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

Reproductive endpoints

Fertility Miscarriage Birth defects Preterm birth Neurobehavioral

function Childhood cancer Others

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

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

Men

Effects on sperm

Genetic effects

Dad exposesmom

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)

50,000 Pesticide Formulations

Organophosphates Carbamates Pyrethroids Herbicides Fungicides Fumigants and nematocides Organochlorines

Mixed pesticide exposure Epidemiologic

studies– Sperm abnormalities– Fertility problems– Miscarriages– Birth defects– Childhood cancer

Study methods are improving

OrganophosphatesMale exposure

Sperm abnormalities in people

– Pesticide manufacturing in China

– Urine tests to confirm exposure• Padungtod, 2000

Ethyl parathion, methamidophos, azinphos-methyl

OrganophosphatesMale exposure

Aneuploidy in people –Wrong # sex chromosomes

– Two different populations, urine tests• Padungtod, 1999

• Recio, 2001

Parathions, methamidophos, possibly dimethoate

OrganophosphatesFemale exposure: neurobehavioral

problems in offspring

Positive rodent studies:

– Chlorpyrifos 25 mg/kg/dayChanda, 1996; Moto, 1992

– Diazinon 9 mg/kg/daySpyker, 1977

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

CarbamatesFemale exposure: neurobehavioral

problems in offspring

Positive animal study:

– Carbaryl

–Monkeys

– 3 mg/kg/day

Anger, 1979

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

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

HerbicidesFemale exposure: Early fetal death

Phenoxyacid herbicide use by woman also increased risk

Arbuckle, 2001

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

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

FungicidesMale exposure

Testicular toxicity in rodents:

– Ethylene bisdithiocarbamates

– Captan

– Benomyl

25 to 50 mg/kg in some studies

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

Fumigants / nematocidesGenetic toxicity

Dibromochloropropane (DBCP)

1,3-dichloropropene

1,2-dichloropropane

Methyl bromide

Formaldehyde

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

Fumigants / nematocidesFemale exposure

Formaldehyde:

– Reduced fertilityTaskinen, 1999

– Increased spontaneous abortionsTaskinen, 1994

OrganochlorinesMale exposure

Lindane

Testicular effects in rats

Dose: 4 to 6 mg/kg

Chowdhury, 1990; Dalsenter, 1996 and 1997

OrganochlorinesFemale exposure

Lindane

Early fetal deaths in mice

Dose: 44 mg/kg

Sircar, 1989

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

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

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

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

Neurobehavioral Development

Harm occurs without gross birth defects of brain

CNS function is complex in humans

Rodent models are limited

Research needsRodent gestational studies

Food Quality Protection Act of 1996

EPA’s 10X Task Force, 1998:

– Require neurobehavioral tests

– Develop immunologic tests

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

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

Conclusions

Education of workers and people at home

Acute toxicity not the only problem

Scrupulous handling practices

Less toxic alternatives