Amount Of Urinary Metabolites Research Articles

Toxicokinetic Modeling of Parathion and its Metabolites in Humans for the Determination of Biological Reference Values

A multi-compartment kinetic model was developed to describe the kinetics of parathion and its metabolites, p-nitrophenol (p-NP) and alkyl phosphates (AP), in order to assess worker exposure and health risks. Model compartments represent body burdens and excreta of parathion and its metabolites; to minimize the number of compartments and free parameters, regrouping was carried out on the basis of the time scales of the kinetic processes involved. Burden variations in time were described mathematically by differential equations that ensure conservation of mass on a mole basis. Model parameter values were determined from statistical fits to published in vivo kinetic data in humans. Except for the dermal absorption fraction and absorption rate, which are known to be subject to wide intra- and inter-individual variability, a single set of parameter values for the internal body kinetics enabled the model to simulate accurately the available kinetic data. For dermal exposure to parathion, with a typical absorption rate of 0.085 h−1, model simulations show that it takes 20 h to recover half of the total amounts of p-NP eventually excreted in urine and 30 h for the AP. The model can be used to estimate the dose of parathion absorbed under different exposure routes and temporal scenarios, based on measurements of amounts of metabolites accumulated in urine over given time periods. Using the above dose-excreta links and the human no-observed-effect level for parathion reported in the literature for the inhibition of cholinesterase activities, biological reference values are proposed in the form of specific amounts of urinary metabolites excreted over chosen time periods.

Subchronic dispositional and toxicological effects of arsenate administered in drinking water to mice.

Exposure to the drinking water contaminant arsenate is a daily occurrence and there are concerns that this exposure may lead to cancer. Although the acute dispositional effects of arsenate have been studied in detail, there is minimal information on the disposition and toxicological effects of it after continuous exposure. The objective of this study was to examine in mice the effect of a 4-wk treatment with arsenate administered in drinking water. Female B6C3F1 mice (3/cage) were housed in metabolism cages and given water and food ad libitum. Two groups (A, B) of mice were treated (4 cages/treatment/group) with distilled water (control, C) or water containing 0.025 mg/L (L) or 2.5 mg/L (H) arsenate. Group A was sacrificed on d 28 and plasma and urine samples were taken for determination of clinical chemistry parameters. Liver and kidney tissue samples were taken for histopathological analysis. The reduced nonprotein sulfhydryl (NPSH) content in several tissues was determined. Group B was gavaged with [73As]arsenate on d 28 and continued the arsenate drinking water exposure for 48 h. Excreta and tissues were collected and analyzed for 73As. Urine was further analyzed for arsenate and its metabolites. There were no effects on the mean daily amount of water and food consumed, whereas the mean daily urine volume excreted was significantly elevated by 10% in the H-treated animals compared to C and L. A dose-related hepatic vacuolar degeneration in the liver was observed, but no histological changes were evident in the kidney. Only clinical chemistry parameters in plasma were altered by the arsenate treatment. Glucose was significantly lower at the H dose compared to C and L, triglycerides were significantly greater in C than L and H, and creatinine was significantly greater in H than C. Hepatic NPSH content in the H animals was significantly lower than C and L animals, whereas no effects in lung and kidney were detected. The weights of liver, lung, and kidney, as well as their tissue/body weight ratios, were significantly decreased in the H animals. 73As was primarily eliminated in urine, and its elimination was not affected by dose. No effects on the 48-h 73As cumulative excretion (urine+fecal) were detected. The 73As distribution was low in amount and widely dispersed throughout the animal (< 3% of the 73As dose). The kidney had the highest 73As concentration of the tissues (0.01% 73As dose/g tissue). Dimethylarsinic acid was the major metabolite detected in urine, with lower amounts of arsenate arsenite, and monomethylarsonate. There were no differences between the treatment groups in the amount of urinary metabolites after a single dose of [73As]arsenate. Several toxicological effects were observed in animals administered arsenate in drinking water, but no changes in the disposition of this arsenical were detected at the doses used in this study.

Measurement of Vibratory Perception Threshold (VPT) in Workers Exposed to Organic Solvents

Vibratory perception threshold (VPT) of 437 workers exposed to organic solvents in various industries was measured using an automated device, Vibrometer TM-31A, at the medial malleolus of the right leg. There were statistically significant correlations between age and VPT ( r s = 0.378, P < 0.01) and job experience and VPT ( r s = 0.125, P < 0.01). Fifty-five out of 437 examinees showed abnormally higher VPT than the previously reported control values, suggesting an existence of potential neuropathy in these individuals. There was no significant correlation between the amount of urinary metabolites and VPT. Neither specific exposure-related subjective symptoms nor clinical neurological signs were found in any workers. The study also discusses the validity of and the future problems in measuring VPT in workers exposed to solvents.

Metabolic disposition of DQ-2556, a new cephalosporin, in rats, rabbits, dogs, and monkeys.

The metabolic disposition of DQ-2556 was studied in rats, rabbits, dogs, and monkeys after an intravenous administration of 20 mg of 14C-labeled drug per kg of body weight. The serum data were analyzed by the two-compartment open model. The mean half-lives for the drug in serum at excretion phase were 18.1, 54.4, 21.8, and 63.6 min in rats, rabbits, dogs, and monkeys, respectively. The volume of distribution and total body clearance ranged from 0.18 to 0.30 liter/kg and 0.065 to 0.45 liter/h/kg, respectively. This compound was distributed to the tissues rapidly and well, especially to the kidney, trachea, liver, thyroid, skin, and lung. Tissue concentrations declined rapidly in a few hours and then very slowly. However, no accumulation was observed in any tissues. The results of a protein-binding study by ultracentrifugation indicated that DQ-2556 was 20 to 30% bound to serum proteins in animals and its affinity was low. Almost 90% of the administered radioactivity was excreted into urine in all species. Biliary excretion in rats was 3.1% of the dose. Nearly 70% of the dose or more was excreted into urine as unchanged drug, and the amounts of urinary metabolites were small except in rabbits, in which substantial amounts of polar metabolites were detected.

Metabolism of benzaldehyde in New Zealand White rabbits

The quantitative metabolism of benzaldehyde (BENZ) has been investigated in male New Zealand White rabbits (3 rabbits/group). A single oral dose of this material was administered to two test groups (low-dose group: 0.35 g/kg/rabbit; high-dose group: 0.75 g/kg/rabbit) whereas water (0.75 g/Kg/rabbit) was given orally to the third group. Urine of all groups was collected daily for 15 consecutive days. Daily monitoring indicated the urinary excretion of the following metabolites: hippuric acid (HA), free (FBA) and conjugated benzoic acid (benzoylglucuronic acid: BGA), benzyl glucuronide (BG) and benzyl mercapturic acid (BMA). Although the total amount of urinary metabolites excreted by the low-dose group (83.2% of the total dose) was not significantly different from that excreted by the high-dose group (82.3% of the total dose), some metabolites showed differences in their urinary output: HA, 69.9% in the low-dose group vs. 66.7% in the high-dose group; BGA, 8.8% in the low-dose group vs. 11.2% in the high-dose group; BG, 2.9% in the low-dose group vs. 3.0% in the high-dose group; FBA, 1.6% in the low-dose group vs. 1.4% in the high-dose group. In both treated groups, BMA was present in trace amounts (< 0.01% of the total dose).

Metabolism of styrene in rats after administration of tetrachloromethane.

Urinary metabolites of styrene, i.e., mandelic acid, phenylglyoxylic acid and hippuric acid, were determined by high performance liquid chromato-graphy. Female Wistar rats were administered various amounts of styrene intraperitoneally, and the metabolites in the urine were determined at suitable intervals after the injection. The amounts of urinary mandelic and phenyl-glyoxylic acids were in proportion to the amount of administered styrene. The amount of urinary metabolites per body weight per hour reached a maximum level in the urine from the 10-24 hr period. In another experiment, tetrachlo-romethane was injected intramuscularly into rats prior to the administration of styrene. The amounts of urinary mandelic, phenylglyoxylic and hippuric acids in the tetrachloromethane-administered group were much less than those of the control group.

Pathogenesis of phenylketonuria: Inhibition of dopa and catecholamine synthesis in patients with phenylketonuria

Urinary excretion of dopamine, HVA, VMA and MHPG has been studied after oral administration of deuterated l-tyrosine in two patients with PKU, one patient with hyperphenylalaninemia and a normal control at low and high plasma phenylalanine levels by gas chromatography-mass spectrometry. The deuterium content served as an index for the formation of metabolites from the precursor. At a high phenylalanine level the excretion of dopa metabolites was low. When plasma phenylalanine was low a large increase in the amount of urinary metabolites was observed. From these studies it seemed that the tyrosine 3-hydroxylase activity in vivo and thus the formation of L-dopa and other biogenic amines depended on the phenylalanine concentration in plasma and also in tissues.