Toxicodynamics /Toxicokinetics Flashcards
what is Toxicokinetics?
The modeling and mathematical description of the time course of disposition of toxicants
What are the major routes of toxicant exposure?
the skin, lungs, and gastro-intestinal tract
the ________ of the molecule is very important to consider since it has to _______________
the lipophilicity of the molecule is very important to consider since it has to cross membranes
When it comes to absorption by the skin, toxicants cross the ________ by __________
Toxicants cross the stratum corneum by diffusion
for absorption of toxicants by lungs, the major source of toxicant is what?
dust
when absorbed by the lungs, where do gas molecules go and where do other particles go?
- Gas molecules diffuse into the blood;
- Particles may be deposited in the tracheobranchial region; they may be swallowed, removed by phagocytosis, or by lymphatics.
Most chemicals cross the GI epithelium by _________ and Rate of transport correlates with _________________
Most chemicals cross the GI epithelium by simple diffusion and Rate of transport correlates with lipid solubility
what are the different specialized barriers? Are they static or dynamic?
- blood-brain barrier (static)
- placenta (dynamic)
what are main bodily fluids used to measure the level/distribution of toxicants?
urine and blood
what are the different body fluids/parts that can be used to measure toxicants?
- urine
- blood
- breastmilk
- umbilical cord fluid (to see what baby was exposed to during pregnancy)
- seminal plasma
- saliva
- hair
What are the major ways in which toxicants are biotransformed?
phase 1:
- hydrolysis, reduction, oxidation
phase 2:
- conjugation
what is an example of a hydrolysis biotransformation enzyme?
Epoxide Hydrolase
what is an example(s) of an oxidation biotransformation enzyme?
Alcohol Dehydrogenase (ADH)
Aldehyde Dehydrogenase (ALDH)
cytochrome P450s
What are the major conjugation reactions for eliminating toxicants?
- glucuronidation
- acetylation
- glutathione conjugation
- sulfonation
- methylation
- amino acid conjugation
what is the function of a conjugation reaction?
add anything that makes a molecule more polar and more easily eliminated
what are different elimination methods?
- Fecal Excretion
- Exhalation
- Urinary Excretion
what does low and high AVD mean?
- low: high plasma protein binding with little distribution in tissue
- high: high tissue uptake and trapping in lysosomes
Vd = ?/?
Dose/C0
in first order elimination, how long does it take to remove at least 95% of a toxicant?
5 half-lives
how much chemical eliminated in zero order kinetics?
A fixed amount is eliminated per unit of time
in first-order kinetics [C] falls ______ and in zero-order, it falls _________
exponentially, linearly
what are the two compartments in the 2-compartment model and what do they represent?
1 - Central compartment represents plasma and tissues that equilibrate rapidly
2 – Peripheral compartment, equilibrates more slowly
To identify a target molecule as responsible
for toxicity, the toxicant must what?
- reach an effective concentration at target site
- react with target and adversely affect function
- alter target in a way that is mechanistically
related to toxicity
what are the two reaction types?
noncovalent binding and covalent binding
what are the targets of noncovalent binding, is it reversible?
- membrane receptors (strychnine to glycine receptor)
- ion channels (saxitoxin to sodium channels)
- enzymes (phorbol esters to protein kinase C)
- reversible
what are the targets of covalent binding, is it reversible, what is the usual property of those toxicants?
- permanently alters endogenous molecules
- toxicant is usually electrophilic & targets nucleophiles
- irreversible
what is the difference between individual and quantal analyses?
- individual: response in relation to graded doses
- quantal: looking at a population’s general response
what are probits and how are they obtained?
- Probability units
- Convert % response to units of deviation from the
mean or “normal equivalent deviations” (NEDs) - “Probit” approach adds 5 to avoid negatives
what is the NOAEL?
No Statistically Observed Adverse Effect Level
what is the LOAEL?
Lowest Observed Adverse Effect Level
what are the modifying factors and why do we have them?
- add a factor of 100 to account for species difference and human variability
- since many differences in exposure route, site; genetic polymorphisms; disease; nutritional status; other drugs/chemicals
what is the LD50 and ED50 of Botulinum toxin? is it still used? if so, for what?
- LD50: 10ng/kg
- ED50: 0.5ng/kg
used for: - uncontrolled eye twitching
- upper motor neuron syndrome
- uncontrolled sweating
- cosmetics (Botox)
what is hormesis?
a part of a curve that doesn’t follow a normal dose-response curve (e.g. vitamins)
what are nonmonotonic dose response curves?
goes against the typical or predicted dose-response relationship
what are low dose effects?
the possibility of having an effect at doses below the NOAEL (maybe due to the curve being non-typical)
what is an additive effect?
effects of more than one substance would be expected to be additive
what is a synergistic effect?
occurs when the effects are more than additive
what is a potentiation effect?
occurs when a substance that has no toxic effect enhances the toxicity of another substance that is toxic
what is an antagonism effect?
occurs when the effects are less than additive
what are some alteration of the biological environment that can occur?
- Chemicals that alter pH in biophase (methanol)
- Uncouplers of oxidative phosphorylation (2,4-dinitrophenol)
- Solvents and detergents (nonoxynol-9 (destabilize membranes))
- Space occupiers (oxalic acid, ethylene glycol (forms water insoluble precipitates in renal tubules))
what are the potential outcomes after the development of toxicity?
- complete repair
- partial repair (may appear normal but partially dysfunctional)
- apoptosis
- necrosis
what are the stages in the development of toxicity after a chemical exposure?
- toxicant delivered
- interacts with target molecules and alteration of biological environment
- leads to cellular dysfunction and injury
- may lead to dysrepair
- leads to toxicity
