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PubMed1993

Carbon disulfide and the central nervous system: a 15-year neurobehavioral surveillance of an exposed population.

Carbon disulfide-induced neurobehavioral effects are well known and do not need further evidence. Carbon disulfide vasculopathy and the syndromic complex resulting in depression, loss of memory and concentration, and behavior disturbances have been widely demonstrated. Less known is the evolution of the symptomatology when the environmental conditions are consistently improved, that is, the reversibility or the progression of the dysfunctions observed. This paper reports on a neurobehavioral follow-up in a viscose rayon factory carried out, in intervals, from 1974 to 1990. Several successive improvements were implemented in the plant through the years, until finally, the most radical changes were made at the end of the Seventies and these resulted in exposure levels far below the current Threshold Limit Values. A total of 493 subjects were examined and some of them were reexamined up to six times. The last examination was completed in September, 1990. In this paper, studies by our group over the 15 years of monitoring are discussed. The results show that the general mental state, as measured by neurobehavioral methods, reflects past and current exposure. This point was explored by dividing the subjects into six groups on the basis of their length of exposure and year of examination and by comparing their performances. The results show that even exposure to levels of carbon disulfide not exceeding 8 mg/m3 may induce absentmindedness and difficulties in perceptive abilities.

Adult↗
PubMed1993

Neuropsychological assessment of organic solvent effects in South Africa: test selection, adaptation, scoring, and validation issues.

The neurobehavioral effects of organic solvent exposure were assessed in 68 South African workers in a paint manufacturing plant in which the maximum current combined solvent level in workplace air was 0.72 of the Threshold Limit Value. A 17-test battery was assembled from the WHO-NCTB, NES 2, and the University of South Africa Neuropsychological Assessment Procedure. Extensive modifications were made to some tests in the battery, using a guided learning rationale derived from the cross-cultural literature. In light of test correlations with demographic variables (age, education, and alcohol consumption), the construct and likely predictive validity of the tests in the battery are reviewed, and promising procedures identified. Finally, it is noted that in developing countries, the results of neuropsychological tests that have been well standardized in the West may be misleading unless the underlying validity issues that arise when a test developed in one culture is applied to another have been addressed.

Adult↗
PubMed1995

Neurobehavioral effects of low-level methanol vapor exposure in healthy human volunteers.

Methanol-powered vehicles are being introduced in the United States as a solution to air pollution. This study assessed whether acute exposure to methanol vapor at the current industrial threshold limit value of 200 ppm for 4 hr has adverse effects on human neurobehavioral performance. Twenty-six healthy subjects (15 men, 11 women; ages 26-51 years) were exposed to methanol or water vapor for 4 hr while seated in a chamber. The subjects served as their own controls in a randomized, double-blind study design. The variables assessed were serum and urine methanol and formate levels; visual performance (color discrimination and contrast sensitivity); and neurophysiological (auditory evoked potentials) and neurobehavioral performances. Exposure to methanol increased serum concentrations and urinary excretions of methanol, but did not affect formate levels. Overall visual, neurophysiological, and neurobehavioral test outcomes were not significantly affected, unless certain between-subject variables are considered. Slight effects on P-300 amplitude and Symbol Digit testing were noted. We conclude that acute exposure of healthy people to low concentrations of methanol had little effect on these measures of neurobehavioral performance.

Administration, Inhalation↗
PubMed1997

Epidemiological update on solvent neurotoxicity.

Epidemiological studies of occupational mixed solvent exposure were reviewed for evidence of exposure-related neuropsychiatric disorders, mental symptoms, and neurobehavioral performance. Studies of workers receiving disability pensions found consistent evidence of an increased risk of neuropsychiatric disability among solvent-exposed workers. Study results differed, however, with respect to relations between solvent exposure and specific diagnostic entities. These differences may be attributed to cross-country differences in diagnostic entities and criteria for disability pension eligibility. Psychiatric morbidity studies found no relation between occupational solvent exposure and admission to a hospital for psychiatric illness. Alcohol abuse and solvent exposure in combination seemed to be a risk factor for dementia and cerebral degeneration. Cross-sectional studies supported the hypothesis that occupational, low-level, long-term solvent exposure may cause adverse central nervous system effects. Several studies that used complex measures of lifetime cumulative and average exposure demonstrated significant dose-response relations between exposure, mental symptoms, and neurobehavioral performance. There were discrepancies, however, in the degree of exposure causing these adverse effects. The cumulative findings strongly suggest that occupational solvent exposure may be the cause of mental and cognitive impairment that may become chronic and disabling. The adverse central nervous system effects observed in these studies seemed to occur at exposure levels well below accepted threshold limit values. Lowering these values should be considered.

Case-Control Studies↗
PubMed2000

Inhalation of low concentrations of toluene induces persistent effects on a learning retention task, beam-walk performance, and cerebrocortical size in the rat.

The organic solvent toluene is widely used in industry. The threshold limit value for extended occupational exposure to toluene is presently set to 200 ppm in the United States. We have investigated the effect of an inhalation exposure of 80 ppm for 4 weeks (6 h/day, 5 days/week), followed by a postexposure period of at least 4 weeks, on behavior and brain features in the rat. Toluene exposure appeared to affect spatial memory, since toluene-exposed rats showed a longer time in the correct quadrant in a Morris swim maze. This effect may indicate that the exposed rats used their praxis strategy longer before they started to look for the platform elsewhere. Toluene-exposed rats showed trends for increases in both locomotion and rearing behaviors and a significantly reduced beam-walk performance. The area of the cerebral cortex, especially the parietal cortex, was decreased by 6-10% in toluene-exposed rats, as shown by magnetic resonance imaging of living rats and autoradiograms of frozen brain sections. The K(D) and B(max) values of the dopamine D(3) agonist [(3)H]PD 128907 were not affected by toluene, as measured in caudate-putamen and subcortical limbic area using biochemical receptor binding assays and in caudate-putamen and islands of Calleja using quantitative receptor autoradiography. Hence, previously demonstrated persistent effects by toluene on the binding characteristics of radioligands binding to both D(2) and D(3) receptors seem to indicate a persistent effect of toluene selectively on dopamine D(2) receptors. Taken together, the present results indicate that exposure to low concentrations of toluene leads to persistent effects on cognitive, neurological, and brain-structural properties in the rat.

Administration, Inhalation↗
PubMed1997

Assessing the relevance of rodent data on chemical interactions for health risk assessment purposes: a case study with dichloromethane-toluene mixture.

Several descriptive studies have reported the occurrence of infra-additive and supra-additive toxic interactions in rodents given high doses of chemicals by routes different from anticipated human exposures. In order to assess the relevance of such rodent data on chemical interactions for humans, the route, species, and dose extrapolations need to be conducted on the basis of proven/hypothetical interaction mechanisms. The present study initially developed a physiologically based model of the toxicological interaction reported in rats receiving high oral doses of dichloromethane (DCM) and toluene (TOL). This predictive model was then used to asses the relevance of DCM-TOL interaction for humans exposed to threshold limit values (TLVs) of these chemicals, following the conduct of the various, essential extrapolations (i.e., rat to human, oral to inhalation, high dose to low dose). The interaction modeling approach involved (i) obtaining validated rat and human physiologically based pharmacokinetic (PBPK) models for TOL and DCM from the literature, and (ii) linking them via the modified Michaelis-Menten equation accounting for hypothetical mechanisms of interactions (no interaction, competitive inhibition, noncompetitive inhibition, and uncompetitive inhibition). Of the various interaction mechanisms investigated, the noncompetitive and uncompetitive metabolic inhibitions were found to adequately describe the reduction of carboxyhemoglobinemia (COHB) observed in rats during combined exposures (18.8 mmol/kg TOL, +6.2 mmol/kg DCM, po; 0.005 mmol/kg TOL, ip +5000 ppm DCM, 1 hr). The simulation model, based on noncompetitive and uncompetitive inhibition mechanisms, suggests that only < 10% reduction in the area under the COHB vs time curve (AUCCOHB) is likely to occur in humans exposed to the current TLVs of DCM and TOL (compared to AUCCOHB resulting from an 8-hr exposure to TLV of DCM alone). The present modeling approach, based on hypothetical mechanisms of interaction, then indicates that rodent data on DCM-TOL interaction are not relevant for humans, particularly with respect to the COHB effect. The application of this kind of a predictive modeling approach should be useful in screening the available reports on chemical interactions for identifying those of greater concern at relevant human exposure levels (RfD, RfC, TLV).

Administration, Inhalation↗
PubMed2000

Use of partition models in setting health guidelines for volatile organic compounds.

Partition models based on the octanol-air partition coefficients and associated quantitative structure-activity relationships (QSARs) have been developed to describe the triggering of odor detection, nasal irritation, and narcosis by common volatile organic compounds (VOCs). This study made use of the QSARs developed by Hau and Connell (1998), Indoor Air 8, 23-33) and Hau et al. (1999a, Toxicol. Sci. 47, 93-98; 1999b, Environ. Toxicol. Pharmacol. 7, 159-167) to predict the odor thresholds, nasal pungency thresholds, and anesthetic potency in humans for four groups of VOCs, namely, alkanes, alcohols, ketones, and acetates. The predicted outcomes with their estimated variability were used to evaluate the relevant guidelines on the airborne concentrations of these test groups. Threshold limit values (TLVs) for the test compounds were found to be generally capable of offering adequate protection against nasal pungency and narcosis, except for the higher alcohols (C6-C8) and sec-amyl acetate. The QSARs can also be used to set tentative guidelines for those compounds not having a TLV; values of 5 and 75 ppm were proposed for heptan-1-ol and dibutyl ketone respectively as examples.

Air Pollutants↗
PubMed2000

Low-level toluene disrupts auditory function in guinea pigs.

Toluene appears to have adverse effects on the human auditory system, but it is difficult to estimate its potency since it is commonly present in the workplace in combination with noise exposure; workplace noise exposures are often highly variable. Studies designed to assess toluene ototoxicity specifically have been limited to high-dose studies in a single laboratory animal model, the rat. Here permanent hearing loss has been observed at concentrations of 1000 ppm toluene and greater after inhalation exposure for 5 days, 6 h/day. The OSHA threshold limit value for toluene is only 100 ppm. The current study focuses on the onset of toluene ototoxicity acutely in the guinea pig and in adducing a mechanism of effect. In this study, evidence is presented for the impairment of auditory function by toluene in the guinea pig, at a concentration substantially lower than that used for studying permanent impairment in the rat. The impaired function was correlated with reduced energy metabolism in outer hair cells. Assessment of auditory function was made using distortion product otoacoustic emissions (DPOAE) with subsequent measurement of succinate dehydrogenase (SDH) staining density in hair cells using surface preparations. Temporary disruption of auditory function in guinea pigs is seen in subjects exposed to 250, 500, and 1000 ppm toluene for 8 h/day, 5 day/week for 1 and 4 weeks. Concentrations as low as 250 ppm toluene were able to disrupt auditory function acutely in the guinea pig, and 500 and 1000 ppm toluene produced greater acute dysfunction. SDH staining suggests that reduced enzyme activity in the midfrequency region of the cochlea occurs acutely following toluene exposure. Although the auditory dysfunction progressed between 1 and 4 weeks of exposure, a permanent loss did not develop for these subjects and hair cell death was not seen. The current study identifies early evidence of auditory system impairment in the guinea pig at low toluene concentration and evidence for impairment of energy production in hair cells. While even a transient auditory impairment has implications for workplace safety, additional study on the transition from such acute effects to permanent impairment is essential.

Animals↗
PubMed1982

Neurophysiological effects of long-term exposure to hydrocarbon mixtures.

Motor nerve conduction velocity (MCV) was measured on median, ulnar and peroneal nerves in a reference group of 52 workers and a group of 95 workers exposed to hydrocarbon mixtures in a shoe factory. Exposure-related changes were found in motor action potential (MAP) amplitudes of the three nerves and in median and peroneal MCVs. Electroneurographic abnormalities were also present in a subgroup of workers exposed to air concentrations near the current ACGIH (1979) recommended threshold limit value (TLV) for the mixture. Our results suggest the need for lowering the TLV for the main components n-hexane and cyclohexane. A synergistic effect of the two hexacarbon solvent might also be considered in the hygienic evaluation of the workplace.

Action Potentials↗
PubMed1985

Circulating steroids in male rats following inhalation of n-alcohols.

The effect of inhaled methanol, ethanol, n-propanol and n-butanol on male reproductive function as measured by the serum concentration of circulating T (testosterone) and LH (luteinizing hormone) has been investigated. The animals were exposed to concentrations of these alcohols equal to the current threshold limit values in industry (methanol: 200 ppm, ethanol: 1000 ppm, n-propanol, n-butanol: 50 ppm) 6 h a day for up to 1 week. A significant depression in the concentration of circulating T was found after the first 6 h exposure to the respective alcohols with restoration after a recovery period of 18 h, except in rats exposed to n-butanol where a depression of 48% could still measured. The concentration of LH was within the normal range in all experimental groups whereas corticosterone was increased after exposure to n-butanol. Exposure for 1 week was not associated with any significant inability of the rat testis to produce T.

1-Butanol↗
PubMed1985

The c-wave of the electroretinogram and the standing potential of the eye as highly sensitive measures of effects of low doses of trichloroethylene, methylchloroform, and halothane.

Low and moderate intravenous doses of trichloroethylene, methylchloroform, and halothane dissolved in a lipid emulsion (Intralipid) were given to cynomolgus monkeys. The DC electroretinogram (ERG) and the standing potential of the eye (SP) were recorded directly with corneal contact lenses, very stable calomel electrodes, and under very constant general anesthesia. Even low doses of the substances (close to the hygienic threshold limit values in Sweden) clearly provoked slow variations with time in the amplitude of the c-wave of the ERG and in the SP level. Both potentials are generated mainly in the pigment epithelium. It is suggested that the effects reflect a direct influence of the chemicals upon the metabolism of the pigment epithelium or on the cell membrane. Thus the method used is a highly sensitive measure of effects of certain halogenated hydrocarbons on structures belonging to the central nervous system.

Animals↗
PubMed1982

Standards for chemical quality of drinking water: a critical assessment.

The author critically reviews present standards for the chemical quality of drinking water, particularly the limits proposed by the Commission of the European Communities (CEC) in 1979. Particularly, the general principles of standard setting are discussed. It appears that there exists a surprisingly high similarity in drinking water limits, issued by various national and international authorities, although for other environmental compartments important discrepancies exist. Usually, drinking water limits lack adequate documentation, and appear often to be copied from other existing lists. There is an apparent lack of logical consistency in limits set for food, ambient or workroom air, and drinking water, probably due to lack of communication between health experts and decision-making authorities. Moreover, there is a lack of toxicologic studies, explicitly aimed at setting limits. Extrapolation from the acceptable daily intakes (ADI) for food or the Threshold Limit Value (TLV)-Maximum Acceptable Concentration (MAC) for workroom air could be undertaken to derive tentative drinking water limits, as long as explicitly designed studies for drinking water are not yet available.

Europe↗
PubMed1980

Peripheral nervous system functions of workers exposed to n-hexane at a low level.

In order to assess the effects on the peripheral nervous system of n-hexane at a low level, an epidemiological study using a questionnaire, neurological examinations, and neurophysiological studies was carried out on two age-matched groups; one, consisting of 14 exposed workers and the other, of 14 control workers. The 8 h time weighted average of n-hexane concentration in the exposure environment was 58 +/- 41 (mean +/- SD) ppm. In the individual worker, no obvious signs could be found indicating damage to the nervous system that were referable to the n-hexane exposure. On the other hand, when the subjects were taken in groups, the results obtained from the exposed group showed a minor partiality for functional impairment of the peripheral nervous system in many test items. In particular, statistically significant differences between the two groups were detected in the following items: (1) inquiries by questionnaire for persistent or transient symptoms regarding muscle weaknesses and dyesthesia of limbs; (2) the jump test on one foot; (3) the tuning fork test for vibration sensation on the radial processes; (4) the maximal velocity and the residual latency of motor nerve conduction of the posterior tibial nerve. In conclusion, it is not likely that at exposure levels less than the current threshold limit value of 100 ppm proposed by ACGIH, n-hexane may induce clinically overt polyneurophathy. However, there is no gainsaying the possibility that in the exposed workers as a whole, small cumulative effects in the peripheral nervous system may be brought about by long-term n-hexane exposure less than 100 ppm.

Adult↗
PubMed1988

Epidemiological study on the hepatotoxicity of occupational toluene exposure.

In a cross-sectional study of 181 male workers of a rotogravure printing plant, most of whom were exposed to toluene levels well above the GDR threshold limit values, 55 subjects revealed pathological liver screening values (activities of serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase; liver size). The differential diagnostic examination showed in 51 out of these 55 subjects an association with competing factors such as alcohol abuse (78%) and overweight (40%), to a slight extent disorders of fat and carbohydrate metabolism and of the gallbladder. Drug intake did not play any role. The variance and regression analyses of the biochemical data have shown that alcohol significantly and considerably increases the activities of all three enzymes tested. Bodyweight had a similar, but less pronounced, significant effect. On the other hand, in subjects with a higher alcohol intake the activities of liver enzymes in highly toluene exposed subgroups were significantly and clearly lower than among slightly toluene exposed workers.

Alanine Transaminase↗
PubMed1988

Biological exposure index of styrene suggested by a physiologico-mathematical model.

We used a physiologico-mathematical model to study the biological exposure index of styrene correlated to the Threshold Limit Value (TLV) suggested by the ACGIH for 1986-87. This model allows the solvent concentrations in blood, alveolar air, fat tissue, and in other biological media to be estimated and simultaneously the kinetics of its metabolites to be followed when a specific exposure is settled. The comparison between the results obtained from the mathematical model and the numerous research projects documented in the literature suggests a reciprocal validation. Moreover, some biological parameters (particularly the alveolar ventilation) can explain the variability of results obtained from studies concerning the solvent pollution of the factories, which used biological monitoring. The ranges of styrene concentrations in blood and alveolar air and the urinary concentrations of its metabolites (mandelic and phenylglioxylic acids) are discussed in connection with the exposure at 215 mg/m3. Important differences correlated to the definition of set-levels of TLV and Biological Exposure Index (BEI) have been found: particularly the TLVs lead to different solvent uptakes according to some biological parameters; the BEI can better explain the individual solvent uptake and body burden.

Environmental Exposure↗
PubMed1991

Biological monitoring of isocyanates and related amines. III. Test chamber exposure of humans to toluene diisocyanate.

Five men were exposed to toluene diisocyanate (TDI) atmospheres for 7.5 h. The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m3 stainless-steel test chamber. The mean air concentration of TDI was ca. 40 micrograms/m3, which corresponds to the threshold limit value (TLV) of Sweden. The inhaled doses of 2,4- and 2,6-TDI were ca. 120 micrograms. TDI in the test chamber air was determined by an HPLC method using the 9-(N-methylaminomethyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. After hydrolysis of plasma and urine, the related amines, 2,4- and 2,6-toluenediamine 2,4-, and 2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas-chromatography using selected ion monitoring (SIM) in the electron-impact mode. The urinary elimination of the TDAs showed a possible biphasic pattern, with rapid first phases for 2,4-TDA (mean t1/2 for the concentration in urine, 1.9 h) and for 2,6-TDA (mean t1/2 for the concentration in urine, 1.6 h). The cumulative amount of 2,4-TDA excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-TDA in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-TDA was 5 micrograms/l in the 6 to 8-h sample (range 2.8-9.6 micrograms/l), and the corresponding value for 2,6-TDA was 8.6 micrograms/l (range, 5.6-16.6 micrograms/l). Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4- and 2,6-TDA in urine is feasible.

Adult↗
PubMed1991

Quantitation of urinary chlorobenzene metabolites by HPLC: concentrations of 4-chlorocatechol and chlorophenols in urine and of chlorobenzene in biological specimens of subjects exposed to chlorobenzene.

A simple method for the determination of 4-chlorocatechol (ClCh, 4-chloro-1,2-benzenediol) and chlorophenols (ClPh), metabolites of monochlorobenzene (ClBz), in urine by high performance liquid chromatography (HPLC) is described. Enzymatic hydrolysates of urine were applied to a stainless-steel column packed with octadecyl-silanized silica gel, and a mixed solution of 20 mM potassium phosphate monobasic: acetonitryl (75:25, v/v) was used as a mobile phase. The procedures for ether extraction and evaporation of extract could be omitted. The accuracy and precision of the present HPLC method were satisfactory. The excretion kinetics of ClCh and p-ClPh were investigated over 35 h after cessation of ClBz inhalation. Proportional relationships between concentrations of ClBz in air and of its metabolites in urine were observed. The slopes of regression lines predicting the levels of ClCh, p-ClPh and total ClPh in urine taken during the last 2 h of exposure to ClBz in air were 6.56, 1.13 and 2.83 mg/g creatinine for 1 ppm ClBz, respectively. ClBz in the blood and the end exhaled air of subjects at the end of exposure were identified by gas chromatography (GC) and mass spectrometry. A proportional relationship was observed between the concentration of ClBz in air and that in blood. The validity of the threshold limit value (TLV) for ClBz as evaluated from the subjective and objective symptoms is discussed.

Adult↗
PubMed1985

Corneal ulcer after exposure to vapours from bone cement (methyl methacrylate and hydroquinone).

An operation nurse repeatedly developed a corneal ulcer while mixing bone cement. It is suggested that the ulcer developed because of a composite effect of vapours from bone cement (methyl methacrylate monomer and hydroquinone), in spite of the fact that the Occupational Health Guidelines and the national threshold limit values for chemical substances had been respected. In-vitro and in-vivo animal studies are reviewed.

Adult↗