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71 Cards in this Set

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Define toxicology?
A study of the deleterious effect of chemical substances on living systems.
List 4 categories that fall within the scope of toxicology.
1. Risk Assessment/Safety Evaluation
(Drugs/Food Additives)
(Environmental/Occupational Chemicals)

2. Forensic Toxicology
(Tissues, Food, Air, Soil, Water, etc)

3. Mechanistic Toxicology

4. Clinical Toxicology
What is mechanistic toxicology used for?
To understand mechanisms and develop antidotes.
Exposure may fall under these categories?
1. Intentional vs. Unintentional

2. Voluntary vs. Involuntary
What is the Delaney Amendment of 1958? What does it state?
It is the Food Additive Amendment. It states that no ADDITIVE shall be deemed to be safe it is found to induce cancer when ingested by man OR animal.
What is aflatoxin?
It is a mold/toxin found on peanuts (legumes). It is an extremely potent liver toxin/carcinogen. It is not man made so it is not an additive and is not covered by the Delaney amendment.
What did the EPA state about cancer in 1999?
Information on the biochemical and biological changes that precede tumor development may provide important info in determining w/r a cancer hazard exists. (This relates it to metabolic processes and mechanism of action).
What is a dilemma of the Delaney act? (illustrated by aflatoxin)
We set legal limits for naturally occuring toxins under the Delaney but for additives there is zero tolerance.
The public perspective of toxins is often influenced by what factors?
Ignorance, Misconceptions, and Fears.
The public often believes that natural means what?
Natural means safe
The public often believes that man-made products must be what?
Man-made must be unsafe.
What does safety equal?
Safety = Zero Risk (there is no such thing in real life)
List 4 aspects/reasons of public ignorance and irresponsible actions.
1. Media Sensationalism

2. Poor or No Science for Claims

3. Contradicts Existing Science

4. Exaggerated/Minimize Risks
Who exaggerates risks?
The media.
Who minimizes risks?
Drug companies.
Define poison.
Any substance causing injury by chemical or physico-chemical means.
What is chemophobia?
Fear of chemicals.
What are some of the consequences of fears and misconceptions?
1. Public Fears

2. Complacency with Real Risks

3. Wasted Resources/Economics

4. Human/Environmental Health Impact
All things are what?
All things are poison.
What makes the poison?
Dose makes the poison.
What is the fundamental principle of toxicology?
"The Dose Makes The Poison". There is a Dose-Response relationship.
List 2 dose response assumptions?
1. Compound produces effect

2. Response Magnitude = [f] Dose
"Compound" is aka ? is aka ?.
Compound = Toxicant = Drug
Response magnitude is a function of what?
Response magnitude is a function of the dose.
List three aspects that fall under the assumption that Response Magnitude is a function of dose.
1. There is a molecular receptor or target : "Site of Action"

2. Response and magnitude = [f][C] and duration at site of action

(so how much is there and how long is it there...this is a function of the dose)

3. [C] and duration at site = [f] dose

[Dose-Response Relationship Exists]
Under the assumption that Response Magnitude = [f] Dose what does the dose determine?
Dose determines

1. Response

2. Nature

3. Magnitude

4. Duration

(this is why dose makes the poison)
List 2 expressions of dose.
1. Single Treatment

2. Multiple Treatments
The term Single Treatment is aka what?
"Acute Exposure"
Give examples of how Single Treatments are expressed.
1. mg/mouse (or dog, person, etc.)

2. mg/kg or mg/M^2
Give examples of how Multiple Treatments are expressed.
1. mg/mouse/day (or dog, person, etc.)

2. mg/kg/day or mg/M^2/day
When a toxicant is injected how is the dose estimated?
No estimation is required when a toxicant is injected.
How are doses estimated in food, water, and air (if concentration is known)?
1. Food = Measure Consumption

2. Water = Assume 2 liters/day/person (adult)

3. Air = Tidal Volume = 500ml X 12 breaths/min = 6 L/min/person
(~9000L/day/person in an adult male)
What kind of info is collected using an Acute Lethality Estimate?
Collect qualitative information at same time.
What kind of measurements are Quantal measurements?
All or None, a Defined Endpoint (ex. acute lethality)

ex. lived or died, black/white
ex. bp dropped 10 ml (yes or no)
What kind of measurements are Quantitative measurements?
Clearly defined CONTINOUS scale

(ex. body temp)
(ex. bp dropped an avg of 10ml)
(not yes or no)
In toxicity testing you are looking at ? statistics.
In toxicity testing you are looking at population statistics.
Is death the only toxic response?
Death is not the only toxic response, just the ultimate.
What does MED/MLD stand for?
Median Effective Dose/Median Lethal Dose
What is hormesis?
The term for generally-favorable biological responses to low exposures to toxins and other stressors. On a quantal linear plot this effect produces a U-shaped curve. (see slide 26 in lecture notes)
What does ED50 mean?
The effective dose in 50% of the population.
List the two characteristics of interest for a D-R (dose-response) curve.
1. Slope

2. Threshold
What does the slope of a D-R curve indicate?
1. Mechanism of Action

2. Influence of ADME
What does the threshold of a D-R curve indicate?
Potency
How are ADME and slope related?
The greater the influence of ADME the smaller the slope.
What does 'NED' stand for?
Normal Equivalent Deviations
What is a probit unit?
NED + 5 (on a frequency dist plot)
+ or -1 NED comprises what percentage of a sample in a frequency distribution?
68%
+ or -2 NED comprises what percentage of a sample in a frequency distribution?
95%
+ or -3 NED comprises what percentage of a sample in a frequency distribution?
>99%
What NED unit is at the mean of a frequency distribution? What probit unit is at the mean of a frequency distribution?
The NED is 0. The probit unit is 5 at the mean.
From -1 to +1 NED = what in probit units?
-1 to +1 NED = 4 to 6 probit units.
From -2 to +2 NED = what in probit units?
-2 to +2 NED = 3 to 7 probit units.
From -3 to +3 NED = what in probit units?
-3 to +3 NED = 2 to 8 in probit units.
What does TD50 stand for?
Toxic dose in 50% of the population.
ED50 and LD50 tell us what about a dose?
They ESTIMATE the dose required to cause the defined effect in 50% of the population.
Give an example of what one must be cautious about when analyzing an LD50.
2 times LD25 may not equal an LD50.
List the 6 toxicity classes.
1. Super toxic

2. Extremely toxic

3. Very toxic

4. Moderately toxic

5. Slightly toxic

6. Practically nontoxic
List the EPA Toxicity Descriptors for acute oral, dietary, mammalian (categories).
Category I = very highly or highly toxic

Category II = moderately toxic

Category III = slightly toxic
Category IV = practically non-toxic
As LD50 increases what happens to toxicity?
Toxicity decreases. (Because more drug and less toxic)
If LD50s are similar in many species then it usually means that the toxic substance is what?
1. Attacking a fundamental target system that is critical to life.

2. That it is probably not much affected by ADME.
What are the two things you look for when comparing D-R curves?
1. Slope
(Look for parallelism)

2. Threshold
When slopes display parallelism does it mean that the thresholds are the same?
No.
What does parallelism of slopes suggest?
Suggest (does not prove) similar mechanisms and ADME properties.
Why can't you compare two substances using only LD50?
See slide #37, p. 19. Two substances can share the same LD50 but have different slopes. For example they may have different LD10s.
In Risk Mgmt what do we assume about humans?
We assume humans are as sensitive as the most sensitive animal (unless we have real data on humans, 'human data always trumps animal data')
How do narcotics cause death?
Respiratory depression.
Since respiratory depression causes death what would we assume on a graph with lines representing both resp. dep. and lethality?
Since resp. dep. causes death we would assume that the line represent resp. dep. is parallel to lethality for a given drug in a given species.
When developing a medication what do you want distance between on a D-R curve?
You want as much distance between lines representing pharmacologic effects and toxicologic effects as possible.
What is the eqn for Therapeutic Index?
TI = LD50/ ED50
If one drug has a therapeutic index of 12 and another is 4 which one would you rather take?
TI 12
What is the eqn for margin of safety?
MOS = LD01/ ED99

(lethality in 1% of pop/ effective dose in 99% pop)