Marike Leijs

Endocrine disruptors and abnormalities of pubertal development.

Onset and development of puberty is regulated by the neuroendocrine system. Population-based studies worldwide have observed secular trends towards earlier puberty development. These changes are apparently caused by environmental factors such as improved socio-economic status, improved health care and nutrition. However, they may also partly result from endocrine-disrupting chemicals in the environment. Epidemiological studies have investigated the relationship between pubertal development and exposure to endocrine-disrupting chemicals (polychlorinated biphenyls, polybrominated biphenyls, 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, phthalate esters, furans and the pesticide endosulfan). Associations with both perinatal and postnatal exposure have been reported. Studies in experimental animals support some of these findings and point to differential endocrine regulatory mechanisms linked to pubertal development acting in the perinatal and the pre-pubertal period. Pubertal development is naturally associated with growth and body composition. There is increasing evidence for a link between prenatal development and pubertal onset. In girls born small for gestational age (SGA), pubertal onset and age at menarche often are advanced, especially if there has been an extensive catch-up growth during the first months of life. In utero growth retardation may have multiple causes including exposure to xenobiotic substances as was suggested for some endocrine-disrupting chemicals. An abnormal perinatal environment of children born SGA may alter the endocrine status and the sensitivity of the receptors for endocrine and metabolic signalling that may have effects on maturation of brain and gonads. However, the causal pathways and the molecular mechanisms that may link the pubertal growth pattern of children born SGA, pubertal development and endocrine-disrupting chemicals need further study.

The effects of PCBs and dioxins on child health

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.

Exposure to multiple environmental agents and their effect

Introduction: All children are exposed to multiple physical, chemical and biological challanges 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).

Children's exposure to polybrominated diphenyl ethers

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.

Today's epidemics in children: possible relations to environmental pollution and suggested preventive measures.

Background: Facts and hypotheses on the relationship between some childrens 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.

Alterations in the programming of energy metabolism in adolescents with background exposure to dioxins, dl-PCBs and PBDEs

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.

Perinatal dioxin exposure in The Netherlands : a long-term follow-up

In 1987, a cohort study was initiated in the Amsterdam/Zaandam region of The Netherlands to study possible effects of dioxins on development and growth in a population of breastfed children selected after an optimal pregnancy and delivery and birth weight above 2500 grams. Effects on thyroid hormone metabolism, liver, haematology and immunology, and retinol binding protein were found in neonates. Follow-up was performed at the age of 2½ years, 8?12 years and 13?18 years. Neonatally an increase in free thyroxine and thyroid stimulating hormone was found, indicating a change in set point. An enhanced psychomotor maturation was seen at the age of 2½ years. Negative effects on lung function and on brain development (studied with neurophysiological tests of visuo-motoric and cognitive performance) were demonstrated in the age of 8?12 years. In adolescence preliminary results show a delay of almost 1 year in breast development in girls in association with higher (above 40 ng International Toxic Equivalents dioxin) prenatal dioxin exposure and again a negative effect on innate immunity. The abnormalities found indicate an increased vulnerability for more stressful circumstances. New chemicals comparable to dioxins or contaminated with dioxins should not be allowed on the market, or if already there, must be banned.

Paediatric environmental health history taking: Why bother?

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.

Exposure to Environmental Contaminants and Lung Function in Adolescents—Is There a Link?

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.

Dioxins and Congenital Malformations

Hot spots of pollution have shown that dioxins can cause congenital malformations, prematurity and intra-uterine growth retardation. In regions with background concentrations, like in Europe, there has generally been no indication of an increase in congenital malformations in relation to dioxins.