Colour vision and occupational toluene exposure: results of repeated examinations

Potential effects of human occupational exposures to toluene on colour vision were investigated in a follow-up study over 4 years with three repeated examinations. Colour vision was measured with the Lanthony desaturated colour vision test D-15d, and the colour confusion index (CCI) was calculated. The mean current exposures were 26+/-21 ppm for printers (high toluene level) and 3+/-4 ppm for end-processors (low toluene level). The mean exposure durations were 23+/-6 years for "long-time exposed" and 7+/-2 years for "short-time exposed" subjects. Repeated analyses (n=162) and multiple regressions (maximum available n=267) did not reveal significant effects of toluene with respect to intensity or duration of current or long-term exposure. Age and occupational qualification were significantly associated with CCI in both kinds of analysis, whereas alcohol consumption (carbohydrate-deficient transferrin, CDT) and smoking habits (cigarettes per day) were not. It is concluded that current industrial exposure limits of toluene provide sufficient protection against possible disturbance of colour vision.     

Diazepam influences urinary bioindicator of occupational toluene exposure

In the present study, we investigated the influence of diazepam (DZP) on the excretion of TOL by examining their urinary metabolites, hippuric acid (HA) and ortho-cresol (o-C). Male Wistar rats were exposed to TOL (20 ppm) in a nose-only exposure chamber (6 h/day, 5 days/week for 6 weeks) with simultaneous administration of DZP (10 mg/kg/day). Urinary o-C levels were determined by GC–MS, while HA, creatinine (CR), DZP and its metabolite, nordiazepam, were analysed by HPLC-DAD. The results of a Mann-Whitney U test showed that DZP influenced the urinary excretion of o-C (p < 0.05). This pioneering study revealed that there was an interaction between DZP and TOL, probably by the inhibition of the CYP isoforms (CYP2B6, CYP2C8, CYP2E1, and CYP1A2) involved in the oxidative metabolism of the solvent. This is relevant information to be considered in the biomonitoring of occupational toluene exposure.     

A meta-analytical approach to neurobehavioural effects of occupational toluene exposure

Twenty-two studies investigating neurobehavioural effects of toluene were reviewed. Repeatedly applied neuropsychological performance tests and appropriately documented results allowed to include 10 of the studies into a meta-analysis based on effect sizes. Mean exposure level of the studies was 57 ppm (range 20–117 ppm) toluene.

Five of the six analyses of neuropsychological tests obtained effect sizes suggesting a negative impact of toluene, but for none of the analyses a significant effect size was estimated at averaged exposure levels between 33 and 89 ppm. The tests represented the psychological domains of attention and constructional performance. Additionally, the relation between exposure conditions (level of exposure, length of exposure), potential confounders (age, verbal intelligence), and effect sizes was analysed. Only pre-exposure intellectual capacity showed a consistent relation to effect sizes.

The study suggests that homogenisation of study groups with respect to intelligence, cultural background and practice trials is important when investigating low-level exposure. Efforts to homogenize studies should be completed by a thorough documentation of feasible influences.     

Inhalation exposure to formaldehyde and toluene in the same occupational and consumer setting

Formaldehyde, a natural component of all mammalian cells, is metabolized to carbon dioxide. It is a colorless gas used as a preservative and a reactant in chemical processes in a wide variety of commercial and consumer products. Toluene is an organic solvent also used in a wide variety of commercial and consumer products. There is a growing concern that chemical exposure from consumer products including cosmetics adds to the overall toxic exposure bioburden. This study was designed to quantify the actual amount of formaldehyde and toluene exposure to professional nail technicians and their customers during the application of cosmetic nail products containing either formaldehyde or toluene. Formaldehyde concentrations were measured on workers and consumers using treated silica gel absorption tubes. Formaldehyde concentrations varied between 0.0012 and 0.0038 ppm. The results of this study clearly demonstrate that neither workers nor consumers are at any additional risk from exposure to formaldehyde or toluene in cosmetic nail products beyond daily exposure from commercial products in a work setting and in the home.     

Risk evaluation of occupational exposure to methylene dianiline and toluene diamine in polyurethane foam

Methylene diphenylisocyanate (MDI) and toluene diisocyanate (TDI) are widely used in industry to produce polyurethane foam products. Small amounts of methylenedianiline (MDA) and toluene diamine (TDA) are released during MDI and TDI polymerization and may be present in newly finished polyurethane foam parts. MDA and TDA concentrations in foam decline exponentially within several hours of demolding. MDA and the 2,4-isomer of TDA are known animal carcinogens and, in addition, have significant non-carcinogenic health effects. Our goal was to determine whether worker exposure to MDA or TDA in freshly produced polyurethane foams was associated with unacceptable health risks. Sampling and analysis of the fresh foam indicated that MDA and TDA concentrations varied considerably among products, but concentrations in all materials evaluated declined rapidly over time. We found that, under a worst-case exposure scenario, cancer risks from TDA exposure were approximately 5 x 10(-6), whereas cancer risks from MDA exposure resulted in a tumorigenic margin of exposure (MOE) of 85 000. Non-cancer chronic hazard indices were well below 1.0. Therefore, the potential cancer and non-cancer health risks from MDA or TDA exposure to newly manufactured foam parts appear to fall well within acceptable health risk criteria.     

Changes in correlation coefficients of exposure markers as a function of intensity of occupational exposure to toluene

This study was initiated to identify a marker of choice to monitor occupational exposure to toluene through quantitative evaluation of changes in correlation coefficients (CCs), taking advantage of a large database. Six known or proposed exposure markers in end-of-shift blood (B) and urine (U) were studied, i.e., toluene in blood (Tol-B) and benzyl alcohol, benzylmercapturic acid, o-cresol, hippuric acid and toluene in urine (BeOH-U, BMA-U, o-CR-U, HA-U, and Tol-U, respectively). To construct a database, data on 8-h time-weighted average intensity of occupational exposure to toluene and resulting levels of the six exposure markers in blood or urine were cited for 901 cases from previous four publications of this study group and combined with 146 new cases. In practice, 874 cases (all men) were available when extremely dilute or dense urine samples were excluded. The 874 cases were classified taking the upper limit (from 120 ppm to 1 ppm) of the toluene exposure concentration, and the CCs for the six markers with TWA toluene exposure intensity were calculated. For further evaluation, the 874 cases were divided into 10%-tiles in terms of TWA toluene exposures, and several 10%-tiles were combined so that sufficient numbers of cases were available for calculation of the CCs at various levels of toluene exposure. Perusal was made to know whether or not and which one of the six makers gave significant CC even at low level of toluene exposure. The CCs for BMA-U, o-CR-U and HA-U with TWA toluene exposure were well >0.7 when toluene exposure was intense (e.g., up to 60–100 ppm as the upper limit of the exposure range), but were reduced when the upper limit of toluene exposure was less than 50 ppm, and the CCs were as small as ≦0.2 when the upper limit was about 10 ppm or less. In contrast, Tol-U and Tol-B were correlated with exposure to toluene down to the ≦3 ppm range. The CC for BeOH-U was <0.1 almost throughout the exposure ranges. Further analyses showed that the CCs for all markers (except the CC for BeOH-U) were >0.4 when the cases in the 60th–100th%-tiles were examined. The CCs for Tol-U and Tol-B were >0.3 also for cases in the 0th–60th or 30th–70th%-tiles, whereas the CCs for other four markers were <0.3. In over-all evaluation, it was concluded that HA and o-CR are among the markers of choice to monitor occupational toluene exposure at high levels, and that only un-metabolized toluene in urine or in blood is recommended when toluene exposure level is low (e.g., 10 ppm or less). Toluene in urine may be preferred rather than that in blood due to practical reasons, such as non-invasiveness.     

Changes in correlation coefficients of exposure markers as a function of intensity of occupational exposure to toluene

This study was initiated to identify a marker of choice to monitor occupational exposure to toluene through quantitative evaluation of changes in correlation coefficients (CCs), taking advantage of a large database. Six known or proposed exposure markers in end-of-shift blood (B) and urine (U) were studied, i.e., toluene in blood (Tol-B) and benzyl alcohol, benzylmercapturic acid, o-cresol, hippuric acid and toluene in urine (BeOH-U, BMA-U, o-CR-U, HA-U, and Tol-U, respectively). To construct a database, data on 8-h time-weighted average intensity of occupational exposure to toluene and resulting levels of the six exposure markers in blood or urine were cited for 901 cases from previous four publications of this study group and combined with 146 new cases. In practice, 874 cases (all men) were available when extremely dilute or dense urine samples were excluded. The 874 cases were classified taking the upper limit (from 120 ppm to 1 ppm) of the toluene exposure concentration, and the CCs for the six markers with TWA toluene exposure intensity were calculated. For further evaluation, the 874 cases were divided into 10 per thousand in terms of TWA toluene exposures, and several 10 per thousand were combined so that sufficient numbers of cases were available for calculation of the CCs at various levels of toluene exposure. Perusal was made to know whether or not and which one of the six makers gave significant CC even at low level of toluene exposure. The CCs for BMA-U, o-CR-U and HA-U with TWA toluene exposure were well >0.7 when toluene exposure was intense (e.g., up to 60-100 ppm as the upper limit of the exposure range), but were reduced when the upper limit of toluene exposure was less than 50 ppm, and the CCs were as small as <==0.2 when the upper limit was about 10 ppm or less. In contrast, Tol-U and Tol-B were correlated with exposure to toluene down to the 0.4 when the cases in the 60th-100th per thousand were examined. The CCs for Tol-U and Tol-B were >0.3 also for cases in the 0th-60th or 30th-70th per thousand, whereas the CCs for other four markers were <0.3. In over-all evaluation, it was concluded that HA and o-CR are among the markers of choice to monitor occupational toluene exposure at high levels, and that only un-metabolized toluene in urine or in blood is recommended when toluene exposure level is low (e.g., 10 ppm or less). Toluene in urine may be preferred rather than that in blood due to practical reasons, such as non-invasiveness.     

Ambient air levels and occupational exposure to benzene,toluene, and xylenes in northwestern Italy

The purpose of this study was to determine benzene, toluene, and xylenes air pollution in two cities in Italy (Biella and Torino) having different traffic intesities and to investigate whether new environmental conditions occurred consequent to the changes of gasoline composition in Europe during the last 20 yr. Furthermore, three types of urban occupational exposure (petrol pump attendants, traffic policemen, and municipal employees) to the same hydrocarbons were compared to verify three different expected levels of exposure. Results in Biella demonstrate a direct relationship between traffic density and level of human exposure to these pollutants. Air concentrations for benzene were 2.3 micrograms/m3 in a suburban area having low traffic and 10.3 micrograms/m3 in the central area having high traffic. The comparison to trend analysis recently carried out in Torino indicates it is possible to improve the situation in the central area of Biella by adopting the same traffic limitations imposed in Torino. Personal sampling devices demonstrated that only the petrol pump attendants show, by means of a multivariate analysis, statistically significant higher levels of benzene compared to the other two professional categories, in both winter and summer. Values found in the present study for petrol pump attendants were around 1 mg/m3. Environmental and occupational exposure to benzene, toluene, and xylenes could be largely lowered by adopting preventive measures including traffic restrictions, the reduction of aromatic chemical content in gasoline, and the recovery of gasoline vapors at petrol pump stations.     

The effects of simultaneous exposure to methyl ethyl ketone and toluene on urinary biomarkers of occupational N,N-dimethylformamide exposure

General regulations and risk assessment regarding toxicants are single-compound oriented even though humans are exposed to multi-chemicals in the general environment. This study investigated the effects of different levels of N,N-dimethylformamide (DMF) and co-exposure levels of methyl ethyl ketone (MEK) and toluene (TOL) on two biomarkers of DMF exposure: non-metabolized urinary (U-)DMF and the DMF metabolite urinary N-methylformamide (NMF). Thirty-five workers were selected from a two-stage field investigation strategy and were classified into four groups based on DMF exposure and co-exposure levels. Breathing-zone air concentrations of DMF, MEK, and TOL as well as dermal DMF exposure were determined. Post-shift U-DMF and U-NMF levels were determined for each individual. U-DMF concentrations were significantly higher in high-DMF groups than in low-DMF groups, but U-NMF concentrations were significantly (P<0.05) lower in the high-DMF-high-co-exposure group than in the high-DMF-low-co-exposure group; there were no significant differences between two low-DMF groups. The ratio of U-NMF to U-DMF showed the biotransformation from DMF to NMF was significantly suppressed at high co-exposure (P<0.001) for high-DMF exposure groups, possibly because of competitive inhibition of CYP2E1, the responsible enzyme involved. Due to the ubiquity of MEK/TOL in DMF-exposed occupational settings, the biological exposure index for occupational DMF exposure should be re-evaluated at high co-exposure levels.     

Developmental neurotoxicity after toluene inhalation exposure in rats.

Rats were exposed to 1200 ppm or 0 ppm toluene (CAS 108-88-3) for 6 h per day from day 7 of pregnancy until day 18 postnatally. Developmental and neurobehavioral effects in the offspring were investigated using a test battery including assessment of functions similar to those in the proposed OECD TG for Developmental Neurotoxicity Study, i.e., physical development, reflex ontogeny, motor function, motor activity, sensory function, and learning and memory. The exposure did not cause maternal toxicity or decreased viability of the offspring. Lower birth weight, delayed ontogeny of reflexes, and increased motor activity in the open field was registered in the exposed offspring. Impaired cognitive function was revealed in the exposed female offspring at the age of 3.5 months, i.e., they used more time to locate the hidden platform in the Morris water maze after platform relocation. The difference was not related to poorer swimming capabilities, because swim speeds were similar to control values. The results show that exposure to 1200 ppm toluene during brain development caused long-lasting developmental neurotoxicity in rats.     

Benzylmercapturic acid is superior to hippuric acid and o-cresol as a urinary marker of occupational exposure to toluene

The present study was initiated to examine whether urinary benzylmercapturic acid (or N-acetyl-S-benzyl cysteine, BMA), a mercapturate metabolite of toluene, increases in relation to the intensity of toluene exposure, and whether this metabolite is a better marker of occupational exposure to toluene than two traditional markers, hippuric acid and o-cresol. Accordingly, end-of-shift urine samples were collected from 122 printers and 30 office clerks (all men) in the second half of a working week. Solvent (toluene) exposure of the day (8 h) was monitored by means of diffusive sampling. Quantitative relation with toluene showed that BMA had a greater correlation coefficient with toluene (r = 0.7) than hippuric acid (r = 0.6) or o-cresol (r = 0.6). The levels in the urine of the non-exposed control subjects were below the detection limit of 0.2 microg/l for BMA, whereas it was at substantial levels for hippuric acid and o-cresol (239 mg/l and 32 microg/l as a geometric mean, respectively). Thus, BMA, hippuric acid and o-cresol could separate the exposed from the non-exposed when toluene was at < 1, 50 and 3 ppm, respectively. Overall, therefore, it appeared reasonable to conclude that BMA is superior to hippuric acid and o-cresol as a marker of occupational exposure to toluene.     

The toxicology of hydroquinone--relevance to occupational and environmental exposure.

Hydroquinone (HQ) is a high-volume commodity chemical used as a reducing agent, antioxidant, polymerization inhibitor, and chemical intermediate. It is also used in over-the-counter (OTC) drugs as an ingredient in skin lighteners and is a natural ingredient in many plant-derived products, including vegetables, fruits, grains, coffee, tea, beer, and wine. While there are few reports of adverse health effects associated with the production and use of HQ, a great deal of research has been conducted with HQ because it is a metabolite of benzene. Physicochemical differences between HQ and benzene play a significant role in altering the pharmacokinetics of directly administered when compared with benzene-derived HQ. HQ is only weakly positive in in vivo chromosomal assays when expected human exposure routes are used. Chromosomal effects are increased significantly when parenteral or in vitro assays are used. In cancer bioassays, HQ has reproducibly produced renal adenomas in male F344 rats. The mechanism of tumorigenesis is unclear but probably involves a species-, strain-, and sex-specific interaction between renal tubule toxicity and an interaction with the chronic progressive nephropathy that is characteristic of aged male rats. Mouse liver tumors (adenomas) and mononuclear cell leukemia (female F344 rat) have also been reported following HQ exposure, but their significance is uncertain. Various tumor initiation/promotion assays with HQ have shown generally negative results. Epidemiological studies with HQ have demonstrated lower death rates and reduced cancer rates in production workers when compared with both general and employed referent populations. Parenteral administration of HQ is associated with changes in several hematopoietic and immunologic endpoints. This toxicity is more severe when combined with parenteral administration of phenol. It is likely that oxidation of HQ within the bone marrow compartment to the semiquinone or p-benzoquinone (BQ), followed by covalent macromolecular binding, is critical to these effects. Bone marrow and hematologic effects are generally not characteristic of HQ exposures in animal studies employing routes of exposure other than parenteral. Myelotoxicity is also not associated with human exposure to HQ. These differences are likely due to significant route-dependent toxicokinetic factors. Fetotoxicity (growth retardation) accompanies repeated administration of HQ at maternally toxic dose levels in animal studies. HQ exposure has not been associated with other reproductive and developmental effects using current USEPA test guidelines. The skin pigment lightening properties of HQ appear to be due to inhibition of melanocyte tyrosinase. Adverse effects associated with OTC use of HQ in FDA-regulated products have been limited to a small number of cases of exogenous ochronosis, although higher incidences of this syndrome have been reported with inappropriate use of unregulated OTC products containing higher HQ concentrations. The most serious human health effect related to HQ is pigmentation of the eye and, in a small number of cases, permanent corneal damage. This effect has been observed in HQ production workers, but the relative contributions of HQ and BQ to this process have not been delineated. Corneal pigmentation and damage has not been reported at current exposure levels of <2 mg/m3. Current work with HQ is being focused on tissue-specific HQ-glutathione metabolites. These metabolites appear to play a critical role in the renal effects observed in F344 rats following HQ exposure and may also be responsible for bone marrow toxicity seen after parenteral exposure to HQ or benzene-derived HQ.     

Risk assessment and management of occupational exposure to pesticides.

Occupational exposure to pesticides in agriculture and public health applications may cause acute and long-term health effects. Prevention of adverse effects in the users requires actions to be undertaken in the pre-marketing and post-marketing phase of these products. The pre-marketing preventive actions are primary responsibility of industry and the public administration. Admission of pesticide use (registration) is carried out by considering the toxicological properties of each pesticide (hazard identification), determining the dose-response relationship (NOEL identification), assessing or predicting the exposure level in the various scenarios of their use, and characterising the risk. The decision about admission takes into consideration the balance between risks and benefits. The post-marketing preventive activities consist of the promotion of a proper risk management at the workplace. Such a management includes the risk assessment of the specific conditions of use, the adoption of proper work practices, and the health surveillance of the workers. Each country should develop an adequate National Plan for Prevention of Pesticide Risk which allocates different roles and tasks at the central, regional and local level.     

Measurement and reduction of occupational exposure to inhaled anaesthetics.

The occupational exposure of hospital staff to inhaled anaesthetics was investigated using a personal sampling device that provides a measure of the average concentrations breathed by a person over a period of time, as distinct from the spot sampling in the general environment. The anaesthetist's average exposure to nitrous oxide and halothane during complete operating sessions was twice that expected from simple dilution of the escaping gases by the operating room ventilation. The sampling technique was also used to evaluate the effect of (1) redirection of the waste gas outflow; (2) active scavenging connected to the piped vacuum system. Short-period studies under controlled conditions in the operating theatres and anaesthesia induction rooms showed that the anaesthetist's exposure could be reduced two- or fourfold by redirecting the outflow and another four- to sixfold by active scavenging. Exposures during complete operating sessions were reduced two- to seven-fold by scavenging.     

Effects of high doses of toluene on color vision

High exposure to toluene may cause optic neuropathy and retinopathy, both associated with dyschromatopsia. Another solvent, ethanol, is known to induce acute blue-yellow dyschromatopsia. This study investigated the acute effects of high doses of toluene on color vision. Eight male printshop workers were examined before and after cleaning printing containers with pure toluene. After cleaning, concentrations of toluene in blood were between 3.61 and 7.37 mg/l. Color vision was tested with the Farnsworth panel D-15 test, the Lanthony desaturated panel D-15 test, and the Standard Pseudoisochromatic Plates part 2. For control of possible acute effects, eight workers of a metal-working factory without any neurotoxic exposure were tested according to the same procedure. Acute exposure to toluene did not cause impairment of color vision. However, statistical power is limited due to the small number of exposed subjects. Color vision of the printshop workers tested before cleaning was slightly impaired (statistically not significant) when compared with unexposed subjects.     

Developmental toxicity of prenatal exposure to toluene

Organic solvents have become ubiquitous in our environment and are essential for industry. Many women of reproductive age are increasingly exposed to solvents such as toluene in occupational settings (ie, long-term, low-concentration exposures) or through inhalant abuse (eg, episodic, binge exposures to high concentrations). The risk for teratogenic outcome is much less with low to moderate occupational solvent exposure compared with the greater potential for adverse pregnancy outcomes, developmental delays, and neurobehavioral problems in children born to women exposed to high concentrations of abused organic solvents such as toluene, 1,1,1-trichloroethane, xylenes, and nitrous oxide. Yet the teratogenic effects of abuse patterns of exposure to toluene and other inhalants remain understudied. We briefly review how animal models can aid substantially in clarifying the developmental risk of exposure to solvents for adverse biobehavioral outcomes following abuse patterns of use and in the absence of associated health problems and co-drug abuse (eg, alcohol). Our studies also begin to establish the importance of dose (concentration) and critical perinatal periods of exposure to specific outcomes. The present results with our clinically relevant animal model of repeated, brief, high-concentration binge prenatal toluene exposure demonstrate the dose-dependent effect of toluene on prenatal development, early postnatal maturation, spontaneous exploration, and amphetamine-induced locomotor activity. The results imply that abuse patterns of toluene exposure may be more deleterious than typical occupational exposure on fetal development and suggest that animal models are effective in studying the mechanisms and risk factors of organic solvent teratogenicity.     

Hypothalamic-pituitary-adrenocortical axis activity and immune function after oral exposure to benzene and toluene.

Benzene and toluene, commonly used solvents, possess neurotoxic and immunotoxic effects. Male CD-1 mice were continuously fed drinking water containing 0, 31, 166 and 790 mg/l benzene and 0, 17, 80 and 405 mg/l toluene, respectively. The concentrations of hypothalamic norepinephrine (NE) and its metabolite vanillylmandelic acid (VMA), circulating corticosterone and adrenocorticotropic hormone (ACTH), and lymphocyte-derived interleukin-2 (IL-2) activity were evaluated after 28 days of exposure to each solvent. Serum corticosterone was also measured at pretreatment, 2, 7, and 14 days of exposure. The concentrations of NE, VMA, ACTH and corticosterone were increased following exposure to these solvents. Benzene increased corticosterone levels in mice after 7 days (166 and 790 mg/l) and at 28 days (790 mg/l). Toluene elevated corticosterone levels at 14 and 28 days at the 405 mg/l exposure. IL-2 production by mouse T-lymphocytes was suppressed in the two higher benzene-treated groups, while toluene decreased IL-2 synthesis at the highest level only. Both benzene and toluene exposures stimulated hypothalamic-pituitary-adrenocortical (HPA) activity. Elevated corticosterone has been reported to inhibit IL-2 production and impair immunocompetence. Organic solvents may have, at least partially, an additive adverse effect on immune function via activated HPA status.     

Acute toluene exposure and rat visual function in proportion to momentary brain concentration.

Acute exposure to toluene was assessed in two experiments to determine the relationship between brain toluene concentration and changes in neurophysiological function. The concentration of toluene in brain tissue at the time of assessment was estimated using a physiologically based pharmacokinetic model. Brain neurophysiological function was measured using pattern-elicited visual evoked potentials (VEP) recorded from electrodes located over visual cortex of adult male Long-Evans rats. In the first experiment, VEPs were recorded before and during exposure to control air or toluene at 1000 ppm for 4 h, 2000 ppm for 2 h, 3000 ppm for 1.3 h, or 4000 ppm for 1 h. In the second experiment, VEPs were recorded during and after exposure to clean air or 3000 or 4000 ppm toluene. In both experiments, the response amplitude of the major spectral component of the VEP (F2 at twice the stimulus rate in steady-state responses) was reduced by toluene. A logistic function was fit to baseline-adjusted F2 amplitudes from the first experiment that described a significant relationship between brain toluene concentration and VEP amplitude deficits. In the second experiment, 3000 ppm caused equivalent VEP deficits during or after exposure as a function of estimated brain concentration, but 4000 ppm showed a rapid partial adaptation to the acute effects of toluene after exposure. In general, however, the neurophysiological deficits caused by acute toluene exposure could be described by estimates of the momentary concentration of toluene in the brain at the time of VEP evaluation.