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Reproductive HealthReproductive Healthand Pesticidesand Pesticides
Linda M. Frazier, MD, MPHLinda M. Frazier, MD, MPH
Department of Preventive Medicine and Public HealthDepartment of Preventive Medicine and Public Health
Department of Obstetrics and GynecologyDepartment of Obstetrics and Gynecology
KU School of Medicine-WichitaKU 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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OrganophosphatesMale 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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OrganophosphatesMale exposure
Aneuploidy in people –Wrong # sex chromosomes
– Two different populations, urine tests• Padungtod, 1999
• Recio, 2001
Parathions, methamidophos, possibly dimethoate
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OrganophosphatesFemale exposure: neurobehavioral
problems in offspring
Positive rodent studies:
– Chlorpyrifos 25 mg/kg/dayChanda, 1996; Moto, 1992
– Diazinon 9 mg/kg/daySpyker, 1977
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CarbamatesMale 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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CarbamatesFemale 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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HerbicidesMale exposure
Sperm abnormalities in farmers
– 2,4-D Lerda, 1991
Miscarriages in farm families
– Phenoxyacid herbicide use by man
– 5-fold increase if he didn’t use protective equipment. Arbuckle, 1999
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HerbicidesFemale exposure: Early fetal death
Phenoxyacid herbicide use by woman also increased risk
Arbuckle, 2001
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HerbicidesFemale 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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FungicidesGenetic 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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FungicidesMale exposure
Testicular toxicity in rodents:
– Ethylene bisdithiocarbamates
– Captan
– Benomyl
25 to 50 mg/kg in some studies
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FungicidesFemale 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
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Fumigants / nematocidesGenetic toxicity
Dibromochloropropane (DBCP)
1,3-dichloropropene
1,2-dichloropropane
Methyl bromide
Formaldehyde
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Fumigants / nematocidesMale 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 / nematocidesFemale exposure
Formaldehyde:
– Reduced fertilityTaskinen, 1999
– Increased spontaneous abortionsTaskinen, 1994
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OrganochlorinesMale exposure
Lindane
Testicular effects in rats
Dose: 4 to 6 mg/kg
Chowdhury, 1990; Dalsenter, 1996 and 1997
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OrganochlorinesFemale exposure
Lindane
Early fetal deaths in mice
Dose: 44 mg/kg
Sircar, 1989
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Endocrine effectsReproductive 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 effectsReceptor 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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SummaryReproductive 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 needsRodent gestational studies
Food Quality Protection Act of 1996
EPA’s 10X Task Force, 1998:
– Require neurobehavioral tests
– Develop immunologic tests
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Research needsRodent gestational studies
Development of male reproductive system:
Lambright’s 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