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71 Cards in this Set
- Front
- Back
Define toxicology?
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A study of the deleterious effect of chemical substances on living systems.
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List 4 categories that fall within the scope of toxicology.
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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 |
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What is mechanistic toxicology used for?
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To understand mechanisms and develop antidotes.
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Exposure may fall under these categories?
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1. Intentional vs. Unintentional
2. Voluntary vs. Involuntary |
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What is the Delaney Amendment of 1958? What does it state?
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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.
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What is aflatoxin?
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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.
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What did the EPA state about cancer in 1999?
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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).
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What is a dilemma of the Delaney act? (illustrated by aflatoxin)
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We set legal limits for naturally occuring toxins under the Delaney but for additives there is zero tolerance.
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The public perspective of toxins is often influenced by what factors?
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Ignorance, Misconceptions, and Fears.
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The public often believes that natural means what?
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Natural means safe
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The public often believes that man-made products must be what?
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Man-made must be unsafe.
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What does safety equal?
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Safety = Zero Risk (there is no such thing in real life)
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List 4 aspects/reasons of public ignorance and irresponsible actions.
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1. Media Sensationalism
2. Poor or No Science for Claims 3. Contradicts Existing Science 4. Exaggerated/Minimize Risks |
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Who exaggerates risks?
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The media.
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Who minimizes risks?
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Drug companies.
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Define poison.
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Any substance causing injury by chemical or physico-chemical means.
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What is chemophobia?
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Fear of chemicals.
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What are some of the consequences of fears and misconceptions?
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1. Public Fears
2. Complacency with Real Risks 3. Wasted Resources/Economics 4. Human/Environmental Health Impact |
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All things are what?
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All things are poison.
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What makes the poison?
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Dose makes the poison.
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What is the fundamental principle of toxicology?
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"The Dose Makes The Poison". There is a Dose-Response relationship.
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List 2 dose response assumptions?
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1. Compound produces effect
2. Response Magnitude = [f] Dose |
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"Compound" is aka ? is aka ?.
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Compound = Toxicant = Drug
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Response magnitude is a function of what?
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Response magnitude is a function of the dose.
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List three aspects that fall under the assumption that Response Magnitude is a function of dose.
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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] |
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Under the assumption that Response Magnitude = [f] Dose what does the dose determine?
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Dose determines
1. Response 2. Nature 3. Magnitude 4. Duration (this is why dose makes the poison) |
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List 2 expressions of dose.
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1. Single Treatment
2. Multiple Treatments |
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The term Single Treatment is aka what?
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"Acute Exposure"
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Give examples of how Single Treatments are expressed.
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1. mg/mouse (or dog, person, etc.)
2. mg/kg or mg/M^2 |
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Give examples of how Multiple Treatments are expressed.
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1. mg/mouse/day (or dog, person, etc.)
2. mg/kg/day or mg/M^2/day |
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When a toxicant is injected how is the dose estimated?
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No estimation is required when a toxicant is injected.
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How are doses estimated in food, water, and air (if concentration is known)?
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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) |
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What kind of info is collected using an Acute Lethality Estimate?
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Collect qualitative information at same time.
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What kind of measurements are Quantal measurements?
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All or None, a Defined Endpoint (ex. acute lethality)
ex. lived or died, black/white ex. bp dropped 10 ml (yes or no) |
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What kind of measurements are Quantitative measurements?
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Clearly defined CONTINOUS scale
(ex. body temp) (ex. bp dropped an avg of 10ml) (not yes or no) |
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In toxicity testing you are looking at ? statistics.
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In toxicity testing you are looking at population statistics.
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Is death the only toxic response?
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Death is not the only toxic response, just the ultimate.
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What does MED/MLD stand for?
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Median Effective Dose/Median Lethal Dose
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What is hormesis?
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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)
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What does ED50 mean?
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The effective dose in 50% of the population.
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List the two characteristics of interest for a D-R (dose-response) curve.
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1. Slope
2. Threshold |
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What does the slope of a D-R curve indicate?
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1. Mechanism of Action
2. Influence of ADME |
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What does the threshold of a D-R curve indicate?
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Potency
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How are ADME and slope related?
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The greater the influence of ADME the smaller the slope.
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What does 'NED' stand for?
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Normal Equivalent Deviations
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What is a probit unit?
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NED + 5 (on a frequency dist plot)
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+ or -1 NED comprises what percentage of a sample in a frequency distribution?
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68%
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+ or -2 NED comprises what percentage of a sample in a frequency distribution?
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95%
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+ or -3 NED comprises what percentage of a sample in a frequency distribution?
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>99%
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What NED unit is at the mean of a frequency distribution? What probit unit is at the mean of a frequency distribution?
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The NED is 0. The probit unit is 5 at the mean.
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From -1 to +1 NED = what in probit units?
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-1 to +1 NED = 4 to 6 probit units.
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From -2 to +2 NED = what in probit units?
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-2 to +2 NED = 3 to 7 probit units.
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From -3 to +3 NED = what in probit units?
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-3 to +3 NED = 2 to 8 in probit units.
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What does TD50 stand for?
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Toxic dose in 50% of the population.
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ED50 and LD50 tell us what about a dose?
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They ESTIMATE the dose required to cause the defined effect in 50% of the population.
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Give an example of what one must be cautious about when analyzing an LD50.
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2 times LD25 may not equal an LD50.
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List the 6 toxicity classes.
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1. Super toxic
2. Extremely toxic 3. Very toxic 4. Moderately toxic 5. Slightly toxic 6. Practically nontoxic |
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List the EPA Toxicity Descriptors for acute oral, dietary, mammalian (categories).
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Category I = very highly or highly toxic
Category II = moderately toxic Category III = slightly toxic Category IV = practically non-toxic |
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As LD50 increases what happens to toxicity?
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Toxicity decreases. (Because more drug and less toxic)
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If LD50s are similar in many species then it usually means that the toxic substance is what?
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1. Attacking a fundamental target system that is critical to life.
2. That it is probably not much affected by ADME. |
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What are the two things you look for when comparing D-R curves?
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1. Slope
(Look for parallelism) 2. Threshold |
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When slopes display parallelism does it mean that the thresholds are the same?
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No.
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What does parallelism of slopes suggest?
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Suggest (does not prove) similar mechanisms and ADME properties.
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Why can't you compare two substances using only LD50?
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See slide #37, p. 19. Two substances can share the same LD50 but have different slopes. For example they may have different LD10s.
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In Risk Mgmt what do we assume about humans?
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We assume humans are as sensitive as the most sensitive animal (unless we have real data on humans, 'human data always trumps animal data')
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How do narcotics cause death?
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Respiratory depression.
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Since respiratory depression causes death what would we assume on a graph with lines representing both resp. dep. and lethality?
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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.
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When developing a medication what do you want distance between on a D-R curve?
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You want as much distance between lines representing pharmacologic effects and toxicologic effects as possible.
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What is the eqn for Therapeutic Index?
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TI = LD50/ ED50
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If one drug has a therapeutic index of 12 and another is 4 which one would you rather take?
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TI 12
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What is the eqn for margin of safety?
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MOS = LD01/ ED99
(lethality in 1% of pop/ effective dose in 99% pop) |