An introduction to reproductive and developmental toxicology
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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 www.asmalldoseof.org www.toxipedia.org. 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

www.asmalldoseof.org

www.toxipedia.org



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


Terms

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.

Terms


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
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


Plants
Plants

  • 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


Thalidomide
Thalidomide

  • 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


Thalidomide1
Thalidomide

Species

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

Dose(LETD)

Fold Difference from Humans

Cross-Species Differences in Responseto Thalidomide


Alcohol

H

H

C

C

OH

H

H

H

Alcohol

(CH3-CH2-OH)






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

Characteristics

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??

Characteristics

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

http://www.ecy.wa.gov/biblio/0203016.html

Legislature saves effort to tackle toxic flame retardants

http://www.ecy.wa.gov/../news/2004news/../2004news/2004-051.html




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

O

Bry

Brx

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 - http://www.ewg.org/reports/inthedust/summary.php


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

From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php



Classes of pesticides

Insecticides (kill insects)

Organochlorines

Organophosphates

Carbamates

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)

60-month-old

female

71-month-old

female

71-month-old

female

71-month-old

female

(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: www.greenflagschools.org)


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

  • http://www.doh.wa.gov/ehp/Pirt/


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

  • www.asmalldoseof.org


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]

Web: www.asmalldoseof.org


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