Mbm 432 Applied molecular toxicology Flashcards
Human chemical carcinogenesis
A multistage process that leads to cancer, caused by exposure to certain chemicals in a human’s environment.
Most of these chemicals do not cause DNA damage directly but are converted into electrophilic carcinogens by the body’s toxin neutralization processes. The electrophiles are then attracted to neutrophiles in the cells (DNA and protein) and bind to them covalently, causing damage. Still, some of these chemicals act directly.
The degree of carcinogenesis caused by these chemicals vary from person to person.
Toxicogenomics
A field that studies the effects of toxins on an organisms’ cells at the genetic level.
It is based on collection, interpretation and storage of information about gene expression and protein activity of cells in response to toxic substances.
Genotoxicity
A property of substances, characterized by their ability to cause genetic damage. This damage may lead to cancer and other genetic diseases.
Mutagenicity
A property characterized by the causation of mutations in the genetic material of an organism.
Used interchangeably with genotoxicity, although all genotoxic substances are mutagenic but not all mutagenic substances are genotoxic.
Epigenetics
The study of how the environment shapes genetic expression.
Unlike mutations, epigenetic changes are reversible and do not change DNA structure.
Toxicological risk assessment
The systematic analysis of potential health risks from exposure to hazardous substances or conditions.
What is risk
The tendency of something to lead to adverse effects
What is risk management?
A set of actions, chosen to reduce risk
5 Objectives of risk assessment
To protect human and ecological health from toxic substances
Balance risks and benefits of substances like pesticides
To establish limits for exposure to toxic substances
Establishes a hierarchy of risk, for regulatory agencies to prioritize handling the most risky exposuresfirst.
Estimation of residual risk after risk reduction steps have been taken
Toxins
Poisonous substances produced through biological activity
Toxicants
Any toxic substance. Includes toxins and poisonous chemicals
Toxic
Poisonous
Toxicity
Describes the degree to which a substance is poisonous.
4 factors Toxicity depends on
Dose,
duration and route of exposure
Shape and structure of the toxic substance
Individual human factors
Dose
Amount of substance actually administered. Does not account for the size and weight of the animal.
10mg of a drug.
Dosage
refers to the amount per body weight of the individual.
10 mg/kg of body weight.
Total dosage
Considers duration of exposure.
A dosage of 10 mg/kg per day for 10 days translates to a Total Dosage of 100 mg/day / kg
Efficacy of an agent
A measure of the maximum effect the agent can have on a system, relative to the ideal effect. can be quantified in a range of 0 to 1, with one being the ideal effect.
Potency
The amount of agent required to produce an intended effect.
Usually stated (in determining toxicant potency) as amount (mg, concentration or total dosage) required to produce half the maximum effect (0.5 efficacy).
A drug that produces this half maximum effect at a lower dose is said to be more potent than one that requires more of it.
Toxication
An instantaneous toxic action resulting from the action of a toxic agent at a given moment in time.
Intoxication
Refers to the effects that occur from being exposed to a toxic substance. Could be instantaneous or not.
Toxicology
The study of poisons, chemical, physical, biological e.t.c.
and their effects on organisms
What is a poison?
A poison is a chemical or physical agent that produces adverse responses in biological organisms, capable of disturbing the normal physiological homeostasis of the exposed body.
What is the significance of the concept of poison being quantitative?
The concept of poison being quantitative means that any substance can be harmful at some doses but may have no harmful effect at lower doses.
There is a range of possible effects between these two limits, from subtle long-term chronic toxicity to immediate lethality.
Provide two examples of substances that demonstrates the quantitative nature of poison?
Vinyl chloride: A potent hepatotoxicant at high doses, a carcinogen with a long latent period at lower doses, and apparently without effect at very low doses.
Aspirin: safe at recommended doses but can cause gastric mucosa damage and is fatal at a dose of about 0.2 to 0.5 g/kg.
Why is measuring toxicity complex?
Toxicity measurement is complex because it may be acute or chronic and can vary from one organ to another, as well as with factors like age, genetics, gender, diet, physiological condition, or the health status of the organism.
What makes classifying a substance as a toxicant complex (2 things)
Due to genetic variation. What is toxic to one organism/species/strain may be harmless to another.
Also some substances are poisonous when combined with others but harmless alone
5 importance of toxicology
Facilitate the development of more selective toxicants like anticancer drugs and pesticides.
To understand how exposure to certain chemicals cause acute and chronic illnesses.
To understand physiology and pharmacology by using toxic agents as chemical probes
For the recognition, Identification and quantification of hazards from occupational exposure to chemicals.
For the development of standards and regulations to protect humans and the environment from adverse effects of toxic chemicals.
3 classifications of toxicity of a substance based on duration and frequency of exposure
Acute: Single or short term dosing causes toxicity
Sub-acute: Repeated applications for a duration less than half-life expectancy of the organsim, causes toxicity
Chronic: Toxicity is shown only after repeated exposure to the substance for a time greater than half the life-expectancy of the organism
3 examples of toxic pesticides and their effects
Organochlorines: Hypersensitivity to light, sound and touch, causes tremors, dizziness, nausea and confusion
Organophosphates and carbamates: Causes nausea, diarrhea, muscle weakness and fatigue
Pyrethroids: May be carcinogenic and affect the reproductive and endocrine system
3 possible sites of toxic actions
Local (non-systemic): Affects wherever it comes in contact with. e.g acids, alkalis
Remote (systemic): Affects a part of the body, far from its entry point
Local and Remote: Can both act locally and remotely. e.g Oxalic acid.
3 sources of toxic substances. Give examples
Chemical: Most common. e.g drugs corrosives
Plants: Cocaine
Animals: least common, most dangerous. e.g Scorpions, spiders, snakes, wasps e.t.c.
4 examples of toxic solvents and vapours with their effects
Benzene: Carcinogenic. At low concentrations, may cause dizziness, headache and loss of appetite. High exposure causes irregular heart beat which leads to death.
Toluene: Neurotoxin
Methyl Chloride: Affects reproductive health.
n-hexane: Neurotoxin
6 branches of Toxicology
Mechanistic
Forensic
Clinical
Environmental
Food
Regulatory
6 examples of toxic plants and their effects
Cashew: Allergic dermatitis
Grasses: Allergic rhinitis
Lilies: Affects the GI tract
Mushrooms: Affects the nervous system
Fugus that grows on peanuts: Liver cancer
Legumes: Affects reproductive system
7 types of toxic agents
Heavy metals
Solvents and vapours
Radiation and radioactive materials
Dioxin/Furans
Pesticides
Plant Toxins
Animal Toxins
8 classifications of toxic agents
According to the target organ they act on e.g hepatotoxic, nephrotoxic
According to their use e.g. drugs, pesticides
According to their source e.g. chemical, animal of plant
According to their effects e.g. Carcinogen, mutagen
According to their physical state e.g gas, liquid
According to their chemistry e.g. Amine, hydrocarbon
According to their poisoning potential e.g. slightly toxic, extremely toxic
According to their biochemical mechanism of action e.g alkylating agent
Definition of the clinical branch of toxicology
Has to do with the treatment of poisonings and injuries caused by xenobiotics
Definition of the Environmental branch of toxicology
A branch that deals with environmental pollutants and their effects on flora and fauna
Definition of the food branch of toxicology
Studies adverse effects of food components, both natural and processed
Definition of the Forensic branch of toxicology
A branch that has to deal with identifying the role of toxic substances in an individual’s death
Definition of the mechanistic branch of toxicology
A branch that deals with the molecular and cellular mechanisms by which chemicals use to bring about toxic responses
Four examples of heavy metals and their effects
Cadmium: Carcinogenic. Smokers are more exposed so lung cancer
Lead: Damage the brain and Kidneys, leading to death. Causes miscarriage and in main damages organs that produce sperm.
Mercury: High levels damage brain, kidneys and foetuses
Selenium: Oral exposure to high levels causes selonosis, characterized by hair loss, brittle nails and neurological issues.
Short-term exposure to high levels in air can cause respiratory tract irritation and stomach pain. Longer-term exposure leads to worsening of these symptoms
Definition of the regulatory branch of toxicology
Assigns risk to substances of commercial importance
Short and long term effects of Dioxin/Furans
Short term: Skin lesions and altered liver function
Long term: Impairment of the immune, nervous, endocrine and reproductive system
Short and long term effects of exposure to radiation
Short term: Acute radiation syndrome (ARS). Symptoms include nausea, vomiting, headache and diarrhea
Long term: Cancer, Abnormal foetuses, Poor mental health
Two examples of toxic animals and their toxic effect
Scorpions: Produces neurotoxin
Snakes: Produce neurotoxin
Types of toxic mechanisms
Direct: The poison itself causes adverse effects e.g. corrosives
Indirect: Toxicity results from interacton of the poison with biological activity, leading to a negative change e.g effects on DNA, Interferenct with enzymatic actions
What is exposure in terms of toxicology
The concentration of chemical involved and frequency of its interaction with people
What is excessive exposure
The degree of exposure that leads to injury or adverse effects
4 ways humans may be exposed to toxicants
Accidental poisoning
Intentional poisoning
Occupational exposure
General environmental exposure
4 Routes of exposure
Skin and mucuous membranes
Lungs (inhalation)
Ingestion
Eyes
2 chemicals that can be absorbed through the skin
Aniline
Hydrogen cyanide
Exposure through the lungs depends on
The size and shape of the particle
Effect of exposure to a toxicant of large size via the lung
Particles >10 micro-meters lodge in brochi/bronchioles.
It is cleared by mucociliary activity and moves via the oesophagus into the gut.
Effect of exposure to a toxicant of small size via the lung
Anything less than 2 micro meter persists in the alveoli and causes harm e.g Asbestos
Macrophages in the lungs attempt engulfing it but are damaged instead. This leads to hydrolytic enzyme leak from the damaged macrophages, causing local tissue damage and fibrosis.
The presentation of adverse effects that occur from ingestion of toxicants could be
Local
Systemic
Both local and Systemic e.g Allergic reaction
Accumulatory: Either harmless (some pesticides like organophosphates accumulate in adipose tissue) or harmful (death of nerve cells following repetitive exposure)
4 factors that affect the degree of adverse effect a toxicant produces at any given moment after ingestion
Balance between absorption and excretion
Balance between injury and repair
Immediate or delayed effect
Reversible or irreversible
3 outcomes interacting chemicals could cause
Additive effect (1+1= 2)
Synergistic effects (1+1 = 4)
Antagonist (1 + 5 = 2)
Define tolerance to a chemical
A decrease in sensitivity to that chemical. Usually after an initial period of exposure
Define resistance to a chemical
Complete insensitivity towards a chemical
What is meant by the word toxicodynamics
The term encompasses the mode of action of a toxicant on a living organism that ultimately leads to the adverse effects it produces
What is the toxicodynamics of liver cirrhosis caused by excessive alcohol
Excessive ethanol injures the liver by blocking metabolism of fat and carbohydrate, leading to the accumulation of fat in the liver cells, a condition known as fatty liver disease (FLD).
Ethanol is converted to acetaldehyde. Acetaldehyde is a key toxin that can cause cellular damage, inflammation, and fibrosis, which contributes to the development of cirrhosis.
