Urine of rats dosed with styrene (240 mg/kg), R-, S- and racemic styrene oxide (150 mg/kg) was analysed for mandelic acid enantiomers and for regioisomers and diastereomers of mercapturic acids by NMR spectrometry. ... R- and S-styrene oxide yielded predominantly R- and S-mandelic acid, respectively, racemic styrene oxide gave predominantly the R-enantiomer whereas styrene yielded almost racemic mandelate. The regioselectivity of mercapturic acid formation was very similar for styrene, R- and S-styrene oxide. These three species yielded a 2:1 mixture of N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine (MA1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)cysteine (MA2). R-Styrene oxide gave higher conversion to mercapturic acids (28%) than the S-isomer (19% of the dose). However, R-styrene oxide yielded stereospecifically S,R-MA1 and R,R-MA2 whereas S-styrene oxide gave R,R-MA1 and S,R-MA2. Styrene yielded a mixture of diastereomeric mercapturic acids. The ratios of R,R-/S,R-isomers were 80:20 and 15:85 for MA1 and MA2, respectively. These data suggest that styrene is metabolized stereoselectively to S-styrene oxide as a major enantiomer in rat in vivo. This enantiomer has been reported to be less mutagenic than R-styrene oxide in vitro.
The major metabolic route for styrene in rats, mice, and humans involves conversion to styrene-7,8-oxide (SO). The purpose of this study was to evaluate blood SO, SO-hemoglobin (SO-Hb) adducts, and urinary metabolites in styrene-exposed human volunteers and to compare these results with data previously obtained for rodents. Four healthy male volunteers were exposed for 2 hr during light physical exercise to 50 ppm (13)C(8)-styrene vapor via a face mask. Levels and time profiles of styrene in exhaled air, blood, and urine (analyzed by GC) and urinary excretion patterns of mandelic acid and phenylglyoxylic acid in urine (analyzed by HPLC) were comparable to previously published volunteer studies. Maximum levels of SO in blood (measured by GC-MS) of 2.5-12.2 (average 6.7) nM were seen after 2 hr, i.e., in the first sample collected after exposure had ended. The styrene blood level in humans was about 1.5 to 2 times higher than in rats and 4 times higher than in mice for equivalent styrene exposures. In contrast the SO levels in human blood was approximately fourfold lower than in mice. The level of hydroxyphenethylvaline (determined by GC-MS-MS) in pooled blood collected after exposure was estimated as 0.3 pmol/g globin corresponding to a SO-Hb adduct increment of about 0.003 pmol/g and ppm hr. NMR analyses of urine showed that a major portion (> 95%) of the excreted (13)C-derived metabolites was derived from hydrolysis of SO, while only a small percentage of the excreted metabolites (< 5%) was derived from metabolism via phenylacetaldehyde. Signals consistent with metabolites derived from other pathways of styrene metabolism in rodents (such as glutathione conjugation with SO or ring epoxidation) were not detected.
来源:Hazardous Substances Data Bank (HSDB)
代谢
STyrene-7,8-oxide (SO) 负担在雄性 Sprague-Dawley 大鼠的孤立肺和雄性 B6C3F1 小鼠的原位制备肺中被调查。 ... STyrene (ST) 暴露范围从 50 到 980 ppm(大鼠)和从 40 到 410 ppm(小鼠)。从流出灌注液中定量 SO。两种物种的肺都将 ST 代谢为 SO。将离体数据数学转换为体内发生的通气和灌注条件后,进行了物种比较。在 ST 浓度达到 410 ppm 的情况下,小鼠肺中的平均 SO 水平达到 0.45 nmol/g 肺,在相同条件的 ST 暴露下,比大鼠肺高出约 2 倍。 ... SO 的肺负担的物种差异被认为太小,不足以解释为什么只有小鼠在暴露于 ST 时会发展肺肿瘤的遗传毒性。
The styrene-7,8-oxide (SO) burden in isolated lungs of male Sprague-Dawley rats and in-situ prepared lungs of male B6C3F1 mice ... /were investigated/. ... Styrene (ST) exposures ranged from 50 to 980 ppm (rats) and from 40 to 410 ppm (mice). SO was quantified from the effluent perfusate. Lungs of both species metabolized ST to SO. After a mathematical translation of the ex-vivo data to ventilation and perfusion conditions as they are occurring in vivo, a species comparison was carried out. At ST concentrations of up to 410 ppm, mean SO levels in mouse lungs ranged up to 0.45 nmol/g lung, about 2 times higher than in rat lungs at equal conditions of ST exposure. ... The species difference in the SO lung burden /appeared/ too small to consider the genotoxicity of SO as sufficient for explaining the fact that only mice developed lung tumors when exposed to ST. ...
... Understanding the relationship of the metabolism of styrene to its toxicity depends upon knowing the balance between the bioactivation of styrene to the epoxide by cytochromes P-450 and the detoxication of the oxide to the glycol by microsomal epoxide hydrolase. When hepatic and pulmonary microsomal preparations from non-Swiss albino (NSA) and Swiss (CD-1) mice were compared for their abilities to metabolize racemic, S- and R-styrene oxide to styrene glycol, enzymic activities were higher in liver than in lung. R-Styrene glycol formation was favored with racemic styrene oxide as the substrate. Only minor strain differences were found that could not account for the differences in reported susceptibility to styrene-induced toxicity. While the oxidation of styrene to styrene oxide was similar in male and female NSA mice, male hepatic microsomes were more active in the metabolism of the oxide to the glycol. Hepatic metabolism of styrene oxide to styrene glycol was inducible by butylated hydroxyanisole, whereas pulmonary metabolism was not. The data indicate that strain differences in susceptibility cannot be accounted for by this detoxication step, and there are sex differences in this reaction.
Evaluation: There is inadequate evidence in humans for the carcinogenicity of styrene-7,8-oxide. There is sufficient evidence in experimental animals for the carcinogenicity of styrene-7,8-oxide. Overall evaluation: Styrene-7,8-oxide is probably carcinogenic to humans (Group 2A).
IARC Monographs:Volume Sup 7: Overall Evaluations of Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42, 1987; 440 pages; ISBN 92-832-1411-0 (out of print)
Volume 60: (1994) Some Industrial Chemicals
Volume 121: (2019) Styrene, Styrene-7,8-oxide, and Quinoline
来源:International Agency for Research on Cancer (IARC)
Rodent species show marked differences in the distribution and regional density of Clara cells within the respiratory tract, as well as in their capacity to produce and eliminate styrene 7,8-oxide (SO)SO. A mode of action-based physiologically based pharmacokinetic (PBPK) model was developed to predict the concentration of ST and SO in blood, liver, and the respiratory-tract tissues, particularly in terminal bronchioles (target tisue), in order to conduct interspecies extrapolations and determine the extent to which there is a pharmacokinetic basis for the observed species specificity. This PBPK model has a multicompartment description of the respiratory tract and incorporates species-specific quantitative information on respiratory-tract physiology, cellular composition, and metabolic capacity. The model is validated against multiple data sets, including blood, liver, and whole lung tissue concentration of styrene (ST) and SO following multiple routes of exposure. The trend in neoplastic incidences in mice correlated well with model-estimated SO concentration in the terminal bronchioles. The PBPK model predicts a 10-fold lower SO concentration in the terminal bronchioles in rats compared to mice, which is consistent with the observed species sensitivity to the development of respiratory-tract neoplasms. The model-based analysis suggests that humans would be expected to be 100-fold less sensitive to ST-inducted lung tumors than mice, based on pharmacokinetic differences. Pharmacodynamic factors are also expected to contribute to species sensitivity, potentially augmenting pharmacokinetics-based differences.
When male rats were injected ip with 460 umol of styrene oxide with radioactive label, liver, brain, kidney, and duodenal contents of styrene oxide were higher than that in blood, lungs, and spinal cord, while ... /amount/ in CNS was small. Removal of injected compound was slow, between 3 and 6 hr after injection ... .
MAIN ROUTE OF EXCRETION OF STYRENE OXIDE METABOLITES IN ANIMALS IS BY WAY OF KIDNEY; IN RABBITS, ABOUT 80% OF SINGLE ORAL DOSE WAS EXCRETED IN URINE. ... /WHEN/ ... INJECTED IP OR INCUBATED IN VITRO /IT/ BINDS COVALENTLY TO MICROSOMES, PROTEIN & NUCLEIC ACID FRACTIONS OF RAT LIVER.