An Introduction to the Principles of Toxicology

A Small Dose of ™ Toxicology An Introduction to the Principles of Toxicology Steven G.Gilbert, PhD,DABT “A Small Dose of Toxicology” www.asmalldoseof.org A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Child Health A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Toxicology Definitions The study of poisons or the adverse effects of chemical and physical agents on living organisms. A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 Environmental 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 Principles of Toxicology – 3/2/04 What do these have in common? • • • • • • • • Hong Kong Princess Diana Ambassador to Mexico Coeur d’Alene, Silver Valley, ID Tacoma $100 Billion, $65 Billion Food, noise, dust 11,000 to 689,000 Children Principles of Toxicology – 3/2/04 A Small Dose of Toxicology Who are these white guys? A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Power To Discover The Truth “It is not the truth that makes you free. It is your possession of the power to discover the truth. Our dilemma is that we do not know how to provide that power.” Richard Lewontin (New York Review of Books, Jan 7, 1997) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 What Is This? O CH3 N 1 CH3 N 7 O 3 N CH3 N A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Key Words Dose / Response Risk = Hazard X Exposure Individual Sensitivity A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Superman A Small Dose of Toxicology Principles of Toxicology – 3/2/04 What Is This? H H C H A Small Dose of Toxicology H C H Principles of Toxicology – 3/2/04 OH (CH3-CH2OH) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 A Small Dose of Toxicology FAS Child Principles of Toxicology – 3/2/04 Mouse – Scanning EM A Small Dose of Toxicology Principles of Toxicology – 3/2/04 A Small Dose of Lead A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead In Homes A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead History Lead Makes the Mind Give Way Greek A Small Dose of Toxicology nd 2 BC Principles of Toxicology – 3/2/04 Lead in Families A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Recycling Lead A Small Dose of Toxicology Principles of Toxicology – 3/2/04 CDC Blood Lead Levels Acceptable Childhood Blood Lead Levels Blood Lead (ug/dl) 40 35 30 25 20 15 10 5 0 CDC 1973 CDC 1975 CDC 1985 WHO 1986 EPA 1986 CDC 1990 40 30 25 20 15 10 Agency and Year Principles of Toxicology – 3/2/04 A Small Dose of Toxicology A Small Dose of Mercury A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Discharge in Minamata Bay A Small Dose of Toxicology Principles of Toxicology – 3/2/04 HG Polluting with Fetal Effects of MeHg A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Life-Long Effects of MeHg A Small Dose of Toxicology Principles of Toxicology – 3/2/04 The Mercury Cycle A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Key Words Dose / Response Risk = Hazard X Exposure Individual Sensitivity A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Effects of Amount on Response A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Effects of Size on Response A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Glasses of Wine - Dose Response All Effected % Difficulty Walking 100 75 50 25 NO Effect Amount half are effected 0 0 1 2 3 4 5 6 7 8 Glasses of Wine A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Dose Response Function All Effected 100 % Response 75 50 25 0 0 10 20 30 40 50 60 70 80 90 100 Half Effected NO Effect Dose (mg/kg body weight) Increasing dose A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Agent 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 LD-50 (mg/kg) 10,000 4,000 1,500 900 500 250 250 10 1 0.01 0.001 0.00001 ?? Principles of Toxicology – 3/2/04 Exposure & Absorption Route of exposure 1) Skin (dermal) 2) Lung (inhalation) 3) Oral (gut) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Frequency Of Exposure Number of Times Time Between 4 Beers in an hour or 4 Beers in 4 Days A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Duration Of Exposure Acute Exposure Sub-chronic Exposure Chronic Exposure A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Distribution Where It Goes (body water, fat, bone) Where It Accumulates A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Metabolism How The Body Breaks It Down What It Turns Into How Fast It Does It A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Caffeine - 1,3,7 Trimethylxanthine O CH3 N 1 CH3 N 7 O 3 N CH3 N A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Half-life How Long It Takes To Go Concentration (µg/ml) 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 Principles of Toxicology – 3/2/04 Susceptibility & Variability • • • • • Young or Old Male or Female Individual Variability Genetics Differences Species Differences A Small Dose of Toxicology Principles of Toxicology – 3/2/04 What Is This? N CH3 N A Small Dose of Toxicology Principles of Toxicology – 3/2/04 The Potential of Children A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Principles of Toxicology A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Additional Information • A Small Dose of Toxicology • www.asmalldoseof.org A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Normal Receptor-Ligand Interaction 1 2 Cell Membrane Ligand binds to receptor Signal Protein Ligand Receptor Outside Cell Inside Cell 3 Positive Response A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Inactivation of Receptor by Toxicant 1 2 Toxicant Toxicant inactivates receptor 3 No Response A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Competition For Receptor 1 2 Ligand Toxicant Toxicant out competes normal ligand 3 Ligand cannot bind receptor No Response A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Susceptibility of Children • • • • • Dose Response Issues Higher metabolic rate Different nutritional requirements Rapidly dividing & migrating cells Immature organs A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Sequence of Human Development Central Nervous System Heart Ears Eyes Limbs Palate External Genetalia 1 2 3 4 5 6 7 8 12 16 Fetal Period 20 38 Implantation Prenatal Death A Small Dose of Toxicology Emryonic period Major Morphological abnormalities Physiological and Functional Defects Principles of Toxicology – 3/2/04 Red - most sensitive, Gray - Less Ancient Awareness  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 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Historical 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 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Historical Events  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) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Structure of PBDEs PolyBrominated Diphenyl Ether O Brx Br y X & Y are number of Bromine atoms Common Penta, Octa, and Deca A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 PBDEs – California Status Legislation to ban - Penta and Octa-PBDE Did not ban Deca-PBDE Must report amount of electronic waste and toxic chemicals in waste such as PBDEs, metals A Small Dose of Toxicology Principles of Toxicology – 3/2/04 ELSI – Children & Toxicology Ethical, Legal, and Social Issues Related to DART Reproductive & Developmental Toxicology: Pharmaceutical, Environmental, and Legal Considerations Northern and Southern California Chapters of the Society of Toxicology - Fall 2004 Meeting Sept 30 – Oct 1, 2004 Steven G.Gilbert, PhD, DABT A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Child Health A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Convergence of Issues • Vision of Child Health • Knowledge of Reproductive and Developmental Toxicology • Policy Approach within an ethical framework • • • • Social responsibilities No technical solutions Restriction of freedoms Precautionary Principle Principles of Toxicology – 3/2/04 A Small Dose of Toxicology WHO Vision for Child Health A World Fit for Children • Promoting healthy lives • Providing quality education • Protecting against abuse, exploitation and violence • Combating HIV/AIDS. http://www.unicef.org/why/why_worldgoals.html A Small Dose of Toxicology Principles of Toxicology – 3/2/04 CDC Vision for Child Health “Environmental Health at CDC strives to promote health and quality of life by preventing or controlling those diseases or deaths that result from interactions between people and their environment.” http://www.cdc.gov/node.do?id=0900f3ec8000e044 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 American Academy of Pediatrics Mission and vision To attain optimal physical, mental and social health and well-being for all infants, children, adolescents and young adults. http://www.aap.org/member/memcore.htm A Small Dose of Toxicology Principles of Toxicology – 3/2/04 American Academy of Pediatrics The APA goes on to state: “To this purpose, the AAP and its members dedicate their efforts and resources. The vision: 1) to advocate for infants, children, adolescents, and young adults and provide for their care; 2) to collaborate with others to assure child health; and …. http://www.aap.org/member/memcore.htm A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Vision for Child Health “Children can develop and mature in an environment that allows them to reach and maintain their full potential.” A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Vision of Environmental Health “Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.” A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Susceptibility of Children • • • • • Dose Response Issues Higher metabolic rate Different nutritional requirements Rapidly dividing & migrating cells Immature organs A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Sequence of Human Development Central Nervous System Heart Ears Eyes Limbs Palate External Genetalia 1 2 3 4 5 6 7 8 12 16 Fetal Period 20 38 Implantation Prenatal Death A Small Dose of Toxicology Emryonic period Major Morphological abnormalities Physiological and Functional Defects Principles of Toxicology – 3/2/04 Red - most sensitive, Gray - Less Ancient Awareness  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 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Historical 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 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Historical Events  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) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Case Studies      Thalidomide Methylmercury Lead Ethanol (Alcohol) PBDEs A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 Fetal Effects of MeHg A Small Dose of Toxicology Principles of Toxicology – 3/2/04 The Mercury Cycle A Small Dose of Toxicology Principles of Toxicology – 3/2/04 WA State Advisory Limit the amount of canned tuna you eat, based on your bodyweight. Guidelines are: Women of childbearing age should limit the amount of canned tuna they eat to about one can per week (six ounces.) A woman who weighs less than 135 pounds should eat less than one can of tuna per week. Children under six should eat less than one half a can of tuna (three ounces) per week. Specific weekly limits for children under six range from one ounce for a twenty pound child, to three ounces for a child weighing about sixty pounds. http://www.doh.wa.gov/fish/FishAdvMercury.htm A Small Dose of Toxicology Principles of Toxicology – 3/2/04 San Francisco – Hg TMDL San Francisco Bay Regional Water Quality Control Board. San Francisco Bay Mercury Total Maximum Daily Load (TMDL) Numeric targets for mercury concentrations in suspended sediment, fish tissue, and bird eggs http://www.swrcb.ca.gov/rwqcb2/sfbaymercurytmdl.htm A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Alcohol H H C H A Small Dose of Toxicology H C H Principles of Toxicology – 3/2/04 OH (CH3-CH2OH) A Small Dose of Toxicology FAS Child Principles of Toxicology – 3/2/04 FAS & FAE Most common preventable cause of adverse CNS development Fetal Alcohol Syndrome (FAS) 4,000-12,000 infants per year in US Fetal Alcohol Effect (FAE) 7,000-36,000 infants per year in US 1 to 3 infants per 1,000 world wide?? A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Policy Approaches • 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 Principles of Toxicology – 3/2/04 • • • A Small Dose of Toxicology Structure of PBDEs PolyBrominated Diphenyl Ether O Brx Br y X & Y are number of Bromine atoms Common Penta, Octa, and Deca A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 PBDEs – California Status Legislation to ban - Penta and Octa-PBDE Did not ban Deca-PBDE Must report amount of electronic waste and toxic chemicals in waste such as PBDEs, metals A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Scientific Process Variability Uncertainty A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Types of Uncertainty • Statistical • Model • Fundamental A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Statistical Uncertainty Reducing Variability • Easiest to examine & reduce • Not knowing the exact value of a variable (inter and intra subject variance) • Sample size A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Model or System Uncertainty • Not fully understanding the relations between variables (mechanism of action) • Which variables are most important (high dose vs low dose) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Fundamental Uncertainty • Not knowing the right questions to ask • Most sensitive end point • “we don’t know what we don’t know” A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Sir Austin Bradford Hill "All scientific work is incomplete - whether it be observational or experimental. All scientific work is liable to be upset or modified by advancing knowledge. That does not confer upon us a freedom to ignore the knowledge we already have or postpone the action that it appears to demand at a given time. " Sir Austin Bradford Hill (1965) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Determining Causation 1. 2. 3. 4. 5. 6. 7. Strength of association Consistency of findings Biological gradient Temporal sequence Biologic or theoretical plausibility Coherence with established knowledge Specificity of association Sir Austin Bradford Hill (1965) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Socially responsible white guys? A Small Dose of Toxicology Principles of Toxicology – 3/2/04 “The Commons” The Tragedy of the Commons By Garrett Hardin, Science, 1968 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 Problems – Solutions?        Lead and kids Fetal alcohol syndrome Nuclear disarmament Bioterrorism Ocean Fisheries Persistent chemicals The Commons A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 Safety & Efficacy vs Harm  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) A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Central components • Taking preventive action in the face of uncertainty • Shifting the burden of proof/responsibility to the proponents of an activity • Exploring a wide range of alternatives to possibly harmful actions • Increasing public participation in decision making Wingspread Conference, 1998. A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Values of the precautionary principle 1) Respect - for the needs and rights of this and future generations as well as others who cannot speak for themselves 2) Humility - towards the natural world and our ability to understand it through science 3) Democracy - giving people a voice in matters that affect their lives 4) Responsibility - government’s public trust responsibility to manage the commonwealth for this and future generations. - Individuals’ including industry, obligation to take responsibility for their actions in the world. A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Seattle Initiative City Comprehensive Plans • Every citizen of Seattle has an equal right to a healthy and safe environment. • Seattle sees the Precautionary Principle approach as its policy framework to develop laws for a healthier and more just Seattle. A Small Dose of Toxicology Principles of Toxicology – 3/2/04 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 Principles of Toxicology – 3/2/04 Citizen Toxicologist Socially Responsible Toxicologist The citizen toxicologist is a thoughtful advocate for human and environmental health, who strives to share their scientific knowledge with the public, speaking to public interests rather than private or special interests. A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Socially Responsible Actions • Testifying • Writing review papers • K-12 class room teaching • Adding expertise to community groups • Education • Mentoring • Speakers Bureau A Small Dose of Toxicology Principles of Toxicology – 3/2/04 SOT - ESLI Specialty Section • Forum in which to discuss the ethical implications of results from our science as well as the resulting legal and social implications. • 2005 SOT meeting – workshop on Conflict of Interest http://www.toxicology.org/memberservices/specsection/specsection.html A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead In Homes A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead History          6500 BC. - Lead discovered in Turkey, first mine. 500 BC-300 AD.- Roman lead smelting produces dangerous emissions. 100 BC. - Greek physicians give clinical description of lead poisoning. “Lead makes the mind give way.” 1904 - Child lead poisoning linked to lead-based paints. 1922 - League of Nations bans white-lead interior paint; U.S. declines to adopt 1923 - Leaded gasoline goes on sale in selected markets 1971- U.S. Lead-Based Paint Poisoning Prevention Act passed 1923 - Leaded gasoline goes on sale in selected markets 1986 - Primary phase out of leaded gas in US completed Principles of Toxicology – 3/2/04 A Small Dose of Toxicology Lead Out of Gasoline 1990 – lead removed from Gasoline Between 1976 and 1994, the mean blood lead concentration in children dropped from 13.7 mcg/dL to 3.2 mcg/dL One of the major public health triumphs of the 20th century A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Workplace Lead Health of lead exposure on workers in London - “Steel dust, stone dust, clay dust, alkali dust, fluff dust, fiber dust- all these things kill, and they are more deadly than machine-guns and pom-poms. Worst of all is the lead dust in the white lead trades”. 1903 book “The People of the Abyss” Jack London A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Agency Blood Lead Levels Acceptable Childhood Blood Lead Levels Blood Lead (ug/dl) 40 35 30 25 20 15 10 5 0 CDC 1973 CDC 1975 CDC 1985 WHO 1986 EPA 1986 CDC 1990 40 30 25 20 15 10 Agency and Year Principles of Toxicology – 3/2/04 A Small Dose of Toxicology Lead - Absorption Orally Consumed Lead Absorbed In Place of Calcium CHILDREN – 30-50% OF LEAD ADULTS – 5-10% OF LEAD Increased During Pregnancy A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead - Nutrition NUTRITIONAL DEFICIENCIES INCREASE ABSORPTION (high fat diets, iron, calcium) VITAMIN D (from sun) INCREASES A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Half-life Of Lead • 25 DAYS -- BLOOD • 40 DAYS -- SOFT TISSUE • 20 YEARS -- BONE A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Children Vulnerability CHILDREN are more vulnerable exposure than ADULTS Size Consume More Food Inhale More Air Developing Nervous System Increased need for Calcium A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Needleman, NEJM, 1979 A Small Dose of Toxicology Principles of Toxicology – 3/2/04 CHILDREN Death Encephalopathy Nephropathy Frank Anemia Colic Blood Lead (ug Pb/dl) 150 100 ADULTS Encephalopathy Decreased Longevity Frank Anemia 50 Hemoglobin Synthesis 40 Hemoglobin Synthesis Peripheral Neuropathies Infertility (MEN) Nephropathy Systolic Blood Pressure (MEN) Hearing Acuity Vitamin D Metabolism 30 Nerve Conduction Velocity Erythrocyte Protoporphyrin Vitamin D Metabolism(?) DEVELOPMENTAL TOXICITY IQ HEARING GROWTH A Small Dose of Toxicology 20 Erythrocyte Protoporphyrin (Women) 10 Hypertension (?) Transplacental Transfer - Low birth weight - Miscarriages, Stillbirth - Premature birth Principles of Toxicology – 3/2/04 Reproductive Effects Of Lead WOMEN • lead crosses the placenta • low infant birth weight • retarded mental development • miscarriages • premature birth • stillbirth MEN • decreased sex drive • impotence • sterility • altered sperm-birth defects A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Childhood Lead Exposure -- LONG TERM PROBLEMS -• LOW GRADES • • ABSENTEEISM • • READING DISABILITY • • HIGH SCHOOL DROP OUT • A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Academic & Social Costs Of Lead Exposure • Increased risk of not graduating from high school (rr 4.8) • Poorer reading scores • Increased evidence of depression • Higher rate of hard drug use • Increased risk for attention deficit disorder • Increased risk for antisocial behavior A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Children Affected 16% of all American children Children with blood leads above 15 UG/DL 7% of economically favored white children 55% of African American children in poverty source: The nature and extent of lead poisoning in children in the US: a report to Congress - ATSDR A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Mechanisms Of Lead Toxicity • Lead-Calcium Interactions • Lead-Protein Interactions • Lead-Dopamine Systems Interactions • Lead-Opioid Systems Interactions A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead Chelating • EDTA, Bal, Succimer • EDTA In Use For 48 Years • Little Knowledge Of Benefits Or Hazards Of These Drugs • The Treatment Is Removing The Source Of Lead A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Lead In Ethnic Remedies Remedy Azarcon (Mexico) Greta (Mexico) Use Digestive problems Digestive problems Cosmetic to improve eye sight Improve slow development Lead Content 76-86% 4-90% Surma (India) Tibet 23-26% 1-3% A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Recycling Lead A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Truth and Lead “How long a useful truth may be known and exist, befort it is generally receiv’d and practis’d on” Benjamin Franklin A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Animals Killed Annually in the U.S. 400 Million Motorists 200 Million Hunters 20 Million Dogs & Cats Abandoned 5 Billion Food Livestock & Poultry 18 Million Rats & Mice Research 2 Million Other Species Research A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Additional Information • A Small Dose of Toxicology • www.asmalldoseof.org A Small Dose of Toxicology Principles of Toxicology – 3/2/04 Authorship Information This presentation is supplement to “A Small Dose of Toxicology” For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org A Small Dose of Toxicology Principles of Toxicology – 3/2/04