Reproductive Health and Pesticides

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Reproductive Healthand Pesticides

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

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Reproductive endpoints

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

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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

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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

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Men

• Effects on sperm
• Genetic effects
• Dad exposesmom

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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)

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50,000 Pesticide Formulations

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

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Mixed pesticide exposure

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

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Organophosphates

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

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Organophosphates

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

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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

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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

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Carbamates

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

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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

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Herbicides

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

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Herbicides

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

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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

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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

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Fungicides

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

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Fungicides

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

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Fumigants / nematocides

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

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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

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Fumigants / nematocides

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

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Organochlorines

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

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Organochlorines

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

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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

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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

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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

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Preconception health

• Pregnancy is not the only vulnerable period
• Control exposure to pesticides before conception
  because
• Germ cells are affected
• Both men and women are at risk
• Remediation takes time

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Neurobehavioral Development

• Harm occurs without gross birth defects of brain
• CNS function is complex in humans
• Rodent models are limited

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Research needs

• Rodent gestational studies
• Food Quality Protection Act of 1996
• EPAs 10X Task Force, 1998
• Require neurobehavioral tests
• Develop immunologic tests

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Research needs

• Rodent gestational studies
• Development of male reproductive system
• Lambrights Linuron study
• Expose after day 15
• Follow through puberty
• Increase sample size
• 20 rats low power

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Research needs

• Screening test batteries
• Endocrine effects
• Other cellular and molecular targets
• Mixtures. Inert ingredients
• Epidemiologic studies
• Blood / urine tests.
• E.g. organophosphates in pregnancy Willis,
  1993

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Conclusions

• Education of workers and people at home
• Acute toxicity not the only problem
• Scrupulous handling practices
• Less toxic alternatives