1. Environmental Impact on Congenital Anomalies CONCLUSIONS Luc Hens Human Ecology Department Vrije Universiteit Brussel E-mail: human.ecology@vub.ac.be

2. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Issues 1. Problem formulation 2. Methodological approaches 3. Mechanisms 4. Communications

3. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Congenital Anomalies 1. Cardiac defects 2. Limb anomalies 3. Chromosomal syndromes 4. Urinary system 5. Central nervous system and neural tube 6. Oral clefts 25%17%12%15%10%6% commonly studied in relation to environmental exposure After Dolk and Vrijheid, 2003

4. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Chemicals associated with congenital anomalies in humans 1. Pharmaceuticals (DES, Thalidomide, Wafarin) 2. Hair dyes 3. Pesticides 4. Non-pesticide ED (bisphenol A, phtalates, TCDD, vinyl chloride) 5. Heavy metals (Pb, Hg, Cd, As, Cr and Ni) 6. Organic solvents (styrene)

5. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Exposure conditions associated with congenital anomalies 1. Drinking water (heavy metals, nitrates, chlorinated substances) 2. Residence near (hazardous) waste deposit sites 3. Pesticides in agricultural areas 4. Air pollution 5. Food contamination (dioxins, PCBs) 6. Industrial point sources (smelters, incinerators) 7. Disasters (Hiroshima, Minamata) 8. (Working conditions : hair dressers) Examples in Kos 2005 workshop After Dolk and Vrijheid, 2003

6. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Problem situation 1. Embryonic and fetal life are sensitive periods to environmental exposures 2. Increasing number of chemicals and exposure conditions are associated with congenital anomalies 3. Increasing prevalence of selected congenital anomalies (hypospadias, cryptorchidism, gastroschisis) in industrialized countries 4. Convergence between pollutants in environmental health outcomes 5. Links between congenital anomalies, fertility and pregnancy loss (mechanisms?, risk factors?)

7. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 evidence Epidemiological evidence 1. “Limited” 2. RR is significant for environmental exposure 3. Limitations 3.1 statistical power, sensitivity, dilution 3.2 consistency of diagnosis (e.g. hypospadias) 3.3 “missing what is real” – “finding what is not real”

8. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Risk figures 1. Living near deposite sites 1.1 Non-chromosomal anomalies 1.33 1.2 Chromosomal anomalies 1.2 Vrijheid and Dolk, 2005 2. Pesticide purchase and tractor pesticide spraying equipment 2.1 Cryptorchidism and vegetable farming 1.7 1.2 Chromosomal anomalies 2.3 Kristensen et al., 1997

9. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Risk figures 3. DDE in mother blood, third trimester of pregnancy 3.1 Cryptorchidism 1.3 3.2 Hypospadia 1.2 4. Total effective xenoestrogen burden (TEXB) 4.1 Cryptorchidism 2.8 Longnecker et al., 2002 Olea et al., 2005

10. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Developmental toxicological evidence 1. Standard tests exist (two generation essay) 2. Interesting developments (e.g. stem cells) 3. No single test

11. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Clinical evidence 1. Historical examples of the alert physician 1.1 Thalidomide 1.2 Anticonvulsants 1.3 PCBs 2. Systematic survelance of public health (Eurocat) 2.1 “Limited” information 2.2 Important methodological challenges 2.3 More coordination necessary

12. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Wildlife evidence 1. Selected cases 1.1 EDs cause abortion in sea lions 1.2 DDT/DDE cause cryptorchidism in rodents 2. Congenital defects in relation to pollution are found in: 2.1 fish: intersex 2.2 amphibians: intersex, gonidal dysgenesis, hermaphroditism 2.3 Mammals: impaired reproduction, hermaphroditism, abnormal testes, impaired spermatogenesis 3. Fast accumulating evidence

13. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Examples of mechanisms 1. Thalidomide : I and F growth factor mediated mechanism 2. Steroidogenesis in testes 3. Testicular dysgenesis syndrome (TDS)

14. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Changing concepts 1. Not only dose matters (“practical threshold”) 2. Exposure window – sensitivity period – timing is crucial 3. Individual susceptibility 4. Long latency 5. Consider mixture (of chemicals, of chemicals with body molecules)

15. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Information 1. Parents prior to conception 2. Prenatal service providers and counsellors (e.g. OTIS) 3. Decision makers 3.1 principles 3.2 messages

16. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Core messages for couples 1. Be aware of pollutants in your lifestyle (cosmetics, medical drugs, food, pesticide use in gardening) 2. Care about your internal environment (long term) 3. Health practices: iodine intake, folic acid, antioxidants and breastfeeding

17. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Core messages for counselors 1. Evaluate environmental aspects (not only genetics) 2. Defining and communicate risk 3. Bring down avoidable medication during pregnancy 3.1 prescription behavior 3.2 alternatives

18. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Principles for decision making 1. “How much evidence is enough?” 1.1 Bradford Hill criteria 1.2 Related models (e.g. IPCC criteria) 2. Preventable conditions 3. Precautionary principles

19. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 Core messages for policy making 1. Even if the proportion of congenital anomalies attributable to environmental pollution might not be high, any excess cases represent a failure of our environmental health protection system 2. Precautionary new generation of standards 3. Growing evidence mainly from wildlife to bring EDCs under prior authorization under REACH

20. Environmental impact on congenital anomalies Conclusions Kos, June 8-11th, 2005 At last 1. Submit manuscripts not later than August 20 th 2005 2. THANK YOU