Part 1: I. Design, Execute and Interpret Toxicology Studies

Question 1

What size/dimension of inhaled particles would favor their deposition in the respiratory (alveolar) region of the lung?
A. ≥2.5 micrometers in diameter
B. <0.01 micrometers in diameter
C. 1 x 200 micrometer elongated fibers
D. between 0.01 and 2.5 micrometers in diameter

Answer 1

Answer: D
Explanation and Reference:
Particles reach the alveolar region on the lung by sedimentation and diffusion. Sedimentation is not favorable for particles ≤0.5 µm aerodynamic diameter but diffusion is favorable for this dimension down to 0.01 µm. Particles >2.5 µm would be trapped in the upper airway by impaction. An elongated fiber would be trapped in the bronchial tree by interception. C&D 8th, pp. 702-703

Question 2

Particles ≤100 nm in at least one dimension are nanoparticles. When inhaled, why do these particles generally result in greater pulmonary inflammation than an equal mass of larger size particles?
A. nanoparticles have a significantly greater surface area to mass ratio
B. nanoparticles deposit deeper in the respiratory tract than larger sized particles
C. nanoparticles are generally more water soluble than larger particles
D. nanoparticles reduce the clearance capability of alveolar macrophages

Answer 2

Answer: A
Explanation and Reference:
The toxicity of nanoparticles is attributed primarily to the increased surface area that can generate secondary reactions (oxidative stress) or carry co-pollutants into the lung. They have no effect on macrophages but may not be effectively cleared by these cells. They do not necessarily deposit deeper in the lungs, depending on their shape. Since most nanoparticles are carbon fibers or metals, it would be incorrect to characterize them generally as “water soluble.” C&D 8th, p. 703

Question 3

For what type of toxicity study is the hen (chicken) used as the test species in the registration package for organophosphate insecticides?
A. teratogenicity
B. acute delayed neurotoxicity
C. 90-day oral toxicity
D. acute oral toxicity

Answer 3

Answer: B
Explanation and Reference:
Chickens are a sensitive species for ChE inhibition. The adult hen is the required animal model for this assay under OECD Guideline 419 and US EPA Health Effects Test Guideline OPPTS 870.6100. C&D 8th p. 938, Table 22-7

Question 4

What modification of the LD50 assay is described by the following? Animals are dosed one at a time, starting at an estimated LD50 dose. If the first animal survives, the next one receives a higher dose. If the first animal dies, the next one receives a lower dose. The spacing of dosing generally is adjusted by a factor of 3.2.
A. the up-and-down method
B. approximate lethal dose method
C. the acute toxic class method
D. the fixed dose procedure

Answer 4

Answer: A
Explanation and Reference:
In the up/down method the animals are monitored for overt signs of toxicity until death. Methods A, B, and D are all modifications of the LD50 assay designed to reduce animal numbers and/or increase quality and quantity of information collected. Hayes 6th p. 1152

Question 5

A 20 kg child has consumed 300 mg of caffeine in a dietary supplement. The volume of distribution (Vd) per kg of body weight for caffeine is 0.75 liter/kg. What is the child’s estimated initial blood level, assuming 100% gastrointestinal absorption?
A. 50 mg/liter
B. 20 mg/liter
C. 5 mg/liter
D. 200 mg/liter

Answer 5

Answer: B
Explanation and Reference:
Vd= Dose/Co, where Co is initial concentration assuming instantaneous equilibration. Rearranging and solving for Co yields a new equation, Dose/Vd = Co. The dose (or dosage) is 300 mg/20 kg = 15 mg/kg divided by the Vd, 0.75 liter/kg = 20 mg/L. C&D 8th p. 372

Question 6

Calculate the achieved dosage in mg/kg/day of a chemical fed to rats at a concentration of 0.5% (5000 ppm) in the diet. The rats had a mid period group mean body weight of 250 g and ate 210 g/week of the chemical diet admixture.
A. 600
B. 42
C. 60
D. 420

Answer 6

Answer: A
Explanation and Reference:
5000 ppm is 5000 mg/kg diet x 0.030 kg diet/day (210 g/wk divided by 7 = 30 g or 0.030 kg diet/day)/
0.25 kg rat = 600 mg/kg-day. Hayes 6th, p. 1217-1220

Question 7

What would be considered an advantage of the Cohort epidemiological study design?
A. requires a small number of subjects
B. suitable for rare diseases
C. yields incidence and risk rates
D. short follow-up period with subjects

Answer 7

Answer: C
Explanation and Reference:
Cohort studies evaluate multiple effects following exposure. They are prospective studies yielding incidence and risk rates. The follow up can last years, in contrast to a cross-sectional study that yields quick results. Case-control studies are best for rare diseases and use small numbers of subjects. C&D 8th p. 131, Table 4-5

Question 8

100 mg of Drug X is administered by rapid IV bolus. Assuming conditions of a one compartment model, what is the apparent volume of distribution (Vd) given a half life of 10 hours and an initial plasma concentration of 4 mg/L?
A. 25 L
B. 10 L
C. 20 L
D. 5 L

Answer 8

Answer: A
Explanation and Reference:
Vd can be in units of L or L/kg. The simple formula is Vd=Dose/Co, where dose can be in mass (mg) or relative mass (mg/kg) and Co is the initial concentration in mass/volume (mg/mL). In this question, Co and dose are given, and applying the formula, 100 mg/4 mg/L=25 L. The t½ in the question is a distractor. One could also calculate Vd knowing t½ and Clearance. C&D 8th pp. 371-373.

Question 9

Conventional approaches to toxicity testing of pharmaceuticals may not be appropriate for biopharmaceuticals. In developing a monoclonal antibody in accordance with ICH S6 guidelines, what is the first consideration when designing IND-enabling in vivo safety studies?
A. selecting a dose level producing clear toxicity
B. assuring the test article is non-immunogenic
C. understanding the mode of action
D. choosing a relevant test species

Answer 9

Answer: D
Explanation and Reference:
Preclinical safety testing should consider: (1) Selection of the relevant animal species; (2) age; (3) physiological state; (4) the manner of delivery, including dose, route of administration, and treatment regimen; and (5) stability of the test material under the conditions of use in that order. Reference: ICH S6, Preclinical Safety Evaluation of Biotechnology-derived Pharmaceuticals, July 1997, pp.2-8. (specifically Section 1.2, Para 2)

Question 10

What IND-enabling preclinical studies are recommended in the ICH S6 and M3 guidelines for both monoclonal antibody and small molecule pharmaceutics?
A. immunogenicity studies
B. tissue cross reactivity studies
C. pharmacokinetic and toxicokinetic studies
D. in vitro genotoxicity studies

Answer 10

Answer: C
Explanation and Reference:
Single and multiple dose pharmacokinetics, toxicokinetics, and tissue distribution studies in relevant species are recommended for both types of programs. Immunogenicity and tissue cross reactivity would be unusual for a small molecule and genotoxicity studies are generally not applicable to biotechnology products. ICH guidelines S6 (Section IV.B.(4.2.1) and IV.G.(4.7) and M3; also Hayes 6th, pp. 332-333, 355

Question 11

In evaluating differences between mean values of clinical chemistry variables from an animal toxicity study on Day 1 vs. Day 14, statistical analyses are used, and a p-value of <0.05 for several comparisons were derived. What does a p-value of <0.05 mean?
A. the differences between the variable means are statistically and biologically significant
B. the significant differences between means were caused by the treatment
C. the probability that the the observed response had no effect is less than 1 in 20
D. the probability that the observed response had no effect is less than 1 in 20

Answer 11

Answer: C
Explanation and Reference:
The significance level is the chance of obtaining a false positive result due to sampling error (known as a Type I error). It is usually set at 5%, although lower levels are sometimes specified. In other words, it is the probability that the null hypothesis is true. Statistical significant tells the investigator nothing about biological significance or whether the differences are true or not. Hayes 6th, p. 377

Question 12

In risk assessment, what results can be obtained by using DNA microarrays in toxicology studies?
A. many genes can be evaluated simultaneously to detect patterns of response to a toxicant
B. detection of differential gene expression, eliminating the need to test the toxicant in whole animals
C. changes in gene expression that can be precisely correlated to changes in organ function
D. measurements of gene expression that can be precisely quantified following exposure to a toxicant

Answer 12

Answer: A
Explanation and Reference:
Sophisticated analysis of microarrays can be used to analyze patterns of gene espresssion between comparative sets of samples. These analyses can be linked to functional intepretations and classic toxicological endpoints. C&D 8th, pp. 140, 1281-1282

Question 13

In evaluating dose-response relationships, the benchmark dose approach offers what advantage over the NOAEL approach?
A. establishes a mode-of-action for threshold effects
B. provides greater certainty with fewer animals
C. establishes a mode-of-action for nonthreshold effects
D. includes a measure of variability in the data set

Answer 13

Answer: D
Explanation and Reference:
The benchmark dose includes a measure of variability whereas the NOAEL does not. It also allows consideration of the shape of the entire dose-response curve and permits a specified benchmark response (BMR) level for RfD calculations. C&D 8th, p. 134-135

Question 14

The following dosages of a test drug were administered to male rats by oral gavage daily for 28 days: 10, 50, and 100 mg/kg. The only observed toxicity was focal hepatocyte necrosis, observed at the 100-mg/kg dose level. Based on these data, what is the no-observed adverse effect (NOAEL)?
A. 10 mg/kg
B. greater than 50 mg/kg, but less than 100 mg/kg
C. 100 mg/kg
D. 50 mg/kg

Answer 14

Answer: D
Explanation and Reference:
The NOAEL is a professional opinion based on the design of the study, indication of the drug, expected pharmacology, and spectrum of off-target effects. It requires a decision of what findings are adverse to the test system under the conditions of study. http://www.fda.gov/CDER/guidance/5541fnl.pdf “Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”; C&D 8th p. 134 (also C&D 9th, pp. 36-37)

Question 15

What analytical method would be used on tissue samples to detect drug-induced alterations in specific RNA sequences?
A. western blot
B. northern blot
C. eastern blot
D. southern blot

Answer 15

Answer: B
Explanation and Reference:
The northern blot is a technique to study gene expression by measuring the cellular production of RNA. Hayes 6th p. 303

Question 16

Fluorescein-conjugated nucleic acid probes are used as tools in a technique called Fluorescence In Situ Hybridization (FISH). For what primary purpose is this technique used in genetic toxicology? A. facilitates counting micronuclei in polychromatic erythrocytes B. locates point mutations in mammalian chromosomes C. more accurately quantitates sister chromatid exchanges D. facilitates cytogenetic analysis by “chromosome painting”

Answer 16

Answer: D
Explanation and Reference:
FISH uses fluorescent probes to bind and visualize nucleic acids with a high degree of similarity. C&D 8th, pp.465-466 and 471-472

Question 17

What in vivo assay is designed and used primarily for the detection chromosomal breakage (clastogenicity)?
A. Drosophila sex-linked recessive lethal assay
B. rodent bone marrow micronucleus assay
C. TK assay in mouse lymphoma cells
D. chromosomal aberration assay in human lymphocytes

Answer 17

Answer: B
Explanation and Reference:
The rodent micronucleus test is the only in vivo assay for detecting clastogenicity. Two chromosomal aberration assays, one in CHO cells and the other in human peripherla blood lymphocytes, are also used, but they are in vitro assays. The mammalian-microsome reverse mutation assay is, like the Ames assay, is intended to detect mutagenicity (e.g. point mutations, forward mutations). Hayes 6th,
pp. 1258-1260, Table 25.4

Question 18

A treatment-related increase in the number of micronucleated cells in a genotoxicity study indicates what type of adverse effect?
A. chromosomal translocation
B. toxicity to bone marrow cells
C. DNA point mutations
D. clastogenicity and/or aneuploidy

Answer 18

Answer: D
Explanation and Reference:
The micronucleus assay measures the number or chromatic erythrocytes, which are remnants of clastogenic DNA damage in mature red blood cells. The technique also detects aneuploidy. C&D 8th, p.466-467

Question 19

What animal model in considered the best predictor of dermal absorption of chemicals for humans?
A. rat
B. pig
C. mouse
D. rabbit

Answer 19

Answer: B
Explanation and Reference:
Historical research has shown that, in general, chemical penetration of the human skin is similar to that of a pig or monkey, and much slower than that of the rat and rabbit. C&D 8th p. 167

Question 20

The single-cell gel electrophoresis assay (Comet test) is used to detect what genotoxic endpoints?
A. single and double strand DNA breaks in cells and tissue
B. point mutations in bacterial and mammalian cells
C. sister chromatid exchanges (SCE) in mammalian cells
D. aneuploidy in bone marrow cells

Answer 20

Answer: A
Explanation and Reference:
The COMET assay measures isolated DNA fragments using a gel electrophoresis method; smaller fragments migrate further in the gel and length can be measured. C&D 8th p. 460 and Table 9-2

Question 21

During a reproductive and developmental toxicology study in mice, a statistically significant and dose related decrease in the number of live fetuses per litter was determined following mating of treated males and naive, untreated females. No decrease in mating and fertility ratios or evidence of pre- implantation loss was found. To what would you attribute the decreased number of live fetuses per litter?
A. a decrease in male libido
B. a dominant lethal mutation in sperm
C. a decrease in the number of ova fertilized
D. a decrease in viable sperm per male

Answer 21

Answer: B
Explanation and Reference:
From the information provided, there are no adverse effects of treatment on mating, fertility, and implantation. The scenario is one of post-implantation loss, and in this case toxicity to sperm is suspect. A test specific for this effect is known as the Dominant Lethal Male Assay for mutagenicity. Hayes 6th, pp. 440-443, 1623

Question 22

In the evaluation of lung exposure to airborne particulates, what is considered the measure of the inspired respiratory volume?
A. forced expiratory volume in 1 sec (FEV1)
B. total inspiratory capacity (IC)
C. breathing rate (f) multiplied by tidal volume (Vt)
D. vital capacity (VC) including the functional residual capacity (FRC)

Answer 22

Answer: C
Explanation and Reference:
Breathing rate multiplied by tidal volume determines minute ventilation, and increased minute ventilation in a polluted atmosphere increases the deposition of toxic materials. C&D 8th, p.699

Question 23

The murine local lymph node assay (LLNA) has been used as a substitute for the guinea pig maximization test (GPMT). What is the measurement endpoint in the LLNA?
A. ear edema using Draize criteria
B. size of the submandibular lymph nodes
C. H3 thymidine uptake into proliferating lymphocytes
D. ear erythema using Draize criteria

Answer 23

Answer: C
Explanation and Reference:
The murine LLNA measures H3 thymidine uptake into proliferating lymphocytes of the lymph nodes draining the injection site. The LLNA is a measure of induction; inflammation and erythema are measures of elicitation. Measuring the size of the submandibular lymph node is too non-specific and variable to be useful. C&D 8th, p.586

Question 24

What characteristics of a xenobiotic would favor dermal absorption?
A. ionic, low molecular weight
B. hydrophobic, low molecular weight
C. nonionic, high molecular weight
D. hydrophilic, low molecular weight

Answer 24

Answer: B
Explanation and Reference:
Compounds that are lipophilic and of low molecular volume are most likely to penetrate the skin. C&D 8th, p. 166

Question 25

What is the disadvantage of using renal component systems (e.g., slices, isolated tubules or isolated perfused kidneys) in mechanistic toxicology research? A. limited viability and correlation to whole-animal B. variables from single-animal sources cannot be controlled C. tubular transport studies cannot be performed D. specific nephron segments of interest cannot be isolated

Answer 25

Answer: A Explanation and Reference: Freshly prepared cell models have limited lifespan (2-24 h); whereas, primary renal cell cultures or cell lines may last several weeks. With all models, however, all models exhibit less differentiated functions and similarity to the in vivo system. C&D 8th p. 778

Question 26

What bacterial strain included in the core strains of the Ames assay can specifically detect mutagens that induce frame-shift mutations, other small deletions, and some complex mutations? A. TA97 B. TA102 C. TA1538 D. TA100

Answer 26

Answer: C Explanation and Reference: TA1538, along with TA98, can measure frameshift, small deletion, and some complex frameshift mutations. C&D 8th, p. 462, Table 9-3

Question 27

What is the most common spontaneous neoplasm in control male Fischer (F344) rats observed in two-year bioassays? A. liver adenoma/carcinoma B. thyroid c-cell adenoma/carcinoma C. testicular interstitial cell tumors D. pituitary adenoma/carcinoma

Answer 27

Answer: C Explanation and Reference: Based on the NTP 2-year rodent carcinogenicity studies, testicular interstitial cell adenomas are the most commonly found neoplasm in controls. C&D 8th, p. 38, fig. 2-15

Question 28

What two genotoxicity assays would detect point mutations? A. in vivo micronucleus assay and in vitro metaphase analysis in CHO cells B. in vitro sister chromatid exchange assay and in vitro micronucleus assay C. in vitro unscheduled DNA synthesis and in vivo mouse heritable translocation assay D. in vitro bacterial reverse mutation (Ames) assay and forward mutation assay with mouse lymphoma L5178Y cells

Answer 28

Answer: D Explanation and Reference: The Ames test (Salmonella typhimurinum), in particular, strains TA100 and TA1538, and the mouse lymphoma assay detect point (substitution) mutations. C&D 8th, pp.425-426, Table 8-21 and pp. 461- 463, Table 9-3

Question 29

In reproductive/developmental toxicology, what is the "gestation index"? A. percent of mated females that deliver viable litters B. percent of matings resulting in pregnancy C. percent animals born that survive four or more days D. percent of animals that survive the 21-day lactation period

Answer 29

Answer: A Explanation and Reference: The gestation index is one of the four primary variables that are of interest in any reproduction study and is defined as given in the correct foil (C). The other three variables are the fertility index, the viability index, and the lactation index. Hayes 6th, p. 440

Question 30

What is the experimental unit in a "Segment II" (ICH S5A Stage C) rat teratology study for the purpose of statistical analysis (i.e., basic unit of comparison)? A. litter or mating pair B. individual live pups born C. treated, fertile maternal animal D. non-viable pups born

Answer 30

Answer: A Explanation and Reference: The primary focus of the Segment II study is to evaluate viability and morphology of the conceptus prior to birth. When employing statistics, the mating pair or litter, not the fetus or neonate should be used as the basic unit of comparison. ICH S5A(R3), Section 8.2, Statistics (2020)

Question 31

What are the primary purpose and limitation of juvenile toxicology studies for pharmaceutical and biotechnology products? A. they are required for all new drug but not pesticide registration B. they assess safety and efficacy but not risk C. they assess the safety but not efficacy of a product . D. they assess the efficacy but not safety of a product

Answer 31

Answer: C Explanation and Reference: Juvenile toxicology studies may be requested by the FDA to evaluate safety under pediatric conditions. Hayes 6th, pp. 362-363

Question 32

Intraocular melanin is involved with drug and environmental chemical toxicity to the retina by what mechanism? A. melanin has low binding affinity for most environmental chemicals B. melanin is not located intraocularly C. binding PAHs, chloroquine, and heavy metals. D. melanin is depleted in the uveal tract between sclera and retina

Answer 32

Answer: C Explanation and Reference: Intraocular melanin exists in multiple regions of the eye, has a high affinity for chloroquine, heavy metals, including lead, and other drugs where they can accumulate, and then are released slowly. C&D, 8th, pp. 52, 780-785

Question 33

What genetic toxicology assay measures not only mutagenic but also recombination, deletion and aneuploidy endpoints? A. mouse micronucleus test B. mouse lymphoma assay C. Ames assay D. comet assay

Answer 33

Answer: B Explanation and Reference: The mouse lymphoma assay has been used traditionally as a core test because it can serve as an in vitro measure of both gene mutation and chromosomal aberrations. This is because mutations of the target gene (TK) can be induced by either base pair substitution at the mutant site or by deletions of the allele through chromosome breakage. The Ames assay measures reverse mutations in bacteria; the micronucleus test and Comet assay measure clastogenicity. C&D 8th, p. 463 and Hayes 6th p. 1186

Question 34

The European Union banned all animal testing for what product category after 2009? A. organohalogens B. cosmetics C. preservatives D. petrochemicals

Answer 34

Answer: B Explanation and Reference: Under the seventh amendment to the EU cosmetics directive, the use of animals in safety assessment for cosmetics is not permitted after 2009. There are no such proscriptions by the EU or any other jurisdiction for the safety testing of organo- halogens, petrochemicals, or preservatives. Hayes, 6th, p.1259

Question 35

The Comet Assay is used for what type of assessment? A. evaluating serum neurotoxic esterase activity B. monitoring carbon monoxide exposure in red blood cells C. measuring DNA damage using single-cell gel electrophoresis D. electrophoretic measurement of sperm motility prior to fertilization

Answer 35

Answer: C Explanation and Reference: COMET measures DNA damage in variable sections that create "tails" that can be measured to determine extent of DNA damage in tissue of concern. C&D 8th, p.460

Question 36

To demonstrate definitively that a chemical has the potential to act as a teratogen in rats, when during gestation would you expose the dam? A. during organogenesis B. pre and post fertilization of the female C. during the implantation period D. throughout the entire gestation period

Answer 36

Answer: A Explanation and Reference: Teratogens are most effective when administered during organogensis (Day 7 to 17 in the rat). C&D 8th, p. 36 and ICH S5(R3), 2020, Annex 1: In Vivo study designs, Section 1.1.2.3, Table 3

Question 37

What actions must be included when assessing embryo-fetal developmental toxicity under ICH S5? A. examination of weanlings for gross and visceral abnormalities B. treatment of male and female rodents for 60 days to assure implantation C. assessments of resorptions, fetal body weights, and fetal malformations D. assessments of neurobehavioral deficits incurred during prenatal exposure

Answer 37

Answer: C Explanation and Reference: These are needed to determine extent of unsuccessful implantations, predictive in fetal toxicity, and diagnostic for teratagens. ICH S5(R3), 2020, Annex 1 In Vivo study designs, Section 1.1.2.3, Table 3

Question 38

The presence of growth retardation, malformations and embryo lethality are commonly considered with what test? A. Segment I: fertility and general reproduction study B. Segment III: perinatal study C. OECD: Extended one-generation reproductive toxicity study D. Segment II: teratogenicity study

Answer 38

Answer: D Explanation and Reference: The endpoints for the Seg II study are viability and anatomy of fetuses prior to birth. This is the classic study for the detection of chemical teratogens where the dams are exposed from implantation (or mating) to the end of organogenesis (or term). C&D 9th pp. 568-570 and Table 10-7.

Question 39

The potential for xenobiotic-induced embryo-fetal developmental toxicity is best evaluated during what gestational period in the rat (where conception=gestation day 0)? A. gestation days 0-21 B. gestation days 6-17 C. gestation days 0-5 D. gestation days 6-21

Answer 39

Answer: B Explanation and Reference: Gestational days 6-17 is the primary period of organogenesis in rodents. This is the period of development that is highly sensitive to teratogenesis. C&D 9th, pp. 554-55 (Table 10-4) and pp. 568- 570 and Table 10-7; also ICH S5 (R3) 2020 Section 1.1.2.3, Table 3.

Question 40

Particle deposition by impaction is most prevalent in what region of the human lung? A. first-generation tracheobronchial B. bronchial tree C. bronchiolar-alveolar D. naso-pharyngeal

Answer 40

Answer: A Explanation and Reference: The deposition of particles in the respiratory system occurs either by interception, impaction, sedimentation, or diffusion. As a result of inertia, particles between 2.5 and 10 µm in aerodynamic diameter would be expected to deposit in the first branches of the upper airway. There is a trick to this question. Particles > 10 µm would be deposited by impaction in the nose and oropharynx but these regions are outside the lung. C&D 9th, pp. 804-805.

Question 41

What feature is common to all four types of hypersensitivity reactions? A. prior antigenic exposure B. production of IgG C. the generation of T cells D. production of IgE

Answer 41

Answer: A Explanation and Reference: Prior antigenic exposure and formation of a protein-hapten conjugate is the common antecedent to all four hypersensitivity-type reactions. C&D 9th, pp. 689-694, Fig. 12-22.

Question 42

What in vivo assay measures only the induction phase of chemical sensitization? A. the guinea pig maximization assay B. the Draize test C. the mouse local lymph node assay D. the Magnusson-Kligman test

Answer 42

Answer: C Explanation and Reference: The murine local lymph node assay measures mitogenesis of immune cells in the mouse lymph nodes following stimulation. It is the only assay that measures only the induction phase of sensitization. All other require a second exposure and measurement of the elicitation phase. Hayes, 5th, p. 11102.

Question 43

Alternative non-animal methods for testing the potential for chemicals to cause topical injury to the eye have been developed by an international consortium and adapted by several regulatory agencies. What animal test do these alternative methods replace? A. the Draize test in rabbits B. the Hay's test in mice C. the maze test in rats D. the gaze test in primates

Answer 43

Answer: A Explanation and Reference: The correct answer is the Draize test in rabbits. This had been the standard since the 1940s but has been criticized in the 21st Century for high inter-laboratory variability, subjective scoring, poor predictive value, and for causing undue pain and distress to the test animals. The gaze test is used to evaluate the ability to generate and hold a steady gaze without drift or gaze-evoked nystagmus. This is a test used in humans and other primates. The maze test is used to test memory, cognition, and behavior, commonly in rats. Hay’s test is a method for detecting bile salts in urine in any species. C&D 9th pp. 885-886.

Question 44

Reticulocytosis following high therapeutic daily doses of a drug is most characteristic of what response? A. a drug-induced normal physiologic response B. drug-induced red blood cell destruction. C. drug-induced polycythemia D. drug-induced aplastic anemia

Answer 44

Answer: B Explanation and Reference: In cases of drug-induced red cell destruction, reticulocyte count can be useful in the diagnosis, because increased destruction is usually accompanied by an increase in reticulocytes (young erythrocytes) into the circulation. Reticulocytosis would not be considered normal drug response, and polycythemia would be expected to decrease the production of new red cells. In the case of aplastic anemia, the bone marrow would be unable to make a response; hence, reticulocytosis would not appear. C&D 9th, p. 496-598

Question 45

Chemicals such as chloramphenicol, phenylbutazone, and phenytoin can cause a condition known as aplastic anemia. What is the specific cellular target of these chemicals? A. colony forming unit-erythrocyte (CFU-E) B. colony forming unit-granulocyte (CFU-G) C. polymorphonuclear cells (PMN) D. hematopoietic stem cell (CFU-S)

Answer 45

Answer: D Explanation and Reference: Aplastic anemia occurs through destruction of RBC stem cells in the bone marrow. C&D 9th pp. 598- 599

Question 46

What cellular enzyme biomarkers in blood indicate the possibility of liver damage? A. lactate dehydrogenase and liver phosphodiesterase B. mitochondrial pyruvate oxygenase and creatine kinase C. serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) D. sorbitol dehydrogenase and serum oxygen transferase

Answer 46

Answer: C Explanation and Reference: Alanine aminotransferase and aspartate aminotransferase are considered two of the standard clinical chemistry tests used in preclinical toxicology studies as indices of hepatocellular injury. Lactate dehydrogenase is not liver specific, and liver phosphodiesterase is not a biomarker of toxicity. While sorbitol dehydrogenase can be used to indicate hepatocellular injury, it is not a standard test and is therefore not recommended. Oxygen transferases are not indicators of liver toxicity nor are mitochondrial pyruvate oxygenases. Creatine kinase is a biomarker for cardiac toxicity. C&D 9th pp. 732-733

Question 47

Clinical assessment of drug-induced liver injury using Hy's Law considers what test results? A. >3-fold increases in serum ALT and >2-fold increases in total bilirubin B. >3-fold increases in ALT, AST, and ALP without increased total bilirubin C. >3-fold increases in ALT, AST and >2-fold increases in total cholesterol D. >3-fold increases in ALT, AST, and ALP with >2-fold increases in total bilirubin

Answer 47

Answer: A Explanation and Reference: Hy's Law is useful as a prognostic indicator in drug-induced liver injury. It combines serum ALT >3XULN and serum total bilirubin >2XULN in making a prediction of outcome. C&D 9th pp. 732-733.

Question 48

Based on current OECD Guidelines, what tester strains of Salmonella typhimurium that revert at GC base pairs should be used in the Ames Assay? A. TA 1536, TA 110, TA 1518, TA 85 B. TA 1548, TA 102, TA 1505, TA 92 C. TA 1535, TA 100, TA 1538, TA 98 D. TA 1540, TA 200, TA 104, TA 80

Answer 48

Answer: C Explanation and Reference: The correct answer lists the recommended tester strains in which reversion by GC base-pair substitutions and frameshift mutations in several DNA sequence contexts can be detected and distinguished. The other answers give wrong numbers for some of the strains. C&D 9th, pp. 520-521

Question 49

The in vivo micronucleus test is often used in a standard battery of genetic toxicity assays. In this test, what do the micronuclei actually represent? A. clumps of ribosomes aggregated around rough endoplasmic reticulum B. binucleated remnants of germ cells in the intracellular space C. membrane-bound structures that contain chromosomal fragments or whole chromosomes D. pyknotic nuclei from a cell with decreased cytoplasmic to nuclear ratios and thickened micronuclear membrane

Answer 49

Answer: C Explanation and Reference: Because the micronuclei represent chromosomal fragments, they are simple indicators of DNA damage, both clastogenesis and aneuploidy. They are not nuclear fragments or ribosomal clumps. The micronucleus test is run in lymphocytes or erythrocytes, not germ cells. The test is widely recognized as one of the most useful and reliable tests for carcinogens that act by causing DNA damage. The test is part of the OECD guidelines for testing chemical safety. C&D 9th, pp. 525-526.

Question 50

What assay is most commonly used to assesses the ability of a test material to induce chromosomal aberrations in vivo? A. thymidine kinase assay B. rodent micronucleus test C. bacterial-Ames assay D. sister chromatid exchange assay

Answer 50

Answer: B Explanation and Reference: The micronucleus test is widely recognized as one of the most useful and reliable tests for carcinogens that act by causing DNA damage. The test is part of the OECD guidelines for testing chemical safety. C&D 9th, pp. 525-526.

Question 51

How, in the Functional Observational Battery, would one evaluate the potential effects of a toxicant on vision? A. evaluation of ocular irritancy B. observing the pupillary response to light C. scoring the degree of lens opacity D. evaluation of rod and cone density

Answer 51

Answer: B Explanation and Reference: Only two visual responses are tested in the FOB; pupil contraction based on light and approach to the eye. C&D 9th, p. 888.

Question 52

What do the Buehler and Maximization assays characterize? A. minipig respiratory efficiency B. potential of a product to produce skin irritation C. ribosomal transcription efficiency D. delayed-contact hypersensitivity

Answer 52

Answer: D Explanation and Reference: The Buehler assay was originally developed to test for moderate and strong contact sensitizers using guinea pigs (GP), while the GP maximization test was designed to maximize the sensitivity of tests utilizing GPs. Both techniques are used to assess contact allergies and reactions are typically scored 24-48 hrs after challenge or re-challenge. Hayes 6th, pp. 1447-1448.

Question 53

During Ames testing for genotoxicity, the test compound is usually treated with a homogenate from mammalian liver before the addition of the bacteria. What is the basis for this treatment? A. IARC and FDA regulations specifically require this step, though it can be omitted when using some of the newer assays B. enzymes from the mammalian liver are needed to degrade and deactivate possible mutagens in the test compound before testing C. many compounds are not mutagenic or carcinogenic, but can be activated into mutagens or carcinogens by metabolism D. the mammalian liver homogenate is used to normalize the test samples for protein concentration in the test

Answer 53

Answer: C Explanation and Reference: The liver homogenate (S-9 fraction) are added to simulate liver metabolism to consider transformation to mutagenic metabolites. C&D 9th, p. 468

Question 54

What genotoxicity endpoint(s) can be detected by the mouse lymphoma assay? A. germ cell cytogenetic changes B. unscheduled DNA synthesis C. micronuclei degradation D. forward mutations in mammalian cells

Answer 54

Answer: D Explanation and Reference: The mouse lymphoma assay identifies evidence of point mutations, deletions and translocations, and recombinations. ICH Guideline S2B, Section VI, Note (2) and C&D 9th p. 468.

Question 55

What primary organ system is affected after consumption of grain treated with mercurial (organic) fungicides? A. respiratory B. hepatic C. renal D. nervous

Answer 55

Answer: D Explanation and Reference: The nervous system is the target for organic mercury compounds. C&D 8th, p. 999.