L14 Intro to toxicology Flashcards
Toxicology
The study of the adverse effects of chemical, physical, or biological agents on living
organisms and the ecosystem
Toxicant
Substance that produces an adverse biological effect.
Includes chemical, physical and biological forms. (drugs, radioactive material and venoms)
Toxicity
Degree at which a toxicant produces harmful effects.
Toxicity factors (not influence)
Route
acute vs chronic
target organ tox vs systemic tox
4 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)
Toxic causality
toxicant has induced the observed effects
NOAEL
no adverse effect level
TD50
the dose at which half of the individuals show response
dose required to produce a particular toxic effect in 50% of animals
Dose-response relationship toxicology: slope of curve
the rate at which toxic effects builds up
The distribution of responses to a given dose of toxicant within a population resembles a ___ curve
bell-shaped
In a bell shaped curve for toxicity responses what are some characteristics of the curve
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)
deviation from dose-response relationships - individuals can display high susceptibility to toxicants. Why do some people deviate?
- idiosyncratic responses
- genetic factor(s)→ abnormal response or metabolism change.
- hypersensitivity (involve immune response)
LD50 (lethal dose, 50%)
the amount of toxicant required in one single dose to kill half of the test population; (mg/kg)
Small LD50 means
Greater toxicity as smaller dose can kill half the test population.
Large LD50 means
Less toxicity as a bigger dose is needed to kill half the test population.
Route and site of exposure to toxicants
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.
Toxicants are less toxic when exposed to which route of administration.
Oral
Why does the oral route make toxicants less toxic?
first-pass metabolism by the gut wall and the liver
Duration and frequency of exposure to toxicants
0-24hrs
24hrs-a month
1month-3months
3months->3months
Acute
Subacute
Subchronic
Chronic
Alcohol acute and chronic toxicity
Acute: CNS depression (effects depend on blood
alcohol concentration)
Chronic: alcohol-related liver disease
Dose fractionation
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.
Latency of toxic response
Toxic response can be observed shortly after exposure to toxicant or after a delay (days to years)
[Latency of toxic response example] tri-ortho-cresylphosphate (TOCP)
- 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?
Tri-ortho-cresylphosphate (TOCP) metabolism
- 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
General mechanisms of toxicity
- lipid peroxidation (NC)
- production of reactive oxygen species(NC)
- depletion of glutathione(NC)
- formation of DNA or protein adducts(C)
Non-covalent general mechanisms of toxicity
- 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
-covalent general mechanisms of toxicity
formation of DNA or protein adducts
* protein adduct → antigen
* DNA adduct → mutagenesis
mutagenesis → carcinogenesis - cancer
or teratogenesis - structural malformations
Organ-on-a-chip
- use of human cells to eliminate inter-species differences.
- dynamic 3D
environment mimics in vivo
physiological conditions
Organ-on-a-chip online definition
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.
conventional models vs organ-on-a-chip
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
Exposome
Complete profile of environmental (i.e., non-genetic) exposure of an individual from conception to death
Exposome specific and general external and internal environments
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)
diethylstilbestrol (DES)*
- 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
thalidomide (limb malformation)
- 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
