A Small Dose of Toxicology Children & Environment – 6/25/05 Children: The Health Effects of A Small Dose of Chemicals A Small Dose of Toxicology Steven G. Gilbert, PhD, DABT Children and Their Environment June 25, 2005

A Small Dose of ToxicologyChildren & Environment – 6/25/05 A Small Dose of Toxicology See: -- smdosesmdose

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Child Health

A Small Dose of ToxicologyChildren & Environment – 6/25/05 "A thing is right when it tends to preserve the integrity, stability, and beauty of the biotic community. It is wrong when it tends otherwise." - Aldo Leopold, 1949, A Sand County Almanac The First Bioethicist Aldo Leopold

A Small Dose of ToxicologyChildren & Environment – 6/25/05 “An ethic, ecologically, is a limitation on freedom of action in the struggle for existence” Aldo Leopold Limits on Freedom

A Small Dose of ToxicologyChildren & Environment – 6/25/05 “The Commons” The Tragedy of the Commons By Garrett Hardin, Science, 1968

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Technical Solutions “It is our considered professional judgment that this dilemma has no technical solution.” The Tragedy of the Commons By Garrett Hardin, Science, 1968

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Problems – Solutions?  Lead and kids  Fetal alcohol syndrome  Nuclear disarmament  Bioterrorism  Ocean Fisheries  Persistent chemicals  The Commons

A Small Dose of ToxicologyChildren & Environment – 6/25/05 The study of poisons or the adverse effects of chemical and physical agents on living organisms. Toxicology Definitions

A Small Dose of ToxicologyChildren & Environment – 6/25/ BC Death of Socrates by Hemlock Socrates was charged with religious heresy and corrupting the morals of local youth. The active chemical used was the alkaloid coniine which, when ingested causes paralysis, convulsions and potentially death. Ancient Awareness

A Small Dose of ToxicologyChildren & Environment – 6/25/05 From Romeo and Juliet - act 5 Come bitter pilot, now at once run on The dashing rocks thy seasick weary bark! Here’s to my love! O true apothecary! Thy drugs are quick. Thus with a kiss I die. Shakespeare Historical Awareness

A Small Dose of ToxicologyChildren & Environment – 6/25/05 “Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.” Steven G. Gilbert, 1999 Environmental & Human Health

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Hong Kong Princess Diana Ambassador to Mexico Coeur d’Alene, Silver Valley, ID Tacoma Seattle Schools $100 Billion, $65 Billion Food, noise, dust 11,000 to 689,000 Children What do these have in common?

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Who are these white guys?

A Small Dose of ToxicologyChildren & Environment – 6/25/05 What Is This? N N N N CH 3 O O 1 3 7

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Key Words Risk = Hazard X Exposure Dose / Response Individual Sensitivity

A Small Dose of ToxicologyChildren & Environment – 6/25/05 “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Paracelsus ( ) Paracelsus

A Small Dose of ToxicologyChildren & Environment – 6/25/05 “The sensitivity of the individual differentiates a poison from a remedy. The fundamental principle of toxicology is the individual’s response to a dose.” S. G. Gilbert (1997) An Individual View

A Small Dose of ToxicologyChildren & Environment – 6/25/05 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 ToxicologyChildren & Environment – 6/25/05 What Is This? C H H HOHC H H (CH 3 -CH 2 - OH)

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Effects of Prenatal Alcohol

A Small Dose of ToxicologyChildren & Environment – 6/25/05 FAS Child

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Fetal Effects of MeHg

A Small Dose of ToxicologyChildren & Environment – 6/25/05 The Mercury Cycle

A Small Dose of Toxicology Children & Environment – 6/25/05 A Small Dose of Lead

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Lead In Homes

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Lead History Greek 2 nd BC Lead Makes the Mind Give Way

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Lead in Families

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Agency Blood Lead Levels

A Small Dose of ToxicologyChildren & Environment – 6/25/05 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 ToxicologyChildren & Environment – 6/25/05 PBDEs in House Dust (ppb) From EWG - Toxic Fire Retardants Contaminate American Homes -

A Small Dose of ToxicologyChildren & Environment – 6/25/05 PBDEs in Breast Milk (ppb) From EWG - Toxic Fire Retardants in Breast Milk from American Mothers -

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Key Words Risk = Hazard X Exposure Dose / Response Individual Sensitivity

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Effects of Amount on Response

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Effects of Size on Response

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Glasses of Wine - Dose Response Glasses of Wine % Difficulty Walking All Effected NO Effect Amount half are effected

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Dose (mg/kg body weight) Increasing dose Dose Response Function % Response NO Effect All Effected Half Effected

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Ethyl alcohol10,000 Salt (sodium chloride)4,000 Iron (Ferrous sulfate)1,500 Morphine 900 Mothballs 500 (paradichlorobenzene) Aspirin250 DDT250 Cyanide10 Nicotine1 Tetrodotoxin (from fish)0.01 Dioxin (TCDD)0.001 Botulinum Toxin Bee Venom?? Agent LD-50 (mg/kg)

A Small Dose of ToxicologyChildren & Environment – 6/25/05 1) Skin (dermal) 2) Lung (inhalation) 3) Oral (gut) Route of exposure Exposure & Absorption

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Number of Times Time Between 4 Beers in an hour or 4 Beers in 4 Days Frequency Of Exposure

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Acute Exposure Sub-chronic Exposure Chronic Exposure Duration Of Exposure

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Where It Goes (body water, fat, bone) Where It Accumulates Distribution

A Small Dose of ToxicologyChildren & Environment – 6/25/05 How The Body Breaks It Down What It Turns Into How Fast It Does It Metabolism

A Small Dose of ToxicologyChildren & Environment – 6/25/05 N N N N CH 3 O O Caffeine - 1,3,7 Trimethylxanthine

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Concentration (µg/ml) Time (hrs) How Long It Takes To Go Half-life

A Small Dose of ToxicologyChildren & Environment – 6/25/05 “Conclusions: Blood lead concentrations, even those below 10 mgc/dL, are inversely associated with children’s IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.” Canfield et al. 2003, NEJM, 384 Canfield et al…, 2003

A Small Dose of ToxicologyChildren & Environment – 6/25/05 25 DAYS -- BLOOD 40 DAYS -- SOFT TISSUE 20 YEARS -- BONE Half-life Of Lead

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Lead Based Paint US medical authorities diagnose childhood lead poisoning Child lead poisoning linked to lead-based paints France, Belgium and Austria ban white-lead interior paint Pediatric lead-paint poisoning death from eating crib paint is described National Lead Company admits lead is a poison League of Nations bans white-lead interior paint; US declines to adopt Report concludes eating lead paint chips causes physical and neurological disorders, behavior, learning and intelligence problems in children Lead-Based Paint Poisoning Prevention Act passed

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Lead Industry Advertisements History of Lead Industry Advertisements (LINK)LINK

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Lead-associated Reading Deficits in U.S. Children Blood lead levels (  g/dl) Reading Score Lanphear BP, et al. Public Health Reports 2000;115: (BL’s slide)

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Canfield R, et al. NEJM 2003;348: IQ and Blood Lead Life time overall Increase in 1 mcg/dl = 0.87 IQ drop Covariates - 1 mcg/dl = 0.46 IQ drop 1 to 10 mcg/dl (bigger drop) Increase in 1 mcg/dl = 1.37 IQ drop Non-linear - 1 mcg/dl = 7.4 IQ drop

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Environmental Pollutants and Disease in American Children: Estimates of Morbidity, and Costs for Lead Poisoning, Asthma, Cancer, and Developmental Disabilities, by Landrigan, P. et al. EHP, 110, July 2002, Cost of Childhood Lead Assumptions in calculating costs All lead is harmful and from environment Blood lead of children age 5 – 2.7 ug/dl (CDC) 5-year old boys (1,960,200) and girls (1,869,800) 1 ug/dl of lead = 0.25 IQ point reduction Cost – boys $27.8 and girls $15.6 Billion Total Costs $43.4 Billion

A Small Dose of Toxicology Children & Environment – 6/25/05 Current CDC Policy Blood lead level µg/dL) b Actions Time frame for beginning intervention 10-14Provide caregiver lead education. Provide follow-up testing. Refer the child for social services if necessary. Within 30 days 15-19Above actions, plus: If BLLs persist (i.e., 2 venous BLLs in this range at least 3 months apart) or increase, proceed according to actions for BLLs Within 2 weeks 20-44Above actions, plus: Provide coordination of care (case management). Provide clinical evaluation and care. c Provide environmental investigation and control current lead hazards. Within 1 week 45-70Above actions.Within 48 hours 70 or higherAbove actions, plus hospitalize child for chelation therapy immediately. Within 24 hours

A Small Dose of Toxicology Children & Environment – 6/25/05 Proposed CDC Policy Blood lead level (µg/dL) ActionsTime frame for beginning intervention <2No action 2-5Provide caregiver lead education. Provide follow-up testing. Refer the child for social services to investigate possible sources of lead exposure. Within 30 days 5-10Above actions, plus:If BLLs persist (i.e., 2 venous BLLs in this range at least 3 months apart) or increase, proceed according to actions for BLLs Within 2 weeks 10-20Above actions, plus: Provide coordination of care (case management). Provide clinical evaluation and care. Provide environmental investigation and control current lead hazards. Within 1 week 20-70Above actions.Within 24 hours 70 or higherAbove actions, plus hospitalize child for chelation therapy immediately. Within 24 hours

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Recycling Lead

A Small Dose of Toxicology Children & Environment – 6/25/05 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.

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Children have a right to a safe, fair and healthy environment Ethical Responsibility to share and use of knowledge Duty to promote health and well being of children Thoughtful public health advocate Knowledge - Responsibility

A Small Dose of ToxicologyChildren & Environment – 6/25/05 The Potential of Children

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Principles of Toxicology

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Additional Information A Small Dose of Toxicology Inst. Children’s Env Health (ICEH) –

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Authorship Information For Additional Information Contact Steven G. Gilbert, PhD, DABT Web: This presentation is supplement to “A Small Dose of Toxicology”

A Small Dose of Toxicology Children & Environment – 6/25/05 An Introduction To The Health Effects of Arsenic (As) A Small Dose of ™ Arsenic

A Small Dose of ToxicologyChildren & Environment – 6/25/05 A Therapeutic Agent and A Poison 2400 Years Ago In Greece and Rome Ancient Awareness

A Small Dose of ToxicologyChildren & Environment – 6/25/05 For many years used to treat syphilis and amebic dysentery But caused skin cancer in patients treated with arsenicals Historical Awareness

A Small Dose of ToxicologyChildren & Environment – 6/25/05 By product of smelting for cooper, lead, zinc Last smelter in Tacoma Washington closed in 1985 – still dealing with pollution issues Annual use 20,000 tons imported Production

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Chronic exposure (drinking water) Skin cancer (recognized 100 years ago) Garlic odor on breath Excessive perspiration Muscle tenderness and weakness Changes in skin pigmentation Paresthesia in hands and feet Peripheral vascular disease Gangrene of feet – Blackfoot disease Chronic - Toxicity

A Small Dose of ToxicologyChildren & Environment – 6/25/05 Exposure  Drinking water  Burning arsenic treated wood  Handling treated wood

A Small Dose of ToxicologyChildren & Environment – 6/25/05 US Arsenic Map

A Small Dose of ToxicologyChildren & Environment – 6/25/05  Arsenic in drinking water is a worldwide human health hazard  Avoid the use of arsenic treated wood  Reduce or avoid arsenic exposure Summary

A Small Dose of Toxicology Children & Environment – 6/25/05 Children with >10 mcg/dL In 1999 and 2000, 2.2% of children 1-5 year age had lead levels that were above 10 mcg/dL. Approximately 20 million children under age 5, thus about 440,000 children in the US have blood lead levels above 10 mcg/dL. From CDC