dioxins and congenital malformations kos 2005 6 juni 2005 janna koppe janna g. koppe * gavin ten...

6 Juni 2005 Janna Koppe

Dioxins and congenital malformations KOS 2005

Janna G. Koppe *Janna G. Koppe *

Gavin ten Tusscher**Gavin ten Tusscher**Marike Leijs**Marike Leijs**Pier de Boer *Pier de Boer *

*NGO Ecobaby*NGO Ecobaby** Emma children’s hospital/AMC, University of Amsterdam** Emma children’s hospital/AMC, University of Amsterdam

Authors:



Severe Dioxin Poisoning

Yushchenko (2004)Yushchenko (2004)

Two Austrian secretaries (1997)Two Austrian secretaries (1997)



Acute Dioxin PoisoningAcute Dioxin Poisoning

Yushchenko autumn 2004, before and after.




Two secretaries in Austria 1997Secretary 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



Acute Dioxin PoisoningAcute Dioxin PoisoningCLINICAL EFFECTSCLINICAL EFFECTS

Chloracne Nausea Vomiting Epigastric pain Appetite loss Weight loss



Acute Dioxin PoisoningAcute Dioxin Poisoning Secretary nr. 1Secretary nr. 1




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



Acute Dioxin PoisoningAcute Dioxin PoisoningSecr. 1Secr. 1 more chloracne, more abnormal hematological more chloracne, more abnormal hematological

effectseffects more abnormal lipid spectrum than nr. 2more abnormal lipid spectrum than nr. 2 no effect on TSH-levelno effect on TSH-level

Secr. 2 Secr. 2 less chloracne , less chloracne , less abnormal hematological effectsless abnormal hematological effects less abnormal lipid spectrumless abnormal lipid spectrum effect on TSH-level (increase) much moreeffect on TSH-level (increase) much more




Bone marrow Anemia Trombocytopenia, NK cells decreased

Lipid spectrum Triglycerides increased Cholesterol increased



Trombocytopenia characteristic for dioxin poisoning

1. BASF workers 1953

2. Japanese workers

3. Two secretaries

4. Dutch children perinatally exposed to background levels




Glycine Succinyl CoA

ALA-synthetase

Pos.PCBs etc.

ALA ALA-dehydratase -------------- NEG. Lead, Heavy metals

PBG

URO’GENURO-decarboxylase --------------- NEG. PCBs etc, Mercury, Lead,

Hexachlorobenzene

COPRO’GENFerrochelatase --------------- NEG. Lead,Heavy Metals

HEMEBilirubin

HEMOPROTEIN P450

Heme synthesis



Back of secretary nr.1 shortly after (c) and one year after the intoxication (d)



AcuteAcute Dioxin PoisoningDioxin PoisoningIn the Long RunIn 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.



Hotspots of Dioxin Poisoning congenital malformations

Seveso (1976)Seveso (1976) Open burning of Chemical waste in Open burning of Chemical waste in

Amsterdam (1963-1968)Amsterdam (1963-1968) Yusho and Yucheng (1968 and 1978)Yusho and Yucheng (1968 and 1978) Vietnam 1975Vietnam 1975 ChapaevskChapaevsk BashkortostanBashkortostan

Seveso 1976 a few days after.Seveso 1976 a few days after.



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



SEX RATIO after SEVESOSEX RATIO after SEVESO

Fathers Fathers concentrationconcentration

Number Number childrenchildren

Sex ratioSex ratio

UnexposedUnexposed15.1-31.315.1-31.3

271271

8080

0.5570.557

0.4380.43831.9-60.731.9-60.7

61.4-117.061.4-117.0 8181

8181

0.5060.506

0.4690.469118.0-264.0118.0-264.0281.0-26400.0281.0-26400.0

8080

8181

0.4000.400

0.3830.383



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 PoisoningAcute Dioxin PoisoningFollow-up SevesoFollow-up Seveso



More cleft lip and palate after open burning of chemicals.More cleft lip and palate after open burning of chemicals.


Dioxins and congenital malformations KOS 2005MEG/EEGMEG/EEG


Dioxins and congenital malformations KOS 2005MEG mappingMEG mapping



Acute PCB and Furan PoisoningAcute PCB and Furan Poisoning

Coca-cola coloured baby stillborn after YUSHO Coca-cola coloured baby stillborn after YUSHO Placental transfer of PCBs and Furans (1968)Placental transfer of PCBs and Furans (1968)



Hotspots of Dioxin PoisoningBashkortostan

Bashkortostan:city close to the Ural with large-scale Bashkortostan:city close to the Ural with large-scale production of the herbicide 2,4,5 T in CHIMPROM a production of the herbicide 2,4,5 T in CHIMPROM a factory opening in 1965. Workers came in contact with factory opening in 1965. Workers came in contact with high doses of dioxins, since the herbicide contained high doses of dioxins, since the herbicide contained between 30-100 mg /kg dioxin.between 30-100 mg /kg dioxin.

Chloracne and toxic melanoderma were seen.Chloracne and toxic melanoderma were seen. 8 years earlier dead due to cancer, aging fast.8 years earlier dead due to cancer, aging fast.

More spontaneous abortions, more girls, chromosome More spontaneous abortions, more girls, chromosome aberrations in peripheral lymfocytes.aberrations in peripheral lymfocytes.



Hotspots of Dioxin PoisoningChapaevsk

Chapaevsk: city close to UFA in the Chapaevsk: city close to UFA in the Ural,poisoned by dioxins due to a factory of Ural,poisoned by dioxins due to a factory of lindane, an insecticide.lindane, an insecticide.

Significantly more congenital hydrocephalus Significantly more congenital hydrocephalus and renal agenesis and dysgenesis in the and renal agenesis and dysgenesis in the offspring.offspring.



Congenital malformations per 1000 births.Congenital malformations per 1000 births.

RANGE (BAND) EUROCAT 1997; Columns Chapaevsk (1982-1997)

*4:cong. Hydrocephalus

8:cardiac malformations

14:kidneys a/dysgenesis



Congenital hydrocephalusCongenital hydrocephalus



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 Congenital hydrocephalus and type 1 diabetesdiabetes



1.1. Dioxins, PCBs and PBBs interfere (blocks) Vitamin A Dioxins, PCBs and PBBs interfere (blocks) Vitamin A metabolism. Vitamin A is necessary for the metabolism. Vitamin A is necessary for the monoglycosylation of proteïns.monoglycosylation of proteïns.

2.2. Disturbance in the glycosylation is also the cause of Disturbance in the glycosylation is also the cause of congenital malformations in the offspring of mothers with congenital malformations in the offspring of mothers with type 1 diabetes.type 1 diabetes.

Both situations lead to the same sort of congenital Both situations lead to the same sort of congenital malformation. In animal experiments effects of PAH’s are malformation. In animal experiments effects of PAH’s are reversed with extra Vitamin A. Retinoic acid is essential for a reversed with extra Vitamin A. Retinoic acid is essential for a good balance in the cardiac progenitor pool. (see notes)good balance in the cardiac progenitor pool. (see notes)

Vitamin AVitamin A



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 AVitamin A



Preconceptional CounselingPreconceptional Counselingandand

Environmental HazardsEnvironmental Hazards

What future parents must What future parents must know!know!



Secondary prevention effects of PBT’sSecondary prevention effects of PBT’s(Persistent Bioaccumulating Toxicants)(Persistent Bioaccumulating Toxicants)

Control thyroid hormone status of the woman, that Control thyroid hormone status of the woman, that wants to become pregnant. All PBT’s can interfere with wants to become pregnant. All PBT’s can interfere with thyroid hormone status and may promote the thyroid hormone status and may promote the development of auto-antibodies against the thyroid.development of auto-antibodies against the thyroid.

Recommend breastfeeding and loving care to mitigate Recommend breastfeeding and loving care to mitigate and cure effects of PBTs.and cure effects of PBTs.

Avoid environmental tobacco smoke, stop smoking, Avoid environmental tobacco smoke, stop smoking, no alcohol.no alcohol.

Use a multivitamin with the vitamins Use a multivitamin with the vitamins AA, B12, folic acid, , B12, folic acid, and eat food high in anti-oxidants.and eat food high in anti-oxidants.



Three months conceptional leave for fathersThree months conceptional leave for fathers

Semen is produced during a three month Semen is produced during a three month cycle.cycle.

Three months before conception the father has Three months before conception the father has to stop smoking, drinking, working (with to stop smoking, drinking, working (with solvents or other hazards), and move out an solvents or other hazards), and move out an air polluted region to avoid PAH’s.air polluted region to avoid PAH’s.



Waste Landfill sitesWaste Landfill sites Living close to (within 3 km) of a landfill site more Living close to (within 3 km) of a landfill site more

congenital malformations are found. (EUROHAZCON congenital malformations are found. (EUROHAZCON project).project).

Significant increase in neural tube defects, Significant increase in neural tube defects, malformations of the cardiac septa and anomalies of malformations of the cardiac septa and anomalies of great arteries and veins.great arteries and veins.

Borderline significant increase in Tracheo-Borderline significant increase in Tracheo-oesophageal anomalies, hypospadias and oesophageal anomalies, hypospadias and gastroschizis gastroschizis

Advice : Use Folic Acid supplementation, Advice : Use Folic Acid supplementation, because these anomalies can be because these anomalies can be prevented with help of Folic Acid. prevented with help of Folic Acid.




Congenital hydrocephalusCongenital hydrocephalusgastroschizisgastroschizis




Congenital hydrocephalusCongenital hydrocephalushypospadiehypospadie




TherapyTherapy

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.



Multiple Exposure 1.Multiple Exposure 1.

Faroe-islands Faroe-islands ((mercury and PCBsmercury and PCBs))

Slovakia Slovakia ((lead and PCBslead and PCBs))

Netherlands (lead and PCBs and Dioxins) Netherlands (lead and PCBs and Dioxins)

Anti-epileptic drugs (phenobarbital)Anti-epileptic drugs (phenobarbital)



Multiple Exposure 2.Multiple Exposure 2.

Alspac study Alspac study (11 cleaning products)(11 cleaning products)

Multiple exposure to pesticides,Multiple exposure to pesticides,

Multiple exposure to air pollutionMultiple exposure to air pollution

Smoking and asbestosSmoking and asbestos

a.a. Primary pollutants mixturePrimary pollutants mixtureb.b. Oxidant pollutants mixtureOxidant pollutants mixture

Guillette Guillette paperpaper



Results:Results:

Exposure Prenatal:Exposure Prenatal:

ADHD 4ADHD 4 Geen ADHD 16Geen ADHD 1654.6854.68 TEQ TEQdioxdiox ng/kgmilkfatng/kgmilkfat 35.35 35.35 TEQTEQdiox diox

ng/kgmilkfatng/kgmilkfat

ExposurePostnatal:ExposurePostnatal:ADHD 4ADHD 4 Geen ADHD 15Geen ADHD 15227.5227.5 ng ng dioxinen gegetendioxinen gegeten 69.4169.41 ng ng dioxinen gegetendioxinen gegeten

Na-onderzoek bij 13 - 18 jaar. Na-onderzoek bij 13 - 18 jaar.

dioxins and congenital malformations kos 2005 6 juni 2005 janna koppe janna g. koppe * gavin ten...

Documents

janna koppe janna

congenital malformations

congenital hydrocephalus

cholesterol increased

centrofacial chloracne

intoxication d slide

severe chloracne

abnormal hematological