Acute, Subacute, Sub-chronic and Chronic Toxicology

Question 1

First principle in using toxicity data from animal models?

Answer 1

Effects produced by a substance in laboratory
animals, when properly qualified* are applicable
to humans (*species to species extrapolation)
- On the basis of dose per unit of body surface area, humans are usually within the same range of toxicity as lab animals
- On a dose per body weight basis, humans are usually more vulnerable by a factor of 10
- Using these principles, relatively safe doses can be calculated for humans

Question 2

Second Principle of Animal Models?

Answer 2

Exposure of animals to range of high doses of a
toxic agent (usually causing death) is a valid
method of discovering possible hazards in
humans
- Based on the concept that the toxic effect in a
population is greater as the dose increases

Question 3

Types of toxicity tests?

Answer 3

May be characterized by route of exposure and/or duration of dosing:

• Acute: single dose, observe thru 14 days
• Subacute: usually 28 day daily dose study
• Subchronic: usually 90 day daily dose study
• Chronic: usually two year daily dose study

Question 4

Do all of the studies in tiered testing approach involve animal testing?

Answer 4

No (i.e. In Vitro Genetic Toxicology)

Question 5

Small numbers of animals are used in these studies,

and the doses delivered are usually large…Why?

Answer 5

Toxicity tests are designed to characterize

what toxic effects a chemical can produce**

Question 6

Endpoints in toxicity tests?

Answer 6

1. .) Death: LD50, LC50
2. ) Organ System Pathology
3. ) Skin sensitization/Eye irritation
4. ) Carcinogenicity (chronic, lifetime study)
5. ) Reproductive Effects (Teratogenicity)

Question 7

Would it help if you conducted a study and saw no

effects?

Answer 7

Not good if all animals live at doses tested!

Not good if all animals die at doses tested!

Question 8

With inhalation and dermal exposure, what
other exposure factor needs to be
considered in addition to concentration?

Answer 8

Time/duration

Question 9

All known chemical carcinogens in
humans are carcinogenic in some species
of laboratory animals, except for…?

Answer 9

Arsenic

Question 10

Not all carcinogenic chemicals in animals

are carcinogenic in humans…Why?

Answer 10

Species extrapolation
(For risk assessment purposes a substance that is
carcinogenic in animals is likely to be carcinogenic
in humans*)

Question 11

Acute Toxicity Testing? Is this type of exposure typical in everyday life?

Answer 11

Assesses the ability of a substance to do
systemic damage as a result of a one-time
exposure of short duration; can be.

Question 12

What does toxicity testing provide information about?

Answer 12

The effect of exposure, not the safety of the

substance being evaluated

Question 13

Uses of Acute Toxicity Data?

Answer 13

1..) Quantitative assessment of LD50 to
compare to other substances
2.) Identify target organs and other clinical
manifestations of acute toxicity
3.) Establish the reversibility of the toxic
response

Question 14

Acute Toxicity tests: Oral?

Answer 14

LD50 is not a biological constant. Many
factors can influence the toxicity and the
estimation of LD50 in a study (i.e. animal strain, age/weight, type of feed, caging)

Question 15

Acute Toxicity Tests: Inhalation?

Answer 15

LC50 is defined as the concentration of
chemical in the air (or water, if aquatic
species) that causes death to 50% of the
animals.

Question 16

What is Haber’s Law based on?

Answer 16

The dose response relationship; the same dose (K) may be delivered by exposure to different concentrations over different durations or times of exposure.

Question 17

What are the units for any concentration,

including LC50? What are the units for “dose”?

Answer 17

Mass per unit volume: e.g. “mg/L”

Mass: e.g. “mg”

Question 18

Why are subacute toxicity tests performed?

Answer 18

To obtain information as to what occurs during more prolonged exposure, 28 – 90 days of exposure

Question 19

Subchronic Exposure?

Answer 19

Exposure: typically daily dose x 90 days
Primarily used to establish NOAEL
- NOAEL: No Observed Adverse Effect Level
Identify target organs affected during repeated exposures
- May be able to establish LOAEL

Question 20

What does chronic toxicity refer to?

Answer 20

The harmful systemic effects
produced by long-term, low-level exposure
to toxicants

Question 21

Long Term (Chronic) studies?

Answer 21

Rodents: > 3 months – 2 years (lifetime)
Dogs: usually 7 years (canine lifetime)
Endpoints:
-       Cumulative organ system toxicity
-       Carcinogenicity
Usually three doses with top dose=Maximum Tolerable Dose (MTD)
Costs of Lifetime studies (rats or dogs)

Question 22

Use of the MTD?

Answer 22

1..) Carcinogenic outcomes based on high
exposures (doses)
2.) Statistical and experimental limitations

Question 23

Data collection of toxicity testing?

Answer 23

1. .) Deaths over study period
2. ) Observation of adverse effects
3. ) Biomarkers (if known)
4. ) Euthanasia/necropsy of surviving animals at end of study

Question 24

Application of Toxicological Data?

Answer 24

1..) Regulatory standards use one or
both (NOAEL and/or LOAEL)
2.) EPA uses NOAEL to calculate reference
dose (RfD)
3.) Used specifically in the Safe Drinking Water Act for the calculation of Maximum Contaminant Level (MCL)

Question 25

Benchmark Dose and Regulations?

Answer 25

Considered an alternative to NOAEL

• Uses all experimental data to fit a dose resp. curve
• Curve(s) used to estimate a “benchmark dose”