Intro Flashcards
what is toxicology
study of adverse effects of chemicals on living organisms
what is a poison
any agent capable of producing a deleterious response in a biological system
what is “any agent capable of producing a deleterious response in a biological system”
a poison
what is a toxin
toxic substance produced by biological systems
what is “toxic substance produced by biological systems”
a toxin
what is a toxicant
a poison of human origin or as a by-product of human activity
what is “a poison of human origin or as a by-product of human activity”
a toxicant
what is a xenobiotic
any compound not normally part of or synthesized by the organism
what is “any compound not normally part of or synthesized by the organism”
a xenobiotic
what are 4 kinds of things that a graded response can be used for and why
BP, liver weight, drug clearance and pain
because it can assume a variety of values
what does quantal mean (basic)
all or none (so there is or isnt a response)
can you use a dose-response graph for quantal things and why
no because it is all or none
when are quantal dose response relationships typically used for
describing variability in pharmacodynamic responses in populations
what do LD50 experiments measure
death
what do TD50 experiments measure
toxicity
what units are quantal dose-response relationships used in
probits
what are probits (2 words)
probability units
what kind of distribution does quantal responses usually have
normal (Gaussian) distribution
is the cumulative or non cumulative quantal response curve a normal distribution (explain)
non cumulative (cumulative keeps increasing)
how does the non cumulative quantal response curve work
at increasing doses, how many animals of the ones left die at that dose
why does the highest dose have little loses in the non cumulative quantal response curve (shouldn’t it be most death)
not many more animals are still alive at that point
how does the cumulative quantal response curve work
at each new dose, you add the new deaths to the old ones
where is the relatively linear portion of the sigmoidal curve (cumulative mortality graph)
between 16 and 84 % death sections
what does the 16% represent
1 SD from the mean, 50-34
what does the 84% represent
1 SD from the mean, 50+34
what % encompasses 1 SD from the mean on one side
34%
what % encompasses 1 SD from the mean on both sides
68%
what is a normal equivalent deviation (NED)
units of deviation from the mean
how many NED with a 50% response (and why)
0 (it is the mean)
how many NED with a 84% response (and why)
+1 (1 SD from the mean)
how many NED with a 16% response (and why)
-1 (1 SD from the mean)
how do you convert NED to probit units
you add 5
what is the probit units with a 50% response (and why)
5 (0+5) (it is the mean)
what is the probit units with a 84% response (and why)
6 (1+5) (1 SD from the mean)
what is the probit units with a 16% response (and why)
4 (-1+5) (1 SD from the mean)
what are 3 reasons to convert quantal data to a straight line ?
- more convenient to obtain information
- too difficult and costly to describe full sigmoidal curve
how do you find the line of best fit in probit linear curves
linear regression
where in the straight line probit quantal analysis graph thing is the mean
5! (cause you add 5 to get to probits)
what is therapeutic index
a measure of safety, ratio between TD50 and ED50
what is the criticism of TI calculations
the slope of the lines (which reflect potency of xenobiotic) is not taken into account
what does the slope of the line represent
potency of xenobiotic
what may be a good replacement to therapeutic index
margin of safety
how do you calculate margin of safety
TD1/ED99
what does the ratio in MOS represent
TD1/ED99 represents the dose that gives the first signs of toxicity (TD1) and the dose that produces the wanted effects in nearly everyone (ED99)
what does a MOS<100 mean
it is very dangerous (that there is overlap with the effective dose and toxic dose - no good)
what does it mean if the ED50 and TD50 lines overlap
that there is overlap with the effective dose and toxic dose - no good
what does it mean if the ED50 and TD50 lines DO NOT overlap
it is likely safer, there is no overlap with the effective dose and toxic dose
can you have different TIs for a single drug and why?
yes, because it depends on which toxic endpoint is measured (like the diff effects, such as cancer or liver failure)
are LD50 values absolute numbers and why
not really because of the inherent variability of the testing procedure (like weight, age, etc)
what are 6 reasons that LD50 values vary a lot
because of weight, age, duration of observation, route of admin species, strain of species
what is an acceptable range of LD50 values
it can span an order of magnitude
are classic LD50 experiments done anymore and why (4)
no
- no info on chronic
- no info on mechanism
- waste of animals
- more important things than just death
what are some endpoints prior to death that may be more important
non-fatal, like liver kidney and brain damage
what are up-and-down tests used for
approximate lethal dose
how do you do the up and down tests (3 main steps)
- dose one animal
- if survives after 1-2 days, test another animal at a higher dose
- if it doesnt survive dose another one at a lower dose
what do you do in the up and down tests to the animal you test
observe it for 7 days to check for delayed deaths
how do you determine the approximate lethal dose using the up and down tests
the case with the lowest tested dose at which lethality occurs
how many animals are often tested in up and down tests (ALD)
6-8
what does ALD stand for
approximate lethal dose
how many animals are often tested in traditional LD50 tests
40-50! bad
what is a con with the up and down tests (ALD) compared to the traditional LD50 tests
it takes longer time to complete (sequential testing)
what is sequential testing
practice of making decision during an A/B test by sequentially monitoring the data as it happens
what are the 4 durations for exposure
acute, subacute, subchronic, chronic
what is acute exposure
exposure to a chemical for less than 24 hours (traditional LD50 experiments)
what is subacute exposure
repeated exposure for 1 month or less
what is subchronic exposure
repeated exposure for 1-3 months
what is chronic exposure
repeated exposure for more than 3 months
how can toxic effects from acute and chronic exposure differ
like CNS depression immediately, or chronic long term
why must you carefully choose the dose in chronic testing
to prevent premature mortality
what does MTD stand for
maximum tolerable dose
what is maximum tolerable dose
the dose that suppresses gain in body weight over 90 days
what are the 3 main doses used in chronic testing
1MTD
- 5 MTD
- 25 MTD
what will be the maximum dose in animals in chronic testing
a daily dose that results in an area under curve (AUC) that is 25X the AUC for the highest dose in humans that is therapeutically useful (from preliminary pharmacokinetic data from humans)
how long do most carcinogenic potential assays take to do
2 years long
what is the basic reason that it is so hard to know if something causes cancer
because lots of time and animals = $$$$
how many animals are usually used in carcinogenic potential assays
usually like 60, but you may need 1000 to prove a statistical significance
why are rare events difficult to find
because small sample sizes makes it less probable that you will catch the rare event (you need like 600+ to have good odds of catching it
what is an issue with extrapolating what happens with high doses to what may happen with low doses
cause high doses may induce systemic toxicity that is triggering DIFFERENT cellular/systematic events than low doses (those things wouldn’t even happen with those low doses)
what is an example of something that happens with high doses that wouldnt happen in low doses
bladder toxicity, cause the high dose would precipitate in urine and affect the tubules
besides dose, what else makes it hard to extrapolate from animal testing
there are sometimes significant intra and interspecies differences in response to xenobiotics
what is an issue with seeing if drugs cause cancer in animal models
cause there is a high baseline tumor incidence in animals anyways, so you dont know if its just caused by the drug
what is a dose issue with animal models
there is a relatively limited number of doses actually tested
