An Introduction to Reproductive and Developmental Toxicology

A Small Dose of Rep & Dev Tox A Small Dose of Toxicology

An Introduction to Reproductive and

Developmental Toxicology

A Small Dose of Developmental Tox

Steven G. Gilbert, PhD, DABT

www.asmalldoseof.orgwww.toxipedia.org

How Chemicals Affect Your Health

A Small Dose of Toxicology A Small Dose of Rep & Dev Tox

Child Health

“Children can develop and mature in an

environment that allows them to reach and maintain their full

potential.”

Vision for Child Health

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

Vision of Environmental Health

• Dose Response Issues

• Higher metabolic rate

• Different nutritional requirements

• Rapidly dividing & migrating cells

• Immature organs

Susceptibility of Children

Life – Potential & Harm

All life depends on reproduction and

development.

What effects this process and harms a child's

potential?

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

1 2 3 4 5 6 7 8 12 16 20 38

Implantation

Prenatal Death

Emryonic period

Major Morphological abnormalities

Fetal Period

Physiological and Functional Defects

Central Nervous System

Palate

External Genetalia

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.

Reproduction – issues associated with the egg and sperm

Pregnancy – the critical environment of early development

Development of the infant.

Three Areas

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

Ancient 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 Awareness

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)

Historical Events

• 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

Current Chemical Facts

• 50% of pregnancies end in miscarriage or spontaneous abortion often before pregnancy is recognized

• 15% of couples of reproductive age are infertile

Human Reproductive Facts

• 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 Toxicity

• Fertility• Menstrual cycle• Sperm count and viability• Sexual behavior

Reproductive Endpoints

Endocrine disruptors• DDT, Dioxin, PBDEs,

Phthalates Heavy metals

• Lead (decreased sperm) Organic Solvents

• Toluene, benzene Drugs

• Alcohol

Reproductive Toxicants

• 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)

Pregnancy Effects the Women

Teratology (physical malformations) Birth weight Growth Neurobehavioral

Decreased intelligence Decreases learning and memory

Developmental Endpoints

Chemicals/Radiation

Chlorobiphenyls Solvents (Toluene) Endocrine disruptors

• DDT, PCBs TCDD X-rays (therapeutic) Atomic fallout

Infections/Medical Conditions

Rubella virus Herpes simplex virus Toxoplasmosis Syphilis

Diabetes

Plants

Skunk cabbage (Veratrum californicum) – sheep & cattle

Parasites (frogs)

Medical Drugs

Antibiotics (tetracylines) Anticancer drugs Anticonvulsants (Valproic Acid) Lithium Retinoids (Vitamin A) Thalidomide Diethylstilbestrol (DES) Anticoagulants (Warfarin)

Recreational Drugs

Alcohol (ethanol) Tobacco Cocaine Solvent abuse

Development

Rodent Development

Case Studies

Thalidomide Ethanol (Alcohol) Methylmercury Lead

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

Thalidomide

Species

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

Dose(LETD)

Fold Difference from Humans

Cross-Species Differences in Responseto Thalidomide

Alcohol

(CH3-CH2-OH)

Effects of Prenatal Alcohol

A Small Dose of Toxicology A Small Dose of Rep & Dev ToxFAS Child

Mouse – Scanning EM

Effects of Prenatal Alcohol

Fetal Alcohol Syndrome (FAS)

Most common preventable cause of adverse CNS development

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

CharacteristicsGrowth retardation

Facial malformationsSmall head

Greatly reduce intelligence

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??

CharacteristicsGrowth deficiency

Learning dysfunctionNervous systems disabilities

• 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

Policy Approaches

Mercury & Toxicology

Fetal Effects of MeHg

Life-Long Effects of MeHg

Iraq Infant - Effects of Mercury

The Mercury Cycle

Atmospheric Hg

Washington State Mercury Chemical

Action Plan

WA State Advisory

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 In Homes

Agency Blood Lead Levels

CDC1960

CDC1973

CDC1975

CDC1985

WHO1986

EPA1986

CDC1990

CDC2006?

Agency and Year

Acceptable Childhood Blood Lead Levels

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

Recycling Lead

Structure of PBDEs

X & Y are number of Bromine atomsCommon Penta, Octa, and Deca

PolyBrominated Diphenyl Ether

BrxBry

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)

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

Pesticide Application

Classes Of Pesticides

Insecticides (kill insects)• Organochlorines• Organophosphates• Carbamates• Synthetic Pyrethroids

Herbicides (kill plants) Rodenticides (kill rodents) Fungicides (kill fungus) Fumigants (kill whatever)

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

Valley Children(chemical agriculture)

Foothill Children(traditional agriculture)

60-month-oldfemale

71-month-oldfemale

(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)

Chronic Pesticide Exposure

• 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

Integrated Pest Management (IPM)

• 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)

National School Green Flag program

Women of childbearing age Pregnant women Men wishing to a parent Infants Children

Who is at Risk?

• Home environment• Drug use• Workplace• Global and local environment

Exposure Issues

FDA – Reproductive and Developmental drug testing requirements

EPA – Testing requirements

Regulatory Status

Pesticide Incident Report and Tracking Panel

http://www.doh.wa.gov/ehp/Pirt/

WA State - PIRT

“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.

Precautionary Principle

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)

Safety & Efficacy vs Harm

The Potential of Children

Children and Toxicology

Additional Information

• A Small Dose of Toxicology• www.asmalldoseof.org

Authorship Information

For Additional Information ContactSteven G. Gilbert, PhD, DABT

E-mail: smdose@asmalldoseof.orgWeb: www.asmalldoseof.org

This presentation is supplement to “A Small Dose of Toxicology”

An Introduction to Reproductive and Developmental Toxicology

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