Intro to toxicology

Question 1

Describe toxicology

Answer 1

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

Question 2

history of poisons

Answer 2

Paracelsus - (“Father of Toxicology”) documented the importance of dose in
determining response

Mathieu Orfila - (“Founder of Modern [Forensic] Toxicology”) refined methods to
detect arsenic

20th-21st centuries - understanding of toxic effects at molecular levels

Question 3

toxicant

Answer 3

a substance that produces adverse biological effects
- chemical form - drugs, tobacco, cleaning products, pesticides
- physical form - radioactive materials and radiation
- biological form - naturally produced by organisms (e.g., venoms, toxins)

Question 4

Toxicity

Answer 4

the degree to which a toxicant produces harmful effects
- acute vs chronic toxicity
- target organ toxicity vs systemic toxicity

Question 5

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

explain the impact of magnitude of exposure on toxicity

Answer 6

anything is toxic if you have enough of it

Question 7

explain the relevance of dose- response relationship to toxicity

Answer 7

the more dosage is given of a substance the higher the likelihood of developing toxic effects

data obtained from the investigation of dose-response relationships can indicate:
- which substance induced toxic effects
- threshold: non adverse effect level
- TD50: when half the pop. experiences toxicity
- slope of curve: how quickly the toxic effects build as dose increases

Question 8

Deviation from dose-response relationships

Answer 8

Individuals can display idiosyncratic responses to toxins making them more sensitive to toxicants

Causes:
Genetic factors
Hypersenstivities

Question 9

Measuring toxicity

Answer 9

LD50 - Lethal dose
the amount of dose that it takes to kill 50% of the pop.
- smaller the LD50 –> greater the toxic effects

Question 10

explain the impact of routes/sites of exposure on toxicity

Answer 10

differing sites of exposure depend on route of administration

• the higher the concentration of a toxicant at exposure the more toxic effect it will take on the exposed organ e.g. smoking –> lungs

Question 11

explain the relevance of pharmacokinetics to toxicity (toxicokinetics)

Answer 11

toxicants are less toxic when exposed to via the oral route than the i.v. route
- mechanisms like first pass metabolism in the gut wall and liver can help decrease toxicity

Question 12

explain the impact of duration and/or frequency of exposure on toxicity with examples

Answer 12

the longer the duration of exposure the worse the toxicity
- alcohol: acute = CNS depression, Chronic = liver disease

Question 13

measuring the duration of exposure

Answer 13

acute - less then 24hrs exposed
subacute- less then one month
subchronic - less then three months
chronic- greater then three months exposed

Question 14

Dose fractionation

Answer 14

Decreases the toxic effects of a drug
- multiple smaller doses are given over a period of time rather then on highly toxic dose
- long-term exposure to carcinogens and mutagens are exceptions

Question 15

explain latency of toxic response

Answer 15

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

Question 16

tri-ortho-cresylphosphate (TOCP)

Answer 16

• organophosphate-induced delayed neuropathy
• appear one week after exposure
• metabolites bind to cholinesterase
• inhibits the breakdown of acetylcholine that
  induces muscle contraction, leading to build up of
  acetylcholine and exposure inhibition

TOCP is metabolised by CYP450 (1A2, 3A4) to form CBDP (toxic) –> CBDP irreversibly binds to cholinesterases –> inhibits the breakdown of acetylcholine inducing muscle contraction

Question 17

diethylstilbestrol (DES)

Answer 17

• 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 18

thalidomide

Answer 18

• 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

Question 19

Non - covalent interaction
toxicity

Answer 19

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

Question 20

Covalent interaction
toxicity

Answer 20

• formation of DNA or proteins adducts:
  protein adduct → antigen
  DNA adduct → mutagenesis –>
  carcinogenesis - cancer OR
  teratogenesis - structural malformations

Question 21

outline main advantages of the use of organ-on-a-chip to assess toxicity

Answer 21

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

Question 22

describe exposome and its relevance to assessing the impact of environment on health

Answer 22

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

• specific external environment e.g. diet
• internal environment e.g. metabolism
• general external environment e.g. social capital, climate
  All interact and can be the trigger that causes the onset of disease