Intro to toxicology Flashcards
Describe toxicology
The study of the adverse effects of chemical, physical, or biological agents on living organisms and the ecosystem
history of poisons
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
toxicant
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)
Toxicity
the degree to which a toxicant produces harmful effects
- acute vs chronic toxicity
- target organ toxicity vs systemic toxicity
Key factors that influence toxicity
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)
explain the impact of magnitude of exposure on toxicity
anything is toxic if you have enough of it
explain the relevance of dose- response relationship to toxicity
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
Deviation from dose-response relationships
Individuals can display idiosyncratic responses to toxins making them more sensitive to toxicants
Causes:
Genetic factors
Hypersenstivities
Measuring toxicity
LD50 - Lethal dose
the amount of dose that it takes to kill 50% of the pop.
- smaller the LD50 –> greater the toxic effects
explain the impact of routes/sites of exposure on toxicity
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
explain the relevance of pharmacokinetics to toxicity (toxicokinetics)
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
explain the impact of duration and/or frequency of exposure on toxicity with examples
the longer the duration of exposure the worse the toxicity
- alcohol: acute = CNS depression, Chronic = liver disease
measuring the duration of exposure
acute - less then 24hrs exposed
subacute- less then one month
subchronic - less then three months
chronic- greater then three months exposed
Dose fractionation
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
explain latency of toxic response
Toxic response can be observed shortly after exposure to toxicant or after a delay (days to years)
tri-ortho-cresylphosphate (TOCP)
- 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
diethylstilbestrol (DES)
- 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
thalidomide
- 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
Non - covalent interaction
toxicity
- 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
Covalent interaction
toxicity
- formation of DNA or proteins adducts:
protein adduct → antigen
DNA adduct → mutagenesis –>
carcinogenesis - cancer OR
teratogenesis - structural malformations
outline main advantages of the use of organ-on-a-chip to assess toxicity
- use of human cells to eliminate
inter-species differences - dynamic 3D
environment mimics in vivo physiological conditions
describe exposome and its relevance to assessing the impact of environment on health
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
