Gerhard Winneke

Environmental exposure to polychlorinated biphenyls and quality of the home environment: effects on psychodevelopment in early childhood

BACKGROUND There is uncertainty whether environmental levels of exposure to polychlorinated biphenyls (PCBs) adversely affect mental and motor development in early childhood. We aimed to establish whether such an effect is of only prenatal or additional postnatal origin, and if a favourable home environment can counteract this effect. METHODS Between 1993 and 1995 we recruited 171 healthy mother-infant pairs and prospectively measured psychodevelopment in newborn infants aged 7, 18, 30, and 42 months. We estimated prenatal and perinatal PCB exposure of newborn babies in cord blood and maternal milk. At 42 months we measured postnatal PCB concentrations in serum. At 18 months the quality of the home environment was assessed using the Home Observation for Measurement of the Environment scale. Mental and psychomotor development of the children were assessed using the Bayley Scales of Infant Development until 30 months and the Kaufman Assessment Battery for Children at 42 months. FINDINGS Negative associations between milk PCB and mental/motor development were reported at all ages, becoming significant from 30 months onwards. Over 30 months, for a PCB increase from 173 (5th percentile) to 679 ng/g lipids in milk (95th percentile) there was a decrease of 8.3 points (95% CI -16.5 to 0.0) in the Bayley Scales of Infant Development mental scores, and a 9.1 point decrease (95% CI -17.2 to -1.02) in the Bayley Scales of Infant Development motor scores. There was also a negative effect of postnatal PCB exposure via breastfeeding at 42 months. Home environment had a positive effect from 30 months onwards (Bayley Scales of Infant Development mental score increase of 9.4 points [95% CI 2.2-16.7]). INTERPRETATION Prenatal PCB exposure at current European background levels inhibits, and a favourable home environment supports, mental and motor development until 42 months of age. PCB exposure also has an effect postnatally.

Functional aspects of developmental toxicity of polyhalogenated aromatic hydrocarbons in experimental animals and human infants

A scientific evaluation was made of functional aspects of developmental toxicity of polychlorinated biphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in experimental animals and in human infants. Persistent neurobehavioral, reproductive and endocrine alterations were observed in experimental animals, following in utero and lactational exposure to PCBs, PCDDs and PCDFs. The lowest observable adverse effect levels (LOAELs) for developmental neurobehavioral and reproduction endpoints, based on body burden of TCDD-toxic equivalents (TEQs) in animals, are within the range of current background human body burdens. Relatively subtle adverse effects on neurobehavioral development and thyroid hormone alterations have also been observed in infants and children exposed to background levels. Exclusive use of the toxic equivalency factor (TEF) approach may underestimate the risk of neurodevelopmental effects, because both Ah receptor dependent and independent mechanisms may be involved in these effects. The use of marker congeners and/or bioassays based on Ah receptor mediated mechanisms are rapid, low cost pre-screening alternatives for expensive and time consuming gas chromatographic-mass spectrometric analysis.

Neuropsychological studies in children with elevated tooth-lead concentrations

SummaryResults from neuropsychological tests, collected under double-blind-precautions, were evaluated for 115 schoolage children (mean age: 9.4 years) living in a lead smelter area (Stolberg, FRG). Tooth-lead concentrations (PbT) from shed incisor teeth as measures of longtime lead-exposure were available for these children (x = 6.16 ppm; range: 1.9–38.5 ppm), and for 83 of them blood-lead concentrations (PbB) were available as well (x = 14.3 μg/dl; range: 6.8-33.8 μg/dl). The following functional capacities were tested: intelligence (German WISC), perceptual-motor integration (Göttinger Formreproduktionstest = GFT, Diagnosticum for Cerebralschüdigung = DCS), reaction performance (Wiener Determinationsgerät), finger-wrist tapping-speed, and repetitive cancellation-performance (Differentieller Leistungstest). In addition standardized behavior ratings were obtained by the examiners, the mothers, and the teachers. Multiple stepwise regression-analysis (forced solution) was calculated for outcome-variables and Pb-tooth, including age, sex, duration of labor, and socio-hereditary background as covariates. Significant (P< 0.05) or near-significant (P< 0.1) association was established between Pb-tooth and GFT-performance (errors), reaction-performance (false reactions), and four behavioral dimensions as rated by the mothers, namely distractability, restlessness, lack of information, and wasting of time; the proportion of explained variance never exceeded 6%, however, No significant association was found between PbT and WISC verbal-IQ after the effects of “socio-hereditary background” had been eliminated, although there was still a tendency for high level-children (PbT > 10 ppm) to be inferior to low level-children (PbT ≦ 4 ppm) by 4.6 IQ-points after correction for confounding. There was a near-significant, inverse relationship between fingerwrist tapping-speed and Pb-blood. The results are discussed within the framework of attention-deficit disorder, and compared to neurobehavioral Pb-effects from animal-experiments, which provide suggestive evidence for a causal relationship between developmental lead-exposure and certain neurobehavioral deficits.

Impairment of long-term potentiation and learning following chronic lead exposure

Chronic lead exposure during brain development is known to affect functions of the central nervous system. We exposed rats chronically to low levels of lead at different developmental stages in order to determine the most sensitive periods of exposure. Active avoidance learning and hippocampal long-term potentiation were tested in the same animals. If the exposure period comprised the prenatal and the early postnatal phase and was continued into adulthood, learning as well as long-term potentiation were impaired. Starting the exposure not before 16 days postnatally, however, neither affected learning nor hippocampal potentiation. These results reflect the higher vulnerability of the immature as compared to the mature hippocampus to lead-induced functional deficits.

Developmental neurotoxicity of polychlorinated biphenyls (PCBS) : cognitive and psychomotor functions in 7-month old children

Neurobehavioral effects of polychlorinated biphenyls (PCBs) at environmental levels of exposure have been reported in cross-sectional and prospective studies in infants and children. However, observations differ for effect spectrum, persistence and effective matrix (cord plasma, maternal plasma or milk). In order to improve risk assessment by clarifying some of these uncertainties, a European multicentric study was set up. Results from the German (Düsseldorf) cohort covering 171 healthy mother-infant pairs are given. The sum of PCB congeners 138, 153 and 180 (sigma PCB) in cord plasma and maternal milk was used to describe neonatal PCB exposure. Mean sigma PCB-concentrations were 0.55 ng/ml in cord plasma and 427 ng/g fat in breastmilk. This report covers the Bayley II mental (MDI) and psychomotor development index (PDI) as well as the Fagan Test of Infant Intelligence (Visual Recognition Memory) taken at 7 months of age in relation to neonatal sigma PCB. After confounder-adjustment significant negative associations were found between sigma PCB in milk and MDI (P < 0.05), whereas the other associations proved insignificant.

PCB-induced neurodevelopmental toxicity in human infants and its potential mediation by endocrine dysfunction

Polychlorinated biphenyls (PCBs) cross the placenta and expose the fetus to the body burden of the mother. Additionally, the breastfed baby is postnatally exposed to PCBs in maternal milk. Among the broad spectrum of biological effects interaction with endocrine systems and developmental neurotoxicity are prominent features of these chemical mixtures. Associations between neurodevelopmental delay and prenatal or early postnatal PCB-exposure at environmental levels have been reported in several cohort studies. Adverse effects were found to be associated with early developmental PCB-exposure, although there are discrepancies between studies in terms of confounding, effective PCB-matrix, as well as spectrum and persistence of effects. From these cohort studies alone the causative role of PCBs in producing neurodevelopmental adversity still cannot be considered proven, but experimental findings do provide evidence for the developmental neurotoxicity of PCBs. The underlying mechanisms of this action is still unknown. However, interaction with endocrine systems, namely the estrogen/androgen and, particularly, the thyroid hormone systems are discussed as a possible explanation for PCB-induced neurodevelopmental adversity. Some evidence in this respect is being reviewed.

Results from the European multicenter study on lead neurotoxicity in children: Implications for risk assessment

In order to improve dose-response information on neurobehavioral effects of environmental lead exposure in children, the World Health Organization, Regional Office for Europe (WHO/EURO), in collaboration with the Commission of the European Communities, initiated this international study which was planned, executed and evaluated between 1984 and 1989. Eight groups from eight European countries (Bulgaria, Denmark, Greece, Hungary, Italy, Roumania, W. Germany and Yugoslavia) took part. A common study protocol with inherent quality assurance elements was developed to achieve comparability. Blood-lead concentrations (PbB) were the main markers of exposure. The WISC (4 subtests) for psychometric intelligence, the Bender Gestalt test (GFT version) and the Trail-Making test for visual-motor integration, the Vienna Reaction Device and a delayed RT task for reaction performance, and the Needleman scales for behavior ratings served as behavioral endpoints. All individual studies taken together represent a sample size of 1879 school-age children and cover a PbB range from below 5 to about 60 micrograms/100 ml. Overall statistical evaluation of outcome was done by multiple regression analysis using a uniform confounder model. The strongest and most consistent effects occurred for the Bender Gestalt test (GFT version) and for serial choice reaction performance (Vienna Device). The degree of association with PbB was significant for these variables, although the contribution of PbB to the observed variance never exceeded 0.8%. Psychometric intelligence was also negatively affected, although the consistency of outcome between studies was poor, and the association with PbB only borderline. An effort towards risk assessment was made by calculating the proportion of children at risk, using the observed regression coefficients as well as means and standard deviations.

Cognitive and Sensorimotor Functions in 6-Year-Old Children in Relation to Lead and Mercury Levels: Adjustment for Intelligence and Contrast Sensitivity in Computerized Testing

Within a larger environmental health screening program neurobehavioral measures were taken in 384 6-year-old children (mean age 74 months) in the cities of Leipzig, Gardelegen, and Duisburg. Lead concentrations in venous blood samples (PbB) and urinary mercury excretion in 24-h samples (HgU) were measured as markers of environmental exposure by electrothermal AAS. Dependent variables included two subtests from the WISC [vocabulary (V) and block design (BD)] as well as five tests from the NES2 [pattern comparison, pattern memory, tapping, simple reaction time, and the continuous performance test (CPT; child version)]. In addition, visual functions [visual acuity (TITMUS-test) and contrast sensitivity (FACT)] were tested as covariates. The overall average PbB (geometric mean) was 42.5 microg/l (upper 95% value = 89 microg/l). The overall average mercury excretion (HgU) was 0.16 microg/24 h. Whereas no significant or borderline associations between HgU and any of the target variables was found, significant negative associations were observed between PbB and verbal intelligence (WISC vocabulary but not WISC Block Design) and false-positive responses (false alarms), as well as false-negative responses (miss) in the CPT. Whereas parental education was the most important confounder for WISC performance, visual contrast sensitivity and computer familiarity also proved predictive for performance in several computer-based NES subtests. It is concluded that non-IQ measures, namely measures of sustained attention, are negatively affected in children with 95% of blood-lead levels below 90 microg/l, even after adjustment for intelligence and contrast sensitivity, whereas the causative role of lead in altering IQ functions remains somewhat equivocal, because important covariates could not be controlled for.

Sensitive periods for behavioral toxicity of polychlorinated biphenyls: Determination by cross-fostering in rats

Polychlorinated biphenyls (PCBs) are transferred to developing organisms via the milk rather than through placental barriers. Recent epidemiological data, however, suggest a greater importance of the prenatal exposure period for the development of neuropsychological disorders. The relative effectiveness of pre- and postnatal PCB exposure was compared in a cross-fostering experiment in rats. Female Wistar rats were fed diets containing 0 or 30 mg PCB/kg. After birth half of the litters in each exposure group were nursed by dams of the other condition. Six different congeners were determined in the brains of the offspring at various ages. Internal exposure to higher chlorinated congeners peaked at weaning in groups with postnatal or permanent exposure, whereas the concentration of a low-chlorinated compound was lower at weaning than at birth or at later age stages. Brain tissue levels in prenatally treated rats declined with aging. In two behavioral paradigms, active avoidance learning and retention of a visual discrimination task, prenatally exposed rats exhibited alterations similar to those of permanently treated subjects, while postnatal exposure caused no detectable behavioral changes. These results support the above-mentioned epidemiological studies which related neurodevelopmental deficits in children to prenatal PCB exposure.

Environmental exposure to lead, but not other neurotoxic metals, relates to core elements of ADHD in Romanian children: Performance and questionnaire data

Neurobehavioral measures of attention, and clinical features of the attention-deficit hyperactivity disorder (ADHD) have been studied in pediatric environmental lead research. However rarely, if ever, have performance measures of attention or executive functions and questionnaire-based quantitative ADHD-observations been studied in the same subjects. We examined associations between pediatric blood lead concentrations (PbB), as well as those of mercury (Hg), and aluminum (Al), and performance in four different attention tasks, as well as behavioral ratings from an ICD-10 (hyperactivity) and DSM-IV-coded (attention deficit) German questionnaire (FBB-ADHS). Asymptomatic, 8-12 year old children from two Romanian cities were studied, namely Bucharest and Pantelimon, a city near a metal-processing plant. Blood was analyzed for Pb, Al, and Hg. Data from 83 children were available for final analysis. We assessed attention performance by means of four tasks of the computer-based ADHD-taylored German KITAP-battery. We also received questionnaire ratings from parents and teachers covering three ADHD-dimensions. Multiple linear regression analysis was used to estimate associations between the three neurotoxic trace metals in blood and the different ADHD features. After adjusting for eleven potentially confounding variables we found consistent borderline to significant associations between Pb, but not other metals, in blood and various performance- and questionnaire data. False alarm responses (FAR) in the KITAP subtests rather than response latencies exhibited positive associations with PbB. Questionnaire ratings for ADHD dimensions also revealed PbB-related adversity. With any two-fold increase of PbB outcome changed markedly, namely up to 35%. Restriction to children with PbBs<10mug/dl had only a marginal influence on outcome.The converging evidence from performance- and questionnaire data confirms that core elements of ADHD are adversely affected by low environmental PbB even below 10mug/dl, but not by other neurotoxic trace metals. Observed effect-sizes are considerably larger than those typically found for lead-related IQ-deficit, thus suggesting that attention deficit could be the more basic adverse effect of lead in children. This is the first study from Central and Eastern Europe dealing with links between environmental exposure of children to neurotoxic metals and ADHD.