ACUTE INHALATION TOXICOLOGY

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ACUTE INHALATION TOXICOLOGY
Yves Alarie, Ph.D Professor Emeritus
University of Pittsburgh,USA
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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.
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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
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• B. LT50

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.
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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
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• 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.

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• D. HABERS 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.

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Table 5. Habers Rule Habers Rule 10 mg/m3
10 min, CT 100 50 mortality 5 mg/m3 20
min, CT 100 50 mortality 1 mg/m3 100
min, CT 100 Probably 0 mortality
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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.
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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)
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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