Chlorine dioxide (ClOJ is currently used in many countries as a drinking water disinfectant. The chlorite ion (CIO, -1 is the primary degradation product of C102 when it is used to treat drinking water. In this study, sodium chlorite was administered daily by gavage to rats for 13 weeks at dose levels of 0, 10,25, or 80 mg/kg/day . At the conclusion of the study, all surviving animals were killed and subjected to a gross necropsy. Hematology, blood chemistry evaluations and urinalysis were performed. At 80 mg/kg/day , there were several treatment-related deaths and morphological changes in erythrocytes were observed. Mean erythrocyte count was decreased in both sexes. In males, hematocrit and hemoglobin levels were decreased and methemoglobin levels were increased. Splenic extrameduilary hemopoiesis was observed in some animals at 80 mg/kg/day. At 25 mg/kg/day, methemoglobin was increased in males. No adverse toxicological effects were noted at 10 mg/kg/day.
The mechanism of inhibition of HCO3 transport by parathyroid hormone (PTH) in the proximal tubule is not clearly defined. Previous studies in vitro have suggested that this effect is mediated via cAMP generation, which acts to inhibit Na/H exchange, resulting in cell acidification. To examine this question in vivo, intracellular pH (pH). was measured in the superficial proximal tubule of the rat using the pH-sensitive fluoroprobes 4-methylumbelliferone (4MU) and 2',7'-bis(carboxyethyl)-(5, and 6)-carboxyfluorescein (BCECF). PITH was found to alkalinize the cell. This alkalinization suggested inhibition of basolateral base exit, which was confirmed by in situ microperfusion studies: lowering HCO3 in peritubular capillaries acidified the cell, an effect blunted by PTH. Removal of luminal Na promoted basolateral base entry, alkalinizing the cell. This response was also blunted by PTH. Readdition of luminal Na stimulated the luminal Na/H exchanger, causing an alkalinization overshoot that was partially inhibited by PTH. cAMP inhibited luminal H secretion but did not alkalinize the cell. Stimulation of phosphatidylinositol-bis-phosphate turnover by PTH was suggested by the effect to the hormone to increase cell Ca. Blocking the PTH-induced rise in cell Ca blunted the effect of the hormone to alkalinize the cell, as did inhibition of phosphatidylinositol breakdown. Furthermore, stimulation of protein kinase C by a phorbol ester and a diacylglycerol applied basolaterally alkalinized the cell and inhibited luminal H secretion. The findings indicate that both arms of the phosphatidylinositol-bis-phosphate cascade play a role in mediating the effect of PlTH on the cell pH. The results are consistent with the view that PTH inhibits base exit in the proximal tubule by activation of the phosphatidylinositol cascade. The resulting alkalinization may contribute, with cAMP, to inhibit apical Na/H exchange and the PTH-induced depression of proximal
Toxicological studies dealing with recent findings of health effects of drinking water disinfectants are reviewed. Experiments with monkeys and rodents indicate that the biological activity of ingested disinfectants is expressed via their chemical interaction with the mucosal epithelia, secretory products, and nutritional contents of the alimentary tract. Evidence exists that a principal partner of this redox interaction is the iodide of nutritional origin that is ubiquitous in the gastrointestinal tract. Thus the observation that subchronic exposure to chlorine dioxide (ClO2) in drinking water decreases serum thyroxine levels in mammalian species can be best explained with changes produced in the chemical form of the bioavailable iodide. Ongoing and previously reported mechanistic studies indicate that oxidizing agents such as chlorine-based disinfectants oxidize the basal iodide content of the gastrointestinal tract. The resulting reactive iodine species readily attaches to organic matter by covalent bonding. Evidence suggests that the extent to which such iodinated organics are formed is proportional to the magnitude of the electromotive force and stoichiometry of the redox couple between iodide and the disinfectant. Because the extent of thyroid uptake of the bioavailable iodide does not decrease during ClO2 ingestion, it seems that ClO2 does not cause iodide deficiency of sufficient magnitude to account for the decrease in hormonogenesis. Absorption of one or more of iodinated molecules, e.g., nutrients, hormones, or cellular constituents of the alimentary tract having thyromimetic or thyroid inhibitory properties, is a better hypothesis for the effects seen.ImagesFIGURE 1. aFIGURE 1. bFIGURE 1. c
Chloride dioxide (CIO,) is currently used in many countries as a drinking water disinfectant. Chlorite ion (ClO,-) is the primary degradation product of C10, when it is used to treat drinking water. In this study, mated female New Zealand white rabbits received either 0, 200, 600, or 1,200 ppm NaC10, in their drinking water from Day 7 to Day 19 of pregnancy, inclusive, and were necropsied on Day 28 of pregnancy. Weight of the gravid uterus, number of corpora lutea, implantation sites, and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for external, visceral, and skeletal abnormalities. Maternal food and water consumption were decreased at 600 and 1,200 ppm, however, no treatment-related maternal abnormalities were observed at necropsy. As expected in the presence of maternal effects, mean fetal weights were slightly lower at 600 and 1,200 ppm, with a slightly higher incidence of incomplete ossification of some bones. There were no treatment-related fetal structural abnormalities. Pre-and postimplantation losses were within expected ranges and other reproductive parameters were similar in all groups. At 200 ppm, there were no maternal or fetal effects. NaClO, was not considered to be teratogenic or a selective developmental toxicant.
In the proximal convoluted tubule (PT), the HCO3 reabsorptive rate is higher in early (EPS) compared with late proximal segments (LPS). To examine the mechanism of this HCO3 reabsorption profile, intracellular pH (pH) was measured along the superficial PT of the rat under free-flow and stationary microperfusion using the pH-sensitive fluorescence of 4-methylumbelliferone (4MU). With 4MU superfusion, pH1 was found to decline along the PT. Observation with 365-nm excitation revealed that EPS were brightly fluorescent and always emerged away from their star vessel. Midproximal segments were darker and closer to the star vessel which was surrounded by the darkest LPS. Decreasing luminal HCO3 from 15 to 0 mM lowered pH, in both EPS and LPS, but pH, remained more alkaline in EPS with both perfusates. Thus the axial decline in pH, along the PT is due to both luminal factors and intrinsic differences in luminal H+ extrusion in PT cells.
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