An Introduction to Reproductive and Developmental Toxicology

1. An Introduction to Reproductive and Developmental Toxicology A Small Dose of Developmental Tox How Chemicals Affect Your Health Steven G. Gilbert, PhD, DABT www.asmalldoseof.org www.toxipedia.org

2. Child Health

3. Vision for Child Health “Children can develop and mature in an environment that allows them to reach and maintain their full potential.”

4. Vision of Environmental Health “Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.”

5. Susceptibility of Children • Dose Response Issues • Higher metabolic rate • Different nutritional requirements • Rapidly dividing & migrating cells • Immature organs

6. All life depends on reproduction and development. What effects this process and harms a child's potential? Life – Potential & Harm

7. Developmental Toxicity Occurrence of adverse effects on the developing organism occurring anytime during the lifetime of the organism that may result from exposure to environmental agents prior to conception (either parent), during prenatal development, or postnatally until the time of puberty.

8. Sequence of Human Development Red - most sensitive, Gray - Less

9. Monster – abnormal or strange animal or plant. From Latin monstrum omen, from monere to warn (abnormal infants reflect the future). Teratology – The study of malformations. From the Greek word for monster – teras. Terms

10. Three Areas • Reproduction – issues associated with the egg and sperm • Pregnancy – the critical environment of early development • Development of the infant.

11. Ancient Awareness • Many ancient cultures had fertility goddess • Many ancient documentation of malformations • Malformations rich aspect of mythology • 6500 BC – Turkey - figurine of conjoined twins • 4000-5000 BC – Australia drawings of twins • 2000 BC - Tablet of Nineveh – describes 62 malformations and predicts the future

12. Historical Awareness • 15th-16th centuries malformations caused by the devil, mother and child killed • 1830’s - Etienne Geoffroy Saint-Hilaire experimented with chicken eggs • 1900’s began acceptance of malformations related to genetics • 1940’s - Josef Warkany – environmental factors affect rat development

13. Historical Events • 1941 – Human malformations linked to rubella virus • 1960’s – Thalidomide (a sedative and anti-nausea drug) found to cause human malformations • 1950’s – Methylmercury recognized as developmental toxicant • 1970’s – Alcohol related to developmental effects – Fetal Alcohol Syndrome (FAS)

14. Current Chemical Facts • Approximately 80,000 chemicals listed by EPA • Most of these chemicals have not been tested for developmental toxicity • For example, High Production Volume (HPV) Chemicals • Chemicals produced at >1 million lbs/year • Approximately 3,000 chemicals identified internationally • Few tested for both reproductive and developmental toxicity

15. Human Reproductive Facts • 50% of pregnancies end in miscarriage or spontaneous abortion often before pregnancy is recognized • 15% of couples of reproductive age are infertile

16. Reproductive Toxicity • The occurrence of biologically adverse effects on the reproductive systems of females or males that may result from exposure to environmental agents. • The toxicity may be expressed as alterations to the female or male reproductive organs, the related endocrine system, or pregnancy outcomes.

17. Reproductive Endpoints • Fertility • Menstrual cycle • Sperm count and viability • Sexual behavior

18. Reproductive Toxicants • Endocrine disruptors • DDT, Dioxin, PBDEs, Phthalates • Heavy metals • Lead (decreased sperm) • Organic Solvents • Toluene, benzene • Drugs • Alcohol

19. Pregnancy Effects the Women • Cardiovascular • Increased - cardiac output heart rate, blood pressure, blood volume expands • Oxygen consumption increases by 15-20% • Urine volume increases • Gut absorption changes • Increases in iron and calcium (toxic lead substitutes for calcium) • Liver metabolism decreases for some drugs or chemicals (caffeine)

20. Developmental Endpoints • Teratology (physical malformations) • Birth weight • Growth • Neurobehavioral • Decreased intelligence • Decreases learning and memory

21. Chemicals/Radiation • Chlorobiphenyls • Solvents (Toluene) • Endocrine disruptors • DDT, PCBs • TCDD • X-rays (therapeutic) • Atomic fallout

22. Infections/Medical Conditions • Rubella virus • Herpes simplex virus • Toxoplasmosis • Syphilis • Diabetes

23. Plants • Skunk cabbage (Veratrum californicum) – sheep & cattle • Parasites (frogs)

24. Medical Drugs • Antibiotics (tetracylines) • Anticancer drugs • Anticonvulsants (Valproic Acid) • Lithium • Retinoids (Vitamin A) • Thalidomide • Diethylstilbestrol (DES) • Anticoagulants (Warfarin)

25. Recreational Drugs • Alcohol (ethanol) • Tobacco • Cocaine • Solvent abuse

26. Development

27. Rodent Development

28. Case Studies • Thalidomide • Ethanol (Alcohol) • Methylmercury • Lead

29. Thalidomide • Introduced in 1956 as sedative (sleeping pill) and to reduce nausea and vomiting during pregnancy • Withdrawn in 1961 • Discovered to be a human teratogen causing absence of limbs or limb malformations in newborns • 5000 to 7000 infants effected • Resulted in new drug testing rules

30. Thalidomide Species Humans 0.5 mg/kg/dayMouse 30 60X Rat 50 100X Dog 100 200X Hamster 350 700X Dose(LETD) Fold Difference from Humans Cross-Species Differences in Responseto Thalidomide

31. H H C C OH H H H Alcohol (CH3-CH2-OH)

32. Effects of Prenatal Alcohol

33. FAS Child

34. Mouse – Scanning EM

35. Effects of Prenatal Alcohol

36. Fetal Alcohol Syndrome (FAS) Most common preventable cause of adverse CNS development 4,000-12,000 infants per year in US Characteristics Growth retardation Facial malformations Small head Greatly reduce intelligence

37. Fetal Alcohol Effect (FAE) Milder form of FAS 7,000-36,000 infants per year in US 1 to 3 infants per 1,000 world wide?? Characteristics Growth deficiency Learning dysfunction Nervous systems disabilities

38. Policy Approaches • 1981 - U.S. Surgeon General first advised that women should not drink alcoholic beverages during pregnancy. • 1988 - U.S. requires warning labels on all alcoholic beverages sold in the United States. • 1990 - U.S. Dietary Guidelines state that women who are pregnant or planning to become pregnant should not drink alcohol. • 1998 - 19 states require the posting of alcohol health warning signs where alcoholic beverages are sold

39. Mercury & Toxicology

40. Fetal Effects of MeHg

41. Life-Long Effects of MeHg

42. Iraq Infant - Effects of Mercury

43. The Mercury Cycle

44. Atmospheric Hg

45. WA State Advisory Washington State Mercury Chemical Action Plan http://www.ecy.wa.gov/biblio/0203016.html Legislature saves effort to tackle toxic flame retardants http://www.ecy.wa.gov/../news/2004news/../2004news/2004-051.html

46. Lead In Homes

47. Agency Blood Lead Levels

48. Lead Health Effects • Children more vulnerable than adults • Orally consumed lead absorbed in place of calcium • CHILDREN absorb 30-50% of oral lead • ADULTS absorb 5-10% of oral lead • Increased absorption during pregnancy • Childhood effects • Decreased intelligence (lower grades) • Hyperactivity (higher school dropout rate) • Growth retardation • Effects at blood lead levels of 10 µq/dl

49. Recycling Lead

50. Structure of PBDEs O Bry Brx PolyBrominated Diphenyl Ether X & Y are number of Bromine atoms Common Penta, Octa, and Deca