7 Analysing Dose-Response Data Flashcards
What are graded DRC used for?
Usually used in PHARMA
* focus on a small organ
* Effect (y-value) is continuous
What are quantal DRC used for?
Usually used for TOXO
* discrete
* for populations
Cooperativity
alteration in binding of subsequent ligands upon binding of an initial ligand by an enzyme/other with multiple binding sites
* the affinity for further binding may be enhanced
Population Dose-Response
Describes the number of individuals responding to given dose
* Quantal
responder vs. non-responder
Responder: subject is killed by dose
Non-responder: subject is not killed
Frequency normal distribution of the responders
- central value = avg. person will be here
- closer to 0 = likely to die
- closer to 100 = likely to live (robust)
Cumulative freq. distribution of responders
Will include specimens that died earlier
Underlying freq. distribution
Use log transformation to approx normal dis.
* X-axis = log scale
* generaly skewed RIGHT if plotted on linear scale
What are the transformations (-1)/x^2 (-1)/x log(x) sqrt(x) used for?
Correcting UPWARD skew
What are the transformations x^2 x^3 antilog(x) used for?
Correcting DOWNWARD skew
What is LD50 used for today?
Assigning labels to classify toxic hazards
* very toxic if swallowed
* toxic if swallowed
* harmful if swallowed
what GHS label is assigned based on LD50?
- very toxic if swallowed < or = 25mg/kg
- toxic if swallowed between 25-200 mg/kg
- harmful if swallowed 200-2000 mg/kg
What can we use to determine lethatility (if it is the desired effect)
LD50!
LD50 – de Lind van Wijngaaden
IV dose compared heart stoppage in each animal
* Noted bell-shaped distribution of dosages required
LD50 Trevan
Was criticised for excessive animal usage but recommended that dose ranges be calculated with few animals > then more 2 confirm
* Identified that midpoint on dose-response curve = dosage to kill 50% of those exposed
LD50 – Chester Intner Bliss
Developed probit analysis
Probit Analysis
Use characteristic of normal dis. to describe what going on with increasing doses
* Convert to Normal Equivalent Deviations
* probit unit 5 = LD50 of curve
Probit line slope analysis
STEEP = small dose ^ produces large mortality rate ^
* POOR safety profile
95% CI
Determine precision of LD50 estimate
LD50 rule of thumb
- Groups of same size
- Dosage groups, 4 to 6 dose levels
- Consider better methods
- c.f. graded dose-response curves and the 20-80% portion of the curve
- Probit analysis is widely used in LD50 calculations and requires fewer animals
