CHLORATE POISONING - MECHANISM OF TOXICITY

Intoxications with chlorate salts are characterized by methaemoglobin formation, haemolysis and renal insufficiency. The toxic effects on th e erythrocyte can be reproduced in vitro. Incubation of human and rabb it erythrocytes with chlorates induces a concentration-dependent oxida tion of haemoglobin. This methaemoglobin formation is followed by dena turation of the globin, a cross-linking of erythrocyte membrane protei ns and an inactivation of membrane enzymes. The high sensitivity of gl ucose-6-phosphate dehydrogenase to denaturation by chlorate explains t he inefficacy of methylene blue to reduce methaemoglobin formed, as th e antidotal effect of methylene blue depends on NADPH formed mainly by the oxidation of glucose-6-phosphate. The observed changes occur only in the presence of methaemoglobin which forms a destabilising complex with chlorate. Methaemoglobin thus autocatalytically increases methae moglobin formation and destruction of the erythrocyte. As the rabbit i s known to have a high methaemoglobin-reduction capacity, human and ra bbit erythrocytes were compared. In vitro, the rabbit erythrocyte is l ess sensitive to oxidative attack than the human red cell. In vivo, an oral dose of sodium chlorate (1 g/kg body wt.) resulted in high serum (16 +/- 4 mM) and urine concentrations (246 +/- 99 mM) in the rabbit. Methaemoglobin was not formed nor could a nephrotoxic effect be obser ved. These experiments also indicate that the nephrotoxicity of chlora te is mediated by methaemoglobin catalysis.