Impact of updated BMD modeling methods on perchlorate and chlorate assessments of human health hazard.

Several exposure limits for perchlorate have been developed based on an early key event, inhibition of radioactive iodide uptake (RAIU) by the thyroid. These assessments have used a variety of definitions of the point of departure. The current assessment revisited the modeling for inhibition of RAIU, using state of the science methods. Bayesian hierarchical modeling was used to account for the repeated measures on the same individuals in the key dataset, and the underlying Beta distribution used for the modeling correctly reflected the bounding of RAIU between 0 and 1. We defined the BMR as a point value of 8% RAIU (rather than a change in RAIU), based on descriptions in the medical literature that RAIU below this value is considered abnormal. Because a definition of the BMR based on the mean response would correspond to about 50% of the population with a response below the BMR at the benchmark dose, we used a hybrid definition of the BMR. That is, the BMD was defined as the dose at which it was estimated that there would be a 10% extra risk in the population of having RAIU of 8% or lower. The resulting point of departure based on the BMDL was 0.03 mg/kg-day.

Expression of the cassava nitrate transporter NRT2.1 enables Arabidopsis low nitrate tolerance.

The cassava grows well on low-nutrient soils because of its high-affinity to absorb nitrate. However, the molecular mechanisms by which cassava adapts itself to this environment remain elusive, although we have cloned a putative gene named MeNRT2.1 which has a crucial role in high-affinity nitrate transporter from cassava seeding. Here, the expression pattern of MeNRT2.1 was further assessed using the GUS activity driven by MeNRT2.1 promoter in Arabidopsis transformation plants. The GUS activity was monitored over time following the reduction of nitrate supply. The GUS gene expression not only peaked in roots after 12 h in 0.2mM nitrate media, but also stained stems and leaves. Arabidopsis plants with overexpression of MeNRT2.1 increased the biomass compared to the wild type on rich nitrogen (N-full) media. However, chlorate sensitivity analysis showed that Arabidopsis plants expressing MeNRT2.1 were more susceptable to chlorate than wild type. Significantly, after growing for 15 days on media containing 0.2mM nitrate concentration, wild-type plants became yellowor died, while the transgenic MeNRT2.1 Arabidopsis plants maintained normal growth. With significant increases in the amount of 15NO- 3 uptake in roots, the MeNRT2.1 plants also increased the contents of chlorophyll and nitrate reductase. Taken together, these results demonstrate that MeNRT2.1 has an important role in adaptation to low nitrate concentration as a nitrate transporter.

Acute renal toxicity of sodium chlorate: Redox imbalance, enhanced DNA damage, metabolic alterations and inhibition of brush border membrane enzymes in rats.

Sodium chlorate (NaClO3 ) is widely used in paper and pulp industries and as a non-selective herbicide. Humans can be exposed to NaClO3 through contaminated drinking water due to its improper and unchecked usage in industries and as herbicide. NaClO3 is also present as a major stable by-product in drinking water that has been disinfected with chlorine dioxide. In this study, we have investigated the effect of a single acute oral dose of NaClO3 on rat kidney. Adult male Wistar rats were divided into one control and four NaClO3 treated groups that were orally given different doses of NaClO3 and euthanized 24 hr after the treatment. Oral administration of NaClO3 resulted in increased hydrogen peroxide levels, lipid, and protein oxidation while thiol and glutathione content and activities of brush border membrane enzymes were decreased in kidney in a NaClO3 dose-dependent manner. Significant alterations in the activities of enzymes involved in carbohydrate metabolism and antioxidant defense were also observed. Administration of NaClO3 induced DNA fragmentation and increased DNA-protein cross-linking. Histological studies showed marked damage in kidney from NaClO3 treated animals. These results strongly suggest that NaClO3 induces nephrotoxicity via redox imbalance that results in DNA and membrane damage, metabolic alterations and brush border membrane enzyme dysfunction.

[Effect of conditioned medium from mesenchymal stem cells on regeneration of endothelium at HCl-induced damage trachea in rats].

The purpose. Respiratory epithelium regeneration is studied in rats with tracheal damage induced by inhaling hydrochloric acid vapor. Method. Regeneration process after the chemical burn was activated by intratracheal administration of preparations obtained from the same-species mesenchymal stem cells (MSC). Results. Tracheal epithelium is shown to recover almost completely on day 3-7 after applying MSC compositions (MSCs). Closed structures containing ciliated cells similar to ciliated cells of the respiratory epithelium lining the trachea are formed in the submucosal epithelium during regeneration. These structures migrate towards epithelium and get incorporated into the damaged epithelium. This phenomenon is apparently indicative of the special mechanism of respiratory epithelium regeneration after HCl-induced injury. Conclusion. It is demonstrated in this study that cell-free MSCs instilled intratracheally promote the recovery of normal submucosal epithelium by either preventing or reducing necrosis and inflammation. Such topical MSCs administration significantly accelerates migration of ciliated cell towards the surface and de novo formation of the ciliary epithelium.

[How does a pesticide residue turn into a contaminant?] / Wie wird ein Pflanzenschutzmittelrückstand zur Kontaminante?

Over the last few years pesticide residues have been repeatedly detected during official food controls that would not be expected from authorized pesticide uses. These residues do not always pose a health risk for consumers. However, the legal and economic consequences of such findings are often far-reaching, especially if the admissible maximum residue limits have been fixed at the LOQ level only. For some example cases, we discuss the real entry pathways into the food chain and under which circumstances residues of such unintentionally added substances could be better regulated under the contaminant legal framework rather than the pesticide legal framework.

Sodium chlorate induces DNA damage and DNA-protein cross-linking in rat intestine: A dose dependent study.

Sodium chlorate (NaClO3) is widely used in paper and pulp industries and as a non-selective herbicide. It is also a major by-product generated upon disinfection of drinking water by chlorine dioxide. In this study, we have investigated the genotoxicity of NaClO3 on the small intestine of rats. Adult male rats were divided into 5 groups: one control and four NaClO3 treated groups. The NaClO3 treated groups were given a single acute oral dose of NaClO3 (100, 250, 500 and 750 mg/kg body weight) and sacrificed 24 h later. Administration of NaClO3 caused significant DNA damage in a dose dependent manner in the rat intestine. This was evident from the comet assay which showed DNA strand breaks and was further confirmed by agarose gel electrophoresis and release of free nucleotides. Increased DNA protein cross-linking in NaClO3 administered groups showed formation of a critical lesion which hampers activities of proteins/enzymes involved in DNA repair, transcription and replication. Thus, oral administration of NaClO3 induces DNA damage in the rat intestine, probably through chlorate induced production of reactive oxygen species.

Sodium chlorate, a major water disinfection byproduct, alters brush border membrane enzymes, carbohydrate metabolism and impairs antioxidant system of Wistar rat intestine.

Sodium chlorate (NaClO3 ) is a widely used nonselective herbicide. It is also generated as a by-product during disinfection of drinking water by chlorine dioxide. The purpose of this study was to evaluate the effect of NaClO3 on rat intestine. Adult male rats were randomly divided into five groups: control and remaining four groups were administered orally different doses of NaClO3 and sacrificed 24 h after the treatment. The administration of NaClO3 produced acute oxidative stress in the intestine, which manifested in the form of markedly enhanced malondialdehyde levels and carbonyl content and lowered total sulfhydryl groups and glutathione levels. The activities of several brush border membrane (BBM) enzymes were greatly reduced as compared to control. There were alterations in the activities of various enzymes of carbohydrate metabolism and those involved in maintaining the antioxidant defense system. Histological studies support the biochemical results showing NaClO3 dose-dependent increase in tissue damage. Thus, the present study shows that oral administration of NaClO3 decreases the activities of BBM enzymes, induces oxidative stress, alters metabolic pathways, and impairs the antioxidant system of rat intestine. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1607-1616, 2017.

Sodium chlorate, a herbicide and major water disinfectant byproduct, generates reactive oxygen species and induces oxidative damage in human erythrocytes.

Sodium chlorate (NaClO3) is a widely used non-selective herbicide. It is also generated as a byproduct during disinfection of drinking water by chlorine dioxide. In the present work, the effects of NaClO3 on human erythrocytes were studied under in vitro conditions. Incubation of erythrocytes with different concentrations of NaClO3 at 37 °C for 90 min resulted in significant hemolysis. Cell lysates were prepared from NaClO3-treated and untreated (control) erythrocytes and assayed for various biochemical parameters. Methemoglobin levels were significantly increased and methemoglobin reductase activity was reduced upon NaClO3 treatment. There was a significant increase in protein oxidation and lipid peroxidation with a decrease in reduced glutathione and total sulfhydryl content. This suggests the induction of oxidative stress in erythrocytes upon exposure to NaClO3. The occurrence of oxidative stress was confirmed by significantly increased generation of reactive oxygen species and lowered antioxidant response of the cells. NaClO3 treatment also increased nitric oxide levels showing induction of nitrosative stress. The activities of major antioxidant and membrane-bound and metabolic enzymes were significantly altered upon incubation of erythrocytes with NaClO3. The erythrocytes became more osmotically fragile while electron microscopic images showed gross morphological alterations in NaClO3-treated cells. These results show that NaClO3 induces oxidative stress in human erythrocytes, which results in extensive membrane damage and lowers the antioxidant response.

Establishment of an in vitro monolayer model of macular corneal dystrophy.

Macular corneal dystrophy (MCD) is characterized by multiple punctate gray-white opacities in the corneal stromal region, due to the accumulation of abnormally sulfated keratan sulfates. We attempted to develop an in vitro model of MCD by simulating the sulfation inhibition using sodium chlorate, a chemical inhibitor of 3'-phosphoadenosine-5'-phosphosulfate (PAPs). The SEM and micro-Raman spectroscopy results showed the hallmark feature of MCD. Further the gene expression studies elucidated the direct effect of sulfation inhibition on the WNT pathway, that in turn downregulated production of matrix metalloproteinases (MMPs), which causes abnormal matrix deposits leading to loss of transparency in vivo. It also resulted in downregulation of integrin and cadherin complexation that leads to disruption of the epithelial layer in the MCD affected corneas. This study offers a promising initial step toward establishing a relevant in vitro MCD disease model, to assess signaling transduction pathways and devise potential treatment strategies based on MMP administration to the MCD affected corneas.

Continuous, low-dose oral exposure to sodium chlorate reduces fecal generic Escherichia coli in sheep feces without inducing clinical chlorate toxicosis.

Our objectives were to determine an effective, yet safe, daily dose of sodium chlorate for reducing fecal shedding of generic Escherichia coli in mature ewes. In a completely randomized experimental design, 25 Targhee ewes (age ∼ 18 mo; BW = 62.5 ± 7.3 kg, mean ± SD) were assigned randomly to 1 of 5 sodium chlorate treatments, which were administered in the drinking water for 5 consecutive days. Treatments were control group (no sodium chlorate) and 4 targeted levels of daily sodium chlorate intake: 30, 60, 90, and 120 mg · kg(-1) BW · d(-1) for 5 d. Individual ewe ad libitum intake of water (with treatments) was measured daily, and BW was measured at the beginning of and 15 and 51 d after the 5-d treatment period. Serum chlorate, whole blood methemoglobin and packed-cell volume (PCV), and fecal generic E. coli and general Enterobacteriaceae coliforms were measured from corresponding samples collected at the end of the 5-d treatment period. Average daily intakes of sodium chlorate from drinking water treatments were 95%, 91%, 90%, and 83% of the target treatment intakes of 30, 60, 90, and 120 mg · kg(-1) BW · d(-1), respectively. Daily sodium chlorate intake remained constant for all treatment groups except for ewes offered 120 mg NaClO3 · kg(-1) BW · d(-1), which decreased (quadratic; P = 0.04) over the course of the 5-d treatment period. This decrease in sodium chlorate intake indicated that the 120-mg NaClO3 level may have induced either toxicity and/or an aversion to the drinking water treatment. Serum chlorate concentrations increased (quadratic; P < 0.001) with increasing sodium chlorate intake. At the end of the 5-d treatment period, mean (least squares ± SEM) serum chlorate concentrations for ewes offered 30, 60, 90, and 120 mg NaClO3 · kg(-1) BW · d(-1) were 15.6 ± 14.1, 32.8 ± 15.8, 52.9 ± 14.1, and 90.3 ± 14.1 µg/mL, respectively. Whole blood methemoglobin and PCV were similar (P = 0.31 to 0.81) among the control group and ewes offered sodium chlorate. Likewise, BW was not affected by sodium chlorate (P > 0.27). Ewes consuming approximately 55 mg NaClO3 · kg(-1) BW · d(-1) or more (i.e., ewes offered 60, 90, and 120 mg) had a >1.4 log unit reduction in fecal E. coli and Enterobacteriaceae coliforms compared with control ewes. We suggest that for a short-term, 5-d dosing strategy, 55 to 81 mg NaClO3 · kg(-1) BW · d(-1) is an effective, yet safe, daily oral dose range for mature ewes to achieve a 97% to 99% reduction in fecal shedding of generic E. coli.

Do subtoxic levels of chlorate influence the desiccation tolerance of Egeria densa?

Among the different factors hypothesized to be responsible for the virtual disappearance of Egeria densa, once a dominant aquatic macrophyte in a southern Chile wetland ecosystem, are the negative effects of certain chemical compounds (mainly chlorate) and harsh environmental conditions (desiccation caused by prolonged atmospheric exposure). The authors performed an integrated experiment in which E. densa plants were first exposed for four weeks inside a mesocosm system to levels of chlorate that existed in the wetland at the time of the plant's demise and then exposed to desiccation conditions that also resembled those that the system had experienced. Hence, the authors tested the hypothesis that E. densa plants exposed to sublethal levels of chlorate are more susceptible to the deleterious effect of desiccation compared with plants that had not been exposed to chlorate. This hypothesis was tested by means of quantifying physiologically related parameters in plants right after the four weeks under water and then after the desiccation period of 6 h. Their results rejected this hypothesis, because all plants, regardless of their history, are equally affected by desiccation.

Invited review: Efficacy, metabolism, and toxic responses to chlorate salts in food and laboratory animals.

For over 100 yr, scientists have explored uses of sodium chlorate in agricultural applications. Sodium chlorate is a strong oxidizer, and thus can be very hazardous when not handled accordingly. Nevertheless, late 19th century agriculturists and scientists attempted to exploit the chemical properties of sodium chlorate as an herbicide and food preservative. It is the herbicidal utility that led to subsequent use of sodium chlorate in the agricultural industry since then. However, in 2000, USDA-ARS scientists proposed a new and targeted use of sodium chlorate against enterobacteria in food animal production. Specifically, when orally dosed in to cattle (Bos taurus), swine (Sus scrofa), broilers (Gallus gallus), turkeys (Meleagris gallopavo), and sheep (Ovis aries), chlorate reduced the fecal shedding of common enteropathogens of the Enterobacteriaceae family. Subsequent to this discovery, the efficacy of chlorate salts has been demonstrated in numerous production classes within species. Doses of sodium chlorate as low as 30 mg/kg BW, but typically 50 to 150 mg/kg BW, have been used to demonstrate efficacy against pathogens. Single or short-duration (<3 d) exposures to oral chlorate at concentrations < 150 mg/kg BW have not produced acute toxicity or clinical signs (labored breathing, methemoglobinemia) in food animals. In all species studied to date, the major biotransformation product of chlorate is chloride ion; chlorite is not present in tissues or excreta of chlorate dosed animals. Chlorate is rapidly eliminated in ruminants and nonruminants, primarily in urine; likewise, residual chlorate in tissues depletes rapidly. Application of any new chemical entity to food animal production carries with it a responsibility to understand adverse reactions that intended and nonintended exposures may have in target and (or) nontarget animals and an understanding of the pathways of elimination that occur after exposure. Therefore, the purpose of this review is to summarize the published data regarding the efficacy, metabolism, and toxicology of chlorate salts in target (livestock) and nontarget species.

Trihalomethanes, chlorite, chlorate in drinking water and risk of congenital anomalies: a population-based case-control study in Northern Italy.

BACKGROUND: Epidemiological evidence of an association between disinfection by-products (DBPs) exposure via drinking water and reproductive outcomes is still inconclusive. OBJECTIVE: The aim of this study was to investigate the association between trihalomethanes (THMs), chlorite and chlorate exposure and congenital anomalies. METHODS: A case-control study was carried out in Emilia-Romagna Region (Italy). Data on 1917 different congenital anomalies (neural tube, cardiac, diaphragm and abdominal wall, oesophagus, cleft lip and palate, respiratory, urinary tract and chromosomal anomalies) observed in the period 2002-2005 were extracted from the Regional Malformation Registry. Four controls (newborns without anomalies) were randomly selected form the Regional Birth Register and frequency matched to cases according to pregnancy period. The network supplying water during the first trimester of pregnancy was identified on the basis of mother's address: DBPs data, technical and structural information were linked to each subject. RESULTS: Overall, THMs exposure was very low (mean: 3.8±3.6 µg/l), and no risk excess was observed. Chlorite and chlorate values were fairly high (mean: 427±184 µg/l and 283±79 µg/l, respectively). Women exposed to chlorite level >700 µg/l were at higher risk of newborns with renal defects (OR: 3.30; 95% IC: 1.35-8.09), abdominal wall defects (OR: 6.88; 95% IC: 1.67-28.33) and cleft palate (OR: 4.1; 95% IC: 0.98-16.8); women exposed to chlorate level >200 µg/l were at higher risk of newborns with obstructive urinary defects (OR: 2.88; 95% IC: 1.09-7.63), cleft palate (OR: 9.60; 95% IC:1.04-88.9) and spina bifida (OR: 4.94; 95% IC:1.10-22). CONCLUSIONS: This was the first study showing an excess risk of different congenital anomalies related to chlorite and chlorate exposure via drinking water: further research is needed to confirm the observed relationships in large datasets, specifically for chlorate, an unregulated DBP.

Effects of short-term sodium chlorate exposure on pigs.

The present study evaluated the effects of exposure to different doses of sodium chlorate in 10-week-old pigs. Twenty pigs were divided into four equal groups and treated with different doses of sodium chlorate: 0, 125, 250 and 500 mg kg-1 body weight per day via the drinking water for 7 consecutive days. The results showed a significant decrease (P < 0.05) in red blood cell and white blood cell counts, packed cell volume, haemoglobin, blood urea nitrogen (P < 0.001) and creatinine levels, and an increase in aspartate aminotransferase and alanine aminotransferase (P < 0.05) activities in swine administered sodium chlorate at a dose of 500 mg kg-1 body weight per day. The histopathological study revealed increased numbers of vacuoles in the convoluted tubules, tubular necrosis and degeneration of the renal tubular epithelial cells, depletion of nuclei and lobular necrosis of the liver in all pigs treated with sodium chlorate at 500 mg kg-1 body weight per day. Thus, 7-day administration of sodium chlorate at 500 mg kg-1 body weight per day to pigs affects the liver and kidney tissues as well as the haematologic and serum biochemical parameters.

Chloric acid(I) affects antioxidant defense of lung epitelial cells.

Generation of chloric acid(I) and reactive oxygen and nitrogen species by activated phagocytes is associated with the course of many inflammatory-related lung diseases. Thus, we studied the effects of HOCl on the redox state of A549 cells as well as on the activity of enzymes involved in cell protection against oxidants. Additionally, we determined the ability of plasma antioxidants to prevent the HOCl-induced cytotoxicity to lung epithelial A549 cells. Cell treatment with HOCl at concentrations above 50 µM for 1h resulted in the loss of cell viability. The decrease of GSH concentration and antioxidant capacity of cell extracts was accompanied by an increase of the level of GSSG and the rate of generation of ROS and peroxyl radicals. Hyperpolarization of the mitochondrial membrane was also observed. HOCl at concentrations of 50 µM significantly decreased the activity of all antioxidant enzymes studied in A549 cells. All antioxidants employed protected cells against the action of HOCl, with the efficiency decreasing as follows: albumin>GSH>uric acid>ascorbate>Trolox. HOCl was found to affect the redox state of A549 by oxidation of GSH, inactivation of antioxidant enzymes and increase of ROS generation.

Evaluation of chlorite and chlorate genotoxicity using plant bioassays and in vitro DNA damage tests.

In the last few years chlorine dioxide has been increasingly used for disinfecting drinking water in many countries. Although it does not react with humic substances, chlorine dioxide added to water is reduced primarily to chlorite and chlorate ions, compounds that are under investigation for their potential adverse effects on human health. The aim of this research was to study the genotoxicity of chlorite and chlorate and their mixtures. The end-points included two plant tests (chromosomal aberration test in Allium cepa and micronucleus assay in Tradescantia, carried out at different times of exposure) and two genotoxicity tests in human HepG2 cells (comet assay and cytokinesis-blocked micronucleus test). Preliminary toxicity tests were carried out for both plant and HepG2 assays. The results showed that chlorite and chlorate are able to induce chromosomal damage to plant systems, particularly chromosomal aberrations in A. cepa root tip cells, even at concentrations lower than the limit established by Italian normative law and WHO guidelines. In HepG2 cells increased DNA damage was only observed for chlorate at the lowest concentration. No increase in micronuclei frequency was detected in any of the samples tested in human HepG2 cells.

Toxic effects of chlorate on three plant species inoculated with arbuscular mycorrhizal fungi.

Pot experiments were conducted to examine the toxic effects of chlorate on bermudagrass, bahiagrass, and longan seedling with a focus on arbuscular mycorrhizal fungi-plant associations. The results show that application of chlorate could cause slight soil acidification, but the resulting pH was still around 5.5, which is unlikely to adversely affect plant growth. Increase in the application rate of chlorate resulted in a decrease in colonization rate of arbuscular mycorrhizal fungi in plant roots, P uptake by the plants and plant biomass. This appears to suggest that the reduction in plant growth may be related to impeded uptake of P by the plants due to the failure of the plants to form sufficient mycorrhizal associations when chlorate is in sufficient amounts to cause toxicity to arbuscular mycorrhizal fungi. Under the experimental conditions set for this study, bermudagrass suffered from stronger chlorate stress than bahiagrass and longan seedling did in terms of plant-arbuscular mycorrhizal fungi (AMF) symbiosis development.

Study on subchronic toxicity of chlorine dioxide and by-products in water.

Subchronic toxicity of the mixture of ClO2, ClO2- and ClO3- in water on rat was studied through feeding test for 90 days. Statistical analyses of variance on weight gained, food utilization efficiency, indexes of blood and serum, liver/bodyweight and kidney/bodyweight ratios, and histopathological examination on liver and kidney were carried out. The results showed that solution of ClO2 and its by-products ClO2- and ClO3- at a concentration of 553 mg/L was not toxic.

Toxicology and carcinogenesis studies of sodium chlorate (Cas No. 7775-09-9) in F344/N rats and B6C3F1 mice (drinking water studies).

BACKGROUND: Sodium chlorate occurs when drinking water is disinfected by chlorine dioxide. We studied the effects of sodium chlorate in rats and mice to identify potential toxic or carcinogenic hazards to humans. METHODS: We gave groups of male and female rats drinking water containing 125, 1,000, or 2,000 milligrams (mg) of sodium chlorate per liter (L) of water for two years. Male and female mice received 500, 1,000, or 2,000 mg/L. Other groups of animals received plain tap water and served as the control groups. At the end of the study, tissues from more than 40 sites were examined for every animal. RESULTS: Male and female rats receiving sodium chlorate had higher rates of follicular cell hypertrophy of the thyroid gland, and the groups receiving 2,000 mg/L had higher rates of thyroid gland cancer, compared with the control groups. Female mice exposed to sodium chlorate had a few pancreatic islet cell tumors. CONCLUSIONS: We conclude that sodium chlorate caused some thyroid gland neoplasms in male and female rats. The pancreatic islet cell tumors in female mice may have been related to sodium chlorate exposure.

A mixture of ammonium perchlorate and sodium chlorate enhances alterations of the pituitary-thyroid axis caused by the individual chemicals in adult male F344 rats.

Ammonium perchlorate (AP) and sodium chlorate (SC) have been detected in public drinking water supplies in many parts of the United States. These chemicals cause perturbations in pituitary-thyroid homeostasis in animals by competitively inhibiting iodide uptake, thus hindering the synthesis of thyroglobulin and reducing circulating T(4) (thyroxine). Little is known about the short-term exposure effects of mixtures of perchlorate and chlorate. The present study investigated the potential for the response to a mixture of these chemicals on the pituitary-thyroid axis in rats to be greater than that induced by the individual chemicals. Adult male F-344 rats were exposed, via their drinking water, to the nominal concentrations of 0.1, 1.0, 10 mg/L AP or 10, 100, 1000 mg/L SC and their mixtures for 7 days. Serum T(4) levels were significantly (p < 0.05) reduced in rats following exposure to the mixtures, but not after exposure to the individual chemicals. Serum T(3) (triiodothyronine) was not altered by treatment and TSH (thyroid stimulating hormone) was only increased after the high-dose chlorate treatment. Histological examination of the thyroid gland showed colloid depletion and hypertrophy of follicular epithelial cells in high-dose single chemical and all mixture-treated rats, while hyperplasia was observed only in some of the rats treated with mixtures (AP 10 + SC 100, AP 0.1 + SC 1000, and AP 10 + SC 1000 mg/L). These data suggest that short-term exposure to the mixture of AP and SC enhances the effect of either chemical alone on the pituitary-thyroid axis in rats.