WDR-23 and SKN-1/Nrf2 Coordinate with the BLI-3 Dual Oxidase in Response to Iodide-Triggered Oxidative Stress.

Animals utilize conserved mechanisms to regulate oxidative stress. The C. elegans SKN-1 protein is homologous to the vertebrate Nrf (NF-E2-related factor) family of cap 'n' collar (CnC) transcription factors and functions as a core regulator of xenobiotic and oxidative stress responses. The WD40 repeat-containing protein WDR-23 is a key negative regulator of SKN-1 activity. We previously found that the oxidative stress induced by excess iodide can be relieved by loss of function in the BLI-3/TSP-15/DOXA-1 dual oxidase complex. To further understand the molecular mechanism of this process, we screened for new mutants that can survive in excess iodide and identified gain-of-function mutations in skn-1 and loss-of-function mutations in wdr-23 The SKN-1C isoform functions in the hypodermis to affect animal's response to excess iodide, while the SKN-1A isoform appears to play a minor role. wdr-23(lf) can interact with bli-3 mutations in a manner different from skn-1(gf) Transcriptome studies suggest that excess iodide causes developmental arrest largely independent of changes in gene expression, and wdr-23(lf) could affect the expression of a subset of genes by a mechanism different from SKN-1 activation. We propose that WDR-23 and SKN-1 coordinate with the BLI-3/TSP-15/DOXA-1 dual oxidase complex in response to iodide-triggered oxidative stress.

In vitro comparative cytotoxicity study of a novel biocidal iodo-thiocyanate complex.

Novel biocides, which avoid the induction of cross-resistance to antibiotics, are an urgent societal requirement. Here, we compared the cytotoxic and bactericidal effects of a new antimicrobial agent, the iodo-thiocyanate complex (ITC), with those of the common antiseptics, hydrogen peroxide (H2O2), povidone iodine (PVP-I) and Lugol's iodine (Lugol). The antimicrobials were co-incubated for 10 min with HeLa and Escherichia coli cells in the presence and absence of organic matter (Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum). The cytotoxic concentrations of ITC were equivalent to its bactericidal concentrations (7.8 µg ml-1). By contrast, cytotoxic effects of H2O2, PVP-I and Lugol were apparent at concentrations lower than their bactericidal concentrations (250, 250 and 125 µg ml-1, respectively). The cellular effects of ITC were not quenched by organic matter, unlike the other antiseptics. ITC, PVP-I and Lugol had hemolytic effect on horse erythrocytes at high concentrations, while H2O2 showed no hemolysis. ITC, at 30 or 300 µg ml-1, did not cause DNA breakage in HeLa cells as assessed by an in vitro comet assay in the absence of S9 metabolic activation, whereas H2O2 caused extensive single-strand DNA breaks. The pronounced antimicrobial potency of ITC and its favorable cytotoxicity profile suggests that ITC should be considered for antiseptic applications.

Autophagy regulates high concentrations of iodide-induced apoptosis in SH-SY5Y cells.

To date, there are many people residing in areas with high levels of iodide in water. Our previous epidemiological study showed that exposure to high iodine in drinking water significantly reduced the intelligence of children although the mechanisms remain unclear. To explore whether high concentrations of iodide may cause cytotoxic effect and the role of autophagy in the high iodide-induced apoptosis, human neuroblastoma cells (SH-SY5Y cells) were exposed to high concentrations of iodide. Morphological phenotypes, cell viability, Hoechst 33258 staining, the expression levels of apoptosis and autophagy-related proteins were detected. A possible effect of an inhibitor (3-methyladenine, 3-MA) or an inducer (rapamycin) of autophagy on high iodide-induced apoptosis also was examined. Results indicated that high iodide changed cellular morphology, decreased cell viability and increased the protein's expression level of apoptosis and autophagy. In addition, high iodide-induced apoptosis was enhanced by inhibition of autophagy and inhibited by activation of autophagy in SH-SY5Y cells. Collectively, high concentrations of iodide are toxic to SH-SY5Y cells, as well as induce apoptosis and autophagy. Furthermore, autophagy plays a regulatory role in high concentrations of iodide-induced apoptosis in SH-SY5Y cells.

Comparative mammalian cell cytotoxicity of wastewater with elevated bromide and iodide after chlorination, chloramination, or ozonation.

Recycling wastewater is becoming more common as communities around the world try to better control their water resources against an increased frequency of either prolonged droughts or intense flooding. For communities in coastal areas, wastewaters may contain elevated levels of bromide (Br-) and iodide (I-) from seawater intrusion or high mineral content of source waters. Disinfection of such wastewater is mandatory to prevent the spread of pathogens, however little is known about the toxicity of wastewater after disinfection in the presence of Br- and I-. In this study we compared the induction of chronic cytotoxicity in mammalian cells in samples of municipal secondary wastewater effluent amended with elevated levels of Br-/I- after disinfection by chlorine, chloramines or ozone to identify which disinfection process generated wastewater with the lowest level of adverse biological response. Chlorination increased mammalian cell cytotoxicity by 5 times as compared to non-disinfected controls. Chloramination produced disinfected wastewater that expressed 6.3 times more cytotoxicity than the non-disinfected controls and was 1.3 times more cytotoxic than the chlorinated samples. Ozonation produced wastewater with cytotoxicity comparable to the non-disinfected controls and was at least 4 times less cytotoxic than the chlorine disinfected wastewaters. These results indicate that compared to chlorination and chloramination, ozonation of wastewater with high Br-/I- levels yielded the lowest mammalian cell cytotoxicity, suggesting its potential as a more favorable method to disinfect wastewater with minimizing the biological toxicity in mind.

Activation of the Nrf2-Keap 1 Pathway in Short-Term Iodide Excess in Thyroid in Rats.

Wistar rats were randomly divided into groups of varying iodide intake: normal iodide; 10 times high iodide; and 100 times high iodide on Days 7, 14, and 28. Insignificant changes were observed in thyroid hormone levels (p > 0.05). Urinary iodine concentration and iodine content in the thyroid glands increased after high consumption of iodide from NI to 100 HI (p < 0.05). The urinary iodine concentration of the 100 HI group on Days 7, 14, and 28 was 60-80 times that of the NI group. The mitochondrial superoxide production and expressions of Nrf2, Srx, and Prx 3 all significantly increased, while Keap 1 significantly decreased in the 100 HI group when compared to the NI or 10 HI group on Days 7, 14, and 28 (p < 0.05). Immunofluorescence staining results showed that Nrf2 was localized in the cytoplasm in NI group. Although Nrf2 was detected in both cytoplasm and nucleus in 10 HI and 100 HI groups, a stronger positive staining was found in the nucleus. We conclude that the activation of the Nrf2-Keap 1 antioxidative defense mechanism may play a crucial role in protecting thyroid function from short-term iodide excess in rats.

Potential risk of acute toxicity induced by AgI cloud seeding on soil and freshwater biota.

Silver iodide is one of the most common nucleating materials used in cloud seeding. Previous cloud seeding studies have concluded that AgI is not practically bioavailable in the environment but instead remains in soils and sediments such that the free Ag amounts are likely too low to induce a toxicological effect. However, none of these studies has considered the continued use of this practice on the same geographical areas and thus the potential cumulative effect of environmental AgI. The aim of this study is to assess the risk of acute toxicity caused by AgI exposure under laboratory conditions at the concentration expected in the environment after repeated treatments on selected soil and aquatic biota. To achieve the aims, the viability of soil bacteria Bacillus cereus and Pseudomonas stutzeri and the survival of the nematode Caenorhabditis elegans exposed to different silver iodide concentrations have been evaluated. Freshwater green algae Dictyosphaerium chlorelloides and cyanobacteria Microcystis aeruginosa were exposed to silver iodide in culture medium, and their cell viability and photosynthetic activity were evaluated. Additionally, BOD5 exertion and the Microtox® toxicity test were included in the battery of toxicological assays. Both tests exhibited a moderate AgI adverse effect at the highest concentration (12.5µM) tested. However, AgI concentrations below 2.5µM increased BOD5. Although no impact on the growth and survival endpoints in the soil worm C. elegans was recorded after AgI exposures, a moderate decrease in cell viability was found for both of the assessed soil bacterial strains at the studied concentrations. Comparison between the studied species showed that the cyanobacteria were more sensitive than green algae. Exposure to AgI at 0.43µM, the reference value used in monitoring environmental impact, induced a significant decrease in photosynthetic activity that is primarily associated with the respiration (80% inhibition) and, to a lesser extent, the net photosynthesis (40% inhibition) in both strains of phytoplankton and a moderate decrease in soil bacteria viability. These results suggest that AgI from cloud seeding may moderately affect biota living in both terrestrial and aquatic ecosystems if cloud seeding is repeatedly applied in a specific area and large amounts of seeding materials accumulate in the environment.

Effects of Excess Fluoride and Iodide on Thyroid Function and Morphology.

Exposure to high levels of iodide in Cangzhou, Shandong Province, China has been associated with increased incidence of thyroid disease; however, whether fluoride can affect the thyroid remains controversial. To investigate the effects of excess fluoride, we evaluated thyroid gland structure and function in rats exposed to fluoride and iodide, either alone or in combination. Five-week-old Wistar rats (n = 160 total) were randomly divided into eight groups: three groups that were given excess fluoride (15, 30, or 60 ppm F); one group given excess iodide (1200 µg/L I); three groups given excess iodide plus fluoride (1200 µg/L I plus 15, 30, or 60 ppm F); and one control group. The serum concentrations of the thyroid hormones TT3 and TT4 on day 150 were significantly reduced for certain fluoride groups; however, no significant differences were observed in concentrations for the pituitary hormone TSH among any groups. Hematoxylin and eosin staining revealed that iodide causes an increase in the areas of the colloid lumens and a decrease in the diameters of epithelial cells and nuclei; however, fluoride causes an increase in nuclear diameters. The damage to follicular epithelial cells upon fluoride or iodide treatment was easily observed by transmission electron microscopy, but the effects were most dramatic upon treatment with both fluoride and iodide. These results suggest that iodide causes the most damage but that fluoride can promote specific changes in the function and morphology of the thyroid, either alone or in combination with iodide.

Mechanistic Study on the Formation of Cl-/Br-/I-Trihalomethanes during Chlorination/Chloramination Combined with a Theoretical Cytotoxicity Evaluation.

Chlorination followed by chloramination can be used to mitigate the formation of potentially toxic iodinated disinfection byproducts (I-DBPs) while controlling the formation of regulated chloro-bromo-DBPs (Cl-/Br-DBPs). Water samples containing dissolved organic matter (DOM) isolates were subjected to 3 disinfection scenarios: NH2Cl, prechlorination followed by ammonia addition, and HOCl alone. A theoretical cytotoxicity evaluation was carried out based on the trihalomethanes (THMs) formed. This study demonstrates that the presence of bromide not only enhances the yield and rate of iodate formation, it also increases the formation of brominated I-THM precursors. A shift in the speciation from CHCl2I to the more toxic CHBr2I, as well as increased iodine incorporation in THMs, was observed in the presence of bromide. For low bromide concentrations, a decrease in I-THM formation and theoretical cytotoxicity was achieved only for high prechlorination times, while for high bromide concentrations, a short prechlorination time enabled the full conversion of iodide to iodate. For low DOM concentrations or DOM with low reactivity, Br-/I-THMs were preferentially formed for short prechlorination times, inducing high cytotoxicity. However, for high chlorine exposures, the cytotoxicity induced by the formation of regulated THMs might outweigh the benefit of I-THM mitigation. For high DOM concentrations or DOM with higher reactivity, mixed I-THMs were formed together with high concentrations of regulated THMs. In this case, based on the cytotoxicity of the THMs formed, the use of NH2Cl is recommended.

Metallothionein-I/II Knockout Mice Aggravate Mitochondrial Superoxide Production and Peroxiredoxin 3 Expression in Thyroid after Excessive Iodide Exposure.

PURPOSE: We aim to figure out the effect of metallothioneins on iodide excess induced oxidative stress in the thyroid. METHODS: Eight-week-old MT-I/II knockout (MT-I/II KO) mice and background-matched wild-type (WT) mice were used. Mitochondrial superoxide production and peroxiredoxin (Prx) 3 expression were measured. RESULTS: In in vitro study, more significant increases in mitochondrial superoxide production and Prx 3 expression were detected in the MT-I/II KO groups. In in vivo study, significantly higher concentrations of urinary iodine level were detected in MT-I/II KO mice in 100 HI group. Compared to the NI group, there was no significant difference existing in serum thyroid hormones level in either groups (P > 0.05), while the mitochondrial superoxide production was significantly increased in 100 HI groups with significantly increased LDH activity and decreased relative cell viability. Compared to WT mice, more significant changes were detected in MT-I/II KO mice in 100 HI groups. No significant differences were detected between the NI group and 10 HI group in both the MT-I/II KO and WT mice groups (P > 0.05). CONCLUSIONS: Iodide excess in a thyroid without MT I/II protection may result in strong mitochondrial oxidative stress, which further leads to the damage of thyrocytes.

The BLI-3/TSP-15/DOXA-1 dual oxidase complex is required for iodide toxicity in Caenorhabditis elegans.

Iodine is an essential trace element for life. Iodide deficiency can lead to defective biosynthesis of thyroid hormones and is a major cause of hypothyroidism and mental retardation. Excess iodide intake, however, has been linked to different thyroidal diseases. How excess iodide causes harmful effects is not well understood. Here, we found that the nematode Caenorhabditis elegans exhibits developmental arrest and other pleiotropic defects when exposed to excess iodide. To identify the responsible genes, we performed a forward genetic screen and isolated 12 mutants that can survive in excess iodide. These mutants define at least four genes, two of which we identified as bli-3 and tsp-15. bli-3 encodes the C. elegans ortholog of the mammalian dual oxidase DUOX1 and tsp-15 encodes the tetraspanin protein TSP-15, which was previously shown to interact with BLI-3. The C. elegans dual oxidase maturation factor DOXA-1 is also required for the arresting effect of excess iodide. Finally, we detected a dramatically increased biogenesis of reactive oxygen species in animals treated with excess iodide, and this effect can be partially suppressed by bli-3 and tsp-15 mutations. We propose that the BLI-3/TSP-15/DOXA-1 dual oxidase complex is required for the toxic pleiotropic effects of excess iodide.

Toxic impact of bromide and iodide on drinking water disinfected with chlorine or chloramines.

Disinfectants inactivate pathogens in source water; however, they also react with organic matter and bromide/iodide to form disinfection byproducts (DBPs). Although only a few DBP classes have been systematically analyzed for toxicity, iodinated and brominated DBPs tend to be the most toxic. The objectives of this research were (1) to determine if monochloramine (NH2Cl) disinfection generated drinking water with less toxicity than water disinfected with free chlorine (HOCl) and (2) to determine the impact of added bromide and iodide in conjunction with HOCl or NH2Cl disinfection on mammalian cell cytotoxicity and genomic DNA damage induction. Water disinfected with chlorine was less cytotoxic but more genotoxic than water disinfected with chloramine. For both disinfectants, the addition of Br(-) and I(-) increased cytotoxicity and genotoxicity with a greater response observed with NH2Cl disinfection. Both cytotoxicity and genotoxicity were highly correlated with TOBr and TOI. However, toxicity was weakly and inversely correlated with TOCl. Thus, the forcing agents for cytotoxicity and genotoxicity were the generation of brominated and iodinated DBPs rather than the formation of chlorinated DBPs. Disinfection practices need careful consideration especially when using source waters containing elevated bromide and iodide.

The role of the IRE1 pathway in excessive iodide- and/or fluoride-induced apoptosis in Nthy-ori 3-1 cells in vitro.

Excessive iodide and fluoride coexist in the groundwater in many regions, causing a potential risk to the human thyroid. To investigate the mechanism of iodide- and fluoride-induced thyroid cytotoxicity, human thyroid follicular epithelial cells (Nthy-ori 3-1) were treated with different concentrations of potassium iodide (KI), with or without sodium fluoride (NaF). Cell morphology, viability, lactate dehydrogenase (LDH) leakage, apoptosis, and expression of inositol-requiring enzyme 1 (IRE1) pathway-related molecules were assessed. Results showed 50 mM of KI, 1 mM of NaF, and 50 mM of KI +1 mM of NaF changed cellular morphology, decreased viability, and increased LDH leakage and apoptosis. Elevated expression of binding protein (BiP), IRE1, and C/EBP homologous protein (CHOP) mRNA and protein, as well as spliced X-box-binding protein-1 (sXBP-1) mRNA, were observed in the 1 mM NaF and 50 mM KI +1 mM NaF groups. Collectively, excessive iodide and/or fluoride is cytotoxic to the human thyroid. Although these data do not manifest iodide could induce the IRE1 pathway, the cytotoxicity followed by exposure to fluoride alone or in combination with iodide may be related to IRE1 pathway-induced apoptosis. Furthermore, exposure to the combination of excessive iodide and fluoride may cause interactive effects on thyroid cytotoxicity.

Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose-response model.

A biologically based dose-response model (BBDR) for the hypothalamic pituitary thyroid (HPT) axis was developed in the near-term pregnant mother and fetus. This model was calibrated to predict serum levels of iodide, total thyroxine (T4), free thyroxine (fT4), and total triiodothyronine (T3) in the mother and fetus for a range of dietary iodide intake. The model was extended to describe perchlorate, an environmental and food contaminant, that competes with the sodium iodide symporter protein for thyroidal uptake of iodide. Using this mode-of-action framework, simulations were performed to determine the daily ingestion rates of perchlorate that would be associated with hypothyroxinemia or onset of hypothyroidism for varying iodide intake. Model simulations suggested that a maternal iodide intake of 75 to 250 µg/day and an environmentally relevant exposure of perchlorate (~0.1 µg/kg/day) did not result in hypothyroxinemia or hypothyroidism. For a daily iodide-sufficient intake of 200 µg/day, the dose of perchlorate required to reduce maternal fT4 levels to a hypothyroxinemic state was estimated at 32.2 µg/kg/day. As iodide intake was lowered to 75 µg/day, the model simulated daily perchlorate dose required to cause hypothyroxinemia was reduced by eightfold. Similarly, the perchlorate intake rates associated with the onset of subclinical hypothyroidism ranged from 54.8 to 21.5 µg/kg/day for daily iodide intake of 250-75 µg/day. This BBDR-HPT axis model for pregnancy provides an example of a novel public health assessment tool that may be expanded to address other endocrine-active chemicals found in food and the environment.

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.

Occurrence and exposure assessment of perchlorate, iodide and nitrate ions from dairy milk and water in Japan and Sri Lanka.

Perchlorate is known to competitively interfere with iodide uptake by the thyroid gland and thereby human exposure to perchlorate is a public health concern. Prevalence of perchlorate in dairy milk is documented; nevertheless, co-occurrence of perchlorate with other thyroid-binding monovalent ions such as iodide and nitrate is not well understood. In this study, we analyzed perchlorate, iodide, and nitrate-N in dairy milk, water and other dairy-related samples collected from Japan and Sri Lanka. Concentrations of perchlorate in Japanese dairy milk samples ranged from 1.03 to 14.1 ng ml(-1); the corresponding concentrations in dairy milk and powdered milk from Sri Lanka were 1.14-38.5 ng ml(-1). Perchlorate concentrations in commercial milk were significantly higher in Japan than in Sri Lanka, while iodide and nitrate levels in milk between the two countries were comparable. All three ions were ubiquitously found in water samples from Japan and Sri Lanka. Analysis of colostrum and raw milk collected from cows fed with the same feed for over 30 days showed no significant temporal variations in perchlorate, iodide and nitrate-N concentrations. A significant positive correlation was found between the concentrations of perchlorate and iodide in Japanese commercial milk. The concentrations of perchlorate and nitrate-N in water samples analyzed from both countries also showed a significant positive correlation. The exposure estimation revealed that dairy milk provides a greater source for perchlorate and iodide, while water predominantly contributes nitrate-N intake for all age groups in both counties. Infants and children demonstrated the highest estimated perchlorate, iodide and nitrate-N intake on a body weight basis in comparison to other age groups. Therefore, further studies of risk associated with perchlorate may need to reconsider co-existence of iodine and other iodide transport inhibitors in food.

Sentinel lymph node mapping by a near-infrared fluorescent heptamethine dye.

We describe a near-infrared fluorescent heptamethine dye (IR-780 iodide) with unique properties for sentinel lymph node (SLN) mapping in both small and large animals. This dye has a significant photobrightening effect in serum and a long retention time in the lymphatic system which allows to acquire much higher signal-to-noise ratios. Injection of only 10 nmol of this dye permits SLNs to be imaged easily in pigs using excitation fluence rates of only 2 microW/cm(2). In addition, this dye has a unique stability property after formalin fixation in tissues which raises the possibility of developing new and sensitive means of detecting lymph nodes in harvested surgical specimens. This dye can be completely cleared from the circulation in a couple of days and does not cause acute systemic toxicity.

Occurrence and mammalian cell toxicity of iodinated disinfection byproducts in drinking water.

An occurrence study was conducted to measure five iodo-acids (iodoacetic acid, bromoiodoacetic acid, (Z)-3-bromo-3-iodo-propenoic acid, (E)-3-bromo-3-iodo-propenoic acid, and (E)-2-iodo-3-methylbutenedioic acid) and two iodo-trihalomethanes (iodo-THMs), (dichloroiodomethane and bromochloroiodomethane) in chloraminated and chlorinated drinking waters from 23 cities in the United States and Canada. Since iodoacetic acid was previouslyfound to be genotoxic in mammalian cells, the iodo-acids and iodo-THMs were analyzed for toxicity. A gas chromatography (GC)/negative chemical ionization-mass spectrometry (MS) method was developed to measure the iodo-acids; iodo-THMs were measured using GC/high resolution electron ionization-MS with isotope dilution. The iodo-acids and iodo-THMs were found in waters from most plants, at maximum levels of 1.7 microg/L (iodoacetic acid), 1.4 microg/L (bromoiodoacetic acid), 0.50 microg/L ((Z)-3-bromo-3-iodopropenoic acid), 0.28 microg/L ((E)-3-bromo-3-iodopropenoic acid), 0.58 microg/L ((E)-2-iodo-3-methylbutenedioic acid), 10.2 microg/L (bromochloroiodomethane), and 7.9 microg/L (dichloroiodomethane). Iodo-acids and iodo-THMs were highest at plants with short free chlorine contact times (< 1 min), and were lowest at a chlorine-only plant or at plants with long free chlorine contact times (> 45 min). Iodide levels in source waters ranged from 0.4 to 104.2 microg/L (when detected), but there was not a consistent correlation between bromide and iodide. The rank order for mammalian cell chronic cytotoxicity of the compounds measured in this study, plus other iodinated compounds, was iodoacetic acid > (E)-3-bromo-2-iodopropenoic acid > iodoform > (E)-3-bromo-3-iodo-propenoic acid > (Z)-3-bromo-3-iodo-propenoic acid > diiodoacetic acid > bromoiodoacetic acid > (E)-2-iodo-3-methylbutenedioic acid > bromodiiodomethane > dibromoiodomethane > bromochloroiodomethane approximately chlorodiiodomethane > dichloroiodomethane. With the exception of iodoform, the iodo-THMs were much less cytotoxic than the iodo-acids. Of the 13 compounds analyzed, 7 were genotoxic; their rank order was iodoacetic acid >> diiodoacetic acid > chlorodiiodomethane > bromoiodoacetic acid > E-2-iodo-3-methylbutenedioic acid > (E)-3-bromo-3-iodo-propenoic acid > (E)-3-bromo-2-iodopropenoic acid. In general, compounds that contain an iodo-group have enhanced mammalian cell cytotoxicity and genotoxicity as compared to their brominated and chlorinated analogues.

A biologically based dose-response model for dietary iodide and the hypothalamic-pituitary-thyroid axis in the adult rat: evaluation of iodide deficiency.

A biologically based dose-response (BBDR) model was developed for dietary iodide and the hypothalamic-pituitary-thyroid (HPT) axis in adult rats. This BBDR-HPT axis model includes submodels for dietary iodide, thyroid-stimulating hormone (TSH), and the thyroid hormones, T(4) and T(3). The submodels are linked together via key biological processes, including (1) the influence of T(4) on TSH production (the HPT axis negative feedback loop), (2) stimulation of thyroidal T(4) and T(3) production by TSH, (3) TSH upregulation of the thyroid sodium (Na(+))/iodide symporter, and (4) recycling of iodide from metabolism of thyroid hormones. The BBDR-HPT axis model was calibrated to predict steady-state concentrations of iodide, T(4), T(3), and TSH for the euthyroid rat whose dietary intake of iodide was 20 mug/day. Then the BBDR-HPT axis model was used to predict perturbations in the HPT axis caused by insufficient dietary iodide intake, and simulation results were compared to experimental findings. The BBDR-HPT axis model was successful in simulating perturbations in serum T(4), TSH, and thyroid iodide stores for low-iodide diets of 0.33-1.14 mug/day. Model predictions of serum T(3) concentrations were inconsistent with observations in some cases. BBDR-HPT axis model simulations show a steep dose-response relationship between dietary intake of iodide and serum T(4) and TSH when dietary iodide intake becomes insufficient (less than 2 mug/day) to sustain the HPT axis. This BBDR-HPT axis model can be linked with physiologically based pharmacokinetic models for thyroid-active chemicals to evaluate and predict dose-dependent HPT axis alterations based on hypothesized modes of action. To support continued development of this model, future studies should include time course data after perturbation of the HPT axis to capture changes in endogenous iodide, serum TSH, T(4), and T(3).

Molecular characterization of thyroid toxicity: anchoring gene expression profiles to biochemical and pathologic end points.

Organic iodides have been shown to induce thyroid hypertrophy and increase alterations in colloid in rats, although the mechanism involved in this toxicity is unclear. To evaluate the effect that free iodide has on thyroid toxicity, we exposed rats for 2 weeks by daily gavage to sodium iodide (NaI). To compare the effects of compounds with alternative mechanisms (increased thyroid hormone metabolism and decreased thyroid hormone synthesis, respectively), we also examined phenobarbital (PB) and propylthiouracil (PTU) as model thyroid toxicants. Follicular cell hypertrophy and pale-staining colloid were present in thyroid glands from PB-treated rats, and more severe hypertrophy/colloid changes along with diffuse hyperplasia were present in thyroid glands from PTU-treated rats. In PB- and PTU-treated rats, thyroid-stimulating hormone (TSH) levels were significantly elevated, and both thyroxine and triiodothyronine hormone levels were significantly decreased. PB induced hepatic uridine diphosphate-glucuronyltransferase (UDPGT) activity almost 2-fold, whereas PTU reduced hepatic 5 -deiodinase I (5 -DI) activity to < 10% of control in support of previous reports regarding the mechanism of action of each chemical. NaI also significantly altered liver weights and UDPGT activity but did not affect thyroid hormone levels or thyroid pathology. Thyroid gene expression analyses using Affymetrix U34A GeneChips, a regularized t-test, and Gene Map Annotator and Pathway Profiler demonstrated significant changes in rhodopsin-like G-protein-coupled receptor transcripts from all chemicals tested. NaI demonstrated dose-dependent changes in multiple oxidative stress-related genes, as also determined by principal component and linear regression analyses. Differential transcript profiles, possibly relevant to rodent follicular cell tumor outcomes, were observed in rats exposed to PB and PTU, including genes involved in Wnt signaling and ribosomal protein expression.