Ce diaporama a bien été signalé.
Nous utilisons votre profil LinkedIn et vos données d’activité pour vous proposer des publicités personnalisées et pertinentes. Vous pouvez changer vos préférences de publicités à tout moment.

Environmental toxicology

Environmental toxicology

  • Soyez le premier à commenter

  • Soyez le premier à aimer ceci

Environmental toxicology

  1. 1. ENVIRONMENTAL TOXICOLOGY Basic Concepts Dr Ahmed-Refat A.G. Refat FOM-TU-KSA-2014 1
  2. 2. “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Paracelsus (1493-1541) Dr.Ahmed-Refat 2 WHAT IS A POISON?
  3. 3. TOXICOLOGY Toxicology is the study of adverse effects of chemicals on living systems. Adverse effects any change from an organism’s normal state dependent upon the concentration of active compound at the target site for a sufficient time. Dr.Ahmed-Refat 3
  4. 4. Branches of Toxicology 1. Clinical —treatments for poisonings and injuries causedby xenobiotics 2. Environmental —environmentalpollutants, effects on flora. 3. Mechanistic—cellular, biochemical and molecular mechanisms by which chemicals cause toxic responses 4. Forensic —cause of death, legal aspects 5. Food —adverse effects of processed or natural food components 6. Regulatory—assigns risk to substances of
  5. 5. CHEMICALS IN THE ENVIRONMENT Roughly 70,000 different synthetic chemicals are on the global market; many others are emitted as by- products of their production, use, or disposal Dr.Ahmed-Refat 5
  6. 6. CHEMICALS IN THE ENVIRONMENT Production of chemicals has increased from less than 0.15 billion kilograms (1935) to more than 150 billion kilograms (1995) Dr.Ahmed-Refat (FOM-TU-KSA-2014) 6
  7. 7. A Small Dose of Toxicology Intro Principles of Toxicology So Many Chemicals so Little Data 78.2% no data 21.4% some data 0.4% good data www.preventingharm.org
  8. 8. A Small Dose of Toxicology Intro Principles of Toxicology • Number of chemicals (1984) • −Pesticides……………3,350 • −Drugs…………………1,815 • −Cosmetics…………….3,410 • −Food additives…….…8,627
  9. 9. A Small Dose of Toxicology Intro Principles of Toxicology Why Don’t We Know More about These Chemicals? • Each year ~1,000 new chemicals come on line • It costs ~ $ 2 million to do a cancer toxicology screen on each chemical . • The cancer toxicology screen takes ~2 years
  10. 10. THE TOXICOLOGICAL PROCESS Dr.Ahmed-Refat 10
  11. 11. THE TOXICOLOGICAL PROCESS Dr.Ahmed-Refat 11
  12. 12. Dr.Ahmed-Refat 12
  13. 13. THE TOXICOLOGICAL PROCESS Dr.Ahmed-Refat 13
  14. 14. MOLECULAR TARGETS CONCEPT The toxic action= interaction of the active form with a molecular target within the living organism Dr.Ahmed-Refat 14
  15. 15. EXPOSURE Route of Exposure  Dermal (skin)  Inhalation (lung)  Oral ingestion (Gastrointestinal)  Injection • The route of exposure may be important if there are tissue- specific toxic responses. • Toxic effects may be local or systemic
  16. 16. ADME: ABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION  The body has defenses:  Membrane barriers  passive and facilitated diffusion, active transport  Biotransformation enzymes, antioxidants  Elimination mechanisms Dr.Ahmed-Refat 16
  17. 17. ABSORPTION:  Ability of a chemical to enter the blood (blood is in equilibrium with tissues Dr.Ahmed-Refat 17
  18. 18. Distribution: Storage and Binding •Storage in Adipose tissue-- •Storage in Bone- •Binding to Plasma proteins. Dr.Ahmed-Refat 18
  19. 19. TARGET ORGANS:  Liver--high blood flow, oxidative reactions  Kidney--high blood flow, concentrates chemicals  Lung--high blood flow, site of exposure  Neurons--oxygen dependent, irreversible damage  Myocardium--oxygen dependent  Bone marrow, intestinal mucosa--rapid divide Dr.Ahmed-Refat 19
  20. 20. EXCRETION:  Urinary excretion  Exhalation  Biliary Excretion via Fecal Excretion  Milk Sweat Saliva Dr.Ahmed-Refat 20
  21. 21. METABOLISM:  Make chemical agents more water soluble and easier to excrete decrease lipid solubility increase ionization  Bioactivation--Biotransformation can result in the formation of reactive metabolites Dr.Ahmed-Refat 21
  22. 22. TOXICOKINETICS  A reflection of how the body handles toxicants .  The end result of these toxicokinetic processes is a biologically effective dose of the toxicant. What We do to the Chemical Dr.Ahmed-Refat 22
  23. 23. TOXICODYNAMICS  the molecular, biochemical, and physiological effects of toxicants or their metabolites in biological systems What the Chemical Does to Us Dr.Ahmed-Refat 23
  24. 24. EXPOSURE Dr.Ahmed-Refat 24 Time of Exposure • How long an organism is exposed to a chemical is important Duration and frequency contribute to dose. Both may alter toxic effects
  25. 25. Exposure: Duration Acute < 24hr usually 1 exposure Subacute 1 month repeated doses Subchronic 1-3mo repeated doses Chronic > 3mo repeated doses 25 Dr.Ahmed-Refat
  26. 26. DOSE The amount of chemical entering the body This is usually given as mg of chemical/kg of body weight = mg/kg Dr.Ahmed-Refat 26
  27. 27. DOSE The dose is dependent upon  The environmental concentration  The properties of the toxicant  The frequency of exposure  The length of exposure  The exposure pathway Dr.Ahmed-Refat 27
  28. 28. WHAT IS A RESPONSE?  Change from normal state  could be on the molecular, cellular, organ, or organism level--the symptoms  Local vs. Systemic  Reversible vs. Irreversible  Immediate vs. Delayed  Graded vs. Quantal  Stochastic vs Non Stochastic Dr.Ahmed-Refat 28
  29. 29. DOSE-RESPONSE CURVE  Stochastic (“Random”) Model  Risk (probability) of response is a function of dose  −Assumes no threshold  −No dose is safe  −Any dose increases the risk (not severity) Dr.Ahmed-Refat 29
  30. 30. DOSE-RESPONSE CURVE  Stochastic (“Random”) Model  For example, cancer  Implies that any exposure increases the risk of cancer, with larger exposures producing a greater risk (but not a bigger tumor) Dr.Ahmed-Refat 30
  31. 31. STOCHASTIC (“RANDOM”) MODEL Dr.Ahmed-Refat 31
  32. 32. DOSE-RESPONSE CURVE  Non-Stochastic (“Deterministic”) Model  Severity of response is a function of dose  −Assumes a threshold  −A “safe”dose exists −Examples  −Cataractogenesis  −Mental retardation following in uteroirradiation  Chloracne Dr.Ahmed-Refat 32
  33. 33. EXAMPLES OF TOXICANTS: CHEMICALSTHAT CAN CAUSE HARM Dioxin poisoning → facial scarring (chloracne) Hg in fish → brain damage www.seco.noaa.gov
  34. 34. DOSE-RESPONSE RELATIONSHIP Dr.Ahmed-Refat 34 Phenobarbital (mg/kg) Log Scale ED50 LD50 Effective Dose Lethal Dose 100 60 80 40 20 100 60 80 40 20 10 20 30 50 100 1 2 3 5 7 10
  35. 35. POPULATION DOSE-RESPONSE Dr.Ahmed-Refat 35 Mild Extreme Many Few Number of Individuals Response to SAME dose Sensitive Individuals Maximal Effect Resistant Individuals Minimal Effect Majorityof Individuals Average Effect
  36. 36. Too high:Anorexia, anemia, nose bleeds, muscleand joint pain SOME CHEMICALS HAVE BOTH THERAPEUTIC AND TOXIC EFFECTS: VITAMIN A Dr.Ahmed-Refat 36 Dose Adverse response Threshold Too low: Blindness, dry skin, increased infections
  37. 37. Toxic Potency Agent LD50 (mg/kg) Ethyl alcohol 10,000 Sodium chloride 4,000 BHA/BHT (antioxidants) 2,000 Morphine sulfate 900 Caffeine 200 Nicotine 1 Curare 0.5 Shellfish toxin 0.01 sarin 0.001 Botulinum toxin 0.00001 slight moderate high Extremely high (<1 mg/kg)
  38. 38. BIOTRANSFORMATION  Key organs in biotransformation  LIVER (high)  Lung, Kidney, Intestine (medium)  Others (low)  Biotransformation Pathways * Phase I--make the toxicant more water soluble * Phase II--Links with a soluble endogenous agent (conjugation) Dr.Ahmed-Refat 38
  39. 39. INDIVIDUALSUSCEPTIBILITY --  Genetics-species, strain variation, interindividual variations (yet still can extrapolate between mammals--similar biological mechanisms)  Gender (gasoline nephrotox in male mice only)  Age--young (old too)  underdeveloped excretory mechanisms  underdeveloped biotransformation enzymes  underdeveloped blood-brain barrier Dr.Ahmed-Refat 39
  40. 40. INDIVIDUAL SUSCEPTIBILITY  Age--old  changes in excretion and metabolism rates, body fat  Nutritional status  Health conditions  Previous or Concurrent Exposures  additive --antagonistic  synergistic Dr.Ahmed-Refat 40
  41. 41. Evaluating Dose-Response Relationships ED: Effective dose (therapeutic dose of a drug) TD: Toxic dose (dose at which toxicity occurs) LD: Lethal dose (dose at which death occurs) NOAEL: no observed adverse effect level LOAEL: lowest observed adverse effect level dose (mg/kg) 10-2 10-1 100 101 102 103 0 20 40 60 80 100 ED TD LD 50 % response LOAEL NOAEL % response
  42. 42. Evaluating Dose-Response Relationships ED50: dose at which 50% of population therapeutically responds.= ?? TD50: dose at which 50% of population experiences toxicity (TD50=?? mg/kg). LD50: dose at which 50% of population dies (LD50=?? mg/kg). dose (mg/kg) 10-2 10-1 100 101 102 103 0 20 40 60 80 100 ED TD LD 50 % response LOAEL NOAEL % response
  43. 43. EXPOSURE Dr.Ahmed-Refat 43 1. Environmental, including home and school 2. Occupational 3. Therapeutic 4. Dietary 5. Accidental 6. Deliberate Sources of exposure to chemicals
  44. 44. DOSE Determines Whether a Chemical Will Be Beneficial or Poisonous Beneficial Dose Toxic Dose Aspirin 300 – 1,000 mg 1,000 – 30,000 mg Vitamin A 5000 units/day 50,000 units/day Oxygen 20% (Air) 50 – 80% (Air)
  45. 45. Dr.Ahmed-Refat 45 TOXICOLOGICAL PARADIGM Exposure Internal Dose Biologically Effective Dose Early Biological Effect Altered Structure & Function Disease Absorption Distribution Metabolism Excretion Storage Toxicokinetics Toxicodynamics What We do to the Chemical What the Chemical Does to Us Susceptibilityand ModifyingFactors (Genetics and Nutritional Status)
  46. 46. TOXICOLOGY- SUMMERY  Exposure + Hazard = Risk  All substances can be a poison  Dose determines the response  Pathway,Duration of Frequency of Exposure and Chemical determine Dose  Absorption,Distribution, Metabolism & Excretion  The extent of the effect is dependent upon the concentration of the active compound at its site of action over time  Bioactivation:compounds to reactive metabolites  Individualvariation of the organism will affect ADME Dr.Ahmed-Refat 46

×