LECTURE 5: INTRODUCTION TO TOXICOLOGY - BASICS Flashcards
CLASSIFICATIONS TOXIC AGENTS
- Physical state – gas, dust, liquid, nanoparticle
- Chemical stability/reactivity – explosive, flammable, oxidizer
- Chemical structure – ie., aromatic amine, halogenated hydrocarbon
- Poisoning potential – extremely toxic, very toxic, slightly toxic
- Biochemical MOA – ie., alkylating agent, endocrine disruptor
- Target organ – liver, kidney, lung
- Use – pesticide, solvent
- Source – animal, plant, human
CLASSIFICATIONS TOXIC AGENTS
No single classification that is applicable to entire spectrum
A combination of classification systems is generally needed
ABSORPTION, DISTRIBUTION, METABOLISM, ELIMINATION
(ADME)
* Fundamental to toxicology
* Similar processes and mechanisms dictate
the fate of the toxin/poison to therapeutic
agents
Exposure – Mechanism of Action
Characteristics of Exposure
* Toxicity requires sufficient concentrations of the
‘active’ form at the site of action for a requisite
period of time
Depends on multiple factors
* Chemical and physical properties
* Dosage
* Route, duration and frequency of exposure
* Influenced by both modifiable (ie., diet,
smoking, sedentary lifestyle) and nonmodifiable (ie., age, sex, genetics) factors
Exposure
acute fx
sub-acute
sub-chronic
chronic
Acute Effects (<24h) –
1. Effect may occur immediately or soon after
2. Usually relatively high dose
3. Usually short duration and reversible
Sub-Acute Effects (<1 month)–
1. Repeated doses
2. Reversible/Irreversible
Sub-Chronic Effects (~1-3 months)–
1. Repeated doses
2. Reversible/Irreversible
Chronic Effects (>3 months)–
1. Effect may occur some time after exposure
2. Repeated lower doses over many months/years
3. Usually irreversible
PROBLEM – LINKING CAUSE AND EFFECT
What is the relationship between the toxic material and an observed effect/response?
Assumptions
1. Strength of association
2. Consistency of findings
3. Biological gradient
4. Temporal sequence
5. Biological or theoretical plausibility
6. Coherence with established knowledge
7. Specificity of association
strength of the association. What do you know about that association, when you observe adverse of fact? Is there pretty lightly? Can you make a very strong association with that toxicant
it. Did you think it might be causing the response?
it happens reliably with exposure to someone’s on a a therapeutic, you know, multiple drugs, and they keep getting that same drug and keeps seeing the same effect. So you get the consistency of findings
biological gradient. This is pretty straightforward. It’s a dose response. You see changes in in concentrations of doses, and you see an increased adverse effect
Temporal sequence - realistic, when do you start seeing AE
Coherence - does it match literature, established knowledge
Specificity - linking patient assessment history as opposed to just general toxicity
SPECTRUM OF EFFECTS
local fx
systemic fx
allergic rxn
idiosyncratic rxn
Local Effects–
Occur at the point of contact
- Xylene (de-fatting of skin), sulphuric acid (irritation/burn), chlorine
(pulmonary inflame)
Systemic Effects–
Occur at a target organ remote to point of contact
- Lead – accumulates in bone but toxic effects occur in soft tissue (brain)
Allergic Reactions–
Immunologically mediated adverse reaction resulting from a previous
sensitization to the toxic agent
- Reactions to nuts, shellfish
Idiosyncratic Reactions–
Genetic or individual sensitivity triggering abnormal reactivity to a chemical
Adverse effects unrelated to therapeutic action not typically observed
- Hepatic (amoxicillin), dermal (antibiotics – amoxicillin), hematologic (heparin)
SPECTRUM OF EFFECTS
immediate vs delayed tox
reversible vs irreversible tox
Immediate vs. Delayed Toxicity –
* Hydrogen cyanide or nerve gases (sarin)
* Thalidomide, Doxorubicin
Reversible vs. Irreversible Toxicity –
* Depends on the ability of injured tissue to adapt, repair and regenerate
* Dose-dependent
SPECTRUM OF EFFECTS
Thalidomide – late 1950’s marketed for anxiety,
sleep disorders, tension and morning sickness
- Teratogenic resulting in malformation of the limbs
- Cancer therapy (multiple myeloma), leprosy
- MOA not clear, inhibit angiogenesis, bind to
androgen receptor
INTERACTIONS
Additive (2+2=4)
Combined effect of 2 substances is equal to the sum of the individual effects
- Toluene and xylene – both are irritant and narcotic, similar chemicals, affect same target organs
Independent (2+2 = 2 and 2)
Toxic effects of each substance is unaffected by simultaneous exposure
- Lead and xylene
Synergistic (2+2=10)
Combined effect is greater than the sum of the individual effects
- carbon tetrachloride (CCl4) and ethanol (both hepatotoxic) but total liver damage is greater than expected
- Smoking and asbestos (lung cancer)
Potentiation (0+2=7)
The enhancement of one agent by another so that the combined effect is greater than the sum of the effects of each on alone
- Isopropanol and CCl4
Antagonism (4+6=8; 4+0=1)
When two chemical administered together interfere with each others actions, or one with the
other
- 4 types: receptor (blocker), chemical, dispositional, functional
INTERACTIONS (POTENTIATION)
carbon tetrachloride tox potentiated by osiopropyl alcohol
Time between carbon tetrachloride exposure and onset of illness of
13 workers in isopropyl alcohol packaging plant. Exact time of onset in one
additional patient is not known. Shaded squares represent hospitalized
workers
Carbon tetrachloride metabolite itself is toxic
It’s going to cause problems to the cell. It’s going to cause, you know, resulting in cell death and hepatic
toxicity
Iso proper alcohol gets metabolized by alcohol, dehydrogenase to acetone
for most part Acetone is not very toxic. It’s not going to cause at the levels. You’d get the metabolism. But what acetone does is it induces CYP 2D1
You get exposure. You metabolize is appropriate alcohol produce acetone. To make more reactive metabolites
INTERACTIONS (ANTAGONISM)
Types: 1) Receptor 2) Chemical 3) Dispositional 4) Functional
Examples antagonism mechanisms:
1) Naloxone antagonizing opioid receptors
2) 2,3-dimercaptosuccinic acid chelating metal ions
3) Activated charcoal preventing absorption
4) Fall in blood pressure caused by barbitur
Receptor: You have chemical a’s binding to receptor you add your chemical B, and it’s going to either compete
for that receptor to prevent the action of the toxin
Chemical: This is where a second chemicals added to basically you know, somehow prevent the the function of the first.
Dispositional: where you’re gonna prevent and enhance the removal. So if you think of activated charcoal as often given to prevent the absorption of a chemical, someone ingest something really quickly, you know, Short window opportunity to administer activated charcoal. basically absorb the the chemicals to prevent it from being absorbed into the body
functional interaction.
This is where you’re adding a second compound to basically work on a different receptor to overact
if we look at barbituates are going to basically cause a fall and blood pressure. By acting through the gap before receptor. You can antagonize this effect by adding a vasopressor norep
Dose-Response Relationships
- Fundamental to toxicology
- Association between the amount of toxicant
administered and extent of observed changes in
biological systems
NOAEL No observable adverse effect level
LOAEL Lowest observable adverse effect level
You get your Tibal Gaussian distribution. Where you get this varying different doses. You get responses how an individuals can respond.
Often get sigmoidal curve
Can be transformed
Noael, a no observable effect level. And this is basically at the level where we don’t see any toxic effects occurring in the individual.
The Loael, or the lowest observable effect Level is this: where we start to see the very first signs of that toxic response
DOSE-RESPONSE RELATIONSHIPS
trhreshold, slope
Threshold – point where toxicity 1st appears Chemical A vs. B?
Slope – Can provide indication of the change in the percent of the population responding as
the dose increases Steep vs. shallow?
a threshold point also is, you know that similar to that, the Loael effect is really where that point that first toxicity appears.
Obviously you can see the threshold point, for chemical B is lower. Then that for chemical a. So the observed effect is going to be occur sooner at a lower dose
compared to chemical A
Shape - is it steep or shallow?
steepness is going to get you at a
increasing dose of toxicity so very slight increase in dose that have an adverse effects.
the red one. You see your thresholds around 10,
and you have a lower, you know, response, and it doesn’t take much to slight increases in dose. You’re going to get an adverse effect.
B is more shallow - so you can handle more increases in dose, and fewer people are going to be affected.
steeper is going to give you the very short increases and dose more. People are going to be affected.
whereas with a flatter curve, shallow curve.
we have more room for less adverse effects.
DOSE-RESPONSE RELATIONSHIPS
ED50
TD50
LD50
ED50 – Effective dose 50% of the population (normally refers to beneficial effects but may
indicated harmful effect)
TD50 – Toxic dose 50% of the population (indicate adverse effects)
LD50 – Lethal dose 50% of the population (common for acute toxicity – not really used)
EVALUATING DOSE-RESPONSE RELATIONSHIPS
TI = TD50/ED50
e.g., Therapeutic Index = is used to compare
the therapeutically effective dose to the toxic
dose of drug – relative safety.
Drug A: TI= 60/20 = 3
Drug B: TI= 300/20 = 15
Drug B has a better TI (safety) than Drug A
Margin of Safety (MOS) MOS = TD10 /ED90
Safety Index (SI) SI = TD10/ED90
Drug A: SI= 35/60 = 0.58
Drug B: SI= 110/60 = 1.83
- Overcome limitations of variable slopes between effective and toxic dose-response curves.
What can you say about these curves?
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