Stereochemical metabolism of styrene in volunteers.
OBJECTIVE
To study the stereochemistry of styrene metabolism in volunteers, and its interindividual variability.


METHODS
Twenty healthy male volunteers (aged 18-37 years) were exposed to 360 mg/m3 styrene for 1 h while they performed 50 W physical exercise. Venous blood was drawn during and for up to 2 h after exposure. Urine was collected at time-intervals up to 24 h after exposure. The following parameters were determined: styrene, free and conjugated styrene glycol (SG) in blood, and conjugated SG, mandelic acid (MA) and phenylglyoxylic acid (PGA) in urine.


RESULTS
Average pulmonary retention of styrene was 62%. Excretion of the acidic metabolites MA and PGA accounted for 58% of the pulmonary uptake. The average maximum concentration (Cmax) and area under the curve (AUC) of free (R)-SG in blood were 1.3 and 1.7 times higher than those of (S)-SG respectively; the half-life of (R)-SG was longer (82 vs 62 min, P < 0.005). Cmax and AUC of the conjugated SG enantiomers in blood did not differ, but again half-life for (R)-SG was longer (72 vs 64 min, P < 0.05). Cumulative excretion and renal clearance of conjugated (S)-SG in urine were three and four times higher, respectively, than that of (R)-SG. Cumulative excretion of (S)-MA was 1.6 times higher than (R)-MA. Interindividual differences in the kinetic parameters of the metabolites were two- to threefold.


CONCLUSIONS
The enantiomeric excess found was different for each metabolite under study, implying different enantioselectivity and/or enantiospecificity of the enzymes and carrier-proteins involved in the biotransformation and excretion. The use of these metabolites as biological indicators for prediction of the enantiomeric excess of the toxic metabolite styrene-7,8-oxide (SO) is therefore not justified. Interindividual differences in the stereochemical metabolism of styrene are moderate.
Wenker
M A
MA
Coronel Institute, Academic Medical Center, University of Amsterdam, The Netherlands. mira.wenker@notox.nl
Kezić
S
S
Monster
A C
AC
de Wolff
F A
FA
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D015415:Biomarkers; D004781:Environmental Exposure / Q000032:analysis*; D015444:Exercise; D006038:Glyoxylates / Q000652:urine; D006207:Half-Life; D006801:Humans; D008297:Male; D008333:Mandelic Acids / Q000652:urine; D012016:Reference Values; D013237:Stereoisomerism; D020058:Styrene / Q000378:metabolism / Q000493:pharmacokinetics*
D015415:Biomarkers; D006038:Glyoxylates; D008333:Mandelic Acids; C012482:phenylglyoxylic acid; D020058:Styrene; C037938:mandelic acid