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Health Care Without Harm Europe Endocrine Disruptors in the Health Care Sector

Health Care Without Harm Europe Endocrine Disruptors in the Health Care Sector Wednesday 24th September 15:30-16:30 CEST. What are EDCs & How does exposure affect human health ?. R. Thomas Zoeller Biology Department College of Natural Sciences. What is an Endocrine Disrupting Chemical?.

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Health Care Without Harm Europe Endocrine Disruptors in the Health Care Sector

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  1. Health Care Without Harm Europe Endocrine Disruptors in the Health Care Sector Wednesday 24th September 15:30-16:30 CEST

  2. What are EDCs&How does exposure affect human health? R. Thomas Zoeller Biology Department College of Natural Sciences

  3. What is an Endocrine Disrupting Chemical?

  4. What is an Endocrine Disrupting Chemical? • “An ED is an exogenous chemical or mixture of chemicals that can interfere with any aspect of hormone action” – Endocrine Society • “interfere” means to trigger or block hormone action • “any aspect” means to interfere with the hormone receptor or with the delivery of the hormone to the receptor • “hormone action” means “what the hormone does”

  5. What is an Endocrine Disrupting Chemical? • To test if a chemical interferes with hormone action, you have to know what the hormone does. • The problem is that hormones do different things in different “places” at different times! • So EDCs may interfere with a hormone’s action selectively…. • Could be receptor isoform specific • Could be “metabolism” specific • Almost certain is differentially sensitive

  6. Example:PCBs, Brain Development and Thyroid Hormone Action

  7. PCB exposure is associated with cognitive deficits SchantzSL, Widholm JJ, Rice DC. Environ Health Perspect. 2003 Mar;111(3):357-576.

  8. Thyroid hormone deficiency produces effects on cognitive function that are similar to that of PCB exposureTherefore, could PCB exposure be producing neurocognitive deficits by reducing thyroid hormone levels?

  9. PCB exposure in animals almost uniformly causes a reduction in serum total and free (not shown) T4.

  10. If PCB – induced reduction in serum T4 is predictive of “downstream” effects, then PCB exposure should reduce the expression of thyroid hormone responsive genes in the developing brain.

  11. PCB effects on serum T4 were not consistent with PCB effect on TH-regulated genes RC3 mRNA in Dentate Gyrus (Density) 60 Cx 55 * * 50 45 DG RC3 40 35 30 25 0 mg/kg 1 mg/kg 4 mg/kg 8 mg/kg Pseudocolor image of Autoradiogram following in situ hybridization for RC3 mRNA A1254 Dose

  12. Are there TR agonists among PCB congeners? Non-ortho PCB congener Coplanar Dioxin-like Mono-ortho PCB congener Non-coplanar Di-ortho PCB congener Non-coplanar PCBs in in vitro and in vivo studies Gauger, KJ. et al, (2007);Envir. Health Pers. 115(11), 1623-1630

  13. Only the right mixture activated the TR PCBs in in vitro and in vivo studies Gauger, KJ. et al, (2007);Envir. Health Pers. 115(11), 1623-1630

  14. 4. Hypothesis TR TR TH target genes TRE PCB 126 coplanar ARNT AHR CYP1A1 XRE CYP1A1 PCB 105 PCB 138 PCB 118 PCB 153 non-coplanar OH OH PCBs in in vitro and in vivo studies

  15. Testing the hypothesis in humans • If environmental chemicals (e.g., PCBs) can be “activated” by CYP1A1 to form TR agonists which then drive (±) TH-response genes independent of serum TH, then: • CYP1A1 expression should be correlated with the expression of TH response genes?

  16. CYP1A1 is Strongly Correlated

  17. CYP1A1 not Correlated with T4

  18. PL&GH-V in CYP±

  19. Conclusions • Animal studies demonstrate that some EDCs can interfere with thyroid hormone action in tissues (e.g., developing brain) in a manner that is not reflected in serum thyroid hormone levels. • Human studies identify associations between toxicant exposures and measures of cognitive function (as well as other outcomes), but relationships with measures of thyroid function have been inconsistent. • Capturing indices of hormone action in tissues will be essential to translate experimental studies to the human population.

  20. “We live in a chemical soup” Is there summation or synergy? • Ingestion: food, dust, water • Inhalation: gases, air particles • Dermal absorption: personal care, dust • Breast Milk

  21. Most Vulnerable Time for Exposure All of the chemicals highlighted before are found in cord blood at birth. But, each baby has a total of about 100 chemicals “on board”. One study. 10 cord samples. 287 commercial chemicals, pesticides, and pollutants.

  22. Health Care Without Harm Europe Endocrine Disruptors in the Health Care Sector Wednesday 24th September 15:30-16:30 CEST

  23. Children are a product of theirenvironment Gavin W. ten Tusscher, M.D., Ph.D., paediatrician Department of Paediatrics and Neonatology Westfriesgasthuis, Hoorn, Netherlands

  24. Overview • What’s the problem? • What’s the danger? • What’s the solution? Gavin ten Tusscher

  25. Health care: a source, but not the primary source, of exposure to toxics Gavin ten Tusscher

  26. Sources of exposure to toxic chemicals in hospitals Gavin ten Tusscher

  27. Most at risk • Foetus, prematurely born, small for gestational age, seriously ill child • Higher fat : water ratio but often less total body fat, long periods of exposure (in hospital) • Often life-long accumulative exposure • Organs (brain) still developing • Less effective blood-brain and blood-testis barrier Gavin ten Tusscher

  28. DEHP • Softeners in plastic (PVC) • Known for 30 years that it leaks out of medical devices • Shown to leak from: • nasogastric tubes, respiratory tubes, endotracheal tubes, umbilical catheters, PVC blood bags, transfusion tubing systems, haemodialysis systems, cardiopulmonary bypass, continuous peritoneal dialysis, ECMO, infusion tubing • Suspected of teratogenicity and endocrine disruption Gavin ten Tusscher

  29. DEHP and children • highly lipophilic (over placenta, in breast milk) • pancreatic lipase most important detoxifier • much lower levels of pancreatic lipase in neonates • greater absorption in children • vulnerable developmental windows Gavin ten Tusscher

  30. NICU exposure to DEHP • 6 premature infants expected to have i.v. infusion for > 2 weeks included • 7 urine samples per infant • DEHP metabolites (mEHHP, mEOHP, mEHP) measured by CDC • 41 samples (1 sample no urine extractable) • 33 samples positive for all 3 metabolites Calafat et al. Pediatrics 2004;113(5):e429-3 Gavin ten Tusscher

  31. Cohort Gavin ten Tusscher

  32. Results Gavin ten Tusscher

  33. Discussion • geometric mean mEHP (100 ng/mL) prems • significantly higher than 19 toddlers 12 – 18 months (4.6 ng/mL) • 26 fold higher than US median for children 6 – 11 yrs • mEHHP and mEOHP 1-2 order of magnitude higher than US population (62 adults and children) • no correlation with specific procedure, GA, birth weight Gavin ten Tusscher

  34. In utero exposure vs gestational age • Cordblood samples obtained in 84 consecutivenewborns (82 singletons, 2 twins) • General practicehospital • 39 males, 45 females • 11 preterm, 3 VSGA, 4 SGA • No in vitro fertilisation • Sampling withglassdevices Latini et al. Environ Health Perspect 2003;111(14):1783-5 Gavin ten Tusscher

  35. Results • Logistic regression: • Significant inverse relation mEHP & GA at birth (38.16 ± 2.34 vs 39.35 ± 1.35 wks) • OR 1.5 (CI 1.013-2.21) presence/absence mEHP Gavin ten Tusscher

  36. Exposure • Endotracheal tubes show 6 – 12 % loss of DEHP during use  most probably into the lungs Latini & Avery. Acta Paediatr 1999;88(10):1174-75 • Priming of ECMO circuits with saline increased circuit degradation Karle et al. Crit Care Med 1997;25(4):696-703 • DEHP negative infants showed 6.1 to 21.6 mcg/mL after a single exchange transfusion • DEHP found in lung tissue in preterms after mechanical ventilation Roth et al. Eur J Pediatr 1988;147(1):42-6 Gavin ten Tusscher

  37. DEHP • “normal” daily exposure 3-30 mcg/kg BW/day • NICU enteral nutrition 40-140 mcg/kg BW/day • NICU parental nutrition up to 2500 mcg/kg BW/day !! • Total daily intake in all children (< 19 yrs) > adults Gavin ten Tusscher

  38. Bear in mind • DEHP toxicity shown in animal studies (long term toxicity & tissue deposition) • DEHP exposure is life-long, ubiquitous environmental contaminant • No longer in toys for children < 3 yrs (EU 1999/815/EG) • US FDA consider NICU patients at particular risk Gavin ten Tusscher

  39. American Medical Association H-135.945 Encouraging Alternatives to PVC/DEHP Products in Healthcare AMA: (1) encourages hospitals and physicians to reduce and phase out polyvinyl chloride (PVC) medical device products, especially those containing Di(2-ethylhexyl)phthalate (DEHP), and urge adoption of safe, cost-effective, alternative products where available; and (2) urges expanded manufacturer development of safe, cost-effective alternative products to PVC medical device products, especially those containing DEHP. (BOT Action in response to referred for decision Res. 502, A-06) Gavin ten Tusscher

  40. Summarising • Clear indications of DEHP exposure from medical devices • Animal studies show negative health effects • Exposure scenario in plastic laden environment • Increased exposure in infants Gavin ten Tusscher

  41. PrecautionaryPrinciple • Safer alternatives for almost all products • We need to actively choose better alternatives • Choose PVC-free/DEHP-free • “When in doubt, throw it out” Gavin ten Tusscher

  42. Database Gavin ten Tusscher

  43. Not easy … Gavin ten Tusscher

  44. Not easy … Gavin ten Tusscher

  45. Gavin ten Tusscher

  46. Gavin ten Tusscher

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  48. Gavin ten Tusscher

  49. Gavin ten Tusscher

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