Lecture 3 PART 2: Dose Response Flashcards
Population mean
highest point on n.d- 50% of the pop has responded to the test
Probit – Probability Units
We swap the y-axis from cumulative response to deviations away from the mean
What does a probit of 5 correspond to?
on a probit plot always corresponds to 50% of the population.
=LD50
What is the ED50?
effective dose- where the drug is doing what we want it to do in 50% of the population
TD50
where adverse effects start happening in 50% of the population- comparing diff end point (look at where you have toxic effect)
therapeutic index (TI)
is the ratio of TD50 and ED50
High values mean that the drug is relatively safe.
Low values usually lead to the rejection of the drug from further clinical testing.
TD50/ ED50
Why do we want a high TD50?
You want the concentration that produces the adverse effect to be quite a bit higher than what we use for actual effectives doses
Want a high TD50 to your ED50- TO MAKE SURE YOU HAVE A LARGE DIFF AWAY FROM WHAT THE DRUG WOULD BEGIN PRODUCING AN ADVERSE EFFECT ON THE ANIMAL
If TD is higher that means you need a higher concentration to be toxic
produce good results at low dose you want the dose that does harm to be way more than the dose that does good
toxic dose should be higher so that someone doesn’t accidentally overprescribe or over consume and suffer toxic effects
if TD50 is higher than ED50, the toxic dose is far from the effective dose so you have a lower chance of overdose
What does a high TI indicate?
=concentration to produce a toxic effect compared with the effective dose is quite different- produces high value for a therapeutic index tells us it relatively safe for public to consume this particular drug
Potency
the amount required to produce an effect of given intensity-Looking at LD50
Efficacy
refers to the maximum response achievable.
- D has a greater efficacy than C
More individuals in the pop. responding
NOEC
No Observable Effect Concentration
Ex- if you using mortality as end point the NOEC would be the highest concentration that had no mortality
LOEC
Lowest Observable Effect Concentration .
1st concentration where you start to see mortality
How do toxicants enter the body?
many toxicants are hydrophobic or lipophilic…
• Often use a “vehicle” or “carrier” to distribute the contaminant to the animals
For aquatic testing hydrophobic compound would need a carrier
Butter is an ex of a compound that can admin a hydrophobic compound in the body
Baking with weed oil you want to infuse that with butter before using it with baking
In reality you want to use some type of industrial solvent when we mix the hydrophobic compounds before we admin into aquatic tanks
nominal dose
the right dosage, what you plan for
Measured concentration
are not what you intended to get but what you hit
True or false
Nominal concentration is less important than measured concentration
True
What other shapes can dose response curves be?
can be U-shaped or inversely U- shaped as well
Provide an example of something that would produce a U shaped curve?
Some essential nutrients can have adverse effects at low and high doses (e.g., iron, chromium, vitamin A and D)
We need essential nutrients from our diet and if we aren’t getting enough of then that can lead to some harmful adverse outcome
Hormesis
can refer to some types of dose-response curves.
Compounds that are beneficial/stimulatory at low doses but toxic at high doses.- produces non linear relationships
Ex- medication- warfarin is a blood thinner used for heart attacks but is also a rat poison- at low doses we use it as a pharmaceutical if you increase it to much than its toxic
This may also apply to some non- nutritional toxins (e.g., ethanol).
- one glass of wine a day tends to have health benefits but to much in a day everyday can cause adverse outcomes
Think of the people who say they play pool better when they drink beer - up until a certain point!
- But the alcohol consumption example is really about chronic consumption.
Does hormesis apply to all toxicants?
This is NOT appropriate for most toxicants (i.e., xenobiotics)
Any type of exposure to a xenobiotic is never beneficial , although stimulatory response its not beneficial
What are Nonmonotonic dose-response curves?
non linear
Often observed with EDCs(endocrine disrupting compounds): toxicants that can have effects at very low levels (i.e., ng/L!).
This relationship is common when talking about hormone signaling and ed compounds
At low levels they interact with a hormonal receptor, leading to a response.
- Can have positive feedback.
At high levels, the receptor can become ‘burned out’, thus the response decreases.
Highlights the danger of extrapolating the effects of high doses to low dose responses.
This relationship is common when talking about hormone signaling and ed compounds
Estrogen mimicking compounds can bind to the estrogen receptor- the target gene that gets transcribed bc the of the compound binding to the receptor causes the cell to produce more estrogen receptors which causes them to respond to more estrogen that helps to produce significant effect even at low concentrations
Describe Other nonmonotonic dose-response curve shapes
Basically curves that are not straight lines
These may indicate thresholds in the response
The inflection points in the dose response curve reflect a physiological threshold in how the animal is responding- when you pass the threshold that’s when you start to cause an adverse effect on the animal
What the worst case scenario for a toxic event?
Death is the worst case scenario for a toxic event!
But usually acute lethality studies are conducted first.
A lot of time animals don’t die and we respond even though we arent dying
• Many (most) toxic events occur before the animals die..
subchronic bioassay
conducted at lower doses than seen in acute lethality tests. Often with more than 1 species at different doses (i.e., 3 doses):
Can use acute exposures to figure out dosing regime for sub chronic bioassays
High dose that causes toxicity, but not more than 10% fatalities (i.e., ≤LC10).
An intermediate dose.
Low dose that should cause no toxic effects.
And a control. Always have control
Exposures for longer periods of time (weeks to months).
• e.g., 90 days.
Why do a subchronic test??
To provide information on all types of sublethal toxicity (other than carcinogenicity) that might occur.
– immunotoxicity, neurotoxicity
To establish dose regimens for chronic studies.
Provide data which will allow an estimate to be made of the MTD (maximum tolerable dose), where there is no significant impairment of growth.
To develop biomarkers of exposure (e.g., gene expression, specific enzyme function).
biomarker
can be described as a cellular or biochemical hormonal response to a toxicant that is measurable in a biological system or sample.
– There are biomarkers to other types of stressors, such as temperature in fish!!!
Biomarkers can include, but are not limited to:
Enzyme activity
Certain enzymes in the blood can indicate liver toxicity
Increase in cytochrome P450 activity for detoxification
Metallothionein induction to bind heavy metals with a 2+ charge
Changes in cellular receptor amount and activity
Estrogen receptor in response to EDCs
iii. Changes in hormone levels
• Increase in cortisol (the ‘stress hormone’)
Iv. increased expression of genes that respond to toxicants
v. Changes in the cell structure to detect cellular damage using histology
chronic bioassay
look at longer-term endpoints like cancer development (months to years).
– Determine whether it is a carcinogenic compound.
