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Polychlorinated biphenyls (PCBs) are one of the original twelve classes of toxic chemicals covered by the Stockholm Convention on Persistent Organic Pollutants (POP), an international environmental treaty signed in 2001. PCBs are present in the environment as mixtures of multiple isomers at different degree of chlorination. These compounds are manmade and possess useful industrial properties including extreme longevity under harsh conditions, heat absorbance, and the ability to form an oily liquid at room temperature that is useful for electrical utilities and in other industrial applications. They have been widely used for a wide range of industrial purposes over the decades. Despite a ban in production in 1979 in the US and many other countries, they remain persistent and ubiquitous in environment as contaminants due to their improper disposal. Humans, independent of where they live, are therefore exposed to PCBs, which are routinely found in random surveys of human and animal tissues. The prolonged exposures to PCBs have been associated with the development of different diseases and disorders, and they are classified as endocrine disruptors. Due to its ability to interact with thyroid hormone, metabolism and function, they are thought to be implicated in the global rise of obesity diabetes, and their potential toxicity for neurodevelopment and disorders, an example of gene by environmental interaction (GxE). The current review is primarily intended to summarize the evidence for the association of PCB exposures with increased risks for metabolic dysfunctions and neurobehavioral disorders. In particular, we present evidence of gene expression alterations in PCB-exposed populations to construct the underlying pathways that may lead to those diseases and disorders in course of life. We conclude the review with future perspectives on biomarker-based research to identify susceptible individuals and populations., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dioxins (polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDF)), polychlorinated biphenyls (PCBs), and brominated flame retardants (BDEs) are well known toxic environmental contaminants. Their possible role in the incidence of respiratory disease is not yet well understood. Previous studies showed a negative effect on lung function in relation to prenatal and lactational dioxin exposure in pre-pubertal children. Effects of BDE exposure on the lung function have not previously been evaluated. As part of a longitudinal cohort study, the effects of perinatal dioxin (PCDD/F) exposure and serum PCDD/F, dl-PCB, and BDE levels on lung function in adolescents were assessed using spirometry, a body box, and diffusion measurements. Thirty-three children (born between 1986 and 1991) consented to the current follow-up study. Prenatal, lactational, and current dioxin, PCB, and BDE concentrations were determined using GC-MS. No relationship was seen between prenatal and lactational dioxin exposure, nor with current PCB body burden, and lung function. Indications of increasing airway obstruction were seen in relation to increasing current BDE exposure. This is a novel finding and certainly warrants further research.

Objectives: Dioxins and PCBs are highly toxic and persistent environmental pollutants that are measurable in humans worldwide. These persistent organic pollutants are associated with a higher incidence of diabetes mellitus. We hypothesise that perinatal (background) exposure to industrial pollutants like dioxins also influences body mass development and energy metabolism in later life., Study Design: In The Netherlands, the perinatal exposure (prenatal exposure and postnatal lactational intake) to dioxins has been studied prospectively since 1987. Fasting glucose, insulin, HbA1c and leptin were analysed in 33 children of the original cohort of 60. BMI, glucose:insulin and BMI:leptin ratios were calculated. Prenatal exposure, lactational intake and current serum levels of dioxins (PCDD/F), dl-PCBs and PBDE concentrations were determined using (HR)GC-MS., Results: Prenatal dioxin (PCDD/F) exposure was positively correlated to the glucose:insulin ratio (p = 0.024) and negatively correlated to the fasting insulin concentration (p = 0.017) in adolescence. Postnatal lactational PCDD/F intake was also negatively correlated to fasting insulin concentration (p = 0.028). Current serum levels of PCDD/Fs and total TEQ (dl-PCBs+PCDD/Fs) were positively correlated to the fasting serum glucose concentration (p = 0.015 and p = 0.037, respectively).No metabolic effects were seen in association with current serum levels of PBDEs. A positive correlation between the insulin and leptin concentrations (p = 0.034) was observed. No effects were found on leptin levels, BMI:leptin ratio, HbA1c levels or BMI., Discussion/conclusion: This study indicates that prenatal and lactational exposure influences glucose metabolism in adolescents, presumably through a negative effect on insulin secretion by pancreatic beta cells. Additionally, the very low recent background exposure to dioxins in puberty possibly has an effect on the glucose level.

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., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The EU 6th Framework Program (FP)-funded Health and Environment Network (HENVINET) aimed to support informed policy making by facilitating the availability of relevant knowledge on different environmental health issues. An approach was developed by which scientific agreement, disagreement, and knowledge gaps could be efficiently identified, and expert advice prepared in a way that is usable for policy makers. There were two aims of the project: 1) to apply the tool to a relevant issue; the potential health impacts of the widely used plasticizers, phthalates, and 2) to evaluate the method and the tool by asking both scientific experts and the target audience, namely policy makers and stakeholders, for their opinions., Methods: The tool consisted of an expert consultation in several steps on the issue of phthalates in environmental health. A diagram depicting the cause-effect chain, from the production and use of phthalates to potential health impacts, was prepared based on existing reviews. This was used as a basis for an online questionnaire, through which experts in the field were consulted. The results of this first round of consultation laid the foundation for a new questionnaire answered by an expert panel that, subsequently, also discussed approaches and results in a workshop. One major task of the expert panel was to pinpoint priorities from the cause-effect chain according to their impact on the extent of potential health risks and their relevance for reducing uncertainty. The results were condensed into a policy brief that was sent to policy makers and stakeholders for their evaluation., Results: The experts agreed about the substantial knowledge gaps within the field of phthalates. The top three priorities for further research and policy action were: 1) intrauterine exposure, 2) reproductive toxicology, and 3) exposure from medical devices. Although not all relevant information from the cause-effect chain is known for phthalates, most experts thought that there are enough indications to justify a precautionary approach and to restrict their general use. Although some of the experts expressed some scepticism about such a tool, most felt that important issues were highlighted., Conclusions: The approach used was an efficient way at summarising priority knowledge gaps as a starting point for health risk assessment of compounds, based on their relevance for the risk assessment outcome. We conclude that this approach is useful for supporting policy makers with state-of-the-art scientific knowledge weighed by experts. The method can assist future evidence-based policy making.

Background: Polychlorinated dioxins and -furans (PCDD/Fs) and polychlorinated-biphenyls (PCBs) are environmental toxicants that have been proven to influence thyroid metabolism both in animal studies and in human beings. In recent years polybrominated diphenyl ethers (PBDEs) also have been found to have a negative influence on thyroid hormone metabolism. The lower brominated flame retardants are now banned in the EU, however higher brominated decabromo-diphenyl ether (DBDE) and the brominated flame retardant hexabromocyclododecane (HBCD) are not yet banned. They too can negatively influence thyroid hormone metabolism. An additional brominated flame retardant that is still in use is tetrabromobisphenol-A (TBBPA), which has also been shown to influence thyroid hormone metabolism.Influences of brominated flame retardants, PCDD/F's and dioxin like-PCBs (dl-PCB's) on thyroid hormone metabolism in adolescence in the Netherlands will be presented in this study and determined if there are reasons for concern to human health for these toxins. In the period 1987-1991, a cohort of mother-baby pairs was formed in order to detect abnormalities in relation to dioxin levels in the perinatal period. The study demonstrated that PCDD/Fs were found around the time of birth, suggesting a modulation of the setpoint of thyroid hormone metabolism with a higher 3,3', 5,5'tetrathyroxine (T4) levels and an increased thyroid stimulating hormone (TSH). While the same serum thyroid hormone tests (- TSH and T4) were again normal by 2 years of age and were still normal at 8-12 years, adolescence is a period with extra stress on thyroid hormone metabolism. Therefore we measured serum levels of TSH, T4, 3,3',5- triiodothyronine (T3), free T4 (FT4), antibodies and thyroxine-binding globulin (TBG) in our adolescent cohort., Methods: Vena puncture was performed to obtain samples for the measurement of thyroid hormone metabolism related parameters and the current serum dioxin (PCDD/Fs), PCB and PBDE levels., Results: The current levels of T3 were positively correlated to BDE-99. A positive trend with FT4 and BDE-99 was also seen, while a positive correlation with T3 and dl-PCB was also seen. No correlation with TBG was seen for any of the contaminants. Neither the prenatal nor the current PCDD/F levels showed a relationship with the thyroid parameters in this relatively small group., Conclusion: Once again the thyroid hormone metabolism (an increase in T3) seems to have been influenced by current background levels of common environmental contaminants: dl-PCBs and BDE-99. T3 is a product of target organs and abnormalities might indicate effects on hormone transporters and could cause pathology. While the influence on T3 levels may have been compensated, because the adolescents functioned normal at the time of the study period, it is questionable if this compensation is enough for all organs depending on thyroid hormones.

Aim: Apply a recently developed expert elicitation procedure to evaluate the state of the current knowledge of the two brominated flame retardants (BFRs) most commonly used today; decabromo-diphenyl ether (decaBDE) and hexabromocyclododecane (HBCD) and their potential impact on human health in order to support policy considerations. This expert elicitation was organized by the HENVINET (Health and Environment Network) Consortium., Method: The HENVINET expert elicitation procedure that was used in the evaluations of decaBDE and HBCD is a rapid assessment tool aimed at highlighting areas of agreement and areas of disagreement on knowledge-related key issues for environment and health policy decision making., Results: The outcome of the expert consultation on BFRs was concrete expert advice for policy makers with specific priorities for further action made clear for both stakeholders and policy makers. The experts were not in agreement whether or not the knowledge currently available on decaBDE or HBCD is sufficient to justify policy actions, but most experts considered that enough data already exists to support a ban or restriction on the use of these compounds. All experts agreed on the necessity of more research on the compounds. Priority issues for further research were, among others:• more studies on the extent of human exposure to the compounds.• more studies on the fate and concentration in the human body of the compounds.

Background: 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., Methods: A literature review was undertaken to assess the evidence for CPF contributing to neurodevelopmental disorders in infants and children. Other literature was consulted in order to formulate a causal chain diagram showing the origins, uptake, and neurological effects of animal and human exposure to CPF.The causal chain diagram and a questionnaire were distributed online to scientific experts who had published in relevant areas of research. They were asked to assess their confidence levels on whether CPF does in fact contribute to adverse neurodevelopment outcomes and rate their confidence in the scientific evidence. A second questionnaire queried experts as to which kind of policy action they consider justifiable based on current knowledge. In a special workshop session at the EuroTox congress in Dresden in 2009 the results of both questionnaires were further discussed with invited experts, as a basis for a policy brief with main messages for policy makers and stakeholders., Results: Most experts who responded to the first questionnaire felt that there was already enough evidence to support a ban on indoor uses of CPF in the EU. However, most felt additional research is still required in several areas. The responses from the first questionnaire were used to formulate the second questionnaire addressing the feasibility of government action. In turn, these expert participants were invited to attend a special session at the EuroTox congress in Dresden in 2009., Conclusions: Some of the evidence that CPF contributes to neurodevelopmental disorders is still disputed among experts, and the overall sense is that further research and public awareness are warranted. There have been campaigns in North America making the potential exposure concerns known, but such information is not widely known in the EU. The ability of government action to produce change is strongly felt in some quarters while others believe better knowledge of consumer use trends would have a greater impact.

Dioxins and PCBs are environmental pollutants, proven to be immunotoxic. In the period 1987-1991 a cohort of mother-baby pairs was initiated to detect abnormalities in relation to dioxin levels in the mother's milk. At birth and at follow-up at 8-12 years, immunological and hematological effects were seen, prompting us to perform a new follow-up during adolescence. In addition, we assessed the immunological and hematological parameters in relation to current levels of PBDEs and PCBs. In the Netherlands, the pre- and postnatal exposure to dioxins have been studied prospectively since 1987. Venapuncture was performed to assess hematological (Hemoglobin, thrombocytes, thrombopoietin) and immunological (leukocytes, leukocyte differentiation) parameters and the current serum levels of dioxin, dioxinlike (dl)-PCBs and PBDEs. A decrease in the number of polymorphic neutrophils was found in adolescents with higher dl-PCBs in their serum (p = 0.021). No relation with total leukocytes, thrombocytes, hemoglobin, or thrombopoietin levels was seen. Similarly, we found no relation between prenatal, nor current dioxin levels and the hematological and the immunological parameters determined. The SigmaPBDEs were negatively associated with the number of lymphocytes (p = 0.01) and positively associated with the hemoglobin concentration (p = 0.003). These effects on the innate immunity by current levels of dl-PCBs and on the adaptive immunity by PBDEs are disconcerting, especially as the dl-PCB (0.04-7.8 WHOTEQ pg/g lipid, mean: 2.2 WHOTEQ pg/g lipid) and SigmaPBDE levels (mean 14.0 ng/g lipid, including one outlier with a sum of 73.6 ng/g lipid) were not high.

Objectives: While many studies have assessed the health impacts of PCDD/Fs and PCBs on animals and humans, long-term consequences for especially adolescents, have not (yet) been well documented. This is certainly also true for the effects of PBDE exposure. As part of a longitudinal cohort study, now well into its second decade, effects of perinatal and current PCDD/F exposure, as well as current dl-PCB and PBDE exposures, on puberty, were assessed., Study Design: Prenatal, lactational and current PCDD/F, dl-PCB and PBDE concentrations were determined using GC-MS. Pubertal development and growth were assessed by means of physical examination and the Tanner scale. 33 Children (born between 1986 and 1991) consented to the current follow-up study. Outcomes were evaluated using linear regression or the non parametric Spearman's correlation coefficient., Results: A delay in initiation of breast development was found in girls (n = 18) with higher prenatal (p = 0.023) and lactational PCDD/F exposure (p = 0.048). The males revealed a negative trend with age at first ejaculation. For other endpoints on puberty and growth (pubic hair, axillary hair, genital stage, length, BMI, testicular volume, menarche) no significant relation was found with any of the measured compounds., Discussion and Conclusion: A relation between prenatal PCDD/F exposure and later initiation of breast development was seen. A Belgian study found a delay in breast development with higher current serum concentrations of dioxin-like compounds. The initiation of puberty is a complex process and it is yet not clear how dioxin-like compounds precisely affect this process prenatally. Further follow-up into adulthood is warranted, in order to detect the possibility of developing malignancies and fertility problems.

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.

Objectives: Prenatal and lactational exposure to Dutch "background" dioxin levels may cause health effects spanning many years. In addition, perinatal studies have shown a relationship between dioxin exposure and thyroid disturbance. To assess the later health effects of prenatal and lactational dioxin exposure on liver function we measured plasma ALAT and ASAT levels amongst our longitudinal cohort, as was done perinatally and at 2(1/2) years. The children underwent a caffeine loading test to determine CYP1A2 activity. To assess the later effects on thyroid function we measured plasma TSH and FT4., Study Design: A longitudinal cohort of 37 healthy children (age 7-12, mean 8.2 years), with documented prenatal and lactational dioxin exposure, ingested 3mg caffeine/kg BW 6h prior to blood withdrawal. Paraxanthine/caffeine molar ratio, ALAT, ASAT, TSH and FT4 were determined in venous blood., Results: Linear regression of ASAT and ALAT revealed no relation with prenatal and lactational dioxin exposure. No correlation was found between the paraxanthine/caffeine molar ratio and prenatal and lactational dioxin exposure. Linear regression of TSH and FT4 revealed no relation with prenatal and lactational dioxin exposure., Conclusion: This follow-up has shown a normalisation of previously abnormal ALAT and ASAT levels, indicating a transient effect. CYP1A2 activity, measured by means of a caffeine-loading test, revealed no correlation with the prenatal and lactational exposures. A normalisation of previously abnormal thyroid hormone homeostasis was seen, also possibly indicating a transient effect. This study provides new data on long-term follow-up after perinatal dioxin exposure to background levels of dioxins.

Cadmium exposure and accumulation in the body start at young age. Exposure routes in children are mainly via food, environmental tobacco smoke and house dust. Excretion from the body is limited. Cadmium accumulation in the kidney is responsible for effects such as nephrotoxicity and osteoporosis which are observed at adult age. Cadmium exposure through inhalation is also associated with lung cancer in adulthood. Although transfer to the neonate through the placenta and through breast milk is limited, teratogenic and developmental effects were observed in experimental animals. The database on human studies involving children is limited, yet effects on motoric and perceptual behaviour in children have been associated with elevated in utero cadmium exposure. In school age children urinary cadmium levels were associated with immune suppressive effects. More studies are needed to confirm these results. Experimental data in vitro and in animals refer to effects of cadmium on the hypothalamus-pituitary axis at different levels. This may lead to disorders of the endocrine and/or immune system. Cadmium exposure at early age should be limited as much as possible to prevent direct effects on children and to prevent accumulation of cadmium which may have serious health effects only becoming manifest at older age.

Background/methods: Current air pollution levels pose a threat to the health of children starting from conception. The scientific evidence is presented for mortality, morbidity, and sub-clinical effects. The first section deals with exposure data, the following sections with the evidence of health effects from epidemiology and toxicology leading to recommendations., Results: Improved air quality reduces the number of infants' deaths as well as disease and pain., Conclusions: Medical doctors have a responsibility to know the facts and to advise their patients. Doctors when visiting their patients' homes should be aware of the possibly grave impact of the indoor environment for the respiratory health of their patients. They should recognize and advise the parents on problems associated with environmental tobacco smoke, poor ventilation, mould growth, and maintenance of heating installations. With regard to outdoor air pollution, doctors could serve as role models and also advise their patients and parents on environmentally friendly behaviour. Such behaviour not only calls for personal commitment but also for the right infrastructure to be provided (e.g. public transport, district heating). Doctors should be proactive in the community and in their country as advocates for a healthier environment for our children.

BACKGROUND/EXPOSURE: Dioxins and PCBs are highly persistent and highly toxic environmental pollutants which at present are derived mainly from waste incineration and food contamination. They are widespread in nature and pollute human food, including breast milk so that basically all children in Europe are exposed to measurable levels. RESULTS/TOXICITY IN CHILDREN: The toxicity of dioxins and PCBs are well described both from animal studies and from a number of human epidemiological studies including several large cohort studies. Especially developmental exposure has been shown to affect endocrine and cognitive systems negatively. Measurable outcomes include reduced IQ and changed behaviour. Foetotoxic effects with reduced birth weight and increased congenital anomalies such as cleft lip have also been described. Exposure to PCBs and dioxins must be considered also in the context of multiple exposure to several toxins simultaneously or sequentially. CONCLUSION/SUGGESTED ACTION: Some measures aimed at reducing exposure to dioxins have been partly successful in that the dioxin content of breast milk is going down. However, further steps to reduce exposure must be taken. We suggest legislative measures for reducing the re-entry of especially PCBs from waste into the environment. Individual pre-conception counselling is recommended in order to reduce developmental exposure and its consequences. Biomonitoring of the substances themselves in breast milk and foods is recommended as well as monitoring possible endocrine effects.

Background: Facts and hypotheses on the relationship between some children's diseases or disorders and external stressors during the developmental stage of a child, both prenatally and postnatally are described in literature. In this paper the following changes in patterns and causes of the main childhood illnesses are summarized and recommendations for actions are made. Prematurity. Intra-uterine growth restriction. Testicular dysgenesis syndrome. Type I and Type II diabetes. Asthma, atopy and hay fever. Autism. Attention deficit hyperactivity disorder (ADHD). Learning disabilities. Cancer. Obesity. Hearing problems., Results: Literature provides a growing amount of information on changing patterns in childhood diseases., Conclusions: The following recommendations for action are formulated: Immediate research on endocrine disrupters in relation to prematurity. Diabetes: avoid Maillard Compounds in liquid baby food and in food in general: promote breastfeeding. Asthma: avoid exposure to smoking, the use of chemical household products, dioxin and dioxin-like chemicals, and avoid air pollution with high levels of particulate matter, especially around conception, during pregnancy and in the first years of life. Autism: more research on incidence and causes. ADHD and learning disabilities: more research on prevalence and causes. Preventions: 1) preconception counselling to avoid potentially harmful substances; 2) controlling and further lowering levels of polychlorinated biphenyls, lead and methyl mercury. Cancer: promote breastfeeding, carry out research into effects of foetal exposure to internal fission-product radionuclides. Obesity: stop smoking in pregnancy, avoid parental obesity, longer night sleep. Hearing problems: lower noise levels in discothèques, promote the day-evening-night level to avoid noise (longer night sleep).

Unlabelled: Almost half of the child population is involuntarily exposed to environmental tobacco smoke (ETS). The ETS exposure gives rise to an excessive risk of several diseases in infancy and childhood, including sudden infant death syndrome, upper and lower respiratory infections, asthma and middle ear diseases. It is also linked to cancer, and behavioural problems and neurocognitive deficits in children., Conclusions: Protecting children from ETS exposure is a complex and important issue. The best improvement in children's health is to be gained when parents stop smoking or, when that is not possible, they stop smoking in their children's environment. Paediatricians, because of their authority, and their frequent and regular contact with parents, play a leading role in protecting children from ETS exposure. An ideal approach to help parents to stop smoking seems to be initial minimal-contact advice provided by their paediatrician with feedback and supplemental printed materials, leading to greater intensity and duration of follow-up home visits.

Environmental health history taking is often not part of standard medical history taking for clinical physicians. During recent years attention has been placed on home environments and asthma and allergies, high caloric intake and obesity and type 2 diabetes mellitus, yet environmental health history taking still remains relatively uncharted terrain for the clinical physicians of today. While the reasons for this are certainly varied, ignorance of environmental influences, ignorance of environmental pollutants, politics and prejudices will certainly play a role. We suggest a simple manner of environmental health history taking, and discuss the importance of the subject in our modern-day clinical practice.

Introduction: All children are exposed to multiple physical, chemical and biological challenges that can result in adverse health effects before and after birth. In this context, the danger of multiple exposures cannot be assessed from a single-chemical approach as used in classical toxicology., Aim: To open up a 'negotiation space' for the problem of multiple exposure to environmental stressors, defined as any physical, chemical or biological entity that can induce an adverse response. In this context, two further questions obtain: to what extent can synergistic risks be assessed, and how far could potential adverse effects be prevented by enhanced regulation?, Methods: A discussion of two general approaches is taken: 1) the investigation of mixtures such as smoking or air pollution without specifying the individual agents, and 2) the investigation of individual substances with a focus on possible interactions in the context of dose to receptor., Results: Although mixtures of compounds can have effects, it may not be possible to ascribe causation to a single compound. Furthermore, cumulative low-dose insult can, in some circumstances, be more toxic than a single high-dose exposure, e.g. endocrine disruptive effects of a combination of PCBs and dioxins which disrupt the thyroid hormone status; this tends to contradict elements of classical toxicology, . These cumulative insults may further combine with heavy metals and can disrupt the heme synthesis. It is possible that groups of pollutants could be used to test their cumulative capacity to multiple stress-susceptible receptor targets as is done in smoking and air pollution. This methodology could be used for further groups of potential pollutants, for example those associated with cleaning products, or cosmetics. Testing individual substances with a focus on interactions means that not only chemicals but also concurrent diseases should be taken into account. We suggest that the enhanced regulation of potential multiple stressors falls into two discrete categories. The first comprises a more precautionary approach (as demonstrated by the banning of chemicals such as some brominated flame retardants in Europe). The second comprises a more 'permissive' liberal approach involving the initial study of an individual compound, and subsequent interrogation of that compound in combination with another (as demonstrated by lowering the carcinogenicity of aflatoxin by vaccination against hepatitis B)., Conclusions: It is necessary to define and study groups of multiple stressors as in US EPA's Framework for Cumulative Risk Assessment (U.S. EPA 2003). Recent increased knowledge of the greater sensitivity of the unborn baby, the infant and the child, has led to general recognition that a higher degree of precaution is now needed in regulating for multiple stressors on the young. The more liberal permissive approach proceeding from established effects of the individual exposures is becoming less acceptable now that we know that there is much we do not understand about chronic effects of stressors during the early development phases. Conflicts over which approach to take may have to be resolved through engagement and negotiation with a wide community of stakeholders. This "community of interest" may include fundamental research scientists, practicing clinical paediatricians, patient groups, and others concerned with the health and wellbeing of infants and children.

Background: Policy recommendations result from the discussions and analysis of the present situation in environment and health. Such analysis was performed in PINCHE. This led to recommendations based on the scientific literature. In the field of children's environmental health the policy process will follow more or less fixed rules, but this process is still at an early level of development. The link between science and policy still faces many challenges. Scientific assessment of environmental risk must recognize and tackle the problems of data sets, variability of human and environmental systems, the range, spatial and temporal diffusion of potential health effects and many biases and confounding factors., Results: The PINCHE network recommends a general improvement of the supporting scientific fields in environment and health. Assessments from epidemiology or toxicology should play a key role in influencing science-policy decisions in programmes that are intended to inform the public policy process. Scientific committees at a local level could play a role. The relation between health and environment needs to be better incorporated in training and education. There is a need for harmonization of data production and use. The priorities in PINCHE focus on the most important issues. A classification of low, medium or high priority for action was used to describe a range of different environmental stressors., Conclusions: PINCHE provided recommendations to reduce exposure for children. Exposure reduction is not always linked to improved health in the short term, but it will reduce the body burden of accumulating chemicals in children. A strategic choice is reduction of exposure of children to compounds by changing production techniques or by increasing the distance of child specific settings to sources. The contribution of all players in the production, distribution and use of scientific knowledge in the field of children's environmental health is necessary.

The reason why mercury is dangerous is that once released into the environment it cannot be removed and is rapidly transformed by microorganisms into organic compounds that tend to bioaccumulate and biomagnify in animals. The principal organic compound is methylmercury (MeHg). The primary route of exposure to MeHg for humans is consumption of fish. The safe dose (reference dose, RfD) of MeHg that can be consumed without neurotoxicological consequences is 0.1 microg per kg b.w./day. According to available data, the whole population of certain European countries or people who consume large quantities of fish are exposed to doses of MeHg that exceed the RfD. Given this level of mercury exposure, in order to avoid or reduce the expected neurotoxic consequences on foetuses we propose the following strategy: 1) At present the most reasonable solution for pregnant women (and small children) is to reduce substantially or completely avoid fish intake. 2) In the medium term the European Community should evaluate the technical and economic feasibility of breeding uncontaminated fish in order to reduce the drawbacks of banning fish consumption. 3) In the long term there is no alternative to substantially reducing mercury emissions worldwide.

Background: Polybrominated biphenyl ethers (PBDEs), a class of brominated flame retardants, are frequently used in consumer products. PBDEs levels in environmental and human samples have increased in recent decades. Children are exposed to PBDEs through diet, mainly through fish, meat and milk. Total dietary exposure of children in Europe was calculated to be 2-3 ng/kg b.w./day. For nursing infants the main source of PBDE exposure is breast milk; exposure levels are around 15 ng/kg b.w./day. PBDE exposure levels in North America are 10 to a 100 times higher. Because of their persistence and their similarity to polychlorinated biphenyls (PCBs), concern has been raised about the effects of PBDEs on human health. Exposure to penta- and octa-BDE led to learning impairment and impaired motor behaviour in rodents. Exposure to penta-, octa- and also deca-BDE caused effects on thyroid homeostasis in animals., Conclusions: The EU has banned the production and use of penta- and octa-BDE since 2004; however, exposure will continue during the coming decades. Based upon current toxicological evidence, human exposure to deca-BDEs is not expected to lead to health effects, but data on exposure to deca-BDE and data on toxicity of deca-BDE are scarce. Therefore, monitoring studies and toxicity studies on deca-BDEs and other BDEs should continue.

Background/methods: The aim of workpackage 5 'Environmental exposures and children's health: impact of socioeconomic factors' in the EU-funded network PINCHE (Policy Interpretation Network on Children's Health and Environment) was to review and interpret the current knowledge of social inequalities in environmental exposures and children's health. Socioeconomic factors may impact on children's environmental health in two ways: 1) environmental exposures may differ according to socioeconomic status; 2) given a certain level of harmful environmental exposure, socioeconomic factors may modify the health effects by influencing the susceptibility characteristics of children., Results: There is a lack of information to evaluate and quantify the effect of socioeconomic factors on environmental exposures and children's health in Europe. In most circumstances there seems to be an inverse social gradient with increased burden concerning exposures and health outcomes in children of lower social status., Conclusions: There is a need to improve research on social inequalities in children's health and environment. Because of the complexity, integrated approaches and a combination of different intervention measures and policies are necessary to reduce environmental exposure and adverse health effects in children. Paediatricians may contribute to improvement of children's environmental health by risk communication and health advocacy at community and governmental level.

Negative effects of perinatal exposure to background levels of dioxins and PCBs in Europe and the USA have been documented. Four facets of development are reviewed in this paper: 1. Brain development and thyroid hormone metabolism. 2. Hepatic effects. 3. Hematopoietic system effects. 4. Lung function. Effects on IQ and behaviour have been documented in children on both sides of the Atlantic Ocean. Non-dioxin-like PCBs, measured in maternal and cord blood and current plasma samples have been implicated. Interference with thyroid hormone metabolism in the mother, in the foetus and in the newborn baby could be responsible for these effects on brain development. During early gestation the foetus is completely dependent on maternal thyroxine (T4). Lower T4 levels in the mother, caused by dioxins and PCBs, might negatively influence (early) brain development. It is plausible that the intrauterine dependency on maternal T4 and the high T4 need shortly after birth makes both these periods vulnerable for environmental influences. Effects of dioxin exposure on thyroid hormone metabolism have been described in the period shortly after birth. These effects are no longer found after two years of age indicating a transient effect. In animal studies, in utero exposure has led to effects on brain development due to abnormal induction of liver enzymes. This induction resulted in lower testosterone and estrogen levels, interfering with brain development in the vulnerable period of language development and the development of visuo-spatial abilities. In humans this developmental period occurs around the thirtieth week of pregnancy. Follow-up studies in puberty and adolescence of the different cohorts studied is necessary to evaluate these negative influences. Damaging effects on the liver found shortly after birth have proven to be transient. Effects on the haematopoietic system are clear immediately after birth, for instance on white blood cells and thrombocytes. An increase in middle ear infections (otitis media) in relation to current levels of PCBs at the age of 4 years was described in the Rotterdam study. Negative effects on lung function in the sense of increased obstruction was found after 8 years in relation to perinatal exposure to dioxins in the Zaandam study. This rather new finding might explain the sharp increase in lung problems in children in the Western world.

Perinatal exposure to Dutch "background" dioxin levels in 1990 was high, but comparable with that of other industrialized Western European countries. Exposure during the sensitive perinatal period may cause permanent disturbances. Therefore, we assessed the health status and various hematologic and immunologic parameters among our longitudinal cohort. A medical history was taken and venipuncture performed in a longitudinal cohort of 27 healthy 8-year-old children who had documented perinatal dioxin exposure. Linear regression revealed a decrease in allergy in relation to prenatal (p = 0.02) and postnatal (p = 0.03) dioxin exposure. Increases in CD4+ T-helper cells (p = 0.006) and in CD45RA+ cells (p = 0.02) were seen in relation to postnatal exposure. A persistently decreased platelet count (p = 0.04) and increased thrombopoietin concentration (p = 0.03) were seen in relation to postnatal exposure. This follow-up has shown a decrease in allergy, persistently decreased thrombocytes, increased thrombopoietin, and increased CD4+ T-helper and increased CD45RA+ cell counts. This study provides indications of effects at the stem cell level of perinatal dioxin exposure, persisting until minimally 8 years after birth.

This is a twin study of the contribution of genetic influences on the pathogenesis of respiratory distress syndrome (RDS). Retrospectively, the files of twins born between 1976 and 1995 in the Academic Medical Centre (before Wilhelmina Gasthuis) of the University of Amsterdam were studied with a gestational age of 30 to 34 weeks and 1 or both with RDS. Data were collected on gestational age, birth weight, Apgar score, or diabetes in the mother as risk factors. All children were born vaginally. One hundred ninety-four pairs of twins were born with a gestational age of 30 to 34 weeks. Twenty-six pairs were excluded, because neither of the babies developed RDS. Of the 168 pairs, we were able to determine zygosity in 80 pairs, of which 18 were monozygotic and 62 were dizygotic twins. This is a normal ratio for the gestational age of 30 to 34 weeks. Risk factors as formulated above were not different between the monozygotic and dizygotic twins. RDS occurred more frequently in both twins when the twins were monozygotic (12 of 18, 67%) than when the twins were dizygotic (18 of 62, 29%). This difference was statistically significant, P < .05 by Chi square analysis. When only 1 twin developed RDS, it was the second born in 4 (67%) of the other 6 pairs of monozygotic twins and in 34 (77%) of the 44 dizygotic twins (77%). This twin study supports the notion of a genetic contribution to RDS.

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.

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., (Copyright 2001 Wiley-Liss, Inc.)

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.

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.

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.

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.

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.

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.