Introduction To Toxicology
Download as PPT, PDF49 likes24,643 views
The document discusses various topics related to toxicology including: - Absorption, distribution, metabolism and excretion of chemicals in the body - Factors that affect absorption such as routes of entry and chemical properties - Threshold doses and variability in individual susceptibility - Acute and chronic effects of toxins - Carcinogens and mutagens and their classification - Dose-response relationships and metrics like LD50 - Toxicity testing methods including the Ames test
Introduction To Toxicology
- 1. Mike Slater Diamond Environmental Ltd
- 2. "All substances are poisons ; there is none which is not a poison. The right dose differentiates a poison from a remedy"
- 4. Homeostasis Chemical reactions which maintain very stable body chemistry against a background of constant environmental change
- 5. Inhalation Skin contact Ingestion
- 8. Absorption Absorbed dose is generally a fraction of exposure dose Toxicant must be able to cross cell membranes
- 9. Factors Affecting Absorption Degree of exposure Routes of entry Properties of chemical
- 10. Absorption Through the Lungs Amount of air inhaled Gases Aerosols
- 12. Particle Deposition Interception Impaction Sedimentation Diffusion
- 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
- 14. Particle Deposition Falling speed is proportional to the density of the particle the square of its diameter
- 15. Aerodynamic Diameter The diameter of a sphere of unit density (i.e. a water droplet) that has the same falling speed as the real particle
- 18. Absorption Through Skin Absorption depends on lipid solubility Uptake greater if skin damaged Uptake varies
- 19. Absorption Through Skin Many organic compounds readily absorbed solvents pesticides organo-metal compounds
- 20. Absorption Through Gut Better absorption with un-ionised, fat soluble substances
- 21. Absorption Through Gut Stomach Acidic Acidic compounds absorbed
- 22. Absorption Through Gut Intestine Alkaline Alkaline compounds absorbed
- 23. Distribution Transport by blood Rate Substances released from storage
- 24. Storage Fat lipophilic compounds e.g. some pesticides (DDT), dioxins, PCBs Bones chemicals similar to calcium fluorine, lead, strontium Blood Liver and kidney Other organs / tissues
- 25. Biotransformation Occurs mainly in liver Also in lungs, kidney & intestine
- 26. Biotransformation Catalysed by enzymes including Cytochrome P450
- 27. Biotransformation Increases water solubility for excretion via kidney
- 28. Biotransformation Metabolites or intermediaries can be toxic
- 29. Phase I reactions Oxidation Reduction hydrolysis Phase II reactions Conjugation Synthesis Metabolites Elimination
- 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
- 31. Biotransformation Sometimes biotransformation increases toxicity
- 32. Biotransformation Examples Benzene n-hexane Methanol Dichloromethane carbon monoxide formed
- 33. Excretion Kidney urine water soluble compounds
- 34. Excretion Lungs volatile compounds gaseous metabolites
- 35. Excretion Liver bile fat soluble compounds
- 36. Excretion Other routes Hair Nails Skin Sweat Milk
- 37. Excretion - the Kidneys Filters the blood of its small molecules and ions and then ...
- 38. Excretion - the Kidneys Reclaims useful materials
- 39. Excretion - the Kidneys Surplus or waste molecules and ions flow out as urine
- 40. Biological Half Life Time taken for half the amount of the substance absorbed to be excreted
- 42. Some Half Lives Toluene ~ 10 hours Selenium ~ 10 days Mercury ~ 6 weeks Cadmium ~ 10 years or more
- 43. Half Lives Mineral dusts Metal compounds Organic solvents & inorganic gases Amphibole asbestos is particularly biopersistent Can remain in lungs for decades
- 47. Threshold Dose
- 48. Threshold Dose The point at which toxicity first appears NOAEL "no observed adverse effect level"
- 49. Susceptibility Variation in susceptibility between individuals Different doses required to produce same effect
- 50. Susceptibility Most susceptible groups include Elderly, Children, People with pre-existing disease Inter-species variation
- 54. Stochastic Effects Probabilistic Increasing probability of effect with increasing dose e.g. carcinogens
- 58. Types of Effect Local at point of contact with the body Systemic following distribution
- 59. Types of Effect chronic sub-chronic sub-acute acute timescale
- 60. Exposure and Effect Acute < 24hr usually 1 exposure Subacute 1 month repeated doses Subchronic 1-3 months repeated doses Chronic > 3months repeated doses
- 61. Harmful Effects Asphyxiant Irritant Corrosive Narcotic Sensitiser Toxic Carcinogen Mutagen Teratogen
- 62. Simple Asphyxiants Inert gases Reduce oxygen concentration in air e.g. nitrogen, argon
- 63. Oxygen Level Effect 21% Normal atmospheric concentration 18% Minimum “acceptable” concentration 17% Breathing faster & deeper 16.25% Flame safety lamp will extinguish 15% Dizziness, buzzing noise, rapid pulse, headache, blurred vision 9% Unconsciousness 6% Breathing stops, cardiac arrest
- 64. Chemical Asphyxiants Interference with oxygen transport, or utilisation of oxygen
- 65. Chemical Asphyxiants Carbon monoxide carboxyhaemoglobin
- 66. Chemical Asphyxiants Methaemoglobin oxidation of haemoglobin Fe2+ to Fe3+ Aniline Nitrobenzene Nitrites
- 67. Chemical Asphyxiants Haemolytic agents destroy blood cells arsine, stibene
- 68. Chemical Asphyxiants Inhibition of cellular respiration cyanide hydrogen sulphide
- 69. Causes local inflammation of tissue
- 70. Destroys tissue
- 71. Depresses Central Nervous System Causes dizziness, nausea, drowsiness
- 72. Causes an allergic reaction in susceptible people
- 73. Sensitisers Cause allergic reaction in susceptible individuals Cannot identify susceptible individuals! Usually develops gradually Not always easy to identify causative agent
- 74. Sensitisers – CHIP Classifications R42 May cause sensitisation by inhalation R43 May cause sensitisation by skin contact
- 75. Sensitisers Respiratory Rhinitis Asthma Allergic alveolitis
- 78. Sensitisers Skin Allergic contact dermatitis
- 79. Skin Allergens Nickel salts Chromium VI compounds Epoxy resins Latex
- 80. Stops body functioning normally
- 81. Classification depends on dose required to cause effect
- 82. Toxic hazards Carcinogens cause cancer Mutagens cause genetic damage Reproductive Hazards Teratogens harm the unborn child
- 83. Cancer Unregulated growth and proliferation of cells
- 84. Cancer Benign tumours Malignant tumours
- 85. Carcinogens Direct acting or metabolites
- 86. Carcinogens Long latency period
- 89. Occupational Cancer HSE estimates 4% of all cancers 6,000 deaths every year
- 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
- 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
- 92. IARC Classification Group 1 Known human carcinogen Group 2A Probable human carcinogen Group 2B Possible human carcinogen Group 3 Not classifiable for human carcinogenicity Group 4 Probably not carcinogenic to humans
- 93. COSHH Schedule 1 Examples of other substances and processes to which definition of “carcinogen” applies
- 94. COSHH Schedule 1 Coal soots, coal tar, pitch, coal tar fumes Hardwood dusts Leather dust in boot and shoe manufacturing Rubber process dust and fume Used engine oils
- 95. Mutagens Most mutagens also carcinogens Not always the case e.g. Vanadium pentoxide (not carcinogenic)
- 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
- 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
- 98. Mixed Exposures Independent effects Interactions
- 99. Interactions Additive Antagonistic Synergistic Potentiation
- 100. Interactions - Independent No interaction
- 101. Interactions - Additive The combined effect is equal to the individual sum of the effects Example – Narcotics, usually same target organ same mechanism
- 102. Interactions - Synergistic Combined effect is greater than sum of individuals e.g. Ethanol & Carbon tetrachloride
- 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
- 104. Interactions - Potentiation Substance increases the effect of a hazardous substance e.g. Isopropanol & carbon tetrachloride, barbiturates and solvents
- 105. Interactions - Antagonistic Substance reduces effect of another substance Cd & Zn – less kidney damage
- 107. Median Lethal Dose - LD50 The dose which will kill 50% of a test population
- 109. Some LD50s ETHYL ALCOHOL 7060 SODIUM CHLORIDE 3000 NAPHTHALENE 1760 FERROUS SULFATE 1500 ASPIRIN 1000 FORMALDEHYDE 800 AMMONIA 350 CAFFEINE 192 PHENOBARBITAL 150 CHLORPHENIRAMINE MALEATE 118 DDT 100 STRYCHNINE SULFATE 2 NICOTINE 1 DIOXIN 0.0001 BOTULINUS TOXIN 0.00001 mg/kg body weight
- 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
- 111. Dose response curve for previous data
- 114. NOAEL LD50
- 115. Toxicity Testing LD50 LDLo LC50 LCLo TD50 TDLo TC50 TCLo
- 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
- 118. Some LD50s ETHYL ALCOHOL 7060 SODIUM CHLORIDE 3000 NAPHTHALENE 1760 FERROUS SULPHATE 1500 ASPIRIN 1000 FORMALDEHYDE 800 AMMONIA 350 CAFFEINE 192 PHENOBARBITAL 150 CHLORPHENIRAMINE MALEATE 118 DDT 100 STRYCHNINE SULPHATE 2 NICOTINE 1 DIOXIN 0.0001 BOTULINUS TOXIN 0.00001
- 121. Toxicological studies are normally carried out over a short timescale.
- 122. What are the implications of this?
- 123. Skin Irritation Draize test Also used for eye irritation
- 124. Ames Test Reverse mutagen test
- 125. Ames Test 90% of known carcinogens are mutagenic in the Ames test
- 126. Ames Test Reverse mutation
- 127. Ames Test Mutant strain of bacterium Salmonella typhimurium
- 128. Ames Test Reverse mutation caused by mutagen results in bacteria which can make histidine growth of colonies on test plate
- 129. Ames Test Some compounds are not mutagenic until metabolised Ames test can include liver enzymes
- 131. Median Lethal Dose - LD50 Must specify Species Route of exposure Dose per kg body weight