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  • 1. Reproductive Health andPesticides Linda M. Frazier, MD, MPH Department of Preventive Medicine and Public Health Department of Obstetrics and Gynecology KU School of Medicine-Wichita

2. Reproductive endpoints

    • Fertility
    • Miscarriage
    • Birth defects
    • Preterm birth
    • Neurobehavioral function
    • Childhood cancer
    • Others

3. Critical periods for structural birth defects

  • Heart: 3 to 8 weeks
  • CNS:3 to 16 weeks
  • Limbs: 4 to 8 weeks
  • Kidneys: 4 to 16 weeks
  • Palate: 6 to 10 weeks

4. Cellular targets

  • Cells vulnerable to toxicants
    • Undifferentiated cells (precursor or stem cells)
    • Cells that are dividing, growing or migrating
    • Cells that are supposed to undergo apoptosis
    • Germ cells

5. Men

  • Effects on sperm
  • Genetic effects
  • Dad exposesmom

6. Molecular targets

  • Vulnerable molecular processes
    • Genes:mutations, genomic imprinting
    • DNA transcription and repair
    • Signal transduction
      • Endocrine disruption
      • Other disruption
    • Other key protein functions
      • Meiosis (separation of chromosomes)

7. 50,000 Pesticide Formulations

  • Organophosphates
  • Carbamates
  • Pyrethroids
  • Herbicides
  • Fungicides
  • Fumigants and nematocides
  • Organochlorines

8. Mixed pesticide exposure

  • Epidemiologic studies
    • Sperm abnormalities
    • Fertility problems
    • Miscarriages
    • Birth defects
    • Childhood cancer
  • Study methods are improving

9. Organophosphates

  • Male exposure
  • Sperm abnormalities in people
    • Pesticide manufacturing in China
    • Urine tests to confirm exposure
      • Padungtod, 2000
  • Ethyl parathion, methamidophos, azinphos-methyl

10. Organophosphates

  • Male exposure
  • Aneuploidy in people
    • Wrong # sex chromosomes
    • Two different populations, urine tests
      • Padungtod, 1999
      • Recio, 2001
  • Parathions, methamidophos, possibly dimethoate

11. Organophosphates

  • Female exposure:neurobehavioral problems in offspring
  • Positive rodent studies:
    • Chlorpyrifos 25 mg/kg/day
    • Chanda, 1996; Moto, 1992
    • Diazinon 9 mg/kg/day
    • Spyker, 1977

12. Carbamates

  • Male exposure
  • Abnormal sperm counts, shape, viability
  • in people (Carbaryl)
    • Wyrobeck, 1981; Juhler, 1991
  • Positive studies in rodents
    • Methomyl: 17 mg/kg/d
    • Carbofuran:0.4 to 2 mg/kg/day
    • Mahgoub, 2001; Chauhan, 2000; Pant, 1997

13. Carbamates

  • Female exposure:neurobehavioral problems in offspring
  • Positive animal study:
    • Carbaryl
    • Monkeys
    • 3 mg/kg/day
    • Anger, 1979

14. Pyrethroids

  • Reproductive studies usually negative
  • Cypermethrin:some male effects
    • Sperm abnormalities.
    • 30 mg/kg/day.Bhunya, 1988
    • Lower fertility.
    • 13 mg/kg/day.Elbetieha, 2001

15. Herbicides

  • Male exposure
  • Sperm abnormalities in farmers
    • 2,4-DLerda, 1991
  • Miscarriages in farm families
    • Phenoxyacid herbicide use by man
    • 5-fold increase if he didnt use protective equipment.Arbuckle, 1999

16. Herbicides

  • Female exposure:Early fetal death
  • Phenoxyacid herbicide use by woman also increased risk
  • Arbuckle, 2001

17. Herbicides

  • Female exposure:Birth defects
  • Linuron.
  • Abnormal development of male reproductive system.
  • Not found with standard toxicology protocol.
    • Must expose during late gestation.
    • Must follow until puberty.Lambright, 2000

18. Fungicides

  • Genetic toxicity
  • Ethylene bisdithiocarbamates
    • Mancozeb, Maneb, Metiram, Nabam
    • Metabolized to ETU, a carcinogen
    • 49 men.Sprayers without protective equipment
    • Sister chromatid exchange, translocations in lymphocytes
    • Steenland, 1997

19. Fungicides

  • Male exposure
  • Testicular toxicity in rodents:
    • Ethylene bisdithiocarbamates
    • Captan
    • Benomyl
  • 25 to 50 mg/kg in some studies

20. Fungicides

  • Female exposure
  • CNS, craniofacial and limb defects
    • Maneb, Mancozeb:> 700 mg/kg/d
    • Nabam:3, 30 and 60 mg/kg/d
    • Benomyl:60 mg/kg/d, especially if protein deficient

21. Fumigants / nematocides

  • Genetic toxicity
  • Dibromochloropropane (DBCP)
  • 1,3-dichloropropene
  • 1,2-dichloropropane
  • Methyl bromide
  • Formaldehyde

22. Fumigants / nematocides

  • Male exposure
  • DBCP:
    • Men in manufacturing facility
    • Absent sperm or reduced counts
    • Not always reversible
    • No birth defects
    • Deficit of male infants
      • Wharton, 1977 and others

23. Fumigants / nematocides

  • Female exposure
  • Formaldehyde:
    • Reduced fertility
      • Taskinen, 1999
    • Increased spontaneous abortions
      • Taskinen, 1994

24. Organochlorines

  • Male exposure
  • Lindane
  • Testicular effects in rats
  • Dose:4 to 6 mg/kg
    • Chowdhury, 1990; Dalsenter, 1996 and 1997

25. Organochlorines

  • Female exposure
  • Lindane
  • Early fetal deaths in mice
  • Dose:44 mg/kg
    • Sircar, 1989

26. Endocrine effects

  • Reproductive hormone levels in people or animals
  • Organochlorines:Beard, 1999
  • Organophosphates:
    • Ethyl parathion, methamidophos
    • Padungtod et al., 1998
  • Herbicides:Atrazine,2,4-D
    • Garry, 2001; Cooper, 2000

27. Endocrine effects

  • Receptor interaction assays
  • Positive effects:
    • Certain organochlorines, organophosphates, carbamates, herbicides
  • Potency 1000-fold lower than estradiol
  • Kuiper et al., 1998;Andersen et al., 2001;
  • Sumida, 2001

28. Summary

  • Reproductive effects of pesticides ?
  • Evidence from in-vitro assays, animals and people
  • Effects in every pesticide class
    • Some pose greater risk than others
  • Need to dispel idea that acute poisoning is the main problem