The possibilities and limitations of using mercapturic acids and protein and DNA adducts for the assessment of internal and effective doses of electrophilic chemicals are reviewed. Electrophilic chemicals may be considered as potential mutagens and/or carcinogens. Mercapturic acids and protein and DNA adducts are considered as selective biomarkers because they reflect the chemical structure of the parent compounds or the reactive electrophilic metabolites formed during biotransformation. In general, mercapturic acids are used for the assessment of recent exposure, whereas protein and DNA adducts are used for the assessment of semichronic or chronic exposure. 2-Hydroxyethyl mercapturic acid has been shown to be the urinary excretion product of five different reactive electrophilic intermediates. Classification of these electrophiles according to their acid-base properties might provide a tool to predict their preference to conjugate with either glutathione and proteins or with DNA. Constant relationships appear to exist in the cases of 1,2-dibromoethane and ethylene oxide between urinary mercapturic acid excretion and DNA and protein adduct concentrations. This suggests that mercapturic acids in some cases may also play a role as a biomarker of effective dose. It is concluded that simultaneous determination of mercapturic acids, protein and DNA adducts, and other metabolites can greatly increase our knowledge of the specific roles these biomarkers play in internal and effective dose assessment. If the relationship between exposure and effect is known, similar to protein and DNA adducts, mercapturic acids might also be helpful in (individual) health risk assessment.

A prospective study was performed in the Dutch flower bulb culture to investigate the possible effects of subchronic exposure to the soil fumigant 1,3-dichloropropene (DCP) on liver and kidney function and on glutathione conjugation capacity in blood. Urine spot samples and venous blood samples from 14 workers applying DCP (applicators) were taken at the start of the season in July, and after the season in October. The parameters of liver function measured were: alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, y-glutamyltranspeptidase, and total bilirubin (conjugated and unconjugated). Total bilirubin was significantly decreased from 9-5 before to 7-0 pmol/l after the season. In combination with an increase in serum y-glutamyltranspeptidase activity from 12-5 to 19 5 UlI this indicates moderate hepatic enzyme induction. To study renal function, creatinine and i2-microglobulin in serum, and f,-microglobulin, albumin, alanine aminopeptidase, f-galactosidase, and retinol binding protein in urine were measured. The glomerular func-R T H van Welie tion parameters albumin in urine and creatinine in serum changed significantly during the season: albumin concentration increased from 5-2 to 7-6 mg/l, whereas creatinine excretion decreased from 93-0 to 87 5 pmol/l. The tubular function parameter retinol binding protein also increased in concentration from 20-0 to 26-9 ug/l. Therefore, a subclinical nephrotoxic effect of subchronic exposure to DCP cannot be excluded. Effects on glutathione conjugation capacity were studied by measuring erythrocyte glutathione S-transferase activity and blood glutathione concentrations. The activity of glutathione S-transferase in erythrocytes was significantly decreased from 4-7 before to 3-3 UIg haemoglobin after the season. The same was true for the blood glutathione concentrations, which decreased from 0-93 to 0-82 mM. Both parameters seem to be affected by exposure to DCP.

Capillary gas chromatographic (GC) methods using sulphur and mass selective detection for the qualitative and quantitative determination of tetrahydrophtalimide (THPI) and 2-thiothiazolidine-4-carboxylic acid (TTCA), urinary metabolites of the fungicide captan in rat and humans, were developed. Urinary detection limits were 2.7 micrograms/l for THPI and 110 micrograms/l for TTCA. Intraperitoneal and oral administration of captan to rats resulted in a 48-h cumulative urinary excretion of THPI of 1%-2% and 3%-9% of the dose, respectively. Cumulative urinary excretion of TTCA over 48 h ranged from 2% to 5% of the captan dose for the respective routes of administration. In urine of non-exposed human subjects, neither THPI nor TTCA could be detected. In urine of fruit-growers who were occupationally exposed to captan, both THPI and TTCA could be detected. Based on these results, THPI and TTCA are proposed as promising parameters for the biological monitoring of occupational exposure to captan.

A biological monitoring study was carried out in the Dutch flower-bulb culture to determine the relationship between respiratory occupational exposure to Z- and E-1,3-dichloropropene (Z- and E-DCP) and urinary excretion of two mercapturic acid metabolites, N-acetyl-S-(Z- and E-3-chloropropenyl-2)-L- cysteine (Z- and E-DCP-MA). Urinary excretion of Z- and E-DCP-MA, either based on excretion rates or on creatinine excretion, followed first order elimination kinetics after exposure. Urinary half-lives of elimination were 5.0 +/- 1.2 hr for Z-DCP-MA and 4.7 +/- 1.3 hr for E-DCP-MA and were not statistically significantly different. Calculated coefficients of variation indicated that the half-lives of elimination of Z- and E-DCP-MA were quite consistent inter- and intra-individually. Strong correlations (r greater than or equal to 0.93) were observed between respiratory 8-hr time weighted average (TWA) exposure to Z- and E-DCP and complete cumulative urinary excretion of Z- and E-DCP-MA. Z-DCP yielded three times more mercapturic acid than E-DCP, probably due to differences in metabolism. Z- and E-DCP were excreted 45 and 14% as their respective mercapturic acid metabolites. A respiratory 8-hr TWA exposure to the Dutch occupational exposure limit of 5 mg.m-3 DCP would result in a complete cumulative excretion of 14.4 mg (95% confidence interval: 11.7-17.0 mg) Z-DCP-MA and 3.2 mg (95% confidence interval: 2.3-4.1 mg) E-DCP-MA.

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