Lecture 4: Factors Influencing Toxicity

Question 1

What are Factors Influencing Toxicity?

Answer 1

Route of exposure (ingestion vs dermal)- QUICKER something gets into the bloodstream the faster the exposure

Endpoints we measure (e.g., death vs gene expression)

Duration of study (acute vs. chronic)

Properties of the compound

Single compound vs. Mixtures

Half-life of the compound

Excretion rate

Tolerance

Resistance

Genetics

Question 2

Additive

Answer 2

when the total amount of toxicity is the sum of the toxicities of the compounds (2 + 2 = 4)

usually due to the fact that the toxins are very similar - they have similar LD50s and/or their targets of toxicity are the same.

Question 3

synergistic

Answer 3

when the total amount of toxicity is greater than the sum of the toxicities of the compounds (2 + 2 = 8). - toxic response is greater than what you would predict

Example 1: Workers exposed to asbestos increase risk of lung cancer by 20 times, smokers have a 26 times increase in risk. The combination of the two increases the risk to 400 times.

Question 4

antagonistic

Answer 4

when the total amount of toxicity is less than the sum of the toxicities of the compounds (2 + 2 = 1). - mixture is causing a less of response than these toxicants on their own

– This is the basis of antidotes!

Question 5

Give an example of an antidote

Answer 5

For example, when a person OD’s on morphine:
Morphine is a μ-opioid receptor agonist (i.e., activates the receptor). Causes analgesia, sedation, euphoria and respiratory depression. If you take to much, you stop breathing.

Naloxone is a μ-opioid receptor antagonist (i.e., deactivates the receptor). When a person has OD’d on opiates, naloxone is administered. It will block the activation of the receptor and thus is antagonistic to morphine.

Question 6

Functional antagonism

Answer 6

2 toxicants produce opposite effects on a physiological function. (stimulant vs sedative)

Question 7

Chemical antagonism

Answer 7

chemical reaction between the compounds leads to an inactivation that produces a less toxic effect.

Question 8

Dispositional antagonism

Answer 8

alters the absorption, biotransformation, distribution or elimination of the toxicants.

– Concentration or excretion at target tissue is affected

Question 9

Receptor antagonism

Answer 9

2 toxicants bind to the same receptor and interfere with the response.(naloxone and morphine)

Question 10

Potentiation

Answer 10

is when a non-toxic chemical(doesn’t create a adverse effect) (at the levels normally administered or encountered) makes a different toxicant even more toxic.

Question 11

Interactions can occur between________

Answer 11

toxicants and abiotic factors

For example, many aquatic organisms react to compounds in different ways in fresh water vs. salt water.

Question 12

Provide an example of Potentiation

Answer 12

Warfarin is an anticoagulant (prevents blood clotting).

– Used as a rat poison… also used as a therapy to prevent heart attacks (anti-thrombosis).

It gets bound to albumin (a sticky protein) in the blood which keeps its “free” levels of warfarin concentration down.

If a low (non-toxic) dose of another drug/toxicant that is also carried by albumin is administered… the warfarin gets displaced off the albumin and can quickly reach toxic levels in the blood.

Question 13

Describe how the some toxicants exist in different chemical forms

Answer 13

These ‘forms’ can be either modified by metabolism by the individual or by environment-driven chemical reactions.

Example: elemental mercury (Hg) is not especially toxic, so its presence in the environment is not usually cause for concern.

However, when it is converted to organic form (methylmercury), it is much more toxic (become lipophilic accumulate in animals and leads to higher levels of mercury in top predators)

*FORM OF COMPOUND CAN DICTATE ITS TOXIC EFFECTS

Question 14

Genotype

Answer 14

the genetic make up of an individual.

Question 15

Phenotype

Answer 15

observable traits due to interactions between the genotype and the environment (i.e., tolerance to a toxicant).

Question 16

Difference in genetic seqence________

Answer 16

can lead to difference in tolerance of toxicants

Question 17

mutation

Answer 17

Exchanging one nucleotide with another

Question 18

single nucleotide polymorphisms (SNPs)

Answer 18

Sequence differences between individuals can be measured using this

to identify different genotypes in individuals/populations/species, etc.

– Better resolution than “older” approaches
• Mitochondrial DNA,microsatellites,etc.

Question 19

nonsynonymous SNPs

Answer 19

Some SNPs can change the amino acid sequence of the protein

which can change how the protein functions

Question 20

synonymous SNP

Answer 20

If it changes nucleotide seq but not amino acid-

Question 21

‘susceptibility factors’

Answer 21

If the protein that changed is a target of a toxicant, then the difference in function can affect the severity of the relative toxic effect.

Question 22

‘resistance factors’.

Answer 22

genes encode enzymes that break down toxicants

Answer 23

We can have difference in how animals respond to exposure to different types of toxicants based on mutations that occur where the toxicant, cellular target for that toxicant and genetic mutations that occur in enzymes that are used to break down toxicants

Question 24

Give an example of how mutations in enzymes can affect a process in humans

Answer 24

Humans have two aldehyde dehydrogenases (one cytosolic, one in the mitochondria). Most acetaldehyde is processed by ALDH2 in the mitochondria of the liver. Some people have a mutation in the mitochondrial form, leading to only having an active cytosolic isoform.

People with this mutation have higher levels of acetaldehyde accumulate, producing a toxic response when they drink alcohol.

Question 25

Provide an example of how mutations in enzymes can affect sea lampreys

Answer 25

TFM is detoxified in many fishes, but not in sea lamprey, through conversion to TFM-glucuronide via the UDP-glucuronyl transferase (UDPGT) enzyme.

This conversion changes TFM to TFM-glucuronide, which is hydrophilic.

– Now can be cleared from the tissues.
– Sea lamprey cannot do this because they lack the appropriate UDPGT enzyme

TFM on its own is very lipophilic so it accumulates in muscle tissue but if they have this enzyme it will convert it from hydrophobic to hydrophilic form making it easier for it to get cleared from body

Question 26

How does resistance evolves in a species or population?

Answer 26

Mutations that alter the function of important detoxifying enzymes are likely how resistance evolves in a species or population.

Different mutations in detoxification enzymes may contribute to each person having their own “distinct complement of enzymes”

Mutations that occur in enzymes can differentiate between how animals can breakdown these different types of toxicants

Question 27

Describe how age and size of an organism are factors that influence toxicity

Answer 27

Developmental stages are very important.
– i.e., child vs adults vs seniors.

Sometimes a toxicant can have a greater effect at one of these stages (often embryos or very young). These differences are in addition to the fact that the very young are smaller (easier for them to receive a toxic dose!)

Some of the liver enzymes that detoxify toxicants have low expression in human children for a few months after birth, later are gradually expressed at higher levels.

An infant’s kidneys are not as effective at eliminating toxicants, therefore toxicants can reach toxic doses easier.

Question 28

What happens if we expose a adult to the same amount of toxicant as a baby?

Answer 28

if we expose a adult to the same amount of toxicant as a baby the baby is smaller so the relative dose is a lot higher for the baby

Question 29

Excretion/Elimination Rate

Answer 29

How long it takes to remove a compound from the tissue or body of an organism.
Excretion from a tissue, eliminated from the body.

Question 30

half-life

Answer 30

time it takes for a concentration to be reduced by half

– This is applied to environmental contaminants as well.

Question 31

Elimination

Answer 31

if a compound is broken down into a different version of the compound technically the parent compound has been eliminated from the body

Question 32

What does it mean if a compound for ex C has a shorter half life than compound A?

Answer 32

C has shorter half life so itll get removed much faster than A

Question 33

Explain why Frequency and duration of exposure are important

Answer 33

– Excretion rate is very important for repeat doses!
If the breakdown of the compound (½) life is less, then intake rate then you can have accumulation of the compound over time and can accumulate repeatedly until it leads to a toxic dose

Question 34

Acute vs chronic exposure

Answer 34

Acute doses can give big effects quickly.

Chronic or repeated doses can eventually reach toxic levels, depending on:
a) The dose at each ‘step’ of repeated exposure

b) How quickly the toxicant is metabolised or excreted

Question 35

Tolerance of the individual

Answer 35

When a prior exposure to a toxicant alters the metabolism or physiology of the organism so that subsequent exposures to the same toxicant result in a reduced effect.

For example, excessive drinking increases the expression of the metabolic enzymes that process ethanol (ADH, ALDH) in the liver. So heavy drinkers can process alcohol more efficiently compared to a non-drinker

Question 36

Cross-tolerance

Answer 36

is where an individual becomes tolerant to different similar toxicants because of exposure to one compound.

Question 37

Give some ex of cross tolerance

Answer 37

For example, heroin users may show an increased tolerance to other opioids.
– They elicit a response through the same cellular receptor.

Similarly, someone on methadone may have a higher tolerance to heroin.

Question 38

Explain how Alcoholics can build up a cross-tolerance to benzodiazepine drugs

Answer 38

Alcoholics can build up a cross-tolerance to benzodiazepine drugs (aka “Benzos”) – a drug used to treat alcohol withdrawal symptoms… – Both act on GABA receptors in the brain to depress the central nervous system.
– Receptors get less responsive with extended use, need to take more to get the “desired effect”.
– Makes it very easy to overdose when mixing the two.

Answer 39

Where the compounds hit the same cellular receptor you get reduced responsiveness of receptor over time meaning the opioids are less effective
(taking more and more opioids bc of cross tolerance which can lead to accidental overdose)

Question 40

Resistance of a population or species

Answer 40

– a genetic basis for the ability of an organism to avoid a toxic response when exposed to a toxicant
• Usually involves mutations and evolution!

Question 41

What are the Mechanisms of resistance over time?

Answer 41

Selection for a resistance factor gene already in a population.
*certain individuals already have a gene that’s more suitable for breaking down certain toxicants becomes selected for and frequency of that particular gene increases in that pop over time

Selection for a new mutation (SNP) in a resistance factor gene. (allows it to breakdown toxicant more efficently)

Multiple copies of a gene already in the organism arise (copy number variation).
i. e.g. multiple copies of a gene for a detoxification enzyme that breaks down a toxicant can lead to resistance to the toxicant.

A brand new gene picked up from the environment or another organism (bacteria can do this).

Genetically engineered into a species.
- e.g., CRISPR (made famous by the CRISPR baby of 2018 in China)

Question 42

selective sweep

Answer 42

Is when a new beneficial mutation rises in frequency in a population.
• Can be very rapid when talking about insecticide resistance.

Question 43

Explain selective sweep

Answer 43

One individual develops mutation that causes one of its detox genes to behave differently then rest of the pop if intense selective pressure is applied then it can lead to a rapid increase of beneficial mutation

*Ex- pesticides that kill most of the individuals in a pop but if mutation occurs that causes a certain individual to not be harmed by a particular pesticide hen that mutation becomes common in pop bc its so beneficial

Question 44

Explain resistance in insects

Answer 44

is a big deal in “pest” management.

Insects become resistant to compounds due to the huge selection pressure of using insecticides.

– i.e., When they are effective at killing most of the individuals but not all if any individual evolved some mutation that makes them not to be harmed by pesticide that causes the mutation to become frequent and become resistant

Question 45

Explain how DDT causes toxic effects and how selective sweep can occur to it

Answer 45

DDT binds to sodium channels and keeps them open how it causes toxic efffect, even when they should be closed. Same mechanism for the pyrethroid pesticide permethrin.

Natural mutations that reduced binding to the channels were rapidly selected for in different mosquito populations and led to resistance to DDT and permethrin.

DDT and permethrin resistant mosquitoes can also have higher expression of key detoxification enzymes (P450s, UDPGTs).

Usually newly arising mutations have low expression in a population. But when a pesticide kills all the individuals in a population that are not resistant, the individuals that have a resistant genotype can quickly become the dominant genotype in the population through selective sweeps.

– This can lead to a resistant population.