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Ecotox & Impact Assessment > Toxicity Testing > Flashcards

Toxicity Testing Flashcards

1
Q

What is toxicology?

A
  • “the science of poisons”

- The study of the adverse effects of chemicals or physical agents on living organisms

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2
Q

What are the adverse effects of chemicals or physical agents on living organisms?

A
  • Death

- More subtle effects that reduce an organism’s fitness, lifespan or reproductive output

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3
Q

Who was the first person to use toxicology?

A
  • Hippocrates (≈400 BCE): first physician to use toxicology principles
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4
Q

Who is often referred to as the father of Toxicology?

A
  • Paracelsus (1493-1541): “the dose makes the poison”
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5
Q

What are the four stages in the development of toxicity?

A
  • Delivery to the target site
  • Interaction with target molecule and alteration of biological environment
  • Cellular dysfunction
  • Exceedance of repair mechanism
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6
Q

How do the four stages of toxicity fit into the process in developing toxicity?

A
  • 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
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7
Q

What is a therapeutic window

A
  • The space between a healthy dose of medicine and a toxic dose of medicine.
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8
Q

What is a dose-response curve?

A
  • 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
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9
Q

What is on the X and Y axis of a dose-response curve?

A
  • X = dose

- Y = % of population affected

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10
Q

What is the point of Departure (“Threshold of toxicity”)

A
  • The point on a dose-response curve where the dosage begins to affect the population
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11
Q

What is LD50?

A
  • 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
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12
Q

What is generally affected as the dose or exposure increases on a dose-response curve?

A
  • 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
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13
Q

What is the Hill Equation?

A
  • 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]

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14
Q

How do you find the Toxic Equivalency Factor when comparing two chemicals?

A
  • The TEF = the LD50 of the less toxic chemical divided by the LD50 of the other
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15
Q

Why is the dose-response relationship important?

A
  • Establishes causality
  • Determines threshold of toxicity (point of departure) = safe dose
  • Slope determines the variability in sensitivity between individuals
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16
Q

What does it mean when a dose-response curve goes into a U shape instead of an S shape?

A
  • 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
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17
Q

Why is the PoD important in toxicology?

A
  • The Point of Departure determines the threshold of toxicity
  • Separates “safe” vs. “not safe”
18
Q

What are NOAEL and LOAEL?

A
  • Until recently, toxicologists used NOAEL and LOAEL to express PoD
19
Q

What does NOAEL stand for?

A
  • No Observable Adverse Effect Level

- The highest dose tested that did not have an adverse affect

20
Q

What does LOAEL stand for?

A
  • Lowest Observable Adverse Effect Level

- The lowest dose that produced an adverse effect

21
Q

What was the problem with NOAEL and LOAEL?

A
  • Can be significantly affected by experimental design, for example: Dose selection, sample size
  • Makes comparison of toxicity between studies problematic
22
Q

What is now being used instead of NOAEL and LOAEL?

A
  • 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%)
23
Q

What are the other things that toxicity depends on?

A
  • “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)
24
Q

What is Selective Toxicity?

A
  • 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
25
Q

What is Mixture toxicity?

A
  • The presence of other chemicals may:
    » Decrease toxicity (antagonism),
    » Add to toxicity (additivity), or
    » Increase toxicity (synergism or potentiation)
26
Q

What are one of the Concepts of mixture toxicity with the abbreviation “CA”?

A
  • Concentration addition (CA)
  • One of the concepts used for mixture toxicity modelling
  • If you have no interaction between chemicals in the mixture and they target the same site with the same mode of action then there will be CA
27
Q

What are one of the Concepts of mixture toxicity with the abbreviation “IA”?

A
  • Independent action (IA)
  • If you have no interaction between chemicals in the mixture and they target different sites with the different modes of action then there will be IA
28
Q

What are the “complex action” and “dependent action” concepts of mixture toxicity?

A
  • Complex action (synergism / antagonism) occurs when you have Interaction between chemicals in mixture with the same target site and the same mode of action.
  • Dependent action (synergism / antagonism) occurs when you have Interaction between chemicals in mixture with different target sites and different modes of action
29
Q

Are complex interaction between chemicals in a mixture common?

A
  • When there are many compounds in a mixture, all at low concentration, interaction between mixture components is rare (ie, relevant in drug development, but less so in environmental science)
  • For example, there can be millions of chemicals at really low concentration in a water sample and you’re most likely going to be dealing with CA or IA.
30
Q

What is Toxicokinetics (TK)?

A
  • Movement of toxicant within living organism
31
Q

What are the four main process of Toxicokinetics?

A
  • Absorption
  • Distribution
  • Metabolism (aka biotransformation)
  • Excretion
32
Q

What parts of a living organism make up the absorption process?

A
  • The Gastrointestinal Tract

- The skin and lungs

33
Q

What parts of a living organism make up the distribution and metabolism process?

A
  • Liver -> Bile
  • Blood and lymph circulation
  • Storage -> Organs, bones and fatty tissues
  • Kidney
  • lung
  • Extracellular fluids
  • Metabolism -> metabolites
34
Q

What parts of a living organism make up the elimination process?

A
  • Feces
  • Urine
  • Expired air
35
Q

Why is absorption important?

A
  • Essential for toxicity to occur
  • Varies depending on route of exposure and chemical properties, for example:
    » Injection&raquo_space;> oral > respiratory&raquo_space;> dermal
    » Lipophilic or small substances (very easily absorbed)&raquo_space;> hydrophilic or large substances (harder to absorbe)
36
Q

What does a chemical need to be able to pass through the phospholipid bilayer?

A
  • Main barrier is the cell membrane = phospholipid bilayer
  • To pass through it, the chemical or compound needs to be Lipophilic, small and have no charge.
  • It can’t be either:
    » Hydrophilic + charged phosphate head
    » Hydrophobic – charged fatty acid tail
37
Q

What are the different types of transport across the cell membrane?

A
  • Passive transport (with concentration gradient)

- Active transport (against concentration gradient)

38
Q

WHat is the major determinant of toxicity?

A
  • A major determinant of toxicity is the lipid solubility of the toxicant
  • Lipid soluble toxicants readily penetrates cell membranes
39
Q

Is there a way to measure how “lipid loving” a chemical is?

A
  • Octanol / water partition coefficient (Kow) is a measure of lipophilicity (“lipid loving”)
    » Generally expressed in log unit (logKow)
  • logKow = 3 → compound is 1,000× more concentrated in octanol than in water
40
Q

What determines where a chemical will be distributed?

A
  • Once absorbed, where the chemical goes in the body (distribution) depends on route of exposure and chemical properties
    » Oral → biotransformation in the liver (“first pass effect”)
    » Respiratory, dermal or injection: no first pass effect, so intact chemical can reach any organ
  • Some chemicals can
    accumulate in tissues
    » Lipophilic chemicals will accumulate in fat
    » Some metals (e.g., Pb, Sr) will accumulate in bone

Ecotox & Impact Assessment (2 decks)

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