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Introduction To Toxicology

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An introductry presentation on Toxicology by Mike Slater of Diamond Environmental Ltd.

Publié dans : Santé & Médecine, Technologie
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Introduction To Toxicology

  1. 1. Mike Slater Diamond Environmental Ltd
  2. 2. "All substances are poisons ; there is none which is not a poison. The right dose differentiates a poison from a remedy"
  3. 3. Chemicals <ul><li>Organic </li></ul><ul><li>Inorganic </li></ul>
  4. 4. Homeostasis <ul><li>Chemical reactions which maintain very stable body chemistry against a background of constant environmental change </li></ul>
  5. 5. Inhalation Skin contact Ingestion
  6. 8. Absorption <ul><li>Absorbed dose is generally a fraction of exposure dose </li></ul><ul><li>Toxicant must be able to cross cell membranes </li></ul>
  7. 9. Factors Affecting Absorption <ul><li>Degree of exposure </li></ul><ul><li>Routes of entry </li></ul><ul><li>Properties of chemical </li></ul>
  8. 10. Absorption Through the Lungs <ul><li>Amount of air inhaled </li></ul><ul><li>Gases </li></ul><ul><li>Aerosols </li></ul>
  9. 12. Particle Deposition <ul><li>Interception </li></ul><ul><li>Impaction </li></ul><ul><li>Sedimentation </li></ul><ul><li>Diffusion </li></ul>
  10. 13. V t = terminal velocity g = acceleration due to gravity d = diameter of particle p p = density of particle p m = density of medium µ = viscosity of medium
  11. 14. Particle Deposition <ul><li>Falling speed is proportional to </li></ul><ul><ul><li>the density of the particle </li></ul></ul><ul><ul><li>the square of its diameter </li></ul></ul>
  12. 15. Aerodynamic Diameter <ul><li>The diameter of a sphere of unit density (i.e. a water droplet) that has the same falling speed as the real particle </li></ul>
  13. 18. Absorption Through Skin <ul><li>Absorption depends on lipid solubility </li></ul><ul><li>Uptake greater if skin damaged </li></ul><ul><li>Uptake varies </li></ul>
  14. 19. Absorption Through Skin <ul><li>Many organic compounds readily absorbed </li></ul><ul><ul><li>solvents </li></ul></ul><ul><ul><li>pesticides </li></ul></ul><ul><ul><li>organo-metal compounds </li></ul></ul>
  15. 20. Absorption Through Gut <ul><li>Better absorption with un-ionised, fat soluble substances </li></ul>
  16. 21. Absorption Through Gut <ul><li>Stomach </li></ul><ul><li>Acidic </li></ul><ul><li>Acidic compounds absorbed </li></ul>
  17. 22. Absorption Through Gut <ul><li>Intestine </li></ul><ul><li>Alkaline </li></ul><ul><li>Alkaline compounds absorbed </li></ul>
  18. 23. Distribution <ul><li>Transport by blood </li></ul><ul><li>Rate </li></ul><ul><li>Substances released from storage </li></ul>
  19. 24. Storage <ul><li>Fat </li></ul><ul><ul><li>lipophilic compounds </li></ul></ul><ul><ul><li>e.g. some pesticides (DDT), dioxins, PCBs </li></ul></ul><ul><li>Bones </li></ul><ul><ul><li>chemicals similar to calcium </li></ul></ul><ul><ul><li>fluorine, lead, strontium </li></ul></ul><ul><li>Blood </li></ul><ul><li>Liver and kidney </li></ul><ul><li>Other organs / tissues </li></ul>
  20. 25. Biotransformation <ul><li>Occurs mainly in liver </li></ul><ul><li>Also in lungs, kidney & intestine </li></ul>
  21. 26. Biotransformation <ul><li>Catalysed by enzymes </li></ul><ul><ul><li>including Cytochrome P450 </li></ul></ul>
  22. 27. Biotransformation <ul><li>Increases water solubility for excretion via kidney </li></ul>
  23. 28. Biotransformation <ul><li>Metabolites or intermediaries can be toxic </li></ul>
  24. 29. <ul><li>Phase I reactions </li></ul><ul><li>Oxidation </li></ul><ul><li>Reduction </li></ul><ul><li>hydrolysis </li></ul><ul><li>Phase II reactions </li></ul><ul><li>Conjugation </li></ul><ul><li>Synthesis </li></ul>Metabolites Elimination
  25. 30. Metabolites - Some Examples Substance Metabolite Benzene Phenol Dichloromethane Carbon monoxide N-hexane 2, 5 hexanedione Methanol Formaldehyde Styrene Mandelic acid Phenylglyoxylic acid Toluene Hippuric acid o- cresol Trichloroethylene Trichloroacetic acid Trichloroethanol Xylene Methyl-hippuric acid
  26. 31. Biotransformation <ul><li>Sometimes biotransformation increases toxicity </li></ul>
  27. 32. Biotransformation <ul><li>Examples </li></ul><ul><ul><li>Benzene </li></ul></ul><ul><ul><li>n-hexane </li></ul></ul><ul><ul><li>Methanol </li></ul></ul><ul><ul><li>Dichloromethane </li></ul></ul><ul><ul><ul><li>carbon monoxide formed </li></ul></ul></ul>
  28. 33. Excretion <ul><li>Kidney </li></ul><ul><ul><li>urine </li></ul></ul><ul><ul><li>water soluble compounds </li></ul></ul>
  29. 34. Excretion <ul><li>Lungs </li></ul><ul><ul><li>volatile compounds </li></ul></ul><ul><ul><li>gaseous metabolites </li></ul></ul>
  30. 35. Excretion <ul><li>Liver </li></ul><ul><ul><li>bile </li></ul></ul><ul><ul><li>fat soluble compounds </li></ul></ul>
  31. 36. Excretion <ul><li>Other routes </li></ul><ul><ul><li>Hair </li></ul></ul><ul><ul><li>Nails </li></ul></ul><ul><ul><li>Skin </li></ul></ul><ul><ul><li>Sweat </li></ul></ul><ul><ul><li>Milk </li></ul></ul>
  32. 37. Excretion - the Kidneys <ul><li>Filters the blood of its small molecules and ions and then ... </li></ul>
  33. 38. Excretion - the Kidneys <ul><li>Reclaims useful materials </li></ul>
  34. 39. Excretion - the Kidneys <ul><li>Surplus or waste molecules and ions flow out as urine </li></ul>
  35. 40. Biological Half Life <ul><li>Time taken for half the amount of the substance absorbed to be excreted </li></ul>
  36. 42. Some Half Lives <ul><li>Toluene ~ 10 hours </li></ul><ul><li>Selenium ~ 10 days </li></ul><ul><li>Mercury ~ 6 weeks </li></ul><ul><li>Cadmium ~ 10 years or more </li></ul>
  37. 43. Half Lives <ul><li>Mineral dusts </li></ul><ul><li>Metal compounds </li></ul><ul><li>Organic solvents & inorganic gases </li></ul>Amphibole asbestos is particularly biopersistent Can remain in lungs for decades
  38. 47. Threshold Dose
  39. 48. Threshold Dose <ul><li>The point at which toxicity first appears </li></ul><ul><li>NOAEL </li></ul><ul><ul><li>&quot;no observed adverse effect level&quot; </li></ul></ul>
  40. 49. Susceptibility <ul><li>Variation in susceptibility between individuals </li></ul><ul><li>Different doses required to produce same effect </li></ul>
  41. 50. Susceptibility <ul><li>Most susceptible groups include </li></ul><ul><ul><li>Elderly, </li></ul></ul><ul><ul><li>Children, </li></ul></ul><ul><ul><li>People with pre-existing disease </li></ul></ul><ul><li>Inter-species variation </li></ul>
  42. 54. Stochastic Effects <ul><li>Probabilistic </li></ul><ul><li>Increasing probability of effect with increasing dose </li></ul><ul><ul><li>e.g. carcinogens </li></ul></ul>
  43. 58. Types of Effect <ul><li>Local </li></ul><ul><ul><li>at point of contact with the body </li></ul></ul><ul><li>Systemic </li></ul><ul><ul><li>following distribution </li></ul></ul>
  44. 59. Types of Effect <ul><li>chronic </li></ul><ul><li>sub-chronic </li></ul><ul><li>sub-acute </li></ul><ul><li>acute </li></ul>timescale
  45. 60. Exposure and Effect <ul><li>Acute < 24hr usually 1 exposure </li></ul><ul><li>Subacute 1 month repeated doses </li></ul><ul><li>Subchronic 1-3 months repeated doses </li></ul><ul><li>Chronic > 3months repeated doses </li></ul>
  46. 61. Harmful Effects <ul><li>Asphyxiant </li></ul><ul><li>Irritant </li></ul><ul><li>Corrosive </li></ul><ul><li>Narcotic </li></ul><ul><li>Sensitiser </li></ul><ul><li>Toxic </li></ul><ul><li>Carcinogen </li></ul><ul><li>Mutagen </li></ul><ul><li>Teratogen </li></ul>
  47. 62. Simple Asphyxiants <ul><li>Inert gases </li></ul><ul><li>Reduce oxygen concentration in air </li></ul><ul><li>e.g. nitrogen, argon </li></ul>
  48. 63. Oxygen Level Effect <ul><li>21% Normal atmospheric concentration </li></ul><ul><li>18% Minimum “acceptable” concentration </li></ul><ul><li>17% Breathing faster & deeper </li></ul><ul><li>16.25% Flame safety lamp will extinguish </li></ul><ul><li>15% Dizziness, buzzing noise, rapid pulse, headache, blurred vision </li></ul><ul><li>9% Unconsciousness </li></ul><ul><li>6% Breathing stops, cardiac arrest </li></ul>
  49. 64. Chemical Asphyxiants <ul><li>Interference with </li></ul><ul><ul><li>oxygen transport, or </li></ul></ul><ul><ul><li>utilisation of oxygen </li></ul></ul>
  50. 65. Chemical Asphyxiants <ul><li>Carbon monoxide </li></ul><ul><li>carboxyhaemoglobin </li></ul>
  51. 66. Chemical Asphyxiants <ul><li>Methaemoglobin </li></ul><ul><li>oxidation of haemoglobin Fe2+ to Fe3+ </li></ul><ul><li>Aniline </li></ul><ul><li>Nitrobenzene </li></ul><ul><li>Nitrites </li></ul>
  52. 67. Chemical Asphyxiants <ul><li>Haemolytic agents </li></ul><ul><li>destroy blood cells </li></ul><ul><li>arsine, stibene </li></ul>
  53. 68. Chemical Asphyxiants <ul><li>Inhibition of cellular respiration </li></ul><ul><li>cyanide </li></ul><ul><li>hydrogen sulphide </li></ul>
  54. 69. Causes local inflammation of tissue
  55. 70. Destroys tissue
  56. 71. Depresses Central Nervous System Causes dizziness, nausea, drowsiness
  57. 72. Causes an allergic reaction in susceptible people
  58. 73. Sensitisers <ul><li>Cause allergic reaction in susceptible individuals </li></ul><ul><li>Cannot identify susceptible individuals! </li></ul><ul><li>Usually develops gradually </li></ul><ul><li>Not always easy to identify causative agent </li></ul>
  59. 74. Sensitisers – CHIP Classifications R42 May cause sensitisation by inhalation R43 May cause sensitisation by skin contact
  60. 75. Sensitisers <ul><li>Respiratory </li></ul><ul><ul><li>Rhinitis </li></ul></ul><ul><ul><li>Asthma </li></ul></ul><ul><ul><li>Allergic alveolitis </li></ul></ul>
  61. 76. Source: http://www.hse.gov.uk/statistics/causdis/asthma.htm
  62. 77. Source: http://www.hse.gov.uk/statistics/causdis/asthma.htm
  63. 78. Sensitisers <ul><li>Skin </li></ul><ul><ul><li>Allergic contact dermatitis </li></ul></ul>
  64. 79. Skin Allergens <ul><li>Nickel salts </li></ul><ul><li>Chromium VI compounds </li></ul><ul><li>Epoxy resins </li></ul><ul><li>Latex </li></ul>
  65. 80. Stops body functioning normally
  66. 81. Classification depends on dose required to cause effect
  67. 82. Toxic hazards <ul><li>Carcinogens </li></ul><ul><ul><li>cause cancer </li></ul></ul><ul><li>Mutagens </li></ul><ul><ul><li>cause genetic damage </li></ul></ul><ul><li>Reproductive Hazards </li></ul><ul><li>Teratogens </li></ul><ul><ul><li>harm the unborn child </li></ul></ul>
  68. 83. Cancer <ul><li>Unregulated growth and proliferation of cells </li></ul>
  69. 84. Cancer <ul><li>Benign tumours </li></ul><ul><li>Malignant tumours </li></ul>
  70. 85. Carcinogens <ul><li>Direct acting or metabolites </li></ul>
  71. 86. Carcinogens <ul><li>Long latency period </li></ul>
  72. 88. Carcinogens <ul><li>Metastasis </li></ul>
  73. 89. Occupational Cancer <ul><li>HSE estimates </li></ul><ul><li>4% of all cancers </li></ul><ul><li>6,000 deaths every year </li></ul>
  74. 90. Carcinogens - CHIP Classification Category 1 Substances known to be carcinogenic in humans R45 May cause cancer Category 2 Evidence of cancer from animal studies R45 May cause cancer Category 3 Suspect carcinogens R40 Limited evidence of a carcinogenic effect
  75. 91. Carcinogens – Some Examples Category 1 Arsenic Asbestos Benzene Benzidine Vinyl chloride monomer R45 May cause cancer Category 2 Beryllium Cadmium oxide Strontium chromate Trichloroethylene R45 May cause cancer Category 3 Chloroform Formaldehyde Hydroquinnone Lead chromate R40 Limited evidence of a carcinogenic effect
  76. 92. IARC Classification <ul><li>Group 1 </li></ul><ul><ul><li>Known human carcinogen </li></ul></ul><ul><li>Group 2A </li></ul><ul><ul><li>Probable human carcinogen </li></ul></ul><ul><li>Group 2B </li></ul><ul><ul><li>Possible human carcinogen </li></ul></ul><ul><li>Group 3 </li></ul><ul><ul><li>Not classifiable for human carcinogenicity </li></ul></ul><ul><li>Group 4 </li></ul><ul><ul><li>Probably not carcinogenic to humans </li></ul></ul>
  77. 93. COSHH Schedule 1 <ul><li>Examples of other substances and processes to which definition of “carcinogen” applies </li></ul>
  78. 94. COSHH Schedule 1 <ul><li>Coal soots, coal tar, pitch, coal tar fumes </li></ul><ul><li>Hardwood dusts </li></ul><ul><li>Leather dust in boot and shoe manufacturing </li></ul><ul><li>Rubber process dust and fume </li></ul><ul><li>Used engine oils </li></ul>
  79. 95. Mutagens <ul><li>Most mutagens also carcinogens </li></ul><ul><li>Not always the case </li></ul><ul><ul><li>e.g. Vanadium pentoxide (not carcinogenic) </li></ul></ul>
  80. 96. Mutagens - CHIP Classification Category 1 Substances known to be mutagenic in humans R46 May heritable genetic damage Category 2 Evidence from animal or in-vitro studies R46 May heritable genetic damage Category 3 Suspected mutagens R68 Possible risk of irreversible effects
  81. 97. Mutagens - CHIP Classification Category 1 R46 May heritable genetic damage Category 2 Butadiene Benzene Sodium chromate R46 May heritable genetic damage Category 3 Aniline Trichloroethylene Vaadium pentoxide R68 Possible risk of irreversible effects
  82. 98. Mixed Exposures <ul><li>Independent effects </li></ul><ul><li>Interactions </li></ul>
  83. 99. Interactions <ul><li>Additive </li></ul><ul><li>Antagonistic </li></ul><ul><li>Synergistic </li></ul><ul><li>Potentiation </li></ul>
  84. 100. Interactions - Independent No interaction
  85. 101. Interactions - Additive The combined effect is equal to the individual sum of the effects Example – Narcotics, usually same target organ same mechanism
  86. 102. Interactions - Synergistic Combined effect is greater than sum of individuals e.g. Ethanol & Carbon tetrachloride
  87. 103. Asbestos and lung cancer (Lung cancer death rates per 100 000 person years) Asbestos worker Smoker Death rate Mortality rate No No 11.3 1 Yes No 58.4 X 5 No Yes 122.8 X 11 Yes Yes 601.6 X 53
  88. 104. Interactions - Potentiation Substance increases the effect of a hazardous substance e.g. Isopropanol & carbon tetrachloride, barbiturates and solvents
  89. 105. Interactions - Antagonistic Substance reduces effect of another substance Cd & Zn – less kidney damage
  90. 107. Median Lethal Dose - LD50 <ul><li>The dose which will kill 50% of a test population </li></ul>
  91. 109. Some LD50s <ul><li>ETHYL ALCOHOL 7060 </li></ul><ul><li>SODIUM CHLORIDE 3000 </li></ul><ul><li>NAPHTHALENE 1760 </li></ul><ul><li>FERROUS SULFATE 1500 </li></ul><ul><li>ASPIRIN 1000 </li></ul><ul><li>FORMALDEHYDE 800 </li></ul><ul><li>AMMONIA 350 </li></ul><ul><li>CAFFEINE 192 </li></ul><ul><li>PHENOBARBITAL 150 </li></ul><ul><li>CHLORPHENIRAMINE MALEATE 118 </li></ul><ul><li>DDT 100 </li></ul><ul><li>STRYCHNINE SULFATE 2 </li></ul><ul><li>NICOTINE 1 </li></ul><ul><li>DIOXIN 0.0001 </li></ul><ul><li>BOTULINUS TOXIN 0.00001 </li></ul>mg/kg body weight
  92. 110. Plot the dose-response curve for the following data dose No. of deaths Group size % deaths 5 0 20 0 10 0 20 0 25 3 20 15 50 7 20 35 100 15 20 75 250 19 20 95 500 20 20 100 1000 20 20 100
  93. 111. Dose response curve for previous data
  94. 114. NOAEL LD50
  95. 115. Toxicity Testing <ul><li>LD50 </li></ul><ul><li>LDLo </li></ul><ul><li>LC50 </li></ul><ul><li>LCLo </li></ul><ul><li>TD50 </li></ul><ul><li>TDLo </li></ul><ul><li>TC50 </li></ul><ul><li>TCLo </li></ul>
  96. 116. Hodge-Sterner Table LD50 Toxicity degree Probable lethal dose <1.0 mg/kg Dangerously Toxic A taste 1-50 mg/kg Seriously Toxic A teaspoon 50-500 mg/kg Highly Toxic An ounce 0.5- 5gm/kg Moderately Toxic A pint 5- 15gm/kg Slightly Toxic A quart >15gm/kg Extremely low Toxicity More than a quart
  97. 118. Some LD50s <ul><li>ETHYL ALCOHOL 7060 </li></ul><ul><li>SODIUM CHLORIDE 3000 </li></ul><ul><li>NAPHTHALENE 1760 </li></ul><ul><li>FERROUS SULPHATE 1500 </li></ul><ul><li>ASPIRIN 1000 </li></ul><ul><li>FORMALDEHYDE 800 </li></ul><ul><li>AMMONIA 350 </li></ul><ul><li>CAFFEINE 192 </li></ul><ul><li>PHENOBARBITAL 150 </li></ul><ul><li>CHLORPHENIRAMINE MALEATE 118 </li></ul><ul><li>DDT 100 </li></ul><ul><li>STRYCHNINE SULPHATE 2 </li></ul><ul><li>NICOTINE 1 </li></ul><ul><li>DIOXIN 0.0001 </li></ul><ul><li>BOTULINUS TOXIN 0.00001 </li></ul>
  98. 121. Toxicological studies are normally carried out over a short timescale.
  99. 122. What are the implications of this?
  100. 123. Skin Irritation <ul><li>Draize test </li></ul><ul><li>Also used for eye irritation </li></ul>
  101. 124. Ames Test <ul><li>Reverse mutagen test </li></ul>
  102. 125. Ames Test <ul><li>90% of known carcinogens are mutagenic in the Ames test </li></ul>
  103. 126. Ames Test <ul><li>Reverse mutation </li></ul>
  104. 127. Ames Test <ul><li>Mutant strain of bacterium Salmonella typhimurium </li></ul>
  105. 128. Ames Test <ul><li>Reverse mutation caused by mutagen results in </li></ul><ul><ul><li>bacteria which can make histidine </li></ul></ul><ul><ul><li>growth of colonies on test plate </li></ul></ul>
  106. 129. Ames Test <ul><li>Some compounds are not mutagenic until metabolised </li></ul><ul><li>Ames test can include liver enzymes </li></ul>
  107. 131. Median Lethal Dose - LD50 <ul><li>Must specify </li></ul><ul><li>Species </li></ul><ul><li>Route of exposure </li></ul><ul><li>Dose per kg body weight </li></ul>