Urinary levels of the acrolein conjugates of carnosine are associated with inhaled toxicants.

OBJECTIVE: The inhalation of air-borne toxicants is associated with adverse health outcomes which can be somewhat mitigated by enhancing endogenous anti-oxidant capacity. Carnosine is a naturally occurring dipeptide (ß-alanine-L-histidine), present in high abundance in skeletal and cardiac muscle. This multi-functional dipeptide has anti-oxidant properties, can buffer intracellular pH, chelate metals, and sequester aldehydes such as acrolein. Due to these chemical properties, carnosine may be protective against inhaled pollutants which can contain metals and aldehydes and can stimulate the generation of electrophiles in exposed tissues. Thus, assessment of carnosine levels, or levels of its acrolein conjugates (carnosine-propanal and carnosine-propanol) may inform on level of exposure and risk assessment. METHODS: We used established mass spectroscopy methods to measure levels of urinary carnosine (n = 605) and its conjugates with acrolein (n = 561) in a subset of participants in the Louisville Healthy Heart Study (mean age = 51 ± 10; 52% male). We then determined associations between these measures and air pollution exposure and smoking behavior using statistical modeling approaches. RESULTS: We found that higher levels of non-conjugated carnosine, carnosine-propanal, and carnosine-propanol were significantly associated with males (p < 0.02) and those of Caucasian ethnicity (p < 0.02). Levels of carnosine-propanol were significantly higher in never-smokers (p = 0.001) but lower in current smokers (p = 0.037). This conjugate also demonstrated a negative association with mean-daily particulate air pollution (PM2.5) levels (p = 0.01). CONCLUSIONS: These findings suggest that urinary levels of carnosine-propanol may inform as to risk from inhaled pollutants.

Assessment of the Role Played by N-propanol Found in Postmortem Blood in the Discrimination Between Antemortem Consumption and Postmortem Formation of Ethanol Using Rats.

This study disproves the reliability of n-propanol as a biomarker to establish whether the ethanol found in postmortem blood is derived from antemortem ingestion or postmortem putrefactive processes. Two groups of rats were given ethanol or normal saline solution, respectively, and sacrificed 1.5 h later. After putrefaction, blood and, in a few cases, urine samples from the rats were analyzed for ethanol and n-propanol by head-space gas chromatography equipped with flame ionization detection. Although the concentration ratios of ethanol/n-propanol in the postmortem blood collected from the bodies without prior alcohol consumption were expected to be <20 (as per limited case reports and previous in vitro studies), in samples from several rats that were on saline solution, this ratio was found to exceed 20. In conclusion, the concentration ratio of ethanol/n-propanol in postmortem blood does not allow for the discernment between antemortem ingestion and the postmortem synthesis of ethanol.

Relationship of inspired anesthetic concentration to plasma concentration and urinary excretion of sevoflurane metabolites in rats.

In patients, plasma concentrations of sevoflurane metabolites may be independent of inspired sevoflurane concentration over a defined dose range. In contrast, studies using rabbits have found that plasma concentrations and urinary excretion of fluoride ion are dose-dependent up to 3% inspired sevoflurane. We measured sevoflurane metabolite concentrations in adult male Sprague-Dawley rats and related them to inspired sevoflurane concentrations. When plasma concentrations and urinary excretion of metabolites were measured in vivo, they were dependent on inspired anesthetic concentration at concentrations less than 1.25%, but became less dose-dependent at higher anesthetic concentrations. Sevoflurane metabolism by precision-cut liver slices in vitro became dose-independent at more than 10-30 microM sevoflurane. No evidence of substrate inhibition was observed. These data provide evidence that sevoflurane metabolite concentrations are almost independent of inspired anesthetic concentration over at least part of the clinically used concentration range.

Occupational exposure to solvent mixtures: effects on health and metabolism.

Exposure monitoring by personal diffusive samplers, biological monitoring of toluene exposure by urinary hippuric acid determination, haematology, serum biochemistry for liver function, and a subjective symptom survey by questionnaire were conducted on 303 male solvent workers. They were exposed to a mixture of solvents including toluene (geometric mean 18 ppm), methyl ethyl ketone (MEK; 16 ppm), isopropyl alcohol (IPA; 7 ppm), and ethyl acetate (9 ppm). The intensity was mostly below unity using the additiveness formula based on current Japanese occupational exposure limits, but more than eight times unity at the maximum. The results were compared with the findings in 135 non-exposed male workers of similar ages. Haematology and liver function tests did not show any exposure related abnormality, and subjective symptoms were mostly related to central nervous system depression and local irritation. Further analysis suggested that the irritation effects were not related to exposure to MEK. Analysis of the relation between toluene exposure and hippuric acid excretion in urine showed that there was no metabolic interaction between MEK and toluene, or between IPA and toluene. Overall, therefore, it is concluded that there was no sign or symptom detected to suggest anything other than toluene toxicity, that there was no evidence to indicate any modification of toluene toxicity or metabolism due to coexposure, and that the additiveness assumption is reasonable for risk assessment for the combination of solvents under these exposure conditions.

Urinary excretion of hexafluoroisopropanol glucuronide and fluoride in patients after sevoflurane anaesthesia.

The excretion of sevoflurane metabolites in the urine collected every 12 h after sevoflurane anaesthesia was measured by ion exchange chromatography. A metabolite, which was converted on incubation with glucuronidase to hexafluoroisopropanol was detected in the urine. The maximum excretion was found in the first 12 h after anaesthesia, none was found in the last collection 3 days after anaesthesia. The excretion half-life for the metabolite was calculated to be 55 h. A significant increase in the urinary excretion of organic and inorganic fluoride was also observed during the first 12 h after anaesthesia. The cumulative organic and inorganic fluoride excretion in the 3 days after sevoflurane anaesthesia was 1588 and 856 mumol, respectively (ratio = 1.85). The excreted half-lives for organic and inorganic fluoride were calculated to be 4028 and 2069 min, respectively. Our study showed that a hexafluoroisopropanol glucuronide is excreted in the urine, and the major part of urinary metabolites of sevoflurane, organic and inorganic fluoride, are excreted within 2 days of sevoflurane inhalation in man.

Biological monitoring of occupational exposure to isopropyl alcohol vapor by urinalysis for acetone.

The relationship of the intensity of occupational vapor exposure to isopropyl alcohol (IPA) with urinary excretion of acetone and unmetabolized IPA was studied in 99 printers of both sexes, who were exposed to up to 66 ppm IPA (as time-weighted average), together with toluene, xylenes, methyl ethyl ketone and/or ethyl acetate. Acetone and IPA concentrations in urine were studied also in 34 non-exposed subjects. Acetone was detectable in the urine of most of the non-exposed, and the urinary acetone concentration increased in proportion to the IPA exposure intensity (r = 0.84 for observed, non-corrected values), whereas the correction for creatinine concentration or specific gravity of urine did not give a larger correlation coefficient. IPA itself was not found in the urine of the non-exposed, and was detectable in urine of only those who were exposed to IPA above a certain level, e.g. 5 ppm. The present study results suggest that urinary acetone is a valuable index for biological monitoring of occupational exposure to IPA as low as 70 ppm.

Isopropanol ingestion: case report with pharmacokinetic analysis.

An unusual case of acute isopropanol overdose which occurred within the confines of the emergency department is reported. Serial serum concentrations of isopropanol and its metabolite acetone were followed for 43 hours. Pharmacokinetic analysis is presented, as well as a brief literature review of diagnosis and management. CNS toxicity was related mainly to isopropanol concentrations. The calculated half-life of isopropanol was 7.3 hours. Because of the pharmacokinetic profile of isopropanol, management decisions regarding the use of hemodialysis should be made within one to two hours of patient presentation.

Isopropyl alcohol poisoning treated with hemodialysis: kinetics of isopropyl alcohol and acetone removal.

A comatose and hypotensive patient was successfully treated with hemodialysis after ingesting 480 mL of isopropyl alcohol. Removal of isopropyl alcohol and its major metabolite acetone was measured in urine, blood, and dialysate. According to dialysate measurements, approximately 19 g of isopropyl alcohol and 7 g of acetone were removed per hour using a standard 1 m2 dialyzer. The average dialysance of isopropyl alcohol and acetone were 137 and 165 mL/min, respectively. Removal of isopropyl alcohol was 52 times and acetone 40 times more efficient through hemodialysis than through urinary excretion. Since coma and hypotension portend a bad prognosis and since urinary excretion is slow relative to hemodialysis removal, hemodialysis may be considered life-saving in patients comatose from isopropyl alcohol poisoning. There have been two previous reports of hemodialysis used for treatment of isopropyl alcohol intoxication [1, 2]. Neither of these reports describes the kinetics of isopropyl alcohol removal. This paper reports a third patient treated with hemodialysis who afforded us the opportunity to study blood, urine, and dialysate levels of isopropyl alcohol and its chief metabolite, acetone. By utilizing these results a comparison was made of urine excretion to dialysis removal of these compounds to compare their respective efficacy. In addition, the estimated removal by dialysance calculations was compared to estimated removal by measurement of dialysate volumes and concentrations.

Studies on drug metabolism by use of isotopes. XXIV-Determination of 3-phenylpropyl carbamate metabolites using stable isotope labelling with deuterium or carbon-13.

Metabolism of 3-phenylproply carbamate was investigated by using a stable isotope tracer technique. 3-Phenylpropanol, 3-hydroxy-3-phenylpropanol, 3-hydroxy-3-phenylpropyl carbamate, 2,3-dihydroxy-3-phenylproply carbamate, benzoic acid and hippuric acid were identified as the rat urinary metabolites. Using the dilution analysis, the amounts of metabolites in urine and faeces in rat and man were determined. In rats, 2,3-dihydroxy-3-phenylproply carbamate and 3-phenylpropanol glucuronide were excreted into the urine as the major metabolites of this drug. On the other hand, in man, the major metabolite was hippuric acid and about 30% of the administered dose was excreted as hippuric acid in the 24 h urine. The tracer technique using a singly labelled drug with carbon-13 employed in the present study provided a reliable methods for the analysis of drug metabolites and was comparable with the tracer technique using a multilabelled drug with deuterium.

Children absorb tris-BP flame retardant from sleepwear: urine contains the mutagenic metabolite, 2,3-dibromopropanol.

The flame retardant, tris(2,3-dibromopropyl)phosphate (tris-BP), which is a mutagen and causes cancer and sterility in animals is absorbed from fabric by people. 2,3-Dibromopropanol, a metboloite of tris-BP and a mutagen itself, has been found in the urine samples of ten children who were wearing or who had worn tris-BP-treated sleepwear. Eight of these children were wearing well-washed sleepwear and the possibility of absorption of tris-BP from well-washed sleepwear discussed. 2,3-Dibromopropanol was not found in the urines of one child and one adult who had never worn tris-BP-treated garments.

Gas chromatographic-mass spectrometric study of volatile organic metabolites in urines of patients with diabetes mellitus.

Abnormally increased concentrations of the aliphatic alcohols ethanol, n-propanol, isobutanol, n-butanol and isopentanol and the ketones 4-heptanone and cyclohexanone in human urine reflect metabolic disorders related to diabetes mellitus. For the determination of these low-molecular-weight metabolites, the components are trapped on an absorbent, separated by gas chromatography and identified by mass spectrometry. After standardization of the adsorption and desorption techniques, the procedure is applicable for comparative studies and for screening.

Specific detection of volatile metabolites in urines of normal subjects and patients with diabetes mellitus using computerized mass fragmentography.

Volatile urinary components are analyzed by a combination of gas chromatography, mass spectrometry and a data-acquisition system. Mass fragmentograms using the mass spectrometric data on magnetic tape are recorded for the primary aliphatic alcohols ethanol, n-propanol, isobutanol and isopentanol and the ketones 4-hepatonone and cyclohexanone. The mass fragmentograms are used as selective profiles to facilitate recognition of abnormalities in the urinary components in cases of diabetes mellitus.