Toxicologic Principles

Question 1

The percentage of mating resulting in pregnancy is called

Answer 1

Fertility index

Question 2

Fertility index

Answer 2

(number of pregnant females ÷ number of matings) × 100

It measures how often mating leads to pregnancy

Question 3

Gestation index

Answer 3

pregnancies that go to term

Question 4

Viability index

Answer 4

pups alive after birth

Question 5

Survival index

Answer 5

pups alive later in life

Question 6

The percentage of pregnancies resulting in live litters is

Answer 6

Viability index

This measures whether pregnancy produced live offspring, not just implantation or gestation

Question 7

The lactation index in rats is the

Answer 7

percentage of animals alive at 4 days that survive the 21-day lactation period

This measures how well pups survive during nursing, not how many were born.
It reflects milk production, maternal care, and neonatal toxicity.

Question 8

The developing nervous system is insensitive to toxicant exposure (T/F)

Answer 8

False

This is exactly backwards. The developing nervous system is highly sensitive to toxicants (e.g., lead, mercury, alcohol).

Question 9

A severe cytokine response causing organ failure occurred in a Phase I study using

Answer 9

a CD28 monoclonal antibody

This refers to the TGN1412 disaster (2006), where a CD28 super-agonist antibody caused a cytokine storm → multiorgan failure in healthy volunteers.

Question 10

What happened in the TGN1412 disaster (2006)?

Answer 10

CD28 super-agonist antibody caused a cytokine storm → multiorgan failure in healthy volunteers

Question 11

How much DNA variability exists between two humans?

Answer 11

0.1%

Question 12

Humans are what percent genetically identical?

Answer 12

99%

Question 13

What can characterize a response to a toxicant?

Answer 13

• Proteomics (protein changes)
• Transcriptomics (RNA expression)
• Metabolomics (small-molecule changes)

Question 14

Paraquat’s target organ is?

Answer 14

the lung

Question 15

Where in the body does lead store?

Answer 15

the bones

Question 16

Acute skin and eye irritation is usually evaluated in a

Answer 16

rabbit

Question 17

Why are rabbits used in skin and eye irritation?

Answer 17

Rabbits have very sensitive eyes and skin

Similar to humans

Question 18

Before a potential pharmaceutical compound can be given to humans

Answer 18

an IND must be filed with the FDA

before any human testing - IND (Investigational New Drug) application must be approved by FDA

Question 19

What is IND stand for?

Answer 19

IND (Investigational New Drug) application

Question 20

Phase I trials determine all except

Answer 20

rare adverse effects

Question 21

What does phase I trials determine?

Answer 21

• Pharmacokinetics
• Safety
• Dose range

Question 22

To determine rare adverse events what phase in the clinical trial should that be and how many participants?

Answer 22

require thousands of patients → Phase III–IV

Question 23

How many participants are in phase I trials?

Answer 23

20–100 healthy volunteers

Question 24

MTD stands for

Answer 24

maximum tolerated dose

Question 25

What is MTD?

Answer 25

highest dose that causes minimal toxicity but no death

Question 26

In what scenario is MTD used?

Answer 26

to select doses for chronic and cancer studies

Question 27

The acute toxicity study in animals provides

Answer 27

* Approximate lethal dose (LD₅₀) * Which organs are injured * Dose ranges for longer studies

Question 28

A subacute toxicity study in rats usually lasts

Answer 28

14 days

Question 29

The period of organogenesis in rats is

Answer 29

day 7 to 17

Question 30

What is the critical window for birth defects when organs are forming in rats?

Answer 30

D7-17

Question 31

A dose that slightly suppresses body weight gain in a 90-day study is

Answer 31

MTD

Question 32

MTD is?

Answer 32

the highest dose causing minimal toxicity, often slight weight suppression

Question 33

A subchronic animal study required by FDA will usually include

Answer 33

* Two species * Both sexes * Three dose levels (low, mid, high)

Question 34

When all receptors are occupied by a toxicant and there is a maximum amount of receptor–toxicant complexes, the response is labeled

Answer 34

Emax ## Footnote receptor saturation → maximum effect

Question 35

Emax

Answer 35

maximum effect achievable when all receptors are occupied

Question 36

Cmax

Answer 36

highest plasma concentration

Question 37

LCmax

Answer 37

not a standard receptor–response term

Question 38

Toxicant–receptor interactions are always reversible (T/F)

Answer 38

False ## Footnote Some toxicants bind irreversibly (e.g., organophosphates to acetylcholinesterase)

Question 39

Receptors for toxicants are always enzymes (T/F)

Answer 39

False ## Footnote Receptors can be: * enzymes * ion channels * DNA * membrane receptors * transporters

Question 40

The toxic response is related more to plasma concentration than the concentration at the site of action (T/F)

Answer 40

False ## Footnote Toxicity correlates best with concentration at the target tissue, not plasma.

Question 41

An increase in free drug concentration will

Answer 41

increase the pharmacologic effect ## Footnote Only free (unbound) drug: * binds receptors * causes toxicity * is filtered by kidneys

Question 42

A toxic substance produced by biological systems is specifically referred to as a

Answer 42

toxin

Question 43

A newly formed hapten–protein complex usually stimulates formation of antibodies in

Answer 43

1 to 2 weeks

Question 44

Why does it take 1-2 weeks for a newly formed hapten–protein complex to stimulates formation of antibodies?

Answer 44

A hapten alone is too small to trigger immunity. Once bound to a protein it becomes an antigen, which triggers the adaptive immune response.

Question 45

Prolonged muscle relaxation after succinylcholine is an example of a/an

Answer 45

idiosyncratic reaction

Question 46

Succinylcholine is metabolized by what?

Answer 46

plasma pseudocholinesterase ## Footnote Some people have genetic variants → slow breakdown → prolonged paralysis.

Question 47

Increased production of methemoglobin is due to decreased activity of

Answer 47

NADH cytochrome b5 reductase

Question 48

NADH cytochrome b5 reductase does what?

Answer 48

This enzyme converts methemoglobin (Fe³⁺) back to hemoglobin (Fe²⁺). Low activity → accumulation of methemoglobin → hypoxia

Question 49

The most common target organ of toxicity is the

Answer 49

CNS (brain and spinal cord)

Question 50

Why is the CNS a common target organ of toxicity?

Answer 50

* gets high blood flow * has lipid-rich membranes * is very sensitive to metabolic disruption

Question 51

The organs least involved in systemic toxicity are

Answer 51

muscle and bone

Question 52

Two organophosphate insecticides together produce

Answer 52

additive effect

Question 53

Why does organophosphate insecticides together produce an additive effect?

Answer 53

They have the same mechanism (AChE inhibition) Same mechanism → additive (not synergy)

Question 54

Ethanol + carbon tetrachloride (chronic) causes

Answer 54

synergy

Question 55

Isopropyl alcohol + carbon tetrachloride (chronic) causes

Answer 55

additive effect

Question 56

Why does Isopropyl alcohol + carbon tetrachloride (chronic) cause an additive effect?

Answer 56

Both cause liver toxicity, but isopropyl alcohol does not induce CYP2E1 like ethanol, so their effects simply add.

Question 57

Diazepam treatment of strychnine seizures is an example of

Answer 57

functional antagonism

Question 58

Diazepam treatment of strychnine seizures is an example of functional antagonism what is the mechanism?

Answer 58

* Strychnine blocks inhibitory glycine → seizures * Diazepam enhances GABA inhibition

Question 59

Antitoxin for snakebite is an example of

Answer 59

chemical antagonism

Question 60

How does antitoxin works?

Answer 60

The antitoxin binds and neutralizes the venom directly.

Question 61

Charcoal to prevent diazepam absorption is

Answer 61

dispositional antagonism ## Footnote Charcoal changes the absorption and distribution of the drug → lowers bioavailability.

Question 62

Tamoxifen for breast cancer is

Answer 62

receptor antagonism

Question 63

Chemicals known to produce dispositional tolerance

Answer 63

trichloroethylene and methylene chloride

Question 64

Dispositional tolerance

Answer 64

tolerance due to changes in ADME, especially increased metabolism (often CYP induction). Many chlorinated solvents can induce metabolic enzymes → faster clearance → less effect at same dose.

Question 65

The most rapid exposure to a chemical would occur through which route?

Answer 65

inhalation

Question 66

Toxic to brain but detoxified in liver → expected to be

Answer 66

more toxic via inhalation than orally

Question 67

The LD50 is calculated from

Answer 67

a quantal dose-response curve

Question 68

What is a quantal endpoint?

Answer 68

dead vs alive

Question 69

A U-shaped graded toxicity dose-response curve is seen in humans with

Answer 69

vitamins

Question 70

U-shaped graph means?

Answer 70

harm at low dose (deficiency) and at high dose (toxicity). Classic example: vitamins and essential nutrients.

Question 71

The TD1/ED99 is called

Answer 71

margin of safety

Question 72

Hereditary differences in a single gene occurring in >1% of the population are

Answer 72

genetic polymorphisms

Question 73

Polymorphism

Answer 73

common genetic variant (≥1% frequency)