Toxicology Flashcards
What is toxicology?
The study of harmful effects of physical, chemical and biological xenobiotics that do not offer a therapeutic use.
Are all chemicals toxic?
The dose makes the perfect poison. A chemical can be present in any substance but, it does not mean it is harmful in the amount present.
What is a xenobiotic?
A chemical substance that is foreign to a particular substance.
Is a drug considered a xenobiotic?
Yes, because drugs are exogenous substances that interact with the body with therapeutic intent.
How can xenobiotics be classified?
Poisons, Toxins, and Venom.
What are poisons?
Chemicals that produce injury, or impairment of function.
Poisons are dose-dependant, as some poisons may or may not have therapeutic implications at lower doses.
What are toxins?
A poison produced by a living organism.
What is venom?
A toxin injected by one organism into another, usually for the purpose of defence.
What are the three types of toxicology disciplines?
- Occupational/Environmental Toxicology
- Analytical Toxicology
- Forensic Toxicology
What is Occupational/Environmental Toxicology concerned with?
Concerned with reducing exposure levels.
What is Analytical Toxicology concerned with?
Concerned with assessing toxin contamination (qualitatively or quantitatively)
What is Forensic Toxicology concerned with?
Application of toxicology principles in the legal system (crime)
How does one get exposed to Poison?
Oral, Inhalation, and dermal (poison ivy).
What is acute exposure?
A single, and large dose or several small doses of poison over a short term period. (Couple days)
What is chronic exposure?
Repeated, typically in smaller doses over a short period of time. (Symptoms usually start to persist after it has accumulated in a high concentration.)
Is the effect of toxicity local or systemic?
It can be both, depending on the pharmacokinetics of the agent.
What is bioaccumulation?
An increased exposure to toxins over the course of an organisms life. This can occur through food/environmental absorption.
Why does bioaccumulation happen?
Due to the fact that intake is greater than the ability for it to be metabolized and excreted.
What is biomagnification?
Toxicity that occurs in species that occupy higher positions on the food chain.
What are the 4 MOA for toxicity?
- Nonspecific macromolecular damage
- Production of reactive species
- Inflammatory or immune-mediated mechanisms
- Enzyme and/or receptor mediated toxicity
What is the MOA for Nonspecific Macromolecular Damage?
Hydrolysis, Oxidation and reduction reactions alter the structure of a macromolecule and denature the protein. This occurs at a non-specific site.
It also causes plasma membrane disruption.
Where does Nonspecific Macromolecular Damage occur?
Usually affects area of direct contact, for example: skin, eyes, GI/ respiratory mucus membranes.
What is the MOA for Reactive Species?
Nucleophiles, Electrophiles or free radicals cause macromolecular damage that alters function at a specific site.
Where does it act?
Damage occurs systemically. Initially the poison absorbs as an inert compound, and is then converted into an active compound.
Where does this MOA occur?
Kidney and liver are most common because they deal with a lot of the body’s metabolism and excretion.
What is the MOA for Inflammatory or immune-mediated toxicity?
Causes secondary damage by affecting the immune system. The substance isn’t necessarily toxic but the body overreacts in its presence causing damage.
ex: hypersensitivity
rare cases: autoimmunity (body attacks itself)
What is the MOA for enzyme and/or receptor mediated toxicity?
Alteration of metabolic pathways or critically functional receptors. Since these receptors are very important, production of acute toxicity usually alters function of neurotransmission, cardiac rhythm, oxygen delivery, ATP generation and intracellular calcium ion channels.
How does one recover toxicity?
This depends on the regenerative capacity of affected tissues and organs and the concentration of toxicity experienced.
What is the regenerative capacity of the heart and CNS?
Very limited regenerative capacity.
What is the regenerative capacity of the lungs?
Medium level regenerative capacity. There is some loss of gas exchange membranes which decreases surface area.
If toxin bioaccumulates, the loss of surface area prevents toxin from getting removed.
What is the regenerative capacity of the liver?
Large regenerative capacity but gradually fibrosis can occur.
What is fibrosis?
Deposit of collagen/extracellular matrix proteins around cells. Also known as scar tissue.
What is NOAEL?
No observed adverse effect level. Determines how much of the toxin you can take into the body before it shows toxic effects.
What is the fudge factor?
Since this test is usually conducted on animals, and applied to humans, the fudge factor divides the result by 1 log unit (10).
What types of treatments are available to fix toxicity?
- Remove the source of exposure
- Artificial ventilation (while waiting for the body to clear agent on its own)
- Facilitate excretion (change urinary pH or inject water to induce flushing)
- Limit further absorption/distribution (induce vomiting, wash thoroughly, or use a tourniquet).
How would a tourniquet help?
It compresses blood vessels by wrapping a tight bandage. Prevents further exposure in blood stream.
What specific agents are used for certain poisons? (HAAC)
- Heavy metal chelators
- anti-venom (snake bites)
- Antagonists/inhibitors (atropine)
- Competitive agents
How do competitive agents help?
Methanol poisoning. Ethanol is a competitive agent that outcompetes methanol for enzymes. This helps methanol leave the body unabsorbed.
How do heavy metal chelators help?
Chelators bind to heavy metals to prevent it from absorbing systemically by keeping it in the stomach.
Most animal venom/toxins are……in nature.
polypeptide
Why do animals have venoms/toxins?
Used for hunting, defence and deter predation.
Animal toxins tend to target what?
Na+/K+ Channels. They alter nerve conduction
Are all animal toxins bad?
No, Ancrod a snake venom has been formulated to be an anticoagulant. This is because it is a fibrinolytic and busts up blood clots by breaking the fibre.
Why do plants have toxins?
For defensive purposes
Give an example of a plant with venom?
Poison ivy, or stinging nettle.
What are Alkaloids?
Nitrogen compounds that can have potential pharmacological effects.
Are all Alkaloids bad?
No some alkaloids in dilute forms have useful therapeutic or social uses. For example: coffee or nicotine.
Some drugs derived from plants are….
- Morphine (analgesic)
- Chemotherapy drugs
- anti-malarial
What types of toxins are found in air pollutants?
- Carbon Monoxide
- Nitrogen Oxide
- Sulphur Oxides
- Hydrocarbons
- Suspended particles, like those found during forest fires
How do particles in the air cause toxicity?
They get in the air and penetrate into the lungs.
How does Carbon Monoxide affect the body?
it is a colourless, odourless, tasteless, and non-irritating substance
CO binds to hemoglobin better than oxygen would. This displaces hemoglobin and causes functional anemia. Functional anemia is a lack of red blood cells carried by oxygen, thus not allowing cells to get oxygen.
What are the side effects of high (>10%) COHb levels?
nausea, dizziness, weakness, or death
What substances have high levels of COHb?
Cigars.
How does one treat COHb?
- remove exposure
- supplemental oxygen (decrease half life)
- artificial respiration
What are the four heavy metals that cause toxicity?
Cadmium, Mercury, Lead and Arsenic.
How do they cause toxicity?
They bind to sulfur/oxygen residues and create inactive metal complexes. This causes nausea, abdominal pain, near deficiencies, diarrhea, and renal damage.
What does Lead do?
distributes extensively, especially hair, bone and teeth.
What does Mercury do?
Has a variance in absorption. Can cause mad hatter disease. (neurological)
What does Arsenic do?
most Lethal, it deposits in hair. This can be useful tactic for forensic testing.
What does Cadmium do?
Causes softening of the bones and associated joint pain.
How do you treat this toxicity?
Chelation therapy using drugs like Dimercaprol which is administered intramuscularly or Sucamar (oral).
Why must chelators be administered with care?
They have their own potential toxicity too.
What pesticides can cause toxicity?
- Insecticides
- Fungicides
- Herbicides
- Rodenticides
How do they cause toxicity?
Low-level exposure through food contamination or acute toxicity if exposed during application (spraying).
What are Organophosphates?
Insecticide that has been banned for toxicity (Parathion). In the past, it was used for chemical ware-fare.
What is the MOA for Organophosphates?
it is irreversibly inhibits Acetylcholinesterase which is used to metabolize ACh to terminate its effects. This causes overstimulation of the parasympathetic system.
What are the side effects of Organophosphates?
Salivation Lacrimation (tears) Urinary incontinence (uncontrollable urination) Diaphoresis (sweating) Gastrointestinal upset Emesis
How is this treated?
- atropine - competitive antagonist of muscarinic receptors
- artificial ventilation
Carcinogenesis
Tumour Initiators - cause mutations that aid in cell proliferation or avoidance or apoptosis (cell death).
Tumour promotors - change signalling pathways/environmental cues and increase proliferation
How do carcinogens act?
- Genotoxic
- Non genotoxic
Genotoxic
- Tumour initiators
- They are metabolized in cells that damage DNA
- Bind covalently
- Can be repaired but if not, progresses to a new mutation
- Location matters (introns - not translated so does not matter vs exons)
Non-genotoxic
- no damage to DNA
- may be tumour initiators or promoters
IARC
IARC carcinogen classification – based on certainty of evidence
Level 1= carcinogenic to humans >smoking, solar radiation, meat
Level 2a= probably carcinogenic > frying, steroids, red meat
Level 2b= possibly > coffee, gasoline
Level 3= not classifiable (inadequate evidence) > tea,
Level 4= probably not (evidence suggests no) > caprolactam (used to make synthetic fibres)
MOA for tumour initiators
Bind to enzymes involved in DNA • repair/replication, increasing the likelihood
of errors
MOA for tumour proliferators
1) Bind to receptors stimulating proliferation, or supportive processes such as angiogenesis (blood vessel formation)
2) stimulate receptors that cause inflammation
inflammation increase production of compounds that cause proliferation
