Comparative Toxicokinetics of Chlorinated and Brominated Haloacetates in F344 Rats

Schultz, Irvin R.; Merdink, James L.; González-León, Alberto; Bull, Richard J.

doi:10.1006/taap.1999.8698

Cited by 43 publications

(52 citation statements)

References 50 publications

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“…The maximum blood concentration of dibromoacetate in F344 rats was reached in one hr after administration by gavage (Schultz et al, 1999). The major metabolites identified in the urine and blood of F344 rats or B6C3F 1 mice administered DCA are glyoxylate, glycolate, and oxalate (Lin et al, 1993;Narayanan et al, 1999).…”

Section: Introductionmentioning

confidence: 93%

Toxicity and carcinogenicity of the water disinfection byproduct, dibromoacetic acid, in rats and mice

et al. 2007

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Dibromoacetic acid (DBA) is a water disinfection byproduct formed by the reaction of chlorine oxidizing compounds with natural organic matter in water containing bromide. Male and female F344/N rats and B6C3F 1 mice were exposed to DBA in drinking water for 2 weeks (N=5), 3 months (N=10), or 2 years (N=50). Concentrations of DBA in drinking water were 0, 125, 250, 500, 1,000, and 2,000 mg/L in the 2-week and 3-month studies, and 0, 50, 500, and 1,000 mg/L in the 2-year studies. Toxic effects of DBA in the prechronic studies were detected in the liver (hepatocellular cytoplasmic vacuolization in rats and mice) and testes (delayed spermiation and atypical residual bodies in male rats and mice, and atrophy of the germinal epithelium in rats). In the 2-year studies, neoplasms were induced at multiple sites in rats and mice exposed to DBA; these included mononuclear cell leukemia and abdominal cavity mesothliomas in rats, and neoplasms of the liver (hepatocellular adenoma or carcinoma and hepatoblastoma) and lung (alveolar adenoma or carcinoma) in mice. The increase in incidence of hepatocellular neoplasms in male mice was significant even at the lowest exposure concentration of 50 mg/L, which is equivalent to an average daily dose of approximately 5 mg/kg. These studies provide critical information for future reevaluations of health-based drinking water standards for haloacetic acids.

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Section: Introductionmentioning

confidence: 93%

Toxicity and carcinogenicity of the water disinfection byproduct, dibromoacetic acid, in rats and mice

et al. 2007

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“…Researchers at the Battelle Pacific Northwest National Laboratory have discovered that biotransformation and urinary clearance of the HAAs (acetates) is influenced by the number and type of halogen substituents (51). They have also discovered that bromochloroacetic acid-the only chiral HAA-exhibits pronounced stereospecific pharmacokinetics in both rat liver and in human liver cytosol (52).…”

Section: New Toxicity Studiesmentioning

confidence: 99%

Peer Reviewed: Disinfection Byproducts: The Next Generation

Richardson

Simmons²,

Rice³

2002

Environ. Sci. Technol.

122

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“…37 As a result, DCA is not eliminated through biliary secretion and is unlikely to go through extensive enterohepatic recirculation. 38 Another evidence for DCA not undergoing enterohepatic recirculation is that the second peak is absent when DCA was administered intravenously, 15 which should persistently exist if the underlying mechanism responsible for the second peak phenomena is enterohepatic recirculation. Variable gastric emptying is also not likely the cause because the fasting or fed condition, which would influence gastric-emptying rate, does not affect the appearance of the second peak.…”

Section: Discussionmentioning

confidence: 99%

A Mechanism-Based Pharmacokinetic Enzyme Turnover Model for Dichloroacetic Acid Autoinhibition in Rats

Jiang

Milavetz

James

et al. 2017

Journal of Pharmaceutical Sciences

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Dichloroacetic acid (DCA), a halogenated organic acid, is a pyruvate dehydrogenase kinase inhibitor that has been used to treat congenital or acquired lactic acidosis and is currently in early-phase clinical trials for cancer treatment. DCA was found to inhibit its own metabolism by irreversibly inactivating glutathione transferase zeta 1 (GSTZ1-1), resulting in nonlinear kinetics and abnormally high accumulation ratio after repeated dosing. In this analysis, a semi-mechanistic pharmacokinetic enzyme turnover model was developed for the first time to capture DCA autoinhibition, gastrointestinal region–dependent absorption, and time-dependent change in bioavailability in rats. The maximum rate constant for DCAinduced GSTZ1-1 inactivation is estimated to be 0.96/h, which is 110 times that of the rate constant for GSTZ1-1 natural degradation (0.00875/h). The model-predicted DCA concentration that corresponds to 50% of maximum enzyme inhibition (EC50) is 4.32 mg/L. The constructed pharmacokinetic enzyme turnover model, when applied to human data, could be used to predict the accumulation of DCA after repeated oral dosing, guide selection of dosing regimens in clinical studies, and facilitate clinical development of DCA.

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Comparative Toxicokinetics of Chlorinated and Brominated Haloacetates in F344 Rats

Cited by 43 publications

References 50 publications

Toxicity and carcinogenicity of the water disinfection byproduct, dibromoacetic acid, in rats and mice

Toxicity and carcinogenicity of the water disinfection byproduct, dibromoacetic acid, in rats and mice

Peer Reviewed: Disinfection Byproducts: The Next Generation

A Mechanism-Based Pharmacokinetic Enzyme Turnover Model for Dichloroacetic Acid Autoinhibition in Rats

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