3. factors effecting toxicity

Question 1

The type of response we observe depends on many factors

Answer 1

1. Route of exposure (ingestion vs dermal)
2. Endpoints we measure (e.g., death vs gene expression)
3. Duration of study (acute vs. chronic)
4. Properties of the compound
5. Single compound vs. mixtures
6. Half-life of the compound
7. Excretion rate
8. Tolerance
9. Resistance
10. Genetics

Question 2

Humans and other organisms virtually never encounter one toxicant at a time!

Answer 2

– Extrapolating from a single compound toxicity study to a complex mixture does not always work.
– Need to know how compounds interact in a mixture. • Additive,synergistic,antagonistic

Question 3

additive

Answer 3

when the total amount of toxicity is the sum of the toxicities of the compounds (2 + 2 = 4). This is usually due to the fact that the toxins are very similar - they have similar LD50s and their targets of toxicity are the same.

Question 4

synergistic

Answer 4

when the when the total amount of toxicity is greater than the sum of the toxicities of the compounds (2 + 2 = 8).

Question 5

antagonistic

Answer 5

when the total amount of toxicity is less than the sum of the toxicities of the compounds (2 + 2 = 1).
– This is the basis of antidotes!
• For example, when a person OD’s on morphine:

Question 6

Interactions can occur between toxicants and abiotic factors.

Answer 6

For example, many aquatic organisms react to compounds in different ways in fresh water vs. salt water.
– Examples, ibuprofen, chlorpyrifos, pyrethroids
Rainbow trout mortality in freshwater (hashed bars) and after saltwater (solid bars)

Question 7

Potentiation

Answer 7

is when a non-toxic chemical (at the levels normally administered or encountered) makes a different toxicant even more toxic

Question 8

Warfarin

Answer 8

is an anticoagulant (prevents blood clotting).
– Used as a rat poison… also used as a therapy to prevent heart attacks
(anti-thrombosis).

Question 9

Some toxicants exist as different chemical forms.

Answer 9

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 or dimethylmercury), it is much more toxic.

Question 10

TFM (3-trifluoromethyl-4-nitrophenol)

Answer 10

is used as a lampricide to control invasive sea lamprey in the Great Lakes.
• TFM is detoxified in many fishes through conversion to TFM-glucuronide via the UDP-glucuronyl transferase (UDPGT) enzyme, but not in sea lamprey.
• This conversion changes TFM to being hydrophilic as TFM-glucuronide.
– Now can be cleared from the tissues.
– Sea lamprey cannot do this because they lack the appropriate UDPGT enzyme.

Question 11

Genetics of the organism

Answer 11

between and within species

Question 12

Genotype

Answer 12

the genetic make up over an individual.

-diff. genotypes b/w diff. pops.

Question 13

Phenotype

Answer 13

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

Question 14

polymorphisms

Answer 14

Differences in the DNA sequences between individuals

Question 15

We can use single nucleotide polymorphisms (SNPs) to

Answer 15

tell the difference between different genotypes in individuals/populations/races/species, etc.
– Way better resolution than “older” approaches • Mitochondrial DNA, microsatellites, etc.
• Some polymorphisms can lead to differences in the amino acid sequence of the encoded protein (i.e., nonsynonymous polymorphisms), which can change how the protein functions.
• If the protein that has changed is a target of a toxicant, then the difference in function can affect how severe the relative toxic effect.
• These are sometimes called ‘susceptibility factors’. Other genes encode enzymes that break down toxicants, thus are ‘resistance factors’.

Question 16

Humans have two aldehyde dehydrogenases

Answer 16

(one cytosolic, one in the mitochondria). 50% of people of east Asian descent have a mutation in the mitochondrial form. This leads to only having an active cytosolic isoform. When people with this mutation drink alcohol higher levels of acetaldehyde accumulate in their bodies, which gives a toxic response.

Question 17

Genome duplication events can facilitate the evolution of resistance or tolerance to a toxicant.

Answer 17

– Random genome duplication can change to ploidy level of a species.
• Humans are diploid (2n) – 2 copies of their genes
• Sturgeon are tetraploid (4n), octoploid (8n), even more depending on the species.
– Because there is an original copy that still functions in its “normal” way.
• Novel function can evolve in the “extra” copies (i.e., isoforms) of the genes
• e.g., zebrafish have 40 UDPGT isoforms and can metabolize TFM, sea lamprey have 6 and cannot
• Many times the isoforms tend to function in a tissue-specific way

Question 18

Age and size of the organism

Answer 18

• As an organism grows from an embryo to an adult, it goes through different developmental stages.
• Sometimes a toxicant can have a greater effect at one of these stages (often on embryos or very young). These differences are aside from the fact that the very young are smaller and it is easier for them to intake a toxic dose!
• For example, 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 the overall levels of a toxicant can reach toxic doses easier.

Question 19

Excretion/Clearance Rate

Answer 19

How long it takes to remove a compound from the tissue or body of an organism.
– Clearance from a tissue, excretion from the body.
• Sometimes also described as the half-life of the compound,

Question 20

half-life

Answer 20

which is the time it takes for a concentration to be halved.

– This is applied to environmental contaminants as well.

Question 21

Frequency and duration of exposure

Answer 21

Excretion rate is very important for repeat doses!

Acute does can give big effects quickly.
Chronic or repeated doses can eventually reach toxic levels, dependent on:
a) The dose at each ‘step’ of repeated exposure
b) How quickly the toxicant is metabolised or eliminated

Question 22

Tolerance of the individual

Answer 22

When a prior exposure of 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 genes that encode the ethanol processing enzymes (ADH, ALDH) in the liver. So alcoholics can process booze more efficiently compared to a non-drinker.

Question 23

Cross-Tolerance

Answer 23

is where an individual becomes tolerant to different similar toxicants because of exposure to one compound.
• For example, heroine users may show an increased tolerance to other opioids.
• Similarly, someone on methadone may have a higher tolerance to heroine.
• 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.

Question 24

Resistance of a population or species

Answer 24

– a genetically encoded ability for an organism to avoid a toxic response when exposed to a toxicant
• Usually involves mutations and evolution!

Question 25

Resistance Mechanisms include:

Answer 25

i. Selection for a polymorphism of a resistance factor gene currently in a population
ii. Selection for a new mutation (thus a new polymorphism) in a resistance factor gene
iii. Multiple copies of a gene already in the organism arise (e.g. multiple copies of a gene encoding an enzyme that breaks down a toxicant -> resistance to said toxicant)
iv. A brand new gene picked up from the environment or another organism (bacteria can do this)
v. Genetically engineered into a species

Question 26

selective sweep

Answer 26

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

Question 27

Resistance is a big deal in “pest” management

Answer 27

– 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
– Example: DDT binds to sodium channels and keeps them open, even when they should be closed. Same mechanism for the pyrethroid pesticide permethrin. Natural polymorphisms that reduced binding to the channels were rapidly selected for and resistance to DDT and permethrin in different mosquito populations.
– 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. This leads to a resistant population.