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PMCOL 303 > Intro > Flashcards

Intro Flashcards

1
Q

what is toxicology

A

study of adverse effects of chemicals on living organisms

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2
Q

what is a poison

A

any agent capable of producing a deleterious response in a biological system

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3
Q

what is “any agent capable of producing a deleterious response in a biological system”

A

a poison

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4
Q

what is a toxin

A

toxic substance produced by biological systems

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5
Q

what is “toxic substance produced by biological systems”

A

a toxin

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6
Q

what is a toxicant

A

a poison of human origin or as a by-product of human activity

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7
Q

what is “a poison of human origin or as a by-product of human activity”

A

a toxicant

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8
Q

what is a xenobiotic

A

any compound not normally part of or synthesized by the organism

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9
Q

what is “any compound not normally part of or synthesized by the organism”

A

a xenobiotic

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10
Q

what are 4 kinds of things that a graded response can be used for and why

A

BP, liver weight, drug clearance and pain

because it can assume a variety of values

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11
Q

what does quantal mean (basic)

A

all or none (so there is or isnt a response)

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12
Q

can you use a dose-response graph for quantal things and why

A

no because it is all or none

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13
Q

when are quantal dose response relationships typically used for

A

describing variability in pharmacodynamic responses in populations

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14
Q

what do LD50 experiments measure

A

death

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15
Q

what do TD50 experiments measure

A

toxicity

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16
Q

what units are quantal dose-response relationships used in

A

probits

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17
Q

what are probits (2 words)

A

probability units

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18
Q

what kind of distribution does quantal responses usually have

A

normal (Gaussian) distribution

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19
Q

is the cumulative or non cumulative quantal response curve a normal distribution (explain)

A

non cumulative (cumulative keeps increasing)

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20
Q

how does the non cumulative quantal response curve work

A

at increasing doses, how many animals of the ones left die at that dose

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21
Q

why does the highest dose have little loses in the non cumulative quantal response curve (shouldn’t it be most death)

A

not many more animals are still alive at that point

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22
Q

how does the cumulative quantal response curve work

A

at each new dose, you add the new deaths to the old ones

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23
Q

where is the relatively linear portion of the sigmoidal curve (cumulative mortality graph)

A

between 16 and 84 % death sections

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24
Q

what does the 16% represent

A

1 SD from the mean, 50-34

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25
Q

what does the 84% represent

A

1 SD from the mean, 50+34

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26
Q

what % encompasses 1 SD from the mean on one side

A

34%

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27
Q

what % encompasses 1 SD from the mean on both sides

A

68%

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28
Q

what is a normal equivalent deviation (NED)

A

units of deviation from the mean

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29
Q

how many NED with a 50% response (and why)

A

0 (it is the mean)

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30
Q

how many NED with a 84% response (and why)

A

+1 (1 SD from the mean)

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31
Q

how many NED with a 16% response (and why)

A

-1 (1 SD from the mean)

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32
Q

how do you convert NED to probit units

A

you add 5

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33
Q

what is the probit units with a 50% response (and why)

A

5 (0+5) (it is the mean)

34
Q

what is the probit units with a 84% response (and why)

A

6 (1+5) (1 SD from the mean)

35
Q

what is the probit units with a 16% response (and why)

A

4 (-1+5) (1 SD from the mean)

36
Q

what are 3 reasons to convert quantal data to a straight line ?

A
  • more convenient to obtain information

- too difficult and costly to describe full sigmoidal curve

37
Q

how do you find the line of best fit in probit linear curves

A

linear regression

38
Q

where in the straight line probit quantal analysis graph thing is the mean

A

5! (cause you add 5 to get to probits)

39
Q

what is therapeutic index

A

a measure of safety, ratio between TD50 and ED50

40
Q

what is the criticism of TI calculations

A

the slope of the lines (which reflect potency of xenobiotic) is not taken into account

41
Q

what does the slope of the line represent

A

potency of xenobiotic

42
Q

what may be a good replacement to therapeutic index

A

margin of safety

43
Q

how do you calculate margin of safety

A

TD1/ED99

44
Q

what does the ratio in MOS represent

A

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)

45
Q

what does a MOS<100 mean

A

it is very dangerous (that there is overlap with the effective dose and toxic dose - no good)

46
Q

what does it mean if the ED50 and TD50 lines overlap

A

that there is overlap with the effective dose and toxic dose - no good

47
Q

what does it mean if the ED50 and TD50 lines DO NOT overlap

A

it is likely safer, there is no overlap with the effective dose and toxic dose

48
Q

can you have different TIs for a single drug and why?

A

yes, because it depends on which toxic endpoint is measured (like the diff effects, such as cancer or liver failure)

49
Q

are LD50 values absolute numbers and why

A

not really because of the inherent variability of the testing procedure (like weight, age, etc)

50
Q

what are 6 reasons that LD50 values vary a lot

A

because of weight, age, duration of observation, route of admin species, strain of species

51
Q

what is an acceptable range of LD50 values

A

it can span an order of magnitude

52
Q

are classic LD50 experiments done anymore and why (4)

A

no

  • no info on chronic
  • no info on mechanism
  • waste of animals
  • more important things than just death
53
Q

what are some endpoints prior to death that may be more important

A

non-fatal, like liver kidney and brain damage

54
Q

what are up-and-down tests used for

A

approximate lethal dose

55
Q

how do you do the up and down tests (3 main steps)

A
  • 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
56
Q

what do you do in the up and down tests to the animal you test

A

observe it for 7 days to check for delayed deaths

57
Q

how do you determine the approximate lethal dose using the up and down tests

A

the case with the lowest tested dose at which lethality occurs

58
Q

how many animals are often tested in up and down tests (ALD)

A

6-8

59
Q

what does ALD stand for

A

approximate lethal dose

60
Q

how many animals are often tested in traditional LD50 tests

A

40-50! bad

61
Q

what is a con with the up and down tests (ALD) compared to the traditional LD50 tests

A

it takes longer time to complete (sequential testing)

62
Q

what is sequential testing

A

practice of making decision during an A/B test by sequentially monitoring the data as it happens

63
Q

what are the 4 durations for exposure

A

acute, subacute, subchronic, chronic

64
Q

what is acute exposure

A

exposure to a chemical for less than 24 hours (traditional LD50 experiments)

65
Q

what is subacute exposure

A

repeated exposure for 1 month or less

66
Q

what is subchronic exposure

A

repeated exposure for 1-3 months

67
Q

what is chronic exposure

A

repeated exposure for more than 3 months

68
Q

how can toxic effects from acute and chronic exposure differ

A

like CNS depression immediately, or chronic long term

69
Q

why must you carefully choose the dose in chronic testing

A

to prevent premature mortality

70
Q

what does MTD stand for

A

maximum tolerable dose

71
Q

what is maximum tolerable dose

A

the dose that suppresses gain in body weight over 90 days

72
Q

what are the 3 main doses used in chronic testing

A

1MTD

  1. 5 MTD
  2. 25 MTD
73
Q

what will be the maximum dose in animals in chronic testing

A

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)

74
Q

how long do most carcinogenic potential assays take to do

A

2 years long

75
Q

what is the basic reason that it is so hard to know if something causes cancer

A

because lots of time and animals = $$$$

76
Q

how many animals are usually used in carcinogenic potential assays

A

usually like 60, but you may need 1000 to prove a statistical significance

77
Q

why are rare events difficult to find

A

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

78
Q

what is an issue with extrapolating what happens with high doses to what may happen with low doses

A

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)

79
Q

what is an example of something that happens with high doses that wouldnt happen in low doses

A

bladder toxicity, cause the high dose would precipitate in urine and affect the tubules

80
Q

besides dose, what else makes it hard to extrapolate from animal testing

A

there are sometimes significant intra and interspecies differences in response to xenobiotics

81
Q

what is an issue with seeing if drugs cause cancer in animal models

A

cause there is a high baseline tumor incidence in animals anyways, so you dont know if its just caused by the drug

82
Q

what is a dose issue with animal models

A

there is a relatively limited number of doses actually tested

PMCOL 303 (25 decks)

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