1. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 An Introduction to the Principles of Toxicology A Small Dose of Toxicology Steven G. Gilbert, PhD, DABT www.asmalldoseof.org www.toxipedia.org ENV H 472 A - ENVIRONMENTAL RISK AND SOCIETY Class 2

2. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 A Small Dose of Toxicology See: www.asmalldoseof.org -- smdosesmdose

3. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Small Dose of Toxicology

4. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Milestones of Toxicology

5. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 www.toxipedia.org A free toxicology encyclopedia and resource center that anyone can edit. Toxipedia provides comprehensive, accurate, and scientifically based information on the hazards and risks of chemical and physical agents, with the goal of advancing human and environmental health. ToxipediaToxipedia

6. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 The World Library of Toxicology

7. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Toxipedia suite of sites www.ipmopedia.org www.healthyworldtheater.org www.wanmec.org www.toxipedia.org www.wltox.org

8. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 LDDI Consensus Statement Scientific Consensus Statement on Environmental Agents Associated with Neurodevelopmental Disorders Developed by the Collaborative on Health and the Environment’s Learning and Developmental Disabilities Initiative November 7, 2007 http://www.iceh.org/LDDI.html

9. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 LDDI Consensus Statement http://www.iceh.org/LDDI.html Given the established knowledge, protecting children from neurotoxic environmental exposures from the earliest stages of fetal development clearly is an essential public health measure if we are to help prevent learning and developmental disorders and create an environment in which children can reach and maintain their full potential.

10. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 NW Public Health See: http://healthlinks.washington.edu/nwcphp/nph/ nwph Public Health and the Precautionary Principle By Steven G. Gilbert

11. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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.

12. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Setting goals (Health indicators) Taking preventive action in the face of uncertainty Shifting the burden of responsibility to the proponents of an activity (Who benefits?) Exploring a wide range of alternatives to possibly harmful actions (Is it necessary?) Increasing public participation in decision making (transparency of information & environmental justice) Central components

13. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Child Health

14. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 So Many Chemicals so Little Data 2863 above 1 Million pounds 78.2% no data 21.4% some data 12 or 0.4% good data www.preventingharm.org

15. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10  Nearly 12 million children (17%) under age 18 in the US suffer from one or more developmental disabilities  Learning disabilities – 5-10% of kids in public school  ADHD – 3-6% of all school kids, maybe higher The Consequences

16. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 "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 ---------- 1887 - 1948 ---------- Aldo Leopold

17. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “An ethic, ecologically, is a limitation on freedom of action in the struggle for existence” Aldo Leopold Limits on Freedom

18. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “The Commons” The Tragedy of the Commons By Garrett Hardin, Science, 1968

19. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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

20. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Problems – Solutions?  Lead and kids  Fetal alcohol syndrome  Nuclear disarmament  Bioterrorism  Ocean Fisheries  Persistent chemicals  The Commons

21. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 The study of poisons or the adverse effects of chemical and physical agents on living organisms. Toxicology Definitions

22. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 399 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. Ancient Awareness

23. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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 (1564-1616) Historical Awareness

24. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “Conditions that ensure that all living things have the best opportunity to reach and maintain their full genetic potential.” Steven G. Gilbert, 1999 Human & Environmental Health

25. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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 What do these have in common?

26. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Who are these white guys?

27. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “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) Power To Discover The Truth

28. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 What Is This? N N N N CH 3 O O 1 3 7

29. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Key Words Risk = Hazard X Exposure Dose / Response Individual Sensitivity

30. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Paracelsus (1493-1541) Paracelsus

31. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “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

32. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Superman

33. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Neuron

34. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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

35. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 What Is This? C H H HOHC H H (CH 3 -CH 2 - OH)

36. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Effects of Prenatal Alcohol

37. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 FAS Child

38. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Mouse – Scanning EM

39. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 A Small Dose of Lead

40. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Lead In Homes

41. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Lead History Greek 2 nd BC Lead Makes the Mind Give Way

42. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Recycling Lead

43. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Agency Blood Lead Levels

44. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 A Small Dose of Mercury

45. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Hg – Like Water

46. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Polluting with HG Discharge in Minamata Bay

47. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Fetal Effects of MeHg

48. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Life-Long Effects of MeHg

49. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 The Mercury Cycle

50. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Pesticide Application

51. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Classes Of Pesticides  Insecticides (kill insects) Organochlorines Organophosphates Carbamates Synthetic Pyrethroids  Herbicides (kill plants)  Rodenticides (kill rodents)  Fungicides (kill fungus)  Fumigants (kill whatever)

52. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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

53. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Focus – long-term prevention of pest problems Reduce or eliminate chemical pest control methods Monitor for the presence of pests before treating Nonchemical strategies (make habitat less attractive, physical controls) Learn about your pests Integrated Pest Management (IPM)

54. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Key Words Risk = Hazard X Exposure Dose / Response Individual Sensitivity

55. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Effects of Amount on Response

56. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Effects of Size on Response

57. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Glasses of Wine - Dose Response 0 25 50 75 100 012345678 Glasses of Wine % Difficulty Walking All Effected NO Effect Amount half are effected

58. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Dose (mg/kg body weight) Increasing dose Dose Response Function 0 25 50 75 100 0102030405060708090100 % Response NO Effect All Effected Half Effected

59. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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 Toxin0.00001 Bee Venom?? Agent LD-50 (mg/kg)

60. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 1) Skin (dermal) 2) Lung (inhalation) 3) Oral (gut) Route of exposure Exposure & Absorption

61. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Number of Times Time Between 4 Beers in an hour or 4 Beers in 4 Days Frequency Of Exposure

62. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Acute Exposure Sub-chronic Exposure Chronic Exposure Duration Of Exposure

63. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Where It Goes (body water, fat, bone) Where It Accumulates Distribution

64. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 How The Body Breaks It Down What It Turns Into How Fast It Does It Metabolism

65. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 N N N N CH 3 O O 1 3 7 Caffeine - 1,3,7 Trimethylxanthine

66. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Concentration (µg/ml) Time (hrs) How Long It Takes To Go Half-life 0 2 4 6 8 10 12 14 01234567891011

67. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Young or Old Male or Female Individual Variability Genetics Differences Species Differences Susceptibility & Variability

68. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 N CH 3 N What Is This?

69. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Structure of PBDEs X & Y are number of Bromine atoms Common Penta, Octa, and Deca PolyBrominated Diphenyl Ether O Br x Br y

70. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 PBDEs in House Dust (ppb) From EWG - Toxic Fire Retardants Contaminate American Homes - http://www.ewg.org/reports/inthedust/summary.php

71. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 PBDEs in Breast Milk (ppb) From EWG - Toxic Fire Retardants in Breast Milk from American Mothers - http://www.ewg.org/reports/mothersmilk/es.php

72. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Estimated Costs - National Best Estimate Low EstimateHigh Estimate Lead Poisoning $43.4 Asthma $2.0$0.7$2.3 Cancer $0.3$0.2$0.7 Neurobehavioral Disorders $9.2$4.6 $18.4 TOTAL$54.9$48.8$64.8 Estimated Costs of Pediatric Disease of Environmental Origin, United States,1997 (billions) (From “Environmental Pollutants and Disease in American Children,” Landrigan, Schechter, et.al., 2002)

73. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Estimated Costs - Washington Diseases and disabilities (asthma, cancer, lead exposure, birth defects, and neurobehavioral effects) attributable to environmental contaminants. Best Estimate Direct Costs Indirect Costs Range Childhood$1,875$310.6$1,565 $1,600- $2,200 Adult & child $2,734$782.1$1,953 $2,800- $3,500 Disease/Disability (2004 $ million) Kate Davies Economic costs of diseases and disabilities attributable to environmental contaminants in Washington State. Antioch University Seattle 2005. http://washington.chenw.org/pdfs/EnvironmentalCosts.pdf

74. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 “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

75. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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. Central components

76. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 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

77. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 The Potential of Children

78. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Principles of Toxicology

79. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Additional Information A Small Dose of Toxicology www.asmalldoseof.org

80. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Authorship Information For Additional Information Contact Steven G. Gilbert, PhD, DABT E-mail: smdose@asmalldoseof.org Web: www.asmalldoseof.org This presentation is supplement to “A Small Dose of Toxicology”

81. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Receptor Ligand Cell Membrane Signal Protein Positive Response Outside Cell Inside Cell Ligand binds to receptor 11 33 22 Normal Receptor-Ligand Interaction

82. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Toxicant 11 inactivates receptor Toxicant inactivates receptor No Response 33 22 Inactivation of Receptor by Toxicant

83. A Small Dose of ToxicologyPrinciples of Toxicology – 01/07/10 Toxicant 1 No Response 3 2 Ligand Toxicant out competes normal ligand Ligand cannot bind receptor Competition For Receptor