Lecture 3 PART 2: Dose Response

Question 1

Population mean

Answer 1

highest point on n.d- 50% of the pop has responded to the test

Question 2

Probit – Probability Units

Answer 2

We swap the y-axis from cumulative response to deviations away from the mean

Question 3

What does a probit of 5 correspond to?

Answer 3

on a probit plot always corresponds to 50% of the population.
=LD50

Question 4

What is the ED50?

Answer 4

effective dose- where the drug is doing what we want it to do in 50% of the population

Question 5

TD50

Answer 5

where adverse effects start happening in 50% of the population- comparing diff end point (look at where you have toxic effect)

Question 6

therapeutic index (TI)

Answer 6

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

Question 7

Why do we want a high TD50?

Answer 7

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

Question 8

What does a high TI indicate?

Answer 8

=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

Question 9

Potency

Answer 9

the amount required to produce an effect of given intensity-Looking at LD50

Question 10

Efficacy

Answer 10

refers to the maximum response achievable.

• D has a greater efficacy than C

More individuals in the pop. responding

Question 11

NOEC

Answer 11

No Observable Effect Concentration

Ex- if you using mortality as end point the NOEC would be the highest concentration that had no mortality

Question 12

LOEC

Answer 12

Lowest Observable Effect Concentration .

1st concentration where you start to see mortality

Question 13

How do toxicants enter the body?

Answer 13

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

Question 14

nominal dose

Answer 14

the right dosage, what you plan for

Question 15

Measured concentration

Answer 15

are not what you intended to get but what you hit

Question 16

True or false

Nominal concentration is less important than measured concentration

Answer 16

True

Question 17

What other shapes can dose response curves be?

Answer 17

can be U-shaped or inversely U- shaped as well

Question 18

Provide an example of something that would produce a U shaped curve?

Answer 18

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

Question 19

Hormesis

Answer 19

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.

Question 20

Does hormesis apply to all toxicants?

Answer 20

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

Question 21

What are Nonmonotonic dose-response curves?

Answer 21

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.

Answer 22

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

Question 23

Describe Other nonmonotonic dose-response curve shapes

Answer 23

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

Question 24

What the worst case scenario for a toxic event?

Answer 24

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..

Question 25

subchronic bioassay

Answer 25

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.

Question 26

Why do a subchronic test??

Answer 26

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).

Question 27

biomarker

Answer 27

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!!!

Question 28

Biomarkers can include, but are not limited to:

Answer 28

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

Question 29

chronic bioassay

Answer 29

look at longer-term endpoints like cancer development (months to years).

– Determine whether it is a carcinogenic compound.