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 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 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  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  15 th -16 th 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 Humans0.5 mg/kg/day Mouse 30 60X Rat 50100X Dog100200X Hamster X Dose (LETD) Fold Difference from Humans Cross-Species Differences in Response to Thalidomide

A Small Dose of Toxicology A Small Dose of Rep & Dev Tox Alcohol C H H HOHC H H (CH 3 -CH 2 - 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 Tox FAS 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 Characteristics Growth retardation Facial malformations Small 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?? Characteristics Growth deficiency Learning dysfunction Nervous systems disabilities

A Small Dose of Toxicology A Small Dose of Rep & Dev Tox U.S. Surgeon General first advised that women should not drink alcoholic beverages during pregnancy U.S. requires warning labels on all alcoholic beverages sold in the United States U.S. Dietary Guidelines state that women who are pregnant or planning to become pregnant should not drink alcohol 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 Legislature saves effort to tackle toxic flame retardants 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

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 atoms Common Penta, Octa, and Deca PolyBrominated Diphenyl Ether O Br x Br y

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 -

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 -

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-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) 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: 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  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, 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

A Small Dose of Toxicology A Small Dose of Rep & Dev Tox Authorship Information For Additional Information Contact Steven G. Gilbert, PhD, DABT Web: This presentation is supplement to “A Small Dose of Toxicology”