William M Provan

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The elimination of radioactivity in two strains of rats and mice following a single po dose of trichloro[14C]ethylene at dose levels from 10 to 2000 mg/kg has shown a marked dose dependence in rats but not in mice. The metabolism of trichloroethylene in the mouse was linear over the range of doses used, whereas in the rat it became constant and independent(More)
AIMS NTBC (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) and mesotrione (2-(4-methylsulphonyl-2-nitrobenzoyl)-1,3-cyclohexanedione) are inhibitors of 4-hydroxyphenyl pyruvate dioxygenase (HPPD). NTBC has been successfully used as a treatment for hereditary tyrosinaemia type 1 (HT-1), while mesotrione has been developed as an herbicide. The(More)
The administration of the compound 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) to rats (10 mg/kg body wt) caused an elevation in the concentration of plasma tyrosine and gave products in urine that were identified as 4-hydroxyphenylpyruvate (HPPA) and 4-hydroxyphenyllactate (HPLA). This observed chemically induced tyrosinemia(More)
The synthetic beta-triketones are a novel family of chemicals, developed as herbicides that have activity on grass and broadleaf weeds and are selective in corn. Toxicological evaluation of a number of these chemicals has established that they interfere with rat hepatic tyrosine catabolism in vivo by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase(More)
NTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity(More)
The in vivo interaction of methylene chloride and its metabolites with F344 rat and B6C3F1 mouse lung and liver DNA was measured after inhalation exposure to 4000 ppm [14C]methylene chloride for 3 hr. DNA was isolated from the tissues 6, 12, and 24 hr after the start of exposure and analyzed for total radioactivity and the distribution of radioactivity(More)
Administration of a single oral dose of 2-(2-nitro-4-trifluoromethylbenzoyl)cyclohexane-1,3-dione (NTBC) to rats produced a marked tyrosinemia in the plasma and aqueous humor. The tyrosinemia was both time- and dose-dependent with the duration being more marked at the higher doses. The dose-response curve was very steep with a single dose of 1.5 micromol(More)
A physiologically based pharmacokinetic (PBPK) model capable of describing the metabolism of vinyl chloride (VC) in rats, mice, and humans has been developed and validated by comparison with experimental data from experiments not used in model development. This PBPK model has been used to predict measures of delivered dose (reactive VC metabolites produced(More)
1. Analysis of urine by (1)H-nuclear magnetic resonance (NMR) spectroscopy is used to detect biochemical disturbances predictive of toxicological changes. Recent studies, using (1)H-NMR spectroscopy have suggested that Alderley Park rats can be classified as hippuric acid (HA) or m-(hydroxyphenyl)propionic acid (m-HPPA) excretors. Evidence exists for the(More)
2-(2-Nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione (NTBC) is a potent inhibitor of rat liver 4-hydroxyphenylpyruvate dioxygenase (HPPD) leading to tyrosinemia and corneal opacity. We examined the effect of NTBC on the extent of tyrosinemia and production of corneal lesions in the beagle dog, rabbit and rhesus monkey, as part of safety evaluation on(More)