Vesa Riihimäki

Metabolic interaction between m-xylene and ethanol.

Ingestion of a moderate dose of ethanol (0.8 g/kg) by volunteers prior to 4-h inhalation exposure to m-xylene (6.0 or 11.5 mmol/m3) caused marked alterations in xylene kinetics. After ethanol intake the blood xylene level rose about 1.5–2.0-fold and urinary methylhippuric acid excretion declined by about 50% suggesting that ethanol decreased the metabolic clearance of xylene by about one half during xylene inhalation. This effect was noticeable up until a few hours after completed xylene exposure. Urinary excretion of 2,4-xylenol, the minor m-xylene metabolite, was generally not decreased by ethanol and sometimes the reverse seemed to be the case. The disturbance of xylene kinetics can be hypothesized to be caused mainly by ethanol-mediated inhibition of microsomal metabolism.When four volunteers who ingested ethanol prior to m-xylene inhalation at the higher concentration were monitored for blood acetaldehyde, transiently raised levels were found without notable effects on ethanol elimination. This observation may explain why some individuals experienced dizziness and nausea during the combined ethanol-xylene exposure.

Urinary disposition of ethylbenzene and m-xylene in man following separate and combined exposure

SummaryFour volunteer subjects were exposed to 150ppm (655 mg/m3) of ethylbenzene and 150ppm (655mg/m3) of m-xylene both separately and in combination. The biotransformation of the solvents was studied on the basis of the metabolites found in the urine. The metabolic conversion of both m-xylene and ethylbenzene proceeded mainly through oxidation of side chains. Ring oxidation seemed to be of minor importance; in the case of ethylbenzene it accounted for 4.0% (combined share of 4-ethylphenol, p- and m-hydroxyacetophenones) and in case of m-xylene for 2.5% (2,4 dimethylphenol), respectively. Mandelic and phenylglyoxylic acids amounted to 90% of the ethylbenzene metabolites, whereas m-xylene were excreted to 97% in the form of m-methylhippuric acid. Almost equimolar amounts in the form of metabolites of both solvents were found in the urine during 24h from the onset of exposure. Most of the ethylbenzene metabolites were excreted at substantially slower rates than those of m-xylene. The combined exposure resulted in a mutual inhibition of the metabolism of ethylbenzene and m-xylene, which was demonstrated by delayed excretion and decreased amounts of metabolites excreted. No sign of alteration in the urinary metabolite patterns of either ethylbenzene or m-xylene could be detected.

Occupational exposure to lead and neuropsychological dysfunction

OBJECTIVE: To evaluate the neuropsychological effects of current low level and previous higher levels of exposure to lead and evaluate the relation between effects of lead and bone lead. METHODS: A neuropsychological test battery was given to 54 storage battery workers with well documented long term exposure to lead. The effect was studied in two subgroups: those whose blood lead had never exceeded 2.4 mmol/l (the low BPbmax group, n = 26), and those with higher exposure about 10 years earlier (the high BPbmax group, n = 28). In both groups, the recent exposure had been low. Correlations between the test scores and the indices of both long term and recent exposure--including the content of lead in the tibial and calcaneal bone--and covariance analyses were used to assess the exposure-effect relation. Age, sex, and education were controlled in these analyses. RESULTS: Analyses within the low BPbmax group showed a decrement in visuospatial and visuomotor function (block design, memory for design, Santa Ana dexterity), attention (digit symbol, digit span), and verbal comprehension (similarities) associated with exposure to lead and also an increased reporting of subjective symptoms. The performance of the high BPbmax group was worse than that of the low BPbmax group for digit symbol, memory for design, and embedded figures, but there was no reporting of symptoms related to exposure, probably due to selection in this group. No relation was found between the output variables and the tibial lead concentration. The calcaneal lead concentrations were related to the symptoms in the low BPbmax group. CONCLUSIONS: Neuropsychological decrements found in subjects with high past and low present exposure indicate that blood lead concentrations rising to 2.5-4.9 mmol/l cause a risk of long lasting or even permanent impairment of central nervous system function. Milder and narrower effects are associated with lower exposures; their reversibility and time course remain to be investigated. History of blood lead gives a more accurate prediction of the neuropsychological effects of lead than do measurements of bone lead.

Decrements in cognitive performance in metal inert gas welders exposed to aluminium.

OBJECTIVES: Often little has been discovered of the cognitive functions affected by occupational toxins because many functions cooperate to produce the single performance scores typically reported from neuropsychological tests. To facilitate the interpretation of neuropsychological scores, the issue of occupational exposure to aluminium was examined with an approach intended to increase understanding of those cognitive processes that may be affected. METHODS: The investigation was a cross sectional study of asymptomatic aluminium welders and a reference group of mild steel welders. Based on urinary aluminium concentrations, welders were classified into a reference (n = 28), low (n = 27), and high (n = 24) exposure group. The mean urinary aluminium concentrations were 0.46, 2.25, and 9.98 mumol/l, respectively. A comprehensive neuropsychological examination was undertaken to assess psychomotor function, simple visual reaction time, attention related tasks, verbal and visual or visuospatial abilities as well as verbal and visual learning and memory. RESULTS: Aluminium welders showed no impairment on the finger tapping, Santa Ana dexterity, simple visual reaction times, any of the verbal memory tasks, the similarities subtest of Wechsler adult intelligence scale, or the Stroop task. However, the low exposed group performed poorer on the memory for designs and on more difficult block design items demanding preliminary visuospatial analysis. The time limited synonym task, embedded figures, digit symbol speed, and the backward counting component of the divided attention task showed exposure-response relations. CONCLUSIONS: The impairments found were circumscribed. When the neuropsychological tasks were scored to show some of the underlying theoretical cognitive structures, the results indicated that performance difficulties were mainly detected in tasks requiring working memory, particularly that relating to processing of visuospatial information. There was also evidence that such impairments are more readily found in time limited tasks involving visually presented material, in which effective visual scanning combined with control of working memory is demanded.

The ototoxic interaction of styrene and noise.

The interaction between noise and inhaled styrene on the structure and function of the auditory organ of the male Wistar rat was studied. The animals were exposed either to 600 ppm, 300 ppm or 100 ppm styrene (12 h/day, 5 days/week, for 4 weeks) alone or in combination with a simultaneous 100-105 dB industrial noise stimulant. Auditory sensitivity was tested by auditory brainstem audiometry at 1.0, 2.0, 4.0 and 8.0 kHz frequencies. Inner ear changes were studied by light microscopy. Exposure to 600 ppm styrene alone caused a 3 dB hearing loss only at the highest test frequency (8 kHz). Quantitative morphological analysis of cochlear hair cells (cytocochleograms) showed a severe outer hair cell (OHC) loss particularly in the third OHC row of the upper basal and lower middle coil. Exposure to noise alone caused only a mild hearing loss (2-9 dB), and only an occasional loss of OHCs (<1% missing). Exposure to the combination of noise and 600 ppm styrene caused a moderate flat hearing loss of 23-27 dB. The cytocochleograms showed a more severe damage of the OHCs than after exposure to 600 ppm styrene alone. The inner hair cells were found to be destroyed in some animals in the upper basal turn only after the combination exposure. Only in combination with noise exposure, the lower styrene concentrations (100 and 300 ppm) induced a hearing loss which was equivalent to that seen after exposure to noise alone. We conclude that: (1) There is an ototoxic interaction between styrene and noise. (2) Synergism is manifested only if styrene is applied in concentrations above the critical level (between 300 and 600 ppm in this study).

Effects of short-term m-xylene exposure and physical exercise on the central nervous system.

SummaryEight male volunteers were exposed on 5 consecutive days and 1 day after the weekend to m-xylene vapour at either a constant (Study I) or a periodically varying (Study Il) concentration of 3.7–8.2 μmol/1(90–200 ppm, time-weighted average). The effects of the exposure on psychophysiological functions, such as reaction time, manual coordination and body balance, and EEG were studied. The same tests were completed on 2 non-exposure days for control purposes in both studies, in which physical exercise of 10O W was included.An inhalation exposure to m-xylene already at a concentration of 3.7 μmol/1 (90 ppm) had acute deleterious effects on the above mentioned psychophysiological functions of non-adapted subjects. EEG indicated lowered vigilance during exposure to varying concentrations with peak exposures of 8.2 μmol/l. Slight exercise, especially at the beginning of the exposure, seemed to antagonize the effects of xylene, particularly when the concentration fluctuated. Tolerance against the observed effects developed over one working week, but some effects were again discernible in the following week. A dose-response relationship between blood m-xylene concentrations and the effects of m-xylene was not found. This was probably due to tolerance.

Kinetics of methyl ethyl ketone in man: absorption, distribution and elimination in inhalation exposure

SummaryThe kinetics of inhaled methyl ethyl ketone (MEK) in human volunteers was studied in an exposure chamber. Relative pulmonary uptake was about 53% throughout a 4-h exposure period at 200 ppm. Blood MEK concentration rose steadily until the end of exposure. Repeated bicycle exercise increased the overall blood MEK level markedly in comparison to sedentary activity, with transient peaks in association with cycling; thus blood MEK concentration depended both on the rate of uptake and the amount taken up. Only 3% of the absorbed dose was excreted unchanged by exhalation. A well-known metabolite of MEK, 2,3-butanediol, was detected in the urine with maximum rates of excretion at about 6 to 12 h from the beginning of exposure. About 2% of the MEK dose taken up by the lungs was excreted in the urine as 2,3-butanediol. The main part of inhaled MEK is supposedly metabolized in the intermediary metabolism. Elimination of MEK in blood appeared to exhibit two phases: the initial alpha-phase (T1/2 = 30min; kel alpha = 0.023) over the first post-exposure hour, followed by the terminal beta-phase (T1/2 = 81 min; kel beta = 0.009).

Physiologically-Based Pharmacokinetic Modeling of Benzene in Humans: A Bayesian Approach

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.

Occupational exposure to aluminum and its biomonitoring in perspective

Exposure to aluminum at work is widespread, and people are exposed to several species of aluminum, which differ markedly as to the kinetics and toxicity. Especially welding of aluminum is widely applied and continuously expanding. Inhalation of fine particles of sparsely soluble aluminum results in the retention of deposited particles in the lungs. From the lungs, aluminum is released to the blood and distributed to bones and the brain, and excreted to urine. Soluble aluminum compounds are not accumulated in the lungs. Neurotoxicity is the critical effect of exposure to sparsely soluble aluminum compounds. Studies on workers exposed to aluminum welding fumes have revealed disturbances of cognitive processes, memory and concentration, and changes in mood and EEG. Early pulmonary effects have been observed among aluminum powder-production workers using high-resolution computed tomography. The primary objective of aluminum biomonitoring (BM) is to help prevent the formation of aluminum burden in the lungs and thereby to prevent harmful accumulation of aluminum in target organs. BM of aluminum can be effectively used for this purpose in the production/use of aluminum powders, aluminum welding, as well as plasma cutting, grinding, polishing and thermal spraying of aluminum. BM of aluminum may also be similarly useful in the smelting of aluminum and probably in the production of corundum. BM can help identify exposed individuals and roughly quantitate transient exposure but cannot predict health effects in the production/use of soluble aluminum salts. For urinary aluminum (U-Al) we propose an action limit of 3 µmol/L, corrected to a relative density of 1.021, in a sample collected preshift after two days without occupational exposure, and without use of aluminum-containing drugs. This value corresponds roughly to 2.3 µmol/g creatinine. Compliance with this limit is expected to protect the worker against the critical effect of aluminum in exposure to sparsely soluble aluminum dusts, the cognitive function of the central nervous system. For serum aluminum (S-Al), we do not propose an action limit because S-Al is less sensitive as an indicator of aluminum load.

Effects of low level exposure to lead on neurophysiological functions among lead battery workers.

OBJECTIVES: Assessment of neurophysiological functions in workers with low level exposure to lead and evaluation of the efficacy of bone lead measurements in the prediction of effects of lead. METHODS: Exposure to lead of 60 workers from a lead battery battery factory was estimated from historical blood lead measurements and analysis of lead in the tibial and calcaneal bones with x ray fluorescence. Peripheral and central nervous system functions were assessed by measuring conduction velocities, sensory distal latencies, sensory amplitudes, and vibration thresholds as well as by quantitative measurement of the absolute and relative powers and mean frequencies of different electroencephalograph (EEG) channels. RESULTS: Sensory amplitudes, and to a smaller degree sensory or motor conduction velocities, showed a negative correlation with long term exposure to lead, most clearly with integrated blood lead concentration and exposure time. Vibration thresholds measured in the arm were related to recent exposure to lead, those measured in the leg to long term exposure. The alpha and beta activities of the EEG were more abundant in subjects with higher long term exposure to lead. Calcaneal lead content reflected short term exposure, tibial lead content reflected long term exposure. Blood lead history showed a closer relation with effects of lead than the tibial or calcaneal lead concentrations. CONCLUSIONS: Vibratory thresholds, quantitative EEG, and to a smaller extent the sensory amplitude, provide sensitive measures of effects of lead in occupationally exposed adults. Most accurate estimates of health risks induced by lead can be obtained from a good history of blood lead measurements. If such a history of blood lead concentrations is not available, analysis of bone lead may be used for the assessment of health risks.