Lecture 1 6 2010-1
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  • \n
  • Spectrum of effects\n
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  • http://pmep.cce.cornell.edu/profiles/extoxnet/TIB/dose-response.html\n
  • http://pmep.cce.cornell.edu/profiles/extoxnet/TIB/dose-response.html\n
  • http://pmep.cce.cornell.edu/profiles/extoxnet/TIB/dose-response.html\n
  • Allergic reactions are special kinds of changes in the immune system; they are not really toxic responses. The difference between allergies and toxic reactions is that a toxic effect is directly the result of the toxic chemical acting on cells. Allergic responses are the result of a chemical stimulating the body to release natural chemicals which are in turn directly responsible for the effects seen. Thus, in an allergic reaction, the chemical acts merely as a trigger, not as the bullet. \n
  • http://pmep.cce.cornell.edu/profiles/extoxnet/TIB/dose-response.html\n
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  • Toxicity tests are conducted with laboratory animals and the conditions can vary.\n
  • Toxicity tests are conducted with laboratory animals and the conditions can vary.\n
  • Toxicity tests are conducted with laboratory animals and the conditions can vary.\n
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  • Non-lethal dose\n
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  • TLV is usually set to prevent minor toxic effects like skin and eye irritation.\n
  • The therapeutic index (also known as therapeutic ratio), is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects. Quantitatively, it is the ratio given by the toxic dose divided by the therapeutic dose. A commonly used measure of therapeutic index is the toxic dose of a drug for 50% of the population (TD50) divided by the minimum effective dose for 50% of the population (ED50). A high therapeutic index is preferable to a low one: this corresponds to a situation in which one would have to take a much higher amount of a drug to do harm than the amount taken to do good.\nSome antibiotics require monitoring to balance efficacy with minimizing adverse effects, including: gentamicin, vancomycin, amphotericin B, and polymyxin B\n
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  • Dengue fever, malaria, west Nile virus, yellow fever, Encephalitis\n
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Transcript

  • 1. The Dose-Response Relationship
  • 2. Dose –Response Relationship The correlation between exposure and effect of a toxin. The most important fundamental concept in toxicology Essential for the study of toxic material.
  • 3. Assumptions to consider… Response is due to the chemical administered. Response is related to the dose. Chemicals interact with receptor site(s) on a molecule to produce a response. Production and degree of response are related to the concentration of the agent at the reactive site. There is a quantifiable and precise means of expressing the toxicity.
  • 4. "The right dose differentiates a poison and a remedy." - Paracelsus
  • 5. "The right dose differentiates a poison and a remedy." - Paracelsus The science of toxicology is based on the principle that there is a relationship between a toxic reaction (the response) and the amount of poison received (the dose).
  • 6. "The right dose differentiates a poison and a remedy." - Paracelsus The science of toxicology is based on the principle that there is a relationship between a toxic reaction (the response) and the amount of poison received (the dose). An important assumption in this relationship is that there is almost always a dose below which no response occurs or can be measured.
  • 7. "The right dose differentiates a poison and a remedy." - Paracelsus The science of toxicology is based on the principle that there is a relationship between a toxic reaction (the response) and the amount of poison received (the dose). An important assumption in this relationship is that there is almost always a dose below which no response occurs or can be measured. A second assumption is that once a maximum response is reached any further increases in the dose will not result in any increased effect.
  • 8. An exception… One particular instance in which this dose-response relationship does not hold true, is in regard to true allergic reactions.
  • 9. Dose-Response Relationship For all other types of toxicity, knowing the dose- response relationship is a necessary part of understanding the cause and effect relationship between chemical exposure and illness. Keep in mind that the toxicity of a chemical is an inherent quality of the chemical and cannot be changed without changing the chemical to another form. The toxic effects on an organism are related to the amount of exposure.
  • 10. Dose-Response Relationship Biological Variation – variation in response among individuals due to differences in susceptibility among these individuals to chemicals. Hypersusceptible – those that respond to very low doses. Resistant – those that will withstand extremely high doses.
  • 11. Measures of Exposure
  • 12. Measures of Exposure Exposure to poisons can be intentional or unintentional.
  • 13. Measures of Exposure Exposure to poisons can be intentional or unintentional. The effects of exposure to poisons vary with the amount of exposure, which is another way of saying "the dose."
  • 14. Measures of Exposure Exposure to poisons can be intentional or unintentional. The effects of exposure to poisons vary with the amount of exposure, which is another way of saying "the dose." Usually when we think of dose, we think in terms of taking one vitamin capsule a day or two aspirin every four hours, or something like that.
  • 15. Food and Water Contamination Contamination of food or water with chemicals can also provide doses of chemicals each time we eat or drink. These measures tell us how much of the chemical is in food, water or air. The amount we eat, drink, or breathe determines the actual dose we receive.
  • 16. Dose Abbreviation Metric equivalent: Approx. amt. in water – parts per million [ppm] milligrams per kilogram mg/ kg = 1 teaspoon per 1,000 gallons parts per billion [ppb] micrograms per kilogram ug/ kg = 1 teaspoon per 1,000,000 gallons
  • 17. Toxicity Assessment
  • 18. Toxicity Assessment Toxicity assessment is quite complex, many factors can affect the results of toxicity tests.
  • 19. Toxicity Assessment Toxicity assessment is quite complex, many factors can affect the results of toxicity tests. Some of these factors include variables like temperature, food, light, and stressful environmental conditions.
  • 20. Toxicity Assessment Toxicity assessment is quite complex, many factors can affect the results of toxicity tests. Some of these factors include variables like temperature, food, light, and stressful environmental conditions. Other factors related to the animal itself include age, sex, health, and hormonal status.
  • 21. LD50 The amount of a substance sufficient to kill 50% of the test animals  Usually at first experimental  Chemical with low LD50 is highly toxic  Chemical with high LD50 is practically non-toxic  Can be major differences between species and route of exposure.
  • 22. ED50 Statistically derived single dose of a substance that can be expected to cause a non-lethal effect of a defined size in 50% of a given population of organisms
  • 23. NOEL The NOEL (no observable effect level) is the highest dose or exposure level of a poison that produces no noticeable toxic effect on animals. From our previous fish example, we know that there is a dose below which no effect is seen. In toxicology, residue tolerance levels of poisons that are permitted in food or in drinking water, for instance, are usually set from 100 to 1,000 times less than the NOEL to provide a wide margin of safety for humans.
  • 24. Median Dose Dose required to result in response in 50% of a population
  • 25. TLV – Threshold Limit Value Indicates the concentration of a chemical substance in the atmosphere that is considered non-hazardous in a persons normal working life
  • 26. TI – Therapeutic Index The difference between the minimum effective dose and maximum tolerated dose of a drug. The larger the value is, the safer the drug.  = LD50/ED50 Ex: Antidepressants, antibiotics require monitoring to be effective.
  • 27. Potency Refers to the relative amount of drug required to produce the desired response. The potency of a toxic chemical refers to the relative amount it takes to elicit a toxic effect compared with other chemicals.
  • 28. Selective Toxicity An agent is selectively toxic if it harms the invading species without harming the host species. Virus is a host to infectious proteins, mosquitoes are hosts a variety of diseases.
  • 29. Interaction of Chemicals Chemical interactions are known to occur in a variety of ways and by a number of mechanisms affecting one or both chemicals such as: Alterations in absorption Protein binding Biotransformation Excretion
  • 30. Tolerance Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a lessening of one or more of the drugs effects over time. Causes  Decreased amount of toxicant reaching site where effect occurs  Reduced response of a tissue to a chemical