Behavioral sexual dimorphism in school-age children and early developmental exposure to dioxins and PCBs: a follow-up study of the Duisburg Cohort.

BACKGROUND: Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) are persistent organic pollutants that have been characterized as endocrine-disrupting chemicals (EDCs). OBJECTIVES: Within the Duisburg birth cohort study, we studied associations of prenatal exposure to PCDD/Fs and PCBs with parent-reported sexually dimorphic behavior in children. METHODS: We measured lipid-based and WHO2005-TEQ (toxic equivalents established in 2005 by the World Health Organization)-standardized PCDD/Fs and PCBs in maternal blood samples and in early breast milk using gas chromatography/high-resolution mass spectrometry. At the child's age of 6-8 years, parents (mostly mothers) reported sex-typical characteristics, preferred toys, and play activities using the Pre-School Activities Inventory (PSAI), which was used to derive feminine, masculine, and difference (feminine - masculine) scores. We estimated exposure-outcome associations using multivariate linear regression. A total of 91-109 children were included in this follow-up. RESULTS: Mean blood levels of summed WHO2005-TEQ-standardized dioxins (ΣPCDD/Fs) were 14.5 ± 6.4 pg/g blood lipids, and ΣPCBs were 6.9 ± 3.8 pg/g blood lipids, with similar values for milk lipids. Regression analyses revealed some highly significant interactions between sex and exposure-such as for ΣPCBs in milk, pronounced positive (boys: ß = 3.24; CI = 1.35, 5.14) or negative (girls: ß = -3.59; CI = -1.10, -6.08) associations with reported femininity. Less pronounced and mostly insignificant but consistent associations were found for the masculinity score, positive for boys and negative for girls. CONCLUSIONS: Given our results and the findings of previous studies, we conclude that there is sufficient evidence that these EDCs modify behavioral sexual dimorphism in children, presumably by interacting with the hypothalamic-pituitary-gonadal axis. CITATION: Winneke G, Ranft U, Wittsiepe J, Kasper-Sonnenberg M, Fürst P, Krämer U, Seitner G, Wilhelm M. 2014. Behavioral sexual dimorphism in school-age children and early developmental exposure to dioxins and PCBs: a follow-up study of the Duisburg Cohort. Environ Health Perspect 122:292-298; http://dx.doi.org/10.1289/ehp.1306533.

Developmental aspects of environmental neurotoxicology: lessons from lead and polychlorinated biphenyls.

The particular vulnerability of the developing nervous system for low-level exposure to chemicals is well established. It has been argued that some degree of developmental neurotoxicity was found for a large number of industrial chemicals. However, for only few of these, namely inorganic lead, arsenic, organic mercury and polychlorinated biphenyls (PCBs), human evidence is available to suggest that these may cause neurodevelopmental adversity and may, thus, be involved in contributing to neurodevelopmental disorders like autism, attention-deficit disorder, mental retardation or cerebral palsy. The focus of this overview is on PCBs and inorganic lead as developmental neurotoxicants at environmental levels of exposure. The adverse effects of inorganic lead on the developing brain have long been studied, and much emphasis has been on subtle degrees of mental retardation in terms of intelligence (IQ). The evidence is consistent, but the effect sizes are typically small. Research interest has also been devoted to studying aspects of "attention-deficit hyperactivity disorder" (ADHD) in children in relation to environmental exposure to lead in both cross-sectional and case-control studies. More recently, we have also studied core elements of ADHD according to ICD-10 and DSM-IV in relation to environmental exposure to lead, mercury and aluminum in asymptomatic school children in Romania. Both, performance measures (several attention tasks) and questionnaire-based behavior ratings from parents and teachers showed that lead, but not Hg or Al, was consistently and adversely associated with core elements of ADHD. These findings in asymptomatic children nicely fit into the overall pattern of observations and suggest that, apart from genetic influences, low-level exposure to lead contributes to this neurodevelopmental disorder. Polychlorinated biphenyls (PCBs) are persistent organic pollutants with lipophilic properties. Due to their persistence, they are still present in environmental media at potentially harmful concentrations, although production and use of PCBs was already banned in the early 1980s. Several prospective cohort studies-including our Düsseldorf study-have demonstrated that pre- and early postnatal exposure to PCBs is associated with deficit or retardation of mental and/or motor development, even after adjusting for maternal intelligence and developmental effects of the quality of the home environment. The pathophysiology is still unclear, although interference with thyroid metabolism during brain development is being discussed. Based on these reviews, three aspects, namely pre- vs. postnatal impact, effect scaling for comparative purposes, and integration of neurobehavioral findings into clinical and neuroscience contexts, are outlined as lessons learned from neurodevelopmental observations in children environmentally exposed to lead or PCBs.

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.

Lack of neurodevelopmental adversity by prenatal exposure of infants to current lowered PCB levels: comparison of two German birth cohort studies.

Polychlorinated biphenyls (PCBs), persistent environmental contaminants, may affect neurodevelopment of infants following prenatal exposure. A negative impact of prenatal PCB exposure on neurodevelopment was found in the Dusseldorf (Germany) cohort study (1993-2000). PCB levels of the sum of the three indicator congeners in breast milk were negatively associated with mental/motor development as assessed by the Bayley Scales of Infant Development (BSID) in infants. Since general exposure to PCB has decreased, a new birth cohort study was initiated in 2000 in the industrial city of Duisburg, which is located 30 km downstream from Dusseldorf on the River Rhine. A subgroup of the Duisburg birth cohort study was used to compare PCB exposure and developmental effects with results from the Dusseldorf cohort. The recruitment phase of the Duisburg cohort study occurred from 2000 to 2002. Mental and motor development was assessed by means of the BSID at the ages of 12 and 24 mo. Prenatal PCB exposure of newborns from Duisburg cohort was about two- to threefold lower than the Dusseldorf cohort. Although in the Dusseldorf birth cohort mental and motor development at ages 18 and 30 mo were negatively associated with PCB exposure, there was no association observed in the Duisburg study. Evidence indicates that exposure to PCB at current exposure levels no longer apparently impair neurodevelopment of infants.

The Duisburg birth cohort study: influence of the prenatal exposure to PCDD/Fs and dioxin-like PCBs on thyroid hormone status in newborns and neurodevelopment of infants until the age of 24 months.

Prenatal exposure to polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) can affect neurobehavioral development of infants and children. This effect may be mediated through disruption of thyroid hormone homeostasis. However, epidemiological studies reveal no consistent influence of PCDD/Fs and PCBs on thyroid status and neurodevelopment at environmental background levels. The effects may resolve with time of further decreasing exposure to these compounds. The aim of this study was to find out if there are still effects related to prenatal PCDD/F and PCB observable at the meanwhile decreased levels of exposure by using the same methods which have been applied in similar studies during the last 10 years in Europe. The birth cohort study was initiated in the year 2000 in the industrialized city of Duisburg, Germany. 232 healthy mother-infant pairs were recruited between 2000 and 2002. Dioxins, dioxin-like PCBs and six indicator PCBs were analyzed in maternal blood during pregnancy and in maternal milk following extraction and sample clean-up by HRGC/HRMS. Thyroid stimulating hormone (TSH), total thyroxine (T4), total triiodothyronine (T3), free thyroxine (FT4) and free triiodothyronine (FT3) were measured in serum samples of the pregnant women and in cord serum samples by chemiluminescent immunometric assay. Neurological examinations were performed at ages 2 weeks and 18 months using the neurological optimality score (NOS), mental and motor development were assessed using the Bayley Scales of Infant Development (BSID) at ages 12 and 24 months. Multiple linear regression analysis was used to describe the association of PCDD/F and PCB in maternal blood or milk with the outcome measurements after adjustment for confounding. Blood levels (n=182) of WHO 2005 toxic equivalents (TEQ) (PCDD/F+PCB) were in the range of 3.8-58.4 pg/glipid base (median: 19.3 pg/glipid base). The corresponding data for human milk (n=149) were 2.6-52.4 pg/glipid base (median: 19.7 pg/glipid base). Multiple regression analysis showed no decrease of thyroid hormones related to WHO 2005 TEQ in blood and milk of mothers and their newborns. Furthermore, no associations between exposure and neurological and developmental measures were observed. This study supports the view that the current decreased exposure to PCDD/Fs and PCBs does not impair thyroid function of newborns and neurodevelopment of infants until the age of 24 months.

Odor frequency and odor annoyance Part II: dose-response associations and their modification by hedonic tone.

OBJECTIVE: Risk-assessment for environmental odors and the development of an appropriate guideline for protection against undue odor annoyance have long been hampered by the difficulties of assessing odor exposure and community annoyance responses. In recent years, however, dose-response associations between frequency of odor events and odor annoyance level in the affected population were established. However, the influence of hedonic tone (pleasantness-unpleasantness) and perceived odor strength (intensity) on the degree of odor annoyance have long been neglected in such studies and accompanying guidelines. In order to close this gap a pertinent field study was conducted in the vicinity of six odor emitting plants, two with pleasant (sweets production, rusk bakery), with neutral (textile production, seed oil production), and with presumably unpleasant odor emissions (fat refinery, cast iron production). METHODS: A standardized sensory method was developed (described in Part I in the accompanying paper) to quantify intensity and hedonic tone within the assessment of odor exposure by systematic field inspection with trained observers. Additionally, exposure-information, the degree of annoyance, and the frequency of general health complaints and irritation symptoms were collected from the exposed residents through direct interviews. Multiple logistic regression analysis was used to establish dose-response associations between odor frequency, intensity and hedonic tone as independent variables and annoyance or symptom reporting as the dependent variable. RESULTS: It is shown that exposure-annoyance as well as exposure-symptom associations are strongly influenced by odor hedonic. Whereas pleasant odors induced little to no annoyance, both neutral and unpleasant ones did. Additional inclusion of odor intensity did not improve the prediction of odor annoyance. Frequency of reported symptoms was found to be exclusively mediated by annoyance. The results are discussed in terms of environmental stress emphasizing the WHO-definition of health. CONCLUSIONS: Based on these findings the existing German guideline against undue odor annoyance was modified.

Odor frequency and odor annoyance. Part I: assessment of frequency, intensity and hedonic tone of environmental odors in the field.

OBJECTIVE: Odors can be evaluated as being pleasant or unpleasant (hedonic tone), but this differentiation was not incorporated into environmental odor regulation. In order to study the hedonic-induced modification of dose-response associations for community odor annoyance a pertinent field study was conducted. This paper covers the first step, namely the development and validation of a standardized human observation strategy for the direct quantification of the frequency, intensity, and hedonic tone of environmental odors in the field. METHODS: Grids with equidistant observation points were located around six industrial odor sources, two with pleasant (sweets, rusk bakery), two with neutral (textile production, seed oil production), and two with unpleasant odor emissions (fat refinery, cast iron production). These points were visited by trained observers, screened for normal olfaction and reliable performance, in a systematic fashion for an observation time of 10 min duration. Exposure-related information from the observers in terms of frequency, intensity (six-point scale) and hedonic tone (nine-point scale) were compared to that of 1,456 residents using the same rating scales. RESULTS: Residents evaluated the industrial odors more intense and more unpleasant than the panelists. Furthermore, for the residents only negative relations between odor intensity and hedonic tone were found while for the observer pleasant odor became more pleasant with increasing intensity. Instead of three classes of industrial odors, namely pleasant, neutral and unpleasant, the responses allowed only for two odor classes, namely pleasant and not pleasant, the latter also covering the neutral category. CONCLUSIONS: The developed methodology has been shown to yield valid information about odor exposure in the field. With regard to different application settings the discrepancies between external observers and affected residents are discussed in terms of different information processing strategies, namely stimulus-based (bottom-up) for the panel and memory-based and, thus, subject to cognitive bias for the residents (top-down).

Environmental exposure to dioxins and polychlorinated biphenyls reduce levels of gonadal hormones in newborns: results from the Duisburg cohort study.

BACKGROUND: Endocrine dysfunction related to the hypothalamic-pituitary-thyroid (HPT) and/or the hypothalamic-pituitary-gonadal axis (HPG) is being discussed as underlying developmental adversity of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs). This study was done to evaluate effects related to the HPG axis. METHODS: A birth-cohort study was initiated in the year 2000. Healthy mother-infant pairs were recruited in the industrialized city of Duisburg, Germany. Dioxins, dioxin-like PCBs and six indicator PCBs were measured in maternal blood during pregnancy and in maternal milk. Testosterone and estradiol levels were measured in maternal and cord serum of 104 mother-infant pairs representing a subsample with a complete data set of the total basic sample of 232 participants. Linear regression analysis was used to describe the association of PCDD/Fs or PCB in maternal blood or milk with sex steroid concentrations after adjustment for confounding. RESULTS: Median concentrations for PCDD/Fs in maternal blood fat and milk fat in terms of WHO-TEq were 15.3 and 13.1pg WHO-TEq/g, respectively, and for the sum of the indicator PCBs (#28, #52, #101, #138, #153, #180) 149 and 177ng/g. The adjusted ratio of geometric means when doubling the concentration of PCDD/Fs in maternal blood fat was 0.86, 95% confidence interval (95% CI): 0.72-1.03 for testosterone and 0.73 (0.61-0.87) for estradiol in cord serum. Typically, testosterone reduction was more pronounced in cord serum of female and estradiol reduction in that of male babies. Reduction of hormone levels was generally more pronounced for dioxins than for indicator PCBs. CONCLUSIONS: The hypothalamic-pituitary-gonadal axis of newborn babies is influenced by prenatal exposure to PCDD/Fs and PCBs in a manner suggestive of AhR-mediation. The clinical relevance of this finding remains to be established, however.

Appraisal of neurobehavioral methods in environmental health research: the developing brain as a target for neurotoxic chemicals.

Psychological tests as developed and validated in the field of differential psychology have a longstanding tradition as tools to study individual differences. In clinical neuropsychology, global or more specific tests are used as neuropsychological tools in the differential diagnosis of various forms of brain damage or neurobehavioral dysfunction following chemical insults, such as mental sequelae of prenatal alcohol consumption by pregnant mothers (fetal alcohol syndrome) or of maternal thyroid deficiency during pregnancy. Psychometric tests are constructed to fulfill basic quality criteria, namely objectivity, reliability and validity. For strictly diagnostic purposes in individual cases they must also possess normative values based on representative reference groups. Intelligence tests or their developmental variants are often used as endpoints in environmental health research for studying neurodevelopmental adversity due to early exposure to neurotoxic chemicals in the environment. Intelligence as treated in psychology is a complex construct made up of specific cognitive functions which usually cover verbal, numerical and spatial skills, as well as perceptual speed, memory and reasoning. In this paper, case studies covering neurodevelopmental adversity of inorganic lead, of methylmercury and of polychlorinated biphenyls (PCBs) are reviewed, and the issue of postnatal behavioral sequelae of prenatal exposure is covered. In such observational studies precautions must be taken in order to avoid pitfalls of causative interpretation of associations between exposure and neurobehavioral outcome. This requires consideration of co-exposure and confounding. Important confounders considered in most modern developmental cohort studies are maternal intelligence and quality of the home environment.

PCDD/F and dioxin-like PCB in human blood and milk from German mothers.

Blood samples of pregnant women aged between 19 and 42 years at the time they gave birth and milk samples from the same women following delivery were collected between September 2000 and January 2003 from 169 participants living in an industrialized area of Germany (Duisburg birth cohort study). All samples were analyzed for their content of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/F) as well as dioxin-like and indicator polychlorinated biphenyls (PCB). Levels of WHO-TEq were in the range of 4.34-97.3 pg/g(lipid base) (median: 26.37, arithmetic mean: 28.36) for blood, or 3.01-78.7 pg/g(lipid base) (median: 26.40, arithmetic mean: 27.27) for milk, respectively. The four congeners 12378-PeCDD, 23478-PeCDF, 33'44'5-PeCB (# 126) and 233'44'5-HxCB (# 156) contribute the main share to total WHO-TEq. The contribution of PCDD/F in relation to PCB to total WHO-TEq was 60:40% in blood and 52:48% in milk. Good correlations of the contaminant levels in lipid base between both matrices were found. The distribution between blood and milk depends on the molecular weight of the substances. Higher chlorinated PCDD/F- and PCB-congeners were found in 2-4-fold higher concentrations in blood in relation to milk and the concentrations of lower chlorinated PCB-congeners were up to 2-fold higher in milk in relation to blood. The body burden of PCDD/F and PCB increases with age and decreases over the total nursing period. Women who had lived outside highly industrialized countries showed lower concentrations of PCDD/F and PCB. In some cases, elevated levels of PCB were observed when the women had previously lived in Eastern Europe for a long time. In comparison with recent data, the decline in human PCDD/F and PCB levels observed during the nineties seems to have stopped. The individual exposures of the infants due to breastfeeding within the first 18 months were calculated to be from 4.4 to 318 ng WHO-TEq (median: 106, arithmetic mean: 118). The actual mean daily exposure of a breastfed infant can be estimated to 131 pg WHO-TEq/kg(body weight).

Chemosensory function and psychological profile in patients with multiple chemical sensitivity: comparison with odor-sensitive and asymptomatic controls.

OBJECTIVE: We addressed the question if patients with multiple chemical sensitivity (MCS) differ from participants with self-reported odor sensitivity without MCS and asymptomatic controls in terms of chemosensory, cognitive, and clinical psychological endpoints. METHODS: In a clinical study 23 MCS patients, 21 participants with self-reported odor sensitivity, and 23 controls were investigated using electrophysiological and psychophysical olfactometric tests [chemosensory-event-related potentials (CSERP), olfactory thresholds, odor identification, trigeminal sensitivity]. The participants filled in a mood list, a list of complaints (BL), a Symptom Check List, a State-Trait Anxiety Inventory (STAI), and an MCS questionnaire. RESULTS: The olfactometric investigations revealed no significant differences between the groups. The MCS group reached significantly higher scores on negative mood states following odorant exposure, on health complaints, global indices, and the somatization subscale of the Symptom Check List, trait and state anxiety and symptoms, and triggering matters of the MCS questionnaire. CONCLUSIONS: Our findings reveal that neither olfactory functions, nor chemosensory or cognitive olfactory information processing are impaired in MCS patients. They rather support findings of altered psychological profile and moderate psychopathology.

PCB-related neurodevelopmental deficit may be transient: follow-up of a cohort at 6 years of age.

UNLABELLED: Based on our own findings from a previous study we aimed to establish if cognitive deficit, shown to be induced by perinatal exposure to polychlorinated biphenyls (PCBs) at earlier ages, persists into school-age. Seventy-seven percent of a cohort last examined at 42 months of age using the Kaufman Assessment Battery for Children were reexamined with the same test at 72 months. At this point, and contrary to the results at 30 and 42 months no adverse PCB-effects were found. However, the positive effect of the home environment became even more pronounced. CONCLUSION: early PCB-exposure at current environmental background levels possibly induces transient delay in cognitive development rather than irreversible deficit.

Developmental neurotoxicity of PHAHs: Endocrine-mediated and general behavioral endpoints in adult male rats.

During development, gonadal steroids exert effects on the nervous system which are long-lasting or organizational, in contrast to the transient activational actions in adulthood. Therefore, disturbance of neuroendocrine functions by developmental exposure to polyhalogenated aromatic hydrocarbons (PHAHs) is likely to affect sex-dependent behavior in adults. Our previous data revealed effects of maternal PCB exposure on sexual differentiation of the brain and subsequent sweet preference as sexually dimorphic behavior in adult offspring. Present research is focused on brominated flame retardants because of their wide-spread use and accumulation in human breast milk. Pregnant Long Evans rats were SC injected with PBDE 99 (2,2',4,4',5-PBDE) daily from gestational day 10 to 18. For comparison, an additional group was exposed to Aroclor 1254. Preliminary results indicate a dose-related increase in sweet preference in adult male offspring exposed to PBDE. Exposure also led to decreases in testosterone and estradiol serum levels. Additional decreases were detected in male anogenital distance. There were no changes of locomotor activity in the open field. On haloperidol-induced catalepsy, latencies were prolonged in all exposed males. In summary, PBDE induced endocrine effects and concomitant changes of sex-dependent behavior similar to PCBs. Outcome of general behavior suggests an involvement of dopaminergic processes in developmental PBDE exposure.

Comparison of polychlorinated biphenyl levels across studies of human neurodevelopment.

Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain, and detectable amounts are in the blood of almost every person in most populations that have been examined. Extensive evidence from animal studies shows that PCBs are neurotoxins, even at low doses. Interpretation of human data regarding low-level, early-life PCB exposure and subsequent neurodevelopment is problematic because levels of exposure were not similarly quantified across studies. We expressed the exposure levels from 10 studies of PCB and neurodevelopment in a uniform manner using a combination of data from original investigators, laboratory reanalyses, calculations based on published data, and expert opinion. The mainstay of our comparison was the median level of PCB 153 in maternal pregnancy serum. The median concentration of PCB 153 in the 10 studies ranged from 30 to 450 ng/g serum lipid, and the median of the 10 medians was 110 ng/g. We found that (a)) the distribution of PCB 153 exposure in most studies overlapped substantially, (b)) exposure levels in the Faroe Islands study were about 3-4-fold higher than in most other studies, and (c)) the exposure levels in the two recent U.S. studies were about one-third of those in the four earlier U.S. studies or recent Dutch, German, and northern Québec studies. Our results will facilitate a direct comparison of the findings on PCBs and neurodevelopment when they are published for all 10 studies.

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.

Persistent organochlorine pollutants in human serum of 50-65 years old women in the Flanders Environmental and Health Study (FLEHS). Part 2: Correlations among PCBs, PCDD/PCDFs and the use of predictive markers.

In 1999, the FLEHS was set by the Flemish Ministry of Health, Belgium to assess pollutant concentrations and related health effect biomarkers in humans living in Flanders. Concentrations of selected organochlorine pesticides, polychlorinated biphenyls (PCB) and polychlorinated dibenzo-p-dioxins (PCDD) and furans (PCDF) were measured by gas chromatography-mass spectrometry and Chemical-Activated LUciferase gene eXpression (CALUX) bioassay in 47 serum pools of 200 women between 50 and 65 years living in two areas of Flanders. Correlation between TEQ values of different groups of compounds were computed in these pool results and it was found that total toxic equivalencies (TEQs) correlated well with the values of the groups of contributing compounds: mono-ortho PCBs (r = 0.77), non-ortho PCBs (r = 0.65) and PCDD/Fs (r = 0.88). The total TEQ was lower correlated to the CALUX-TEQ (r = 0.57). When calculating associations between those classes of compounds in the two studied regions separately, they were all higher correlated in the urban area compared to the more rural region. High correlation coefficients (r > 0.80) were also calculated between individual compounds and groups of compounds. It was suggested that in this studied background-exposed population, some compounds could be good predictors for a group: e.g. PCB 153 for indicator and total PCBs, PCB 118 for total PCB TEQ, PCB 156 for mono-ortho PCB-TEQs and total TEQ, 2,3,4,7,8-P5CDF for PCDD/F TEQs and total TEQs. This means that in pooled serum samples correlations between persistent organochlorine compounds are as strong as for individual POP measurements observed in earlier studies.

Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek's hypothesis revisited.

Polychlorinated aromatic hydrocarbons (PCAHs) have been described as endocrine disruptors in animals and in accidentally or occupationally exposed humans. In the present study we examined the effect of moderate exposure to PCAHs on sexual maturation. Two hundred adolescents (mean age, 17.4 years) who resided in two polluted suburbs and a rural control area in Flanders (Belgium) participated. We measured the serum concentration of polychlorinated biphenyl (PCB) congeners 138, 153, and 180 and dioxin-like compounds [chemically activated luciferase expression (CALUX) assay] as biomarkers of exposure. School physicians assessed the pubertal development of boys and girls and measured testicular volume. In one suburb near two waste incinerators, compared with the other suburb and the control area, fewer boys (p < 0.001) had reached the adult stages of genital development (62% vs. 92% and 100%, respectively) and pubic hair growth (48% vs. 77% and 100%). Also, in the same suburb, fewer girls (p = 0.04) had reached the adult stage of breast development (67% vs. 90% and 79%). In individual boys, a doubling of the serum concentration of PCB congener 138 increased the odds of not having matured into the adult stage of genital development by 3.5 (p = 0.04); similarly for PCB congener 153 in relation to male pubic hair growth, the odds ratio was 3.5 (p = 0.04). In girls, a doubling of the serum dioxin concentration increased the odds of not having reached the adult stage of breast development by 2.3 (p = 0.02). Left plus right testicular volume was lower in both polluted areas than in the control area (42.4 mL vs. 47.3 mL, p = 0.005) but was not related to the current exposure of the adolescents to PCAHs. Through endocrine disruption, environmental exposure to PCAHs may interfere with sexual maturation and in the long-run adversely affect human reproduction.

Host and environmental determinants of polychlorinated aromatic hydrocarbons in serum of adolescents.

This study investigated host factors and environmental factors as potential determinants of polychlorinated aromatic hydrocarbons (PCAHs) in serum of adolescents. We recruited 200 participants (80 boys and 120 girls), with a mean age of 17.4 years (SD, 0.8), in Belgium from a rural control area (Peer) and from two polluted suburbs of Antwerp where a nonferrous smelter (Hoboken) and waste incinerators (Wilrijk) are located. We quantified polychlorinated biphenyls (PCBs; congeners 138, 153, and 180) in serum by gas chromatography and obtained the toxic equivalents (TEQs) of PCAHs in serum with the chemically activated luciferase gene expression bioassay (CALUX). Serum PCB concentration was higher in boys than in girls (1.67 vs. 1.02 nmol/L or 377 vs. 210 pmol/g serum lipids; p< 0.001). In the whole adolescent group, multiple regression showed that serum PCB concentration decreased 0.06 nmol/L per 1% increase in body fat content (p< 0.001) and increased 0.39 nmol/L and 0.14 nmol/L per 1 mmol/L increase in serum concentrations of triglycerides (p < 0.001) and cholesterol (p = 0.002), respectively. Host factors explained 44% of the serum PCB variance. In the same model, serum PCB concentration increased 0.14 nmol/L with 10 weeks of breast-feeding (p< 0.001) and 0.06 nmol/L with intake of 10 g animal fat per day (p < 0.001), and was associated with residence in the waste incinerator area (9% higher; p = 0.04); 11% of the variance could be explained by these environmental factors. The geometric mean of the serum TEQ value was similar in boys and girls (0.15 TEQ ng/L or 33.0 pg/g serum lipids). In multiple regression, TEQ in serum decreased 0.03 ng/L per centimeter increase in triceps skinfold (p = 0.006) and was 29% higher in subjects living close to the nonferrous smelter (p < 0.001). This study showed that in 16- to 18-year-old teenagers host factors are important determinants of serum concentrations of PCAHs, whereas environmentally related determinants may to some extent contribute independently to human exposure to these persistent chemicals in the environment.

Effects of maternal exposure to a reconstituted mixture of polychlorinated biphenyls on sex-dependent behaviors and steroid hormone concentrations in rats: dose-response relationship.

In a previous experiment, maternal exposure to a polychlorinated biphenyl (PCB) mixture reconstituted according to the congener pattern found in human breast milk resulted in decreased aromatase activity in the brain of newborn male rats, together with feminization of sweet preference behavior in adult male littermates. Both mixtures led to similar reductions of serum testosterone and testes weights. The purpose of the present study was (1) to examine the dose-response relationship for the reconstituted mixture and (2) to study if the rewarding properties of testosterone are affected at levels sufficient to alter sweet preference behavior. Female rats were fed diets with 0, 5, 20, or 40 mg PCBs/kg diet, resulting in an average daily intake of 0, 0.5, 2, or 4 mg/kg body wt. Exposure started 50 days prior to mating and was continued until birth of the offspring. A dose-dependent elevation of sweet preference was found in adult male offspring, indicating feminization of this sexually dimorphic behavior. Examination of conditioned place preference revealed a preference for the testosterone-paired side at the highest exposure condition. In weanling female offspring, dose-dependent reductions of serum testosterone and estradiol concentrations were detected. In addition, testosterone concentrations were reduced in a dose-dependent manner in adult male littermates long after termination of exposure. PCB concentrations in adipose tissue from offspring of the low dose group (0.5 mg/kg body wt) were approximately 10 times higher than values at the upper margin of current human exposure. Taken together, results indicate long-lasting and dose-dependent changes in sex-dependent behaviors and levels of sex steroid hormones in rats following developmental exposure to a PCB mixture that resembles the breast milk pattern.