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ACUTE INHALATION TOXICOLOGY

ACUTE INHALATION TOXICOLOGY. Yves Alarie, Ph.D Professor Emeritus U niversity of Pittsburgh,USA. A. LC 50

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ACUTE INHALATION TOXICOLOGY

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  1. ACUTE INHALATION TOXICOLOGY YvesAlarie, Ph.D Professor Emeritus University of Pittsburgh,USA

  2. A. LC50 • LC50 is the atmospheric concentration, statistically estimated, to kill 50% of the animals when exposed for a fixed time period and observed for a specified post-exposure observation period.

  3. ¯¯¯¯¯Deaths EXPOSURE POST-EXPOSURE¯¯¯¯¯¯Deaths Exposure: 1hour,Observation period 14 days Exposure :4 hours, Observation Period 14 days Exposure Time: Fixed Concentrations: Variable, to arrive at lethality between 0 and 100%

  4. The LT50 is the time for 50% of the animals to die at a particular exposure concentration, also called median time to death. Often used for saturated vapor concentration of a liquid (i.e., maximum amount that can be present in air) to simulate a spill. Not a measure of toxicity (potency) because the answer is time, not amount. It is not a statistically calculated number with 95% C.I. as with the LC50. B. LT50

  5. ¯¯¯¯¯5/9 deaths EXPOSURE POST-EXPOSURE¯¯¯¯¯5/9 deaths Time: Variable Concentration: Fixed, usually the maximum that can exist, i.e., Cs Fast acting, slow acting, hazard concept at a particular exposure concentration

  6. C. LCT50 LCT50 = mg ´ min/m3 or ppm ´ min, i.e., concentration ´ time of exposure. Used to compare apples and oranges. For example, the 60-minute LC50 for chemical A is 100 ppm when the observation period is 7 days. Therefore the LCT50 is 6,000 ppm ´ min. The 10-minute LC50 for chemical B is 600 ppm when the observation period is 7 days. Therefore the LCT50 is 6,000 ppm ´ min. Since the LCT50 is 6,000 ppm ´ min for both chemical A and B it is then concluded that they are equally toxic.

  7. D. HABER’S RULE, WORKS WITHIN LIMITED RANGE Level of Response: C ´ T = k, i.e. exposure concentration ´ duration of exposure being a constant, the same level of response will be obtained. Can be used only for the same chemical, not to compare chemicals. Varying C or T within a factor of 2 or 3 will be fine to predict the level of effect. Will not work with substances having obvious threshold (CO, HCN) unless quite above threshold. Works better with progressive, cumulative effect (O3, COCI2), which is the type of work Haber was doing, i.e., pulmonary toxicity of COCI2 when he proposed this concept.

  8. Table 5. Haber’s Rule Haber’s Rule 10 mg/m3´ 10 min, C´T = 100 = 50% mortality 5 mg/m3´ 20 min, C´T = 100 = 50% mortality 1 mg/m3´ 100 min, C´T = 100 = Probably 0% mortality

  9. E. BESTFix the duration of exposure, according to situations you want to model (i.e. spills, workday, etc.). Various concentrations are then used to obtain concentration-response relationship.For LC50 determination try to get deaths toward end of exposure or beginning of post-exposure period (no more than 1/3 of the duration of exposure). Calculate LC50.Also observe animals for 14 days (or appropriate period) and calculate LC50 including this longer post-exposure period. Ratio of the two LC50s gives indication of delayed toxicity.

  10. F. SECOND BESTWhen it is mechanically impossible to generate concentrations high enough for acute lethality to occur for the exposure period of interest, the duration of exposure can be increased so that lethality is achieved. However, increasing the duration by a factor of 2 or 3 above the desired duration is risky, as explained above.

  11. G. COMPARING LC50a) Regardless of statistical significance, LC50 for two materials are comparable if within a factor of 3.b) If above a factor of 3: start to think about it.c) If above a factor of 10: will definitely make a difference in real life situations.

  12. H. COMPARING LT50 No good general rule. Use LT50 to compare rapidity of effect of two chemicals at similar exposure concentration or for two chemicals for the same situation, i.e. saturated vapor, to get an idea of tenability limits, hazard concept.

  13. When comparing LT50, make sure that you are comparing the same level of effect. For example, 9 rats are exposed for 4 hours to a saturated vapor atmosphere of chemical A or chemical B. For material A the 5th death occurred at 2 hours and the 6th death occurred by 4 hours with no further deaths after exposure. For material B the 5th death occurred at 2 hours and all the animals were dead by 3 hours. Comparing LT50 is a very tricky business. Both chemicals would have the same LT50, i.e., 2 hours. However the total number of deaths is not the same. Dr. Smyth tried to arrive at some general rule to compare LT50 but was never able to find one. Therefore the LT50 value is information that is useful for a particular chemical, rather than for comparing chemicals.

  14. I. COMPARING BOTH LC50 AND LT50 SIMULTANEOUSLY • This requires that a “standard” be used and then comparisons are made to the standard. First a period of time must be selected, relevant to the situation to be investigated. In the example below, 30 minutes was selected for the exposure period and 10 minutes for the post-exposure period. Then the LC50 was determined, arranging so that 50% of the animals died close to the end of the exposure period. This time will be the LT50, 22 minutes in the example given below, for wood smoke taken as the “standard” material.

  15. This concept of concentration to produce a given level of effect and time required to do so does not belong only to inhalation experiments. It is also of importance in chronic studies when considering the dose to produce 50% effect (such as tumors) and the time required for this given level of effect to occur. The same applies in aquatic toxicology.

  16. J. USE OF LC50 AND LT50 IN REGULATIONS As far as I know LT50 is not used. LC50 is used (among other data) by the Occupational Safety and Health Administration (OSHA) and by the National Institute for Occupational Safety and Health (NIOSH) to establish “Immediately Dangerous to Life or Health (IDLH)” Concentrations. See www.cdc.gov/niosh/idlh for documentation.

  17. Unfortunately there are 3 definitions for IDLH depending upon circumstances: • 1) hazardous waste and emergency response regulation (OSHA) • 2) permit-required confined spaces regulation (OSHA) • 3) respirator selection process (NIOSH)

  18. K. EXPRESSION OF TOXICITY • Dose = mg/kg body weight (proper terminology is body mass but seldom used by toxicologists) • Dose = mg/m2 body surface area • Dose = mg/m2 lung surface area • Dose = mg/ml of blood

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