Delivery and Effects of Toxicants

Question 1

Define Toxicokinetics

Answer 1

The modelling and mathematical description of the time course of disposition of toxicants.
Broken down into ADME:
-Absorption
-Distribution
-Metabolism
-Elimination

Question 2

Three major routes of toxicant exposure

Answer 2

• Lungs (Gases diffused into blood, particles deposited)
• GI tract (simple diffusion, rate proportional to lipid solubility)
• Skin (diffusion through stratum corneum)

Question 3

Four Steps in Toxicant Metabolism

Answer 3

1) Hydrolysis
2) Reduction
3) Oxidaton
4) Conjugation

Question 4

Phase I of Toxicant metabolism turns ____ molecules into ____ intermediates though _______ (two sets of answers)

Answer 4

1) Lipophilic, electrophiles, oxidation

2) Lipophilic, nucleophiles, (Hyrolysis or Reduction)

Question 5

Phase II of Toxicant metabolism creates ____ compounds from ____ using _____ (two answers)

Answer 5

1) Hydrophilic, electrophiles, glutathione conjugation

2) Hydrophilic, nucleophiles, (Sulfation, Acetylation, or Glucuronidation)

Question 6

Most common Cytochrome P450

Answer 6

CYP3A4/5

Question 7

Three methods of elimination

Answer 7

1) Fecal Excretion
2) Exhalation
3) Urinary excretion

Question 8

Define the equation for apparent volume of distribution

Answer 8

AVd = Dose of drug administered/plasma Concentration (at a given time t)

eg Warfarin (Vd = 0.1 has high plasma protein binding, does not distribute into tissues)

eg Chloroquine (Vd = 100 high tissue uptake and trapping in lysosomes)

Question 9

Compare 1st order and Zero order elimination

Answer 9

First order: constant fraction eliminated per unit time (semilogarithmic)

Zero order: constant amount eliminated per unit time (linear)

Question 10

What happens to rates when you add a compartment?

Answer 10

Equilibrium is reached more slowly

Question 11

What must happen for a target molecule to be responsible for toxicity (3 things)

Answer 11

• Reach an effective concentration at the target site
• React with target and ADVERSELY affect function
• Alter target in a way that is mechanistically related to toxicity

Question 12

Name different reaction types for a toxicant and its target

Answer 12

Noncovalent binding (reversible)

• membrane receptors (eg strychnine to glycine receptor)
• ion channels (saxitoxin to sodium channels)
• enzymes (phorbol esters to protein kinase C)

Covalent binding (irreversible)

• permanently alters endogenous molecules
• toxicant is usually electrophilic, attacking nucleophilic targets
• action by:
  
  • hydrogen abstraction
  • electron transfer
  • enzymatic reaction

Question 13

2. Difference between a graded or quantal relationship

Answer 13

Graded - for an individual - measure toxicity as a function of dose

Quantal - for a population - measure individuals affected as a function of dose

n Probit units = 5 + nSD
5 PU = 50%
8 PU = 99.99%

Question 14

Define dose response relationship terms. (8 terms)

Answer 14

• NOAEL: no observed adverse effect level
• LOAEL: lowest observed adverse effect level
• Point of departure: point where graph departs from estimation
• ED50, dose where 50% of population are effected therapeutically
• LD50, dose where 50% of population dies
• Reference dose (RfD), maximum acceptable dose of a toxic substance
• UF, uncertainty factor
• MR. Modifying factor
  RfD = NOAEL/(UFxMF)

Question 15

Define a nonmonotonic Dose Response Curve

Answer 15

Any D-R curve that is not sigmoidal

Question 16

Define potential interaction types: (4 types)

Answer 16

Additive (2 + 2 = 4) normal

Synergistic (2 + 2 = 10)
Potentiated (0 + 2 = 8)
Antagonistic (2 + 2 = 3)

Question 17

From a physiological standpoint, what are the two main causes of toxicity?

Answer 17

• Cellular dysfunction/injury

- Disrepair of body organs