M Huisman

Perinatal exposure to polychlorinated biphenyls and dioxins and its effect on neonatal neurological development

Polychlorinated biphenyls (PCBs) and dioxins (polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs)) are widespread environmental contaminants which are neurotoxic in animals. Perinatal exposure to PCBs, PCDDs, and PCDFs occurs prenatally via the placenta and postnatally via breast milk. To investigate whether such an exposure affects the neonatal neurological condition, the neurological optimality of 418 Dutch newborns was evaluated with the Prechtl neurological examination. Half of the infants were breast-fed, the other half were formula-fed, representing a relatively high against a relatively low postnatally exposed group, respectively. As an index of prenatal exposure, four non-planar PCBs in cord and maternal plasma were used. These PCB levels were not related to neurological function. As measures of combined pre- and early neonatal exposure, 17 dioxin congeners, three planar, and 23 non-planar PCB congeners were determined in human milk in the second week after delivery. Higher levels of PCBs, PCDDs, and PCDFs in breast milk were related to reduced neonatal neurological optimality. Higher levels of planar PCBs in breast milk were associated with a higher incidence of hypotonia. This study confirms previous reports about the neurotoxic effects of these compounds on the developing brain of newborn infants.

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.

Neurological condition in 18-month-old children perinatally exposed to polychlorinated biphenyls and dioxins

The neurological optimality of 418 Dutch children was evaluated at the age of 18 months, in order to determine whether prenatal and breast milk mediated exposure to polychlorinated biphenyls (PCBs) and dioxins affected neurological development. Half of the infants were breast-fed, the other half were formula-fed. PCB concentrations in cord and maternal plasma were used as a measure of prenatal exposure to PCBs. To measure postnatal exposure, PCB and dioxin congeners were determined in human milk and in formula milk. After adjusting for covariates, transplacental PCB exposure was negatively related to the neurological condition at 18 months. Although greater amounts of PCBs and dioxins are transferred via nursing than via placental passage, an effect of lactational exposure to PCBs and dioxins could not be detected. We even found a beneficial effect of breast-feeding on the fluency of movements. We conclude that transplacental PCB passage has a small negative effect on the neurological condition in 18-month-old toddlers.

PCB AND DIOXIN LEVELS IN PLASMA AND HUMAN MILK OF 418 DUTCH WOMEN AND THEIR INFANTS. PREDICTIVE VALUE OF PCB CONGENER LEVELS IN MATERNAL PLASMA FOR FETAL AND INFANT'S EXPOSURE TO PCBs AND DIOXINS.

Polychlorinated biphenyls (PCBs) as well as dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs)) are potentially hazardous compounds in the environment for human beings. In order to investigate PCB and dioxin exposure of Dutch women and their neonates, levels were examined in 418 mother-infant pairs. Four non-planar PCB congener levels (PCB 118, 138, 153 and 180) were measured in maternal plasma and in umbilical cord plasma. The 209 mothers who breast-fed their infants collected human milk samples for the analysis of seventeen 2,3,7,8-substituted PCDD and PCDF congener levels, three planar PCB and twenty-three non-planar PCB congener levels. The dioxin and planar PCB levels we measured in human milk (mean 30 respectively 16 pg TEQ/g fat), belong to the highest background levels analysed all over the world but they are in the normal range for highly industrialised, densely populated countries in Western Europe. Correlation coefficients between PCB 118, 138, 153 and 180 congener levels in maternal plasma and PCB levels in cord plasma or PCB and dioxin levels in human milk are highly significant. However, the 95% predictive interval is too wide to predict accurately the PCB and dioxin levels to which an individual infant is exposed in utero or postnatally by breast-feeding, from the PCB levels in maternal plasma.

EFFECTS OF POLYCHLORINATED-BIPHENYLS (PCBS) AND DIOXINS ON GROWTH AND DEVELOPMENT

Polychlorinated biphenyls (PCBs) and dioxins are potentially toxic compounds which occur widely in the environment. Their effects on the growth and development of infants at the levels currently found in highly industrialised western countries is not well known. This Dutch multicenter study, combining animal and human studies, tries to answer this question. Animal studies showed that PCB 169, given once during pregnancy at a dose of 1.8 g kg-1 bodyweight, has an effect on developmental parameters, dopamine regulation and fertility. Effects on thyroid hormones were also found in animals, probably due to both a competitive binding of PCB metabolites to the thyroxine binding protein and increased glucuronidation, Perhaps to compensate for this, an increased diodase activity in the brain was found. Human studies involved 400 mother-infant pairs, half of them being breast-fed, the other half were fed a formula devoid of PCBs and dioxins. PCB levels were measured in serum and dioxin and PCB levels in breastmilk. Levels were found to be as high as previously found in highly industrialised countries. Growth and development were carefully documented, but no data are as yet available. In pregnant women, a significant negative correlation was found between some dioxin and PCB congeners in milk and plasma thyroid hormones, while newborn infants showed higher thyroid stimulating hormone (TSH) at higher levels of dioxin exposure. In summary, data from this combined multicenter study involving animals and humans increases our insight into the potentially negative effects of PCBs and dioxins on growth and development.

Dioxin and PCB levels in blood and human milk in relation to living areas in the Netherlands

Dioxins and polychlorinated biphenyls (PCBs) are ubiquitous toxic compounds in the environment. Negative influences of these compounds on the health status of human beings have been described. Especially susceptible might be the fetus, which is exposed in utero, and the newborn breast-fed infant, since both are exposed to relatively high levels of dioxins and PCBs during a critical period of organ growth and development. We investigated PCB levels in 406 maternal plasma samples as well as PCB and dioxin levels in 172 human milk samples with relation to living area of women living for at least five years in the western industrialized part of the Netherlands or the northern more rural part. The western part was further subdivided into one urban and two highly industrialized areas. After correction for covariates, we found significantly higher levels of PCB 118 in maternal plasma as well as significantly higher levels of the dioxin-TEQ and of ten individual dioxin and PCB congener levels in human milk in the western more industrialized areas of the Netherlands compared to the northern more rural part. We did not find significant differences in planar, mono-ortho or di-ortho PCB-TEQ levels in human milk between all different areas. We conclude that significantly higher levels of a number of dioxin and PCB congeners are found in women living in industrialized areas compared to women living in rural areas in the Netherlands.

Polychlorinated Biphenyls in Adipose Tissue, Liver, and Brain from Nine Stillborns of Varying Gestational Ages

We analyzed polychlorinated biphenyls (PCBs) in s.c. adipose tissue, liver, and brain of nine fetuses who died in utero. Their median(range) gestational ages and birth weights were 34 (17-40) wk and 2050(162-3225) g. Three fetuses were small for gestational age. The levels of PCB congener nos. 118, 138, 153, and 180, and the sum of these (ΣPCB), were calculated in terms of tissue total fat content (ng/g fat). The median(range) ΣPCB (in ng/g fat) amounted to adipose tissue 235 (97-768), liver 198 (67-362), and brain 50 (22-122). Median (range) ΣPCB levels in liver and brain were 0.8 (0.4-0.9) and 0.2 (0.1-0.3) times, respectively, as high as the ΣPCB levels in adipose tissue. There were strong relations between ΣPCB in adipose tissue and ΣPCB in liver(r = 0.98; p < 0.01), and between ΣPCB in adipose tissue and ΣPCB in brain (r = 0.91;p < 0.01). Adipose tissue, liver, and brain did not show differences in the distribution of congeners 118, 138, 153, and 180, and there was no statistically significant association between tissue PCB levels and gestational age (r varied between 0.22 and 0.47). MedianΣPCB levels in fetal adipose tissue proved to be comparable with our previously established ΣPCB levels in mature breast milk of 93 Dutch women (median 414; range 158-969 ng/g of fat). The PCB congeneric distribution of fetal adipose tissue was not different from that of human milk. We conclude that maternal PCBs have a tendency to accumulate notably in fetal tissues with high triglyceride contents. They are easily transferred across the placenta and seem to become equilibrated among the apolar parts of maternal and fetal lipids.

Estimation of 24-hour polyamine intake from mature human milk

It has been suggested that milk polyamines stimulate GI tract proliferation and maturation in newborns. We determined human milk polyamine concentrations and estimated 24-h outputs on days 16 +/- 4 (n = 98), 44 +/- 3 (n = 97) and 91 +/- 6 (n = 25) after delivery. Median concentrations in micromolars were, respectively, putrescine 0.77, 0.63, and 0.63; spermidine 4.54, 3.07, and 2.73; spermine 3.76, 2.90, and 2.22; and total polyamines 9.82, 6.83, and 5.71. Concentrations of spermidine, spermine, and total polyamines decreased during the observation period. Putrescine, spermidine, and spermine milk/maternal plasma ratios were estimated to be 16-19, 14-24, and 44-75, respectively. It would appear that milk polyamines are derived from the high polyamine contents in the mammary gland and that they may be important in infant nutrition.

The Dutch PCB/dioxin study Contents of dioxins, planar and other PCBs in human milk from the Rotterdam and Groningen area

In two areas (Groningen and Rotterdam): individual human milk samples (24 hr.) were obtained 10 and 42 days after delivery from about 200 mothers. In all samples non-planar PCBs, including some monoorthochlorine substituted PCBs were determined. All first samples, and a smaller number of the second samples were analysed for dioxins and coplanar PCBs. The obtained results are in the same order of magnitude as earlier Dutch results and do in general not differ from the situation in neighbouring countries. No differences could be observed between the analytical results of both areas.

The Effects on Mammals of Pre- and Postnatal Environmental Exposure to PCBs1 The Dutch Collaborative PCB/Dioxin Study

Five institutes2 are collaborating in the Netherlands in a national study concerning the long-term effects of foetal and neonatal exposure to polychlorobiphenyls and dioxins. This collaborative study started in 1990 and was funded by the Dutch Toxicology Research Promotion Programme and the Health Research Stimulation Programme. The study includes both human and animal studies.