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An Introduction to Reproductive and Developmental Toxicology. A Small Dose of Developmental Tox. How Chemicals Affect Your Health. Steven G. Gilbert, PhD, DABT Child Health. Vision for Child Health.

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An introduction to reproductive and developmental toxicology

An Introduction to Reproductive and Developmental Toxicology

A Small Dose of Developmental Tox

How Chemicals Affect Your Health

Steven G. Gilbert, PhD, DABT

Vision for child health
Vision for Child Health

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

Vision of environmental health
Vision of Environmental Health

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

Susceptibility of children
Susceptibility of Children

  • Dose Response Issues

  • Higher metabolic rate

  • Different nutritional requirements

  • Rapidly dividing & migrating cells

  • Immature organs

Life potential harm

All life depends on reproduction and development.

What effects this process and harms a child's potential?

Life – Potential & Harm

Developmental toxicity
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.

Sequence of human development
Sequence of Human Development

Red - most sensitive, Gray - Less


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.


Three areas
Three Areas

  • Reproduction – issues associated with the egg and sperm

  • Pregnancy – the critical environment of early development

  • Development of the infant.

Ancient awareness
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

Historical awareness
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

Historical events
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)

Current chemical facts
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

Human reproductive facts
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

Reproductive toxicity
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.

Reproductive endpoints
Reproductive Endpoints

  • Fertility

  • Menstrual cycle

  • Sperm count and viability

  • Sexual behavior

Reproductive toxicants
Reproductive Toxicants

  • Endocrine disruptors

    • DDT, Dioxin, PBDEs, Phthalates

  • Heavy metals

    • Lead (decreased sperm)

  • Organic Solvents

    • Toluene, benzene

  • Drugs

    • Alcohol

Pregnancy effects the women
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)

Developmental endpoints
Developmental Endpoints

  • Teratology (physical malformations)

  • Birth weight

  • Growth

  • Neurobehavioral

    • Decreased intelligence

    • Decreases learning and memory

Chemicals radiation

  • Chlorobiphenyls

  • Solvents (Toluene)

  • Endocrine disruptors

    • DDT, PCBs

  • TCDD

  • X-rays (therapeutic)

  • Atomic fallout

Infections medical conditions
Infections/Medical Conditions

  • Rubella virus

  • Herpes simplex virus

  • Toxoplasmosis

  • Syphilis

  • Diabetes


  • Skunk cabbage (Veratrum californicum) – sheep & cattle

  • Parasites (frogs)

Medical drugs
Medical Drugs

  • Antibiotics (tetracylines)

  • Anticancer drugs

  • Anticonvulsants (Valproic Acid)

  • Lithium

  • Retinoids (Vitamin A)

  • Thalidomide

  • Diethylstilbestrol (DES)

  • Anticoagulants (Warfarin)

Recreational drugs
Recreational Drugs

  • Alcohol (ethanol)

  • Tobacco

  • Cocaine

  • Solvent abuse

Case studies
Case Studies

  • Thalidomide

  • Ethanol (Alcohol)

  • Methylmercury

  • Lead


  • 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



Humans 0.5 mg/kg/dayMouse 30 60X Rat 50 100X Dog 100 200X Hamster 350 700X


Fold Difference from Humans

Cross-Species Differences in Responseto Thalidomide












Fetal alcohol syndrome fas
Fetal Alcohol Syndrome (FAS)

Most common preventable cause of adverse CNS development

4,000-12,000 infants per year in US


Growth retardation

Facial malformations

Small head

Greatly reduce intelligence

Fetal alcohol effect fae
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??


Growth deficiency

Learning dysfunction

Nervous systems disabilities

Policy approaches
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

Wa state advisory
WA State Advisory

Washington State Mercury Chemical Action Plan

Legislature saves effort to tackle toxic flame retardants

Lead health effects
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

Structure of pbdes
Structure of PBDEs




PolyBrominated Diphenyl Ether

X & Y are number of Bromine atoms

Common Penta, Octa, and Deca

Pbdes in house dust ppb
PBDEs in House Dust (ppb)

From EWG - Toxic Fire Retardants Contaminate American Homes -

Pbdes in breast milk ppb
PBDEs in Breast Milk (ppb)

From EWG - Toxic Fire Retardants in Breast Milk from American Mothers -

Classes of pesticides

Insecticides (kill insects)




Synthetic Pyrethroids

Herbicides (kill plants)

Rodenticides (kill rodents)

Fungicides (kill fungus)

Fumigants (kill whatever)

Classes Of Pesticides

Other exposure

Dietary exposure

Pesticide residues on crops, dust –hand to mouth

Community exposure

Airborne drift from commercial app

Contaminated drinking water

Leaching from soils to ground water

Other Exposure

Chronic pesticide exposure
Chronic Pesticide Exposure

Foothill Children

(traditional agriculture)

Valley Children

(chemical agriculture)









(Guillette, et. al.,An Anthropological Approach to the Evaluation of Preschool Children Exposed to Pesticides in Mexico, Environmental Health Perspectives, Vol. 106, No. 6, June 1998)

Integrated pest management ipm
Integrated Pest Management (IPM)

  • Focus – long-term prevention of pest problems

  • Reduce or eliminate chemical pest control methods

  • Monitor for the presence of pests before treating

  • Non chemical strategies (make habitat less attractive, physical controls)

  • Learn about your pests

National school green flag program
National School Green Flag program

  • National School Green Flag program for middle and high schools

  • “The Green Flag Program is a project of the Child Proofing Our Communities Campaign, coordinated by the Center for Health, Environment and Justice. The goal of the program is for students, teachers, parents, and administrative and facilities departments to work together through an investigative process to pass safer and healthier school policies in the program's four issue areas: Indoor Air Quality, Integrated Pest Management (IPM), Reduce, Reuse Recycle, and Non-Toxic Products.” (from:

Who is at risk
Who is at Risk?

  • Women of childbearing age

  • Pregnant women

  • Men wishing to a parent

  • Infants

  • Children

Exposure issues
Exposure Issues

  • Home environment

  • Drug use

  • Workplace

  • Global and local environment

Regulatory status
Regulatory Status

  • FDA – Reproductive and Developmental drug testing requirements

  • EPA – Testing requirements

Wa state pirt
WA State - PIRT

  • Pesticide Incident Report and Tracking Panel


Precautionary principle
Precautionary Principle

“When an activity raises threats of harm to human health or the environment, precautionary measures should be take even if some cause and effect relationships are not fully established scientifically.”

Wingspread Conference, 1998.

Safety efficacy vs harm
Safety & Efficacy vs Harm

  • FDA regulations of Drugs (1938)

  • FDA regulations of Dietary Supplements (Dietary Supplement Health and Education Act of 1994 (DSHEA))

  • Ephedra present an unreasonable risk of illness or injury (Dec, 2003)

Additional information
Additional Information

  • A Small Dose of Toxicology


Authorship information
Authorship Information

This presentation is supplement to

“A Small Dose of Toxicology”

For Additional Information Contact

Steven G. Gilbert, PhD, DABT

E-mail: [email protected]