L14 Intro to toxicology

Question 1

Toxicology

Answer 1

The study of the adverse effects of chemical, physical, or biological agents on living
organisms and the ecosystem

Question 2

Toxicant

Answer 2

Substance that produces an adverse biological effect.
Includes chemical, physical and biological forms. (drugs, radioactive material and venoms)

Question 3

Toxicity

Answer 3

Degree at which a toxicant produces harmful effects.

Question 4

Toxicity factors (not influence)

Answer 4

Route
acute vs chronic
target organ tox vs systemic tox

Question 5

4 key factors that influence toxicity

Answer 5

Magnitude of exposure (i.e., “dose”)
* dose-response relationship is fundamental
Route and site of exposure
* inhalation / ingestion / topical / parenteral
Duration and frequency of exposure
* acute / subacute / subchronic / chronic
Latency of toxic response
* immediate or delayed effect (e.g., in utero exposure)

Question 6

Toxic causality

Answer 6

toxicant has induced the observed effects

Question 7

NOAEL

Answer 7

no adverse effect level

Question 8

TD50

Answer 8

the dose at which half of the individuals show response

dose required to produce a particular toxic effect in 50% of animals

Question 9

Dose-response relationship toxicology: slope of curve

Answer 9

the rate at which toxic effects builds up

Question 10

The distribution of responses to a given dose of toxicant within a population resembles a ___ curve

Answer 10

bell-shaped

Question 11

In a bell shaped curve for toxicity responses what are some characteristics of the curve

Answer 11

Most ppl will response similarly being the majority of the curve (middle major).
However, a small proportion will show servere responses (susceptible) or mild responses. (res)

Question 12

deviation from dose-response relationships - individuals can display high susceptibility to toxicants. Why do some people deviate?

Answer 12

• idiosyncratic responses
• genetic factor(s)→ abnormal response or metabolism change.
• hypersensitivity (involve immune response)

Question 13

LD50 (lethal dose, 50%)

Answer 13

the amount of toxicant required in one single dose to kill half of the test population; (mg/kg)

Question 14

Small LD50 means

Answer 14

Greater toxicity as smaller dose can kill half the test population.

Question 15

Large LD50 means

Answer 15

Less toxicity as a bigger dose is needed to kill half the test population.

Question 16

Route and site of exposure to toxicants

Answer 16

Topical contact (skin and eyes): chemicals, microorganisms
Ingestion (GI tract): drugs (including overdose), food poisoning.
Parenteral: bites from venomous animals
Inhalation (lungs): smoking, air pollution, volatile chemicals.

Question 17

Toxicants are less toxic when exposed to which route of administration.

Answer 17

Oral

Question 18

Why does the oral route make toxicants less toxic?

Answer 18

first-pass metabolism by the gut wall and the liver

Question 19

Duration and frequency of exposure to toxicants
0-24hrs
24hrs-a month
1month-3months
3months->3months

Answer 19

Acute
Subacute
Subchronic
Chronic

Question 20

Alcohol acute and chronic toxicity

Answer 20

Acute: CNS depression (effects depend on blood
alcohol concentration)
Chronic: alcohol-related liver disease

Question 21

Dose fractionation

Answer 21

Reduces toxic effects by administering multiple smaller doses are given over a period of time. e.g radiotherapy.

single 100mg dose vs 20mg per week x 5weeks

Exceptions: long-term exposure to carcinogens or mutagens.

Question 22

Latency of toxic response

Answer 22

Toxic response can be observed shortly after exposure to toxicant or after a delay (days to years)

Question 23

[Latency of toxic response example] tri-ortho-cresylphosphate (TOCP)

Answer 23

• an organophosphate used in industry as a lubricant or a plasticiser
• organophosphate-induced delayed neuropathy by degradation of axons of the spinal cord and peripheral neurons - muscle weakness, ataxia
• appear one week after exposure
• aerotoxic syndrome?

Question 24

Tri-ortho-cresylphosphate (TOCP) metabolism

Answer 24

• TOCP is metabolised by CYP450 (1A2, 3A4) to form CBDP (toxic metabolite)
• CBDP irreversibly binds to cholinesterases and will inhibit breakdown of Ach that induces muscle contraction
• Ataxia: loss of control of full body movement.
  *mechanism-based inhibition

Question 25

General mechanisms of toxicity

Answer 25

* lipid peroxidation (NC) * production of reactive oxygen species(NC) * depletion of glutathione(NC) * formation of DNA or protein adducts(C)

Question 26

Non-covalent general mechanisms of toxicity

Answer 26

* **lipid peroxidation**: change membrane permeability and subsequent cell damage and death * **production of reactive oxygen species**: lead to excitotoxicity and neuronal death * **depletion of glutathione**: Reduce the ability to protect cells from oxidative stress, and therefore cell death

Question 27

-covalent general mechanisms of toxicity

Answer 27

**formation of DNA or protein adducts** * protein adduct → antigen * DNA adduct → mutagenesis mutagenesis → carcinogenesis - cancer *or* teratogenesis - structural malformations

Question 28

Organ-on-a-chip

Answer 28

* use of human cells to eliminate inter-species differences. * dynamic 3D environment mimics in vivo physiological conditions

Question 29

Organ-on-a-chip online definition

Answer 29

An organ-on-a-chip is a micro-scale system used for mimicking the human body environment. The goal for organ-on-a-chip is to develop human tissue models for disease modeling and drug testing. They use microfluidics, along with cells, to imitate the physiological and mechanical conditions experienced in the body.

Question 30

conventional models vs organ-on-a-chip

Answer 30

With conventional: inter-species differences limit the use of animal models and in vitro models lack dynamic 3D tissue environment While Ooac: * use of human cells to eliminate inter-species differences. * dynamic 3D environment mimics in vivo physiological conditions

Question 31

Exposome

Answer 31

Complete profile of environmental (i.e., non-genetic) exposure of an individual from conception to death

Question 32

Exposome specific and general external and internal environments

Answer 32

specific external environment (e.g., diet, tobacco, alcohol) general external environment (e.g.,climate, education, social capital) Internal environment (e.g., metabolic factors, gut microbiome)

Question 33

diethylstilbestrol (DES)*

Answer 33

* a synthetic non-steroidal estrogen * treatment for threatened miscarriage between 1941-71 * clear-cell adenocarcinoma of the vagina in female offspring of DES-treated mothers - long delay (15 years or more) between in utero exposure and toxicity

Question 34

thalidomide (limb malformation)

Answer 34

* introduced as a non-addictive, non-barbiturate sedative * an antiemetic to treat morning sickness in pregnant women * early reports of peripheral neuropathy * thalidomide-induced severe birth defects like limbs * mostly effects newborns