Neurodevelopmental retardation, as assessed clinically and with magnetoencephalography and electroencephalography, associated with perinatal dioxin exposure.

UNLABELLED: In 1980s Western Europe, human perinatal exposure to background levels of dioxins was rather high. We therefore evaluated the neurodevelopment of our cohort during the prepubertal period and in adolescence. At prepubertal age (7-12 years) 41 children were tested. Both neuromotor functioning and psychological testing were performed (Dutch version of the Wechsler Intelligence Scale for Children (WISC-R) and the Dutch version of the Child Behavior Checklist for ages 4-18 years (CBCL 4-18) and the Teacher Report Form (TRF)). Neurophysiological tests were performed using magnetoencephalography and electroencephalography. In adolescence (14-18 years) the behavior of 33 children was studied again (CBCL and TRF). And the levels of dioxins and dioxin-like PCBs (dl-PCBs) were measured in serum. RESULTS: At prepubertal age no association was found between perinatal dioxin exposure and verbal, performal and total IQ or with the Touwen's test for neuromotor development. There were behavioral problems associated with both prenatal and postnatal dioxin exposure. In adolescence there were problems associated with the current dioxin levels and dioxin-like-PCBs. Neurophysiological tests revealed clear negative dysfunction. An increase in latency time after a motion stimulus (N2b) of 13 ms (= a delay of 10%) is associated with the higher prenatal dioxin exposure. A similar delay was measured in testing cognitive ability by analyzing the odd ball measurements, N200 and P300, together with an amplitude decrease of 12 %. The delay is indicative of a defective myelinisation and the decrease in amplitude of a loss of neurons. CONCLUSION: We found effects on behavior in association with the perinatal dioxin exposure and in adolescence in association with the current dioxin levels. Neurophysiological testing is instrumental in the detection of effects of perinatal background levels of chemicals on brain development in normal, healthy children. The clinical, neurological and psychological tests commonly used are not sensitive enough to detect important effects.

Chlorpyrifos and neurodevelopmental effects: a literature review and expert elicitation on research and policy

Organophosphate pesticides are widely used on food crops grown in the EU. While they have been banned from indoor use in the US for a decade due to adverse health effects, they are still the most prevalent pesticides in the EU, with Chlorpyrifos (CPF) being the most commonly applied. It has been suggested CPF affects neurodevelopment even at levels below toxicity guidelines. Younger individuals may be more susceptible than adults due to biological factors and exposure settings.

Assessment of current serum levels of PCDD/Fs, dl-PCBs and PBDEs in a Dutch cohort with known perinatal PCDD/F exposure.

As part of a longitudinal cohort study, now in its second decade, we determined PCDDs/Fs dl-PCBs and PBDEs in serum of adolescents with known perinatal PCDD/F exposure. Of the original cohort, 33 adolescents aged 14-19 years, who had been studied previously during their neonatal (n=60), toddler and pre-pubertal period (n=41) agreed to participate in the current follow-up. PCDD/F-, dl-PCB- and PBDE congeners were measured using GC/MS. Current serum levels of PCDD/Fs determined in our cohort were relatively low (mean of 2.2 pg/g) compared to the perinatal exposure. No correlation between perinatal exposure and current serum PCDD/F was found. Planar PCB TEQ levels were 2.2 pg/g. Current summation operatorPBDE levels were 8.7 ng/g lipid. There was one outlier with a summation operatorPBDE of 74 ng/g lipid. The presence of this high value indicates that the exposure pathway is different from PCDD/F and PCB, most likely by dust and food contaminated with dust. Concluding we can say that current PCDD/F levels are quite low compared to the perinatal PCDD/F exposure of the cohort. PBDE levels however are relatively high compared to other European countries, more research on possible health effects of these levels, especially for subjects with outlier concentrations, should be performed.

Association of prenatal phenobarbital and phenytoin exposure with genital anomalies and menstrual disorders.

BACKGROUND: Animal studies demonstrated that early exposure to phenobarbital decreases reproductive function. This study investigates whether prenatal exposure to these anticonvulsants affects human genital tract development. METHODS: Genital anomalies at birth were studied retrospectively in 90 phenobarbital-exposed, 108 phenobarbital plus phenytoin-exposed, and 198 matched control infants. Of this group, 72 drug-exposed males, 75 drug-exposed females, and 147 matched control subjects participated in a follow-up and were interviewed at age 19-35. Differences between groups were tested by chi-square and t-tests. RESULTS: A total of 15% of the phenobarbital-exposed boys versus 2.8% control boys had undescended testes at birth. More anticonvulsant-exposed (24%) than control males (11%) had received medical treatment for genital anomalies. Anticonvulsant-exposed females more often had irregularities in menstrual cycles (31% vs. 17%) and bleeding (15% vs. 3%) and reported more problems during pregnancy. CONCLUSIONS: Prenatal exposure to anticonvulsants seems to induce minor genital anomalies and may affect reproductive function.

Decreased lung function associated with perinatal exposure to Dutch background levels of dioxins.

UNLABELLED: Perinatal exposure to Dutch background dioxin levels is rather high. Studies of calamities have shown that dioxins negatively influence the respiratory system. It was hypothesized that perinatal exposure to background dioxin levels leads to lung suboptimality, probably through developmental interference. This study aimed to assess lung function in relation to perinatal dioxin exposure. Spirometry was performed in 41 healthy children (aged 7-12 y. mean 8.2 y) with known perinatal dioxin exposure. The ratio of forced expiratory volume in I s to forced vital capacity (FEV1/FVC ratio) was determined. A complete medical history was taken. The prenatal exposure ranged from 8.74 to 88.8 (mean 34.6) ng TEQ dioxin kg fat(-1), measured in breast milk. The postnatal exposure ranged from 4.34 to 384.51 (mean 75.4) ng TEQ dioxin. Twelve children had to be excluded. A significant decrease in lung function in relation to both prenatal (p = 0.045) and postnatal (p = 0.0002) dioxin exposure was seen in the 29 non-excluded children. A clinical association between chest congestion and perinatal dioxin exposure was seen. CONCLUSION: Perinatal background dioxin exposure may be inversely associated with the FEV1/ FVC ratio.

Predictive value of neonatal neurological tests for developmental outcome of preterm infants.

BACKGROUND: There is a need to identify, as early as possible, infants who are at risk for long-term neurological morbidity. METHODS: To predict neurodevelopment outcome of preterm infants <30 weeks' gestation in a population of 100 infants, we used several neonatal and neurobehavioral tests, including cranial ultrasonography, the Prechtl neurological test, quality of spontaneous general movements, and quality of sleep-wake organization. RESULTS: The Prechtl test at corrected term age and findings on cranial sonograms both had high specificity, but the Prechtl test had better overall positive predictive power for normal neurological and developmental outcomes at 2 years' corrected age. Developmental changes in sleep and the amount of indeterminate sleep did not correlate with outcome. Scoring general movement quality did not predict outcome and did not augment the positive predictive power of the Prechtl test. CONCLUSIONS: The Prechtl test at corrected term age (independent of the other tests) is the best positive predictor of normal neurological outcome and Bayley test results at 2 years' corrected age.

Twenty-year follow-up of antenatal corticosteroid treatment.

OBJECTIVE: To study late side effects of antenatal corticosteroid treatment on health and sexual development in subjects 20 to 22 years old. METHODS: A follow-up study among young adults whose mothers had, because of a threatening delivery, participated in a randomized, double-blind, placebo- controlled trial of betamethasone to prevent neonatal respiratory distress syndrome. Measurements were taken on general health, growth, development in puberty, reproductivity, genital or gynecological complaints, gender development, sexual orientation, sex-specific cognitive functioning, and psychoneuroticism. In addition, some measurements were performed on family diseases, socioeconomic status, and education. RESULTS: No differences were found between the corticosteroid-treated and placebo groups as to medical or psychological variables. In general, the subjects were healthy and had normal intellectual capacities. Groups did not differ on gender development, sexual orientation, sex-specific cognitive functioning, and psychoneuroticism. Systolic blood pressure was significantly lower in the corticosteroid group, but the groups did not differ as to diastolic blood pressure. CONCLUSIONS: Our 20-year follow-up study indicates that 1 course of antenatally administered corticosteroid to prevent respiratory distress syndrome does not have adverse effects up to adulthood.

Association of prenatal phenobarbital and phenytoin exposure with small head size at birth and with learning problems.

UNLABELLED: Small head size has been observed in prenatally anticonvulsant-exposed neonates. In infancy, cognitive impairments were revealed. It is presently unknown whether these impairments are permanent or disappear after puberty. We studied the link between the prenatal influence of anticonvulsants on brain development and cognitive functioning in adulthood: a retrospective study on head size and a follow-up assessing cognitive capacities among adults who had been included in the retrospective study. The retrospective study comprised 172 exposed and 168 control neonates, matched with respect to age, sex and their mothers' age. Prenatally phenobarbital + phenytoin-exposed neonates had a significantly smaller occipitofrontal circumference (OFC) than prenatally phenobarbital-monotherapy-exposed and control neonates (mean difference of 0.7 cm). In the follow-up, no difference in cognitive functioning was found between the exposed and the control groups. Most of the prenatally anticonvulsant-exposed subjects had normal intellectual capacity. However, 12% of the exposed subjects versus 1% of the controls had persistent learning problems. In addition, more of the exposed subjects were mentally retarded. There was no clear relationship between learning problems and small OFC, maternal epilepsy or unfavourable family climate. CONCLUSIONS: We conclude that the combination of phenobarbital + phenytoin affects the fetal OFC. The smaller OFC does not seem to be related to cognitive functioning in adulthood, but learning problems and mental retardation proved to be more prevalent among exposed subjects. Phenobarbital and phenytoin may therefore affect cognitive capacity but only in infants who are susceptible to this particular influence of the drugs.

Open chemical combustions resulting in a local increased incidence of orofacial clefts.

HYPOTHESIS: The open chemical combustions in Zeeburg, Amsterdam, The Netherlands, during the years 1961 up to and including 1969, resulted in a local increased incidence of orofacial clefts during this period. STUDY: A retrospective observational epidemiological study was performed, comparing the trend of the incidence of non-syndromal orofacial clefts during the sixties, for the Zeeburg maternity with that of the Wilhelmina Gasthuis. Both clinics were situated in Amsterdam, but varying in distance and compass direction from the incineration works. Thereafter, the addresses of the mothers giving birth to infants with orofacial clefts were plotted on a map of Amsterdam. RESULTS: Of the 8803 children born in the Zeeburg clinic during this period, 21 had a non-syndromal orofacial cleft, producing an average incidence of 2.4 per 1000 births. For the years 1963 through 1965 the incidence rose dramatically to peak at 7.1 per 1000, before plateauing at an average incidence of 1.68 per 1000 births, still 155% higher than in the Wilhelmina clinic (average incidence of 0.66 per 1000 during the years 1966 through 1969). During the 10 year period the Wilhelmina clinic exhibited no such rise. The incidence of non-syndromal orofacial clefts at the Wilhelmina clinic at no time exceeded 2.3 per 1000 births during the 10 year period. The addresses of the mothers of the Zeeburg clefts were grouped primarily to the northwest (and a smaller group to the west) of the incineration works. CONCLUSION: A relation between the open incineration of the chemicals and a local increased incidence of orofacial clefts seems very likely.

Validation of a high-performance liquid chromatography assay for quantification of caffeine and paraxanthine in human serum in the context of CYP1A2 phenotyping.

In this study the validation of a reversed-phase high-performance liquid chromatography (HPLC) method, with UV-detection, for both caffeine and paraxanthine in human serum is described. This method is feasible for cytochrome P450 1A2 (CYP1A2) phenotyping, according to the results of a pilot study. With this HPLC method caffeine and paraxanthine can be determined selectively and specifically. In the expected concentration range, caffeine recoveries were 98-108% (within-run variation 4.0-6.4%, between-run variation 6.4-8.8%), paraxanthine recoveries were 96.6-97.5% (within-run variation 5.0-7.2%, between-run variation 7.2-10.8%). The limits of detection for caffeine and paraxanthine using this HPLC system were 0.3 and 0.1 mg/L, respectively. Linear calibration curves for both caffeine and paraxanthine were obtained in the concentration range 0.5-30 mg/L (r > 0.9999. Serum samples were stable for a week, when stored at -20 and +4 degrees C.

Prenatal exposure to anticonvulsants and psychosexual development.

Animal studies have shown that prenatal exposure to the anticonvulsant drugs phenobarbital and phenytoin alters steroid hormone levels which consequently leads to disturbed sexual differentiation. In this study, possible sequelae of prenatal exposure to these anticonvulsants on gender development in humans were investigated. A follow-up study was carried out in phenobarbital- and phenytoin-exposed subjects and control subjects matched for age, sex, and the mothers' ages. Subjects were born in the Academic Medical Center between 1957 and 1972. Out of 243 exposed and 222 control subjects who were asked to volunteer, 147 exposed subjects (72 male, 75 female) and equal numbers of their matched control subjects participated in the follow-up study. They were interviewed and were asked to fill out questionnaires on gender role behavior, gender development, and sexual orientation. As a group, exposed and control subjects did not differ with respect to gender role behavior, although higher numbers of prenatally anticonvulsant-exposed subjects reported current or past cross-gender behavior and/or gender dysphoria. Three prenatally anticonvulsant-exposed subjects were transsexuals and had undergone sex reassignment surgery, a remarkably high rate given the rarity of transsexualism. In addition, two exposed males had exclusively homosexual experiences, whereas none of the control males reported exclusive homosexual behavior. The groups did not differ in attainment of pubertal psychosexual milestones.

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,2',4,4',5,5'-hexachlorobiphenyl on vitamin K-dependent blood coagulation in male and female WAG/Rij-rats.

Newborns are susceptible to hemorrhages (hemorrhagic disease of the newborn or HDN) due to vitamin K deficiency. Induction of cytochrome P450 in the fetal liver by maternal anticonvulsant therapy such as phenobarbital or phenytoin is considered to be a major cause. An observed increase in late hemorrhagic disease (LHD) in breast fed neonates gave rise to the hypothesis that PCBs and dioxins, P450-inducing contaminants present in human milk, might effect vitamin K-dependent blood coagulation. This hypothesis was studied in rats. Administration of a single oral dose of 0.003, 0.03, 0.3, 3 or 30 nmol 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) per kg bodyweight or 0.75, 4, 20, 100 or 500 micromol 2,2',4,4',5,5'-hexachlorobiphenyl/kg bw (HxCB) to female and male rats resulted in dose-related reductions of the vitamin K-dependent coagulation factor VII. The highest factor VII reduction in female rats was 44%, observed after TCDD exposure. The Lowest Observed Adverse Effect Level (LOAEL) of TCDD on female factor VII levels was 0.3 nmol/kg bw (96 ng/kg). There was a significant inverse correlation between Factor VII levels and induction of hepatic ethoxyresorufin O-deethylating (EROD) activity, reflecting CYP1A1, and total P450 content. HxCB had no effect on female coagulation factors. In contrast, in male rats only exposure to HxCB, which induces mainly CYP2B1 and 2B2, decreased both coagulation factors dramatically up to 88%. The LOAEL of HxCB on factor VII in male rats was 100 micromol/kg bw (36 mg/kg). In general, effects on coagulation factors in male rats exceeded those in females. In addition, sex-dependent differences of TCDD and HxCB were observed on the hepatic vitamin K cycle enzyme activities in female and male rats. Vitamin K-dependent (gamma-glutamyl carboxylase activity was mainly induced in female rats; 2.3-fold in the highest dose group of TCDD. In male rats only vitamin K 2,3-epoxide reductase (KO-reductase) activity was induced 1.7-fold by the highest dose of HxCB. KO-reductase activity in female rats was also increased by TCDD, however, less pronounced than the carboxylase activity. Concluding, the hepatic vitamin K cycle still functions and is not blocked by TCDD or HxCB, thus explaining the observed reduction in factor VII. Finally, the possible role of P450 in vitamin K deficiency is discussed. Based on these results it is suggested to investigate the possible role of PCBs and dioxin-like compounds in LHD in more detail.

Pneumothorax monitoring by remittance measurement: comparison between experimental model and animal studies.

Pneumothorax monitoring by remittance measurement in neonatology is investigated using model experiments. The results are compared to previous animal experiments. A multifibre probe is used to measure the change in remittance at 632.8 nm and 790 nm as a function of the thickness of a layer of air between a model chest wall (optically matched to piglet chest walls) and a model lung. An increase in thickness of this layer of air results in a decrease in remittance. Only when a relatively thin model chest wall is used (thickness 4 or 6 mm) and detection fibres are at some distance from the source, is this decrease in remittance preceded by an initial increase in remittance. Relative changes in remittance are larger at 790 nm then at 632.8 nm. The results in general correspond to the results of the animal experiments. However, not all results of the animal experiments could be explained. We conclude that our assumptions for the model experiments did not cover all aspects of the development of a pneumothorax and dynamic models with changing optical properties should be used instead. In conclusion, the results in general confirm and help understand the results of the animal experiments and indicate that pneumothorax monitoring by remittance measurement is feasible.

The impact of surfactant replacement therapy on cerebral and systemic circulation and lung function.

UNLABELLED: The influence of surfactant administration on cerebral and systemic circulation and on lung function was evaluated in 12 premature mechanically ventilated infants (mean birth weight 1,560 +/- 770 g, mean gestational age 30.0 +/- 3.2 weeks) with respiratory distress syndrome (RDS) receiving surfactant replacement therapy. We measured mean cerebral blood flow velocity (MCBFV), heart rate (HR), mean arterial pressure (MAP), static compliance (Crs), resistance of respiratory system (Rrs), functional residual capacity (FRC) and fraction of inspired oxygen (FiO2). In addition to a very low compliance and a moderately elevated resistance of the respiratory system a significant drop in MAP, HR, MCBFV and FiO2 was noticed after surfactant administration. After 30 min HR, MAP and MCBFV values returned to baseline levels. We postulate that the drop in MCBFV, MAP, HR and FiO2 with a minor, though not significant improvement of the FRC can most likely be explained by a "relative" hypovolaemia in other organs and parts of the body due to expansion of the lung vascular bed. Compensation for the redistribution of circulatory volume occurred within several minutes. Blood pressure control and treatment of hypovolaemia is mandatory before surfactant is administered. CONCLUSION: In RDS patients there is a significant drop of MAP, HR, MCBFV and FiO2 after bolus surfactant administration.

Missing effects of background dioxin exposure on development of breast-fed infants during the first half year of life.

Fetal exposure to higher levels of PCBs can result in low birth weight and neurological disorders of the newborn. In this study the effects of exposure to the highly toxic dioxins and dibenzofurans, structurally related to PCBs, was investigated in a population of 38 healthy infants. The infants were divided into two groups, according to concentrations of dioxins and dibenzofurans in their mothers milk fat. Neonatal body weight, length, Quetelet index and liver size were determined at different time points during the first half year of life. Additionally neurological development was determined. Comparing these items between the high and low exposure groups did not show any statistically significant differences. The results of this study do not reveal any effect of exposure to background levels of dioxins and dibenzofurans, but in utero exposure to these toxic agents may result in symptoms later in life. Therefore follow-up study of this well defined group will be performed.