Toxicity Testing Flashcards
What is toxicology?
- “the science of poisons”
- The study of the adverse effects of chemicals or physical agents on living organisms
What are the adverse effects of chemicals or physical agents on living organisms?
- Death
- More subtle effects that reduce an organism’s fitness, lifespan or reproductive output
Who was the first person to use toxicology?
- Hippocrates (≈400 BCE): first physician to use toxicology principles
Who is often referred to as the father of Toxicology?
- Paracelsus (1493-1541): “the dose makes the poison”
What are the four stages in the development of toxicity?
- Delivery to the target site
- Interaction with target molecule and alteration of biological environment
- Cellular dysfunction
- Exceedance of repair mechanism
How do the four stages of toxicity fit into the process in developing toxicity?
- The first thing is that you need to have the toxicant
- Then stage one (delivery to target site) needs to be completed
- Then stage 2a: Interaction with target molecule
- Or stage 2b: Alteration of biological environment
- This then leads to stage 3 (Cellular dysfunction)
- After stage three there are many repair mechanisms which can be used to overcome cellular dysfunction
- If the repair mechanisms are exceeded by the toxicant in stage four then Toxicity can or has been reached
What is a therapeutic window
- The space between a healthy dose of medicine and a toxic dose of medicine.
What is a dose-response curve?
- The dose–response curve describes the magnitude of the response of an organism, as a function of exposure to a stimulus or stress after a certain exposure time
What is on the X and Y axis of a dose-response curve?
- X = dose
- Y = % of population affected
What is the point of Departure (“Threshold of toxicity”)
- The point on a dose-response curve where the dosage begins to affect the population
What is LD50?
- LD50 stands for Lethal dose which affects 50% of the population
- It is a point on the dose-response curve where the lethal dose is most likely to be
What is generally affected as the dose or exposure increases on a dose-response curve?
- Bio-molecule will be affected first (e.g.enzyme). However this is not fatal because of the repair mechanisms which are still able to fix them
- Cell will be affected as the dosage or exposure increases slightly
- Then organ
- Then the entire organism
What is the Hill Equation?
- Commonly used to estimate the number of ligand molecules that are required to bind to the receptor in order to produce a functional effect.
effect (%) = 0 + (100 – 0) / 1+10 ^ [(logLD50 – logx) * slope]
How do you find the Toxic Equivalency Factor when comparing two chemicals?
- The TEF = the LD50 of the less toxic chemical divided by the LD50 of the other
Why is the dose-response relationship important?
- Establishes causality
- Determines threshold of toxicity (point of departure) = safe dose
- Slope determines the variability in sensitivity between individuals
What does it mean when a dose-response curve goes into a U shape instead of an S shape?
- The middle section is the healthy range where the dosage is good
- The left hand side is a deficient dosage
- The right hand side is a Toxic dosage
Why is the PoD important in toxicology?
- The Point of Departure determines the threshold of toxicity
- Separates “safe” vs. “not safe”
What are NOAEL and LOAEL?
- Until recently, toxicologists used NOAEL and LOAEL to express PoD
What does NOAEL stand for?
- No Observable Adverse Effect Level
- The highest dose tested that did not have an adverse affect
What does LOAEL stand for?
- Lowest Observable Adverse Effect Level
- The lowest dose that produced an adverse effect
What was the problem with NOAEL and LOAEL?
- Can be significantly affected by experimental design, for example: Dose selection, sample size
- Makes comparison of toxicity between studies problematic
What is now being used instead of NOAEL and LOAEL?
- Benchmark Dose (BMD)
- BMD takes into account the whole D/R, it’s much less influenced by dose selection
- Allows standardised comparison of toxicity between studies
- For example you could calculate a BMD that affects 10% of the population. First you would find 10% on the y-axis, then find where that intersects with the relationship on the x-axis and that would be you BMD10 (10 is for 10%)
What are the other things that toxicity depends on?
- “The dose makes the poison” but toxicity also depends on:
- Species
- Age, gender
- Sensitive windows of exposure (e.g., embryonic development)
- Exposure duration (acute vs. chronic; continuous vs. pulse)
- Presence of other toxicants (“mixture toxicity”)
- Exposure route (dermal, respiratory, oral …)
- Toxicokinetics (absorption, distribution, metabolism and excretion)
What is Selective Toxicity?
- Species differences usually attributable to differences in metabolism, although some may be due to physiological differences
» E.g., rats cannot vomit ≠ humans and dogs - Selective toxicity refers to species differences in toxicity
» E.g., insecticide lethal to insects but relatively nontoxic to mammals