Overview of Toxicology Flashcards
Toxicology
A branch of science that studies the adverse effects of chemical, physical or biological agents on living systems and the ecosystem, including the prevention and the amelioration of such adverse effects
Descriptive Toxicology
- Focuses on testing of toxic substances
- Typically using animals and then correlating finding to humans
- Provides information for safety evaluation and regulation, such as dose-response information
E.x., Assessing the reproductive toxicity of BPA
Mechanistic Toxicology
- Identify and understand the mechanisms that underlie the toxic effects of drugs or chemicals on living systems
- Also identifies whether the effects are genotoxic, teratogenic, carcinogenic, neurotoxic, etc.
E.x., Study identifying targets of gymnodimines
Regulatory Toxicology
- Assessing whether a drug or chemical poses a risk to human health
- Uses information gathered from toxicity testing
- Establishes standards and/or guidelines for safe exposure
E.x., guidance for the consumption of bitter apricot kernels
Forensic Toxicology
- Concerned with the medico-logical aspects of the harmful effects of toxic substances, environmental chemicals or poisonous products on human animals
Determines the cause of death in a post-mortem investigation
E.x., red tide in Florida linked to dolphin deaths
Clinical Toxicology
- Concerned with disease states caused by or associated with toxic substances
- Usually involves physicians or individuals specialized in emergency medicine and/or poison management
E.x., New study linked exposure to second-hand tobacco smoke can predict cardiac arrhythmia
Environmental Toxicology
- Concerned with the impact of physical and chemical pollutants in the environment on biological organisms
- Includes the effects on human health and non-human organisms (such as fish, birds, and terrestrial animals)
E.x., Micro-plastics in bottled water
Ecotoxicology
- Specialized are within environmental toxicology that is concerned with the impacts of toxic substances on population dynamics in an ecosystem
-Also evaluate the transport, fate, and interactions of toxic substances in the environment
E.x., studying the effects of glyphosate (herbicide) on honey bees
Toxins
peptides or proteins produced by living cells or organisms
E.x., natural toxins like phytotoxins
Toxicants
Substances that are synthetic
E.x., man made things like bisphenol A (BPA)
Poisons
Any synthetic or natural substance that is harmful to health
Xenobiotic
Foreign substance taken into the body
- may produce beneficial effects (i.e., pharmaceuticals)
- may produce toxic effects (i.e., heavy metals)
Toxic Agents
Anything that can produce an adverse biological effect
- Can be chemical (cyanide), physical (radiation), or biological (snake venom)
Toxic Substances
Any material that has toxic properties
- Can be a discrete toxic chemical (lead) or a mixture of chemicals (gasoline)
Toxicity
The degree to which a substance can harm humans or animals
- can be acute, sub-chronic, or chronic
Toxicity can result from?
Averse
- cellular changes (e.x., cell death (cytotoxins))
- biochemical changes (e.x., elevated liver enzymes(hepatotoxins))
- Macromolecular changes (e.x., altered insulin signalling (diabetogens))
Acute Toxicity
- Adverse effects occurring in an organism after a single exposure or short-term exposure (<24 hours)
- Exposure to a large dose (weak toxin) or a small dose (potent toxin)
- The onset of symptoms is sudden and severe in nature
- Rapidly changing course of progress
E.x., Novichok poisoning (inhibits acetylcholinesterase)
Sub-chronic Toxicity
- Due to repeated exposure for several weeks of months
- The ability of a toxic substance to cause adverse effects for more the lifetime of the exposure organism
E.x., Warfarin (blood thinner)- internal bleeding
Chronic Toxicity
- The ability of a toxic substance to cause adverse effects over an extended period, usually repeated or continuous exposure, sometimes lasting for the entire life of the exposed organism
- Cumulative damage
- Damage becomes so severe that the organ can no longer function as normal
E.x., Cirrhosis in alcoholics
Toxic response: Local vs Systemic
Local: effects at the site of contact (e.x., lungs)
Systemic: effects distant form exposure site (e.x., central nervous system)
- some can be both
Toxic responses: Specific vs Widespread
Specific: affects only specific target organs
Widespread: can damage any cell or tissue that it come in contact with
- some can be both
Toxic responses: Immediate vs Delayed
Immediate: response minutes to hours after a dingle exposure (e.x., azaspiracides)
Delayed: response days to years after exposure (e.x., PMAA)
- some can be both
Toxic responses: Reversible vs Irreversible
Reversible: rapidly regenerating tissue (e.x., liver)
Irreversible: not regenerating or recovery (e.x., carcinogenesis)
Influencing factors
- tissue involved
- length of exposure
- magnitude of toxic
Direct Toxicity
substances or their metabolites themselves are toxic (e.x., phthalates)
Indirect Toxicity
Some substances may be toxic by indirect modifying an essential biochemical function, interfering with nutrition, or altering a physiological mechanism
(e.x., TiO2 nanoparticles)
Three phases of toxicology
- Exposure (contact)
- how an organism come sin contact with a toxin - Toxicokinetic (movement)
- the study of the movement of the toxin within the body
- absorption, distribution, metabolism, and excretion (ADME) - Toxicodynamic (effects)
- the study of what the toxin does to the body
- physiological, biochemical, molecular (PBM)
Exposure Phase: Sources
- Consumer products,
- Clothing
- Residential and other water
- Indoor and outdoor air, tobacco smoke, household dust
- Food, beverages, and food packaging
- Toys
- Furniture, carpeting, paint, and other building materials
Exposure Phase: Route
- oral
- dermal
- inhalation
- injection
Exposure Phase: Duration
- Acute (<24 hours)
- Subacute (<1 month)
- Sub-chronic (1-3 months)
- Chronic (>3 months)
How to Assess Exposure
- An individuals’ exposed to a substance can be assessed based on the relationship between a person’s body weight and
- The concentration of the substance
- Amount of a substance taken into the body
- Duration and frequency of exposure
- This will determine the dose of a substance that an individual is exposed to
Exposure
Any condition which provides an opportunity for an external environment substance to enter the body
Dose
The amount of a substance actually deposited within the body
- A dose can be affected by route, duration, frequency, amount, concentration as well as body weight, sex, age, time etc.
Exposure Units
mg/L in water
mg/kg in food
mg/m3 in air
Dosage Units
Amount of substance per unit weight of the exposed organism
Dosage = mg (dose)/ kg (body weight)/day (duration)
Administered Dose
The quantity administered to an organism at one time
Internal Dose
The about of a toxin that stays in an organism’s body
Total Dose
Sum of all individuals doses
Total dose= concentration X amount X frequency X duration
Response (endpoint)
The biological response to a substance
Change in structure or function, morbidity or mortality
Dose Response Relationship
Quantitative analysis or mathematical description of the association between dose (or exposure) and a toxic response (or endpoint)
- association relationship
- responses follow normal frequency distribution
Normal Distribution
- Graph of individual responses to a substance to show how a population will be affected
- Response (from mild to severe) along the x-axis
- # of individuals (few to many) with each type of response along the y-axis
- If graph the individual responses you end up with a bell-shaped curved (also known as a standard distribution)
- Largest # of individuals fall within the highest area of the graph (mean response)
- Standard deviation (SD) is a measure that indicates variation or dispersion of a set of values
- Greater the SD, the greater the variability within a population
- SD of 0 means most of the values fall near the mean
- Indicates majority of responses to a substance are similar within a specific population
- SD from -1 to 1 accounts for approximately 68% of the individuals
- SD of -2 to 2 accounts for approximately 95% of the individuals
Dose Response Curve
- A quantitative relationship between dose and response can be plotted on a graph
- Dose (or exposure) on the x-axis – usually in a logarithmic scale (increase by a power of 10)
- Response (or endpoint) on the y-axis – usually as the percentage of individuals that show a response
- Dose-response curve normally takes the form of a sigmoid curve shaped like the letter “S”
NOAEL
No Observed Adverse Effect Level
- highest dose at which no toxic effects observed
LOAEL
Lowest Observed Adverse Effect Level
- lowest dose at which toxic or adverse effects observed
LD50
Can extrapolate from dose-response curve
- response vs dose meeting point along the graphed line
Toxicokinetic: Absorption
- Normally cells in solid tissues are so tightly compacted that substances cannot pass between them
- Not going to have a toxic effect if not absorbed readily
- In order to reach the site where it exerts is toxic effects the substance often has to pass through several membrane barriers
- Substances that cross the cell membrane use either
- Passive transfer
- Facilitated transport (facilitated diffusion, active transportation, and endocytosis)
Absorption: Passive Transfer
- Consists of simple diffusion
- No cellular energy or assistance is required
- Most common way that toxins cross cell membranes
- Two factors determine the rate of passive transfer
- Concentration gradient (high or low)
- Movement through small pores small pores in membrane or lipophilic interior of the membrane
Properties affecting a chemical substance for passive transfer include
- Lipid solubility
- Molecular size
- Degree of ionization
Absorption: Facilitated diffusion
Requires special transport proteins embedded within the cell membrane to facilitate movement of molecules across the membrane
- Compared to passive transport
- Faster and can move larger molecules
Absorption: Active Transport
Some substances are unable to move with diffusion, dissolve in the lipid layer or are too large to pass through aqueous channels or movement may be against the concentration gradient
- Requires cellular energy (ATP)
- E.x., sodium transfer pump
Absorption: Endocytosis
Cell surrounds the substance within a section of its cell wall
Toxicokinetic: Distribution
Distribution is the process in which an absorbed chemical moves away from the site of absorption to other areas of the body
- blood can distribute chemicals
- liver, kidneys, bone can store chemicals
- barriers are in place for protection (e.x., BBB)
Toxicokinetic: Metabolism
Conversion of a chemical from one form to another by biological organism
- two types
Detoxification and Bioactivation
Metabolism: Biotransformation
Something is happening to the compound, either making it more or less toxic
- Phase I reactions
Modify the chemical by adding a functional structure group
- Phase II reaction
Conjugate the modified substance with another substance
Toxicokinetic: Detoxification
Chemical substance is converted to a less toxic form
Generally speaking lipid-soluble compounds are converted to polar compounds
Toxicokinetic: Bioactivation
Chemical substance is converted to more reactive or toxic forms
DEHP vs. MEHP
Excretion
Sites of excretion include the Kidneys (main), GI tract, Lungs, sweat, tears, and breast milk
Factors influencing Toxicity
- innate chemical activity of a substance
- dosage
- exposure rate
- absorption
- species
- age of organism
- gender of organism
- metabolism
- distribution within the body
- health status
- circadian rhythms
- presence/interaction of other chemicals
Interaction: Addictive
Effects of two or more chemicals are equal to sum of the effects of each agent given along
2+3=5
Interaction: Synergistic Effects
Effects of two or more chemicals are greater to sum of the effects of each agent given alone
2+2=20
Interaction: potentiation effects
Occurs when one chemical that does not normally have toxic effect is added to another chemical, making the second chemical more toxic
0+2=10
Interaction: Antagonistic effects
Effect of two or more chemicals interfere with each other’s action
Often a desirable effect in toxicology and the basis for most antidotes
- 4+0=1 (one chemical has no effect on its own)
- 4+ (-4) = 0 (one chemical has the opposite effects)
- 4+6=8 (both have toxic effects, less toxic when combined)
physiological antagonism
Severe drop in blood pressure due to a barbiturate overdose reversed by administration of vasopressor
chemical antagonism
Mercury toxicity can be reduced by chelating the mercury ions with dimercaprol
dispositional antagonism
Swallowed poison is absorbed by introducing charcoal into the stomach reducing duration of chemical at target organ
receptor antagonism
Carbon monoxide poisoning is treated with oxygen to displace the carbon monoxide from the hemoglobin receptors
