Urinary metabolites after human exposure

Bimer G, Vamvakas S, Dekant W, et al. 1993. Nephrotoxic and genotoxic N-acetyl-S-dichlorovinyl-L-cysteine is a urinary metabolite after occupational 1,1,2-trichloroethene exposure in humans Implications for the risk of trichloroethene exposure. Environ Health Perspect 99 281-284. 

No studies were located regarding excretion of 1,3,5-TNB after dermal exposure in humans. In the only study that evaluated 1,3-DNB urinary metabolites in humans after dermal exposure, amino and... 

Very little information is available about the nature of urinary metabolites of 1,3-DNB in humans. In a study that evaluated 1,3-DNB urinary metabolites after a single dermal exposure, amino and nitro metabolites were grouped together and reported as a single value relative to the level of 2,4-dinitrophenol as a standard (Ishihara et al. 1976). Amino and nitro metabolites may be derived from a variety of nitroaromatic compounds thus, they are not specific for 1,3-DNB. 

Xylenes are absorbed after inhalation and dermal exposure. Elimination after human exposure is rapid and mostly as urinary metabolites after oxidation to the methylbenzyl alcohols, methylbenzoic acids and their glycine and glucuronic acid conjugates. In mice inhaling /7 ra-xylene, methylhippurate accumulated in the nasal mucosa and olfactory bulb. 

Animal studies show that piperazine is readily absorbed from the gastrointestinal tract, excreted primarily in the urine with the peak plasma concentration reported Ih after dosing. Most of the parent compound is excreted unchanged during the first 48 h. N-Mononitrosopiperazine has been identified as the primary urinary metabolite. Limited human data indicate a similar toxicokinetic profile to animals. There are no data available on the toxicokinetics of piperazine following dermal or inhalation exposure. 

Aliphatic EC5-EC8 Fraction. Examination of urinary metabolites in humans and rats after exposure to /7-hexane indicates that hydrocarbons in this fraction may be oxidatively metabolized via cytochrome P-450 oxidases to several alcohol, ketone, and carboxylic acid derivatives. Based on... 

Following inhalation exposure to trichloroethylene in humans, the unmetabolized parent compound is exhaled, whereas its metabolites are primarily eliminated in the urine. Excretion of trichloroethylene in the bile apparently represents a minor pathway of elimination. Balance studies in humans have shown that following single or sequential daily exposures of 50-380 ppm trichloroethylene, 11% and 2% of the dose was eliminated unchanged and as trichloroethanol, respectively, in the lungs 58% was eliminated as urinary metabolites and approximately 30% was unaccounted for (Monster et al. 1976, 1979). Exhaled air contained notable concentrations of trichloroethylene 18 hours after exposure ended because of the relatively long half-life for elimination of trichloroethylene from the adipose tissue (i.e., 3.5-5 hours) compared to other tissues (Fernandez et al. 1977 Monster et al. 1979). 

Absorption, Distribution, Metabolism, and Excretion. There are no data available on the absorption, distribution, metabolism, or excretion of diisopropyl methylphosphonate in humans. Limited animal data suggest that diisopropyl methylphosphonate is absorbed following oral and dermal exposure. Fat tissues do not appear to concentrate diisopropyl methylphosphonate or its metabolites to any significant extent. Nearly complete metabolism of diisopropyl methylphosphonate can be inferred based on the identification and quantification of its urinary metabolites however, at high doses the metabolism of diisopropyl methylphosphonate appears to be saturated. Animal studies have indicated that the urine is the principal excretory route for removal of diisopropyl methylphosphonate after oral and dermal administration. Because in most of the animal toxicity studies administration of diisopropyl methylphosphonate is in food, a pharmacokinetic study with the compound in food would be especially useful. It could help determine if the metabolism of diisopropyl methylphosphonate becomes saturated when given in the diet and if the levels of saturation are similar to those that result in significant adverse effects. 

When male Wistar rats were exposed to -hexane at concentrations up to 3,074 ppm for 8 hours, analysis of urine showed that 2-hexanol was the major metabolite, accounting for about 60-70% of the total metabolites collected over the 48-hour collecting period (Fedtke and Bolt 1987). This is in contrast to humans, in which the major urinary metabolite is 2,5-hexanedione (Perbellini et al. 1981). The amounts of metabolites excreted were linearly dependent on the exposure concentration, up to an exposure of about 300 ppm. 2-Hexanol and 2-hexanone were detected in the first sample (obtained during the 8-hour exposure) excretion of 2,5-hexanedione was delayed and was not detected until 8-16 hours after exposure began. The amount of 2,5-hexanedione detected depended on sample treatment total excreted amounts over 48 hours were approximately 350 g/kg 2,5-hexanedione without acid treatment and 3,000 g/kg with total acid hydrolysis, indicating conversion of 4,5-dihydroxy-2-hexanone with acid treatment. 

Excretion. Some -hexane is exhaled following cessation of exposure. This could amount to approximately 10% of that absorbed (Mutti et al. 1984 Veulemans et al. 1982). Excretion is rapid and biphasic with half-lives of 0.2 hours and 1.7 hours. Most -hexane is excreted in the urine as metabolites. Radiolabeled 14C02 in exhaled air has been detected after animal exposure to l4C] -hexane (Bus et al. 1982), indicating that intermediary metabolism of some metabolites takes place. 2,5-Hexanedione and 4,5-dihydroxy-2-hexanone are the major urinary metabolites of -hexane in humans. Half-lives of excretion have been estimated to be 13-14 hours (Perbellini et al. 1981, 1986). 

No studies were located regarding excretion of bromomethane in humans after inhalation exposure. In animals exposed to bromomethane vapors, excretion occurs mainly by expiration of carbon dioxide or by urinary excretion of nonvolatile metabolites (Bond et al. 1985 Jaskot et al. 1988 Medinsky et al. 1985). Only small amounts are excreted in the feces. Very little parent bromomethane is exhaled (Jaskot et al. 1988 Medinsky et al. 1985), and tissue levels of parent bromomethane decrease with a half-life of only about 15-30 minutes (Honma et al. 1985 Jaskot et al. 1988). Half-lives for clearance of metabolites from the body and most tissues range from 2 to 10 hours (Honma et al. 1985 Jaskot et al. 1988). 

No studies were located regarding excretion in humans after oral exposure to 1,2-diphenylhydrazine. The identification of unchanged 1,2-diphenylhydrazine and metabolites in the urine following oral dosing of rats with 1,2-diphenylhydrazine (Dutkiewicz and Szymanska 1973) indicates that some urinary excretion occurs. 

There are limited data on the excretion of chlorobenzene. In humans exposed via the inhalation and oral routes, chlorobenzene and its metabolites were detected in urine and there were differences in excretion patterns via the two routes. Chlorobenzene and its metabolites were also detected in exhaled air of rats following inhalation and in exhaled air and urine in rabbits after oral exposure. The urinary metabolite profile appeared to be dose dependent and there were changes in excretion patterns due to multiple versus single exposures. No data on excretion following dermal exposure are available. Additional studies would be useful in determining the significance of these differences with regard to risk associated with different routes of exposure. 

White Phosphorus. No studies were located that specifically address white phosphorus excretion in humans after oral exposure However, two animal studies (Cameron and Patrick 1966 Lee et al. 1975) indicate rapid urinary and fecal excretion of white phosphorus, metabolites, or unabsorbed inorganic breakdown products. 

There have been studies of the metabolism of DEHP in humans after oral exposures as reflected by its urinary excretory products. In two volunteers exposed to 30 mg DEHP, metabolites I, II, III, IV, V, VI, VII, and VIII were identified in the urine by mass spectroscopy (Schmid and Schlatter 1985). MEHP accounted for 6-12% of the measured metabolites. Metabolite VI was approximately 20% of the excreted material, Metabolite IX approximately 30% and Metabolite V approximately 30%. The remaining metabolites were each less than 5% of the excreted material. Based on a comparison of the metabolites in the hydrolyzed urine as compared to the unhydrolyzed urine, approximately 65% of DEHP metabolites are excreted as glucuronide conjugates in humans. Each of these major metabolites is the product of oxidation of a different carbon in the 2-ethylhexyl substituent. 

Aliphatic EC5-EC8 Fraction. Studies with humans and animals exposed to rc-hexane suggest that hydrocarbons in this fraction, under low-exposure conditions, may be eliminated predominately as urinary metabolites and to a lesser extent in exhaled air as unchanged compound. Studies with rats indicate that the importance of exhalation of unchanged hexane as an elimination pathway increased from about 12% to 62% of body burden after inhalation exposure to 500 ppm and 10,000 ppm, respectively (ATSDR 1999b). 

Exhalation of CO and urinary excretion of metabolites (trichloroethanol and trichloroacetic acid) represent minor elimination pathways for inhaled 1,1,1-thchloroethane. Nevertheless, observed correlations between urinary concentrations of 1,1,1-trichloroethane metabolites and exposure concentrations indicate that urine analysis may be a useful method of exposure assessment (Caperos et al. 1982 Ghittori et al. 1987 Imbriani et al. 1988 Kawai et al. 1991 Seki et al. 1975). Estimated half-lives for the elimination of trichloroethanol and trichloroacetic acid from human blood after inhalation exposures to 1.1.1 -thchloroethane were 10-27 hours for trichloroethanol and 70-85 hours for trichloroacetic acid (Monster et al. 1979 Nolan et al. 1984). The long half- life of... 

Animal studies indicate that 2-butoxyacetic acid, the urinary metabolite found in humans, is also found in laboratory animals after inhalation exposure (Carpenter et al. 1956 Ghanayem et al. 1987a Jonsson and Steen 1978 Sabourin et al. 1992a). Twenty-seven female rats were exposed to 400 ppm ( 561 mg/d),... 

Analysis of Blood Samples. Urinary metabolites undergo relatively rapid elimination from the body, whereas blood components offer biomarkers that have the potential to be used for verification of sulfur mustard exposure long after the exposure incident. Three different approaches have been used for blood biomarker analysis. The intact macromolecule such as protein or DNA with the sulfur mustard adducts still attached can be analyzed. To date, this approach has only been demonstrated for hemoglobin using in vitro experiments. For proteins, an alternate approach is to enzymatically digest them to produce a smaller peptide with the sulfur mustard adduct still attached. Methods of this type have been developed for both hemoglobin and albumin. A third approach has been to cleave the sulfur mustard adduct from the macromolecule and analyze in a fashion similar to that used for free metabolites found in the urine. The later two approaches have both been successfully used to verify human exposure of sulfur mustard. 

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