2 MOAs & AOPs

Question 1

what are the learning objectives of this lecture?

Answer 1

-understand the concept of toxicodynamics and how it relates mechanism of action
-identify different levels of biological organization where a toxicant can exert effects on a biological system
-provide reasons for why it is important to understand mechanism of action by which chemicals cause their toxic effect
-identify components of the adverse outcome pathway and how AOPs can enhance our understanding of toxicity
-explain how the use of AOPs can streamline toxicity testing

Question 2

what is the graph of toxicodynamics and toxicokinetics?

Answer 2

Question 3

what is mechanistic toxicology?

Answer 3

-the study of how chemical or physical agents interact with living organisms to cause toxicity=mechanism of action

dont like to use random, instead use non-specific
-DNA is the easiest to describe because they dont target specific nucleotides, and can cause strand breaks between DNA strands
-lipid membranes can also be non specific, so lipophilic molecules can disrupt the fluidity

Question 4

what are mechanisms of action?

Answer 4

there are thresholds for each domino to fall

cellular responses
-apoptosis and necrosis
-cell hypertrophy
-fat accumulation=steatosis
-water accumulation
-accumulation of inflammatory mediators

tissue responses (between cellular and organ)

organ responses
-scar tissue/fibrosis
-fat deposition (fatty liver)

individual response
-disease
-death
-cognitive deficits
-MeHg and parkinsons

Question 5

how so we currently regulate chemicals? how do we assess their potential impact on human and animal health?

Answer 5

-we look at individual and population responses

-take the to the lab and assess in a control environment

Question 6

why understand mechanisms of action?

Answer 6

1. to improve assessment of risk to human health (and animal health)
2. to define a high-risk subgroups in human populations
3. to define threshold of exposure level for toxic compounds
4. to guide/accelerate the development of safer therapeutic drugs
5. to develop antidotes for prevention of acute intoxications and therapy for their treatment
6. to develop biomarkers (early indicators) that alert to the exposure to toxins and potential development of chronic toxicity

Question 7

what is the example of unleaded gasoline

Answer 7

-chronic exposure to UG increases kidney tumors in rats

-heavy alcohol is part of UG and binds to protein in rats
-understanding species differences (human vs. rats)

Question 8

what is an adverse outcome pathway (AOP)?

Answer 8

-a model that identifies the sequence of biochemical events required to produce a toxic effect (adverse outcome) when an organism is exposed to a substance

-is chemically agnostic: AOP is not specific to a chemical, any chemical can use the AOP

Question 9

what are the terms used in AOPs?

Answer 9

-a molecules initiating event: an interaction between the toxic substance and an organism, such as binding of the substance to a receptor or protein
-key events: characterize the progression of the toxicity. Often multiple key events, not always linear
-adverse outcomes: may occur at individual or population levels. Current chemical guidelines are based on toxicity tests measuring adverse outcomes

Question 10

what is the example of an AOP of fibrosis?

Answer 10

exposure and chemically agnostic (what we dont see)
-A “chemically agnostic” AOP describes a biological cause-effect pathway that applies to any chemical capable of triggering the same molecular initiating event — the focus is on the biology, not the identity of the chemical

Question 11

what is the example of AOP in animals?

Answer 11

Question 12

WATCH video

Answer 12