of four selected acute toxicity bioassays. We focused on tetramethylammonium hydroxide (TMAH, CAS No. 75-59-2), a widely utilized etchant. The toxicity of TMAH was low when tested in the 72 h-algal growth inhibition test (Pseudokirchneriellia subcapitata, EC50=360 mg L(-1)) and the Microtox® test (Vibrio fischeri, IC50=6.4 g L(-1)). In contrast, the 24h-microcrustacean immobilization and the 96 h-fish mortality tests showed relatively higher toxicity (Daphnia magna, EC50=32 mg L(-1) and Oryzias latipes, LC50=154 mg L(-1)). Isobologram and mixture toxicity index analyses revealed apparent synergism of the mixture of TMAH and potassium iodide when examined with the D. magna immobilization test. The synergistic action was unique to iodide over other halide salts i.e. fluoride, chloride and bromide. Quaternary ammonium ions with longer alkyl chains such as tetraethylammonium and tetrabutylammonium were more toxic than TMAH in the D. magna immobilization test.

The effects and underlying mechanism of excessive iodide on excessive fluoride-induced thyroid cytotoxicity.

In many regions, excessive fluoride and excessive iodide coexist in groundwater, which may lead to biphasic hazards to human thyroid. To explore fluoride-induced thyroid cytotoxicity and the mechanism underlying the effects of excessive iodide on fluoride-induced cytotoxicity, a thyroid cell line (Nthy-ori 3-1) was exposed to excessive fluoride and/or excessive iodide. Cell viability, lactate dehydrogenase (LDH) leakage, reactive oxygen species (ROS) formation, apoptosis, and the expression levels of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were detected. Fluoride and/or iodide decreased cell viability and increased LDH leakage and apoptosis. ROS, the expression levels of glucose-regulated protein 78 (GRP78), IRE1, C/EBP homologous protein (CHOP), and spliced X-box-binding protein-1 (sXBP-1) were enhanced by fluoride or the combination of the two elements. Collectively, excessive fluoride and excessive iodide have detrimental influences on human thyroid cells. Furthermore, an antagonistic interaction between fluoride and excessive iodide exists, and cytotoxicity may be related to IRE1 pathway-induced apoptosis.

National surveillance for radiological exposures and intentional potassium iodide and iodine product ingestions in the United States associated with the 2011 Japan radiological incident.

BACKGROUND: In March of 2011, an earthquake struck Japan causing a tsunami that resulted in a radiological release from the damaged Fukushima Daiichi nuclear power plant. Surveillance for potential radiological and any iodine/iodide product exposures was initiated on the National Poison Data System (NPDS) to target public health messaging needs within the United States (US). Our objectives are to describe self-reported exposures to radiation, potassium iodide (KI) and other iodine/iodide products which occurred during the US federal response and discuss its public health impact. METHODS: All calls to poison centers associated with the Japan incident were identified from March 11, 2011 to April 18, 2011 in NPDS. Exposure, demographic and health outcome information were collected. Calls about reported radiation exposures and KI or other iodine/iodide product ingestions were then categorized with regard to exposure likelihood based on follow-up information obtained from the PC where each call originated. Reported exposures were subsequently classified as probable exposures (high likelihood of exposure), probable non-exposures (low likelihood of exposure), and suspect exposure (unknown likelihood of exposure). RESULTS: We identified 400 calls to PCs associated with the incident, with 340 information requests (no exposure reported) and 60 reported exposures. The majority (n = 194; 57%) of the information requests mentioned one or more substances. Radiation was inquired about most frequently (n = 88; 45%), followed by KI (n = 86; 44%) and other iodine/iodide products (n = 47; 24%). Of the 60 reported exposures, KI was reported most frequently (n = 25; 42%), followed by radiation (n = 22; 37%) and other iodine/iodide products (n = 13; 22%). Among reported KI exposures, most were classified as probable exposures (n = 24; 96%); one was a probable non-exposure. Among reported other iodine/iodide product exposures, most were probable exposures (n = 10, 77%) and the rest were suspect exposures (n = 3; 23%). The reported radiation exposures were classified as suspect exposures (n = 16, 73%) or probable non-exposures (n = 6; 27%). No radiation exposures were classified as probable exposures. A small number of the probable exposures to KI and other iodide/iodine products reported adverse signs or symptoms (n = 9; 26%). The majority of probable exposures had no adverse outcomes (n = 28; 82%). These data identified a potential public health information gap regarding KI and other iodine/iodide products which was then addressed through public health messaging activities. CONCLUSION: During the Japan incident response, surveillance activities using NPDS identified KI and other iodine/iodide products as potential public health concerns within the US, which guided CDC's public health messaging and communication activities. Regional PCs can provide timely and additional information during a public health emergency to enhance data collected from surveillance activities, which in turn can be used to inform public health decision-making.

Expression of Bcl-2 and Bax proteins in thyroid glands of rats in experimental thyroiditis.

In the recent years, iodine was associated to the development of apoptosis in thyroid diseases. The aim of the present study is to determine the expression of pro-apoptotic and anti-apoptotic proteins, Bax and Bcl-2, in a Wistar rat experimental model of thyroiditis induced by administration of different doses of potassium iodide. Immunohistochemical staining was done with chromogen diaminobenzidine on avidin-biotin peroxidase using the Animal Research Kit (ARK), stained with antibodies to Bcl-2 and Bax proteins. The intensity and distribution of positive staining were evaluated by light microscopy on a scale of 0 to 4. Bax protein was expressed in the area of regenerating follicular cells in high percent in potassium iodide treated rats, but was not expressed in thyrocytes from control rats. Bcl-2 expression was constantly observed in thyrocytes of the control group and in the mantle-zone of lymphoid follicular infiltrates. Our results show that Bax expression is significantly higher in the Wistar rat experimental model of thyroiditis than in the control group. These data suggest that the increased expression of Bax may contribute to the role of apoptosis in the pathogenesis of experimental thyroiditis.

Standardization of the perchlorate discharge assay for thyroid toxicity testing in rats.

The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect thyroid toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and beta-naphthoflavone (indirect toxic mechanism) enhanced thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on thyroid: blood (125)I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T(3)), thyroxine (T(4)) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe thyroid follicular cell hypertrophy and hyperplasia, reduced serum T(3) and T(4) levels and increased serum TSH levels, and reduced thyroidal radioiodide accumulation; perchlorate administration significantly reduced thyroid: blood (125)I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked thyroidal radioiodide accumulation, without significant effects on serum T(3), T(4), and TSH levels and a microscopic correlate for higher thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect thyroid toxicity mechanisms.

Studies on the carcinogenicity of potassium iodide in F344 rats.

A chronic toxicity and carcinogenicity study, in which male and female F344/DuCrj rats were given potassium iodide (KI) in the drinking water at concentrations of 0, 10, 100 or 1000 ppm for 104 weeks, and a two-stage carcinogenicity study of application at 0 or 1000 ppm for 83 weeks following a single injection of N-bis(2-hydroxypropyl)nitrosamine (DHPN), were conducted. In the former, squamous cell carcinomas were induced in the salivary glands of the 1000 ppm group, but no tumors were observed in the thyroid. In the two-stage carcinogenicity study, thyroidal weights and the incidence of thyroid tumors derived from the follicular epithelium were significantly increased in the DHPN+KI as compared with the DHPN alone group. The results of our studies suggest that excess KI has a thyroid tumor-promoting effect, but KI per se does not induce thyroid tumors in rats. In the salivary gland, KI was suggested to have carcinogenic potential via an epigenetic mechanism, only active at a high dose.

Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress.

Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyroid cell line (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent apoptosis, as evidenced by morphological changes, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment, reactive oxygen species were produced, and lipid peroxide levels increased markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2, Bcl-XL, and Bax protein expression did not change when cells were treated with iodide. These data indicate that excess molecular iodide, generated by oxidation of ionic iodine by endogenous peroxidases, induces apoptosis in thyroid cells through a mechanism involving generation of free radicals. This type of apoptosis is p53 independent, does not require protein synthesis, and is not induced by modulation of Bcl-2, Bcl-XL, or Bax protein expression.

Induction of squamous cell carcinomas in the salivary glands of rats by potassium iodide.

In a 2-year carcinogenicity study of potassium iodide (KI) in F344/DuCrj rats, squamous cell carcinomas (SCCs) were observed in the salivary glands of 4/40 males and 3/40 females receiving 1000 ppm KI in the drinking water. Ductular proliferation with lobular atrophy was observed at high incidence in the submandibular glands of the high-dose animals, and squamous metaplasia was frequently evident within the proliferative ductules and the larger interlobular ducts. A transition from metaplasia to SCC was apparent. The results suggest that squamous metaplasia in proliferative ductules, occurring secondarily to lobular impairment induced by KI, may develop into SCCs via a non-genotoxic, proliferation-dependent mechanism.

Effects of a six-week exposure to excess iodide on thyroid glands of growing and nongrowing male Fischer-344 rats.

A 6-wk exposure to excess iodide intake (EII) via drinking water (260 mg potassium iodide/L) demonstrated different effects on growing (4-wk old) and nongrowing (45-wk old) male Fischer-344 rats. In growing rats, EII induced a significant increase in thyroid weight, pituitary weight, serum thyroid-stimulating hormone (TSH), and thyroxine (T4). The labeling index (LI) of thyroid follicular cells was slightly increased, although not statistically significant. Histologically, an increase in follicular cell height, an increase in colloid accumulation, and evidence of colloid absorption were noted. The effect of bovine TSH (bTSH) and protirelin tartrate (TRH-t) on LI was significantly augmented by EII. In nongrowing rats, EII induced a significant increase in thyroid weight and serum T4 but no increase in pituitary weight, serum TSH, and the LI of follicular cells. Histologically, an increase in colloid accumulation was found in small follicles. EII did not augment the effect of bTSH and TRH-t on the LI of follicular cells. This study suggests that growing rats are still susceptible to acute hypothyroidism even after 6 wk of continuous exposure to excess iodide, whereas nongrowing rats are refractory within an equivalent treatment period.

Developmental toxicity and psychotoxicity of potassium iodide in rats: a case for the inclusion of behaviour in toxicological assessment.

Potassium iodide (KI) was fed to male and female rats before and during breeding, to females only during gestation and lactation, and to their offspring after weaning (day 21 after birth) through to day 90, at levels of 0, 0.025, 0.05 or 0.1% (w/w) of the diet. Dams in a fifth group (positive controls) were given 4 mg/kg ip of the anti-mitotic/cytotoxic drug 5-azacytidine on day 17 of gestation. All offspring were reared by their natural dams and were evaluated blind with respect to treatment in a battery of standardized behavioural tests between 3 and 90 days of age. KI produced no significant reductions in parental body weight or food consumption, though it significantly reduced litter size and increased offspring mortality at the highest dose, and decreased weight gain at the two highest doses throughout the first 90 days after birth. Functionally, KI delayed auditory startle at the two highest doses, delayed olfactory orientation to the home-cage scent at the middle dose and decreased female running-wheel activity at all dose levels. In rats killed on day 90 after birth KI reduced brain and body weight at a dose of 0.1% of the diet, and reduced body but not brain weight at a dose of 0.05% of the diet. No significant effect was found on absolute or relative thyroid weight at 90 days of age. Several additional behavioural effects were observed in the low-dose KI group, but because these effects were not dose-dependent, they were not regarded as reliable. 5-Azacytidine produced evidence of substantially greater developmental toxicity than KI. It was concluded that KI produced evidence of developmental toxicity consistent with a picture of impaired thyroid function. The inclusion of tests of functional development added useful evidence to the overall picture of KI developmental toxicity.

Sterile cutaneous pustules: a manifestation of primary irritancy? Identification of contact pustulogens.

An animal model (the rabbit) was used to define which of 8 chemicals caused pustule formation on topical application. Large occlusive chambers (diameter 12 mm), petrolatum as the vehicle and wrapping contributed to efficient occlusion and pustulation. Sodium lauryl sulfate and mecuric chloride gave reproducible results and clear dose-responses indicating that this pustulation is an expression of primary irritancy. Ammonium fluoride pustulation was not reproducible; croton oil pustules were more difficult to evaluate due to simultaneous erythema and edema. Sodium arsentate, nickel sulfate and potassium iodide pustules developed at sites where the skin barriers had been damaged by a stab injury. Benzalkonium chloride caused yellow staining and edema but not pustules. Because of lack of epidemiologic data, we do not know how frequently similar findings occur in man.

Assessment of somatogenotoxicity of povidone-iodine using two in vitro assays.

The mutagenic potential of povidone-iodine (PVP-I) and some related compounds were studied using the L5178Y mouse (TK+/-) lymphoma assay. The established mutagens ethyl methanesulfonate (EMS) and dimethylnitrosamine (DMN) were highly active in this assay, whereas PVP-I, polyvinyl pyrolidone (PVP), potassium iodide (KI), and iodine (I2) were inactive. Furthermore, in the presence of a rat liver microsomal activating fraction (S-9), PVP-I and I2 had only marginal activity as mutagens. Using the Balb/c 3T3 transformation assay we assessed the transformational capacities of these same agents and the positive mutagen N-methyl-N-nitro-N-nitrosoguanidine (MNNG). All concentrations of the compounds tested were inactive in this assay except for PVP-I (5 mg/ml) and MNNG (5 micrograms/ml). However, the response with PVP-I was only marginal. We concluded from these studies that PVP, PVP-I, KI, and I2 did not possess any biologically significant mutagenic or cell transforming ability.

The effect of iodide administration on hog thyroid gland and the composition of thyroglobulin and 27-S iodoprotein.

The effect of excess iodide on hog thyroid gland has been examined with regard to the change in the chemical composition of thyroglobulin and in the accumulation of 27-S iodoprotein by the in vivo treatment of hogs with iodide for various lengths of time. The iodine content of thyroglobulin was either unchanged by short term administration of excess iodide, or somewhat lowered. However, the iodine content as well as the total amount of thyroglobulin increased in the glands enlarged by prolonged treatment with iodide. The iodine highest reached 1.17% of the protein on an average. On the other hand, 27-S iodoprotein decreased and finally disappeared after the chronic treatment. Monoiodotyrosine and diiodotyrosine increased in parallel with the increase in the iodine content (0.15 to 1.17%) caused by the iodide treatment, while thyroxine increased but reached a plateau at the level of three residues per mole of thyroglobulin, and no change was observed even in the proteins with the higher iodine content than 0.75%. Proteolytic activity measured by amino acid release from the thyroid protein was depressed by the chronic treatment. On the other hand, the amount of iodocompound released by the autoproteolysis, which may reflect hormone secretion, increased, possibly because of the marked increase in the iodine content of thyroglobulin.