Principles Of Toxicology (Chapter 2 EOT) Flashcards
The study of adverse effects of chemical, biological, or physical agents on living organisms and the environment
Toxicology
Foreign or synthetic substances with different intended purposes that are harmful are called ? or ?.
Xenobiotics or toxicants
Naturally occurring harmful substances that originate from plants, microbial organisms, or venoms are called ?
Toxins
Dose of chemicals needed to produce death in 50% of treated animals
LD50
Limitations of using the LD50 include:
Doesn’t reflect full spectrum of toxicity (carcinogens, teratogens, neurobehavior effects); doesn’t take into account individual variability which makes increases susceptibility to a toxin
Type of toxicologist that identifies cellular, biochemical, and molecular mechanisms by which chemicals exert toxic effects on living organisms
Mechanistic toxicologist
Hypersensitivity or allergic reactions require what in order to occur?
Prior exposure to the same or structurally similar chemical
The abnormal reactivity of an individual to a chemical based on their genetics or other individual sensitivity factors
Chemical idiosyncrasy
Idiosyncratic Drug reactions involve a combination of individual differences in the ability to:
1)form a reactive intermediate usually through oxidation to an electrophilic intermediate
2) detoxify the reactive intermediate through hydrolysis or conjugation
3) mount an immune response through human leukocyte antigens (HLAs) and T cells
4) cause cell death
What factors beyond genetics can cause idiosyncratic reactions?
Inflammatory stress, infection, mitochondrial dysfunction, environmental factors
What organ systems are most likely to be affected by idiosyncratic reactions?
Skin, Liver, hematopoietic and immune systems
The likelihood of a toxic response to be reversed largely depends on ?
The ability of the injured tissue to adapt, repair and regenerate
The target organ of toxicity and the site of the highest concentration of the exposed chemical are almost always the same.
False
This type of effect occurs when the combined responses of two chemicals are equal to the sum of the responses to each chemical given alone
Additive effect (2+3=5)
Type of effect when the combined responses of two chemicals are much greater than the sum of the response to each chemical when given alone
Synergistic effect (2+2=20)
Occurs when one substance does not produce any toxicity on a particular tissue or system, but when added to another chemical makes that chemical much more toxic
Potentiation (0 + 2 =10)
Occurs when two chemicals administered together interfere with each other’s actions or one interferes with the action of another
Antagonism (4+6= 8), (4+ (-4)= 0), (4+0=1)
Four types of antagonism are:
Receptor, chemical, dispositional, functional
Receptor antagonists are also known as
Blockers
Chemical antagonism is also known as
Inactivation
Chelation of metal ions is an example of what kind of antagonism
Chemical
Type of antagonism when the absorption, distribution, biotransformation, or excretion of a chemical is altered so the concentration or duration of chemical at target organ is reduced
Dispositional
Type of antagonism when 2 chemicals counterbalance each other by producing opposing effects on the same physiological function often by using different signaling pathways
Functional antagonism
This type of tolerance results from a lower availability of receptors and/or mediators (neurotransmitters)
Chemical or cellular tolerance
Type of tolerance when the amount of the chemical reaching the target organ decreases over time
Dispositional tolerance
Chemicals with higher LD50 values are more/less fatal than those with lower LD50 values
Less fatal
VX nerve gas has an LD50 that is 5x higher/lower than botulinum toxin
True: VX nerve gas 1 mg/kg, botulinum toxin .00001 mg/kg
A chemical given by inhalation would be more or less effective if given orally
Less
Order of effectiveness is: IV, inhalation, IP, SQ, IM, PO, topical
Acute exposure is defined as less than how many hours
24
Acute exposure by inhalation is usually for how many hours
4 but can be up to 24
Subacute exposure is repeated exposure for up to how many months
1 month or less
Subchronic exposure is repeated exposure for how many months
1 to 3 months
Chronic exposure is repeated exposure for how many months
More than 3; usually refers to a year of dosing
The minimal effective dose of any chemical that evokes a stated all or none response is a
Threshold dose
Quantal dose- response relationship curves usually follow what type of distribution
Normal or Gaussian distribution curves
The linear portion of a sigmoid curve represents what
The limits of one standard deviation of the mean and median in a normal distribution population
The mean +/- one, two and three SD’s in a normal distribution is equivalent to what percent of the population
68.3%, 95.5%, 99.7% respectively
What is an NED and how is it obtained
Normal equivalent deviation, calculated by using % response to derive units of deviation from the mean when using a normal distribution curve
An 80% response would give what NED
+/- 1
What is a probit unit
Converted NEDs by adding 5 to the value; used to avoid negative numbers; short form of probability unit
An NED of -2 would equate to what in probit units
3
(-2 + 5)
A probit transformation would adjust a normal distribution of quantal data to what
A straight line
How is the ED50 obtained from a probit unit diagram
Drawing a horizontal line at the probit unit 5 mark through the dose effect line. The intersection is the ED50 on the abscissa
Field of study that examines the relationship between body weight and various other physiological parameters (basal metabolic rate, heart rate, blood flow)
Allometry
What formula is used in allometrix studies
Y= a W^b
Y is biological parameter of interest
A and b are constants that relate Y to body weight
Formula for comparing body weight to body surface area
SA=10.5 x (body weight in g)^0.67
How do you calculate the human equivalent dose
HED= animal dose in mg/kg x (animal weight in kg/human weight in kg)
What is PBPK modeling
Physiologically based pharmacokinetic modeling; a type of computer modeling that is used to scale doses across species
What is a monotonic response?
Increasing dose will cause a steady unidirectional change in response; can be uphill or downhill curves
Type of dose-response curve when multiple inflection points exist along a curve that changes shape
Nonmonotonic
U, J, or inverted U shaped curves are examples of what types of dose-responses
Nonmonotonic
Hormetic effects or hormesis occurs when chemicals exhibit what kind of effect at low exposures but opposite kinds of effects at high doses
Beneficial at low; harmful at high
Type of model where it’s assumed there is a direct and proportional relationship between dose and response even at very low doses
Linear, nonthreshold
Dose at which toxicity is first observed
Threshold
Concept that there are levels of exposure for chemicals below which the risk to human health is not appreciable
Threshold of toxicologic concern (TTC)
Essential nutrients for organisms frequently fall under what type of graded dose-response curve
U shaped (linear, nonmonotonic)
An example of hormesis is
Alcohol consumption reducing risks of coronary artery disease at low consumption but increasing risks of cancer at high consumption
The nonmonotonic dose-response curves observed with endocrine disruptors can be explained by what mechanisms
Dose-dependent cytotoxicity, cell and tissue specific receptors and cofactors, receptor selectivity and down-regulation, receptor competition, endocrine negative feedback loops
The ratio of the dose required to cause a toxic effect to the dose required produce the desired therapeutic response
Therapeutic index; TD59/ED50
How is margin of safety calculated?
MOS= TD1/ED99
How is chronicity index calculated? What is ideal value? What are the units?
One dose TD50 (mg/kg) /90 dose TD50 (mg/kg/day); ideal is 1; no units
