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

A Small Dose of Toxicology See: www. asmalldoseof. org -- smdose A Small Dose A Small Dose of Toxicology See: www. asmalldoseof. org -- smdose A Small Dose of Toxicology Children & Environment – 6/25/05

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

The First Bioethicist Aldo Leopold The First Bioethicist Aldo Leopold "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 ----- 1887 - 1948 ----- A Small Dose of Toxicology Children & Environment – 6/25/05

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

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

Technical Solutions “It is our considered professional judgment that this dilemma has no technical 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 Toxicology Children & Environment – 6/25/05

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

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

Ancient Awareness 399 BC Death of Socrates by Hemlock Socrates was charged with religious Ancient Awareness 399 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. A Small Dose of Toxicology Children & Environment – 6/25/05

Historical Awareness From Romeo and Juliet - act 5 Come bitter pilot, now at Historical Awareness 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 A Small Dose of Toxicology Children & Environment – 6/25/05

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

What do these have in common? • • • Hong Kong Princess Diana Ambassador What do these have in common? • • • 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 A Small Dose of Toxicology Children & Environment – 6/25/05

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

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

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

Paracelsus “All substances are poisons; there is none which is not a poison. The Paracelsus “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy. ” Paracelsus (1493 -1541) A Small Dose of Toxicology Children & Environment – 6/25/05

An Individual View “The sensitivity of the individual differentiates a poison from a remedy. An Individual View “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) A Small Dose of Toxicology Children & Environment – 6/25/05

Thalidomide Ø Introduced in 1956 as sedative (sleeping pill) and to reduce nausea and Thalidomide Ø Introduced in 1956 as sedative (sleeping pill) and to reduce nausea and vomiting during pregnancy Ø Withdrawn in 1961 Ø Discovered to be a human teratogen causing absence of limbs or limb malformations in newborns Ø 5000 to 7000 infants effected Ø Resulted in new drug testing rules A Small Dose of Toxicology Children & Environment – 6/25/05

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

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

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

Fetal Effects of Me. Hg A Small Dose of Toxicology Children & Environment – Fetal Effects of Me. Hg A Small Dose of Toxicology Children & Environment – 6/25/05

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

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

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

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

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

Structure of PBDEs Poly. Brominated Diphenyl Ether O Brx Bry X & Y are Structure of PBDEs Poly. Brominated Diphenyl Ether O Brx Bry X & Y are number of Bromine atoms Common Penta, Octa, and Deca A Small Dose of Toxicology Children & Environment – 6/25/05

PBDEs in House Dust (ppb) From EWG - Toxic Fire Retardants Contaminate American Homes 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 Children & Environment – 6/25/05

PBDEs in Breast Milk (ppb) From EWG - Toxic Fire Retardants in Breast Milk 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 Children & Environment – 6/25/05

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

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

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

Glasses of Wine - Dose Response % Difficulty Walking All Effected 100 75 50 Glasses of Wine - Dose Response % Difficulty Walking All Effected 100 75 50 Amount half are effected 25 NO Effect 0 0 1 2 3 4 5 6 7 8 Glasses of Wine A Small Dose of Toxicology Children & Environment – 6/25/05

Dose Response Function All Effected % Response 100 75 50 Half Effected 25 NO Dose Response Function All Effected % Response 100 75 50 Half Effected 25 NO Effect 0 0 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg body weight) Increasing dose A Small Dose of Toxicology Children & Environment – 6/25/05

Agent LD-50 (mg/kg) Ethyl alcohol Salt (sodium chloride) Iron (Ferrous sulfate) Morphine Mothballs (paradichlorobenzene) Agent LD-50 (mg/kg) Ethyl alcohol Salt (sodium chloride) Iron (Ferrous sulfate) Morphine Mothballs (paradichlorobenzene) Aspirin DDT Cyanide Nicotine Tetrodotoxin (from fish) Dioxin (TCDD) Botulinum Toxin Bee Venom A Small Dose of Toxicology 10, 000 4, 000 1, 500 900 500 250 10 1 0. 001 0. 00001 ? ? Children & Environment – 6/25/05

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

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

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

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

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

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

Half-life Concentration (µg/ml) How Long It Takes To Go 14 12 10 8 6 Half-life Concentration (µg/ml) How Long It Takes To Go 14 12 10 8 6 4 2 0 0 1 2 3 4 5 6 7 8 9 10 11 Time (hrs) A Small Dose of Toxicology Children & Environment – 6/25/05

Canfield et al…, 2003 “Conclusions: Blood lead concentrations, even those below 10 mgc/d. L, Canfield et al…, 2003 “Conclusions: Blood lead concentrations, even those below 10 mgc/d. L, 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 A Small Dose of Toxicology Children & Environment – 6/25/05

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

Lead Based Paint 1887 - US medical authorities diagnose childhood lead poisoning 1904 - Lead Based Paint 1887 - US medical authorities diagnose childhood lead poisoning 1904 - Child lead poisoning linked to lead-based paints 1909 - France, Belgium and Austria ban white-lead interior paint 1914 - Pediatric lead-paint poisoning death from eating crib paint is described 1921 - National Lead Company admits lead is a poison 1922 - League of Nations bans white-lead interior paint; US declines to adopt 1943 - Report concludes eating lead paint chips causes physical and neurological disorders, behavior, learning and intelligence problems in children 1971 - Lead-Based Paint Poisoning Prevention Act passed A Small Dose of Toxicology Children & Environment – 6/25/05

Lead Industry Advertisements History of Lead Industry Advertisements (LINK) h http: //www. cincinnatichildrens. org/research/project/enviro/hazard/lead-advertising/default. Lead Industry Advertisements History of Lead Industry Advertisements (LINK) h http: //www. cincinnatichildrens. org/research/project/enviro/hazard/lead-advertising/default. htm t A Small Dose of Toxicology t Children & Environment – 6/25/05

Reading Score Lead-associated Reading Deficits in U. S. Children Blood lead levels ( g/dl) Reading Score Lead-associated Reading Deficits in U. S. Children Blood lead levels ( g/dl) Lanphear BP, et al. Public Health Reports 2000; 115: 521 -529. (BL’s slide) A Small Dose of Toxicology Children & Environment – 6/25/05

IQ and Blood Lead Life time overall • Increase in 1 mcg/dl = 0. 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 Canfield R, et al. NEJM 2003; 348: 1517 -1526 A Small Dose of Toxicology Children & Environment – 6/25/05

Cost of Childhood Lead Assumptions in calculating costs • All lead is harmful and 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 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, 721 -728. A Small Dose of Toxicology Children & Environment – 6/25/05

Current CDC Policy Blood lead level µg/d. L)b Actions Time frame for beginning intervention Current CDC Policy Blood lead level µg/d. L)b Actions Time frame for beginning intervention 10 -14 Provide caregiver lead education. Provide follow-up testing. Refer the child for social services if necessary. Within 30 days 15 -19 Above 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 20 -44. Within 2 weeks 20 -44 Above 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 -70 Above actions. Within 48 hours 70 or higher Above 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/d. L) Actions <2 No action 2 -5 Proposed CDC Policy Blood lead level (µg/d. L) Actions <2 No action 2 -5 Provide caregiver lead education. Provide follow-up testing. Refer the child for social services to investigate possible sources of lead exposure. Within 30 days 5 -10 Above 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 10 -20. Within 2 weeks 10 -20 Above 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 -70 Above actions. Within 24 hours 70 or higher Above actions, plus hospitalize child for chelation therapy immediately. Within 24 hours A Small Dose of Toxicology Time frame for beginning intervention Children & Environment – 6/25/05

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

Knowledge - Responsibility • Children have a right to a safe, fair and healthy Knowledge - Responsibility • 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 A Small Dose of Toxicology Children & Environment – 6/25/05

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

Principles of Toxicology www. asmalldoseof. org A Small Dose of Toxicology Children & Environment Principles of Toxicology www. asmalldoseof. org A Small Dose of Toxicology Children & Environment – 6/25/05

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

Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Information Contact Steven G. Gilbert, Ph. D, DABT E-mail: [email protected] org Web: www. asmalldoseof. org A Small Dose of Toxicology Children & Environment – 6/25/05

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

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

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

Production • By product of smelting for cooper, lead, zinc • Last smelter in Production • 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 A Small Dose of Toxicology Children & Environment – 6/25/05

Chronic - Toxicity Chronic exposure (drinking water) • • Skin cancer (recognized 100 years Chronic - Toxicity 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 A Small Dose of Toxicology Children & Environment – 6/25/05

Exposure Ø Drinking water Ø Burning arsenic treated wood Ø Handling treated wood A Exposure Ø Drinking water Ø Burning arsenic treated wood Ø Handling treated wood A Small Dose of Toxicology Children & Environment – 6/25/05

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

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

Children with >10 mcg/d. L In 1999 and 2000, 2. 2% of children 1 Children with >10 mcg/d. L In 1999 and 2000, 2. 2% of children 1 -5 year age had levels that were above 10 mcg/d. L. Approximately 20 million children under age 5, thus about 440, 000 children in the US have blood lead levels above 10 mcg/d. L. From CDC A Small Dose of Toxicology Children & Environment – 6/25/05