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166 Cards in this Set

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Knowledge of toxicity is primarily obtained in what three ways?
1. By the study and observation of people during normal use of a substance or from accidental exposures

2. By experimental studies using animals

3. By studies using cells (human, animal, plant)
Most chemicals are now subject to stringent government requirements for what? This is especially true for what 4 things?
Most chemicals are now subject to stringent government requirements for safety testing before they can be marketed. This is especially true for pharmaceuticals, food additives, pesticides, and industrial chemicals.
Exposure of the public to what has resulted in several notable disasters?
Exposure of the public to inadequately tested drugs or environmental agents has resulted in several notable disasters.
Give 3 examples of how exposure of the public to inadequately tested drugs or environmental agents has resulted in disaster.
1. Severe toxicity from the use of arsenic to treat syphilis

2. Deaths from a solvent (ethylene glycol) used in sulfanilamide preparations (one of the first antibiotics)

3. Thousands of children born with severe birth defects resulting from pregnant women using thalidomide, an anti-nausea medicine
By the mid-twentieth century, disasters were becoming commonplace with the increasing rate of what? Knowledge of potential toxicity was absent prior what?
By the mid-twentieth century, disasters were becoming commonplace with the increasing rate of development of new synthetic chemicals. Knowledge of potential toxicity was absent prior to exposures of the general public.
List 5 federal regulatory agencies that were established to assure public safety.
1. Food and Drug Administration

2. Environmental Protection Agency

3. Consumer Product Safety Commission

4. Department of Transportation

5. Occupational Safety and Health Administration
What does the Food and Drug Administration regulate?
Pharmaceuticals, food additives, and medical devices.
What does the Environmental Protection Agency regulate?
Agricultural and industrial chemicals released to the environment.
What does the Consumer Product Safety Commission regulate?
Toxins present in consumer products
What does the Department of Transportation regulate?
The shipment of toxic chemicals
What does the Occupational Safety and Health Administration regulate?
Exposure to chemicals in the workplace
List the three methods that are used to derive knowledge about the toxicity of xenobiotics to humans?
1. Clinical Investigations

2. Epidemiological Studies

3. Adverse reactions to drug reports
What are clinical investigations?
Administration of chemicals to human subjects with careful clinical observations and laboratory measurements.
What are epidemiological studies?
Observations of humans that have been exposed to xenobiotics in the normal course of their life or occupation.
What are 'adverse reactions to drug reports'?
Reports voluntarily submitted by physicians to the FDA after a drug has been approved and is in widespread use.
Clinical investigations are a component of what?
Clinical investigations are a component of the Investigational New Drug Applications (IND) submitted to FDA.
When are clinical investigations conducted?
Clinical investigations are conducted only after the non-clinical laboratory studies have been completed.
Toxicity studies using human subjects require strict what?
Toxicity studies using human subjects require strict ethical considerations.
What are toxicity studies primarily conducted for?
They are primarily conducted for new pharmaceutical applications submitted to FDA for approval.
Generally, toxicity found in animal studies occurs with ? and ? in humans.
Generally, toxicity found in animal studies occurs with similar incidence and severity in humans.
Why are clinical tests with humans needed?
Differences between humans and animal studies sometimes occur, thus clinical tests with humans are needed to confirm the results of non-clinical laboratory studies.
FDA clinical investigations are conducted in how many phases?
FDA clinical investigations are conducted in three phases
What does phase 1 of FDA clinical investigations consist of?
Testing the drug in a small group of 20-80 patients. Information obtained in Phase 1 studies is used to design Phase 2 studies. In particular to:


1. Determine the drug's pharmacokinetics and pharmacological effects

2. Elucidate its metabolism

3. Study the mechanism of action of the drug
What does phase 2 of FDA clinical investigations consist of?
Phase 2 are more extensive than phase 1 and involve several hundred patients and are used to:

1. Determine the short-term side effects of the drug

2. Determine the risks associated with the drug

3. Evaluate the effectiveness of the drug for treatment of a particular disease or condition
What does phase 3 of FDA clinical investigations consist of?
They are expanded controlled and uncontrolled trials conducted with several hundred to several thousand patients. They are designed to:

1. Gather additional information about effectiveness and safety

2. Evaluate overall benefit-risk relationship of the drug

3. Provide the basis for the precautionary information that accompanies the drug
Epidemiology studies are conducted using human populations to evaluate what?
Epidemiology studies are conducted using human populations to evaluate whether there is a causal relationship between exposure to a substance and adverse health effects.
How do epideiology studies differ from clinical investigations?
These studies differ from clinical investigations in that individuals have already been administered the drug during medical treatment or have been exposed to it in the workplace or environment.
Epidemiological studies measure the risk of what?
Epidemiological studies measure the risk of illness or death in an exposed population compared to that risk in an identical (e.g., same age, sex, race, social status, etc.), unexposed population.
List the 4 primary types of epidemiological studies?
1. Cohort studies

2. Case control studies

3. Cross-sectional studies

4. Ecological studies
Describe cohort studies?
A cohort (group) of individuals with exposure to a chemical and a cohort without exposure are followed over time to compare disease occurrence.
Describe Case control studies?
Individuals with a disease (ex. cancer) are compared with similar individuals without the disease to determine if there is an association of the disease with prior exposure to an agent.
Describe cross-sectional studies?
The prevalence of a disease or clinical parameter among one or more exposed groups is studied. For example, the prevalence of respiratory conditions among furniture makers.
Describe ecological studies.
The incidence of a disease in one geographical area is compare to that of another area. For example, cancer mortality in areas with hazardous waste sites as compared to areas without waste sites.
What are the most commonly conducted epidemiology studies?
Cohort studies are the most commonly conducted epidemiology studies.
Cohort studies frequently involve what? Why?
They frequently involve occupational exposures. Exposed persons are easy to identify and the exposure levels are usually higher than in the general public.
List the two types of cohort studies.
1. Prospective cohort study

2. Retrospective cohort study
Describe a prospective cohort study.
Cohorts are identified based on current exposures and followed into the future.
What is a retrospective cohort study?
Cohorts are identified based on past exposure conditions and follow-up proceeds forward in time.
What do cohort studies frequently involve and why are they the most commonly conducted epidemiological studies?
They frequently involve occupational exposures. Exposed persons are easy to identify and the exposure levels are usually higher than in the general public.
What is done to determine if epidemiological data are meaningful?
To determine if epidemiological data are meaningful, standard, quantitative measures of effect are employed.
What are the most commonly used quantitative measures of effect that are employed to determine if epidemiological data are meaningful?
1. Odds Ratio (O/R)

2. Standardized Mortality Ratio (SMR)

3. Relative Risk (RR)
What is an Odds Ratio?
The ratio of risk of disease in a case-control study for an exposed group to an unexposed group. An O/R = 2 means that the exposed group has twice the risk as the non-exposed group.
What is a Standardized Mortality Ratio?
The relative risk of death based on a comparison of an exposed group to non-exposed group. An SMR = 150 indicates that there is a 50% greater risk.
What is a Relative Risk?
The ratio expressing the occurence of disease in an exposed population to that of an unexposed population. An RR = 175 indicates a 75% increase in risk.
There are a number of aspects in designing an epidemiology study. What are the most critical?
The most critical are appropriate controls, adequate time span, and statistical ability to detect an effect.
The control population used as a comparison group must be what?
The control population used as a comparison group must be as similar as possible to that of the test group, e.g., same age, sex, race, social status, geographical area, and environmental and lifestyle influences.
Many epidemiology studies evaluate the potential for an agent to cause what?
Many epidemiology studies evaluate the potential for an agent to cause cancer. Since most cancers require long latency periods, e.g., 20 years, the study must cover that period of time.
The statistical ability to detect an effect is referred to as what?
The statistical ability to detect an effect is referred to as the power of the study.
To gain precision, the study and control populations should be what?
To gain precision, the study and control populations should be as large as possible.
Epidemiologists attempt to control what that may occur in the collection of data?
Epidemiologists attempt to control errors that may occur in the collection of data. These errors are known as bias errors.
List the 3 main types of bias errors.
1. Selection bias

2. Information bias

3. Confounding factors
Describe selection bias.
Occurs when the study group is not representative of the population from which it came.
Describe information bias.
Occurs when study subjects are misclassified as to disease or exposure status. Recall bias occurs when individuals are asked to remember exposures or conditions that occurred years before.
Describe compounding factors.
Occur when the study and control populations differ with respect to factors which might influence the occurence of disease. For example, smoking might be a compounding factor and should be considered when designing studies.
In testing a pharmaceutical to comply with FDA requirements, the initial testing consists of:





Clinical investigations




Non-clinical laboratory studies




Epidemiology studies
In testing a pharmaceutical to comply with FDA requirements, the initial testing consists of non-clinical laboratory studies. These tests are performed with laboratory animals and provide the basis for human clinical investigations.
The primary goal of a Phase 1 clinical study is to:





Evaluate the effectiveness of a drug for treating disease.




Obtain information in order to design a more definitive Phase 2 clinical study.




Provide the basis for physician labeling.
The primary goal of a Phase 1 clinical study is to bbtain information in order to design a more definitive Phase 2 clinical study. Phase 1 consists of testing the drug in a small group of 20-80 patients to obtain the information needed to design the Phase 2 studies.
Determining the overall risk versus the benefit of a new pharmaceutical is part of:





Phase 2 clinical study




Phase 3 clinical study




Epidemiology study
Determining the overall risk versus the benefit of a new pharmaceutical is part of Phase 3 clinical study. The risk versus benefit is one of the last steps in the drug evaluation process.
The type of epidemiology study in which individuals are identified according to exposure and followed to determine subsequent disease risk is known as:





Cohort study




Case control study




Cross-Sectional study




Ecological study
The type of epidemiology study in which individuals are identified according to exposure and followed to determine subsequent disease risk is known as a cohort study. In a cohort study individuals are selected to be part of the group based on their exposure to a particular substance.
An epidemiological study in which the individuals that make up the test cohort are identified according to past exposures is known as:





Case control study




Prospective cohort study




Retrospective cohort study
An epidemiological study in which the individuals that make up the test cohort are identified according to past exposures is known as a retrospective cohort study. As the name implies, retrospective cohorts are identified according to past exposure conditions and the follow-up study proceeds forward in time.
The measure of relative risk of death based on a comparison of those in the exposed cohort to those in the non-exposed cohort is known as the:





Standardized Mortality Ratio




Odds Ratio




Relative Risk
The relative risk of death based on a comparison of an exposed group to a non-exposed group is referred to as Standardized Mortality Ratio (SMR). It is the most commonly used measure for cohort studies.
When are animal tests for toxicity conducted?
Animal tests for toxicity are conducted prior to human clinical investigations as part of the non-clinical laboratory tests of pharmaceuticals.
What is rarely conducted for pesticides and industrial chemicals?
For pesticides and industrial chemicals, human testing is rarely conducted. Animal test results often represent the only means by which toxicity in humans can be effectively predicted.
List 4 benefits of animal studies?
1. Chemical exposure can be precisely controlled

2. Environmental conditions can be well-controlled

3. Virtually any type of toxic effect can be evaluated

4. The mechanism by which toxicity occurs can be studied
Methods to evaluate toxicity exist for a what?
Methods to evaluate toxicity exist for a wide variety of toxic effects.
Some procedures for routine safety testing have been what?
Some procedures for routine safety testing have been standardized.
Standardized animal toxicity tests are highly effective in detecting what?
Standardized animal toxicity tests are highly effective in detecting toxicity that may occur in humans.
Concern for animal welfare has resulted in what?
Concern for animal welfare has resulted in tests that use humane procedures and only the number of animals needed for statistical reliability.
To be standardized, a test procedure must have what?
To be standardized, a test procedure must have scientific acceptance as the most meaningful assay for the toxic effect.
Toxicity testing can be ? ? for a particular effect, such as dermal irritation, or it may be ?, such as testing for unknown chronic effects.
Toxicity testing can be very specific for a particular effect, such as dermal irritation, or it may be general, such as testing for unknown chronic effects.
List 10 effects that standardized test have been developed for.
1. Acute Toxicity

2. Subchronic Toxicity

3. Chronic Toxicity

4. Carcinogenicity

5. Reproductive Toxicity

6. Developmental Toxicity

7. Dermal Toxicity

8. Ocular Toxicity

9. Neurotoxicity

10. Genetic Toxicity
What varies with the toxicity test to be performed?
Species selection varies with the toxicity test to be performed. There is no single species of animal that can be used for all toxicity tests.
What may be needed to assess different types of toxicity?
Different species may be needed to assess different types of toxicity.
In some cases, it may not be possible to use the most desirable animal for testing because of what?
In some cases, it may not be possible to use the most desirable animal for testing because of animal welfare or cost considerations. For example, use of monkeys and dogs is restricted to special cases, even though they represent the species that may react closest to humans
What are the most commonly used laboratory species? Why?
Rodents and rabbits are the most commonly used laboratory species due to their availability, low costs in breeding and housing, and past history in producing reliable results.
The toxicologist attempts to design an experiment that duplicates what?
The toxicologist attempts to design an experiment to duplicate the potential exposure of humans as closely as possible.
Experimental route of exposure should simulate that of what? Most standard tests use what?
The route of exposure should simulate that of human exposure. Most standard tests use inhalation, oral, or dermal routes of exposure.
The age of test animals should relate to that of who? Testing is normally conducted with what?
The age of test animals should relate to that of humans. Testing is normally conducted with young adults, although newborn or pregnant animals may be used in some cases.
For most routine tests, both sexes are used. Why?
Sex differences in toxic response are minimal, except for toxic substances with hormonal properties.
Dose levels are normally selected so as to determine what? Usually, a minimum of how many dose levels are used?
Dose levels are normally selected so as to determine the threshold as well as dose-response relationship. Usually, a minimum of three dose levels are used.
What tests are generally the first tests conducted?
Acute toxicity tests are generally the first tests conducted.
Acute toxicity tests provide data on what? Standardized tests are available for ?, ?, and ? exposures.
They provide data on the relative toxicity likely to arise from a single or brief exposure. Standardized tests are available for oral, dermal, and inhalation exposures.
List the 5 basic parameters of acute toxicity tests?
1. Species

2. Age

3. Number of animals

4. Dosage

5. Observation period
What are the basic standardized parameters for the species of an acute toxicity test?
Rats are preferred for oral and inhalation tests.


Rabbits are preferred for dermal tests.
What is the basic standardized parameter for the age of an acute toxicity test?
Young adults.
What are is the basic standardized parameter for the number of animals in an acute toxicity test?
5 of each sex per dose level.
What are the basic standardized parameters for the dose in an acute toxicity test?
Three dose levels recommended. Exposures are single doses or fractionated doses up to 24 hours for oral and dermal studies and 4 hour exposure for inhalation studies.
What is the basic standardized parameter for the observation period of an acute toxicity test?
14 days
Subchronic toxicity tests are employed to determine what?
Subchronic toxicity tests are employed to determine toxicity likely to arise from repeated exposures of several weeks to several months.
Standardized Subchronic toxicity tests are available for what exposures?
Standardized tests are available for oral, dermal, and inhalation exposures.
What is the basic standardized parameter for the species of a subchronic toxicity test?
Rodents (usually rats) are preferred for oral and inhalation studies.

Rabbits are preferred for dermal studies.

Non-rodents (usually dogs) are recommended as a second species for oral tests.
What is the basic standardized parameter for age in a subchronic toxicity test?
Young adult
What is the basic standardized parameter for the number of animals in a subchronic toxicity test?
10 of each sex of rodents; 4 of each sex of non-rodents for each dose level.
What is the basic standardized parameter for the dosage in a subchronic toxicity test?
Three dose levels plus a control group. Include a toxic dose level plus NOAEL. Exposures are 90 days.
What is the basic standardized parameter for the observation period of a subchronic toxicity test?
90 days (same as treatment period)
Chronic toxicity tests determine what? What are they similar to?
Chronic toxicity tests determine toxicity from exposure for a substantial portion of a subject's life. They are similar to the subchronic tests except that they extend over a longer period of time and involve larger groups of animals.
What is the basic standardized parameter for the species of a chronic toxicity test?
Two species recommended. Rodent and non-rodent (rat and dog).
What is the basic standardized parameter for age in a chronic toxicity test?
Young adults.
What is the basic standardized parameter for the number of animals in a chronic toxicity test?
20 of each sex for rodents. 4 for each sex of non-rodents per dose level.
What is the basic standardized parameter for the dosage in a chronic toxicity test?
Three dose levels recommended. Include a toxic dose level and NOAEL. Exposures generally for 12 months. FDA request 24 months for food chemicals.
What is the basic standardized parameter for the observation period of a chronic toxicity test?
12 - 24 months.
What is a carcinogenicity tests similar to?
Carcinogenicity tests are similar to chronic toxicity tests. However, they extend over a longer period of time and require larger groups of animals in order to assess the potential for cancer.
What is the basic standardized parameter for the species of a carcinogenicity test?
Testing in two rodent species. The rat and mouse are preferred due to their relatively short life spans.
What is the basic standardized parameter for age in a carcinogenicity test?
Young adults.
What is the basic standardized parameter for the number of animals in a carcinogenicity test?
50 of each sex per dose level.
What is the basic standardized parameter for the dosage in a carcinogenicity test?
Three dose levels recommended. Highest should produce minimal toxicity. Exposure periods are at least 18 months for mice and 24 months for rats.
What is the basic standardized parameter for the observation period of a carcinogenicity test?
18-24 months for mice and 24-30 months for rats.
Reproductive toxicity testing is intended to determine what?
Reproductive toxicity testing is intended to determine the effects of substances on gonadal function, conception, birth, and the growth and development of the offspring.
What route is preferred in reproductive toxicity testing?
Oral route is preferred.
What is the standardized basic parameter for species in reproductive toxicity testing?
Rat is recommended.
What is the standardized basic parameter for age in reproductive toxicity testing?
Young adults.
What is the standardized basic parameter for number of animals in reproductive toxicity testing?
20 of each sex per dose level.
What is the standardized basic parameter for dosage in reproductive toxicity testing?
Three dose levels recommended. Highest dose should produced toxicity but not mortality in parents. The lowest dose should not produce toxicity.
What is the standardized basic parameter for observation period in reproductive toxicity testing?
Test substance given to parental animals (P1) prior to mating, during pregnancy and through weaning of F1 offspring. Substance then given to selected F1 offspring during their growth into adulthood, mating, and production of an F2 generation, until the F2 generation is 21 days old.
Developmental toxicity testing detects what?
Developmental toxicity testing detects the potential for substances to produce embryotoxicity and birth defects.
What is the standardized basic parameter for species in developmental toxicity testing?
Two species recommended: rat, mouse, hamster, and rabbit most commonly used.
What is the standardized basic parameter for age in developmental toxicity testing?
Young adult females.
What is the standardized basic parameter for number of animals in developmental toxicity testing?
20 pregnant females per dose level.
What is the standardized basic parameter for dosage in developmental toxicity testing?
At least three dose levels are used. Used throughout organ development in the fetus for teratogenic effects. Starts with the parents prior to breeding. Continues during pregnancy for all developmental effects.
What is the standardized basic parameter for observation period in developmental toxicity testing?
Offspring sacrificed and examined a day prior to expected birth for teratogenic effects. Offspring observed for growth retardation and abnormal function through infancy and examined for teratogenic effects.
Dermal toxicity tests determine for what? This may be the result of what?
Dermal toxicity tests determine the potential for an agent to cause irritation and inflammation of the skin. This may be the result of direct damage to the skin cells by a substance. It may also be an indirect response due to sensitization from prior exposure.
List the two dermal toxicity tests.
1. Primary dermal irritation.

2. Dermal sensitization.
Describe primary dermal irritation toxicity tests.
Determines direct toxicity. The substance is applied to the skin of 6 albino rabbits for 4 hours and the rabbits are observed for 72 hours for irritation.
Describe dermal sensitization toxicity tests.
Assays for immune hypersensitivity of the skin. It consists of two phases.

1. Sensitization Phase : The substance is applied to the skin of guinea pigs for 4 hours. There should be no skin inflammation. At least one week later, the substance is reapplied to the skin.

2. This is known as the challenge phase. An inflammatory rxn indicates that the skin has been sensitized to the substance.

2.
How is ocular toxicity determined?
Ocular toxicity is determined by applying a test substance for one second to the eyes of 6 test animals, usually rabbits. The eyes are then carefully examined for 72-hours, using a magnifying instrument to detect minor effects.
For ocular toxicity the ocular reaction may occur where?
The ocular reaction may occur on the cornea, conjunctiva, or iris.
For occular toxicity the irritation may be what?
It may be simple irritation that is reversible and quickly disappears or the irritation may be severe and produce corrosion, an irreversible condition.
The eye irritation test is commonly known as what?
The eye irritation test is commonly known as the "Draize Test."
Describe the "Draize Test"?
This test has been targeted by animal welfare groups as an inhumane procedure due to pain that may be induced in the eye. The test allows the use of an eye anesthetic in the event pain is evident. The Draize Test is a reliable predictor of human eye response. However, research to develop alternative testing procedures that do not use live animals is underway. While some cell and tissue assays are promising, they have not as yet proved as reliable as the animal test.
A battery of what has recently been developed to supplement the what in domestic chickens (hens)?
A battery of standardized neurotoxicity tests has recently been developed to supplement the delayed neurotoxicity test in domestic chickens (hens).
The hen assay determines what?
The hen assay determines delayed neurotoxicity resulting from exposure to anticholinergic substances, such as certain pesticides.
The hens are protected from the what?
The hens are protected from the immediate neurological effects of the test substance and observed for 21 days for delayed . (delayed neurological toxicity test)
Other than the hens, list 3 other neurological toxicity tests.
1. Motor activity

2. Peripheral nerve conduction

3. Neuropathology
Describe neurological test for motor activity.
Tests for decreased motor activity, such as cage movement. Rats or mice are used.
Describe neurological test for peripheral nerve conduction.
Tests for electrical conduction in motor and sensory nerves. Rodents are exposed for 90 days to the test substance.
Describe neurotoxicity tests for neuropathology.
Tests for nerve damage by microscopic examination. This is one aspect of other standardized toxicity tests.
Genetic toxicity is determined using what?
Genetic toxicity is determined using a wide range of test species including whole animals and plants (e.g., rodents, insects, and corn), microorganisms, and mammalian cells. A large variety of tests have been developed to measure gene mutations, chromosome changes, and DNA activity.
The most common gene mutation tests involves what?
1. Microorganisms

2. Mammalian cells

3. Fruit flies

4. Mice
Describe test involving microorganisms involved with genetic toxicity?
Salmonella typhimurium and E. Coli are commonly used bacterial tests. The S. typhimurium assay is known as the AMES TEST. Yeast are also used to detect gene mutations in culture systems.
Describe test involving mammalian cells involved with genetic toxicity?
The two main cell lines are mouse lymphoma and chinese hamster ovary (CHO) cells.
Describe test involving fruit flies involved with genetic toxicity?
Drosophilia melanogaster is used to detect sex-linked recessive lethal mutations.
Describe test involving mice involved with genetic toxicity?
The Mouse Specific Locus Test is the major gene mutation test that employs whole animals. Exposed mice are bred and observed for hereditary changes.
Chromosomal effects can be detected by what?
Chromosomal effects can be detected by a variety of tests, some involving whole animals (in vivo). Some use cell systems (in vitro). Several assays are available to test for chemically induced chromosome aberrations in whole animals.
List the two most common tests for chromosomal effects.
1. Rodent chromosomal assay
(in vivo)


2. Dominant lethal assay
Describe Rodent chromosomal assays for chromosomal effects.
Involves exposure of mice or rats to a single dose of a substance. Their bone marrow is analyzed for chromosome aberrations over a 48 hour period.
Describe dominant lethal assays for chromosomal effects.
Exposed male mice or rats are mated with untreated females. The presence of dead implants or fetuses is the result of the fertilized ovum receiving damaged DNA from the sperm. This leads to the death of the embryo or fetus. The genetic defect in the sperm is thus a heritable dominant lethal mutation.
List 3 additional in vivo chromosomal assays.
1. Micronucleus test

2. Heritable translocation assay

3. Sister chromatid exchange assay (SCE)

4.
Describe in vivo micronucleus tests.
Mice are exposed once and their bone marrow or peripheral blood cells are examined for 72 hours for the presence of micronuclei, such as broken pieces of chromosomes surrounded by a nuclear membrane.
Describe in vivo heritable translocation assay.
Exposed male Drosophilia or mice are bred to non-exposed females. The offspring males (F1 generation) are then bred to detect chromosomal translocations.
Describe in vivo sister chromatid exchange assays (SCE).
Mice are exposed to a substance and their bone marrow cells or lymphocytes are microscopically examined for complete chromosomal breakage. This is indicated by by chromatid fragments joining sister chromatid rather than their own.
In vitro tests for chromosomal effects involve what?
In vitro tests for chromosomal effects involve the exposure of cell cultures and microscopic examination for chromosome damage.
The most commonly used cell lines for in vivo test are what?
The most commonly used cell lines are Chinese Hamster Ovary (CHO) cells and human lymphocyte cells.
Why are Chinese Hamster Ovary (CHO) cells used for in vivo tests?
The CHO cells are easy to culture, grow rapidly, and have a low chromosome number (22) which makes for easier identification of chromosome damage. Human lymphocytes are more difficult to culture.
Describe human lymphocyte cells used for in vivo test.
They are obtained from healthy human donors with known medical histories. The results of these assays are potentially more relevant to determine effects of xenobiotics which induce mutations in humans.
What is considered the first step in the process of mutagenesis?
DNA damage is considered the first step in the process of mutagenesis.
The most commonly used test for what involves exposure of mammalian cells in culture to a test substance?
The most commonly used test for unscheduled DNA synthesis (UDS) involves exposure of mammalian cells in culture to a test substance.
DNA damage can not be what? So what happens to these cells?
DNA damage can not be repaired so the cells die or their growth may be inhibited.
Rodents and rabbits are the most commonly used species in toxicity testing because of:





Similarity of their metabolism to that of humans




Availability and low cost of breeding and housing




Exemption from animal welfare concerns
Rodents and rabbits are the most commonly used species in toxicity testing because of availability and low cost of breeding and housing. Since there are numerous toxicity tests that must be conducted to assure safety, it is necessary to use species that can be obtained in large numbers, housed in small cages, and have a relatively short lifespan.
The toxicity test designed to detect toxic effects from a single or brief exposure is known as the:





Acute toxicity test




Subchronic toxicity test




Chronic toxicity test
The toxicity test designed to detect toxic effects from a single or brief exposure is known as the the acute toxicity test. It provides data on toxicity likely to arise from a single dose or a brief exposure within a 24 hour period.
The species of animals generally recommended for subchronic and chronic tests are:





Rabbits and guinea pigs




Rats and mice




Rats and dogs
The species of animals generally recommended for subchronic and chronic tests are rats and dogs. Two species, a rodent and non-rodent are recommended for both the subchronic and chronic toxicity tests. The rat is the preferred rodent and the dog is the recommended non-rodent species.
The duration of a carcinogenicity test in mice is at least:





90 days




12 months




18 months
The recommended treatment and observation time for a carcinogenicity test in mice is 18-24 months.
The standard developmental toxicity test:





Detects the potential for substances to produce birth defects.




Determines the effects of substances on growth and development of offspring.




Determines the effects of substances on gonadal function.
The standard developmental toxicity test detects the potential for substances to produce birth defects. The animals are dosed during the period of major organ development of the fetus which is the 6th to the 15th day of gestation in mice and rats.
The method used in the primary dermal irritation test





Employs two doses, a sensitizing dose and a challenge dose




Consists of applying a substance to the skin of rabbits for 4 hours and observing them for 72 hours for dermal effects




Requires the repeated application of a substance to the skin for 14 days
The primary dermal irritation test determines direct toxicity. The substance is applied to the skin of 6 albino rabbits for 4 hours. The skin is observed for the next 72 hours for irritation.
The Draize Test is used to determine:





Dermal sensitization




Neurotoxicity




Eye irritation
The Draize Test assays for ocular toxicity by applying a substance for one second to the eyes of 6 test animals, usually rabbits. The eyes of the test animals are observed for the next 72 hours for reactions of the cornea, conjunctiva, or iris
The delayed neurotoxicity test is:





A test that involves administering a substance to adult female chickens with observation for 21 days to see if delayed neurotoxicity develops.




A test that is conducted with rats exposed for 12 months to determine if neurotoxicity develops late in life after long term exposure.




A test that consists of observing the movement of rats or mice in their cages
The delayed neurotoxicity test involves administering the substance once to adult female chickens and observing them for 21 days. The neurotoxicity does not occur immediately but is delayed, developing only after several days. The test determines if anticholinergic substances, such as pesticides, can cause such delayed neurological effects.
The Ames Test involves:





The use of Drosophila melanogaster, the common fruit fly, to detect point mutations.




The use of the bacterium, Salmonella thyphimurium, to detect gene mutations.




The use of E. coli, a bacterium, to determine gene mutations.
The Ames Test involves The use of the bacterium, Salmonella thyphimurium, to detect gene mutations. It was named after Dr. Bruce Ames, who developed the test. A positive response is indicated by counting mutated colonies on culture plates after exposure to the test substance.
The Dominant Lethal Test assays for:





Heritable lethal mutations induced in sperm by exposure to a mutagen.




The complete breakage of a chromosome so that both chromatids are severed in approximately the same location.




The presence of Unscheduled DNA Synthesis (UDS).
The Dominant Lethal Test assays for heritable lethal mutations induced in sperm by exposure to a mutagen. The test consists of mating exposed male mice or rats with untreated females. Dead fetuses indicate that the fertilized ovum received damaged DNA from the sperm causing death of the embryo or fetus.