Gavin W. ten Tusscher

Delayed initiation of breast development in girls with higher prenatal dioxin exposure; a longitudinal cohort study

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 Spearmans 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.

Thyroid hormone metabolism and environmental chemical exposure

BackgroundPolychlorinated 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.MethodsVena 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.ResultsThe 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.ConclusionOnce 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.

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.

Perinatal dioxin exposure and later effects: a review

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.

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.

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.

Policy and science in children's health and environment: Recommendations from the PINCHE project

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 childrens 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.

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.