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.

Research Note: Evaluation of dietary administration of sodium chlorate and sodium nitrate for Histomonas meleagridis prophylaxis in turkeys.

Histomoniasis is currently a re-emerging disease of major significance for many commercial turkey and broiler breeder production companies because of the unavailability of drugs or vaccines. The protozoa Histomonas meleagridis (HM) requires the presence of enteric microflora to promote the disease. The objectives of this research note were to evaluate the effect of dietary administration of sodium chlorate (SC) and sodium nitrate (SN) in vitro and in vivo for HM prophylaxis in poults. A total of 128 day-of-hatch female poults obtained from a commercial hatchery were wing-tagged and randomly assigned into 1 of 4 experimental groups: negative control (NC), positive control, dietary inclusion of SC (3,200 ppm) and SN (500 ppm). Poults from groups SC and SN started on their respective diets on day 12. All groups, except the NC, were challenged with 2 × 105 HM on day 19. Controls were fed a basal diet, identical to the treatment diets but not supplemented with SC or SN. Body weight gain (BWG) was determined weekly, starting on day 1 until day 28, and postchallenge morbidity and mortality were recorded. On day 28 of age, all surviving poults were lesion scored for hepatic and cecal lesions. Ceca and distal ileum were collected on day 28 for bacterial recovery on selective media for total aerobic, lactic acid bacteria, or gram-negative bacteria. The addition of SC and SN in the in vitro growth of HM greatly reduced the growth of the protozoa after 20 h of incubation when compared with the control nontreated group (P < 0.05). However, dietary supplementation of SC and SN had no effect against HM in vivo, as was demonstrated by BWG, the severity of lesions in the liver and ceca or bacterial recovery of treated poults when compared with the positive control group.

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.

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.

Development of a novel malarial vaccine design: a hypothetical approach.

P. falciparum is highly virulent in nature because of its ability to modify the infected host red blood cells, adherence to the vascular endothelium and changes in antigenicity at different stages. Also slow migration time in the dermal and endothelial cells leads to decreased immune response. To overcome the problems, there is a need to design a vaccine which increases the migration time of the parasite, enhances the immune response, enables recognition of surface antigens and causes minimal clinical infection as a side-effect. An ITI-based (Infection-Treatment Immunization) vaccine development strategy is to be adopted to develop this novel vaccine. This will include administration of a liquid solution of purified, non-attenuated sporozoites from an infected female Anopheles mosquito, AS02A adjuvant and chlorate (a metabolic inhibitor of sulfation that decreases the extent of GAG sulfation). To control infection, a drug-cover of artemisinin will be administered as a part of the vaccination strategy along with a specific protease inhibitor MRT12113 which prevents RBC rupture and reinvasion by the parasite. This vaccine will intend to increase the overall migration time of the parasite in blood which is otherwise approximately 30 minutes, resulting in an overall enhanced immune response. It also intends to reduce parasite invasion in cells and their consequent rupture thus preventing the clinical condition-malaria.

Sulfonation pathway inhibitors block reactivation of latent HIV-1.

Long-lived pools of latently infected cells are a significant barrier to the development of a cure for HIV-1 infection. A better understanding of the mechanisms of reactivation from latency is needed to facilitate the development of novel therapies that address this problem. Here we show that chemical inhibitors of the sulfonation pathway prevent virus reactivation, both in latently infected J-Lat and U1 cell lines and in a primary human CD4+ T cell model of latency. In each of these models, sulfonation inhibitors decreased transcription initiation from the HIV-1 promoter. These inhibitors block transcription initiation at a step that lies downstream of nucleosome remodeling and affects RNA polymerase II recruitment to the viral promoter. These results suggest that the sulfonation pathway acts by a novel mechanism to regulate efficient virus transcription initiation during reactivation from latency, and further that augmentation of this pathway could be therapeutically useful.

Effects of repeated-low level sodium chlorate administration on ruminal and fecal coliforms in sheep.

Abstract The objective of this study was to evaluate the efficacy of oral sodium chlorate administration on reducing total coliform populations in ewes. A 30% sodium chlorate product or a sodium chloride placebo was administered to twelve lactating Dorper X Blackbelly or Pelibuey crossbred ewes averaging 65 kg body weight. The ewes were adapted to diet and management. Ewes were randomly assigned (4/treatment) to one of three treatments which were administered twice daily by oral gavage for five consecutive days: a control (TC) consisting of 3 g sodium chloride/animal/d, a T3 treatment consisting of 1.8 g of sodium chlorate/animal/d, and a T9 treatment consisting of 5.4 g sodium chlorate/animal/d; the latter was intended to approximate a lowest known effective dose. Ruminal samples collected by stomach tube and freshly voided fecal samples were collected daily beginning 3 days before treatment initiation and for 6 days thereafter. Contents were cultured quantitatively to enumerate total coliforms. There were no significant differences in total coliform numbers (log10 cfu/g) in the feces between treatments (P = 0.832). There were differences (P < 0.02) in ruminal coliform counts (log10 cfu/mL) between treatments (4.1, 4.3 and 5.0 log10/mL contents in TC, T3 and T9 Treatments, respectively) which tended to increase from the beginning of treatment until the 5th day of treatment (P < 0.05). Overall, we did not obtain the expected results with oral administration of sodium chloride at the applied doses. By comparing the trends in coliform populations in the rumen contents in all treatments, there was an increase over the days. The opposite trend occurred in the feces, due mainly to differences among rumen contents and feces in ewes administered the T9 treatment (P = 0.06). These results suggest that the low chlorate doses used here were suboptimal for the control of coliforms in the gastrointestinal tract of ewes.

Effect of intravenous or oral sodium chlorate administration on the fecal shedding of Escherichia coli in sheep.

The effect of gavage or intravenous (i.v.) administration of sodium chlorate salts on the fecal shedding of generic Escherichia coli in wether lambs was studied. To this end, 9 lambs (27 ± 2.5 kg) were administered 150 mg NaClO3/kg BW by gavage or i.v. infusion in a crossover design with saline-dosed controls. The crossover design allowed each animal to receive each treatment during 1 of 3 trial periods, resulting in 9 observations for each treatment. Immediately before and subsequent to dosing, jugular blood and rectal fecal samples were collected at 4, 8, 16, 24, and 36 h. Endpoints measured were fecal generic E. coli concentrations, blood packed cell volume (PCV), blood methemoglobin concentration, and serum and fecal sodium chlorate concentrations. Sodium chlorate had no effects (P > 0.05) on blood PVC or methemoglobin. Fecal generic E. coli concentrations were decreased (P < 0.05) approximately 2 log units (99%) relative to controls 16 and 24 h after sodium chlorate infusion and 24 h after sodium chlorate gavage. Within and across time and treatment, fecal chlorate concentrations were highly variable for both gavage and i.v. lambs. Average fecal sodium chlorate concentrations never exceeded 100 µg/g and were typically less than 60 µg/g from 4 to 24 h after dosing. Times of maximal average fecal sodium chlorate concentration did not correspond with times of lowered average generic E. coli concentrations. Within route of administration, serum sodium chlorate concentrations were greatest (P < 0.01) 4 h after dosing; at the same time point, serum chlorate was greater (P< 0.01) in i.v.-dosed lambs than gavaged lambs but not at 16 or 24 h (P > 0.05). At 8 h, serum chlorate concentrations of gavaged lambs were greater (P < 0.05) than in i.v.-dosed lambs. Serum chlorate data are consistent with earlier studies indicating very rapid transfer of orally dosed chlorate to systemic circulation, and fecal chlorate data are consistent with earlier data showing the excretion of low to marginal concentrations of sodium chlorate in orally dosed animals. Efficacy of sodium chlorate at reducing fecal E. coli concentrations after i.v. infusion suggests that low concentrations of chlorate in gastrointestinal contents, delivered by biliary excretion, intestinal cell sloughing, or simple diffusion, are effective at reducing fecal E. coli levels. Alternatively, chlorate could be eliciting systemic effects that influence fecal E. coli populations.

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.

Kinetics and disposition of orally dosed sodium chlorate in sheep.

Experiments were conducted in sheep to determine excretory characteristics of sodium chlorate after a single oral dose. In Exp. 1, lambs (n = 16; age = 8.1 ± 1.7 d; BW = 8.2 ± 1.1 kg; mean ± SD) were dosed orally with 0, 30, 60, or 90 mg/kg BW of sodium chlorate. Twenty-four hours after exposure chlorate residues were dose dependent (P < 0.05) in small intestinal contents, serum, and urine, but chlorate residues were not consistently detected in cecal or colonic contents. In Exp. 2, non-pregnant yearling ewes (BW = 74.8 ± 5.6 kg; mean ± SD) were orally dosed with 0, 150, 300, or 450 mg/kg BW of sodium chlorate. Across dose, chlorate residues averaged from 47 to 114, 0.6 to 4.5, and were not detectable to 0.2 µg/mL at 24, 48, and 72 h, respectively, in serum of treated animals; in feces, residues averaged 29 to 82, 0.8 to 14, and were not detectable to 1.2 µg/mL at the same respective time periods. In Exp. 3, six lactating ewes (BW = 76.3 ± 8.0 kg) were dosed orally with 450 mg/kg BW of sodium chlorate; residues were measured in serum, milk, urine and feces in periods encompassing 0 to 8, 8 to 16, 16 to 24, 24 to 32, 32 to 40, and 40 to 48 h. Chlorate residues in milk were detectable at all time periods with concentrations averaging from 287 ± 67 to 26 ± 13 µg/mL during the first and last collection periods, respectively. Urine contained the greatest concentration of chlorate at each time point and averaged 480 ± 268 µg/mL at 40 to 48 h. Depletion half-lives in serum, milk, urine, and feces were estimated to be 6.2, 27, 19, and 10 h, respectively; milk, urinary and fecal half-lives are likely overestimated due to the fact that 8-h sample pools were used in half-life estimations. In Exp. 4, three wethers (BW = 87.1 ± 5.3 kg) each were orally dosed with 14 or 42 mg/kg BW of sodium chlorate; blood samples were serially collected for 48 h, and urine samples were collected at 0 to 8, 8 to 16, 16 to 24, 24 to 36, and 36 to 48 h. Estimates of absorption and elimination half-lives based on serum chlorate concentrations were about 0.4 and 2.5 h, respectively. Urine collected during the 6 h immediately following dosing contained the greatest concentrations of chlorate residues relative to subsequent collection periods. Rapid removal of chlorate from the gastrointestinal lumen suggests that effects of chlorate on colonic and fecal gastrointestinal bacteria may occur through mechanisms other than direct luminal contact between microbe and chlorate salts.

Role of acidification elicited by sialylation and sulfation of zona glycoproteins during oocyte maturation in porcine sperm-zona pellucida interactions.

The porcine zona pellucida (ZP) undergoes biochemical changes during the final phase of maturation prior to fertilization. The present study was conducted to elucidate whether the acidification of ZP glycoproteins during porcine oocyte maturation influences sperm-ZP interactions. Two-dimensional gel electrophoresis clearly demonstrated that ZP acidification occurred in accordance with the sialylation and sulfation of ZP glycoproteins in oocytes matured for 44 h. The increases in the incidences of sperm penetration and polyspermy with the progress of the IVM culture period were significantly suppressed by ZP desialylation on treatment with neuraminidase as a consequence of reductions in the number of sperm bound to ZPs and the acrosome reaction (AR) in ZP-bound sperm (P<0.05). In contrast, the blocking of ZP sulfation by NaClO(3) treatment during IVM markedly reduced the incidence of polyspermy with no inhibitory effect on penetration, but the number of sperm bound to ZPs and the rate of AR-inducing sperm were decreased to the same level as in desialylated oocytes. The results indicate that ZP sulfation influences sperm-ZP interactions in a ZP sialylation-independent manner. Moreover, sialylation and sulfation were not associated with a protective proteolytic modification of the ZP matrix before fertilization. These findings suggest that ZP acidification elicited by the sialylation and sulfation of ZP glycoproteins during oocyte maturation contributes to the porcine ZP acquiring the capacity to accept sperm.

Chlorate analyses in matrices of animal origin.

Sodium chlorate is being developed as a potential food-safety tool for use in the livestock industry because of its effectiveness in decreasing concentrations of certain Gram-negative pathogens in the gastrointestinal tracts of food animals. A number of studies with sodium chlorate in animals have demonstrated that concentrations of chlorate in meat, milk, wastes, and gastrointestinal contents range from parts per billion to parts per thousand, depending upon chlorate dose, matrix, and time lapse after dosing. Although a number of analytical methods exist for chlorate salts, very few were developed for use in animal-derived matrices, and none have anticipated the range of chlorate concentrations that have been observed in animal wastes and products. To meet the analytical needs of this development work, LC-MS, ion chromatographic, and colorimetric methods were developed to measure chlorate residues in a variety of matrices. The LC-MS method utilizes a Cl(18)O(3)(-) internal standard, is applicable to a variety of matrices, and provides quantitative assessment of samples from 0.050 to 2.5 ppm. Due to ion suppression, matrix-matched standard curves are appropriate when using LC-MS to measure chlorate in animal-derived matrices. A colorimetric assay based on the acid-catalyzed oxidation of o-tolidine proved valuable for measuring ≥20 ppm quantities of chlorate in blood serum and milk, but not urine, samples. Ion chromatography was useful for measuring chlorate residues in urine and in feces when chlorate concentrations exceeded 100 ppm, but no effort was made to maximize ion chromatographic sensitivity. Collectively, these methods offer the utility of measuring chlorate in a variety of animal-derived matrices over a wide range of chlorate concentrations.

Continuous infusion of calcium gluconate in 5% albumin is safe and prevents most hypocalcemic reactions during therapeutic plasma exchange.

While therapeutic plasma exchanges (TPEs) performed with 5% albumin are considered safe, concerns regarding venous access and hypocalcemic toxicity remain. We reviewed the frequency of complications during TPEs performed with 5% albumin supplemented with calcium gluconate and potassium chloride for a 5 year period in our institution. Eighty-four adult patients (46 males and 38 females) underwent 581 plasma exchanges during the study period. The most common indications were myasthenia gravis (37%), acute inflammatory demyelinating polyradiculoneuropathy (31%), and chronic inflammatory demyelinating polyneuropathy (13%). All procedures used 2.2% ACD-A delivered at a calculated average rate of 0.26 mg/kg/min, which led to a mean dose of citrate per TPE of 2.18 +/- 0.48 g or 27.8 +/- 5.24 mg/kg of body weight. Venous access difficulties occurred in 85 procedures (14.6%), but most TPEs were completed successfully. Hypotension and citrate toxicity were seen in <5% of the TPEs and were mostly reversible. Only 17 exchanges (3%) had to be aborted because of the loss of venous access (n = 9), hypocalcemic toxicity (n = 3), hypotension (n = 2), panic attacks (n = 2), and one atypical reaction due to the interaction with an angiotensin converting enzyme inhibitor. Comparison between pre- and post-TPE potassium levels showed a statistically significant mean decrease of 7%, from 4.1 mequiv/l to 3.8 mequiv/l (P < 0.0001). We attribute the low rate of hypocalcemia to our practice of adding calcium and potassium to the replacement fluid and suggest that this method could become standard of care.

Pharmacokinetics of ruminally dosed sodium [36Cl]chlorate in beef cattle.

The recently recognized potential of sodium chlorate as a possible preharvest food safety tool for pathogen reduction in meat animals has spurred interest in the pharmacokinetics of intraruminally dosed chlorate. Six Loala cattle were assigned (one heifer and one steer per treatment) to one of three intraruminal doses of radiolabeled sodium [36Cl]chlorate (21, 42, or 63 mg/kg body weight) administered in four equal aliquots over a 24-h period. Blood and serum were collected (29 samples in 48 h). Total radioactive residues were measured and the radioactive moieties were speciated. Chlorate appeared rapidly in blood and serum after dosing. For animals administered a dose of 42 or 63 mg/kg, the half-life of absorption was estimated at 0.6-0.9 h. Serum chlorate concentrations progressively increased with aliquot administration until peaking at 6-21 parts per million at 26 h. Between aliquot administrations, serum chlorate levels typically peaked in 3.5 h or less. The half-life of chlorate elimination ranged between 6.9 and 11 h, depending on the dose. Ultimately, absorption of chlorate removes it from its desired site of action, the lower gastrointestinal tract, thereby reducing its efficacy. Further research is needed to develop a chlorate formulation that will allow passage to the lower gastrointestinal tract.

Total radioactive residues and residues of [36Cl]chlorate in market size broilers.

The oral administration of chlorate salts reduces the numbers of Gram-negative pathogens in gastrointestinal tracts of live food animals. Although the efficacy of chlorate salts has been demonstrated repeatedly, the technology cannot be introduced into commercial settings without first demonstrating that chlorate residues, and metabolites of chlorate remaining in edible tissues, represent a negligible risk to consumers. Typically, a first step in this risk assessment is to quantify the parent compound and to identify metabolites remaining in edible tissues of animals treated with the experimental compound. The objectives of this study were to determine the pathway(s) of chlorate metabolism in market broilers and to determine the magnitude of chlorate residues remaining in edible tissues. To this end, 12 broilers (6 weeks; 2.70+/-0.34 kg) were randomly assigned to three treatments of 7.4, 15.0, and 22.5 mM sodium [36Cl]chlorate dissolved in drinking water (n=4 broilers per treatment). Exposure to chlorate, dissolved in drinking water, occurred at 0 and 24 h (250 mL per exposure), feed was withdrawn at hour 38, water was removed at hour 48, and birds were slaughtered at hour 54 (16 h after feed removal and 8 h after water removal). The radioactivity was rapidly eliminated in excreta with 69-78% of the total administered radioactivity being excreted by slaughter. Total radioactive residues were proportional to dose in all edible tissues with chloride ion comprising greater than 98.5% of the radioactive residue for the tissue (9.4-97.8 ppm chlorate equivalents). Chlorate residues were typically greatest in the skin (0.33-0.82 ppm), gizzard (0.1-0.137 ppm), and dark muscle (0.05-0.14 ppm). Adipose, liver, and white muscle tissue contained chlorate concentrations from 0.03 to 0.13 ppm. In contrast, chlorate concentrations in excreta eliminated during the 6 h period prior to slaughter ranged from 53 to 71 ppm. Collectively, these data indicate that broilers rapidly convert chlorate residues to an innocuous metabolite, chloride ion, and that chlorate residues in excreta remain fairly high during the time around slaughter. Because the target tissue of chlorate is the lower gastrointestinal tract, the relatively high distribution of parent chlorate to inedible gastrointestinal tissues and low distribution to edible tissues is favorable for the biological activity and for food safety considerations. These data, when used in conjunction with a toxicological assessment of chlorate, can be used to determine a likely risk/benefit ratio for chlorate.

Effect of sodium [36Cl]chlorate dose on total radioactive residues and residues of parent chlorate in growing swine.

An experimental chlorate-based product has been shown to be efficacious in eliminating economically important, Gram-negative human pathogens in the gastrointestinal tracts of food animals. Prior to the commercial marketing of such a product, the magnitude and chemical nature of residues remaining in edible tissues must be determined. Thus, the objective of this study was to determine the tissue distribution and elimination of sodium [36Cl]chlorate in orally dosed swine. Three sets of pigs, each consisting of a barrow and a gilt, were orally dosed with a total of 20, 40, or 60 mg of sodium [36Cl]chlorate per kg body weight via the drinking water. Urine and feces were collected throughout the 30 h study. Twenty-four hours after the last exposure to [36Cl]chlorate, each pig was harvested and both edible and inedible tissues were collected. Urine and tissue samples were analyzed for total radioactive residues and for chlorate metabolites. Elimination of radioactivity in urine averaged 81.6, 83.7, and 83.9% of the total dose for the low, medium, and high doses, respectively. Fecal elimination of radioactivity averaged 1.1% of the dosed radiochlorine across all doses. Parent chlorate always represented greater than 97.4% of the urinary radiochlorine with the remaining radiochlorine being excreted as chloride ion. Chlorate represented 39-77% of fecal radioactivity, depending upon dose. Chlorate concentrations in edible tissues ranged from 0.01 to 0.49 ppm, with residues in liver and skeletal muscle generally lower than those in kidney and adipose tissue. Chlorate residues were concentrated in thyroid tissues (7.7-25.4 ppm) relative to edible tissues. No evidence for the presence of chlorite was observed in excreta or in tissues. Results of this study suggest that further development of chlorate as a preharvest food safety tool in swine merits consideration.

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.

Effect of sodium [36Cl]chlorate dose on total radioactive residues and residues of parent chlorate in beef cattle.

The objectives of this study were to determine total radioactive residues and chlorate residues in edible tissues of cattle administered at three levels of sodium [36Cl]chlorate over a 24-h period and slaughtered after a 24-h withdrawal period. Three sets of cattle, each consisting of a heifer and a steer, were intraruminally dosed with a total of 21, 42, or 63 mg of sodium [36Cl]chlorate/kg of body weight. To simulate a 24-h exposure, equal aliquots of the respective doses were administered to each animal at 0, 8, 16, and 24 h. Urine and feces were collected in 12-h increments for the duration of the 48-h study. At 24 h after the last chlorate exposure, cattle were slaughtered and edible tissues were collected. Urine and tissue samples were analyzed for total radioactive residues and for metabolites. Elimination of radioactivity in urine and feces equaled 20, 33, and 48% of the total dose for the low, medium, and high doses, respectively. Chlorate and chloride were the only radioactive chlorine species present in urine; the fraction of chlorate present as a percentage of the total urine radioactivity decreased with time regardless of the dose. Chloride was the major radioactive residue present in edible tissues, comprising over 98% of the tissue radioactivity for all animals. Chlorate concentrations in edible tissues ranged from nondetectable to an average of 0.41 ppm in skeletal muscle of the high-dosed animals. No evidence for the presence of chlorite was observed in any tissue. Results of this study suggest that further development of chlorate as a preharvest food safety tool merits consideration.

Tissue distribution, elimination, and metabolism of dietary sodium [36Cl]chlorate in beef cattle.

Two steers (approximately 195 kg) were each dosed with 62.5 or 130.6 mg/kg body weight sodium [36Cl]chlorate for three consecutive days. All excreta were collected during the dosing and 8 h withdrawal periods. The apparent radiochlorine absorption was 62-68% of the total dose with the major excretory route being urine. Parent chlorate was 65-100% of the urinary radiochlorine; chloride was the only other radiochlorine species present. Similarly, residues in edible tissues were composed of chloride and chlorate with chloride being the major radiolabeled species present. Chlorate represented 28-57% of the total radioactive residues in skeletal muscle; in liver, kidney, and adipose tissues, chlorate ion represented a smaller percentage of the total residues. Chlorate residues in the low dose steer were 26 ppm in kidney, 14 ppm in skeletal muscle, 2.0 ppm in adipose tissue, and 0.7 ppm in liver. These data indicate that sodium chlorate may be a viable preharvest food safety tool for use by the cattle industry.

Novel preharvest strategies involving the use of experimental chlorate preparations and nitro-based compounds to prevent colonization of food-producing animals by foodborne pathogens.

Foodborne diseases caused by enterohemorrhagic Escherichia coli, Salmonella, and Campylobacter species are of public health and economic significance. Shedding of these pathogens during production and slaughter are risks for contamination of products for human consumption. Consequently, strategies are sought to prevent or reduce the carriage of these pathogens in food animals before slaughter. Experimental products containing chlorate salts have been proven efficacious in reducing concentrations of E. coli and Salmonella Typhimurium in the gut of cattle, sheep, swine, and poultry when administered as feed or water additives. Mechanistically, chlorate selectively targets bacteria expressing respiratory nitrate reductase activity, such as most members of the family Enterobacteriaceae, as this enzyme catalyzes the reduction of chlorate to lethal chlorite. Most beneficial gut bacteria lack respiratory nitrate reductase activity, and thus the technology appears compatible with many bacteria exhibiting competitive exclusion capabilities. More recently, select nitrocompounds have been investigated as potential feed additives, and although these nitrocompounds significantly reduce pathogens on their own, evidence indicates that they may most effectively be used to complement the bactericidal activity of chlorate. A particularly attractive aspect of the nitrocompound technology is that, as potent inhibitors of ruminal methanogenesis, they may allow producers the opportunity to recoup costs associated with their use. At present, neither chlorate nor the nitrocompounds have been approved as feed additives by the US Food and Drug Administration, and consequently they are not yet available for commercial use.