Mass or total surface area with aerosol size distribution as exposure metrics for inflammatory, cytotoxic and oxidative lung responses in rats exposed to titanium dioxide nanoparticles.

There is currently no consensus on the best exposure metric(s) for expressing nanoparticle (NP) dose. Although surface area has been extensively studied for inflammatory responses, it has not been as thoroughly validated for cytotoxicity or oxidative stress effects. Since inhaled NPs deposit and interact with lung cells based on agglomerate size, we hypothesize that mass concentration combined with aerosol size distribution is suitable for NP risk assessment. The objective of this study was to evaluate different exposure metrics for inhaled 5 nm titanium dioxide aerosols composed of small (SA < 100 nm) or large (LA > 100 nm) agglomerates at 2, 7, and 20 mg/m3 on rat lung inflammatory, cytotoxicity, and oxidative stress responses. We found a significant positive correlation ( r = 0.98, p < 0.01) with the inflammatory reaction, measured by the number of neutrophils and the mass concentration when considering all six (SA + LA) aerosols. This correlation was similar ( r = 0.87) for total surface area. Regarding cytotoxicity and oxidative stress responses, measured by lactate dehydrogenase and 8-isoprostane, respectively, and mass or total surface area as an exposure metric, we observed significant positive correlations only with SA aerosols for both the mass concentration and size distribution ( r > 0.91, p < 0.01), as well as for the total surface area ( r > 0.97, p < 0.01). These data show that mass or total surface area concentrations alone are insufficient to adequately predict oxidant and cytotoxic pulmonary effects. Overall, our study indicates that considering NP size distribution along with mass or total surface area concentrations contributes to a more mechanistic discrimination of pulmonary responses to NP exposure.

Evaluation of occupational exposure: comparison of biological and environmental variabilities using physiologically based toxicokinetic modeling.

PURPOSE: Few studies compare the variabilities that characterize environmental (EM) and biological monitoring (BM) data. Indeed, comparing their respective variabilities can help to identify the best strategy for evaluating occupational exposure. The objective of this study is to quantify the biological variability associated with 18 bio-indicators currently used in work environments. METHOD: Intra-individual (BV(intra)), inter-individual (BV(inter)), and total biological variability (BV(total)) were quantified using validated physiologically based toxicokinetic (PBTK) models coupled with Monte Carlo simulations. Two environmental exposure profiles with different levels of variability were considered (GSD of 1.5 and 2.0). RESULTS: PBTK models coupled with Monte Carlo simulations were successfully used to predict the biological variability of biological exposure indicators. The predicted values follow a lognormal distribution, characterized by GSD ranging from 1.1 to 2.3. Our results show that there is a link between biological variability and the half-life of bio-indicators, since BV(intra) and BV(total) both decrease as the biological indicator half-lives increase. BV(intra) is always lower than the variability in the air concentrations. On an individual basis, this means that the variability associated with the measurement of biological indicators is always lower than the variability characterizing airborne levels of contaminants. For a group of workers, BM is less variable than EM for bio-indicators with half-lives longer than 10-15 h. CONCLUSION: The variability data obtained in the present study can be useful in the development of BM strategies for exposure assessment and can be used to calculate the number of samples required for guiding industrial hygienists or medical doctors in decision-making.

Effects of inhaled nano-TiO2 aerosols showing two distinct agglomeration states on rat lungs.

Nano-aerosols composed of large agglomerates (LA) (>100nm) are more likely to promote pulmonary clearance via macrophages phagocytosis. Small agglomerates (SA) (<100nm) seem to escape this first defense mechanism and are more likely to interact directly with biological material. These different mechanisms can influence pulmonary toxicity. This hypothesis was evaluated by comparing the relative pulmonary toxicity induced by aerosolized nano-TiO(2) showing two different agglomeration states: SA (<100nm) and LA (>100nm) at mass concentrations of 2 or 7mg/m(3). Groups of Fisher 344 male rats were nose-only exposed for 6h. The median number aerodynamic diameters were 30 and 185nm at 2mg/m(3), and 31 and 194nm at 7mg/m(3). We found in rat's bronchoalveolar lavage fluids (BALF) a significant 2.1-fold increase in the number of neutrophils (p<0.05) in the group exposed to the 7mg/m(3) LA nano-aerosol suggesting a mild inflammatory response. Rats exposed to the 7mg/m(3) SA nano-aerosol showed a 1.8-fold increase in LDH activity and 8-isoprostane concentration in BALF, providing evidence for cytotoxic and oxidative stress effects. Our results indicate that biological responses to nanoparticles (NP) might depend on the dimension and concentration of NP agglomerates.

Impact of emerging pollutants on pulmonary inflammation in asthmatic rats: ethanol vapors and agglomerated TiO2 nanoparticles.

CONTEXT: Titanium dioxide nanoparticles (nano-TiO(2)) and ethanol vapors are air contaminants with increasing importance. The presence of a pathological pulmonary condition, such as asthma, may increase lung susceptibility to such contaminants. OBJECTIVE: This study aimed to investigate if exposure to inhaled ethanol vapors or nano-TiO(2) can modulate the rat pulmonary inflammatory response resulting from an allergic asthmatic reaction. MATERIALS AND METHODS: Brown Norway rats were sensitized (sc) and challenged (15 min inhalation, 14 days later) with chicken egg ovalbumin (OVA). Leukocytes were counted in bronchoalveolar lavages (BAL) performed at 6, 24, 36, 48 and 72 h following the challenge and either after ethanol exposures (3000 ppm, 6 h/day, daily) or at 48 h (peak inflammation) for nano-TiO(2) exposures (9.35 mg/m(3) aerosol for 6 and 42 h after the OVA challenge). For the nano-TiO(2) exposures, plasma and BAL cytokines were measured and lung histological analyzes were performed. RESULTS: Exposure to ethanol did not significantly affect BAL leukocytes after OVA challenge. Exposure to nano-TiO(2) significantly decreased BAL leukocytes compared to OVA-challenged controls. Plasma and BAL IL-4, IL-6, and INF-γ levels were also decreased in the nano-TiO(2) group. DISCUSSION: While ethanol vapors do not modify the pulmonary inflammation in rats during an asthmatic response, a surprising protective effect for agglomerated nano-TiO(2) was observed. A putative mechanistic basis involving a decrease in the Th2 response caused by OVA is proposed. CONCLUSION: Allergic pulmonary inflammation is not up-regulated by inhalation of the pollutants ethanol and nano-TiO(2). On the contrary, nano-TiO(2) decreases lung inflammation in asthmatic rats.

A weight of evidence approach for the assessment of the ototoxic potential of industrial chemicals.

There is accumulating epidemiological evidence that exposure to some solvents, metals, asphyxiants and other substances in humans is associated with an increased risk of acquiring hearing loss. Furthermore, simultaneous and successive exposure to certain chemicals along with noise can increase the susceptibility to noise-induced hearing loss. There are no regulations that require hearing monitoring of workers who are employed at locations in which occupational exposure to potentially ototoxic chemicals occurs in the absence of noise exposure. This project was undertaken to develop a toxicological database allowing the identification of possible ototoxic substances present in the work environment alone or in combination with noise exposure. Critical toxicological data were compiled for chemical substances included in the Quebec occupational health regulation. The data were evaluated only for noise exposure levels that can be encountered in the workplace and for realistic exposure concentrations up to the short-term exposure limit or ceiling value (CV) or 5 times the 8-h time-weighted average occupational exposure limit (TWA OEL) for human data and up to 100 times the 8-h TWA OEL or CV for animal studies. In total, 224 studies (in 150 articles of which 44 evaluated the combined exposure to noise and a chemical) covering 29 substances were evaluated using a weight of evidence approach. For the majority of cases where potential ototoxicity was previously proposed, there is a paucity of toxicological data in the primary literature. Human and animal studies indicate that lead, styrene, toluene and trichloroethylene are ototoxic and ethyl benzene, n-hexane and p-xylene are possibly ototoxic at concentrations that are relevant to the occupational setting. Carbon monoxide appears to exacerbate noise-induced hearing dysfunction. Toluene interacts with noise to induce more severe hearing losses than the noise alone.

Impact of biological and environmental variabilities on biological monitoring--an approach using toxicokinetic models.

Biological monitoring of occupational exposure is characterized by important variability, due both to variability in the environment and to biological differences between workers. A quantitative description and understanding of this variability is important for a dependable application of biological monitoring. This work describes this variability, using a toxicokinetic model, for a large range of chemicals for which reference biological reference values exist. A toxicokinetic compartmental model describing both the parent compound and its metabolites was used. For each chemical, compartments were given physiological meaning. Models were elaborated based on physiological, physicochemical, and biochemical data when available, and on half-lives and central compartment concentrations when not available. Fourteen chemicals were studied (arsenic, cadmium, carbon monoxide, chromium, cobalt, ethylbenzene, ethyleneglycol monomethylether, fluorides, lead, mercury, methyl isobutyl ketone, penthachlorophenol, phenol, and toluene), representing 20 biological indicators. Occupational exposures were simulated using Monte Carlo techniques with realistic distributions of both individual physiological parameters and exposure conditions. Resulting biological indicator levels were then analyzed to identify the contribution of environmental and biological variability to total variability. Comparison of predicted biological indicator levels with biological exposure limits showed a high correlation with the model for 19 out of 20 indicators. Variability associated with changes in exposure levels (GSD of 1.5 and 2.0) is shown to be mainly influenced by the kinetics of the biological indicator. Thus, with regard to variability, we can conclude that, for the 14 chemicals modeled, biological monitoring would be preferable to air monitoring. For short half-lives (less than 7 hr), this is very similar to the environmental variability. However, for longer half-lives, estimated variability decreased.

Ethyl benzene should be considered ototoxic at occupationally relevant exposure concentrations.

Organic solvents can produce ototoxic effects in both man and experimental animals. The objective of this study was to review the literature on the effects of low-level exposure to ethyl benzene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible exposure limits. In Quebec, the Time-Weighed Average Exposure Value for 8A h (TWAEV) is 100A ppm (434A mg/m(3)) and the Short-Term Exposure Value for 15A min (STEV) is 125A ppm (543A mg/m(3)). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. In workers, there is no evidence of either ethyl benzene-induced hearing losses or ototoxic interaction after combined exposure to ethyl benzene and noise. In rats, ethyl benzene affects the auditory function mainly in the cochlear mid-frequency range and ototoxic interaction was observed after combined exposure to noise and ethyl benzene. Further studies with sufficient data on the ethyl benzene exposure of workers are necessary to make a definitive conclusion. Given the current evidence from animal studies, we recommend considering ethyl benzene as an ototoxic agent.

Occupational ototoxicity of n-hexane.

The ability of chemicals to produce hearing loss themselves or to promote noise-induced hearing loss has been reported for some organic solvents. The objective of this study was to review the literature on the effects of low-level exposure to n-hexane on the auditory system and consider its relevance for occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the permissible inhalation exposure limits. In Quebec, the time-weighted average exposure value (TWAEV) for 8 h is 50 ppm. In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at five times the TWAEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of n-hexane-induced hearing loss in workers. In rats, n-hexane seems to affect auditory function; however, the site of these alterations cannot be determined from the present data. Further studies with sufficient data on the exposure of workers to n-hexane are necessary to make a definitive conclusion. In the interim, we recommend considering n-hexane as a possibly ototoxic agent.

Ototoxicity of trichloroethylene in concentrations relevant for the working environment.

Organic solvents can cause hearing loss themselves or promote noise-induced hearing loss. The objective of this study was to review the literature on the effects of low-level exposure to trichloroethylene on the auditory system and consider its relevance for the occupational settings. Both human and animal investigations were evaluated only for realistic exposure concentrations based on the Quebec permissible exposure limits: 50 ppm 8-h time-weighed average exposure value (TWAEV) and 200 ppm short-term exposure value (STEV). In humans, the upper limit for considering ototoxicity data relevant to the occupational exposure situation was set at the STEV. Animal data were evaluated only for exposure concentrations up to 100 times the TWAEV. There is no convincing evidence of trichloroethylene-induced hearing losses in workers. In rats, trichloroethylene affects the auditory function mainly in the cochlear mid- to high-frequency range with a lowest observed adverse effect level (LOAEL) of 2000 ppm. No studies on ototoxic interaction after combined exposure to noise and trichloroethylene were identified in humans. In rats, supra-additive interaction was reported. Further studies with sufficient data on the trichloroethylene exposure of workers are necessary to make a definitive conclusion. In the interim, we recommend considering trichloroethylene as an ototoxic agent.

Physiologically based modeling of n-hexane kinetics in humans following inhalation exposure at rest and under physical exertion: impact on free 2,5-hexanedione in urine and on n-hexane in alveolar air.

We used a modified physiologically based pharmacokinetic (PBPK) to describe/predict n-hexane (HEX) alveolar air concentrations and free 2,5-HD urinary concentrations in humans exposed to n-HEX by inhalation during a typical workweek. The effect of an increase in workload intensity on these two exposure indicators was assessed and, using Monte Carlo simulation, the impact of biological variability was investigated. The model predicted HEX alveolar air concentrations at rest of 19.0 ppm (25 ppm exposure) and 38.7 ppm (50 ppm exposure) at the end of the last working day (day 5), while free 2,5-HD urinary concentrations of 3.4 micromol/L (25 ppm) and 6.3 micromol/L (50 ppm) were predicted for the same period (last 4.5 hours of Day 5). Monte Carlo simulations showed that the range of values expected to occur in a group of 1000 individuals exposed to 50 ppm of HEX (95% confidence interval) for free 2,5-HD (1.7-14.7 micromol/L) is much higher compared with alveolar air HEX (33.4-46 ppm). Simulations of exposure at 50 ppm with different workloads predicted that an increase in workload intensity would not greatly affect both indicators studied. However, the alveolar air HEX concentration is more sensitive to modifications of workload intensity and time of sampling, after the end of exposure, compared with 2,5-HD. The PBPK model successfully described the HEX alveolar air concentrations and free 2,5-HD urinary concentrations measured in human volunteers and is the first, to our knowledge, to describe the excretion kinetics of free 2,5-HD in humans over a 5-day period.

Comparison of unchanged n-hexane in alveolar air and 2,5-hexanedione in urine for the biological monitoring of n-hexane exposure in human volunteers.

INTRODUCTION AND AIM: Biological monitoring of n-hexane (HEX) is based on the measurement of urinary 2,5-hexanedione (2,5-HD). In 2001, the American Conference of Governmental Industrial Hygienists modified the biological exposure index (BEI) for HEX and suggested measuring free urinary 2,5-HD (without hydrolysis) (3.5 micromol/l) instead of total 2,5-HD (acid hydrolysis). This BEI value was derived from four field studies that involved worker exposures to variable concentrations of HEX and other solvents. This study was undertaken to characterize, for 5 consecutive days, the relationship between HEX exposure (25 ppm and 50 ppm) and (1). 2,5-HD urinary excretion and (2). HEX in alveolar air. METHODS: Five volunteers (three women, two men) were exposed to HEX in an exposure chamber for 2 non-consecutive weeks (7 h/day). They were exposed to 50 ppm HEX, during the first week and to 25 ppm during the second week. Alveolar air and urine samples were collected at different intervals before, during and after the exposures. The concentration of unchanged HEX in alveolar air and the concentration of urinary 2,5-HD under three analytical conditions (with acid, or enzymatic hydrolysis and without hydrolysis) were measured. RESULTS: The results show that the mean concentrations of HEX in alveolar air were 18 ppm (25 ppm) and 37 ppm (50 ppm), which indicates that approximately 73% of inspired HEX was expired unchanged in alveolar air by the volunteers. The mean (+/- SD) concentrations of urinary 2,5-HD for the last 4 h of exposure at the end of the week (day 5) following exposure to 50 ppm HEX were 30.4 micromol/l (+/-7.8 micromol/l) (acid hydrolysis); 5.8 micromol/l (+/-1.0 micromol/l) (enzymatic hydrolysis); 6.2 micromol/l (+/-0.9 micro mol/l) (without hydrolysis). Following the volunteers' exposure to 25 ppm HEX, the urinary excretion concentrations were 15.2 micromol/l +/- 1.9 micromol/l, 3.1 micromol/l +/- 0.7 micromol/l and 3.7 micromol/l +/- 0.5 micromol/l, respectively. CONCLUSION: Both free urinary 2,5-HD and HEX in alveolar air measurements could be used for the biological monitoring of HEX. Between these two indicators, HEX in alveolar air is less variable than 2,5-HD in urine, but the sampling time is more critical. Therefore, biological monitoring of HEX based on the measurement of free urinary 2,5-HD is preferable to HEX in alveolar air. Additionally, we believe that the 2,5-HD values reported in this study better reflect the actual levels of exposure to HEX alone than what has been previously reported in studies that involved co-exposure to other solvents, and that the current BEI value for HEX is most likely more protective than what has been believed up until now.

Adjustment of permissible exposure values to unusual work schedules.

Research activities sought development of a method to adjust exposure limits for 694 substances for unusual work schedules. A consensus was established on the basic toxicological principle for adjustment; criteria for adjustment were selected by a panel of scientists coordinated by a committee of international experts and supported by toxicokinetic modeling; and a group of toxicologists attributed primary health effects and related adjustment category to each substance. A consensus among scientists and employers' and workers' representatives was established on the protocol of the application, in the field, of the adjusted exposure limits. The guiding toxicological principle for adjusting exposure standards to unusual work schedules is to guarantee an equivalent degree of protection for workers with unusual schedules as for workers with a conventional schedule of 8 hours per day, 5 days per week. The process of the adjustment is inspired from the Occupational Safety and Health Administration logic for attribution of primary health effects and adjustment categories ranging from no adjustment to daily or weekly adjustments. The adjusted exposure limits are calculated according to Haber's rule. Decisions on attribution of adjustment categories for the following toxicological effects were reached: respiratory sensitizers (asthma); skin sensitizers; tissue irritants versus tissue toxicants; methemoglobinenia-causing agents; cholinesterase inhibitors; and reproductive system toxicants and teratogens. A simple procedure is presented to facilitate the calculation, application, and interpretation of the adjusted exposure limits.

o-cresol: a good indicator of exposure to low levels of toluene.

This study evaluates the suitability of using urinary excretion of o-cresol (o-CR) as a biological marker of occupational exposure to various concentrations of toluene (TOL). Thirty-eight individuals from three plants involved in the manufacture of paints or inks agreed to participate in the environmental and biological monitoring evaluations, which lasted one to two days. In all, 62 measurements of environmental TOL and urinary o-CR and hippuric acid (HA) levels were made. The eight-hour TOL exposure (time-weighted average [TWA]) ranged from 0 to 111 ppm, depending on plant and job title. TOL exposure was well correlated to post-shift urinary o-CR (r = 0.89) and HA (r = 0.67) levels. At low exposure levels (below 50 ppm), however, o-CR shows a stronger correlation (r = 0.71) than HA (r = 0.24). Based on our results, occupational exposure to 50 ppm of TOL would result in end-of-shift urinary o-CR concentration of 0.72 mumol/mmol creatinine (0.69 mg/L, assuming a urinary creatinine concentration of 1 g/L). This value is of the same order of magnitude as the level proposed by the American Conference of Governmental Industrial Hygienists (ACGIH) in 1998 for exposure to 50 ppm of TOL, namely 0.5 mg/L. Our results suggest that the level of urinary o-CR is a more sensitive index of exposure to low concentrations of TOL than is the urinary concentration of HA.

Pilot study of peripheral markers of catecholaminergic systems among workers occupationally exposed to toluene.

In a pilot study, serum dopamine beta-hydroxylase (DBH), platelets monoamine oxidase type B (MAO B) activities and basal plasma prolactin (PRL) were measured, among 10 workers occupationally exposed to toluene and 10 control subjects, preceding and immediately following vacation. Six exposed subjects were employed in an adhesive tape making industry and 4 in a paint making industry. Their median basal levels of urinary hippuric acid were 0.44 mmole/mmole creatinine (cr) (range 0.23-1.97) and 0.18 mmole/mmole cr (range 0.15-0.19) respectively, the second to last morning of the work week, preceding vacation. The level of basal urinary hippuric acid among the control group was 0.26 mmole/mmole cr (range 0.03-0.38). The workers from the adhesive tape plant reported a significantly higher number of symptoms experienced frequently (Kruskal, Wallis, p < 0.05). On a group basis, serum DBH was lowest among the workers from the adhesive tape plant, who had the highest levels of basal urinary hippuric acid. In addition, a negative relation was observed between hippuric acid and serum DBH, preceding and following vacation (Rho = -0.46, p = 0.05; Rho = -0.51, p = 0.03). The observed changes in serum DBH activity are consistent with its decrease in human, following long-term exposure to styrene, another aromatic hydrocarbon. The findings of this pilot study, on a limited number of individuals suggest that DBH may be a sensitive peripheral bioindicator. Further studies of larger groups should be done to confirm the decrease in serum DBH activity with toluene exposure and explore whether this alteration is related to the neurotoxic impairments associated with exposure.

Surveillance of early neurotoxic dysfunction.

Surveillance of early neurotoxic alterations was undertaken in 3 reinforced plastics plants, with a view to preventive intervention. Using a longitudinal study design, exposure parameters (environmental styrene in the respiratory zone of each worker and end-shift mandelic acid (MA)) and neurobehavioral performance (Neurobehavioral Core Test Battery and Field Assessment: Sensory Tests), were assessed at time zero (T0); recommendations were made to reduce exposure at jobsites with the highest risk. Reassessment was made two years later (T2). Complete exposure data was available for 118 workers at T0; 75 were still employed at T2; of these, 57 (76%) returned for testing. Those who returned had more seniority (p < 0.001) and higher MA (p < 0.01) and styrene (p < 0.05) levels at T0 than the others. Analyses, performed on the T0-T2 differences, showed improvement in exposure parameters in Plant 3, where lower levels were observed at T2 for styrene (p < 0.05) and MA (p < 0.001). workers in Plant 3 (n = 29) performed better (p < 0.05) at T2 for short term memory, perceptuo-motor speed, motor precision and manual dexterity; they reported more vigor (p < 0.05) and less anger (p = 0.07). This was not the case for the workers from the other plants. Generally, the T0-T2 difference in MA was associated (Spearman's Rho) with differences in color vision (p < 0.001), simple reaction time (mean and standard deviation), digit span forward, tension, fatigue and the number of symptoms (p < 0.05); aiming precision showed a similar tendency (p < 0.10). These findings suggest that group surveillance of early nervous system changes for jobs with exposure to neurotoxins, using a sensitive neurofunctional test battery, may be useful for preventive intervention.

Gas chromatographic determination of urinary o-cresol for the monitoring of toluene exposure.

A sensitive and reproducible gas chromatographic procedure for the quantitative determination of urinary o-cresol is described. The first step involves acid hydrolysis (2N HCl, 100 degrees C, 10 min), which yields unconjugated o-cresol. After extraction (methylene chloride, pH 2), the organic layer is concentrated by evaporation and samples are analyzed by gas chromatography-flame ionization detection with a DB-5 column (30 m x 0.25 mm, 0.25 microns). Initial oven temperature is set at 30 degrees C for 12 min and the increased 2 degrees C/min to 93 decrees C. 3,4-Dimethylphenol is used as the internal standard. The detection limit of the method is 0.36 mumol/L (1 microL injection). Additional validation data were obtained by analysis of urine samples collected from volunteers exposed to various concentrations of toluene: 10, 20, 30, 50, and 100 ppm over 7 h. Urinary o-cresol concentrations (0-3, 3-7, 7-24, and 0-24 h) were highly correlated with toluene exposure.

Visual dysfunction among styrene-exposed workers.

OBJECTIVES: The present study was undertaken to examine the relation between visual functions and occupational exposure to styrene. METHODS: A total of 128 workers (85% of the total population), from three glass-reinforced plastics plants in Canada, agreed to participate in the study. Environmental and biological measures were made on the day(s) prior to the assessment of near visual acuity (National Optical Visual Chart), chromatic discrimination (Lanthony D-15 desaturated panel), and near contrast sensitivity (Vistech 6000). The analyses were performed on 81 workers with near visual acuity of at least 1 min of arc at 0.5 m. RESULTS: The subjects were relatively young [29 (SD 8) years], with little seniority [5 (SD 4) years]. Styrene exposure for 8 h ranged from 6 to 937 (first quartile 21 mg.m-3, third quartile 303 mg.m-3), depending on the job site. The end-shift concentrations of urinary mandelic acid ranged from nondetectable to 1.90 mmol.mmol creatinine-1. Significant positive relations were found between the internal and external styrene exposure measurements and color vision loss adjusted for age, alcohol consumption, and seniority in a multiple regression analysis. The multiple regression analysis is also showed that the end-shift concentration of urinary mandelic acid was inversely related to contrast sensitivity at 6 and 12 cycles.degree-1. Logistic multiple regression models indicated that the end-shift concentration of urinary mandelic acid was related to the prevalences of blurred vision, tearing, and eye irritation. CONCLUSIONS: These findings suggest that there is a positive relation between styrene exposure and early color and contrast vision dysfunction.

Kidney function in male and female rats chronically exposed to potassium dichromate.

Male and female Wistar rats were given 25 mg l-1 chromium (as potassium dichromate) in drinking water for 6 months. Lactate dehydrogenase, lysozyme, total proteins, N-acetyl-beta-D-glucosaminidase, albumin and beta 2-microglobulin (beta 2-m) were measured in 24-h urine after 3 and 6 months of exposure. Body and kidney weight and chromium excretion were also examined. Except for the chromium excretion, no statistically significant changes were observed in the exposed male rats. In female rats there were significant increases in the urinary excretion of albumin after 3 and 6 months of exposure and the urinary excretion of beta 2-m after 3 months of exposure.

Simultaneous determination of urinary mandelic, phenylglyoxylic, and mercapturic acids of styrene by high-performance liquid chromatography.

We have developed a relatively simple and reproducible HPLC procedure for the determination of urinary metabolites of styrene. Urine samples (pH 2) are extracted with ethyl acetate, the organic layer is evaporated to dryness, and the residues are dissolved in water-methanol (1:1). Samples are analyzed by HPLC with a C18 reversed-phase column and a water (pH 6, 5mM tetrabutylammonium dihydrogen phosphate)-acetonitrile gradient and ultraviolet detection at 225 nm. Using this method, it is possible to determine simultaneously mandelic and phenylglyoxylic acids, N-acetyl-S-(1-phenyl-2-hydroxyethyl)-L-cysteine (M1), and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-L-cysteine (M2). The internal standard is p-hydroxybenzoic acid. Additional validation data are obtained by analysis of urine samples obtained from rats treated with a wide range of styrene doses.