Safety testing

Question 1

T/F: New drugs for humans and veterinary use, pesticides, feed additives and industrial chemicals have to be assessed for their safety and toxicity before marketing.

Answer 1

TRUE

Question 2

What are the general types of toxicology tests?

Answer 2

• Acute toxicity
• Subacute
• Chronic

Question 3

What are the special types of toxicology tests?

Answer 3

• Reproduction and fertility
• Teratogenicity
• Mutagenicity
• Carcinogenicity
• Skin, eye, or muscle irritation
• Hemolysis

Question 4

What are the most commonly used species in safety testing?

Answer 4

Rats and dogs

Question 5

What is an important factor in safety testing? What are target species?

Answer 5

• Cost is an important factor
• Target species are species that will be exposed to the compound

Question 6

3 properties of a testing compound?

Answer 6

• Should be pure or as it is commercially produced
• A vehicle should be inert and does not alter the properties of the compound
• A control vehicle should be used

Question 7

Dosages

Answer 7

• For subchronic and chronic toxicity usually 3 dose levels are used:
  
  • High dose that produces clinical signs
  • Mid-dose that produces mild toxicosis
  • Low dose which is the largest dose that does not produce toxicosis

Question 8

Acute toxicity tests:

What type of experiment is it?

Exposure amount/time?

Observation period?

Species tested?

Answer 8

1. Is an acute LD50 or LC50 experiment depending on the species
2. Single or multiple exposures w/in 24 hour period
3. Observation period is usually 1 day, but sometimes up to 14 days
4. Usually more than one species of rodent is used

Question 9

Subchronic toxicity testing:

Exposure period?

Dosages?

Group size/division?

Analyses?

Postmortem?

Other data?

Answer 9

1. Period of exposure is 1-90 days
2. Rats and dogs are usually used at 3 different dosages + a control group
3. Rodents: size of the group is 30-40 animals equally divided by sex
4. Dogs: size of the group is 6-10 equally divided by sex
5. Hematologic and biochemical analyses are made at intervals
6. Postmortem examination is performed at the end of the experiment
7. Other data including weekly body weight, feed/water consumption, and clinical signs are also recorded

Question 10

Chronic toxicity testing

Similar to which test?

Exposure?

Answer 10

• Similar to the subchronic toxicity testing except the period of exposure is 90 days or more
  
  • Usually up to 18 months in mice and 24 months in rats, dogs, or primates

Question 11

Reproduction and fertility tests

Effects of toxins at what stages?

How many generations of rats?

Testing process?

Parameters recorded?

Answer 11

• Tests the effects of toxicants on any stage of reproduction (ovulation, conception, implantation, gestation, embryo dev., fetal dev., parturition, lactation, and early embryonic growth)
• Usually 2-3 successive generations of rats are used
• Adult males and females are dosed for 60 days before mating, then femalse are also treated during gestation and lactation and the offspring are dosed from weaning until lactation
• The parameters recorded at each step include fertility index, length of gestation pd., live births, still births, survival at 5 days and at weaning, # of ea. sex, BW and gross abnormalities, microscopic examination of selected offspring

Question 12

Teratogenicity testing:

What is a teratogen?

Embryotoxic/fetotoxic substance?

Species?

Exposure specifics?

Answer 12

• Teratogen is any substance that produces non-lethal structural or functional abnormalities in the fetus
• Embryotoxic or fetotoxic is a substance that causes death of the embryo or fetus
• Testing is usually done in mice, rats, or rabbits
• The females are exposed to the tested compound during the period of organogenesis (organ dev.) (6-15 days of pregnancy in mice/rats and 6-18 days of pregnancy in rabbits)

Question 13

What is the process of teratogenicity testing (4 steps)?

Answer 13

• The first day of gestation is determined in rats by sperm-positive vaginal smear and the presence of a vaginal plug in mice after mating with adult males overnight
• Fetuses are removed surgically one day before the expected day of parturition
• The fetuses are examined for gross changes, # of live and dead, # of resorptions, BW, sex, and any external malformations
• The fetuses are then examined for skeletal and visceral malformations

Question 14

Mutagenicity–what is it? What are the 3 tests assoc. w/ it?

Answer 14

• Mutagenesis is the induction of chromosomal changes
• Dominant lethal test
• Cytologic tests
• Host-mediated microbial assay

Question 15

Carcinogenicity testing:

Species?

Exposure?

Final stage?

Answer 15

• Tests are usually done in rats and mice
• Exposure to the tested compound is for the life of the animal and starts from weaning
• Animals are necropsied and the incidence of tumors is compared between the treated and control

Question 16

Eye irritation testing

Answer 16

• Formulations used for the eye or if the eye will be exposed have to be tested for ocular irritation
• The drug is instilled in the conjunctival sac of one eye in an albino rabbit and the other eye serves as a control
• The tissue response is scored at periodic intervals of 72 hours

Question 17

Skin irritation testing

Answer 17

• The test compound is applied on a shaved area of the skin of an albino rabbit
• The response is scored at periodic intervals

Question 18

Injection irritation tests

Answer 18

For drugs used by IM, SC, or intramammary administration are tested for tissue irritation by evaluating inflammation or necrosis

Question 19

Hemolysis testing

Required for what compounds?

Process?

Answer 19

• Required for compounds administered by the IV route
• The drug is administered intravenously and the hemoglobin content of a plasma sample one minute after injection is compared with that of a sample before injection