Significant association between decreased ALDH2 activity and increased sensitivity to genotoxic effects in workers occupationally exposed to styrene.

ALDH2 is involved in the metabolism of styrene, a widely used industrial material, but no data are available regarding the influence of this enzyme on the metabolic fate as well as toxic effects of this chemical. In this study, we recruited 329 workers occupationally exposed to styrene and 152 unexposed controls. DNA strand breaks, DNA-base oxidation in leukocytes and urinary 8-hydroxydeoxyguanosine (8-OH-dG) were assayed as biomarkers to measure genotoxic effects. Meanwhile, we examined the genetic polymorphisms, including ALDH2, EXPH1, GSTM1, GSTT1 and CYP2E1, and also analyzed the levels of styrene exposure through detecting urinary styrene metabolites and styrene concentration in air. In terms of DNA damage, the three genotoxic biomarkers were significantly increased in exposed workers as compared with controls. And the styrene-exposed workers with inactive ALDH2 *2 allele were subjected to genotoxicity in a higher degree than those with ALDH2 *1/*1 genotype. Also, lower levels of urinary styrene metabolites (MA + PGA) were observed in styrene-exposed workers carrying ALDH2 *2 allele, suggesting slower metabolism of styrene. The polymorphisms of other enzymes showed less effect. These results suggested that styrene metabolism and styrene-induced genotoxicity could be particularly modified by ALDH2 polymorphisms. The important role of ALDH2 indicated that the accumulation of styrene glycoaldehyde, a possible genotoxic intermediate of styrene, could account for the genotoxicity observed, and should be taken as an increased risk of cancer.

Exposición a solventes y disfunción auditiva central: revisión de la evidencia científica / Solvent exposure and central auditory dysfunction: a literature review on the scientific evidence

Diversos estudios han demostrado que los solventes orgánicos pueden inducir una disfunción auditiva. Los modelos animales han mostrado que los solventes son capaces de dañar las células ciliadas externas. Estudios de campo en trabajadores expuestos a solventes han encontrado por una parte, una mayor prevalencia de hipoacusia sensorioneural en comparación a grupos controles, y por otra, una dis función auditiva central asociada a la exposición a solventes. El presente trabajo tiene como objetivo revisar y discutir la evidencia científica acerca de la disfunción auditiva central asociada a la exposición a solventes como el tolueno, estireno, xileno, bisulfato de carbono, y mezcla de ellos. Se discuten los resultados de las investigaciones llevadas a cabo en humanos expuestos laboralmente a estos agentes. Se discuten además, los mecanismos de ototoxicidady neurotoxidad de los solventes y sus implicancias en la evaluación de la hipoacusia inducida por solventes.

Different studies have demonstrated that solvents may induce an auditory dysfunction. Animal models have shown that solvents can injure the outer hair cells. Studies conducted in workers exposed to solvents have found on one hand, a higher prevalence of sensorineural hearing loss in comparison to non-exposed control group subjects. On the other hand, these studies have found a central auditory dysfunction associated with solvent exposure. The present manuscript aims at revising and discussing the scientific evidence on central auditory dysfunction associated with exposure to solvents such as toluene, styrene, xylene, carbon disulphate, and mixtures. Results from studies conducted in humans occupationally exposed to solvents are discussed. Also, the oto-and neuro-toxicity induced by solvents and the implications for the assessment of solvent-induced hearing loss are addressed.

Exterior exposure estimation using a one-compartment toxicokinetic model with blood sample measurements.

Exposure assessment of individuals exposed to certain chemicals plays an important role in the analysis of occupational-as well as environmental-health problems. Biological monitoring, as an alternative to direct environmental measurements, may be applied to relate the exterior exposure with the amount of individual intake. In this paper, we estimate individuals' (inhalation) exposure retrospectively from their blood concentrations via a simplified one-compartment toxicokinetic model. Considering stochastic variations to the toxicokinetic model, the solution to the resultant stochastic differential equation (SDE), together with measurement error, is transformed into a dynamic linear state-space model. The unknown model parameters and the mean inhalation concentration are then estimated via Markov Chain Monte Carlo (MCMC) simulations. The proposed method is used in the analysis of the styrene data (Wang et al. in Occup Environ Med 53:601-605, 1996) to backward estimate the inhalation concentration, assuming it is unknown. The data analysis showed that the internal stochastic variations, often ignored in toxicokinetic model analysis, outweighed in standard deviation almost twice that of the measurement error. Also, the simulation results showed that the method performed relatively well to the approach considering measurement error only.

Solvent-induced hearing loss: mechanisms and prevention strategy.

While noise exposure is the most significant contributor to occupational hearing loss, evidence gained over the last 10 years, has pointed to organic solvents as additional contributors to occupational hearing disorders. Despite the implications of this finding, no significant measure has been undertaken to limit exposure to occupational solvents, or to occupational solvents and noise, within the European community. Guidelines for improving hearing protection of people exposed to solvents, or to solvents and noise, are addressed in the present article. Recently, it has been shown that the lowest-observed-adverse-effect level (LOAEL) of styrene was 300 ppm in active (working wheel) rats, and that the same amount of styrene-induced hearing loss (SIHL) can be obtained with styrene concentration difference of 200 ppm between active and sedentary (inactive) rats. Supported by a reasonable safety factor (SF) of 10, the authors proposed to decrease the French threshold limit value of styrene from 50 to 30 ppm (RfD=LOAEL/SF) to ensure a higher level of protection for human hearing. It is widely acknowledged that outer hair cells in the organ of Corti can be considered as the first target tissue of solvents, while little is known about the action of aromatic solvents on the auditory efferent system. In a recent experiment using both the cochlear microphonic and compound action potentials, the authors have shown that toluene can inhibit the action of the middle ear reflex by modifying the cholinergic receptors. It is likely that toluene affects the cholinergic receptors at the brainstem level. By its anticholinergic-like effect, toluene could allow higher acoustic energy penetration into the cochlea exposed to both noise and solvent. Based on this phenomenon, the authors recommend the use of hearing protection for the lower exposure action value: Lex,8h=80 dB(A) in noisy environments polluted by solvents.

Relationship between styrene exposure and hearing loss: review of human studies.

Styrene is an aromatic solvent belonging to the alkylbenzene family. Occupational exposure to styrene occurs mainly in the manufacturing of fiberglass-reinforced polyester products, e.g. reinforced plastics and composites. Since 1988, nine studies have been published on the relationship between occupational exposure to styrene and hearing loss. All studies were the cross-sectional epidemiological studies or clinical studies from occupational health clinics. A total of more than 1000 workers exposed to styrene, both with and without concurrent noise exposure, were examined using different outcome measures for hearing loss. Exposure assessment was usually based on styrene measurements in the breathing zone during several hours of one working day. Some of the studies employed also the biological monitoring of styrene exposure based on determination of its urinary metabolites. The current exposures to styrene varied between 2 and 35 ppm. In some studies, lifetime exposure was calculated using company records and questionnaire data. The current exposure to noise was estimated by noise dosimetry or standard noise measurements. Lifetime noise exposure was assessed using questionnaire data and occupational noise estimates. In many studies, noise-exposed groups were used as controls together with the unexposed workers. Of the nine studies, seven show some effects on the auditory system that were associated with styrene-alone exposure. These effects are examined using different outcome measures such as pure tone audiometry, high frequency hearing loss, and central hearing tests. In some studies, an increased risk for hearing loss was associated with exposure estimates.

The ototoxicity of styrene: a review of occupational investigations.

OBJECTIVES: The objective of this study was to review critically a number of occupational investigations of the exposure and effect relation between inhaled styrene vapour and hearing loss. There is concern that workers' hearing may be impaired by exposure to styrene, as used in industries making plastics and fibreglass-reinforced products. METHODS: Seven occupational studies, each dealing with the ototoxicity of styrene, were examined. Factors assessed included the experimental design and number of subjects within exposure groups, measurement of the styrene-in-air concentration, confirmation of the styrene exposure by blood or urine analysis, determination of the hearing threshold levels for the exposure and control groups, and measurement of any occupational noise in the subjects' workplaces. Consideration was also given to statistical relations between high-frequency hearing loss and lifetime exposure indices for styrene and noise. RESULTS: The results are equivocal. Four investigations failed to find any effect of styrene on hearing thresholds. In contrast, other investigations claimed to have demonstrated styrene-induced hearing loss in industrial populations, with synergism between styrene and noise. However, these reports exhibited shortcomings of experimental design and data analysis. CONCLUSIONS: Considering the body of evidence as a whole, hearing deficits due to occupational exposure to styrene at low concentrations have not been demonstrated by scientifically reliable argument. There is some suggestion of an association between styrene exposure, occupational noise, and hearing dysfunction. Further studies in humans are necessary to clarify this question.

Influence of genetic polymorphisms of styrene-metabolizing enzymes and smoking habits on levels of urinary metabolites after occupational exposure to styrene.

Here we evaluate the influence of individual genetic polymorphisms of drug-metabolizing enzymes as well as body mass index (BMI) and lifestyle (smoking, alcohol consumption) on urinary metabolites after occupational exposure to styrene. Seventy-three workers exposed to styrene in a reinforced-plastics workplace were studied. The personal styrene exposure in the air and the urinary styrene metabolites mandelic acid and phenylglyoxylic acid were measured. The subjects' genetic polymorphisms in the genes that encode the styrene-metabolizing enzymes CYP2E1, CYP2B6, EPHX1, GSTM1, GSTT1 and GSTP1 were determined. Neither genotype nor lifestyle significantly affected urinary metabolites. There was, however, an interaction between the CYP2E1 genotype and smoking. Among non-smokers, urinary styrene metabolites were significantly decreased in subjects with c1/c1 alleles of CYP2E1 as compared with those with the c1/c2 genotype. There was no significant difference in urinary metabolites among smokers. When the combined influence of the CYP2B6 genotype and the predicted activity of EPHX1 were examined, urinary metabolites in subjects with low enzyme activity were lower than in those with medium or high activity after high styrene exposure (>or=50 ppm). The results suggest that genetic susceptibility and lifestyle should be considered in biological monitoring of exposure to styrene.

Human neurobehavioral effects of long-term exposure to styrene: a meta-analysis.

Many reports in the literature suggest that long-term exposure to styrene may exert a variety of effects on the nervous system, including increased choice reaction time and decreased performance of color discrimination and color arrangement tasks. Sufficient information exists to perform a meta-analysis of these observations quantifying the relationships between exposure (estimated from biomarkers) and effects on two measures of central nervous system function: reaction time and color vision. To perform the meta-analysis, we pooled data into a single database for each end point. End-point data were transformed to a common metric of effect magnitude (percentage of baseline). We estimated styrene concentration from biomarkers of exposure and fitted linear least-squares equations to the pooled data to produce dose-effect relationships. Statistically significant relationships were demonstrated between cumulative styrene exposure and increased choice reaction time as well as increased color confusion index. Eight work-years of exposure to 20 ppm styrene was estimated to produce a 6.5% increase in choice reaction time, which has been shown to significantly increase the probability of automobile accidents. The same exposure history was predicted to increase the color confusion index as much as 1.7 additional years of age in men.

Cytogenetic markers, DNA single-strand breaks, urinary metabolites, and DNA repair rates in styrene-exposed lamination workers.

The effect of occupational exposure to styrene on frequencies of chromosomal aberrations and binucleated cells with micronuclei and on single-strand break levels in peripheral blood lymphocytes was studied in 86 reinforced plastic workers and 42 control individuals (including 16 maintenance workers with intermittent, low-dose exposure). In these individuals, the irradiation-specific DNA repair rates and the repair rates of 8-oxoguanines were investigated. We assessed the exposure by measuring the concentrations of styrene in air and in blood and of mandelic acid, phenylglyoxylic acid, 4-vinyl phenol conjugates and regioisomeric phenyl hydroxyethyl mercapturic acids in urine. All these parameters correlated with one another. No clear relationship was found between the styrene exposure and the frequencies of chromosomal aberrations. Binucleated cells with micronuclei were moderately related to the parameters of styrene exposure. We found a negative correlation between all exposure parameters and single-strand breaks. The positive correlation between exposure parameters and DNA repair rates suggests that particular DNA repair pathways may be induced by styrene exposure.

Neurobehavioral effects of experimental exposures to low levels of styrene.

Two experimental studies were conducted with the intention to simulate exposure characteristics of work places with styrene exposure and to investigate the risk for neurobehavioral impairments. In experiment I 16 volunteers (8 in the morning, 8 in the afternoon) were exposed to 0.5 and 20 ppm styrene on a constant level for 3h. In experiment II 24 volunteers (12 in the morning, 12 in the afternoon) were exposed for 4h to 0.5 and 20 ppm styrene on a constant level as well as to a changing exposure between 0.5 and 40 ppm with a TWA of 14 ppm. Simple reaction, choice reaction, attention, acute symptoms, and ratings for well-being were measured. Exposure related performance effects could not be detected. However, 6h time change resulted in delayed choice reactions in the morning hours. Analysing acute symptoms and the state of well-being the impact of styrene did not reach adverse extents of impaired well-being.

Combined effects of exposure to styrene and ethanol on the auditory function in the rat.

In order to study the auditory effects of a metabolic interaction between ethanol and styrene, a first group of rats was gavaged once a day with ethanol (4 g/kg), a second group was exposed to 750 ppm styrene by inhalation, and a third group was exposed to both ethanol and styrene (5 days/week, 4 weeks). Auditory function was tested by recording brainstem (inferior colliculus) auditory evoked potentials, and cochlear hair cell loss was estimated by light microscopy. Cytochrome P450 2E1 and the main urinary styrene metabolites, namely mandelic, phenylglyoxylic and hippuric acids, were measured by high-performance liquid chromatography to check the effects of ethanol on styrene metabolism. In our experimental conditions, ethanol alone did not have any effect on auditory sensitivity, whereas styrene alone caused permanent threshold shifts and outer hair cell damage. Hearing and outer hair cell losses were larger after the exposure to both ethanol and styrene than those induced by styrene alone, indicating a clear potentiation of styrene ototoxicity by ethanol. As expected, metabolic data showed that ethanol alters styrene metabolism and can therefore be considered a modifying factor of styrene toxicokinetics.

Evaluation of half-mask respirator protection in styrene-exposed workers.

OBJECTIVE: The protection afforded by respirators to styrene (St)-exposed workers varies considerably. Our objective was to study the effective 'in the field' reduction in St exposure obtained by negative-pressure half-mask respirators worn by a group of fiberglass-reinforced plastics (FRP) workers. Protection was evaluated by measuring the reduction in urinary St (StU) excretion. METHODS: Seven FRP workers not using respiratory protection devices were studied for a week. External exposure to St was evaluated by personal passive sampling, and the internal dose by StU measurement. Then workers were asked to use a half-mask respirator for a week for the entire morning half-shift, and St exposure and internal dose were re-assessed. RESULTS: Mean environmental levels of St during the morning half-shift were 230-280 mg/m3, i.e., about three times the current limit proposed by ACGIH; the difference among days was not significant. Using respirators was accompanied by a large inter-individual and also intra-individual variability: the estimated reduction of StU values ranged from 30% to 90% (mean 60%). Mean StU values increased by 50% from Monday to Friday, while environmental St concentrations remained steady. Furthermore, the proportion of workers exceeding the biological equivalent exposure limit (BEEL) was 14% on Monday, double (33%) on Thursday, and triple (43%) on Friday. These data suggest a decrease of protection during the week. CONCLUSIONS: The protection afforded by negative-pressure half-mask respirators varies widely, which stresses the need to assess the effective reduction of exposure whenever these devices are introduced for St-exposed workers. If respirators are to be re-used for several days, their performance must be evaluated during the last shift of use. Measurement of urinary excretion of unmodified St proved a useful tool for the evaluation of respirator effectiveness in exposed workers.

Distúrbios otoneurológicos relacionados aos agentes químicos - revisäo de literatura de 2 caos de intoxicaçäo por mercúrio / Otoneurological disturbances related to chemical agents - literature review and report of 2 cases of mercury intoxication

Os autores fazem uma revisão de literatura sobre alterações do sistema otoneurológico, decorrente da ação de agentes químicos como solventes e metais pesados, na maioria das ocasiões por exposição no trabalho. Relatam dois casos de intoxicação ocupacional por mercúrio, comentando a importância dos exames complementares para o diagnóstico.

Styrene-induced peripheral neuropathy.

CASE REPORT: Styrene is a colorless, oily liquid most commonly found in paints, plastics, and resins. Like many solvents, styrene can cause intoxication and central nervous system depression when inhaled in high concentrations for extended periods. Rarely, styrene has been implicated as a cause of peripheral neuropathy. We describe a case of a previously healthy 57-year-old man who developed signs and symptoms consistent with a peripheral neuropathy after applying a fiberglass resin to the inside of a septic tank over a 2-day period. Nerve conduction tests verified examination findings. Styrene exposure should be minimized through the use of respirators and protective clothing to prevent this type of toxicity.