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PHAR 303 (toxicology) > Toxicodynamics /Toxicokinetics > Flashcards

Toxicodynamics /Toxicokinetics Flashcards

1
Q

what is Toxicokinetics?

A

The modeling and mathematical description of the time course of disposition of toxicants

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2
Q

What are the major routes of toxicant exposure?

A

the skin, lungs, and gastro-intestinal tract

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3
Q

the ________ of the molecule is very important to consider since it has to _______________

A

the lipophilicity of the molecule is very important to consider since it has to cross membranes

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4
Q

When it comes to absorption by the skin, toxicants cross the ________ by __________

A

Toxicants cross the stratum corneum by diffusion

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5
Q

for absorption of toxicants by lungs, the major source of toxicant is what?

A

dust

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6
Q

when absorbed by the lungs, where do gas molecules go and where do other particles go?

A
  • Gas molecules diffuse into the blood;
  • Particles may be deposited in the tracheobranchial region; they may be swallowed, removed by phagocytosis, or by lymphatics.
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7
Q

Most chemicals cross the GI epithelium by _________ and Rate of transport correlates with _________________

A

Most chemicals cross the GI epithelium by simple diffusion and Rate of transport correlates with lipid solubility

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8
Q

what are the different specialized barriers? Are they static or dynamic?

A
  • blood-brain barrier (static)
  • placenta (dynamic)
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9
Q

what are main bodily fluids used to measure the level/distribution of toxicants?

A

urine and blood

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10
Q

what are the different body fluids/parts that can be used to measure toxicants?

A
  • urine
  • blood
  • breastmilk
  • umbilical cord fluid (to see what baby was exposed to during pregnancy)
  • seminal plasma
  • saliva
  • hair
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11
Q

What are the major ways in which toxicants are biotransformed?

A

phase 1:
- hydrolysis, reduction, oxidation

phase 2:
- conjugation

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12
Q

what is an example of a hydrolysis biotransformation enzyme?

A

Epoxide Hydrolase

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13
Q

what is an example(s) of an oxidation biotransformation enzyme?

A

Alcohol Dehydrogenase (ADH)
Aldehyde Dehydrogenase (ALDH)
cytochrome P450s

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14
Q

What are the major conjugation reactions for eliminating toxicants?

A
  • glucuronidation
  • acetylation
  • glutathione conjugation
  • sulfonation
  • methylation
  • amino acid conjugation
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15
Q

what is the function of a conjugation reaction?

A

add anything that makes a molecule more polar and more easily eliminated

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16
Q

what are different elimination methods?

A
  • Fecal Excretion
  • Exhalation
  • Urinary Excretion
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17
Q

what does low and high AVD mean?

A
  • low: high plasma protein binding with little distribution in tissue
  • high: high tissue uptake and trapping in lysosomes
18
Q

Vd = ?/?

A

Dose/C0

19
Q

in first order elimination, how long does it take to remove at least 95% of a toxicant?

A

5 half-lives

20
Q

how much chemical eliminated in zero order kinetics?

A

A fixed amount is eliminated per unit of time

21
Q

in first-order kinetics [C] falls ______ and in zero-order, it falls _________

A

exponentially, linearly

22
Q

what are the two compartments in the 2-compartment model and what do they represent?

A

1 - Central compartment represents plasma and tissues that equilibrate rapidly
2 – Peripheral compartment, equilibrates more slowly

23
Q

To identify a target molecule as responsible
for toxicity, the toxicant must what?

A
  • 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
24
Q

what are the two reaction types?

A

noncovalent binding and covalent binding

25
Q

what are the targets of noncovalent binding, is it reversible?

A
  • membrane receptors (strychnine to glycine receptor)
  • ion channels (saxitoxin to sodium channels)
  • enzymes (phorbol esters to protein kinase C)
  • reversible
26
Q

what are the targets of covalent binding, is it reversible, what is the usual property of those toxicants?

A
  • permanently alters endogenous molecules
  • toxicant is usually electrophilic & targets nucleophiles
  • irreversible
27
Q

what is the difference between individual and quantal analyses?

A
  • individual: response in relation to graded doses
  • quantal: looking at a population’s general response
28
Q

what are probits and how are they obtained?

A
  • Probability units
  • Convert % response to units of deviation from the
    mean or “normal equivalent deviations” (NEDs)
  • “Probit” approach adds 5 to avoid negatives
29
Q

what is the NOAEL?

A

No Statistically Observed Adverse Effect Level

30
Q

what is the LOAEL?

A

Lowest Observed Adverse Effect Level

31
Q

what are the modifying factors and why do we have them?

A
  • 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
32
Q

what is the LD50 and ED50 of Botulinum toxin? is it still used? if so, for what?

A
  • LD50: 10ng/kg
  • ED50: 0.5ng/kg
    used for:
  • uncontrolled eye twitching
  • upper motor neuron syndrome
  • uncontrolled sweating
  • cosmetics (Botox)
33
Q

what is hormesis?

A

a part of a curve that doesn’t follow a normal dose-response curve (e.g. vitamins)

34
Q

what are nonmonotonic dose response curves?

A

goes against the typical or predicted dose-response relationship

35
Q

what are low dose effects?

A

the possibility of having an effect at doses below the NOAEL (maybe due to the curve being non-typical)

36
Q

what is an additive effect?

A

effects of more than one substance would be expected to be additive

37
Q

what is a synergistic effect?

A

occurs when the effects are more than additive

38
Q

what is a potentiation effect?

A

occurs when a substance that has no toxic effect enhances the toxicity of another substance that is toxic

39
Q

what is an antagonism effect?

A

occurs when the effects are less than additive

40
Q

what are some alteration of the biological environment that can occur?

A
  • 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))
41
Q

what are the potential outcomes after the development of toxicity?

A
  • complete repair
  • partial repair (may appear normal but partially dysfunctional)
  • apoptosis
  • necrosis
42
Q

what are the stages in the development of toxicity after a chemical exposure?

A
  1. toxicant delivered
  2. interacts with target molecules and alteration of biological environment
  3. leads to cellular dysfunction and injury
  4. may lead to dysrepair
  5. leads to toxicity

PHAR 303 (toxicology) (14 decks)

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