1. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Janna G. Koppe * Gavin ten Tusscher** Marike Leijs** Pier de Boer * *NGO Ecobaby ** Emma children’s hospital/AMC, University of Amsterdam Authors:

2. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Severe Dioxin Poisoning  Yushchenko (2004)  Two Austrian secretaries (1997)

3. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Yushchenko autumn 2004, before and after.

4. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Two secretaries in Austria 1997 Secretary nr. 1, 30 years old   TCDD-level: 144.000 pg/g fat in blood   Intake: 1,5 mg dioxin   Soon (few days) after moving in a new office in autumn 1997 : centro-facial chloracne

5. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning CLINICAL EFFECTS   Chloracne   Nausea   Vomiting   Epigastric pain   Appetite loss   Weight loss

6. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Secretary nr. 1

7. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Secretary nr.2: 27 years old   TCDD-level : 26.000 pg/g fat in blood, Intake: 0,4 mg dioxin   Gastro-intestinal symptoms during several months since autumn 1997   Not so severe chloracne on the cheeks

8. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Secr. 1  more chloracne, more abnormal hematological effects  more abnormal lipid spectrum than nr. 2  no effect on TSH-level Secr. 2  less chloracne,  less abnormal hematological effects  less abnormal lipid spectrum  effect on TSH-level (increase) much more

9. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Bone marrow   Anemia   Trombocytopenia,   NK cells decreased Lipid spectrum   Triglycerides increased   Cholesterol increased

10. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Trombocytopenia characteristic for dioxin poisoning 1. 1.BASF workers 1953 2. 2.Japanese workers 3. 3.Two secretaries 4.Dutch children perinatally exposed to background levels Acute Dioxin Poisoning

11. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Glycine Succinyl CoA ALA-synthetase Pos.PCBs etc. ALA ALA-dehydratase -------------- NEG. Lead, Heavy metals PBG URO’GEN URO-decarboxylase --------------- NEG. PCBs etc, Mercury, Lead, Hexachlorobenzene COPRO’GEN Ferrochelatase --------------- NEG. Lead,Heavy Metals HEME Bilirubin HEMOPROTEIN P450 Heme synthesis

12. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Back of secretary nr.1 shortly after (c) and one year after the intoxication (d)

13. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning In the Long Run   Chloracne improves during 25 years   More cancer and 8 years earlier.   More diabetes and earlier in life.   More hypertension.   More miscarriages, prematurity, congenital malformations: congenital hydrocephalus and renal agenesis, and altered sex ratio.   More auto-antibodies to different tissues.

14. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Hotspots of Dioxin Poisoning congenital malformations  Seveso (1976)  Open burning of Chemical waste in Amsterdam (1963-1968)  Yusho and Yucheng (1968 and 1978)  Vietnam 1975  Chapaevsk  Bashkortostan

15. Seveso 1976 a few days after.

16. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe   Abnormal liver function tests in Seveso children: increase in   γ-glutamyltransferase (GGT)   Alanine aminotransferase (ALT)   In induced abortions in the period 1976-78 the incidence of aberrant cytogenetic findings was increased as was the number of miscarriages in general. SEVESO 1976-1978

17. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe SEX RATIO after SEVESO Fathers concentration Number children Sex ratio Unexposed15.1-31.3271 80 800.5570.438 31.9-60.761.4-117.0 81 81 0.5060.469 118.0-264.0281.0-26400.0 80 80810.4000.383

18. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe   Sex, distance from the accident site and meat consumption were significantly associated with an increased TCDD concentration.   Abnormal sex ratio (more girls) in relation to paternal exposure.   TCDD- concentration in breastmilk after 25 years still twice as high.   Increase in all cancers (rectum, lympho-hemopoietic, myeloid, thyroid gland and pleura) Acute Dioxin Poisoning Follow-up Seveso

19. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe More cleft lip and palate after open burning of chemicals. More cleft lip and palate after open burning of chemicals.

20. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna KoppeMEG/EEG

21. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe MEG mapping

22. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute PCB and Furan Poisoning Coca-cola coloured baby stillborn after YUSHO Placental transfer of PCBs and Furans (1968)

23. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Hotspots of Dioxin Poisoning Bashkortostan  Bashkortostan:city close to the Ural with large-scale production of the herbicide 2,4,5 T in CHIMPROM a factory opening in 1965. Workers came in contact with high doses of dioxins, since the herbicide contained between 30-100 mg /kg dioxin.  Chloracne and toxic melanoderma were seen.  8 years earlier dead due to cancer, aging fast.  More spontaneous abortions, more girls, chromosome aberrations in peripheral lymfocytes.

24. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Hotspots of Dioxin Poisoning Chapaevsk  Chapaevsk: city close to UFA in the Ural,poisoned by dioxins due to a factory of lindane, an insecticide.  Significantly more congenital hydrocephalus and renal agenesis and dysgenesis in the offspring.

25. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Congenital malformations per 1000 births. RANGE (BAND) EUROCAT 1997; Columns Chapaevsk (1982-1997) *4:cong. Hydrocephalus 8:cardiac malformations 14:kidneys a/dysgenesis

26. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Congenital hydrocephalus

27. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Lecorché in 1895 published on two cases of congenital hydrocephalus in the offspring of mothers with type 1 diabetes. 173 mothers with type 1 diabetes (University of Amsterdam 1963-1979): 10 % congenital malformations: 2 congenital hydrocephalus, 2 sacral agenesis, 4 vitium cordis, a.o. Congenital hydrocephalus and type 1 diabetes

28. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe 1.Dioxins, PCBs and PBBs interfere (blocks) Vitamin A metabolism. Vitamin A is necessary for the monoglycosylation of proteïns. 2.Disturbance in the glycosylation is also the cause of congenital malformations in the offspring of mothers with type 1 diabetes. Both situations lead to the same sort of congenital malformation. In animal experiments effects of PAH’s are reversed with extra Vitamin A. Retinoic acid is essential for a good balance in the cardiac progenitor pool. (see notes) Vitamin A

29. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe In the Netherlands 48 % of women, that want to become pregnant have a diet deficiënt in Vitamin A. Advice: Better control of Vitamin A in nutrition preconceptionally; especially in women with type 1 diabetes. Vitamin A

30. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Preconceptional Counseling and Environmental Hazards What future parents must know!

31. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Secondary prevention effects of PBT’s (Persistent Bioaccumulating Toxicants)  Control thyroid hormone status of the woman, that wants to become pregnant. All PBT’s can interfere with thyroid hormone status and may promote the development of auto-antibodies against the thyroid.  Recommend breastfeeding and loving care to mitigate and cure effects of PBTs.  Avoid environmental tobacco smoke, stop smoking, no alcohol.  Use a multivitamin with the vitamins A, B12, folic acid, and eat food high in anti-oxidants.

32. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Three months conceptional leave for fathers  Semen is produced during a three month cycle.  Three months before conception the father has to stop smoking, drinking, working (with solvents or other hazards), and move out an air polluted region to avoid PAH’s.

33. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Waste Landfill sites  Living close to (within 3 km) of a landfill site more congenital malformations are found. (EUROHAZCON project).  Significant increase in neural tube defects, malformations of the cardiac septa and anomalies of great arteries and veins.  Borderline significant increase in Tracheo- oesophageal anomalies, hypospadias and gastroschizis  Advice : Use Folic Acid supplementation, because these anomalies can be prevented with help of Folic Acid.

34. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe gastroschizis

35. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe hypospadie

36. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Acute Dioxin Poisoning Therapy   There is no effective therapy.   Acne therapy with isotretinoin creme may help to treat chloracne   Olestra, a resin that absorbs fat in the intestines, interferes with the entero-hepatic cycle and helps removing dioxin- molecules that are excreted in the gall   Lactation and liposuction are other possibilities to remove dioxins.

37. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Multiple Exposure 1.  Faroe-islands ( mercury and PCBs )  Slovakia ( lead and PCBs )  Netherlands (lead and PCBs and Dioxins)  Anti-epileptic drugs (phenobarbital)

38. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Multiple Exposure 2.  Alspac study (11 cleaning products)  Multiple exposure to pesticides,  Multiple exposure to air pollution  Smoking and asbestos a.Primary pollutants mixture b.Oxidant pollutants mixture Guillette paper

39. Dioxins and congenital malformations KOS 2005 6 Juni 2005 Janna Koppe Results: Exposure Prenatal: ADHD 4Geen ADHD 16 54.68 TEQ diox ng/kgmilkfat 35.35 TEQ diox ng/kgmilkfat ExposurePostnatal: ADHD 4Geen ADHD 15 227.5 ng dioxinen gegeten 69.41 ng dioxinen gegeten Na-onderzoek bij 13 - 18 jaar.