Mineke Viaene

Neurobehavioural effects of occupational exposure to cadmium: a cross sectional epidemiological study

BACKGROUND A patient with unexplained minor behavioural changes associated with an axonal sensorimotor polyneuropathy had a history of chronic occupational exposure to cadmium (Cd). Although animal studies have shown that Cd is a potent neurotoxicant, little is known about its toxicity for the human central nervous system. The aim of this study was to investigate the toxic potential of chronic occupational exposure to Cd on neurobehavioural functions. METHODS A cross sectional epidemiological study was conducted in a group of Cd workers and an age matched control group. Eighty nine adult men (42 exposed to Cd and 47 control workers) were given a blinded standardised examination that consisted of computer assisted neurobehavioural tests (neurobehavioural examination system), a validated questionnaire to assess neurotoxic complaints (neurotoxicity symptom checklist-60, NSC-60), and a standardised self administered questionnaire to detect complaints consistent with peripheral neuropathy and dysfunction of the autonomic nervous system. Historical and current data on biomonitoring of exposure to Cd, either the highest value of Cd in urine (CdU in μg Cd/g creatinine) of each Cd worker during work (CdUmax) or the current value (CdUcurrent) of each control, were available as well as data on microproteinuria. RESULTS Cd workers (CdUmax: mean (range), 12.6 (0.4–38.4)) performed worse than the controls (CdUcurrent: mean (range), 0.7 (0.1–2.0)) on visuomotor tasks, symbol digit substitution (p=0.008), and simple reaction time to direction (p=0.058) or location (p=0.042) of a stimulus. In multiple linear regression analysis, symbol digit substitution, simple direction reaction time test, and simple location reaction time test were significantly related to CdUmax, (β=0.35 ( p<0.001), β= 0.25 (p=0.012), and β=0.23 (p=0.021) respectively). More complaints consistent with peripheral neuropathy (p=0.004), complaints about equilibrium (p=0.015), and complaints about concentration ability (p=0.053) were found in the group exposed to Cd than in the control group, and these variables correlated positively with CdUmax (peripheral neuropathy: β=0.38, p<0.001; equilibrium: β=0.22, p=0.057; concentration ability: β=0.27, p=0.020). CONCLUSION Slowing of visuomotor functioning on neurobehavioural testing and increase in complaints consistent with peripheral neuropathy, complaints about equilibrium, and complaints about concentration ability were dose dependently associated with CdU. Age, exposure to other neurotoxicants, or status of renal function could not explain these findings. The present study also indicates that an excess of complaints may be detected in Cd workers before signs of microproteinuria induced by Cd occur.

Neurobehavioral function and low-level exposure to brominated flame retardants in adolescents: a cross-sectional study

BackgroundAnimal and in vitro studies demonstrated a neurotoxic potential of brominated flame retardants, a group of chemicals used in many household and commercial products to prevent fire. Although the first reports of detrimental neurobehavioral effects in rodents appeared more than ten years ago, human data are sparse.MethodsAs a part of a biomonitoring program for environmental health surveillance in Flanders, Belgium, we assessed the neurobehavioral function with the Neurobehavioral Evaluation System (NES-3), and collected blood samples in a group of high school students. Cross-sectional data on 515 adolescents (13.6-17 years of age) was available for the analysis. Multiple regression models accounting for potential confounders were used to investigate the associations between biomarkers of internal exposure to brominated flame retardants [serum levels of polybrominated diphenyl ether (PBDE) congeners 47, 99, 100, 153, 209, hexabromocyclododecane (HBCD), and tetrabromobisphenol A (TBBPA)] and cognitive performance. In addition, we investigated the association between brominated flame retardants and serum levels of FT3, FT4, and TSH.ResultsA two-fold increase of the sum of serum PBDE’s was associated with a decrease of the number of taps with the preferred-hand in the Finger Tapping test by 5.31 (95% CI: 0.56 to 10.05, p = 0.029). The effects of the individual PBDE congeners on the motor speed were consistent. Serum levels above the level of quantification were associated with an average decrease of FT3 level by 0.18 pg/mL (95% CI: 0.03 to 0.34, p = 0.020) for PBDE-99 and by 0.15 pg/mL (95% CI: 0.004 to 0.29, p = 0.045) for PBDE-100, compared with concentrations below the level of quantification. PBDE-47 level above the level of quantification was associated with an average increase of TSH levels by 10.1% (95% CI: 0.8% to 20.2%, p = 0.033), compared with concentrations below the level of quantification. We did not observe effects of PBDE’s on neurobehavioral domains other than the motor function. HBCD and TBBPA did not show consistent associations with performance in the neurobehavioral tests.ConclusionsThis study is one of few studies and so far the largest one investigating the neurobehavioral effects of brominated flame retardants in humans. Consistently with experimental animal data, PBDE exposure was associated with changes in the motor function and the serum levels of the thyroid hormones.

Neurobehavioural changes and persistence of complaints in workers exposed to styrene in a polyester boat building plant: influence of exposure characteristics and microsomal epoxide hydrolase phenotype

OBJECTIVES To investigate neurobehavioural effects and the persistence of complaints in workers exposed to styrene relative to exposure characteristics and the enzyme microsomal epoxide hydrolase (mEH) activity. METHODS A cross sectional study was performed in a retrospective cohort of workers of a polyester boat building plant 3 years after the main activity shut down in 1989. Workers still currently exposed to a much lower concentration of styrene in air than before (n=27) and formerly exposed workers (n=90) were compared with matched control workers (n=64). Currently and formerly exposed workers laminated 4700 and 3610 hours on average at mean exposure to styrene concentrations of 148 and 157 mg/m3 respectively. A structured neurological anamnesis into former and present complaints, the NSC-60 questionnaire, and computer assisted neurobehavioural tests (NES) were administered. The mEH phenotype activity was measured in lymphocytes with a novel gas chromatography-mass spectroscopy (GC-MS) method. RESULTS For the period before 1989, currently and formerly exposed workers reported more complaints than control workers which related well with the mean exposure to airborn styrene concentration (p=0.03). Most complaints disappeared after the end of exposure, although the chest, equilibrium, and somatic category scores of NSC-60 and the number of workers reporting diminished sense of smell remained increased in formerly exposed workers (p⩽0.05). Symbol-digit substitution and digit span forwards test results were worse in currently and formerly exposed workers (p⩽0.01). In the combined group of currently and formerly exposed workers, the symbol-digit substitution and colour-word vigilance results related well to duration of exposure (p<0.01 and p=0.03) and mEH phenotype activity (p=0.01 and p=0.05), whereas the digit span forwards results only showed associations of borderline significance (duration of exposure (p=0.08) and mEH phenotype activity (p=0.08)). CONCLUSION Most subjective symptoms were reversible but some persisted after the end of exposure to styrene, whereas dysfunction of visuomotor performance and perceptual speed seemed to persist. Duration of exposure at lamination tasks and the interaction, duration of exposure×concentration of exposure, were found to be the best predictors of worsening visuomotor and perceptual speed performances. Activity of the mEH phenotype may play a modulating part in styrene neurotoxicity. The results suggested that less than 10 years of exposure to atmospheric styrene at an average concentration of 155 mg/m3 may result in persistent neurotoxic effects.

Neurobehavioral performance in adolescents is inversely associated with traffic exposure

On the basis of animal research and epidemiological studies in children and elderly there is a growing concern that traffic exposure may affect the brain. The aim of our study was to investigate the association between traffic exposure and neurobehavioral performance in adolescents. We examined 606 adolescents. To model the exposure, we constructed a traffic exposure factor based on a biomarker of benzene (urinary trans,trans-muconic acid) and the amount of contact with traffic preceding the neurobehavioral examination (using distance-weighted traffic density and time spent in traffic). We used a Bayesian structural equation model to investigate the association between traffic exposure and three neurobehavioral domains: sustained attention, short-term memory, and manual motor speed. A one standard deviation increase in traffic exposure was associated with a 0.26 standard deviation decrease in sustained attention (95% credible interval: -0.02 to -0.51), adjusting for gender, age, smoking, passive smoking, level of education of the mother, socioeconomic status, time of the day, and day of the week. The associations between traffic exposure and the other neurobehavioral domains studied had the same direction but did not reach the level of statistical significance. The results remained consistent in the sensitivity analysis excluding smokers and passive smokers. The inverse association between sustained attention and traffic exposure was independent of the blood lead level. Our study in adolescents supports the recent findings in children and elderly suggesting that traffic exposure adversely affects the neurobehavioral function.

Recent versus chronic exposure to particulate matter air pollution in association with neurobehavioral performance in a panel study of primary schoolchildren.

Childrens neuropsychological abilities are in a developmental stage. Recent air pollution exposure and neurobehavioral performance are scarcely studied. In a panel study, we repeatedly administered to each child the following neurobehavioral tests: Stroop Test (selective attention) and Continuous Performance Test (sustained attention), Digit Span Forward and Backward Tests (short-term memory), and Digit-Symbol and Pattern Comparison Tests (visual information processing speed). At school, recent inside classroom particulate matter ≤2.5 or 10μm exposure (PM2.5, PM10) was monitored on each examination day. At the childs residence, recent (same day up to 2days before) and chronic (365days before examination) exposures to PM2.5, PM10 and black carbon (BC) were modeled. Repeated neurobehavioral test performances (n=894) of the children (n=310) reflected slower Stroop Test (p=0.05) and Digit-Symbol Test (p=0.01) performances with increasing recent inside classroom PM2.5 exposure. An interquartile range (IQR) increment in recent residential outdoor PM2.5 exposure was associated with an increase in average latency of 0.087s (SE: ±0.034; p=0.01) in the Pattern Comparison Test. Regarding chronic exposure at residence, an IQR increment of PM2.5 exposure was associated with slower performances in the Continuous Performance (9.45±3.47msec; p=0.007) and Stroop Tests (59.9±26.5msec; p=0.02). Similar results were obtained for PM10 exposure. In essence, we showed differential neurobehavioral changes robustly and adversely associated with recent or chronic ambient exposure to PM air pollution at residence, i.e., with recent exposure for visual information processing speed (Pattern Comparison Test) and with chronic exposure for sustained and selective attention.

Urinary t,t-muconic acid as a proxy-biomarker of car exhaust and neurobehavioral performance in 15-year olds

INTRODUCTION Traffic-related air pollution has been shown to induce neurotoxicity in rodents. Several recent epidemiological studies reported negative associations between residential outdoor air pollution and neurobehavioral performance. We investigated in a population of non-smoker adolescents the associations between the urinary concentration of trans, trans-muconic acid (t,t-MA-U), a metabolite of benzene and used as proxy-biomarker of traffic exposure, and two neurobehavioral domains, i.e. sustained attention and short-term memory. METHODS In the framework of an environmental health surveillance study in Flanders (Belgium), we examined between 2008 and 2014 grade nine high school students (n=895). We used reaction time, number of omission errors, and number of commission errors in the Continuous Performance Test to evaluate sustained attention, and for the evaluation of short-term memory we used maximum digit span forward and backward of the Digit Span Test. We measured blood lead (PbB) to assess the independent effect of t,t-MA-U on neurobehavioral outcomes. RESULTS This neurobehavioral examination study showed that a ten-fold increase in t,t-MA-U was associated with a 0.14 SD lower sustained attention (95% Confidence Interval: -0.26 to -0.019; p=0.02) and a 0.17 SD diminished short-term memory (95% CI: -0.31 to -0.030; p=0.02). For the same increment in t,t-MA-U, the Continuous Performance Test showed a 12.2ms higher mean reaction time (95% CI: 4.86-19.5; p=0.001) and 0.51 more numbers of errors of omission (95% CI: 0.057-0.97; p=0.028), while no significant association was found with errors of commission. For the Digit Span Tests, the maximum digit span forward was associated with a 0.20 lower number of digits (95% CI: -0.38 to -0.026; p=0.025) and maximum digit span backward with -0.15 digits (95% CI: -0.32 to 0.022; p=0.088). These associations were independent of PbB, parental education and other important covariates including gender, age, passive smoking, ethnicity, urinary creatinine, time of the day, and examination day of the week. For PbB, an independent association was only found with mean reaction time of the Continuous Performance Test (19.1ms, 95% CI: 2.43-35.8; p=0.025). CONCLUSIONS In adolescents, a ten-fold increase in the concentration of t,t-MA-U, used as a proxy-biomarker for traffic-related exposure, was associated with a significant deficit in sustained attention and short-term memory. The public health implications of this finding cannot be overlooked as the effect-size for these neurobehavioral domains was about 40% of the effect-size of parental education.

Neurobehavioral function and low-level metal exposure in adolescents

An excessive metal exposure is harmful to the brain. However, many aspects of metal neurotoxicity remain unclear including the magnitude of the low-level exposure effects and the level of exposure that can be assumed safe. The aim of our study was to investigate the association between a low-level metal exposure and three neurobehavioral domains (sustained attention, short-term memory, and manual motor speed). We measured Cd, Cu, Mn, Pb, and Tl in blood, Cd, Ni, and toxicologically relevant As in urine and methyl Hg in hair in 606 adolescents between 13.6 and 17 years of age. A two-fold increase in blood Cu was associated with a 0.37 standard deviations decrease in sustained attention (95% CI: -0.67 to -0.07, p=0.02) and 0.39 standard deviations decrease in short-term memory (95% CI: -0.70 to -0.07, p=0.02), accounting for gender, age, smoking, passive smoking, household income per capita, occupation of the parents, and education level of the mother. None of the other metals was significantly associated with the neurobehavioral domains that were measured. The observed associations between blood Cu and neurobehavioral performance are in line with recent studies in elderly. However, the relevance of our results for public health remains to be elucidated.

395 Solvent-induced DNA methylation changes: A translational study

Objectives Workers exposed to solvents are at risk for developing cancer and neurobehavioral diseases. Evidence is growing on the role of epigenetic alterations involved in the development of both diseases. In this project, we set up a translational study to investigate the impact of solvents on DNA methylation alterations and neurobehavioral changes. Methods First, we assessed global DNA methylation changes in human lymphoblastoid (TK6) cells in vitro in response to 10 solvents. Next, a cross sectional study was set-up to validate these results in 128 solvent workers. Liquid chromatography-mass spectrometry was used to quantify global DNA methylation profile in TK6 cells and in lymphocytes of the workers. Each participant underwent a series of tests based on the Neurobehavioral Evaluation System. Results Benzene, hydroquinone, styrene, carbon tetrachloride and trichloroethylene induced global DNA hypomethylation in TK6 cells. DNA methylation in solvent-workers was, after correction for age, negatively associated with total exposure time (r = -0.198, p = 0,025) and the cumulative exposure index (r = -0.244, p = 0,006). Age and smoking were associated with a global DNA hypomethylation, while use of alcohol was associated with hypermethylation. Interestingly, both DNA methylation and exposure were significant predictors for neurobehavioral effects in the multivariate regression models. Conclusions We report changes in global DNA methylation as an early event in response to solvents. Global unmethylated DNA is known to dysregulate transcription, which has an impact on the gene expression and the function of cells, e.g. loss of control of cell division. These results are suggestive for the possible involvement of epigenetic mechanisms in neurodegenerative diseases and cancer. Lymphocytes are not necessarily the target tissue, but might be a good surrogate because of their accessibility and the high correlation with methylation profiles in somatic tissues.