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Raman Govindarajan, MD, PhD. Regional Director Medical and Scientific Affairs Johnson and Johnson Asia Pacific

Toxicology Fundamentals. Raman Govindarajan, MD, PhD. Regional Director Medical and Scientific Affairs Johnson and Johnson Asia Pacific. A Day in Toxicology. The Fundamentals of Toxicology Preclinical Safety Assessment of Cosmetics & Toiletries How? Case Studies.

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Raman Govindarajan, MD, PhD. Regional Director Medical and Scientific Affairs Johnson and Johnson Asia Pacific

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  1. Toxicology Fundamentals Raman Govindarajan, MD, PhD. Regional Director Medical and Scientific Affairs Johnson and Johnson Asia Pacific

  2. A Day in Toxicology • The Fundamentals of Toxicology • Preclinical Safety Assessment of Cosmetics & Toiletries How? Case Studies

  3. Toxicology: Fundamentals • What is Toxicology? The traditional definition of toxicology: " the science of toxin ”.

  4. Toxicology: Fundamentals • What is Toxicology? A more descriptive definition of toxicology: "the study of the adverse effects of chemicals or physical agents on living organisms".

  5. Toxicology: Fundamentals Which one of the following is a toxin? 1.Alcohol 2. Aspirin 3. Water 4. Table salt

  6. Toxicology: Fundamentals Toxicity depends on the DOSE

  7. Toxicology: Fundamentals “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” -- Paracelsus

  8. Toxicology: Fundamentals • Toxicity depends on the dose • High oxygen level cause “oxygen intoxication”

  9. Toxicology: Fundamentals • Toxicity depends on the dose • High oxygen level cause “oxygen intoxication” • Too much water (several gallons) can cause osmotic imbalance and brain damage

  10. Toxicology: Fundamentals • Toxicity depends on the dose • High oxygen level cause “oxygen intoxication” • Too much water (several gallons) can cause osmotic imbalance and brain damage • 1 beer vs. a six pack of beer

  11. Toxicology: Fundamentals • Toxicity depends on the dose • High oxygen level cause “oxygen intoxication” • Too much water (several gallons) can cause osmotic imbalance and brain damage • 1 beer vs. a six pack of beer • 1 sleeping pill vs. a bottle of sleeping pills

  12. Toxicology: Fundamentals • Toxicity depends on the dose • High oxygen level cause “oxygen intoxication” • Too much water (several gallons) can cause osmotic imbalance and brain damage • 1 beer vs. a six pack of beer • 1 sleeping pill vs. a bottle of sleeping pills • 1 aspirin vs. a bottle of aspirins

  13. Toxicology: Fundamentals What is LD 50 ? 1. Fifty Lead molecules 2. A famous singer in 1950’s 3. A Latin dance introduced in 1950’s 4. A means to measure toxicity

  14. Toxicology: Fundamentals How is Toxicity measured by?

  15. Toxicology: Fundamentals Toxicity is measured by LD50: Lethal Dose that kills 50% of the population

  16. Toxicology: Fundamentals Toxicity is measured by: • LD50: Lethal Dose that kills 50% of the population • Dosage measured in weight of toxin per body weight

  17. Toxicology: Fundamentals Dose-response curves are used to derive dose estimates of chemical substances. A common dose estimate for acute toxicity is the LD50 (Lethal Dose 50%).

  18. Toxicology: Fundamentals Examples of LD50: Chemical LD50 (ppm) Nicotine 1 DDT 100 Table Salt 3000 Trichloroethylene 5000

  19. Toxicology: Fundamentals What is ED 10 ? 1. The 10th version of ET movie 2. Brief for the 10th Edward in the family 3. The 10th Executive Director in a company 4. Indication of the effectiveness of a substance

  20. Toxicology: Fundamentals Effective Doses (EDs) are used to indicate the effectiveness of a substance. Normally, effective dose refers to a beneficial effect (relief of pain). It might also stand for a harmful effect (paralysis). Thus the specific endpoint must be indicated.

  21. Toxicology: Fundamentals Effective Dose

  22. Toxicology: Fundamentals What does EC stands for? • 1. Title for a TV show starring a talking horse • 2. Effective concentration • 3. Exposure concentration • 4. New musical show in Broadway

  23. Toxicology: Fundamentals • EC10 This is the commonly used abbreviation for the exposure concentration of a toxicant causing a defined effect on 10% of a test population

  24. Toxicology: Fundamentals Absorption is the process whereby a substance moves from outside the body into the body.

  25. Toxicology: Fundamentals

  26. Toxicology: Fundamentals Definition

  27. Toxicology: Fundamentals What is Toxicokinetics? Toxicokinetics is the study of "how a substance gets into the body and what happens to it in the body". Essentially, it is the study of “the kinetics of all toxic substances”.

  28. Toxicology: Fundamentals Toxicity/Preclinical Safety Review • Single Dose Study • Multiple Dose Study: Subacute, Subchronic, Chronic • Mutagenicity/Carcinogenicity Study

  29. Toxicology: Fundamentals Acute toxicity results from a single exposure to a poisonous substance. Route of administration: Oral, IV, IP, Dermal, Subcutaneous

  30. Toxicology: Fundamentals Acute toxicity results from a single exposure to a poisonous substance • Usually has an immediate life-threatening effect

  31. Toxicology: Fundamentals Acute toxicity results from a single exposure to a poisonous substance • Usually has an immediate life-threatening effect • Usually easily diagnosed

  32. Toxicology: Fundamentals Acute toxicity results from a single exposure to a poisonous substance • Usually has an immediate life-threatening effect • Usually easily diagnosed • Most of the time there are antidotes that can reduce the toxicity of the chemical

  33. Toxicology: Fundamentals Multiple Dose Tests: Subacute: days to 2 wks Subchronic: 4 - 13 wks Chronic: 6 - 12 months in rodents 7 - 10 years in non-rodents Study design depending on the objective of the study

  34. Toxicology: Fundamentals Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time

  35. Toxicology: Fundamentals Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time • No immediate effect but could be life-threatening in the long term

  36. Toxicology: Fundamentals Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time • No immediate effect but could be life-threatening in the long term • Usually hard to diagnose and treat

  37. Toxicology: Fundamentals Chronic toxicity results from prolonged exposure to a poisonous substance over a long period of time • No immediate effect but could be life-threatening in the long term • Usually hard to diagnose and treat • Hard to distinguish effects from other influences

  38. Toxicology: Fundamentals What is mutagenic? 1. Something to do with music 2. Something to do with DNA 3. Something to do with mutes

  39. Toxicology: Fundamentals • Mutagenesis The process whereby a substance damagesDNA and produces alterations in or loss of genes or chromosomes.

  40. Toxicology: Fundamentals Mutagenicity Tests • Ames Test • Mammalian Chromosomal Aberration • Micronucleus Test (in vivo)

  41. Toxicology: Fundamentals What is carcinogenic ? 1. A place that makes cars 2. Something to do with gambling 3. Something that can cause tumors 4. A place that repairs cars

  42. Toxicology: Fundamentals • Carcinogen A carcinogen is any substance which causes cancer

  43. Toxicology: Fundamentals Carcinogenicity Studies • Traditional 2-year Bioassay • different routes of administration, use rats and mice • two year duration, expensive, labor-intensive • interspecies extrapolation problem, especially mice

  44. Toxicology: Fundamentals Carcinogenicity Studies • Traditional Testing • different routes of administration, use rats and mice • two year duration, expensive, labor-intensive • interspecies extrapolation problem, especially mice • Transgenic Animal Testing • P53, Neonatal, TgAc, XPA, XPA/P53 and RasH2 models • shorter testing period, less expensive, less labor-intensive • have genes relevant to humans • predictability? -- not enough data

  45. Toxicology: Fundamentals What is a reproductive toxin?

  46. Toxicology: Basic Reproductive toxicity is defined as adverse effects on the male and female reproductive systems that result from exposure to chemical substances.

  47. Toxicology: Fundamentals Which of the following causes reproductive toxicity? 1.Alcohol 2. Vitamin A 3. Tobacco smoke (primary) 4. Aspirin

  48. Toxicology: Fundamentals Special Toxicity Studies • Eye Irritation • Skin Irritation • Contact Sensitization • Comedogenicity • Genital/Mucus Membrane Irritation

  49. Toxicology: Fundamentals Irritation: Any substance causing inflammation following immediate, prolonged, or repeated contact with skin or mucous membrane.

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