an introduction to reproductive and developmental toxicology
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
“Children can develop and mature in an
environment that allows them to reach and maintain their full
potential.”
Vision for Child Health
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
“Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.”
Vision of Environmental Health
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• Dose Response Issues
• Higher metabolic rate
• Different nutritional requirements
• Rapidly dividing & migrating cells
• Immature organs
Susceptibility of Children
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Life – Potential & Harm
All life depends on reproduction and
development.
What effects this process and harms a child's
potential?
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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.
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
Heart
Ears
Eyes
Limbs
Palate
External Genetalia
Red - most sensitive, Gray - Less
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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.
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Reproduction – issues associated with the egg and sperm
Pregnancy – the critical environment of early development
Development of the infant.
Three Areas
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• Fertility• Menstrual cycle• Sperm count and viability• Sexual behavior
Reproductive Endpoints
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Endocrine disruptors• DDT, Dioxin, PBDEs,
Phthalates Heavy metals
• Lead (decreased sperm) Organic Solvents
• Toluene, benzene Drugs
• Alcohol
Reproductive Toxicants
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Teratology (physical malformations) Birth weight Growth Neurobehavioral
Decreased intelligence Decreases learning and memory
Developmental Endpoints
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Chemicals/Radiation
Chlorobiphenyls Solvents (Toluene) Endocrine disruptors
• DDT, PCBs TCDD X-rays (therapeutic) Atomic fallout
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Infections/Medical Conditions
Rubella virus Herpes simplex virus Toxoplasmosis Syphilis
Diabetes
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Plants
Skunk cabbage (Veratrum californicum) – sheep & cattle
Parasites (frogs)
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Medical Drugs
Antibiotics (tetracylines) Anticancer drugs Anticonvulsants (Valproic Acid) Lithium Retinoids (Vitamin A) Thalidomide Diethylstilbestrol (DES) Anticoagulants (Warfarin)
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Recreational Drugs
Alcohol (ethanol) Tobacco Cocaine Solvent abuse
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Development
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Rodent Development
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Case Studies
Thalidomide Ethanol (Alcohol) Methylmercury Lead
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Alcohol
CH
H
H
OHC
H
H
(CH3-CH2-OH)
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Effects of Prenatal Alcohol
A Small Dose of Toxicology A Small Dose of Rep & Dev ToxFAS Child
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Mouse – Scanning EM
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Effects of Prenatal Alcohol
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Mercury & Toxicology
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Fetal Effects of MeHg
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Life-Long Effects of MeHg
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Iraq Infant - Effects of Mercury
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
The Mercury Cycle
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Atmospheric Hg
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Lead In Homes
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Agency Blood Lead Levels
60
40
3025
2015
10
20
10
20
30
40
50
60
Blo
od
Lea
d (
ug
/dl)
CDC1960
CDC1973
CDC1975
CDC1985
WHO1986
EPA1986
CDC1990
CDC2006?
Agency and Year
Acceptable Childhood Blood Lead Levels
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Recycling Lead
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Structure of PBDEs
X & Y are number of Bromine atomsCommon Penta, Octa, and Deca
PolyBrominated Diphenyl Ether
O
BrxBry
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
PBDEs in House Dust (ppb)
From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
PBDEs in Breast Milk (ppb)
From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Pesticide Application
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Classes Of Pesticides
Insecticides (kill insects)• Organochlorines• Organophosphates• Carbamates• Synthetic Pyrethroids
Herbicides (kill plants) Rodenticides (kill rodents) Fungicides (kill fungus) Fumigants (kill whatever)
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Valley Children(chemical agriculture)
Foothill Children(traditional agriculture)
60-month-oldfemale
71-month-oldfemale
71-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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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)
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• 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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Women of childbearing age Pregnant women Men wishing to a parent Infants Children
Who is at Risk?
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
• Home environment• Drug use• Workplace• Global and local environment
Exposure Issues
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
FDA – Reproductive and Developmental drug testing requirements
EPA – Testing requirements
Regulatory Status
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Pesticide Incident Report and Tracking Panel
http://www.doh.wa.gov/ehp/Pirt/
WA State - PIRT
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
“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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
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
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
The Potential of Children
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Children and Toxicology
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Additional Information
• A Small Dose of Toxicology• www.asmalldoseof.org
A Small Dose of Toxicology A Small Dose of Rep & Dev Tox
Authorship Information
For Additional Information ContactSteven G. Gilbert, PhD, DABT
E-mail: [email protected]: www.asmalldoseof.org
This presentation is supplement to “A Small Dose of Toxicology”