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

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

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

11. 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.

12. 25 30 35 40 45 50 55 60 RC3 mRNA in Dentate Gyrus (Density) * * RC3 Pseudocolor image of Autoradiogram following in situ hybridization for RC3 mRNA Cx DG 0 mg/kg1 mg/kg4 mg/kg8 mg/kg A1254 Dose PCB effects on serum T4 were not consistent with PCB effect on TH- regulated genes

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

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

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

16. 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?

17. CYP1A1 is Strongly Correlated

18. CYP1A1 not Correlated with T4

19. PL&GH-V in CYP±

20. 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.

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

22. 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.

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

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

25. Webinar, 24/09/2014 Gavin ten Tusscher25 Overview –What’s the problem? –What’s the danger? –What’s the solution?

26. Webinar, 24/09/2014 Gavin ten Tusscher26 Health care: a source, but not the primary source, of exposure to toxics

27. Webinar, 24/09/2014 Gavin ten Tusscher27 Sources of exposure to toxic chemicals in hospitals

28. Webinar, 24/09/2014 Gavin ten Tusscher28 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

29. Webinar, 24/09/2014 Gavin ten Tusscher29 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

30. Webinar, 24/09/2014 Gavin ten Tusscher30 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

31. Webinar, 24/09/2014 Gavin ten Tusscher31 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

32. Webinar, 24/09/2014 Gavin ten Tusscher32 Cohort

33. Webinar, 24/09/2014 Gavin ten Tusscher33 Results

34. Webinar, 24/09/2014 Gavin ten Tusscher34 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

35. Webinar, 24/09/2014 Gavin ten Tusscher35 In utero exposure vs gestational age –Cord blood samples obtained in 84 consecutive newborns (82 singletons, 2 twins) –General practice hospital –39 males, 45 females –11 preterm, 3 VSGA, 4 SGA –No in vitro fertilisation –Sampling with glass devices Latini et al. Environ Health Perspect 2003;111(14):1783-5

36. Webinar, 24/09/2014 Gavin ten Tusscher36 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

37. Webinar, 24/09/2014 Gavin ten Tusscher37 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

38. Webinar, 24/09/2014 Gavin ten Tusscher38 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 ( adults

39. Webinar, 24/09/2014 Gavin ten Tusscher39 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

40. Webinar, 24/09/2014 Gavin ten Tusscher40 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)

41. Webinar, 24/09/2014 Gavin ten Tusscher41 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

42. Webinar, 24/09/2014 Gavin ten Tusscher42 Precautionary Principle –Safer alternatives for almost all products –We need to actively choose better alternatives –Choose PVC-free/DEHP-free –“When in doubt, throw it out”

43. Webinar, 24/09/2014 Gavin ten Tusscher43 Database Glucose 3.75%-NaCl 0.225%IV bagsPVC-Free VoluvenIV bagsPVC-Free NaCl 0.9%IV bagsPVC-Free Glucose 20%IV bagsNon-PVC Metronidazol 5mg/mlIV bagsNon-PVC GelofusineIV bagsEcobag® PVC-vrij Air Inlet Needle With ValvePVC-Free Infuus Medi-Cath 24GIntravenous Cannula BD Neoflon 24GIntravenous Cannula BD Vasculon 22GIntravenous Cannula Bioflow 24GIntravenous Cannula Microflex Infusion Set 27G

44. Not easy … London, 18/11/2011 Gavin ten Tusscher44

45. Not easy … London, 18/11/2011 Gavin ten Tusscher45

46. London, 18/11/2011 Gavin ten Tusscher46

47. London, 18/11/2011 Gavin ten Tusscher47

48. London, 18/11/2011 Gavin ten Tusscher48

49. London, 18/11/2011 Gavin ten Tusscher49

50. London, 18/11/2011 Gavin ten Tusscher50

51. London, 18/11/2011 Gavin ten Tusscher51

52. London, 18/11/2011 Gavin ten Tusscher52

53. London, 18/11/2011 Gavin ten Tusscher53

54. London, 18/11/2011 Gavin ten Tusscher54

55. London, 18/11/2011 Gavin ten Tusscher55

56. London, 18/11/2011 Gavin ten Tusscher56

57. London, 18/11/2011 Gavin ten Tusscher57

58. Webinar, 24/09/2014 Gavin ten Tusscher58 Concluding –Our children are already being exposed to chemicals in concentrations that are too high –It is not wise to risk the health and development of our children

59. Webinar, 24/09/2014 Gavin ten Tusscher59 Take home message –Let us learn from our mistakes and implement these lessons with other chemicals, especially when treating our patients –First do no harm !!! –Thank you for your attention!

60. To find PVC/phthalate-free alternatives: safermedicaldevices.org For more on EDCs: noharm-europe.org EDCs Free campaign page: edc-free-europe.org Global Green and Healthy Hospitals: greenhospitals.net

61. Health Care Without Harm Europe Endocrine Disruptors in the Health Care Sector Q&A