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PubMed1990

Analysis of styrene oxide-globin adducts based upon reaction with Raney nickel.

A new method has been developed for determination of styrene oxide-globin adducts. The technique takes advantage of the reaction between alkylated globin and Raney nickel, which cleaves the carbon-sulfur bond in the styrene oxide-cysteine adduct to form 1-phenylethanol (1-PE) and 2-phenylethanol (2-PE). These alcohols are then reacted with pentafluorobenzoyl chloride and analyzed by GC-ECD. The method appears useful for biological monitoring of individuals exposed to styrene and, potentially, to other chemicals or their electrophilic metabolites which can react with cysteine residues in available proteins. The detection limit of the method, which is 0.04 nmol adducts/sample, indicates that it should be possible to detect adducts in the blood of people who are occupationally exposed to at least 18 mg/m3 of styrene. Analysis of globin from human whole blood which had been modified with [14C]styrene oxide indicated that 6% of the total globin adducts were detected. The method was applied to human and rat blood which had been treated with styrene oxide in vitro and to blood from rats given a single i.p. dose of styrene in vivo. Results from these experiments indicate that 77 times more adducts were detected at a given dose from rat globin than from human globin and that only 0.015% of the styrene dose was bioavailable as styrene oxide in the blood of rats. The reaction with Raney nickel is conducted at 5 degrees C to minimize unfavorable side reactions, such as degradation of 1- and 2-PE and conversion of styrene glycol to 1- and 2-PE. The optimal amount of Raney nickel was found to be 5-6 g/g globin. Since the recovery of 1-PE was not reproducible, only 2-PE is used for quantitation.

Animals↗
PubMed2006

Cloning and functional characterization of the styE gene, involved in styrene transport in Pseudomonas putida CA-3.

A 1.5-kb region immediately downstream of the styABCD operon involved in styrene degradation in Pseudomonas putida CA-3 has been cloned. Sequence analysis revealed a 1,296-bp open reading frame, designated styE, and BLAST P database comparisons of the deduced StyE amino acid sequence revealed 33 to 98% identity with several membrane-associated ATPase-dependent kinase proteins involved in the active transport of aromatic hydrocarbons across bacterial membranes and also with FadL, an outer membrane protein necessary for the uptake of long-chain fatty acids in Escherichia coli. Transcription of styE is styrene dependent, and the gene is cotranscribed with the styABCD structural genes. StyE appears to be membrane associated, with a corresponding 45.9-kDa band being identified following sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of membrane preparations from styrene-grown cells. P. putida CA-3 cells in which the styE gene had been interrupted were no longer capable of growth on styrene. In contrast, overexpression of styE in P. putida CA-3 resulted in a 4.2-fold increase in styrene monooxygenase activity compared with wild-type cells grown on styrene, with a concomitant 8-fold increase in styA mRNA transcript levels. Experiments with the classic, ATPase inhibitor vanadate revealed that growth of wild-type cells on styrene was inhibited at a concentration of 1 mM, while 1.75 mM was required to achieve a similar effect in the StyE overexpression strain. Growth of either strain on citrate was not inhibited in the presence of up to 7 mM vanadate. These findings suggest a role for StyE in the active transport of styrene in Pseudomonas putida CA-3 and identify styrene transport as a potentially limiting factor with respect to mRNA transcript levels and associated enzymatic activity of the styrene degradative pathway.

Adenosine Triphosphatases↗
PubMed2001

Serum hepatic biochemical activity in two populations of workers exposed to styrene.

OBJECTIVE: To determine whether hepatic biochemical changes, as measured by routinely available tests indicative of hepatocellular necrosis, cholestasis, or altered hepatic clearance of bilirubin, occur in association with low to moderate exposure to styrene commonly experienced in industrial production. METHODS: Two independent cross sectional studies were performed comparing serum hepatic transaminases (alanine aminotransferase (ALT) and aspartate aminotransferase (AST)), cholestatic enzymes (alkaline phosphatase (AP) and gamma glutamyl transpeptidase (GGT)), and bilirubin in (a) 47 workers of fibreglass reinforced plastics who were exposed to styrene and (b) 21 boat and tank fabricators, with separate referent groups of unexposed workers. Exposure to styrene was assessed in air by dosimetry, and in venous blood by headspace analysis. Hepatic biochemical variables were assessed across strata of exposure to styrene defined as 25 ppm in air, or 0.275 mg/l in blood, adjusting for age, sex, body mass index, and ethanol consumption. RESULTS: A consistent and significant linear trend for increasing direct bilirubin and direct/total bilirubin ratio was found in association with increasing exposure to styrene, by both air and blood monitoring, in both studies. Mean direct bilirubin concentrations increased from 0.05-0.08 mg% in referents to 0.12-0.19 in workers exposed above 25 ppm, with a significant exposure-response trend (p<0.005). Significantly increased direct/total bilirubin ratios, ranging from 0.22 to 0.35 were associated with exposure to styrene (p<0.001), indicating diminished hepatic clearance of conjugated bilirubin. Also, a significant linear association between the hepatic transaminases ALT and AST and exposure to styrene was found in pooled regression analyses, with an increase in AP of about 10 IU/ml in workers exposed above 25 ppm air or 0.275 mg/l blood styrene in pooled analyses from both studies. CONCLUSIONS: The consistent finding of increased direct bilirubin and AP concentrations in these two independent studies provides evidence for diminished hepatic clearance of conjugated bilirubin with associated cholestasis in workers exposed to styrene. The finding of a significant linear association between hepatic transaminase concentrations and exposure to styrene in pooled analyses is consistent with mild hepatic injury and associated metabolic dysfunction.

Adult↗
PubMed2002

Relation between colour vision loss and occupational styrene exposure level.

AIMS: To investigate the relation between colour vision loss and the exposure level of styrene. Exposure level included the current exposure concentration, past cumulative exposure, and the maximum exposure level in the past. METHODS: Colour vision was examined by the Lanthony desaturated panel D-15 test for 76 subjects exposed to styrene in a fibreglass reinforced plastics boat plant (as an exposed group) and 102 non-exposed subjects (as a control group). The current exposure level was expressed by the concentration of atmospheric styrene and end shift urinary mandelic acid (MA) and phenylglyoxylic acid (PGA) levels. The individual cumulative exposure index (CEI) was calculated, based on the exposure frequency and urinary MA concentrations measured for the past eight years. RESULTS: The Colour Confusion Index (CCI) of the exposed group showed a significant difference from the age matched controls. However, only a slight significant relation was found between CCI and the concentration of urinary MA plus PGA. In this study, the exposed group was further divided into two subgroups (as sub-MA+PGA groups) by the median of urinary MA plus PGA of each subject. The dividing line between the subgroups was 0.24 g/g creatinine, which was equivalent to an atmospheric concentration of styrene of about 10 ppm. The CCI values of both the sub-MA+PGA groups were significantly higher than that of the control group. The relation between CCI value and the maximum exposure concentration in the past eight years was examined. It was found that the CCI values of the group with the maximum exposure concentration of styrene over 50 ppm were significantly higher than that of the other groups. CONCLUSIONS: Exposure to styrene would impair colour vision even if the exposure concentration was lower than 10 ppm. Furthermore, if the maximum concentration of styrene exposure transiently exceeded 50 ppm in the past, the styrene related damage might remain. Thus, the safe limit of exposure to styrene and the relation between exposure to styrene and the degree of damage to ocular structure, retina, optic nerve, and brain need to be re-examined.

Adult↗
PubMed1983

Genetic toxicity of styrene and some of its derivatives.

Styrene, an important plastic monomer, is mutagenic after metabolic activation in several test systems. Probably because of an unfavorable activation : inactivation ratio, some mutagenicity assays have not, however, found styrene mutagenic. Styrene is converted by microsomal monooxygenases in vivo to styrene-7,8-oxide, which is a well-known mutagen. Arene oxides have also been proposed as the reactive metabolites of styrene, but the significance of these compounds is not yet fully understood. Only few derivatives of styrene have been tested for mutagenicity. The results are characterized by difficulties in metabolic activation. Many styrene-7,8-oxide analogues substituted at the phenyl ring are electrophilic reactants and mutagenic in vitro. Human whole-blood lymphocyte cultures have a peculiar feature, ie, styrene and many of its analogues substituted at the ring or vinyl chain induce sister chromatid exchanges in the cultured cells without exogenous metabolizing systems. This activation is brought about by erythrocytes present in the cultures and probably results from the conversion of styrenes to styrene-7,8-oxides.

Animals↗
PubMed2002

Case-cohort study of styrene exposure and ischemic heart disease.

Recent epidemiologic studies have consistently reported increased daily mortalities and hospital admissions associated with exposure to particulate air pollution. Ischemic heart disease (IHD*, International Classification of Diseases, Eighth Revision [ICD-8], codes 410-414) is among those diseases that contribute in large measure to this excess mortality. Some occupational studies have suggested elevated risk of IHD among workers exposed for short periods to styrene, which can be emitted from fossil fuel combustion, aircraft exhausts, and motor vehicle exhausts. Styrene is found in ambient air at average concentrations of a few micrograms per cubic meter or less but may reach very high concentrations at particular locations and times. Unmeasured aerosols of styrene may also increase population exposures. This case-cohort study explored a possible association and dose-response relation between styrene exposure and risk of acute IHD in an occupational setting. The population under study was 6587 male workers employed between 1943 and 1982 in two US plants manufacturing styrene-butadiene polymers used in synthetic rubber. The study assessed all 498 subjects who died from IHD along with a subcohort of twice that size, 997 subjects, selected as a 15% random sample of the full target cohort. IHD deaths during the study led to some overlap between cases and the subcohort, leaving 1424 unique subjects. Job histories were collected for all subjects. Industrial hygienists and engineers from the industry estimated relative exposures for all jobs. Exposure data were collected for many of the jobs from different sources. For any job with no available exposure measurements, z scores were used to estimate job exposure in each plant from the relative exposure level for that job in similar plants and the measurement distribution parameters of the study plant. Standardized mortality ratio (SMR) analyses were used to examine the overall risk of dying from IHD among study subjects compared with the US general population. A significantly elevated SMR of 1.47 with a 95% confidence interval (95% CI) of 1.17 to 1.77 for chronic IHD was found among black workers who had left the plants. A modification of the Cox proportional hazard regression model was used to control for confounders and examine dose-response relations between styrene exposure and the risk of IHD. Employment time-weighted average (TWA) styrene concentration intensity for the most recent 2 years was found significantly associated with death from acute IHD among active workers with a relative hazard of 3.26 to 6.60, depending on duration of employment. In this analysis, the highest relative hazard of 6.60 (95% CI, 1.78-24.54) was among active workers who had been employed for at least 5 years. The results suggest that the exposure intensity was more important than duration of exposure. On the basis of the dose-response relation established in this study, we estimate that for each 10 microg/m3 increase in ambient styrene, acute IHD mortality might increase 0.4%. At normal ambient styrene levels, the relative risk would be increased, at most, 0.1% compared with no exposure. At certain locations and times, however, ambient styrene could reach levels that would result in a relative hazard for acute IHD mortality as high as 3.386-fold the risk at no exposure.

Canada↗
PubMed1991

Effect of styrene oxide on rat brain glutathione.

Glutathione (GSH) plays a primary role in protecting cells from oxidative stress and in detoxifying foreign compounds. The functions and regulations of GSH in nervous tissue have not been thoroughly investigated. This study examines the effects of styrene oxide, a reactive metabolite of the neurotoxic solvent styrene, on GSH metabolism in six regions of the rat brain (cortex, cerebellum, medulla-pons, hippocampus, striatum and hypothalamus). Control levels of GSH in brain regions ranged from 1.6 mM in medulla-pons to 2.7 mM in striatum. Styrene oxide (100-400 mg/kg, ip) depleted GSH in a dose- and time-dependent manner in all brain regions studied. Histochemical studies indicated a predominantly glial distribution of GSH and confirmed the depletion of GSH by styrene oxide in brain. Studies with [8(-14)C] styrene oxide revealed no differences in the distribution of styrene oxide/metabolites among brain regions. gamma-Glutamylcysteine synthetase, the rate-limiting enzyme in GSH biosynthesis, was not affected by styrene oxide in any brain region, either in vitro or following in vivo administration. Glutathione S-transferase activity in different brain regions, measured using p-nitrostyrene oxide as a substrate, correlated quantitatively with GSH depletion by styrene oxide. Depletion of brain GSH by styrene oxide may contribute to oxidative injury to neuronal and glial cells and may be involved in styrene neurotoxicity.

Animals↗
PubMed1997

Detection of 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage, in white blood cells of workers occupationally exposed to styrene.

Styrene-7,8-oxide (SO), the major in vivo metabolite of styrene, is a genotoxic compound and a potential carcinogenic hazard to occupationally exposed workers. The aim of the present work was to investigate the ability of styrene exposure to induce formation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in white blood cells (WBC) of boatbuilders occupationally exposed to styrene. The study of these adducts was conducted to see if styrene exposure can cause oxidative damage of DNA. The 8-OHdG/10(5) dG ratio from 17 styrene-exposed workers showed significant increases (mean +/- SD, 2.23 +/- 0.54, median 2.35, P < 0.001) in comparison to the controls (1.52 +/- 0.45, median 1.50). However, 11 out of 17 workers who were between the ages of 32 and 60 years and had been occupationally exposed to styrene for > 10 years showed higher 8-OHdG/10(5) dG ratios (2.31 +/- 0.62, median 2.37) in comparison to 6 workers with < 6 years of occupational styrene-exposure (2.11 +/- 0.36, median 2.05; P > 0.05, no significant difference between the two groups of workers). The studies presented here provide an indication that styrene exposure can result in oxidative DNA damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Bacterial degradation of styrene in waste gases using a peat filter.

A biofiltration process was developed for styrene-containing off-gases using peat as filter material. The average styrene reduction ratio after 190 days of operation was 70% (max. 98%) and the mean styrene elimination capacity was 12 g m-3 h-1 (max. 30 g m-3 h-1). Efficient styrene degradation required addition of nutrients to the peat, adjustment of the pH to a neutral level and efficient control of the humidity. Maintenance of the water balance was easier in a down-flow than in an up-flow process, the former consequently resulting in much better filtration efficiency. The optimum operation temperature was around 23 degrees C, but the styrene removal was still satisfactory at 12 degrees C. Seven different bacterial isolates belonging to the genera Tsukamurella, Pseudomonas, Sphingomonas, Xanthomonas and an unidentified genus in the gamma group of the Proteobacteria isolated from the microflora of active peat filter material were capable of styrene degradation. The isolates differed in their capacity to decompose styrene to carbon dioxide and assimilate it to biomass. No toxic intermediate degradation products of styrene were detected in the filter outlet gas or in growing cultures of isolated bacteria. The use of these isolates in industrial biofilters is beneficial at low styrene concentrations and is safe from both the environmental and public health points of view.

Biodegradation, Environmental↗
PubMed1997

Cytochrome P450 isozymes responsible for the metabolism of toluene and styrene in human liver microsomes.

1. Cytochrome P450 isozymes from Asian (31 Chinese subjects) and Caucasian (14 Finnish subjects) livers were examined for their roles in the metabolism of toluene (rates of benzyl alcohol, o- and p-cresol formation) and styrene (rates of styrene glycol formation). 2. For toluene, the overall rate of metabolism was higher in samples from Finnish than from Chinese subjects. At 0-20 mM toluene, the rate of o-cresol formation was significantly higher in Finnish microsomes than in Chinese ones. The formation rates of benzyl alcohol and p-cresol in Finnish samples were also higher than those of Chinese samples, but only at a high substrate concentration (5.0 mM). For styrene metabolism, the Chinese liver microsomes showed higher metabolic rates than the Finnish ones at 0.085 mM styrene, but not at the higher substrate concentration. 3. Mean expression levels of immunochemically detected CYP1A2/1 and CYP2B6 were almost 3-fold higher in Finnish microsomes, whereas CYP2E1 was 1.7-fold higher in Chinese samples. 4. Correlation analysis showed that CYP2E1 (benzyl alcohol formation) and CYP1A2/1 (o-cresol formation) contributed to the metabolism of toluene at the low substrate concentration, whereas CYP2C8 was the form more actively involved at the higher toluene concentrations. At the higher concentration (1.8 mM) of styrene, CYP2B6 was most active isozyme to catalyse the formation of styrene oxide from styrene. 5. These results suggest that CYP2E1 and CYP1A2/1 are the main isoforms responsible for the metabolism of toluene at low substrate concentrations in human liver microsomes, CYP2E1 at low styrene concentration, and CYP2C8 and CYP2B6 at high concentrations of toluene and styrene respectively.

Adolescent↗
PubMed1986

Kinetics of styrene in workers from a plastics industry after controlled exposure: a comparison with subjects not previously exposed.

Eight male workers from a glass reinforced plastics industry were experimentally exposed for 2 hours to 2.84 mmol/m3 (296 mg/m3) styrene during light physical exercise (50 W). About 63% of the amount supplied (4.6 mmol styrene) was taken up in the body. The arterial blood concentration of styrene reached a relatively stable level of 15 mumol/l at the end of exposure which was about 70% of the blood concentration in a group of volunteers with no previous exposure to solvents. The apparent blood clearance was significantly higher in the occupationally exposed subjects 2.01/h X kg compared with 1.51/h X kg. Contrary to the relatively stable level of styrene at the end of exposure the concentration of non-conjugated styrene glycol increased throughout the exposure and reached about 3 mumol/l in both groups. Like styrene, the non-conjugated styrene glycol seemed to be eliminated faster from the occupationally exposed workers. The blood concentration of styrene-7,8-oxide was low and seldom exceeded the detection limit of 0.02 mumol/l. The results show that long term exposure in a glass reinforced plastics industry may facilitate the metabolism of styrene.

Adult↗
PubMed1996

Comparison of average estimated metabolic rates for styrene in previously exposed and unexposed groups with pharmacokinetic modelling.

OBJECTIVE: To understand whether previous styrene exposure increases the human liver's ability to convert styrene into styrene oxide. METHODS: The hypothesis was tested that the average linear metabolic rate constant kappa was the same in both exposed and unexposed groups, when the exposed group comprised people with a history of styrene exposure and the unexposed group had no exposure. In an experimental chamber, these two groups of subjects were exposed to a concentration of 80 ppm styrene for two hours. A three compartment pharmacokinetic model was used to define kappa. Based on large sample theory, the comparison of estimated mean values of kappa in the exposed and unexposed groups was shown to be equivalent to a comparison of the estimated mean values of the hepatic clearance X in the two groups. A method was developed to estimate X for each subject in both groups from the subject's height, weight, and estimated asymptotic styrene decay constant alpha. Here, alpha was estimated individually from observed blood concentrations over time when sufficient time had elapsed after the controlled exposure. RESULTS: The proposed methodology of comparing the estimated mean values of kappa in exposed and unexposed groups reduced the number of specific physiological variables involved to three, all of which were estimable from data based on simple direct measurements. In contrast, other methods based on pharmacokinetic models usually involved many variables that were non-estimable on an individual basis. Consequently, statistical comparisons were impossible. These methods were applied to analyse previously published data on the time course of styrene concentrations in arterial blood of subjects in both exposed and unexposed groups. A Wilcoxon non-parametric rank sum test with the individually estimated X values was used, and no significant difference in the means of X in the two groups was found. CONCLUSION: The linear metabolic rate constant kappa for humans is probably not altered by previous exposure to styrene. This result is in agreement with some experimental studies on animals. However, in the data analysis, it was noted that the number of subjects in each group was small (6-7) and that the styrene concentration data did not exactly reflect true behaviour of asymptotic decay. Further studies are still needed to draw more definitive conclusions.

Adipose Tissue↗
PubMed1994

Styrene production, use, and human exposure.

Styrene is an extremely important commodity chemical used extensively in the manufacture of numerous polymers and copolymers, including polystyrene, acrylonitrile-butadiene-styrene (ABS), styrene-acrylonitrile (SAN), styrene-butadiene latex, and styrene-butadiene rubber. Styrene is a component of cigarette smoke and automobile exhaust, and it may occur naturally at low levels in various types of foods. The highest potential human exposures to styrene occur in occupational settings, particularly those involving the production of large glass-reinforced polyester products such as boats, which require manual lay-up and spray-up operations. Substantially lower occupational exposures occur in styrene monomer and polymer production facilities. The general public is exposed to very low concentrations of styrene in ambient air, indoor air, food, and drinking water.

Environmental Pollution↗
PubMed1994

Urinary mandelic acid and hemoglobin adducts in fiberglass-reinforced plastics workers exposed to styrene.

OBJECTIVES: A field study was undertaken to investigate the effects of occupational styrene exposure on mandelic acid excretion and the formation of styrene-7,8-oxide hemoglobin adducts. Especially the sensitivity of a gas chromatography-mass spectrometry method for determining hemoglobin adducts was evaluated. METHODS: Over a four-week period, each individual of a group of 52 fiberglass-reinforced plastics workers was monitored once a week by the simultaneous measurement of styrene in the air and urinary postshift mandelic acid. In addition mandelic acid and hemoglobin adducts were monitored in a group of 24 unexposed referents. At the end of the monitoring period styrene-7,8-oxide adduct formation on N-terminal valine in hemoglobin was examined by gas chromatography-mass spectrometry according to the modified Edman degradation technique. RESULTS: Personal air samples showed an average styrene exposure of 31 mg.m-3. The average postshift mandelic acid was 98 mg.g creatinine-1. For workers not wearing respirators and not showing breath ethanol, the correlation coefficient between styrene and mandelic acid was 0.78. The blood samples were analyzed for styrene-7,8-oxide adducts on hemoglobin. With a detection limit of 10 pmol.g-1, no styrene-7,8-oxide adducts were found under these exposure conditions. CONCLUSION: Adduct formation in humans is less effective than in mice. In comparison with ethylene, styrene is at least 70 times less effective in forming hemoglobin adducts. Investigating adduct formation in humans at or below the exposure levels reported in this study would require a detection limit of about one order of magnitude better.

Adult↗
PubMed1993

Monitoring occupational exposure to styrene from hemoglobin adducts and metabolites in blood.

Monitoring occupational exposure to styrene was achieved through quantification of adducts of styrene 7,8-oxide to N-terminal valine in hemoglobin (Hb) on the basis of the enrichment of adducted globin chains by ion-exchange chromatography and gas chromatographic-mass spectrometric analysis by the use of the N-alkyl Edman method. Application to blood samples from reinforced plastics workers exposed to styrene and from referents showed Hb adduct levels correlating with the blood styrene glycol and urinary mandelic acid concentrations. The blood styrene glycol and styrene 7,8-oxide levels of the exposed workers averaged 2.5 mumol.l-1 (17 subjects) and 0.09 mumol.l-1 (7 subjects), respectively. The blood styrene glycol and urinary mandelic acid content (mean 9.5 mmol.l-1, 17 subjects) suggested a styrene concentration of about 300 mg.m-3 (75 ppm) in the workplace air. The Hb adduct levels were low (mean 28 pmol.g-1), indicating rapid detoxification of styrene 7,8-oxide in humans.

Adult↗
PubMed1986

The formation of styrene glutathione adducts catalyzed by prostaglandin H synthase. A possible new mechanism for the formation of glutathione conjugates.

The metabolism of styrene by prostaglandin hydroperoxidase and horseradish peroxidase was examined. Ram seminal vesicle microsomes in the presence of arachidonic acid or hydrogen peroxide and glutathione converted styrene to glutathione adducts. Neither styrene 7,8-oxide nor styrene glycol was detected as a product in the incubation. Also, the addition of styrene 7,8-oxide and glutathione to ram seminal vesicle microsomes did not yield styrene glutathione adducts. The peroxidase-generated styrene glutathione adducts were isolated by high pressure liquid chromatography and characterized by NMR and tandem mass spectrometry as a mixture of (2R)- and (2S)-S-(2-phenyl-2-hydroxyethyl)glutathione. (1R)- and (1S)-S-(1-phenyl-2-hydroxyethyl)glutathione were not formed by the peroxidase system. The addition of phenol or aminopyrine to incubations, which greatly enhances the oxidation of glutathione to a thiyl radical by peroxidases, increased the formation of styrene glutathione adducts. We propose a new mechanism for the formation of glutathione adducts that is independent of epoxide formation but dependent on the initial oxidation of glutathione to a thiyl radical by the peroxidase, and the subsequent reaction of the thiyl radical with a suitable substrate, such as styrene.

Animals↗
PubMed1983

Metabolic activation of styrene by erythrocytes detected as increased sister chromatid exchanges in cultured human lymphocytes.

Styrene induces sister chromatid exchanges (SCEs) in human whole-blood lymphocyte cultures without exogenous metabolizing systems, which indicates that styrene is metabolically activated in this in vitro system. Whole-blood lymphocyte cultures from 11 male donors showed a clear increase in SCEs after a 48-hr treatment with styrene (2 mM) or with the reactive metabolite styrene 7,8-oxide (0.15 mM). Styrene (0.5 to 4 mM) induced a distinct dose-dependent increase of SCEs in whole-blood cultures (with 200 to 400 million red blood cells/ml) but only a slight effect in purified lymphocyte cultures (with 20,000 red blood cells/ml). SCE induction by styrene (2 mM) depended on the amount of red blood cells (0.02 to 2000 million/ml) added to the purified lymphocyte cultures. Cyclophosphamide, studied for comparison, clearly increased SCEs irrespective of the presence of erythrocytes. The results show that erythrocytes are essential for the activation of styrene in the lymphocyte test system. This activation probably results from the conversion of styrene into styrene 7,8-oxide by oxyhemoglobin.

Biotransformation↗
PubMed1997

Urinary excretion of specific mercapturic acids in workers exposed to styrene.

Styrene is an important chemical of wide industrial use, particularly in the manufacture of polymers and reinforced plastics. Environmental and occupational exposures to styrene occur predominantly via inhalation. Styrene undergoes biotransformation mainly by side chain oxidation catalyzed by cytochrome P-450 enzymes to its reactive metabolite, styrene oxide. The (R)- and (S)-enantiomers of styrene oxide can be conjugated with glutathione to both (R)- and (S)-diastereoisomers of specific mercapturic acids, N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine (M1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (M2). We conducted this biomonitoring study with the aim of evaluating the association between excretion of specific mercapturic acids (M1 and M2) and level of exposure to styrene among occupationally exposed people. The mean time-weighted average (TWA) exposure was about one-half the current threshold limit value, the range of the values varied from 44 to 228 mg/m3. Geometric mean (GM) concentrations of 650, 1,084, and 31.8 micrograms/g creatinine were measured, respectively, for M1-S, M2, and M1-R. The environmental styrene concentration exhibited a significant correlation with total specific mercapturic acid (Mtot = sum of M1-R, M1-S, and M2), making it possible for the first time to calculate the approximate relationship between styrene uptake and excretion of these substances. The M2 mercapturic acid had a better correlation (r = 0.56) with respect to M1-R and M1-S. Significant correlations were found also between the excretion of specific mercapturic acids and biological exposure indices (i.e., mandelic and phenylglyoxylic acids and urinary styrene).

Acetylcysteine↗