Casarret & Doulls Flashcards
1
Q
What is Descriptive Toxicology?
A
The emphasis is on the testing of toxicants, typically on animals. It focuses on the dose–response relationship and extrapolation to humans.
2
Q
What is Mechanistic Toxicology?
A
Looks at how the agent induces its biochemical or physiological effect on the organism, that is, modes
of action. Biochemical and Molecular Toxicology is a synonym
for this branch.
3
Q
What is Clinical Toxicology
A
This branch’s focus is on the effects of drugs
and other chemicals on humans, particularly, but also on other
animals.
4
Q
What is Forensic Toxicology?
A
Concerned with the cause of death from toxic
agents, often in instances of drug abuse or misuse
5
Q
What is Environmental Toxicology?
A
Investigates the effects of toxicant exposures on the general environment and living organisms therein. Thus,
pollution of air, water, and soil, and effects on plants and wildlife
would fall within this branch. Ecotoxicology, a more specialized
area, is devoted to the effects of toxic chemicals on populations,
communities, and terrestrial, freshwater, and marine ecosystems.
6
Q
What is Occupational Toxicology?
A
Deals with the study of chemical and
other agents in the workplace, worker exposures, safety and
health, and standard setting.
7
Q
What is Regulatory Toxicology?
A
Focuses on ways in which humans and the
environment can be protected from toxic effects, through regulations and standard setting. Considers scientific decision-making
within a societal and legal framework. Relies heavily upon risk
assessment.
8
Q
What is Toxicogenomics?
A
Concerned with the compilation and synthesis of information regarding gene and protein expression in
order to understand molecular mechanisms involved in toxicity. Toxicogenomics calls upon proteomics, metabolomics, and
transcriptomics to identify biomarkers that predict toxicity and
genetic susceptibility to harmful substances
9
Q
What is Computational Toxicolo9gy?
A
Deals with the use of modern computational approaches and information technologies to elucidate mechanisms of toxicity. May also be referred to as
toxicoinformatics
10
Q
Aflatoxin is an example of what fungus that grows on foods such as corn and nuts? Exposure cases an increase in what clinical disease?
A
Aspergillus; liver cancer
11
Q
Cloracne, is observed in individuals exposed to what chemical?
A
TCCD (2,3,7,8-tetrachlordibenzo-p-dioxin)
12
Q
Which regulatory body is responsible for enforcing the Comprehensive
Environmental Response, Compensation and Liability Act
(CERCLA, later revised as the Superfund Amendments
Reauthorization Act [SARA]), more commonly called the
Superfund Act
A
EPA
13
Q
What regulatory body is responsible for conducting research and making recommendations for the prevention of
work-related injury and illness, making occupational toxicology
an important component of regulatory toxicology
A
The National Institute
for Occupational Safety and Health (NIOSH) as part of the Centers
for Disease Control and Prevention (CDC) in the Department of
Health and Human Services (DHHS)
14
Q
What is Chemical idiosyncrasy?
A
The abnormal reactivity of an
individual to a chemical based on its genetics or other individual
sensitivity factors. Idiosyncratic reactions can occur in any organ system; however, the skin, liver, hematopoietic, and immune systems are the
most often affected
15
Q
What are the differences between additive, synergistic, potentiation and antagonism effcets?
A
An additive effect occurs when the combined responses of two
chemicals is equal to the sum of the responses to each chemical given alone.
A synergistic effect is observed when the combined responses
of two chemicals are much greater than the sum of the response
to each chemical when given alone.
Potentiation occurs when one substance does not produce any
toxicity on a particular tissue or system but when added to
another chemical makes that chemical much more toxic.
Antagonism occurs when two chemicals administered together
interfere with each other’s actions or one interferes with the
action of the other.
16
Q
Define Dispositional tolerance.
A
Occurs when the amount of chemical
reaching the site of action decreases over time, leading to the
reduced responsiveness of the tissue to stimulation.
A chemical known to produce dispositional tolerance is phenobarbital.
The barbiturate, phenobarbital, produces tolerance to itself
by increasing the expression of enzymes in the liver that are
responsible for its biotransformation to pharmacologically
inactive products, a process known as “biotransformation
enzyme induction.”
17
Q
What are the two major factors that influence toxicity as it relates to the exposure of a specific chemical?
A
Route
Duration & Frequency
18
Q
What is a Threshold of toxicological concern (TTC)?
A
TTC suggests
that there are levels of exposure for chemicals below which the
risk to human health is not appreciable. It was first proposed in
the context of food safety.
19
Q
What shape is a nonmonotonic dose-response curve?
A
For natural or endogenous chemicals that
are required for normal physiological function and survival (e.g.,
vitamins and essential trace elements such as chromium, cobalt,
zinc, manganese, and selenium), the “graded” dose–response relationship in an individual over the entire dose range can be U-shaped
20
Q
On the non-monotonic dose response curve, what is the region of homeostasis?
A
The dose range that doesn’t induce deficiencies or toxicities. It lies below the threshold for adverse responses.
21
Q
What is assessed in the therapeutic index?
A
Toxic dose / effective dose
TD50/ED50
22
Q
What is assessed in the margin of safety?
A
TD1/ED99
No cumulative effect would be 1, where a cumulative effect would be 90.
23
Q
What is the differences between efficacy and potency?
A
Efficacy is an assessment of the extent to which a chemical can
elicit a response and is often interpreted using the ordinate axis
(or y-axis). By comparison, the potency is determined by the range
of doses (on the x-axis) over which a chemical produces increasing responses.
24
Q
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
A
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
25
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: 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
26
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: 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
27
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: 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
28
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: 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
29
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: 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
30
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: 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
31
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: 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.
31
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: 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)
32
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: 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
33
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: 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
34
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: 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
35
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: 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
36
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: 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)
37
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: 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
37
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: 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
38
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: 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
39
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: 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
40
What animal model in considered the best predictor of dermal absorption of chemicals for humans?
A. rat
B. pig
C. mouse
D. rabbit
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
41
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: 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
41
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 preimplantation
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: 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
42
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: 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
43
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: 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
44
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: 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
45
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: 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
46
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: 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
47
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: 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
48
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: 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
49
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: 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
50
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: 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
50
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: 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)
50
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: C
Explanation and Reference:
Juvenile toxicology studies may be requested by the FDA to evaluate safety under pediatric
conditions. Hayes 6th, pp. 362-363
50
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: 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
51
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: 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
52
The European Union banned all animal testing for what product category after 2009?
A. organohalogens
B. cosmetics
C. preservatives
D. petrochemicals
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
53
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: 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
54
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: 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
54
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: 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.
55
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: 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.
56
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: 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.
57
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: 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.
58
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: 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.
59
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: 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.
60
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: 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
61
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: D
Explanation and Reference:
Aplastic anemia occurs through destruction of RBC stem cells in the bone marrow. C&D 9th pp. 598-
599
62
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: 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
63
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: 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.
64
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: 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
65
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: 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.
66
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: 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.
67
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: 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.
68
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: 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.
69
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: 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
70
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: 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.
71
What primary organ system is affected after consumption of grain treated with mercurial (organic)
fungicides?
A. respiratory
B. hepatic
C. renal
D. nervous
Answer: D
Explanation and Reference:
The nervous system is the target for organic mercury compounds. C&D 8th, p. 999.
72
What effect is clearly indicative of exposure to nickel?
A. nephropathy
B. Menkes disease
C. contact dermatitis
D. encephalopathy
Answer: C
Explanation and Reference:
Nickel-induced contact dermatitis is found in 10-20% of the population.
73
Exposure to ethylene glycol monomethyl ether (EGME) and/or one of its metabolites, methoxyacetic
acid (MAA), will induce testicular damage in rats by primarily affecting what cell types?
A. Leydig cell
B. Cowper's gland
C. Sertoli cell
D. myoepithelial peritubular cell
Answer: C
Explanation and Reference:
Mechanistic studies have shown the Sertoli cell to be affected which disrupts spermatocyte
maturation. C&D 8th, pp. 1078-1079
74
What organ systems are classic targets of acute and chronic carbon disulfide exposure?
A. upper and lower respiratory system
B. skeletal and cardiac muscle
C. central and peripheral nervous system
D. vascular and lymphatic system
Answer: C
Explanation and Reference:
Exposure to CS2 (dithiocarbonic anhydride) affects a number of organ systems. The effects are
prominent in central and periphernal nervous, system, retina, and as an atherogenic agent. Classic
lesions of CS2 exposure are found in both the peripheral and central nervous systems. There is
evidence that CS2 also modifies low density lipoprotein and enhances arterial fatty de
75
The Local Lymph Node Assay (LLNA) is an internationally approved method to detect what
pathogenic response?
A. induction of carcinogenesis by a chemical applied to the skin
B. elicitation of sensitivity to a chemical applied to the skin
C. elicitation of carcinogenesis by a chemical applied intratracheally
D. induction of allergic contact dermatitis
Answer: D
Explanation and Reference:
The LLNA is a refinement of the classic GP-MAX and Buehler assys for allergic contact dermatitis.
Whereas the classsic assays measure both induction and elicitation of skin sensitization, the LLNA
only measures induction, resulting in a shorter assay. The LLNA is now the recommended method
for determining allergic contact dermatitis potential of chemicals. Hayes 6th, pp. 1100-1102.
76
Acetaminophen hepatotoxicity requires what intermediate step?
A. the toxicity does not depend on metabolism of acetaminophen
B. interaction with sodium nitrosulfate
C. binding to cellular macromolecules
D. inhibition by ethanol co-administration
Answer: C
Explanation and Reference:
The toxic metabolite of acetaminophen binds to glutathione; when cellular glutathione is depleted, the
metabolite binds to cellular macromolecules, particularly proteins. C&D, 8th, pp. 651.
77
Several inhibitors of cyclooxygenase-2 (COX-2) have been removed from the market due to what
potential type of toxicity?
A. hepatic
B. neurologic
C. cardiovascular
D. renal
Answer: C
Explanation and Reference:
These compounds may cause hypertension which elevates the risk of heart attack and stroke. C&D,
8th, pp. 819-824.
78
What substance is the most effective agent for treating acute mild inorganic mercury intoxication?
A. British Anti-Lewisite (BAL)
B. hydrochlorothiazide
C. intravenous glucose
D. aminophylline
Answer: A
Explanation and Reference:
The chelating agent BAL, also called as dimercaprol, is effective with inorganic poisoning. C&D 8th,
p. 999
79
Why is beryllium unique among metals?
A. it causes injury in skin and lung through an immune mechanism
B. it is not excreted in the urine following uptake in lymph
C. it cannot be absorbed orally
D. it is readily absorbed through the skin
Answer: A
Explanation and Reference:
Beryllium causes an inflammatory immune reaction. C&D 8th, pp. 989-999
80
Organic solvents are a group of compounds that have what characteristics?
A. low vapor pressure at room temperature
B. high molecular weight side chains including -OH groups
C. cannot be absorbed across the skin in significant amounts
D. common effects on the central nervous system
Answer: D
Explanation and Reference:
CNS effects are common to solvents. C&D 8th, pp. 1031-1036.
81
The "Elixir Sulfanilamide" tragedy, resulted in the passage of the Copeland Bill in 1938 due to what
environmental effects?
A. diethylene glycol induced acute kidney failure
B. ethanol induced liver toxicity and blindness
C. diethylene glycol induced acute liver failure
D. polyethylene glycol induced renal failure
Answer: A
Explanation and Reference:
The drug was found to be more soluble in diethylene glycol and sold as that formulation, but
diethylene glycol caused acute renal failure in several patients. C&D 9th, p. 12
82
Acute poisoning by malathion is recognized by what group of effects?
A. acute renal failure followed by lacrimation and defecation
B. burning and discoloration of the mucous membranes
C. salivation, lacrimation, headache, and dizziness
D. pulmonary fluid accumulation and respiratory failure
Answer: C
Explanation and Reference:
Malathion is an OP with symptoms as described in C&D 8th, p. 941, Table 22-9
83
For most systemically administered drugs, what measure is used to convert the animal dose to a
human equivalent dose (HED)?
A. mg/m2
B. Cmax
C. AUC
D. mg/kg
Answer: A
Explanation and Reference:
mg/m2 is the recommended conversion, the other values should be adjusted depending on toxicity
observed in animal studies. FDA Guidance (2010) M3(R2), Table 3
84
Organophosphates and carbamates exhibit which characteristics?
A. they act by a common mechanism, but arise from two distinctively different chemical classes
B. they do not undergo extensive biotransformation in most species
C. their binding to the acetylcholinesterase is irreversible except in rare instances
D. they were first developed as warfare agents during World War I
Answer: A
Explanation and Reference:
Organophosphates and carbamates both inhibit acetylcholinesterase. C&D 8th, pp. 939-947
85
Based on your knowledge of toxicology, what is the general line of treatment for scombrotoxicosis?
A. induced emesis with apomorphine
B. intramuscular injection of cortisone
C. intravenous injection of sodium nitrite
D. enteral or parenteral administration of antihistamine
Answer: D
Explanation and Reference:
Histidine occurs naturally in many fish, and at temperatures above 60°F on air contact it is converted
to the biogenic amine histamine via the enzyme histidine decarboxylase produced by enteric bacteria.
Histamine is not destroyed by normal cooking temperatures, so even people eating properly cooked
fish can be affected. Hayes 6th, pp. 662-663
86
What oxidation state of arsenic is considered to be the most toxic?
A. divalent
B. pentavelent
C. trivalent
D. hexavalent
Answer: C
Explanation and Reference:
Trivalent forms of As are more toxic compared to pentavalent forms. C&D, 8th ed., 986-989.
87
What characteristic clinical sign is associated with industrial exposure to vanadium pentoxide dust?
A. non-fibrotic pneumoconiosis
B. greenish-black discoloration of the tongue
C. glucosuria
D. gastroenteritis, polyneuropathy, and alopecia
Answer: B
Explanation and Reference:
Glucosuria is a common sign of uranium-related renal toxicity; non-fibrotic pneumoconiosis is
commonly assocxiated with chornic exposure to tin; gastroenteritis, polyneuropathy, and alopecia are
classic signs of thallium poisoning. The blue-green discoloration of the tongue is very characteristic
of Vanadium exposure in industrial settings. C&D 8th, pp. 1018-1021.
88
What is the recommended treatment for methanol intoxication?
A. intravenous hemoperfusion
B. forced diuresis with emetic.
C. inhibition of alcohol dehydrogenase by 4-methylpyrazole (fomepizole)
D. inhibition of aldehyde dehydrogenase by disulfiram
Answer: C
Explanation and Reference:
Metabolic blockade by ethanol or 4-methylpryazole is first line treatment. Sodium bicarbonate by i.v
can by used to correct metabolic acidosis and folate can be used to enhance formate excretion. C&D
8th p. 1073.
89
What is the basis for the use of ethanol as an antidote for accidental oral methanol poisoning?
A. it binds with methanol and increases urinary excretion
B. it competitively inhibits the metabolism of methanol
C. it increases metabolism of methanol to formaldehyde
D. it chemically alters methanol to formate
Answer: B
Explanation and Reference:
Inhibits alcohol dehydrogenase blocking the formation of formic acid. Folate is also given to enhance
efficiency of formate oxidation. C&D 7th, pp 1012-1014; C&D 8th, p. 1073
90
What is the most effective treatment for mammalian organophosphate (OP) toxicity?
A. atropine
B. diazepam
C. 2-PAM
D. epinephrine
Answer: A
Explanation and Reference:
As a muscarinic receptor antagonist, atropine prevents the action of accumulating acetylcholine on
cholinergic receptors. The administration of pralidoxime (2-PAM) early after OP exposure can help
prevent acetylcholinesterase aging. Diazepam may be used for relieving anxiety, muscle
fasciculations, and convulsions. C&D 7th, p.891; C&D 8th p. 941.
91
What is the preferred treatment of cyanide poisoning?
A. sodium nitrite
B. atropine followed by 2-PAM
C. dimercaprol and pralidoxime
D. calcium disodium edetate (EDTA)
Answer: A
Explanation and Reference:
Nitrite converts hemoglobin to methemoglobin which in turn competes effectively for CN with the
mitochondrial cytochrome oxidase complex. Hayes 6th p. 22
92
In the field of epidemiology, what parameter is defined as the risk difference between exposed and
unexposed groups, divided by the risk in the exposed group?
A. attributable risk
B. relative risk
C. proportional mortality ratio
D. absolute risk
Answer: A
Explanation and Reference:
Absolute risk is more a concept than a calculation and revolves around the question whether a
specific disease among an exposed group is greater than the absolute risk of that same disease in an
unexposed group. Relative risk (RR) is the ratio of incidence rates in two different groups (e.g.,
exposed versus unexposed). The proportional mortality ratio (PMR) is not to be confused with RR or
absolute risk. This is the number of deaths within a population due to a specific disease or cause
divided by the total number of deaths in the population during a time period such as a year. The
correct answer (A) is attributable risk where rate ratios and rate differences are based on exposure
status. The attributable risk gives a better indication of causality than the other indices. Hayes 6th, p
535.
93
What are the classic clinical features of the anticholinergic toxidrome?
A. mydriasis, hyperalert, increased pulse, increased blood pressure
B. miosis, decreased pulse, altered mental status
C. miosis, decreased level of consciousness, decreased pulse, no change in blood pressure
D. mydriasis, altered mental status, increased pulse, no change in blood pressure
Answer: D
Explanation and Reference:
Anticholinergic syndrome is produced by the inhibition of cholinergic neurotransmission at muscarinic
receptor sites. Signs include ileus, urine retention, tachycardia, hypertension, confusion, fever, dry
skin, mydriasis. A number of plant exposures can produce this syndrome through the action of
natural constituents such as atropine and scopolomine. Hayes 6th, p. 961.
94
What is the first step in treating a suspected poisoning victim?
A. submission of blood and urine for immediate analysis
B. administration of the antidote
C. prevention of further toxin absorption
D. stabilization of the patient
Answer: D
Explanation and Reference:
First step is almost always stabilization of the patient (breathing, pulse, etc.). C&D 9th, p. 1533
95
What is a major limitation of epidemiology studies?
A. exposure conditions are unrealistic
B. exposure is not well-defined or controlled
C. effects are measured in humans
D. interactive effects among individual chemicals cannot be measured
Answer: B
Explanation and Reference:
Exposure is often not well defined and controlled in epidemiological studies especially environmental.
C&D 9th, p. 136
96
Data from standard toxicology studies conducted with pharmaceuticals are evaluated for signs of
immunotoxic potential. According to ICH S8, what is evidence of immunotoxic potential?
A. alterations in immune system organ weights and/or histology
B. decreased incidence of infections
C. hematological changes such as erythrocytopenia/erythrocytosis
D. mild thymic atrophy accompanied by decreased food consumption and a significant decrease in
body weight gain
Answer: A
Explanation and Reference:
Changes in the hematology panel would not suggest mild changes in the immune system; therefore,
it would be a very insensitive high-level index of immunotoxicity. Similarly, mild thymic atrophy could
be caused by many things including stress. In animals showing decreased food consumption and
body weight, thymic atrophy would be a common finding and not indicative of immunotoxicity. Finally
an increased incidence of infections would suggest immunocompromise; however, a decreased
incidence of infections has little meaning in a preclinical safety study. The correct answer (B),
changes in immune system organ weights and histology, would be routinely measured in a preclinical
study and would require further immune system testing. ICH S8 Harmonized Tripartite Guideline
Immunotoxicity Studies for Human Pharmaceuticals S8, 15 September 2005, Section 2.1.1 page 3.
97
A 16-year-old harvester was brought to the emergency room after working for 2 days in rain-soaked
tobacco fields. He complained of vomiting, weakness, dizziness, headache, and dyspnea. His vital
signs were a heart rate of 120 beats/minute, blood pressure
A. organophosphates
B. pyrethrin
C. nicotine
D. paraquat
Answer: C
Explanation and Reference:
Green tobacco sickness (GTS) is an illness resulting from dermal exposure to dissolved nicotine from
wet tobacco leaves; it is characterized by nausea, vomiting, weakness, and dizziness and sometimes
fluctuations in blood pressure or heart rate Green Leaf Tobacco Sickness. C&D 9th, p. 858
98
Repeated occupational exposure to toluene diisocyanates are a common cause of what condition?
A. fibrotic lung disease
B. asthma
C. hemangiosarcoma
D. peripheral neuropathy
Answer: B
Explanation and Reference:
Some individuals develop an allergic reaction to toluene diisocyanates following inhalation exposure.
Re-exposure to the chemical can cause severe asthma symptoms that can be immediate or delayed
for an hour or more. However this usually happens in the workplace and the general public is not
expected to be exposed to such levels. Long-term inhalation exposure can also cause lung damage.
C&D 9th, p. 689-690
99
What prospective epidemiological study design assesses development of disease in a population of
known exposure?
A. cross-sectional
B. case-control
C. cohort
D. cross-over
Answer: C
Explanation and Reference:
Case Control - two source populations; assumption that non-cases are representative of the source
population of cases; Correct Answer: Cohort uses exposed and non-exposed populations; Cross over
- longitudinal study in which subjects receive a sequence of different treatments (or exposures);
Cross-sectional - where only ONE set of observations is collected for every unit in the study, at a
certain point in time, disregarding the length of time of the study as a whole; C&D 9th, pp. 136-137
100
What is the "prevalence" of a disease?
A. the incidence rate
B. the number of cases at a specified moment of time
C. the rate at which new cases develop
D. the cure rate
Answer: B
Explanation and Reference:
Prevalence is what is observed at a single point in chronological or biological time. Hayes 6th, p. 531
101
What type of epidemiological study is used to compare disease prevalence or health status between
groups of workers classified according to job titles, work site, or exposure status in present time?
A. case-control
B. cross-sectional
C. retrospective cohort
D. prospective cohort
Answer: B
Explanation and Reference:
Cohort studies are always prospective and report out incidence. Case-control studies are
retrospective and report out fractional percent of disease vs non-disease subjects. Only the crosssectional
study design reports out prevalence- where only ONE set of observations is collected for
every unit in the study, at a certain point in time, disregarding the length of time of the study as a
whole. C&D 8th, p. 131.
102
An individual has taken an overdose of atropine. What is the appropriate treatment/antidote?
A. methyl-atropine, another competitive acetylcholine antagonist
B. nicotine, a nicotinic antagonist
C. physostigmine, an acetylcholinesterase inhibitor
D. succinylcholine, a nicotine antagonist
Answer: C
Explanation and Reference:
Physostigmine, given as an atropine antidote by slow intravenous injection of 1 to 4 mg (0.5 to 1.0 mg
in children), rapidly abolishes delirium and coma caused by large doses of atropine. Since
physostigmine is rapidly destroyed, the patient may again lapse into coma after one to two hours, and
repeated doses may be required. Artificial respiration with oxygen may be necessary. Ice bags and
alcohol sponges help to reduce fever, especially in children. C&D 9th, p. 1064
103
What is the most frequently encountered xenobiotic among emergency toxicology cases?
A. ethanol
B. methamphetamine
C. painkillers
D. heroine
Answer: A
Explanation and Reference:
Nearly 88,000 people die annually in the United States as a direct or indirect exposure to alcohol.
C&D 9th, p. 1525
104
What testicular tumor is a frequently occurring endocrine tumor in rodent chronic
toxicity/carcinogenicity studies (i.e., observed at a background incidence in the F344 rat of 70-90%)?
A. granulosa cell tumor
B. dendritic cell tumor
C. Leydig cell tumor
D. Sertoli cell tumor
Answer: C
Explanation and Reference:
Control F344 rats have an extremely high spontaneous incidence of Leydig cell tumors. Therefore,
these tumors are believed to be irrelevant to men. C&D, 8th ed., pp. 1055-1056.
105
What is a common observation in rodent models when thyroid hormone homeostasis is disrupted?
A. increased incidence of thyroid tumors
B. disruption in body temperature maintenance
C. reductions in overall animal body weight
D. Due to reserve capacity of the thyroid, hormone disruption does not result in observable toxicity.
Answer: A
Explanation and Reference:
A reduction of thyroid hormone concentrations and increased thyroid-stimulating hormones have
shown to induce neoplasia in the rodent thyroid. C&D 8th, pp. 412-413.
106
Delayed Type Hypersensitivity is associated with what characteristic?
A. chemical presentation to Langerhans cells
B. absence of inflammation
C. clonal expansion of B cells
D. cell-mediated response
Answer: D
Explanation and Reference:
Delayed Type Hypersensitivity (DTH) is cell, not antibody mediated. C&D 9th, p. 1038-1040
107
What would produce a level of great concern for the development of human cancer, based on
preclinical laboratory and animal data?
A. toxicity associated tumors
B. not genotoxic
C. a finding of tumor site concordance between species
D. single species effect
Answer: C
Explanation and Reference:
Examples shows a weight of evidence approach between species to extrapolate to humans. C&D 9th,
p. 478
108
Different cell populations of the mammalian testes exhibit different thresholds of sensitivity to different
toxicants. What region/cell type in the testes is generally considered to be the most sensitive to
chemical insult?
A. rete testis
B. germ cells
C. the seminiferous epithelium
D. Leydig cells
Answer: B
Explanation and Reference:
Germ cells are typically the most sensitive. C&D 8th,pp. 874-878.
109
Where is inhibin, a regulator of FSH production and a biomarker for male reproductive damage,
secreted/produced from?
A. Leydig cells
B. spermatogonia
C. Sertoli cells
D. epididymides
Answer: C
Explanation and Reference:
Inhibin is produced by Sertoli cells in the seminiferous tubules, not in the spermatogonia or
epididymides. Leydig cells are the sites of testosterone biosynthesis. Hayes 6th, p. 1621.
110
What is the fate of very water-soluble gases in the respiratory system?
A. trapped by bronchiolar mucus and removed by the mucociliary escalator
B. transported directly to the deep lung and absorbed into the general circulation
C. absorbed into the systemic circulation through the capillaries of the nose
D. transported directly to the deep lung where they react chemically with Type II pneumocytes
Answer: A
Explanation and Reference:
Highly water-soluble gases are filtered through the nasal turbinates and are efficiencly absorpbed
from that site. Such gas species rarely make it to the respiratory sections of lung. C&D 8th, p. 692
111
What common characteristic is shared by all four types of hypersensitivity responses?
A. involves formation of specific immunoglobulin molecules
B. requires prior exposure to an antigen
C. involves activation of mast cells in respiratory bronchioles
D. are cell-mediated responses that are delayed
Answer: B
Explanation and Reference:
One characteristic common to all four types of hypersensitivity reactions is the necessity of prior
exposure leading to sensitization in order to eliciti a reaction upon subsequent challenge. C&D 9th
edition, page 646
112
What pair of immune-mediated hypersensitivity reactions to chemicals is the most frequently reported
in humans?
A. Type I and Type III
B. Type IV and Type I
C. Type II and Type IV
D. Type III and Type IV
Answer: B
Explanation and Reference:
Mostly manifested as contact and respiratory sensitization, respectively. C&D 9th, p. 660
113
Which ocular structure is most often affected following systemic long-term or high dose use of
corticosteroids in humans?
A. cornea
B. lens
C. retina
D. iris
Answer: B
Explanation and Reference:
Long-term systemic use of corticosteriouds is implicated in cataracts. C&D 9th edition, page 880
114
Exposure of rats to a naphthalene-derived pesticide resulted in a loss of circulating erythrocytes that
was accompanied by reticulocytosis and hemoglobinuria. No pathological changes were observed in
the bone marrow; however, spleens were found to be enla
A. anemia due to iron deficiency
B. mechanical (march) hemoglobinuria
C. aplastic anemia
D. non-immune hemolytic anemia
Answer: D
Explanation and Reference:
The data in this case suggest mature red blood cell destruction, possibly caused by xenobiotic
production of reactive oxygen species (explaining the decreased reduced glutathione). The
reticuloytosis suggests that the bone marrow is intact and producing new red cells, so iron-deficient
and aplastic anemias are ruled out. There is no history of mechanical stress. A chemically induced,
non-immune hemolytic anemia is the most likely diagnosis given the history and clinical data. C&D
9th, p. 602-603
115
Most inhaled particles with a mean aerodynamic diameter of 1 micron are deposited in what
respiratory region?
A. alveoli
B. nasopharyngeal region
C. bronchioles
D. bifurcations of major bronchi
Answer: A
Explanation and Reference:
Particles of ~1 μm are typically deposited in the alveolar region. C&D 9th, p. 795
116
What is the primary factor that determines the region of the respiratory tract where a particle or an
aerosol will be deposited?
A. size of the particle
B. chemical composition of the particle
C. particle shape
D. respiratory rate
Answer: A
Explanation and Reference:
The efficiency of particle deposition in various regions of the respiratory tract depends mainly on
particle size. C&D 9th, p. 803
117
Type III hypersensitivity reactions are mediated by what combination of immunoglobulin or cell type?
A. IgG and antigen
B. IgE and macrophages
C. T lymphocytes and macrophages
D. IgE and mast cells
Answer: A
Explanation and Reference:
Type III Hypersensitivity involve the IgG against soluble antigen in the serum. C&D 9th, p. 647
118
What ocular structure is the target of chronic, high-dose tamoxifen therapy?
A. cornea
B. lens
C. retina
D. conjunctiva
Answer: C
Explanation and Reference:
Tamoxifen, a nonsteroidal antiestrogenic drug that competes with estrogen for its receptor sites and
used for treatment of metastatic breast carcinoma, causes retinopathy following chronic high-dose
therapy. C&D, 9th ed. p. 892
119
What toxico-pathological feature characterizes hepatic steatosis?
A. accumulation of smooth endoplasmic reticulum in hepatocytes
B. accumulation of lipids in hepatocytes
C. hepatocyte nuclear lysis
D. retention of bilirubin
Answer: B
Explanation and Reference:
Steatosis or "fatty liver" is the accumulation of lipids, primarily triglycerides, within the hepatocytes.
Hayes, 6th ed., pp. 1447-1448; C&D 9th pp. 727-728.
120
What toxic food contaminant is a major by-product of cooking at high-temperatures?
A. heterocyclic amine
B. botulinum toxin
C. fumonisin
D. trichothecene
Answer: A
Explanation and Reference:
Heterocyclic amines are formed as a result of high-temperature cooking of foods high in proteins and
carbohydrates. C&D 9th, p1350
121
The presence of melamine as an adulterant in infant formula and pet food was associated with
mortalities in human infants and pets in the mid-2000s. What was the mechanism of action
underlying melamine-related toxicity?
A. acute hepatic toxicity
B. acute cardiac toxicity
C. blockade of mitochondrial oxidative phosphorylation
D. formation of crystaline precipitates in renal tubules
Answer: D
Explanation and Reference:
Melamine often in combination with cyanuric acid has been associated with renal failure in children
and companion animals. The mechanism of toxicity is crystal formation in the tubules and bladder.
The source of melamine was its illegal addition to increase nitrogen content in order deceive test
inspections for protein content. Torres and Bobst, Toxicological Risk Assessment for Beginners, p.
23.
122
Ethanol, retinoids, valproic acid, and the angiotensin converting enzyme (ACE) inhibitors share what
common toxicological characteristic?
A. cause liver toxicity
B. have central nervous system effects
C. are human developmental toxicants
D. lower blood pressure
Answer: C
Explanation and Reference:
These are known to cause craniofacial malformations, heart and limb malformations oligohydramnios,
fetal growth retardation, pulmonary hypoplasia, joint contractures, hypocalvaria, neonatal renal
failure, hypotension, and death. C&D 9th, p. 550, 551,
123
What adverse effect related to low level exposure to lead in blood is of greatest public health concern
?
A. anemia
B. proximal tubular nephropathy in the elderly
C. cognitive delays and behavioral changes in children
D. encephalopathy
Answer: C
Explanation and Reference:
Neurological changes in the developing brain are the most sensitive and greatest concern from lead
exposure. C&D 9th, p 863
124
John really enjoys grapefruit juice and consumes several large glasses per day. He recently started
taking a new medication and has begun to experience severe muscle aches. Lab tests have
revealed elevated creatine kinase and alanine aminotransferase le
A. acetaminophen
B. atorvastatin
C. naproxen
D. cyclosporine
Answer: B
Explanation and Reference:
Components in grapefruit juice inhibit intestinal CYP3A4 which blocks the metabolism of statins such
as atorvastatin. C&D 9th, p 290-291, 307-310
125
Why might epidemiological data be considered to be preferable for dose-response modeling in certain
cases?
A. by using biomarkers, the doses associated with effects can be more precisely defined, thereby
avoiding the need for external dose estimation
B. it is possible to model dose-response relationships directly in humans, thereby avoiding concern
for species differences
C. the impact of exposure over a lifetime can be more easily examined than in a multiyear laboratory
animal study
D. the causal relationship between dose and response can be easily established
Answer: B
Explanation and Reference:
Epidemiology studies do monitor dose-response relationships in humans by directly evaluating
human data on exposure and incidence. Confounding factors such as life style, multiple exposures
and robust exposure estimates impact the outcome. C&D 9th, p 136
126
Two contractors hired by a health club to refinish the racquetball court floors were using a varnish
stripper to remove the old finish. They were found dead on the court after the management requested
they seal the air vents due to patron complaints about
A. myocardial sensitization due to the use of n-hexane
B. narcosis and chemical hypoxia from the use of methylene chloride
C. central nervous system depression from carbon disulfide exposure
D. pulmonary edema from the use of methyl n-butyl ketone
Answer: B
Explanation and Reference:
Metabolism of methylene chloride releases carbon monoxide resulting in carboxyhemoglobin and
tissue hypoxia. C&D 7th, p. 1003
127
Cutaneous paresthesia is the primary adverse effect from occupational exposure to what pesticide?
A. deltamethrin
B. parathion
C. carbaryl
D. dichlorodiphenyltrichloroethane (DDT)
Answer: A
Explanation and Reference:
Metabolism of methylene chloride releases carbon monoxide resulting in carboxyhemoglobin and
tissue hypoxia. C&D 9th, 1191
128
Cadmium may accumulate in the kidney without toxic effect for what reason?
A. cadmium decreases the excretion of urinary proteins
B. cadmium binds to metallothionein and forms a metal-protein complex
C. cadmium increases renal tubular absorption of phosphate
D. cadmium produces oliguria
Answer: B
Explanation and Reference:
Cadmium induces metallothionine with subsequestration of cadmium as Cd-MT complex. C&D 9th p.
783`
128
What primary factor would increase the oral bio-availability of metals from a soil matrix?
A. increased fraction of metals tightly bound to the soil matrix
B. increased ratio of soil lead: arsenic dissolving in gastric acid
C. increased age of the exposed individual
D. increased water solubility profiles of metals in the soil matrix
Answer: D
Explanation and Reference:
This is the primary effect from occupational exposure to pyrethroids such as deltamethrin. C&D 9th,
p. 1073
129
What is the primary target organ for xylene and ethylbenzene toxicity?
A. central nervous system
B. lungs
C. bone marrow
D. reproductive organs
Answer: A
Explanation and Reference:
These compounds have limited capacity to adversely affect organs other than the CNS. C&D 9th p
1202
130
What is the mechanism for a polar organic solvent to enter the body via the skin?
A. inhibition of oxidative phosphorylation in the stratum granulosum
B. inhibition of acetyl coenzyme A in melanocytes of the subdermis
C. affects fatty acid synthesis in the dermis
D. disruption of lipids in the stratum corneum thereby increasing the skin's permeability
Answer: D
Explanation and Reference:
Solvents can (1) remove much of the lipid matrix of the stratum corneum, making holes on artificial
shunts in the penetration barrier; (2) alter keratin configuration to change protein structure; and (3)
function as a swelling agent. Hayes 5th, pp. 692-693, C&D 9th, 9th p. 173
131
Inhibition of what enzyme is involved in acute toxicity of organophosphate insecticides?
A. carboxylesterase
B. acetylcholinesterase
C. neuropathy target esterase
D. butyrylcholinesterase
Answer: B
Explanation and Reference:
The target of organophosphate and carbamate insecticides is acetylcholinesterase. Both AChE and
NTE may be targets for OPs, but AChE is responsible for the actue effects, and NTE is responsible
for delayed effects (OPIDN) for some OPs. C&D 9th, p. 1064
132
Paraquat is a herbicide associated with what mechanism of toxicity?
A. alkylating DNA
B. GABA Inhibition
C. free radical formation
D. anticholinesterase inhibition
Answer: C
Explanation and Reference:
Paraquat is associated with free radical formation through its redox potential. DNA alkylation is not a
primary mechanism of pesticides. Organophosphate and carbamate insecticides inhibit acetylcholine
esterases. Type II pyrethroid, cyclodiene, and phenylpyrazole insecticides inhibit GABA receptors.
C&D 9th p. 1085 and Table 22-8
133
What is the mechanism of toxicity of carbon monoxide?
A. methemoglobinemia
B. inhibition of cytochrome oxidase
C. formation of cyanohemoglobin
D. formation of carboxyhemoglobin
Answer: D
Explanation and Reference:
The toxic action of CO is formation of carboxyhemoglobin preventing oxygenation of the blood.
Cyanide inhibits cytochrome oxidase. Methemoglobin can be induced using sodium nitrite as an
antidote to cyanide poisoning to facilitate the formation of cyanohemoglobin. C&D 9th, p. 1499
134
What inhaled particles typically deposited in the nasopharyngeal region of an adult human?
A. 2 - 3 μm
B. > 10 μm
C. < 0.5 nm
D. 0.1 - 1.0 μm
Answer: B
Explanation and Reference:
Particles larger than 5 micrometers are generally trapped in the upper airways. (Nasopharyngeal: >10
um; Tracheobronchiolar: 2.5-10 um; Alveoli: <5 um) C&D 9th, p. 795
135
What type of radiation has the highest linear energy transfer (LET)?
A. alpha particles
B. beta particles
C. gamma rays
D. x-rays
Answer: A
Explanation and Reference:
Alpha particles are characterized by a high energy loss per unit path length and a high ionization
density along the track length, i.e., high LET. X-rays, gamma-rays, and β particles of similar energies
produce sparse ionization tracks and are classified as low-LET radiation. C&D 9th, p. 1258
136
What elements are essential nutrients?
A. iron, nickel, copper
B. zinc, copper, cobalt
C. vanadium, thallium, manganese
D. copper, beryllium, selenium
Answer: B
Explanation and Reference:
Cobalt, copper, iron, magnesium, manganese, molybdenum, selenium, zinc, and contraversially,
trivalent chromium are essential metals. Nickel, beryllium, thallium, and vanadium are not essential
nutrients. C&D 9th, pp. 1131-1140
137
How does 4-methylpyrazole inhibit ethylene glycol poisoning?
A. blocks the metabolic activation of ethylene glycol
B. increases glucuronide conjugation of ethylene glycol
C. increases in the glomerular filtration of ethylene glycol
D. blocks the absorption of ethylene glycol
Answer: A
Explanation and Reference:
4-Methylpyrazole (fomepizole) is an alcohol dehydrogenase (ADH) inhibitor which blocks metabolic
bioactivation of ethylene glycol (EG). C&D 9th, p. 1211
138
What is the mechanism of DDT toxicity?
A. inhibition of GABA receptors
B. inhibition of acetylcholine receptors
C. activation of sodium channels
D. activation of acetylcholinesterase
Answer: C
Explanation and Reference:
DDT and Type I pyrethroids activate sodium channels. Type II pyrethroid, cyclodiene, and
phenylpyrazole insecticides inhibit GABA receptors. Activation of acetylcholine esterase is not a
primary mechanism of pesticides. Organophosphate and carbamate insecticides inhibit acetylcholine
esterases. C&D 9th, p. 1062, Table 22-8;
139
Piperonyl butoxide inhibits CYP450 and increases the toxicity of which compounds
A. mirex
B. carbamates
C. organophosphates
D. pyrethroids
Answer: D
Explanation and Reference:
Inhibition of CYP450 by piperonyl butoxide increases the toxicity of pyrethroids. C&D 9th, p. 1071
140
What reaction is responsible for the neurotoxic effects induced by pyrethroid insecticides?
A. activation of chloride channels
B. modification of sodium channel gating
C. inhibition of acetylcholinesterase
D. inhibition of glutamine synthetase
Answer: B
Explanation and Reference:
The principal mode of action of pyrethroids in mammals is the same as in insects: disruption of the
voltage-gated sodium channels. Type II pyrethroids, but not type I compounds, also bind to and inhibit
GABAA-gated chloride channels. Other reported targets for pyrethroids include calcium ATPase and
voltage-gated calcium channels. C&D 9th, p. 1093
140
What is the mechanism of fluoroacetate/ fluoroacetamide rodenticide toxicity?
A. inhibition of the Kreb's cycle
B. inhibition of coagulation
C. induction of GI tract necrosis
D. displacement of oxygen from heme
Answer: A
Explanation and Reference:
Fluoroacetate is incorporated into fluoroacetyl-coenzyme A, which condenses with oxaloacetate to
form fluorocitrate, which inhibits mitochondrial aconitase. This results in inhibition of the Krebs cycle,
leading to lowered energy production, reduced oxygen consumption, and reduced cellular
concentration of ATP. Blockage of energy metabolism is believed to account for most signs of toxicity.
C&D 9th, p. 1093
141
What is the mechanism of ingested zinc phosphide toxicity?
A. phosphoric acid released from hydrolytic reaction of water in the stomach
B. phosphorus released from hydrolytic reaction of water in the stomach
C. phosphine gas formed from hydrolytic reaction of water in the stomach
D. zinc salts released from hydrolytic reaction of water in the stomach
Answer: C
Explanation and Reference:
Phosphine is highly toxic causing widespread cellular damage to the G.I. tract, liver, and kidney. Zinc
would form insoluble salts at this pH without any adverse effects. It is unlikely that any significant
amounts of phosphide would be converted to phosphorus (non-toxic). Phosphoric acid is a FDAapproved
GRAS substance and commonly found in soft drinks. It is essentially non-toxic. C&D 9th, p.
1093
142
What is the cellular mechanism of hydrogen sulfide toxicity?
A. damage of mitochondrial DNA
B. depletion of ATP reserves
C. inhibition of cytochrome oxidase
D. disruption of cell membranes
Answer: C
Explanation and Reference:
Hydrogen sulfide forms a complex bond with iron in the mitochondrial cytochrome enzymes, thus
preventing cellular respiration. C&D 9th, p. 93, Table 3-5 and p. 601
143
Fungistatic azole drugs block the synthesis of what critical cell membrane components?
A. cholesterol
B. usnic acid
C. mevalonate
D. ergosterol
Answer: D
Explanation and Reference:
They inhibit the synthesis of ergosterol (the main fungal sterol). C&D 9th, p. 1091; G&G 12th, p. 1576
144
What is the primary mechanism of action for mercury-induced non-specific cell injury or cell death?
A. cellular mimicry and replacement of divalent zinc in metalloenzymes
B. formation of DNA adducts or DNA-protein crosslinks
C. uncoupling of mitochondrial oxidative phosphorylation
D. high-affinity binding of divalent mercury to sulfhydryl groups of proteins
Answer: D
Explanation and Reference:
Oxidative stress plays a significant role in Hg toxicity. C&D 9th p. 1129
145
What is the first step in the enzymatic biotransformation of ethylene glycol to the ultimate toxic
metablite oxalic acid?
A. microsomal oxidation
B. alcohol dehydrogenase oxidation
C. microsomal o-dealkylation
D. cytosolic aldehyde oxidase oxidation
Answer: B
Explanation and Reference:
The first step in ethylene glycol metabolism is oxidation via alcohol dehydrogenase to glycolic acid,
which is further oxidized to oxalic acid. C&D 9th p. 1209, Figure 24-11
146
What is the first critcal step in transforming carbon tetrachloride into a hepatotoxin?
A. formation of trichloromethyl radicals via CYP2E1 metabolism
B. generation of HCl via oxidative dehalogenation
C. generation of aldehydes by alcohol deydrogenase
D. formation of toxic metabolites via glutathione s-transferase
Answer: A
Explanation and Reference:
For CCl4 to be toxic it must be biotransformed by CYP450 enzymes to highly reactive trichloromethyl
radicals that covalently bind to critical cellular components resulting in lipoperoxidation and loss of
membrane integrity. C&D 9th, p 742
147
What enzyme is involved in organophosphate-induced delayed polyneuropathy?
A. butyrylcholinesterase
B. ATPase
C. neuropathy target esterase
D. acetylcholinesterase
Answer: C
Explanation and Reference:
NPTE causes digital sensorimotor axonopathy. C&D 9th, p. 1066
148
What is the plant-specific toxicity resulting from glutamine synthetase inhibition by the herbicide
glufosinate?
A. a toxic build up of aldehydes
B. a toxic build up of ammonia
C. a toxic build up of reactive nitrogen species
D. a toxic build up of glutamine
Answer: B
Explanation and Reference:
Because of the enzyme inhibition, plants die of ammonia accumulation and lack of glutamine, both of
which result in inhibiting photosynthesis and respiration. Mammals have other enzyme systems that
compensate for the effects on glutamine synthetase, so it is relatively non-toxic. High exposure levels,
however, may affect brain and cardiovascular function in humans. C&D 9th, p. 1088
149
What is the mechanism of pyrethroid toxicity?
A. activation of a a2-adrenergic receptors
B. interference of hormone metabolism
C. disruption of voltage-gated sodium channels
D. inhibition of acetylcholinesterase (AChE)
Answer: C
Explanation and Reference:
Pyrethroids act through disruption of sodium channels. C&D 9th, p. 1072
150
How do coumarin derivative rodenticides antagonize the synthesis of clotting factors II, VII, IX and X?
A. inhibition of Vitamin K epoxide reductase
B. inhibition of Vitamin D reductase
C. inhibition of Vitamin K epoxide carboxylase
D. inhibition of Vitamin D epoxide reductase
Answer: A
Explanation and Reference:
Coumarins antagonize the action of vitamin K in the synthesis of clotting factors (factors II, VII, IX,
and X). Their specific mechanism involves inhibition of the enzyme vitamin K epoxide reductase,
which regenerates reduced vitamin K necessary for sustained carboxylation and synthesis of relevant
clotting factors. C&D 9th, p. 1092
151
What chemical asphyxiant forms carboxyhemoglobin and prevents oxygenation of blood?
A. carbon monoxide
B. natural gas
C. kerosene
D. carbon disulfide
Answer: A
Explanation and Reference:
Carbon monoxide has a high affinity for hemoglobin forming carboxyhemoglobin and producing tissue
hypoxia by blocking the reversible binding of oxygen to hemoglobin. Natural gas (methane) is an
asphyxiant because it displaces oxygen from the atmosphere decreasing the percentage of oxygen
available for respiration. Kerosene (jet fuel) is not an asphyxiant and does not form
carboxyhemoglobin. It's toxicity is most associated with ingestion and aspiration pneumonia.
Similarly, carbon disulfide is not an asphyxiant, with both acute and chronic exposures associated
with nervous and cardiovascular system lesions. C&D 9th pp. 1499-1500, p. 1556 Table 34-2
152
Oligomycin, cyhexatin, DDT, and chlordecone interfere with mitochondrial ATP synthesis by what
mechanism?
A. inhibition of ADP phosphorylation by acting on ATP synthase
B. inhibition of electron transport complex I (NADH-coenzyme Q reductase)
C. inhibition of oxygen delivery to the electron transport chain
D. inhibition of transcription of key mitochondrial proteins
Answer: A
Explanation and Reference:
These four compounds are classic inhibitors of ATP synthase (A). Inhibitors of the electron transport
chain include rotenone, paraquat, cyanide, and antimycin-A. Classic inhibitors of oxygen delivery to
the electron transport chain include those compounds that would affect the respiratory system,
including gas exchange, and the ability of hemoglobin to carry oxygen. Antiviral drugs and antibiotics
have been associated with impaired transcription of key mitochondrial proteins. C&D 9th, p. 93 Table
3-5
152
Small insoluble particles that reach the lower respiratory tract (alveolar region) will be cleared
predominantly by what mechanism?
A. diffusion into the blood
B. mucociliary escalator
C. macrophage phagocytosis
D. dissolution in lung fluid
Answer: C
Explanation and Reference:
Deposition of small soluble particles as far as the terminal bronchioles would be cleared by the
mucocilarily escalator. Insoluble particles deposited into the terminal airways and alveoli occurs
below the mucocilarily apparatus would be cleared by alveolar macrophages. Dissolution in lung fluid
is not a clearance mechanism. Insoluble particles would not be expected to cross the alveolar lining
into the blood. C&D 9th p. 808
153
What liver enzyme defect causes some individuals within ethnic populations, such as Asians and
Native Americans, to have difficulty metabolizing alcohol?
A. CYP1A2
B. alcohol dehydrogenase
C. acetaldehyde dehydrogenase
D. CYP2E1
Answer: C
Explanation and Reference:
Inactive allele for ALDH results in acetaldehyde-induced flushing, tachycardia, nausea, vomiting and
hyperventilation. C&D 9th p. 244-246
154
By what mechanism do phenobarbital and the peroxisomal proliferator nafenopin cause cancer?
A. hypomethylation of exon regions of growth factor genes
B. inhibition of apoptosis promoting clonal expansion
C. inhibition of DNA replication
D. hypermethylation of promoter regions of DNA
Answer: B
Explanation and Reference:
Apoptosis or controlled cell death is one of the mechanisms by which cells prevent the clonal
expansion of mutated precancerous cells. Both phenobarbital and nafenopin inhibit apoptosis of
initiated cells thereby acting as promoters. Promotors are also referred to as epigenetic carcinogens.
C&D 8th p. 115-116, Fig 3-34
155
What is the mechanism of thalidomide teratogenicity?
A. cytotoxicity to osteoblasts
B. proliferation of hematopoietic stem cells
C. inhibition of angiogenesis
D. stimulation of autoimmunity
Answer: C
Explanation and Reference:
Interferes with the expression of genes responsible for blood vessel formation, i.e. angiogenesis.
C&D 9th pp. 27, 81, 549
156
What is the most abundant hepatic cytochrome P450 sub-family in humans?
A. CYP2A
B. CYP2B
C. CYP3A4
D. CYP1A
Answer: C
Explanation and Reference:
CYP3A4 is abundantly expressed in both small intestine and liver and biotransforms many drugs,
herbals and food constituents. C&D 9th p. 288 Table 6-16
157
How do thiocyanate and perchlorate affect the thyroid?
A. inhibition of thyroid peroxidase
B. inhibition of iodide transport
C. inhibition of thyroid hormone secretion
D. stimulation of the sodium-iodide symporter
Answer: B
Explanation and Reference:
Perchlorate competitively blocks iodide from entering the thyroid by an effect on the Na+/I- symporter
thus preventing the further synthesis of thyroid hormone. C&D 9th, pp. 992, 1339
158
How is benzene detoxified in first phase metabolic reactions?
A. electrophilic regions of the molecular are conjugated with glutathione
B. mixed disulfides are formed with protein thiols
C. a functional group such as hydroxyl or carboxyl is introduced into the molecule
D. nucleophiles are formed and conjugated by sulfation
Answer: C
Explanation and Reference:
Phase I biotransformation reactions are typically hydrolysis, oxidation or reduction reactions and
prepare the substrate for conjugation in Phase II biotransformation reactions. C&D 9th, p. 73
159
What is the most effective treatment for protecting against systemic effects from hydrogen fluoride
(HF) burns?
A. sodium nitrite
B. potassium gluconate
C. calcium gluconate
D. sodium gluconate
Answer: C
Explanation and Reference:
Treatment of hydrogen fluoride (HF) burns commonly includes calcium-containing topical
medications. C&D 8th, p. 845, Table 19-2
160
What is the biochemical mechanism underlying lethality of ricin ?
A. damage to cellular DNA, specifically it causes non-repairable double strand breaks in the nuclear
DNA
B. stimulation of the host immune response, specifically activation of T-lymphocytes releasing proinflammatory
cytokines
C. blockage of ribosomal protein synthesis, specifically inhibition of the 28s rRNA of the ribosome
D. altered neurotransmitter release, specifically inhibition of release of acetylcholine from nerve
terminals
Answer: C
Explanation and Reference:
Ricin is an abundant protein component of Ricinus communis seeds (castor beans) that is exquisitely
toxic to mammalian cells. It consists of an enzymic polypeptide that catalyzes the N-glycosidic
cleavage of a specific adenine residue from 28S ribosomal RNA, joined by a single disulfide bond to a
galactose (cell)-binding lectin. The enzymatic activity renders ribosomes containing depurinated 28S
RNA incapable of protein synthesis. C&D 9th, p. 1280
161
The in vitro hERG assay is frequently used to evaluate the potential to cause QTc prolongation by
measuring what endpoint?
A. inhibition of sodium channels
B. inhibition of calcium channels
C. inhibition of potassium channels
D. inhibition of chloride channels
Answer: C
Explanation and Reference:
Almost all drugs that have been associated with QT prolongation block the rapid component of the
delayed rectifier potassium channel (IKR), which is coded by the human ether-a-go-go related gene
(hERG) . Blocking the IKR channel results in prolonging the action potential which appears as
lengthening of the QT on the ECG. This delayed ventricular repolarization leads to early after
depolarizations, which can result in just focal activity or re-entrant pathways, and thence TdP. ICH
Harmonised Tripartite Guideline S7B, May 12, 2005, pp. 2, 4
http://www.fda.gov/RegulatoryInformation/Guidances/ucm129121.htm
162
What anatomic or physiologic features limits access of some chemicals to the brain?
A. low blood flow to the brain compared to other tissues
B. higher concentration of phospholipids in brain tissue
C. presence of ATP-dependent efflux transporters in brain capillary endothelial cells
D. higher protein concentration in the interstitial tissue of the brain relative to other body fluids
Answer: C
Explanation and Reference:
Blood flow to the brain is greater than most other tissues. Carrier-mediated efflux transport enables
molecules with low lipid solubility to traverse the blood—brain barrier. The protein concentration in the
interstitial tissue of the brain relative to other body fluids is reduced. There are low levels of xenobiotic
metabolizing enzymes in the brain tissue. The higher concentration of phospholipids in brain tissue
limits the entrance to very lipophilic compounds The development of the cerebral microvasculature
and the morphological changes plus developmental changes in the endothelial cell carrier transport
systems affects brain uptake of substrates that may be substantially higher in neonates relative to
adults. C&D 9th, p. 840
162
An organic weak acid with pKa of about 4 is swallowed. What is the likelihood of absorption via
passive diffusion from the stomach (pH about 2) into the blood (pH about 7)?
A. passive diffusion cannot occur with substances capable of ionization; it would have to be
absorbed by a specialized ion transport mechanism
B. an acid cannot be absorbed directly from the stomach; it would have to pass into the small
intestine first
C. absorption will be favored because the acid will be largely non-ionized and diffusible in the
stomach, and largely ionized, non-diffusible and ion-trapped in the blood
D. absorption will not be favored, because the acid will be largely ionized (nondiffusible) and iontrapped
in the stomach and largely non-ionized (diffusible) in the blood
Answer: C
Explanation and Reference:
Organic weak acids are exceptions to diffusion. At pKa, 50% of a weak acid/base is polar
(cationic/anionic) and 50% is non-polar. Using the Henderson-Hasselbalch equation, weak acids are
greater than 50% non-polar in the presnece of a strong acid. The lower the pH, the more non-polar
the weak acid becomes. Therefore, at pH 2 the weak acid will be non-polar and absorbed. At pH 7
the weak acid will be polar and not readily absorbed. C&D 9th, p. 162 Figure 5-4
163
164
What is the cause of Heinz body formation?
A. irreversible denaturing of hemoglobin
B. an increased number of heme groups per cell
C. impairment of hemolysis
D. reduction of methemoglobin by methemoglobin reductase
Answer: A
Explanation and Reference:
Heinz bodies are formed by damage to the hemoglobin component molecules, usually through
oxidant damage, or from an inherited mutation (i.e. change of an internal amino acid residue). As a
result, an electron from the hemoglobin is transferred to an oxygen molecule, which creates a
reactive oxygen species (ROS) that can cause severe cell damage leading to premature cell lysis.
Damaged cells are cleared by macrophages in the spleen, where the precipitate and damaged
membrane are removed, leading to characteristic "bite cells". The denaturing process is irreversible
and the continual elimination of damaged cells leads to Heinz body anemia. Hayes 6th, p. 1319
165
The pathway in both humans and non-human primates for the metabolism of methanol to
formaldehyde is mediated by what enzyme?
A. hydrogen peroxide catalase
B. formaldehyde dehydrogenase
C. formyl-tetrahydrofolate dehydrogenase
D. alcohol dehydrogenase
Answer: D
Explanation and Reference:
In nonprimates, methanol is oxidized by the catalase-peroxidase system, whereas in primates (Nonhuman
and human), the alcohol dehydrogenase system takes the main role in methanol oxidation.
C&D 9th, p. 1207
166
What is a cofactor for human cytochrome P450-mediated xenobiotic transformation reactions?
A. glutathione
B. NAD+ (nicotinamide adenine dinucleotide, oxidized)
C. NADPH (nicotinamide adenine dinucleotide phosphate, reduced)
D. UDP (uridine diphosphate)-glucuronic acid
Answer: C
Explanation and Reference:
Protons (H+) are usually delivered from the cofactor NADH or NADPH through specific amino acids in
the CYP enzyme, which relay the protons to the active site, where they are essential for a reductive
splitting of the oxygen so a single atom can be added to the substrate. C&D 9th, p. 272-274; 1442.
167
Among the cytochrome P450 (CYP) isoforms, which is the most abundantly expressed and involved
in the metabolism of about 50% of all clinically used drugs?
A. 3A4
B. 2D6
C. 1A2
D. 2C19
Answer: A
Explanation and Reference:
Cytochrome P450 3A4 (abbreviated CYP3A4) is an important enzyme in the body, mainly found in
the liver and in the intestine. Its purpose is to oxidize small foreign organic molecules (xenobiotics),
such as toxins or drugs, so that they can be removed from the body. C&D 9th, p. 307
168
Through what actions do both 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polychlorinated
biphenyls (PCBs) function as environmental endocrine disrupters?
A. retinoid agonists
B. estrogen antagonists
C. Ah receptor agonists
D. androgen agonists
Answer: C
Explanation and Reference:
The common mechanistic pathway for both TCDD and PCBs with regard to endocrine disruption is
binding to the aryl hydrocarbon receptor (AHR). The AHR is a cytosolic nuclear transcription factor
expressed in many tissues. Binding of xenobiotics to the AHR can affect many normal functions
including the immune system and in utero development. See Endocrine Disruptor Screening
Program at EPA [http://www.epa.gov/endo/] C&D 8th, p. 884; C&D 9th, pp. 318-320, 1438-1440.
169
To what is the difference in sensitivity of the human fetus to carbon monoxide (CO) compared to that
of adults attributed?
A. to the chemical asphyxiant properties of CO
B. to the shorter elimination time of CO from the fetus compared to adults
C. to the higher fetal COHb concentration compared to maternal COHb at the same CO
concentration
D. to the higher tissue oxygenation concentration in the fetus at identical carboxyhemoglobin (COHb)
levels
Answer: C
Explanation and Reference:
Fetal hemoglobin, or foetal haemoglobin, (also hemoglobin F, HbF, or α2γ2) is the main oxygen
transport protein in the human fetus during the last seven months of development in the uterus and
persists in the newborn until roughly 6 months old. Functionally, fetal hemoglobin differs most from
adult hemoglobin in that it is able to bind oxygen with greater affinity than the adult form, giving the
developing fetus better access to oxygen from the mother's bloodstream. This would predispose it to
CO poisoning. C&D 9th, p. 1499-1500
170
The accumulation of cyclic GMP in the corpus cavernosum is enhanced by phosphodiesterase 5
(PDE5) inhibitors such as Viagra. What molecular mechanism of action is responsible for hypotension
induced in men taking Viagra for erectile dysfunction?
A. the formation and the accumulation of cyclic GMP are stimulated by NO and enhanced by the
PDE5 inhibitor, respectively, leading to contraction of vascular smooth muscles
B. the formation and the accumulation of cyclic GMP are stimulated by NO and enhanced by the
PDE5 inhibitor, respectively, leading to relaxation of vascular smooth muscles
C. the formation and the accumulation of cyclic GMP are inhibited by NO and by the PDE5 inhibitor,
respectively, leading to relaxation of vascular smooth muscles
D. the formation and the accumulation of cyclic GMP are inhibited by NO and by the PDE5 inhibitor,
respectively, leading to contraction of vascular smooth muscles
Answer: B
Explanation and Reference:
By blocking the degradation of cGMP, Viagra (sildenafil), as a PDE5 inhibitor, maintains and
increases the vasodilatory signal to the corpus cavernosum allowing and enhancing erection. It is
also a non-specific inhibitor of PDE3. When given alone to men with coronary artery disease, Viagra
can cause a 10% decrease in blood pressure; however, an interaction with organic nitrates can result
in dangerous hypotension. C&D 9th p. 937 and G&G 11th, p. 829-830.
171
Thiouracil and other goitrogenic compounds produce follicular cell adenomas in rats through what
mechanism?
A. decreasing the secretion of pituitary thyroid stimulating hormone (TSH)
B. receptor-mediated stimulation of thyroid gland by TSH
C. stimulation of the conversion of T4 to T3
D. inhibition of thyroid peroxidase- catalyzed oxidation of iodine (I2) to iodide (I-)
Answer: B
Explanation and Reference:
Many goitrogenic xenobiotics that increase the incidence of thyroid tumors in rodents exert a direct
effect on the thyroid gland to disrupt one of several possible steps in the biosynthesis and secretion of
thyroid hormones. This includes blockage of organic binding of iodine and coupling of iodothyronines
to form thyroxine (T4) and triiodothyronine (T3) (e.g. sulfonamides, thiourea, methimazole, and
aminotriazole, amongst others). This lowers circulating T3 levels which results in a compensatory
increased secretion of thyroid stimulating hormone (TSH), follicular cell hypertrophy and hyperplasia,
and an increased incidence of follicular cell tumors in 2-year or lifetime studies in rats. C&D 9th, p.
327
172
What is likely to precipitate a severe hypertensive crisis in a patient taking a monoamine oxidase
inhibitor?
A. grapefruit juice (CYP3A-inhibiting flavones)
B. tyramine-containing foods (sympathomimetic)
C. amitriptyline (tricyclic antidepressant)
D. hydroxocobalamine (vitamin B12 precursor)
Answer: B
Explanation and Reference:
A hypertensive crisis can result from ingestion of tyramine-rich foods in conjunction with monoamine
oxidase inhibitors (MAOIs). C&D 9th, p. 945
173
What is the underlying mechanism of paraquat lung toxicity?
A. increase in mRNA coding for fibronectin and procollagen preceded by release of cytokines such
as TGF-b and TNF
B. remodeling of the vascular bed with hyperplasia of capillary endothelial cells
C. oxidation of cellular NADPH and eventual depletion of the NADPH content of pulmonary cells
D. degradation of pulmonary surfactant causing accumulation of toxic substances in the pulmonary
phagocytic cells
Answer: C
Explanation and Reference:
Produces a superoxide radical while reducing NADPH + H+ to NADP in pulmonary cells. C&D 9th, p.
1084-1085
174
What is the mechanism of toxicity of the rodenticide fluoroacetate?
A. metabolism to fluorocitrate and inhibition of aconitase
B. inhibition of mitochondrial ATPase
C. obstruction of renal tubules by precipitation as calcium fluroacetate
D. release of fluoride with subsequent inhibition of water reabsorption by the kidney
Answer: A
Explanation and Reference:
Fluoroacetate is similar to acetate, which has a pivotal role in cellular metabolism. Fluoroacetate
disrupts the citric acid cycle (also known as the Krebs cycle) by combining with coenzyme A to form
fluoroacetyl CoA, which reacts with citrate synthase to produce fluorocitrate which binds very tightly to
aconitase, thereby halting the citric acid cycle. This inhibition results in an accumulation of citrate in
the blood. Citrate and fluorocitrate are allosteric inhibitors of phosphofructokinase-1 (PFK-1), a key
enzyme in the breakdown of sugars. As PFK-1 is inhibited cells are no longer able to metabolize
carbohydrates, depriving them of energy. C&D 9th, p. 92, 857
175
At what site in DNA is the most abundant alkyl adducts produced by alkylating agents, a site that has
the highest negative electrostatic potential?
A. N7 position of guanine
B. N1 position of adenosine
C. N3 position of cytosine
D. O6 position of thymidine
Answer: A
Explanation and Reference:
An important and abundant source of nucleophiles is contained not only in the DNA bases, but also in
the phosphodiester backbone. Although carcinogen–DNA adducts may be formed at all sites in DNA,
the most common sites of alkylation include the N7 of guanine, the N3 of adenine, the N1 of adenine,
the N3 of guanine, and the O6 of guanine . As the most nucleophilic site in DNA, the guanine N7
atom is a major site of adduction by a large number of alkylating mutagens and carcinogens. Aflatoxin
B1, a powerful mutagen, is believed to act through its reaction with this DNA site. C&D 9th, p. 506
176
Why is the adrenal cortex predisposed to the toxic effects of many hydrophobic xenobiotic chemicals?
A. a lack of cytochrome P450 enzymes
B. pituitary hormone actions
C. bioactivation of long chain aliphatic compounds
D. large stores of lipids
Answer: D
Explanation and Reference:
Adrenal lipophilic steroid hormones are so hydrophobic they must be bound to serum lipids to be
transported. The adrenal cortex is predisposed to the toxic effects of xenobiotic chemicals for three
reasons. 1. the adrenocortical cells contain large stores of lipids for steroidogenesis. 2. membranes of
the adrenocortical cells contain high levels of unsaturated fatty acids that are susceptible to the
generation of reactive species such as free radicals via lipid peroxidation. 3. adrenocortical cells
express enzymes involved in steroidogenesis, including those of the cytochrome P450 (CYP) family,
which are capable of metabolizing xenobiotic chemicals to reactive toxic species. Thus the adrenals
are particularly sensitive to hydrophobic xenobiotics. C&D 9th, pp. 977, 981
177
What is a recognized mechanism of toxicity for endotoxins?
A. release of inflammatory mediators from Kupffer cells
B. covalent binding to DNA
C. activation of Ito cells
D. inhibition of mitochondrial oxidative phosphorylation
Answer: A
Explanation and Reference:
Kupffer cells are a type of phagocytic cell that forms the lining of the sinusoids of the liver and can
react to endotoxins (bacterial toxins such as lipopolysaccharides) exacerbating their influence in
manifesting toxicity through the release of reactive oxygen and pro-inflammatory cytokines (i.e., TNFalpha,
IL-1B, IL-6, IL-10). C&D 9th, p. 729 Figure 13-9, 731
178
What features characterize apoptosis?
A. nuclear chromatin patterns become predominantly euchromatic
B. cytoplasmic shrinkage and nuclear fragmentation
C. intracellular organelles swell and disintegrate with membrane lysis
D. inflammatory mediators respond to cell debris in the extracellular matrix
Answer: B
Explanation and Reference:
Characteristic signs of apoptosis include the shrinking of the cell with fragmentation and condensation
of both nuclear and cytoplasmic materials. The cell then breaks into membrane-bound fragments that
are phagocytized. Chromatin condensation is not a feature of apoptosis and neither is the swelling of
intracellular organelles. Apoptosis is the opposite of necrosis and does not initiate an inflammatory
response. Apoptosis is distinct from necrosis in that necrosis results from cellular damage whereas
apoptosis is a tightly regulated suicide of the cell. C&D 9th, pp. 97-98.
179
What cytochrome P450 (CYP) is the most abundant in the normal human liver?
A. CYP2D6
B. CYP3A4
C. CYP2E1
D. CYP1A2
Answer: B
Explanation and Reference:
CYP3A4 Is present in large amounts both in liver and small intestine. This isozyme metabolizes a
wide range of drugs and natural products it is very important in some drug-drug interactions. There
are as many as 60 CYPs in the normal human liver, of which CYP3A4 is one of the most important.
C&D 9th, pp. 307-309.
180
How is the mechanism of flushing syndrome observed after alcohol consumption in a high percentage
of the Pacific Rim Asian population is explained?
A. decreased aldehyde dehydrogenase activity
B. decreased alcohol dehydrogenase activity
C. immediate hypersensitivity
D. increased CYP2E1 activity
Answer: A
Explanation and Reference:
There are a large number of people of Asia-Pacific origin who have a mutation in the gene coding for
the enzyme aldehyde dehydrogenase. This is a single-nucleotide polymorphism (SNP). The clinical
consequence of this mutation is that ethanol is rapidly metabolized by alcohol dehydrogenase to
acetaldehyde where it accumulates because of the decreased aldehyde dehydrogenase activity. It is
the accumulation of acetaldehyde that causes the characteristic flushing of the face and
extremities.The flushing reaction is the result of an accumulation of acetaldehyde in the skin. C&D
9th, p. 740-741, Figure 13-16
181
What is the most important mechanism for deposition of ultrafine particles <0.2 microns aerodynamic
diameter in lung alveoli?
A. diffusion
B. inertial impaction
C. sedimentation
D. condensation
Answer: A
Explanation and Reference:
Diffusion is the correct answer as most particles <0.5 um will reach the lower lung and alveoli by this
mechanism. Most particles >10 um will be deposited in the nose and pharyx by impaction. While
sedimentation of fine particles (>5 microns) controls deposition in the smaller bronchi, the
bronchioles, and the alveolar spaces, sedimentation is not a signifcant route of ultrafine particle
deposition at sizes <0.5 um. Condensation is not a mechanism of particle deposition. C&D 9th, p.
795, Figure 15-1; p. 805 Figure 15-7
182
The ability of metallothionein to bind metallic cations is a function of its high content of what
molecule?
A. methionine
B. cysteine
C. lysine
D. N-acetylcysteine
Answer: B
Explanation and Reference:
Metallothioneins (MTs) include any inducible low molecular weight cytosolic protein with highly
conserved cysteines and numerous cysteinyl thiol groups allowing them to bind to a diverse group of
metals. Hayes 6th, p. 2095; C&D 9th p. 1111-1112.
183
The cytochrome P-450 monooxygenases are concentrated mainly in what two cell types in the lung?
A. Type 1 and Type 2 epithelial cells
B. Type 1 epithelial and Clara cells
C. Clara and Type 2 epithelial cells
D. Type 1 epithelial and endothelial cells
Answer: C
Explanation and Reference:
The major Phase-1 metabolic activities in the lung are primarily mediated by cytochrome P450
enzymes. The cells with the highest concentrations of P450 in the lung are the Clara cell followed by
the Type 2 pneumocyte. Clara, or Club cells, are old terms for the mucus-producing bronchiolar
secretoglobin cells (BSCs). Type 2 cells, also called great alveolar cells or septal cells, are granular
and generally cuboidal in shape. C&D 9th, p. 801
184
What is the mechanism of carbon disulfide neurotoxicity?
A. impaired protein synthesis
B. interference with acetylcholine
C. neurofilament cross-linking
D. depolymerization of microtubules
Answer: C
Explanation and Reference:
Carbon disulfide (CS2)-induced peripheral neuropathy results from the reaction of CS2 with protein
amino groups to yield initial adducts (dithiocarbamate derivatives). The adducts decompose to an
electrophile (isothiocyanate), which in turn reacts with protein nucleophiles on neurofilaments to
cause covalent protein cross-linking. Progressive cross-linking of neurofilaments occurs during
neurofilament transport along the axon, and covalently cross-linked masses of neurofilaments are
thought to occlude axonal transport at the nodes of Ranvier, ultimately resulting in axonal swelling
and degeneration Crosslinking reagents, such as carbon disulfide, are molecules that contain two or
more reactive atoms capable of binding primary amines, sulfhydryls or other reactive components of
proteins or nucleic acids. C&D 9th, pp. 1225-1226
185
Cocaine initially causes euphoria, hyperactivity and talkativeness. What mechanism explains this
effect for cocaine?
A. blocking of potassium channels and the reuptake pump in the parasympathetic nervous system
where acetylcholine is the neurotransmitter
B. blocking the reuptake of dopamine, norepinephrine, and serotonin; as well as release of dopamine
from storage vesicles.
C. inhibition of the release of the neurotransmitter in the synapses of the parasympathetic nervous
system and blocking calcium channels
D. blocking of the reuptake of neurotransmitters in synapses of the parasympathetic nervous system
and opening caclium channels
Answer: B
Explanation and Reference:
Cocaine blocks the reuptake of dopamine, norepinephrine, and serotonin; as well as release of
dopamine from storage vesicles. These events are credited with the addictive and euphoric
responses to this drug. C&D, 8th ed., pp. 753.
186
What is a key characteristic of urticaria?
A. responses are independent of histamine
B. contact urticaria is produced by only a few substances
C. reactions occur through a Type 4 hypersensitivity reaction
D. responses are primarily mediated through mast cells
Answer: D
Explanation and Reference:
Urticaria is a skin reaction following release of histamine from sensitized mast cells. The release of
histamine is triggered by exposure of allergens to IgE antibodies on the mast cell surfaces. This is an
immediate-type hypersensitivity response in contrast to a Type-4 cell-mediated hypersensitivity
reaction. Urticaria is common, produced by many substances. C&D 8th, pp. 852-853; C&D 9th, p.
966.
187
For non-corrosive agents, what characteristics are likely to have the greatest impact on absorption
through the skin?
A. hydrophobic agents with low molecular weight
B. hydrophobic agents with high molecular weight
C. hydrophilic agents with high molecular weight
D. hydrophilic agents with low molecular weight
Answer: A
Explanation and Reference:
While the skin is generally a very good barrier to xenobiotic exposure, small, hydrophobic molecules
can move easily through the skin into the bloodstream. For certain exposure pathways this can be a
major source of internal dose. C&D 9th, p. 955
188
What is the term given to the severe, acute dermatologic hypersensitivity reaction to various drugs,
characterized by epidermal sloughing leading to a true medical emergency and lethality in some
cases?
A. toxic epidermal necrolysis
B. Grover's Disease
C. chondrodermatitis helicis
D. Schamberg's Disease
Answer: A
Explanation and Reference:
Toxic epidermal necrolysis is a rare but life-threatening skin disease resulting from hypersensitivity
reactions to drugs. The Stevens-Johnson syndrome is a milder form of this disease but can still be
fatal. Recovery from Stevens-Johnson reactions can take months and requires avoidance of the
offending drug and similar chemical analogs for life. C&D 9th, p.969
189
Why is allyl alcohol primarily associated with periportal (zone 1) hepatocellular necrosis?
A. higher concentration of P450 isozyme for bioactivation to acrylic acid
B. disruption of hepatocellular cytoskeletons by binding to actin filaments
C. higher periportal oxygen concentration for bioactivation to acrolein
D. canalicular cholestasis as a consequence of bioactivation to acrolein
Answer: C
Explanation and Reference:
Allyl alcohol is bioactivated by alcohol dehydrogenase oxidation to acrolein and produces periportal
liver injury. Acrolein is a highly reactive α,β-unsaturated aldehyde. It rapidly binds to and depletes
cellular nucleophiles such as glutathione. Because periportal (zone 1) has the highest concentration
of glutathione and oxygen to oxidize allyl alcohol to acrolein, this is the region of toxicity. C&D 9th, p.
742 Figure 13-8; pp. 721-22
190
What region of the eye is more susceptible to systemic toxicants?
A. cornea and ciliary body
B. retinal pigment epithelium (RPE) and photoreceptors
C. iris and lens
D. cornea and iris
Answer: B
Explanation and Reference:
More vascularized regions of the eye are more susceptible to systemic toxicants. C&D C&D 9th, p.
884, Figure 17-3; p. 890
191
What is the main liver cell type that produces extracellular matrix proteins and is central to the
development of fibrosis?
A. stellate cell
B. Kupffer cell
C. endothelial cell
D. hepatocyte
Answer: A
Explanation and Reference:
Stellate cells are located between the hepatocytes and the sinusoids (the sinusoidal space). Thus
they are susceptible to toxicant damage and initiation of fibrosis. These cells express smooth muscle
actin; they are contractile and appear to control local flow of blood in the sinusoids. When activated,
especially during chronic injury to the liver, stellate cells can assume a myofibroblastic phenotype,
synthesizing and secreting collagen and other extracellular matrix proteins and thereby can initiate
liver fibrosis. C&D 9th, p. 723
192
What is the toxicological consequence of ingestion of large amounts of rhubarb leaves?
A. presence of oils capable of eliciting local irritation to the GI tract
B. high concentration of oxalate in the leaves leading to ethylene-glycol-like nephrotoxicity
C. high concentration of hyaluronidase in the leaves leading to local tissue necrosis
D. presence of cyanogenic peptides
Answer: B
Explanation and Reference:
Rhubarb (Rheum rhaponticum) is one of many plants that cause gastrointestinal irritation following
the release of raphides of oxalates. C&D 9th pp. 1278-1279, Table 26-4.
193
Indicators of kidney function after toxic damage include blood (serum) urea nitrogen(BUN), serum
creatinine, and urine specific gravity. Renal function can be assessed by what method?
A. comparing serum creatine kinase (CK) with serum creatinine
B. ratios of urine sorbitol dehydrogenase (SDH) or lactate dehydrogenase (LDH)
C. calculating glomerular filtration rate and/or Cystatin C clearance
D. measurement of urine output (volume over time)
Answer: C
Explanation and Reference:
Cystatin C is a protein coded by the CST3 gene and primarily used as a biomarker for kidney
function. C&D 9th, p. 777
194
Non-steroidal anti-inflammatory drugs (NSAIDs) induce acute renal failure which is reversible and
characterized by decreased renal blood flow, glomerular filtration rate, and oliguria in patients
suffering from hypotension, hypovolemia and/or cardiac insu
A. inhibition of lysosomal hydrolases
B. suppression of prostaglandin synthesis
C. disruption of mitochondrial membranes
D. accumulation in renal tubular fluid
Answer: B
Explanation and Reference:
NSAIDs act through the inhibition of prostaglandin synthesis. When the normal production of
vasodilatory prostaglandins (e.g., PGE2 and PGI2) is inhibited by NSAIDs, vasoconstriction induced
by circulating catecholamines and angiotensin II is unrestricted, resulting in decreased renal blood
flow and ischemia. C&D 9th, p. 785
195
What is the mechanism by which saccharin causes urinary bladder tumors in rats?
A. formation of DNA-reactive free radical metabolites of saccharin in the acidic environment of the
urine
B. the major urinary metabolite of saccharin causes cross-linking of DNA in bladder epithelial cells
C. DNA mutations in transitional epithelial cells of the bladder
D. precipitation of saccharin crystals in the bladder leading to local irritation and hyperplasia
Answer: D
Explanation and Reference:
Bladder cancer in rats administered saccharin only occurred under conditions where the compound
was at such high concentrations in the urine that it formed a crystalline precipitate. It was determined
that these findings were not relevant to humans at normal dietary intakes and beyond. Even at levels
of excessive dietary consumption, such high concentrations would not be achieved in humans. There
is no evidence that saccharin or its metabolites is mutagenic. C&D 9th, p. 135, Table 4-5.
196
What is the mode of action by which peroxisome proliferator activated receptor alpha (PPARalpha)
agonists cause tumors in rodent livers?
A. hypertrophy and hyperplasia of hepatocytes
B. increased apoptosis and decreased cell proliferation
C. decreased peroxisomal fatty acid degradation
D. decrease in hydrogen-peroxide-generating catalase in hepatocytes
Answer: A
Explanation and Reference:
Chronic administration of peroxisome proliferating chemicals to rats and mice causes hepatomegaly
and ultimate carcinogenesis through non–DNA-reactive mechanisms. PPARα plays a central role in
lipid metabolism and acts as a transcription factor to modulate gene expression following ligand
activation. This latter effect arises through the heterodimerization of PPARα and RXRα, which results
in binding to response elements (PPREs) and subsequent modulation of target gene transcription.
Following this event is the induction of cell proliferation and suppression of apoptosis. Relevance of
this effect to humans is a matter of controversy. C&D 9th, pp 451-452, Figure 8-17
197
What can cause follicular cell adenoma formation in the rat thyroid?
A. iodine-catalyzed free radical production
B. secondary induction of thyroperoxidase
C. excessive secretion of TSH
D. retarded metabolism of T3 to T4 in peripheral tissues
Answer: C
Explanation and Reference:
Excessive secretion of TSH can act in a proliferating manner. C&D 9th p. 454
198
The nucleotide excision repair system is initiated by what type of DNA lesion?
A. removal of bulky lesions from DNA
B. induction of aneuploidy
C. damage to individual DNA bases
D. DNA ligation as an initiating event
Answer: A
Explanation and Reference:
The NER system provides a mechanism to remove bulky lesions from DNA. Basic excision repair
mechanisms would be activated in cases of DNA-based damage. DNA ligation and the induction of
aneuploidy are not triggers for the NER system. C&D 8th, p. 452; C&D 9th p. 508.
199
The O6-methylguanine DNA methyltransferase repair mechanism is a process that protects cells
against DNA damage caused by what class of compounds?
A. ultraviolet light
B. ionizing radiation
C. alkylating agents
D. free oxygen radicals
Answer: C
Explanation and Reference:
Many anti neoplastic drugs are alkylating agents used to inhibit cell division by tumor tissues. C&D
9th, pp. 442, 510
200
What is considered an acute response of the lung to injury?
A. emphysema
B. interstitial granulomatosis
C. pulmonary edema
D. fibrosis
Answer: C
Explanation and Reference:
Lung injury due to inhalation of acid gas can result in lethal pulmonary edema within hours. C&D 9th,
pp. 813-814
201
The delayed neurotoxicity observed after exposure to tri-ortho-cresyl phosphate (TOCP) is best
attributed to what process?
A. inhibition of oxidative phosphorylation
B. a genetic polymorphism in the gene responsible for myelination
C. neurofilament protein crosslinking
D. covalent modification of neuropathy target esterase
Answer: D
Explanation and Reference:
TOCP modifies NTE which initiates degeneration of long axons in the peripheral nervous system.
C&D 9th, p. 851-52
201
The toxicity profile of an inhaled gas or vapor is determined by its site of pulmonary deposition. As a
general rule, where along the respiratory tract are water-insoluble gases such as nitrogen dioxide,
ozone, and methylene chloride absorbed?
A. they bypass the upper respiratory tract and are absorbed in the deep lung
B. they are completely absorbed in the nasal cavity
C. they are readily absorbed by the mucus covering of the conducting airways
D. they must be combined with particulates to reach the deepest areas of the lung
Answer: A
Explanation and Reference:
There are a number of determinants of where a gas or vapor will be absorbed along the respiratory
tract, but as a general rule, highly water soluble gases/vapors tend to be absorbed in the nasal cavity
whereas insoluble gases tend to deposit and be absorbed deeper in the lung. Other factors include
physico-chemical characteristics of the gas or vapor, such as diffusivity, partition coefficient, and
chemical reactivity. C&D 9th. p. 803; Hayes 6th p. 1414.
202
What is the mode of action for the neurotoxicity of compounds such as n-hexane and carbon
disulfide?
A. destruction of synaptic neurotransmitters
B. distal axonal swelling and degeneration
C. damage to the myelin sheath disrupting signal transmission
D. damage to dendritic processes in neuromuscular junctions
Answer: B
Explanation and Reference:
Both and-hexane and carbon disulfide cause a clinical polyneuropathy. The mode of action is
damage to peripheral axons characterized by axonal swelling and degeneration. The mechanism of
action at the molecular level is unclear; however, there are several working hypotheses. Hayes 6th,
pp. 698-700; C&D 9th 848-851, Table 16-2.
203
Botulinum toxin A causes flaccid paralysis of skeletal muscle by what mechanism?
A. blocking the release of acetylcholine from synaptic vesicles by exocytosis through the presynaptic
membrane of the neuromuscular junction
B. acting as a competitive antagonist that blocks the nicotinic acetylcholine receptors on the postsynaptic
membrane of the neuromuscular junction
C. blocking the release of neurotransmitters from synaptic vesicles by exocytosis from inhibitory
neurons that synapse with motor neurons
D. stimulating the release of acetylcholine from synaptic vesicles by exocytosis through the
presynaptic membrane of the neuromuscular junction
Answer: A
Explanation and Reference:
Botulinum toxin interferes with a key enzymatic reaction. It is a zinc protease that hydrolyzes the the
fusion proteins necessary for the exocytosis of acetylcholine, preventing its release, and leading to
paralysis. C&D 9th p. 75.
204
What is the significance of the "aging" reaction with respect to the acute cholinergic neurotoxicity of
an organophosphorus (OP) compound?
A. it slowly reverses the paralysis caused by delayed neuropathy
B. it renders the inhibited acetylcholinesterase (AChE) intractable to reactivation by therapeutic
oximes, such as 2-pralidoxime methiodide (2-PAM)
C. it accounts for the greater resistance of young animals to cholinergic agents
D. it catalyzes the destruction of excess OP compounds in the blood by butyrylcholinesterase
(BChE)
Answer: B
Explanation and Reference:
The characteristics of the aging process is highly dependent upon the type of organic phosphate
involved. C&D 9th, p. 1064
205
Kupffer and microglia cells are components of the body's innate cellular immunity. From what cell
line are these cells terminally differentiated?
A. polymorphonuclear cells
B. natural killer cells
C. monocytes
D. T-lymphocytes
Answer: C
Explanation and Reference:
Kupffer cells and microglia are specialized macrophages residing in the liver and brain, respectively.
They are terminally differentiated monocytes (myeloid lineage). T-lymphocytes, natural killer cells,
and PMNs develop along different pathways from bone marrow stem cells (lymphoid lineage). C&D
9th, pp.637-38
206
A deficiency of folate or vitamin B12 results in an inhibition of thymidine synthesis. This can lead to
the development of what condition?
A. megaloblastic anemia
B. pure red cell aplasia
C. microcytic anemia
D. methemoglobinemia
Answer: A
Explanation and Reference:
A pure red cell aplasia is uncommon and is related to decrease erythroid production in the bone
marrow, but it is not related to deficiencies of either vitamin B12 or folate. Methemoglobinemia is
caused by agents that oxidize the heme protein; vitamin B12 and folate do not do this. Iron deficiency
is the most common cause of microcytic anemia, not deficiencies in vitamin B12 or folate.
Megaloblastic anemia is the characteristic morphological feature of vitamin B12 and folate deficiency.
C&D 9th, pp. 597-98
207
Of what importance is alpha-2 microglobulin nephropathy in humans?
A. it accumulates in the mitochondria of proximal tubular cells interfering with cellular respiration
B. it is actively secreted by the S2 segment of proximal tubular cells
C. elevated alpha-2μ-globulin is associated with renal hyperplasia
D. humans are not generally considered to be at risk of alpha-2?-globulin nephropathy
Answer: D
Explanation and Reference:
Alpha-2 microglobulin nephropathy is sex-and species-specific. Humans are not believed to be at risk
because 1) humans do not synthesize alpha-2 microglobulin, 2) humans secrete less proteins than
rats, and 3) low molecular weight proteins in human urine are not related to alpha-2 microglobulin.
C&D 9th, p. 783
208
What is the most common site of toxicant-induced renal injury?
A. glomerulus
B. connecting tubule
C. proximal tubule
D. loop of Henle
Answer: C
Explanation and Reference:
The proximal tubule is the most metabolically active area of the kidney and often the target of
xenobiotic activity. The glomerulus is the primary site for immune complexes, the loop of
Henle/collecting ducts for fluoride ions, and the medulla/papilla for chronically consumed analgesic
mixtures. C&D 9th, p. 776
209
What compound causes neurotoxicity by mechanism other than interfering with aerobic metabolism
(hypoxia)?
A. carbon disulfide
B. hydrogen sulfide
C. carbon monoxide
D. hydrogen cyanide
Answer: A
Explanation and Reference:
Carbon disulfide (CS2)-induced peripheral neuropathy results progressive cross-linking of
neurofilaments along the axon. C&D 9th, pp. 1224-1227
210
In what zone of the liver would you expect to see the most damage from CCl4 intoxication?
A. All Zones
B. Zone I
C. Zone II
D. Zone III
Answer: D
Explanation and Reference:
CYP2E1 is associated with activation of CCl4 to its active metabolite, and the highest concentration
of this P450 is in Zone 3 of the liver adjacent to the terminal hepatic venules. Zones 1 and 2 are not
highly associated with metabolic activation and are more rich in mitochondria. "All zones" is not
correct because CCl4 toxicity has been shown to be zone specific. C&D 9th, pp. 721-22, Figure 13-2
211
What is the basis for the renal toxicity of metals?
A. binding to carbonyl groups
B. initiation of lipid peroxidation
C. generation of reactive oxygen species
D. binding to sulfhydryl groups
Answer: D
Explanation and Reference:
Metals may bind to sulfhydryl group of proteins important to tissue function and survival. C&D 9th, p.
781
212
Allelic loss of what gene(s) may result in early age onset of cancers?
A. DNA repair genes
B. oncogenes
C. tumor suppressor genes
D. cell cycle genes
Answer: C
Explanation and Reference:
Tumor suppressor genes are comprised of two alleles. Allelic loss of one or both genes would
decrease tumor suppressing activity. Proto-oncogenes and oncogenes also play a role in cancer
induction; however, it is often through mutations that increase the activity of these genes. C&D 9th,
p. 463, Table 8-17
213
Alteration of normal microtubules function is the primary toxic effect for what compound?
A. cuprizone
B. carbon disulfide
C. taxol
D. atropine
Answer: C
Explanation and Reference:
Taxol (Paclitaxel) binds to tubules and stabilizes the polymerized form in the presence of calcium, a
condition that typically results in dissociation - can result in axonopathy. Carbon disulfide disrupts
neurofilaments causing axonopathy. Cuprizone acts to demyelinate axons causing axonopathy.
Atropine is an anticholineric agent causing acute neurotoxicity. C&D 9th, pp. 848-849, Table 16-2,
854,
214
What physiological response is characteristic of xenobiotic-induced Gell and Coombs Type I
immunopathy?
A. IgE binding to mast cells and basophils
B. hapten-carrier complex processed by Th1 cells
C. activation of naive T cells
D. complement-dependent lysis
Answer: A
Explanation and Reference:
Type I Hypersensitivity involves the production of IgE which activate mast cells. C&D 9th, p. 646-649
215
What is a key contribution of Kupffer cells with respect to hepatic toxicity?
A. drug protein adduct presentation does not produce immune activation
B. release of TNF-alpha contributes to idiosyncratic hepatotoxicity
C. activation is a common mechanism of acute hepatotoxicity of a compound
D. hepatotoxicity is due to direct effects of cytokines on hepatocytes
Answer: B
Explanation and Reference:
Kupffer cells release reactive oxygen and pro-inflammatory cytokines (i.e., TNF alpha, IL-1B, IL-6, IL-
10). TNF alpha has been shown to cause/contribute to hepatotoxicity in patients. C&D 9th, pp. 729,
Table 13-9, 730
216
What compound is a direct activating carcinogen that does not require metabolic activation to induce
cancer?
A. nitrogen mustard
B. azo dyes
C. aflatoxin
D. aromatic amines
Answer: A
Explanation and Reference:
Direct-acting carcinogens do not require metabolic activation or modification to induce cancer.
Examples include epoxides, imines, alkyl and sulfate esters, and mustard gases. Direct-acting
electrophilic carcinogenic chemicals typically test positive in the Ames test without additional
bioactivation with a liver metabolic fraction. Mustard is a direct acting carcinogen that can directly bind
to DNA. Azo dyes, aflatoxin, and aromatic amines are all indirect-acting genotoxic carcinogens that
require metabolic activation to induce cancer. C&D 9th, p. 440, Table 8-8
217
In the context of carcinogenesis, what are the correct respective designations for benzo[a]pyrene,
benzo[a]pyrene 7, 8 epoxide, and benzo[a]pyrene 7,8 diol-9, 10-epoxide?
A. procarcinogen, proximate carcinogen, and ultimate carcinogen
B. proximate carcinogen, ultimate carcinogen, and procarcinogen
C. carcinogen, partially detoxified carcinogen, and totally detoxified carcinogen
D. fluorescent carcinogen, phosphorescent carcinogen, and phototoxic carcinogen
Answer: A
Explanation and Reference:
BaP is a procarcinogen until metabolized by CYP1A1 to the oxide (proximate carcinogen), which is
further metabolided by epoxide hydrolase to the diol (proximate carcinogen), then metabolized again
by CYP1A1 to the epoxide (ultimate carcinogen). C&D 9th, p. 441, Table 8-4; p. 447
218
What is considered evidence of a mutagenic event and not a type of DNA damage?
A. adduct formation
B. intercalation
C. base substitution
D. strand breaks
Answer: C
Explanation and Reference:
Mutations occur from errors in DNA repair or replications. C&D 9th p 441-445
219
What is the key event of "promotion" in a multistage carcinogenesis model?
A. establishment of a stable, heritable change
B. additional mutagenic changes by chemical agents
C. the selective clonal expansion of initiated cells to produce a neoplastic lesion
D. conversion of benign preneoplastic lesions into neoplasia
Answer: C
Explanation and Reference:
In the multistage carcinogenesis model, initiation is damage to DNA that is stable and heritable and is
the first step in this process. Progression is the final step in this multi-step process whereby a benign
pre-neoplastic lesion becomes an active cancer. The middle step is promotion, and this step is
characterized by a selective clonal expansion of initiated cells to produce a preneoplastic lesion.
Promotion does not involve any additional mutagenic changes, and chemicals characterized as
"promoters" are not mutagenic and generally not able to cause tumors by themselves. They act
through mechanisms that involve changes in gene expresseion that in turn result in sustained cell
number in the target tissue either through cell proliferation and mitogenesis and/or the inhibition of
apoptosis. C&D 9th p 438-439
219
What is the purpose of including cytochalasin B in the in vitro micronucleus assay?
A. to improve assay sensitivity by increasing cellular proliferation rates
B. to facilitate automated scoring by improving uptake of stains for micronuclei in the treated cells
C. to detect kinetochores and enable distinguishing between micronucleus formation by aneugenic
versus clastogenic mechanisms
D. to block cytokinesis and avoid confusion associated with differences in cell proliferation kinetics
Answer: D
Explanation and Reference:
Cytochalasin B is used to block cytokinesis, inhibiting cell division. This results in binucleated and
multinucleated cells. C&D 9th p 441-445
220
An increase in abnormal sperm morphology indicates that a toxic agent has affected what cell type or
body compartment?
A. hepatocytes
B. caudal epididymis
C. germ cells
D. systemic circulation
Answer: C
Explanation and Reference:
As a general rule, an increase in abnormal sperm morphology suggests affects on germ cells. Effects
of a toxic agent on the systemic circulation or hepatocytes would not necessarily affect sperm
morphology. The caudal epididymis is a preferred site for sampling for both sperm number and
morphology. Hayes 6th, p. 1616
221
What toxic agent causes reproductive or developmental toxicity by damaging DNA directly?
A. diethylstilbestrol
B. thalidomide
C. retinoic acid
D. radiation
Answer: D
Explanation and Reference:
Of the listed developmental toxicants, radiation is the only agent that exerts its toxicity by directly
interacting with DNA. C&D, 8th ed., pp. 483-486, Table 10-1.
222
To what can the majority of maternal toxicity during pregnancy be attributed?
A. alcohol and smoking
B. prescription pharmaceuticals in the first trimester
C. unknown etiologies
D. chemical and other environmental exposures
Answer: C
Explanation and Reference:
Overt maternal toxicity can result from a number of underlying mechanisms, which are typically
unknown. C&D 9th p 563
223
What event or mechanism describes endocrine disruptors?
A. results in increased sperm counts in humans
B. no effect on reproductive tract organogenesis
C. receptor competition or inhibition of steroidogenesis
D. affects only female reproduction
Answer: C
Explanation and Reference:
Endocrine active chemicals are exogenous chemicals that exert their primary toxic effects via
modification of hormonal responses, at relatively low doses that are not seen at higher doses. Diverse
mechanisms have been proposed to eplain the shape of the nonmonotonic dose-response curves for
endrocrine active chemicasls, including dose-dependent cycotoxicity, cell- and tissue-specific
receptors and cofactors, receptor selectivity and down-regulation, receptor competition, and
endocrine negative feedback loops. C&D 9th p 40
224
Naphthalene induces extensive necrosis in the bronchiolar epithelium in mice, but much less in
rats and hamsters. What is believed to be the reason for this response?
A. a unique aryl hydrocarbon receptor in the mouse
B. absence of glutathione transferase in mouse bronchiolar epithelium
C. CYP2F2, a unique isoform, rapidly activates naphthalene in mice
D. anatomical differences that result in a higher tissue dose in the mouse
Answer: C
Explanation and Reference:
CYP2F2 is specific to mice. C&D 9th, p. 824
225
What is the mechanism by which ozone causes acute cellular injury in the respiratory tract?
A. oxidation of fatty acids in cell membranes leading to lipid radicals and auto-oxidation of cell
macromolecules
B. inhibition of macrophage function and mucociliary clearance
C. hyperplasia and hypertrophy of type I alveolar cells and alterations of Clara cells in the small
airways
D. inhibition of oxidative phosphorylation
Answer: A
Explanation and Reference:
The generation of oxygen free-radicals from polyunsaturated fatty acids in the cell membrane
degrades membrane integrity and leads to subsequent cellular necrosis. C&D 9th p 1495
226
In the upper and lower airways, what cell types are the most sensitive to ozone?
A. Clara cells and Type 1 cells
B. ciliated cells and Type 2 cells
C. ciliated cells and Type 1 cells
D. Clara cells and Type 2 cells
Answer: C
Explanation and Reference:
Animal studies indicate that the acute morphologic responses to ozone involve epithelial lining cells
along the entire respiratory tract. Ciliated and Type 1 cells are the most sensitive cells in the airway to
ozone. Clara and Type 2 are the least affected by ozone because they have greater metabolic
capacity and, in the case of Type 2 cells, serve as stem cells for replacement of Type I cells. C&D
9th, p 1495
227
What physicochemical properties have a role in the toxicity of nanoparticles used in drug
delivery?
A. chemical composition, shape, size, surface properties and solubility
B. chemical purity, chemical make-up and hydrodynamic diameter
C. solubility, surface reactivity, and size distribution
D. surface reactivity, solubility, shape and surface groups
Answer: A
Explanation and Reference:
Chemical composition, shape, size, surface properties and solubility are all important factors
influencing toxicity of nanoparticles. C&D 9th p 1394
228
What compound causes neurotoxicity because of its high affinity for a specific monoamine
oxidase?
A. tetraethyl lead
B. 3-acetylpyridine
C. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
D. trimethyltin
Answer: C
Explanation and Reference:
MPTP crosses the blood brain barrier, where it is a substrate for B isozyme of monoamine oxidase
(MAO-B). MPTP is metabolized to MPP+ inside the astrocytes, where it acts as a general
mitochondrial toxicant, blocking respiration at complex I. C&D 9th p 860
229
Doxorubicin causes toxicity at what specific site or sites in the body?
A. central nervous system
B. in the dorsal root and autonomic ganglia of the peripheral nervous system
C. proximal tubular cells of the renal cortex
D. in cardiomyocytes
Answer: B
Explanation and Reference:
In experimental animals, doxorubicin can cause progressive ataxia primarily by injury to neurons in
the dorsal root and autonomic ganglia of the PNS. C&D 9th p 846
230
Chronic exposure to what compound is associated with peripheral neuropathy characterized as
large swellings of distal axons and axonal degeneration?
A. carbon monoxide
B. methyl-n-butyl ketone
C. ethanol
D. hexachlorophene
Answer: B
Explanation and Reference:
Methyl n-butyl ketone produces a classical axonal degeneration with neurofilamentous swelling.
Hexachlorophene, on the other hand, produces neuronal edema leading to the formation of vacuoles
("spongiosis"). Carbon monoxide is not associated with neuronal pathology, rather direct damage to
vascular endothelium and smooth muscle. While ethanol is a depressant, it is not associated with
specific neuronal histopathological lesions. C&D 9th, Tables 16-1, 16-2
231
Contact hypersensitivity reactions are commonly associated with direct and prolonged contact
with what element?
A. nickel
B. lithium
C. iron
D. lead
Answer: A
Explanation and Reference:
Nickel has been reported to elicit contact urticaria C&D 9th p 966-967
232
What immunoglobulin class is most commonly associated with immediate onset of allergic
reactions in humans?
A. IgE
B. IgM
C. IgA
D. IgG
Answer: A
Explanation and Reference:
IgE is the primary immunoglobin responsible for allergic responses in humans. C&D 9th p 640
233
What molecule is recognized to cause dermal hyperpigmentation?
A. TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin)
B. furocoumarins (psoralens)
C. butylated hydroxytoluene
D. p-tertbutylphenol
Answer: B
Explanation and Reference:
Furocoumarins (lime juice) can cause increased dermal pigmentation. C&D 9th Fig 19-2f, p 968
234
What mechanism explains chloroquine accumulation in the eye resulting in retinopathy?
A. reversible intracellular binding to melanin
B. increased permeability of the blood-aqueous barrier
C. decreased aqueous humor outflow
D. porosity of the retinal pigment epithelium
Answer: A
Explanation and Reference:
Chloroquine and its metabolites have a high affinity to melanin, which results in very high
concentrations accumulating in the choroid and retinal pigment epithelium
235
Overdoses of acetaminophen produce what type of liver injury in humans?
A. hepatic steatosis
B. hepatocarcinogenicity
C. hepatocyte necrosis
D. bile duct damage and proliferation
Answer: C
Explanation and Reference:
Acetaminophen toxicity occurs through protein binding following GSH depletion resulting in inhibition
in mitochondrial respiration leading to necrosis. C&D 9th p 735-736
236
Angiotensin converting enzyme (ACE) inhibitors are indicated for the treatment of heart failure. By
what mechanism can these drugs cause renal artery stenosis and acute renal failure?
A. increased production of red blood cells overwhelms glomerular filtration
B. ACE inhibitors block vasoconstriction, leading to decreased filtration pressure
C. vasoconstriction is increased with decreased prostaglandin synthesis, leading to decreased renal
blood flow
D. formation of hyaline droplets from ACE inhibitors binding to alpha-2u-globulin
Answer: B
Explanation and Reference:
Angiotensin converting enzyme inhibitors affect vasoconstriction at the arterioles at the glomerus
reducing glomerular flow rate. C&D 9th p 776
237
What mechanism is associated with development of renal tubular lesions common to both
chloroform and tetrafluoroethylene?
A. alpha-2μ-globulin accumulation in the proximal tubule
B. biotransformation by cysteine conjugate ?-lyase
C. proximal tubular reabsorption
D. bioactivation and covalent binding of reactive metabolites to cellular macromolecules
Answer: D
Explanation and Reference:
Chloroform and tetrafluoroethylene are halogenated hydrocarbons and both produce nephrotoxicity
through biotransformation. There is a correlation between the cysteine conjugate and nephrotoxicity,
but this is not the mechanism. Neither is alpha-2μ-globulin nephropathy the mechanism of action with
these two chemicals. "Proximal tubular reabsorption" is a nonsense distractor and is not a specific
mechanism of action. It is normal physiology. C&D 9th, p. 784
238
What agent causes acute renal failure due to deposition of calcium monohydrate crystals in
kidney tubules?
A. d-limonene
B. cisplatin
C. cadmium
D. ethylene glycol
Answer: D
Explanation and Reference:
Metabolism of ethylene glycol leads to the formation of oxalate acid which forms the basis for oxalate
crystals that deposit in the tubules causing damage. C&D 9th p 1208-1211
239
What is the metabolic pathway of propylene glycol?
A. metabolized by alcohol dehydrogenase
B. glucuronidated and eliminated
C. not metabolized
D. reduced by glutathione S-transferase
Answer: A
Explanation and Reference:
Propylene glycol is generally nontoxic with a short half-life in humans. Approximately 55% is
metabolized by alcohol dehydrogenase to lactaldehyde while the remainder is excreted unchanged
by the kidney. C&D 9th p 1213
240
Stimulation of what receptor type is responsible for the toxic action of carbamate insecticides?
A. serotonergic
B. glutamate
C. muscarinic
D. dopamine
Answer: C
Explanation and Reference:
Carbamate insecticides inhibit acetylcholinesterase enzymes, which results in increased acetylcholine
concentrations and subsequent stimulation of muscarinic receptors. C&D 9th, p. 1062, 1069-1070
241
What is the mechanism of the insecticidal activity of organophosphates?
A. inhibition of acetylcholinesterase
B. inhibition of the mitochondrial respiratory chain
C. modification of voltage-sensitive sodium channels
D. anticoagulation
Answer: A
Explanation and Reference:
Inhibition of acetylcholinesterase is the mechanism of organophosphates; the other answers describe
the mechanism for warfarin, pyrethroids and rotenoids, respectively. C&D 7th, pp .884, 889-90
242
Pyrethroids are a class of insecticides that are widely used in agriculture and in homes. The
effects of pyrethroids are mediated through what mechanism?
A. delayed inactivation of sodium channels in cells
B. inhibition of ATPases
C. inhibition of the enzyme cholinesterase
D. delayed activation of potassium channels in cells
Answer: A
Explanation and Reference:
Pyrethroids are insect neurotoxicants that modify the kinetics of voltage-sensitive sodium channels,
which mediate the transient increase in the sodium permeability of the news membrane that underlies
the nerve action potential. This leads to a stable hyperexcitable state. C&D 9th p 1070-1071
243
Insoluble particles that deposit in regions of the nose other than the anterior portion are mainly
cleared by what mechanism?
A. absorption into the blood
B. mucociliary clearance
C. phagocytosis by macrophages
D. exhalation
Answer: B
Explanation and Reference:
In humans, the proximal airway and a portion of the nasal passage are covered by pseudostratified
respiratory epithelium that contains a number of specialized cells included ciliated, mucous, and basal
cells. These cells work together to form a mucous layer that traps and removes inhaled material via
mucociliary clearance. C&D 9th p 798.
244
What mechanism is chiefly responsible for the repair of non-bulky damage to DNA?
A. direct repair
B. base excision repair
C. recombinational repair
D. gene lesion repair
Answer: B
Explanation and Reference:
DNA lesions that do not cause major distortion of the DNA helix typically are removed by base
excision. C&D 9th, p. 507.
245
What is the toxic effect and mechanism of action for venom from the Black Widow Spider?
A. acts in the central nervous system by stimulating the pre-synaptic release of serotonin causing
hallucinations
B. acts at the neuromuscular synaptic junction causing the release of neurotransmitters causing
muscle pain and cramps
C. acts by stimulation of the Purkinje fibers in the heart causing sudden cardiac death
D. acts by stimulating histamine release from mast cells causing an anaphylactic reaction
Answer: B
Explanation and Reference:
Alpha latrotoxin is a presynaptic protein that is toxic only to vertebrates, but nut insects or
crustaceans. It depolarizes neurons by increasing intracellular [Ca2+], and stimulating exocytosis of
neurotransmitters from nerve terminals, with pain and muscle cramps as the major symptoms
observed. C&D 9th p 1293
246
Wasp envenomation (family Vespidae) works primarily in mammals through what mechanism?
A. inhibition of acetylcholinesterase
B. release of histamine from mast cells
C. fibrinolytic enzyme activity
D. hemorrhagic metalloproteinase activity
Answer: B
Explanation and Reference:
The venom of wasps contain mastoparan peptides that release histamine from mast cells. Other
wasp kinins cause immediate paid, vasodilation and increased vascular permeability leading to
edema. C&D 9th p 1297
247
What is the difference in effects between humans and rodents following prolonged elevation of
Thyroid Stimulating Hormone?
A. In rodents, there is an increase in development of thyroid neopasia and follicular tumors. No
effects in humans due to the negative feedback loop of TSH regulation.
B. There is no difference, both result in thyroid neoplasia.
C. There are no effects in rodents, but humans develop a reversible enlargement of the thyroid gland
(goiter).
D. In rodents, there s an increase in the development of thyroid follicular tumors. In humans, a
reversible enlargement of the thyroid gland (goiter).
Answer: D
Explanation and Reference:
TSH increases in rodents commonly result in increased follicular cell hypertrophy, hyperplasia, and
often neoplasia. In humans, increased TSH can result in a reversible increase in the thyroid gland
(i.e., goiter). C&D 9th p327
248
During what stage of pregnancy in women would a drug most likely produce teratogenic effects
on the skeletal system?
A. second trimester
B. at conception
C. first trimester
D. third trimester
Answer: C
Explanation and Reference:
Generally teratogens are most easily detected when administered during the period of organogenesis
(the first trimester), although teratogens can act at any time during development. For animal testing
purposes, xenobiotic exposure is during organogenesis. Hayes 6th pp. 1639 and 1650 and Table
35.6.
249
In healthy individuals, how long does it take the mucociliary escalator to clear inhale particles
deposited in the lower airways the tracheobronchial tree?
A. 24-48 hours
B. >7 days
C. 3-6 days
D. < 1 hour
Answer: A
Explanation and Reference:
Inhaled particles that impact in the mucous surface of the tracheobronchial tree usually are cleared
via the mucociliary escalator with 24 - 48 hours in health individuals. C&D 9th, p. 808.
250
What is the primary factor determining how deeply a gas penetrates into the lung?
A. water solubility
B. molecular weight
C. vapor density
D. vapor pressure
Answer: A
Explanation and Reference:
Water solubility is the major factor in depth of gas penetration in the lung. Highly water soluble gases
do not penetrate farther than nose unless doses are very high. Less water soluble gases penetrate
more deeply into the lung and reach alveoli. C&D 9th, p. 803
251
What critical factor determines the site of deposition within the respiratory tract for an inhaled
particle?
A. shape of the particle
B. respiratory rate
C. particle size
D. tidal volume
Answer: C
Explanation and Reference:
Particle size determines depth of penetration. Larger particle impact earlier. C&D 9th, p. 795, Figure
15-1
252
What is considered to be the mechanistic basis of acrylamide neurotoxicity?
A. segmental demyelination
B. axonal degeneration
C. neurofibrillar aggregates
D. necrosis of basal ganglia
Answer: B
Explanation and Reference:
For the past 3 decades, the dstal axonopathy was believed to be the lesion responsible for
neurological signs and symptoms (e.g., ataxia and numbness in extremities). However, in more
recent studies, neurological symptoms and nerve terminal degeneration were similarly observed in
both short-term and long-term low-dose animals in the rat PNS, while axonal degeneration occurred
only in low-dose studies subsequent to neurological alteration. C&D 9th p 851
253
What is the primary pathological change caused by exposure to n-hexane and carbon disulfide?
A. lymphopenia
B. renal tubular necrosis
C. formation of Heinz bodies
D. axonal degeneration
Answer: D
Explanation and Reference:
Axonal degeneration occurs with neurofilamentous swelling in the early stages from exposure to
carbon disulfide and n-hexane. C&D 9th, pp. 849-851
254
Which immune cell is defined by all of the following characteristics: derived from bone marrow,
produces interferon gamma, plays a major role in cytolysis, and is a cellular component of the innate
immune system?
A. NK cells
B. Kupffer cells
C. Dendritic cells
D. B-cells
Answer: A
Explanation and Reference:
NK cells are a predominant producer of interferon gamma which helps dendritic cells to mature thus
facilitating the innate-adaptive immunity bridge, but they do not directly possess immunologic memory
or produce antibodies. C&D 9th, p.638, 723
255
What is the metabolite of methanol that is associated with disruption of oxidative energy
metabolism resulting in retinal and optic nerve toxicity in humans?
A. metholic acid
B. methyl alcohol
C. formic acid
D. methane
Answer: C
Explanation and Reference:
Humans and primates are highly sensitive to the permanent structural alterations in the optic nerve
and retina induced by methanol due to their limited ability to oxidize formic acid to less toxic
metabolites. C&D 8th, p. 785
256
The small molecule (MW=300) chemical X, has been shown in preclinical models to have potent
allergenic effects, even upon initial contact. Furthermore, in human clinical studies in which it was
administered systemically, subjects reported symptoms of hea
A. contact urticaria
B. allergic contact dermatitis
C. contact chemical burn
D. contact irritation
Answer: B
Explanation and Reference:
Contact irritant reactions are generally proportional to applied dose whereas allergic contact
dermatitis may be elicited by very small doses, although a higher initial dose does increase the
liklihood of sensitization, and doses below a certain threshold may have a cumulative effect in
inducing sensitization. C&D 9th, p. 646
257
Chloracne is a persistent skin disease caused by overexposure to certain halogenated aromatic
hydrocarbons like 2,3,7,8-tetrachlorodibenzo-p-dioxin. What is the prominent target tissue for
chloracnegenic agents within the skin matrix?
A. stratum corneum
B. sweat glands
C. sebaceous (oil) glands
D. subcutaneous adipose
Answer: C
Explanation and Reference:
Halogenated aromatics like dioxin induce progress degeneration of the sebaceous gland cells
including transition to keratinizing cells and hyperkeratosis of in the follicular canal. C&D 9th, pp.
968-69
258
Which ocular tissue is highly vulnerable to systemic, toxicant induced structural and/or functional
damage?
A. cornea
B. retina
C. lens
D. iris
Answer: B
Explanation and Reference:
Alterations in retinal and visual function are among the most common early signs of chemical
exposure damaging the ocular system which has been interpreted as their being particularly
vulnerable to toxic insults. C&D 8th, p.780-781.
259
Xenobiotics such as omeprazole or zidovudine can contribute to a deficiency of vitamin B12.
Subsequently, this deficiency can result in changes in erythroid and myeloid lineages in bone marrow.
These events can result in what type of anemia?
A. sideroblastic anemia
B. iron-deficiency anemia
C. megaloblastic anemia
D. aplastic anemia
Answer: C
Explanation and Reference:
Megaloblastic anemia is characterized by both morphological (e.g. pancytopenia, changes in red
blood cell shape) and biochemical (e.g., increased serum iron, hypokalemia) changes in peripheral
blood cells. Vitamin B12 is necessary to maintain synthesis of thymidine for incorporation into DNA
to support hematopoiesis. C&D 8th, p.530-531, Table 11-2, 11-3.
260
The oral anticoagulant, warfarin, modulates hemostasis by interfering with vitamin K metabolism.
What is the actual cause of the resulting functional deficiency in Vitamin K that occurs from this
interference?
A. decreased vitamin K epoxide levels
B. decreased clotting factors IX and X
C. decreased fibrogen levels
D. increased fibrinolytic activity
Answer: B
Explanation and Reference:
Factors IX and X are dependent on Vitamin K for their complete synthesis, and oral anticoagulants
interfere with Vit. K synthesis by by preventing the reduction of Vitamin K epoxide (resulting in its
accumlation) and causing a resulting functional deficiency in Vitamin K. C&D 8th, p. 546-547, Table
11-10.
261
What circulating biomarker, considered to be predominately expressed in cardiomyoctes, is used
to detect myocardial injury?
A. creatine kinase-MM (CK-MM)
B. C-reactive protein (CRP)
C. B-type natriuretic factor (BNP)
D. cardiac troponins T and I (cTnT and cTnI)
Answer: D
Explanation and Reference:
Cardiac troponins are of absolute myocardial specificity and generally undetectable in healthy
persons and their elevation is regarded as a clinical "gold standard" for diagnosis of acute myocardial
infarction. C&D 8th, p.818
262
What liver cell type is most prone to the toxic side effect of Vitamin A due to site-selective
storage, accumulation and engorgement at high levels?
A. stellate cells
B. bile duct cells
C. Kupffer cells
D. hepatocytes
Answer: A
Explanation and Reference:
The stellate cells actively extract and store vitamin A. Early responses to high-dose vitamin A therapy
are stellate cell engorgement, activation, increase in number, a protrusion into the sinusoid.
Hepatocytes may be secondarily affected, but the initial insult is to the stellate cells. Kupffer cells, or
the liver macrophages, are not involved in vitamin A toxicity. Bile duct cells are not affected by vitamin
A.C&D 8th, p.650, table 13-3.
263
What is the primary function for Kupffer cells in the liver?
A. play a major role in the formation of bile
B. provide nutrient homeostasis
C. macrophages that ingest and degrade particulate matter
D. support the cords of hepatocytes in the liver
Answer: C
Explanation and Reference:
Kupffer cells are the resident hepatic macrophages lining the lumen of the liver sinusoid. They are
also a major source of cytokines and can act as antigen presenting cells. C&D 8th, p. 641
264
Iron (Fe) is an essential mineral but overdoses result in damage to hepatocytes in which region of
the liver?
A. midzonal
B. periportal
C. centrilobular
D. bile canuliculi
Answer: B
Explanation and Reference:
The zone 1 hepatocytes both preferentially accumulate iron and since they are closer to the oxygenrich
blood entering the sinusoid and the higher oxygen concentration faciliates lipid peroxidation.
C&D 8th, p. 650, Table 13-3
265
What region of the kidney is the most common site for xenobiotic-induced kidney damage as a
result of selective accumulation and susceptibility to ischemic injury?
A. proximal tubule
B. macula densa
C. glomerulus
D. distal tubule
Answer: A
Explanation and Reference:
While the glomerulus is the initial site of chemical exposure within the kidney, the proximal tubule is
the most common site for kidney damage. This is partly due to the selective accumulation of
xenobiotics in this region of the nephron - both due to segmental differences in distribution of
transporters and xenobiotic metabolizing enzymes, as well as being more susceptible to ischemic
injury compared to distal nephron segments. C&D 8th, p. 674
266
What is the primary site of kidney injury resulting from exposure to chloroform?
A. loop of Henle
B. distal tubule/collecting duct
C. proximal tubule
D. glomerulus
Answer: C
Explanation and Reference:
Chloroform is transformed to a toxic metabolite by P450 enzymes within the proximal tubule. C&D
8th, p. 681-682
267
Which organ system is most susceptible to cisplatin toxicity?
A. heart
B. CNS
C. liver
D. kidney
Answer: D
Explanation and Reference:
The kidney is a primary site of accumulation of cisplatin. Toxic effects on the kidney include acute
and chronic renal failure. C&D 8th p. 686
268
Clinical chemistry profiles that show large increases in alanine aminotransferase (ALT), sorbitol
dehydrogenase (SDH) and aspartate aminotransferase (AST) activities commonly relate to which
target organ?
A. kidney
B. liver
C. heart
D. brain
Answer: B
Explanation and Reference:
ALT, AST and OCT are present in hepatocytes and are released into the general circulation following
liver disease or injury. They can be used a biomarkers. C&D 9th pp. 732-733.
269
What metabolic pathway protects tissue and cellular function from damage by highly electrophilic
metabolites of xenobiotics?
A. amino acid conjugation
B. glutathione conjugation
C. glucuronide conjugation
D. sulfate conjugation
Answer: B
Explanation and Reference:
Unlike glucuronidation, sulfation and amino acids that conjugate with nucleophiles, glutathione is a
free radical scavenger the conjugates with electrophiles. This mechanism is a major detoxification
pathway preventing damage to important cellular components caused by reactive oxygen species.
However, there are instances where glutathionylation can enhance the toxicity of a metabolite.
Hayes 6th pp. 186-187; C&D 9th, pp. 361-373.
270
What metabolic reaction is associated with glutathione transferase?
A. conjugation
B. hydrolysis
C. reduction
D. oxidation
Answer: A
Explanation and Reference:
Glutathione transferase is required for conjugation reactions. C&D 9th, p. 201
271
high apparent volume of distribution is indicative that a xenobiotic predominantly remains in
what physiologic compartment?
A. total body water
B. adipose tissue
C. cerebrospinal fluid
D. intracellular fluid
Answer: B
Explanation and Reference:
The apparent volume of distribution (Vd) of a xenobiotic is an estimate of the total blood and bloodequivalent
volume in which a compound is equally distributed . Xenobiotics limited to the vascular
space would have a small Vd (equal to total blood volume (TBV)); whereas, xenobiotics sequestered
in extravascular tissues, such as fat would have high Vds. The Vd for any compound can be
calculated knowing the tissue:blood partition coefficient (Ptb) and TBV. Vd = TBV + (Ptb x TBV),
where Ptb x TB is the blood-equivalent volume. C&D 9th pp.404-405, Fig 7-4 and Table 7-2.
272
Elimination half-life (T1/2) of a toxicant increases in proportion to which two pharmacokinetic
parameters?
A. absorption and hepatic blood flow
B. hepatic blood flow and clearance
C. dose and absorption
D. clearance and volume of distribution
Answer: D
Explanation and Reference:
Elimination half-life (T1/2) is proportional to volume of distribution and clearance. C&D 9th, p. 406
273
Rhabdomyolysis is a potential adverse response with statin drugs. What is rhabdomyolysis?
A. liver failure due to cholesterol deficiency
B. primary muscle damage which causes secondary kidney failure
C. toxicity to the small intestine
D. a direct toxic effect on the lungs which causes secondary muscle damage
Answer: B
Explanation and Reference:
Rhabdomyolysis is a condition in which damaged skeletal striated muscle breaks down rapidly.
Breakdown products of damaged muscle cells are released into the bloodstream; some of these,
such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure. C&D 9th,
p. 185
274
What is the primary mechanism of hypersensitivity to peanuts?
A. Type 1 hypersensitivity
B. Type 4 hypersensitivity
C. Type 3 hypersensitivity
D. Type 2 hypersensitivity
Answer: A
Explanation and Reference:
Peanut allergies illicit Type 1 hypersensitivity via increases in IgE and compliment. C&D 9th, p.1353,
646
275
What factors enhance the metabolic activation of polycyclic aromatic hydrocarbons, a family of
pro-carcinogenic carcinogens, to their ultimate carcinogenic form?
A. polymorphism of the NAT2 (N-acetyltransferase) conjugating enzyme
B. the inhibition of CYP3A4/5 by a constituent of grapefruit juice
C. the presence of CYP3A4/5 isoforms in the intestine and kidney
D. the presence of isoforms such as CYP1A1/2, CYP1B1, and CYP2S1
Answer: D
Explanation and Reference:
Polyaromatic hydrocarbons bind to the aryl hydrocarbon receptor that specifically induces CYP1A1/2,
CYP1B1, and CYP2S1 all of which act to activate the pro-carcinogen PAH to the active carcinogen;
the other answers are activated by other receptors and represent enzyme systems not involved in
PAH activation. C&D 9th, p. 676-677
276
What is the principle application of PBPK models in toxicology?
A. interpret gene array data
B. assess structure activity relationship between a group of chemicals
C. predict the target tissue dose of the toxic parent chemical or its reactive metabolites
D. determine the appropriate species for testing a pesticide ingredient
Answer: C
Explanation and Reference:
Only one answer is correct for PBPK models which extrapolate observed kinetic behavior from
laboratory animals to humans to predict dose at the target tissue. C&D 9th, p. 410
277
What are the two major enzymes that are known to be directly inhibited by lead?
A. d-aminolevulinate synthase, porphobilinogen deaminase
B. d-aminolevulinate dehydrogenase, ferrochelatase
C. porphobilinogen deaminase, uroporphyrinogen III cosynthase
D. urophorphyrinogen decarboxylase, porphobilinogen deaminase
Answer: B
Explanation and Reference:
Among the possible answers there are only two which are directly inhibited by lead. C&D 9th, p.
1124-1125
278
If a toxicant remains in the blood due to extensive protein binding and is not taken up by tissues,
the volume of distribution will approximate what physiologic compartment?
A. extracellular fluid volume
B. total body water volume
C. cellular fluid volume
D. blood volume
Answer: D
Explanation and Reference:
Volume of distribution is the quotient of dose and the concentration in plasma. Thus, if the toxicant
remains in the blood due to extensive protein binding and is not taken up by tissues, the volume of
distribution will be approximately that of the blood volume. C&D 9th, pp. 404-405
279
What is the initiating mechanism behind induction of torsade de pointes and resulting cardiac
toxicity?
A. inhibition of IKr, a potassium current
B. inhibition of INa, a sodium current
C. inhibition of ICl, a chloride current
D. inhibition of ICa, a calcium current
Answer: A
Explanation and Reference:
The rapidly and slowly activating components of the delayed rectifier potassium current, Ikr and Iks,
seem to have the most influential role in determining the duration of the action potential and thus the
QT interval. Sodium and calcium channels may play secondary roles in arrhythmias such as torsades
de pointes. Thus, a drug which inhibited the Ikr component would prolong the QT interval. ICH
S7B, Section 1.2, May 2005; C&D 9th pp. 927-929.
280
What is the characteristic hallmark of the initiation stage in the carcinogenesis process?
A. conversion of benign neoplastic lesions into neoplastic cancer
B. single event that is sufficient for neoplastic formation
C. rapid, irreversible process resulting in carcinogen-induced mutational event
D. selection of clonal expansion of initiated cells to produce a preneoplastic lesion
Answer: C
Explanation and Reference:
The first step in tumor formation is irregular cell growth that occurs from disruption in regulatory
mechanisms controlled by genetic components. C&D 8th, p. 397
281
What genotoxic agent causes pyrimidine dimer formation from thymine or cytosine bases in
DNA?
A. ultraviolet radiation
B. ionizing radiation
C. 9-aminoacridine
D. endogenous oxygen radicals
Answer: A
Explanation and Reference:
Pyrimidine dimers are molecular lesions formed from thymine or cytosine bases in DNA via
photochemical reactions. C&D 8th, p. 450, Figure 9-2
282
What types of molecules are commonly identified using two-dimensional polyacrylamide gel
electrophoresis?
A. proteins
B. DNA adducts
C. nucleotide mutations
D. cDNA
Answer: A
Explanation and Reference:
2-D electrophoresis separates the molecules in a direction 90 degrees from the first. Since it is
unlikely that two molecules will be similar in two distinct properties, proteins are more effectively
separated in 2-D electrophoresis than in 1-D electrophoresis. Hayes 6th, p. 305
283
What type of DNA damage is caused by ionizing radiation?
A. double-strand breaks
B. intrastrand cross links
C. unscheduled DNA synthesis
D. alkylation
Answer: A
Explanation and Reference:
Ionizing radiation (x-rays, gamma rays, alpha particles) cause a wide range of DNA damage but
predominantly single-and double-strand breaks in addition to base damages. Radiation is not directly
correlated with unscheduled synthesis, alkylation, or cross-linking. C&D 8th, p. 450, figure 9-2
284
What is a key attribute of allergic contact dermatitis?
A. it is caused by a single exposure to the allergen
B. it is mediated by sensitized B lymphocytes
C. the skin manifestation is immediate in nature
D. it is caused by a single exposure to the allergen
Answer: D
Explanation and Reference:
Allergic contact dermatitis is typically a DTH reaction. C&D 8th, p.574, 845-848
285
What is the cause of Vitamin A hepatotoxicity?
A. depletion of hepatic glutathione (GSH) levels
B. uptake and accumulation within stellate liver cells
C. activation of cytochrome P450 enzymes
D. formation of free radicals that initiate lipid peroxidation
Answer: B
Explanation and Reference:
Stellate cells preferentially extract and store this vitamin. C&D 8h, p. 650, Table 13-3
286
What is the primary psychoactive analyte of marijuana?
A. tetrahydrocannabinol
B. hydroxycannabidiol
C. trihydrocannabinol
D. cannabidiol
Answer: A
Explanation and Reference:
This is the compound that produces most of the characteristic psychoactive effects of smoked
marijuana. G&G 11th, p. 622-623; C&D 9th 685-686.
287
By what action does the antineoplastic drug methotrexate cause ocular toxicity?
A. anti-metabolite
B. oxidative stress
C. mitotic inhibitor
D. alkylation
Answer: A
Explanation and Reference:
Methotrexate is a folate antagonist (anti-metabolite) that inhibits dihydrofolate reductase required for
thymidylate and purine synthesis (G&G 11th, p. 1335-1336). Because the retina has a high metabolic
rate and its choroidal circulation is unique to the eye, it is vulnerable to various cytotoxic drugs,
including methotrexate. Alkylating agents include cisplatin; and docetaxel is a mitotic inhibitor.
Oxidative stress is a general cause of cellular dysfunction but is not the specific mechanism of action
in this case (C&D 9th, p. 89).
288
What metal causes acrodynia (pink disease), a disease characterized by erythema of the
extremities, chest and face with photophobia, diaphoresis, anorexia, tachycardia, and either
constipation or diarrhea in people?
A. zinc
B. inorganic mercury
C. lead
D. copper
Answer: B
Explanation and Reference:
Acrodynia was described in children exposed to inorganic mercury in teething powder and diaper
disinfectants. C&D 9th, p. 1129
289
What is the proposed mechanism of chronic pulmonary toxicity of beryllium after repeated
inhalation exposure in humans?
A. foreign-body reaction
B. non-immune inflammatory reaction
C. Type IV cell-mediated hypersensitivity reaction
D. antigen-specific IgE allergenic reaction
Answer: C
Explanation and Reference:
Chronic beryllium disease involves antigen-stimulated, cell-mediated immune response. C&D 9th, p.
691,1118
290
What is the common and predominant CYP450-dependent metabolite produced in the metabolic
pathways of both trichloroethylene (TCE) and tetrachloroethylene (PERC)?
A. trichloroethanol (TCOH)
B. trichloroacetic acid (TCA)
C. trichloroethanol (TCOH) glucuronide
D. dichloroacetate (DCA)
Answer: B
Explanation and Reference:
Although the metabolic pathways are slightly different, the common metabolite for both TCE and
PERC is trichloroacetic acid (TCA). TCOH and TCOH-glucuronide are associated with TCE and not
PERC. For both compounds, some TCA is converted to DCA, but DCA should not be considered a
common metabolic pathway for these two compounds. C&D 9th, p. 1181-1183, 1187
291
Survivors of moderate to severe paraquat poisoning may still die from progressive dysfunction of
what organ?
A. kidney
B. liver
C. pancreas
D. lung
Answer: D
Explanation and Reference:
This is due to proliferation of the fibroblast in the lung leading to intensive fibrosis. C&D 9th, p. 1084-
1085
292
What biochemical phenomena is characteristic of the periodic tremoring effects induced by
insecticides of the DDT (dichlorodiphenyltrichloroethane) class?
A. blockage of gamma-aminobutyric acid (GABA)-induced uptake of chloride ions by neurons in CNS
B. inhibition of acetylcholinesterase in the central nervous system (CNS)
C. inhibition of acetylcholinesterase at the neuromuscular junction
D. prolongation of the negative afterpotential in depolarized nerves following repetitive sensory
stimulation
Answer: D
Explanation and Reference:
This is the mechanism of action of DDT; the other answers describe mechanisms for different types
of pesticides. C&D 9th, p. 1073-1074
293
What is the antidote recommended for cyanide poisoning?
A. fomepizole
B. sodium nitrate/sodium thiosulfate
C. N-acetylcysteine
D. activated charcoal/water
Answer: B
Explanation and Reference:
The antidote, sodium or amyl nitrites, convert hemoglobin to methemoglobin where methemoglobin
competes with cytochrome oxidase for cyanide forming cyanmethemoglobin. Co-administration of
sodium thiosulfate converts free cyanide present in the blood to thiocyanate, which is eliminated in
the urine. As free cyanide in the blood decreases, additional cyanide dissociates from
cyanmethemoglobin and is eliminated. Fomepizole (4-methylpyrazole) is an antidote for ethylene
glycol poisoning; N-acetylcysteine has been shown to be an effective antidote for acetaminophen
toxicity. Activated charcoal is a general antidote for orally ingested toxins and is not specific for any
particular poison. Hayes 6th, pp. 22, 653; C&D 9th p. 1542.
294
What is the commonly used serum biomarker for nicotine exposure?
A. cotinine
B. cadmium
C. norcotinine
D. nicotine-N'-oxide
Answer: A
Explanation and Reference:
Although cadmium may be present in tobacco smoke, it is not a biomarker for nicotine exposure.
Nocotinine and nicotine-and N'-oxide are nonsense distractors. Hayes 6th pp. 1975-1976.
295
Interception is the primary mechanism for pulmonary deposition of fibers having a large aspect
ratio. Under what conditions does interception occur?
A. inertia drives the fiber into an airway bifurcation or surface
B. Brownian motion forces the fiber into contact with an airway surface
C. the airflow slows and the fiber settles out due to gravity
D. the trajectory of the fiber brings it near enough to an airway surface to touch it
Answer: D
Explanation and Reference:
This is how certain fibers are deposited in the respiratory tract. C&D 8th, p. 703
296
What are the toxicity characteristics of ultrafine particles (<0.1 micron) when compared to fine
particles (2.5 microns) ?
A. are similar to nanoparticles in that they can penetrate deep into the lung, whereas fine particles
cannot reach this region
B. Ultrafine particles are lower in mass but higher in number, and thus provide substantial reactive
partcile surface to interact with biological substances, or they can more easily penetrate through the
lung surface and impart their effects systematically.
C. are more toxic and do not activate alveolar macrophages
D. have reduced toxicity because they contribute almost negligible mass
Answer: B
Explanation and Reference:
UFPs are higher in number than mass, so there is more total particle surface area to participate in
biological interations. The fractional deposition of UFPs into the alveolar region of the lung is higher
than for fine particles. C&D 9th Fig 29-14 and p 1488-1489
296
What is the only in vitro test that has been validated and accepted by regulatory bodies as an
animal alternative model for testing requirements for pesticide registration?
A. photosensitization
B. genotoxicity
C. primary skin irritation
D. eye irritation
Answer: C
Explanation and Reference:
There is a battery of basic testing requirements for pesticide registration most of which involve direct
animal testing (genotoxicity studies can be done using bacteria, cell cultures, and fruit flies). With
those exceptions, the only in vitro test currently validated and accepted by regulatory bodies is an in
vitro test for primary skin irritation.C&D 9th edition Table 22-7 (text in footnotes), p 1061
297
What is the mechanism, location of effect and symptoms of the outdoor air pollutant sulfur dioxide
(SO2)?
A. potent irritant and oxidant primarily affecting the deep lung where injury results in pulmonary
edema
B. oxidative stress in the entire respiratory system affecting type 2 epithelial cells resulting in
excessive mucous secretion
C. water soluble sensory irritant gas primarily affecting the upper airways causing
bronchoconstriction and mucous secretion
D. chemical asphyxiant exerting its effect in the distal lung by irreversibly binding to hemoglobin to
form sulfoxyhemoglobin
Answer: C
Explanation and Reference:
Sulfur dioxide is an irritant gas in the upper airways and causes bronchoconstriction. C&D 8th, p.
1250
298
What is the major adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)
reductase inhibitors (statin drugs)?
A. body weight gain
B. impaired (blue) vision
C. myopathy
D. hypertension
Answer: C
Explanation and Reference:
Myopathy is the major effect of clinical significance in statin use. G&G 11th, p. 948, 951-952; C&D 9th
pp. 185-186, Fig. 5-16.
299
What is the mechanism by which penicillin causes thrombocytopenia?
A. It binds to GP IIb/IIIa receptor and produces a conformational change which permits naturally
occurring antibodies to bind to and cause clearance of platelets.
B. It initiates an exposure of a neoepitope on a platelet membrane glycoprotein which then elicits an
antibody reaction.
C. It has been observed to be associated with acquired thrombotic thrombocytopenia purpura (TTP)
in which an antibody is developed against the von Willebrand Factor-cleaving (vWF) protease.
D. It acts as a hapten and by binding to a platelet membrane component produces an immune
response to that component that is specific to penicillin.
Answer: D
Explanation and Reference:
Pencillin acts as a hapten, binding to platelet membrane components and elicits a drug-specific
response that increases platelet clearance and causes the clinical effect of bleeding. C&D 8th, p. 544,
Table 11-9.
300
What is the mechanism by which methylmercury accumulates in the mammalian central nervous
system?
A. transport of the cysteine conjugate of methylmercury across the endothelial cells of the blood
brain barrier
B. methylation of inorganic mercury by brain methyltransferases
C. low affinity for sulfhydryl groups
D. conjugation of methylmercury to glutathione
Answer: A
Explanation and Reference:
The methylmercury-cysteine conjugate mimics methionine to cross the blood-brain barrier.
Methylmercury has a high affinity for sulfhydryl groups. Conjugation of methylmercury to glutathione
prevents accumulation in the brain by enhancing elimination. Once methylmercury crosses the
blood-brain barrier, the act of demethylation to the inorganic form traps mercury in the brain. C&D
9th, p. 845
301
What is the major human health effect of methyl mercury toxicity?
A. motor dysfunction (parathesias, ataxia, spasticity)
B. inflammation of the gums (gingivitis)
C. salivation, insomnia, loss of appetite
D. emotional lability (irritability, excitability, withdrawal)
Answer: A
Explanation and Reference:
Clinical manifestations of neuortoxicity include parethesia (numbness and tingling sensation around
the mouth, lips), ataxia (clumsy, stumbling gait, difficulty swallowing and articulating words),
neurasthenia (sensation of weakness), vision and hearing loss, spastacity and tremor C&D 9th p
1128
302
What are the target systems of toxicity affected by naphthalene?
A. ocular and respiratory
B. endocrine and immunological
C. hepatic and renal
D. neurologic and cardiovascular
Answer: A
Explanation and Reference:
In rodent studies, naphthalene metabolites have been shown to ablate bronchiolar secretoglobin
cells, and bind covalently to cellular proteins in the respiratory tract. Accidental expsoure to
naphthalene results in cortical cataracts (via the metabolite 1,2-dihydroxynaphthalene) and retinal
degeneration C&D 9th p 874, 878 Table 17-1
303
What is the rate limiting step in the metabolism of ethylene glycol?
A. conversion of glyoxylic acid to glycine
B. conversion of glycoaldehyde to glycolic acid
C. conversion of glycolic acid to glyoxylic acid
D. conversion of glyoxilic acid to oxalic acid
Answer: C
Explanation and Reference:
The rate limiting step is conversion of glycolic acid to glyoxylic acid by glycolate oxidase. The
conversion of glyoxylic acid to glycine (via vitamin B6) and the conversion of glycoaldehyde to glycolic
acid are not rate limiting. Glycolate oxidase readily converts glyoxylic acid to oxalic acid. C&D 9th p
1209, figure 24-11
304
What is the mechanism of action by which pyrethroid Type I and II esters exert their toxic effects?
A. modification of the gating kinetics of voltage-sensitive sodium channels
B. reversible inhibition of acetylcholinesterase
C. interaction with the gamma aminobutyric acid (GABA)-receptor complex
D. irreversible inhibition of acetylcholinesterase
Answer: A
Explanation and Reference:
This is the mechanism of action of pyrethroids; the other answers describe mechanisms for different
types of pesticides. C&D 9th p 1070
305
For the safety determination of a Food Contact Substance (FCS), the US Food and Drug
Administration (FDA) recommends the submission of a food additive petition for an estimated
exposure greater than what concentration?
A. 0.5 ppm
B. 0.05 ppm
C. 1 ppm
D. 0.1 ppm
Answer: C
Explanation and Reference:
FDA recommends submission of a food additive petition for estimated exposure greater than 1 ppm.
C&D 9th p 1334
306
Hepatotoxicity has been associated with ingestion of high doses of what metal?
A. zinc
B. mercury
C. copper
D. selenium
Answer: C
Explanation and Reference:
Ingestion of copper salts, most frequently copper sulfate, may produce hepatic necrosis and death
C&D 9th p 1133. Acute selenium toxicity can result in pulmonary edema and cardiovascular collapse
(C&D p 1138). Ingestion of high doses of zinc can result in gastrointestinal distress and diarrhea
(C&D 9th p 1139). Ingestion of mercury targets the brain and kidneys (C&D 9th p 1128).
306
What has been identified as a toxicological endpoint associated with ethylene glycol and methanol
intoxication?
A. damage of peripheral axons
B. retinal formation of oxalate crystals
C. hemorrhagic gastritis
D. metabolic acidosis
Answer: D
Explanation and Reference:
Only metabolic acidosis is common to both compounds. C&D 9th p 1206-1211
307
Exposure to what solvent has been associated with elevated blood carboxyhemoglobin levels?
A. methylene chloride
B. chloroform
C. benzene
D. toluene
Answer: A
Explanation and Reference:
Methylene chloride is metabolized to carbon monoxide in the mixed function oxidase pathway.
Carbon monoxide binds to hemoglobin forming carboxyhemoglobin. C&D 9th p 1191-1192 Fig 24-7
308
What pesticide class has a primary adverse effect of paresthesia following dermal occupational
exposure(characterized by burning, tingling, and stinging sensations)?
A. avermectins
B. organophosphates
C. pyrethroids
D. organochlorines
Answer: C
Explanation and Reference:
This is the primary effect from occupational exposure to pyrethroids. C&D 9th p 1073
309
What exposure pathway provided the high concentrations of radioactive iodine to children following
the Chernobyl disaster?
A. consumption of contaminated green leafy vegetables
B. exposure to precipitation fallout from rain and snow
C. consumption of fish and shellfish that bioconcentrated iodine
D. consumption of milk from cows grazing on contaminated pastures
Answer: D
Explanation and Reference:
Radioactive Plutonium 239, Strontium 90, Cesium 134 and 137, and Iodine 131 were released from
the accident. Because iodine is taken up by the thyroid, there was a dose response relationship
observed between Iodine 131 dose to the thyroid received in childhood within 15 years after the
accident, and thyroid cancer risk. The primary source of the radioactive iodine was milk from cows
grazing on contaminated pastures. C&D 9th p 1269, Hayes 6th p. 898
310
What is the primary target organ for toxicity following exposure to ochratoxin A?
A. the brain
B. the spleen
C. the heart
D. the kidney
Answer: D
Explanation and Reference:
Ochratoxin A mainly causes endemic nephropathy and carcinogenesis by inhibiting the enzymes
involved in phenylalanine metabolism, including phenylalanine-tRNA synthetase. It also inhibits
mitohondrial ATP production and stimulates lipid peroxidation. C&D 9th p 1350
311
Measurement of what metal in hair can be used as a reliable indicator of exposure?
A. lead
B. selenium
C. cadmium
D. mercury
Answer: D
Explanation and Reference:
Hair levels of mercury have been found to be a reliable measure of exposure to methylmercury. For
most other metals, hair is not a reliable tissue for measuring exposure due to concerns with external
contamination that complicate analysis. C&D 8th, p. 985.
312
What is the primary target organ or system of toluene toxicity?
A. kidney
B. liver
C. central nervous system
D. hematopoietic system
Answer: C
Explanation and Reference:
The CNS is the primary target organ of toluene and other alkylbenzenes, due to its lipophilicity. It is
commonly misused due to alcohol-like effects of euphoria and excitation. Toluene intoxication can
lead to motor incoordination, dizziness, relaxation, lightheadedness, and hallucinations. Prolonged
abuse ("huffing") can lead to apathy, memory dysfunction and dimished visuospatial skills. Cardiac,
renal and hepatic toxicities as well a getal alcohol-like syndrome have occasionally been reported.
C&D 9th p 1201
313
What is the primary mammalian target organ system adversely affected by the most commonly used
insecticides?
A. endocrine system
B. respiratory system
C. cardiovascular system
D. nervous system
Answer: D
Explanation and Reference:
The CNS is the primary target for the most commonly used classes of pesticides (organophosphates
and carbamates). The CNS of insects is highliy developed and not unlike that of mammaels, and
there are similarities. C&D 9th p 1061, Table 22-8
314
What rodenticide gets hydrolyzed in the stomach and produces a gas that causes necrosis of the
gastrointestinal tract and injury to the liver and kidney?
A. warfarin
B. zinc phosphide
C. sodium fluroacetate
D. strychnine
Answer: B
Explanation and Reference:
Zinc phosphide ingestion leads to formation of phosphine gas (PH3) upon readtions with water or
acids. C&D 9th p 1093
315
What toxicological consequence has been reported following sub chronic exposure to DEET (N, NDiethyl-
m-toluamide)?
A. alpha 2μ-globulin induced nephropathy in male rats
B. chloracne on the face and upper back in humans
C. reproductive toxicity of failure for midline and palate closure in rabbits
D. paralysis in rodents
Answer: A
Explanation and Reference:
DEET does not pose a significant health concern to humans when used as directed. Subchronic
toxicity studies in various species did not reveal major toxic effects, with the exception of renal lesions
in male rats, which are considred to be unique to male rat physiology (α2μ-globulin induced
nephropathy). C&D 9th p 1082
316
Terrestrial environmental exposure to organic tin compounds is associated with the use of what?
A. paint
B. feed additives
C. machinery grease
D. fungicides
Answer: D
Explanation and Reference:
The key phrase is "terrestrial envrionment." Triphenyltin is used as a fungicide. Tributyl tin was used
as an antifouling agent in marine paints. C&D 9th p 1091
317
How is the dose response relationship of a vitamin or trace element described?
A. Both low and high doses exhibit adverse effects.
B. Deficiency and excessive doses always demonstrate the same toxicities.
C. At very low doses, there are no adverse effects on living organisms.
D. Each vitamin and trace element has a unique dose response curve.
Answer: A
Explanation and Reference:
Hormesis is the characteristic dose-response curve of vitamins and trace minerals. This is a "Ushaped"
curve where too little or too much of the compound in question may lead to toxicity.Example
of a U-shaped curve with Vitamins and minerals. C&D 9th p 40 Fig 2-11
318
What are the four key steps in the risk assessment process?
A. research, dose-response assessment, exposure assessment, risk communication
B. hazard identification, dose-response assessment, exposure assessment, risk characterization
C. research, hazard assessment, exposure calculation, risk characterization
D. hazard identification, exposure assessment, risk characterization, risk management
Answer: B
Explanation and Reference:
Only the correct answer contains the four defined steps of risk assessment. C&D 9th p 128 Fig 4-1
319
What electrocardiogram (ECG) change identifies a risk of chemical-induced torsades de pointes?
A. prolonged QT interval
B. inverted T wave
C. P wave notching
D. elevated R wave amplitude
Answer: A
Explanation and Reference:
Torsades de Pointes occurs with an average increase in QT interval by 200 msec. This can be a life
threatening ventricular arrhythmia and has been the focus of drug discovery and development in the
last 2 decades. C&D 9th p 927
320
What is a chemotherapeutic compound commonly associated with myocardial toxicity?
A. doxorubicin
B. arabic gum
C. calcium acetate
D. carbon disulfide
Answer: A
Explanation and Reference:
Doxorubicin has high affinity for cardiolipin, a phospholipid found on the inner mitochondrial
membrane, where NADH dehydrogenase converts the drug to a semiquinone radical. In the presence
of oxygen, this radical is responsible for the generation of ROS, which then may peroxidize
unsaturated membrane lipids and initiate myocardial cell injury. C&D 9th p 935
321
What is the most common initial adverse hepatic effect of valproic acid?
A. canalicular cholestasis
B. fatty liver
C. hepatocyte necrosis
D. hepatoma
Answer: B
Explanation and Reference:
Valproic acid effects fatty acid metabolism in liver mitochondria, via the depletion of L-carnitine. C&D
9th p 1547
322
Co-exposure to what compound or element would enhance the hepatotoxic potential of high
therapeutic doses of the analgesic agent, acetaminophen?
A. mercury
B. ozone
C. ethanol
D. lead
Answer: C
Explanation and Reference:
Metabolism of acetaminophen by CYP2E1 results in a potentially toxic metabolite that is normally
detoxified by conjugation with glutathione and excreted as a mercapturate. Ethanol also induces
CYP2E1, and concurrent use may result in hepatotoxicity. C&D 9th p 1544
323
What is the mechanism of ocular toxicity associated with digitoxin attributed to?
A. formation of reactive intermediates
B. lipid peroxidation
C. inhibition of Na+/K+/-ATPase
D. inhibition of P-glycoprotein
Answer: C
Explanation and Reference:
The retina has the highest concentration of Na+/K+/-ATPase anywhere in the eye and inhibition of
this enzyme is the primary target of digitalis. C&D 9th p 891
324
Exposure to benzene has been causally linked with development of what myeloid leukemia type?
A. acute myelogenous leukemia
B. chronic myelogenous leukemia
C. chronic lymphocytic leukemia
D. non-Hodgkin's lymphoma
Answer: A
Explanation and Reference:
There is strong evidence from epidemiological studies that high-level benzene exposures result in an
increased risk of acute myelogenous leukemia. C&D, 8th ed., pp 1063.
325
Liver damage through lipid peroxidation been reported following exposure to what environmental
compound?
A. carbon monoxide
B. sulfur dioxide
C. natural gas
D. 1,2-dichlorobenzene
Answer: D
Explanation and Reference:
A primary target for lipid peroxidation by dichlorobenzene is the liver cell membrane. Hayes 6th p
1463
326
How is the nephrotoxicity associated with amino glycoside antibiotics characterized?
A. renal papillary necrosis with interstitial nephritis
B. glomerular sclerosis with interstitial fibrosis
C. renal proximal tubular degeneration/necrosis
D. increased medullary fibrosis
Answer: C
Explanation and Reference:
Nephrotoxicity occurs in 10-50% of patients treated with aminoglycoside antibiotics. Histologically,
the target is the proximal renal tubular cell leading to necrosis. C&D 9th p 787
327
What has been characterized as the ultimate carcinogen formed from the polycyclic aromatic
hydrocarbon, benzo(a)pyrene?
A. benzo(a)pyrene-7,8-epoxide
B. benzo(a)pyrene-9,10-diol
C. benzo(a)pyrene-7,8-diol-9,10-epoxide
D. benzo(a)pyrene-7,8-diol
Answer: C
Explanation and Reference:
The ultimate carcinogen is the benzo(a)pyrene-7,8-diol-9,10-epoxide, formed following 3 separate
reactions, two involving CYP450 and one requiring epoxide hydrolase. The other compounds are not
important metabolistes of benzo(a)pyrene. C&D 9th p 447, Fig 8-10b
328
In the context of environmental studies, to what does a trophic level transfer of contaminants refer?
A. exposure through food web
B. a traditional method used to assess changes in tissue concentrations
C. chemical transport through different geological strata
D. the bioavailability of a chemical
Answer: A
Explanation and Reference:
A trophic system is a food web, where individuals in a community can feed on different species
depending on their life stage, seasons and relative abundancies of prey species. C&D 9th p 1451
329
The adrenal cortex has been shown to be particularly sensitive to the toxic effects of many
xenobiotics. What does this sensitivity primarily result from?
A. Adrenal cortical cells having impaired DNA repair enzyme pathways which result in higher
accumulations of mutations than other tissues as the animal/person ages.
B. Levels of metabolic enzymes within the adrenal cortical cells are lower than most other cells
types, making the tissue more susceptible to the toxic effects of xenobiotics.
C. The high lipid content of adrenal cortical cells with high levels of unsaturated fatty acids results in
greater accumulation of lipophilic xenobiotic compounds and thus higher tissue exposures than many
organs.
D. Dendritic cells present in this region of the adrenal gland have particularly tight connections to the
adrenal cortical cells, resulting in elevated hypersensitivity reactions.
Answer: C
Explanation and Reference:
Primary sensitivity results from high lipid content and high levels of unsaturated fatty acids. C&D 9th p
981
330
When describing wildlife exposure to contaminants, what is meant by "biologically effective dose"?
A. the difference between external dose and internal dose
B. the amount that actually reaches cells, sites or membranes where adverse effects occur
C. the external dose due to direct contact
D. the total dose that has been effectively biotransformed
Answer: B
Explanation and Reference:
The biologically effective dose is the amount of a compound that actually reaches cells, sites, or
membranes where adverse effects occur. This definition is not limited to wildlife exposure. Hayes
6th, p. 458.
331
It is generally recognized that there are three categories of biomarkers: biomarkers of exposure,
biomarkers of response or effect, and biomarkers of susceptibility. What would be a biomarker of
exposure for benzene?
A. elevated hemeoxygenase in blood
B. phenyl mercapturic acid in urine
C. decreased erythrocyte cholinesterase
D. elevated serum ALT
Answer: B
Explanation and Reference:
Phenyl mercapturic acid in urine is a biomarker for Benzene exposure. C&D, 8th, pp 1066.
332
What is the advantage of applying the Benchmark Dose (BMD) approach instead of the NOAEL
approach, in deriving a U.S. EPA Reference Dose (RfD)?
A. It may be influenced by the choice of experimental doses.
B. It eliminates consideration of variability in the dose-response data.
C. It takes into account all the dose-response curve, includes confidence limit and uses a consistent
Benchmark Response level for RfD calculations across studies.
D. It eliminates the need for uncertainty factors.
Answer: C
Explanation and Reference:
The BMD provides a point of departure from which to then consider extrapolation of study data to
chronic human general population applications. C&D 9th, pp. 138-141
333
When a sigmoid dose-response curve of cumulative percent response versus log dose is replotted as
probit versus log dose, what probit value corresponds to a cumulative percent response of 50%?
A. 1
B. 0.5
C. 3.33
D. 5
Answer: D
Explanation and Reference:
Probit values (probability units) are used to plot a dose response in a way that avoids negative
numbers. Since quantal-dose responses are usually normally distributed, percent response can be
converted to units of deviation from the mean or normal equivalent deviation (NED). The probit is then
by definition the NED +5, and a 50% response would be a probit value of 5.0. C&D 9th p. 23, Fig. 2-4
333
According to the US Interagency Staff Group on Carcinogens, what key feature distinguishes the
maximum tolerated dose (MTD) from other dose classifications?
A. not a non-toxic dose, but rather produces some level of toxicity to indicate the animals were
satisfactorily challenged
B. estimated from the results of acute toxicity studies
C. expected to produce at least some degree of life shortening in the test animals lifespan
D. selected as the maximum dose not producing toxic effects
Answer: A
Explanation and Reference:
The US Interagency Staff Group on Carcinogens has defined the MTD as follows: "The highest dose
currently recommended is that which, when given for the duration of the chronic study, is just high
enough to elicit signs of minimal toxicity without significantly altering the animal's normal lifespan due
to effects other than carcinogenicity. This dose, sometimes called the maximum tolerated dose
(MTD), is determined in a subchronic study (usually 90 days duration) primarily on the basis of
mortality, toxicity and pathology criteria. The MTD should not produce morphologic evidence of
toxicity of a severity that would interfere with the interpretation of the study. Nor should it comprise so
large a fraction of the animal's diet that the nutritional composition of the diet is altered, leading to
nutritional imbalance.” DOSE SELECTION FOR CARCINOGENICITY STUDIES OF
PHARMACEUTICALS, S1C(R2) 2008; Hayes, 4th ed. p. 37
333
If the total daily intake of a specific chemical agent via drinking water is 0.1 mg/kg/day, and the
NOAEL (no observed adverse effect level) for neurotoxicity is 100 mg/kg/day, what is the MOE
(margin of exposure) for neurotoxicity via the oral route?
A. 10
B. 0.001
C. 1000
D. MOE cannot be calculated without an uncertainty factor (UF)
Answer: C
Explanation and Reference:
The MOE is the ratio of the NOAEL determined in animals compared with the level to which a human
may be exposed [(100 mg/kg/day)/(0.1 mg/kg/day) = 1000]. C&D 9th p 29-30, 134
334
The therapeutic index of a drug is an approximate statement about the relative safety of a drug
expressed as which of the following? What expression is frequently used to designate the
therapeutic index of a drug?
A. (LD50-ED50)/ED50
B. TD50/ED50
C. TD01/ED99
D. ED50/LD50
Answer: B
Explanation and Reference:
The ratio of the toxic dose to the effective or therapeutic dose at the 50th percentile. C&D 9th p. 29.
335
What are the intrinsic factors that determine the rate of absorption of a substance applied to the
surface of the skin of a test animal?
A. sex of test animal, anatomical site of application, pH of the dosing solution, temperature
B. age of test animal, anatomical site of application, concentration of the dosing solution, condition of
the skin (disease state)
C. age of test animal, weight of the test animal, anatomical site of application
D. age of test animal, weight of the test animal, concentration of the dosing solution
Answer: B
Explanation and Reference:
Skin thickness affects penetration, which varies according to age and location; aduvants (vehicles)
can greatly affect absorption as well as disease state/condition of the skin. Hayes 6th, 1348-1349
336
Why are alcohol-containing beverages considered Group 1 carcinogens by the International Agency
for Research on Cancer (IARC)?
A. There is clear evidence that ethanol is mutagenic .
B. It causes forestomach tumors in mice.
C. Epidemiologic studies associate the alcoholic beverage consumption to an increased incidence of
several tumor types in humans.
D. There is clear evidence that ethanol is carcinogenic in laboratory animals
Answer: C
Explanation and Reference:
The IARC rating is based on the occurrence of a variety of tumors in humans that have been causally
related to ingestion of alcohol. Hayes 6th, p. 701; C&D 8th, pp. 1069-72
337
What is the primary health effect in humans associated with agricultural use of elemental sulfur as a
pesticide?
A. alopecia
B. dermatitis
C. neurotoxicity
D. male reproductive effect
Answer: B
Explanation and Reference:
Dermatitis is the primary health effect observed. C&D 8th, p. 970
338
What hydrolysis product is primarily responsible for the soil fumigant toxic action of metam sodium
toward nematodes, fungi and weed seeds?
A. methamidophos
B. methyl parathion
C. methyl isothiocyanate
D. alpha-methyl cyanuric acid
Answer: C
Explanation and Reference:
Methylisothiocyanate is the active toxic hydrolysis product. C&D 8th, p. 970
339
What is the largest single outdoor source of the air pollutant, carbon monoxide?
A. refuse disposal plants
B. power and heating plants
C. petroleum refining
D. vehicle emissions
Answer: D
Explanation and Reference:
Motor vehicles account for two thirds of urban carbon monoxide. C&D 8th, p. 1265-1266
340
What agent, when inhaled, is associated with onset of Silo-Filler's Disease?
A. hydrogen sulfide
B. carbon dioxide
C. phosgene
D. nitrogen dioxide
Answer: D
Explanation and Reference:
Nitrogen dioxide can be liberated from fermenting fresh silage and displace oxygen from the base of
a silo; this is a real-world problem for farmers. C&D 8th, p. 1262-1263
341
What group of spiders are associated with the most serious spider envenomations in North America?
A. funnel-web spiders
B. black widow spiders
C. banana spiders
D. grass spiders
Answer: B
Explanation and Reference:
These spiders are found in all climates and are very common. C&D 8th, p. 1148-49
341
What rare type of respiratory cancer is causally linked to exposure to some forms of asbestos?
A. mesothelioma
B. endothelial cell carcinoma
C. small cell carcinoma
D. pulmonary adenoma
Answer: A
Explanation and Reference:
Mesothelioma is a rare tumor associated with asbestos exposure.
https://www.epa.gov/asbestos/learn-about-asbestos#effects (accessed 4 October 2020); C&D 8th, p.
720
342
What group of toxic responses are most prominently linked to consumption of oleander, foxglove, lilyof-
the-valley, and/or mistletoe?
A. dermal sensitization reactions
B. seizures, disorientation, and/or coma
C. irregular heart rates, arrhythmias and/or cardiovascular collapse
D. hepatotoxicity with elevation of ALT and AST serum enzymes
Answer: C
Explanation and Reference:
This group of plants are all identified as being toxic to the cardiovascular system. C&D 8th, p. 1137-
1138, Table 26-6
343
In most parts of the world, what is recognized as by far the greatest food-borne risk facing
consumers?
A. microbial contamination
B. food allergy
C. Aflatoxin B1
D. pesticide residues
Answer: A
Explanation and Reference:
Microbial contamination is the greatest food-borne risk for most of the world's consumers. C&D 8th, p.
1342-1343/
344
What glycol ether is both a male and female reproductive toxicant and a teratogen?
A. propylene glycol methyl ether acetate
B. ethylene glycol monobutyl ether
C. ethylene glycol monomethyl ether
D. propylene glycol monomethyl ether
Answer: C
Explanation and Reference:
EGME is metabolized to methoxyacetic acid which can affect both the testes and ovary as well as the
developing fetus. C&D 8th, p. 878-880, 1078-1079
345
What is the most commonly used antidote in the treatment of anticholinesterase poisoning?
A. desferrioxamine
B. atropine
C. N-acetylcysteine
D. dithiocarbamate
Answer: B
Explanation and Reference:
Atropine is the cornerstone of treatment for OP poisoning. C&D 8th, p. 941
346
The WHO-recommended classification of pesticides by hazard is based, in part, on what model of
toxicity?
A. inhalation LC50 in rats
B. carcinogenicity studies in rats and mice
C. oral LD50 in rats
D. dermal LD10 in rats
Answer: C
Explanation and Reference:
Oral acute lethality in rats is used by WHO to classify pesticides by hazard. C&D 8th, p. 937, Table
22-6
347
What substance produced by a mold found on spoiled sweet clover has been associated with a
hemorrhagic disorder in cattle?
A. coumarol
B. dicoumarol
C. chlorophacinone
D. brodifacoum
Answer: B
Explanation and Reference:
Dicoumarol is the toxic agent in Sweet Clover Disease of cattle. Research into the cause of this
disease lead to the development of anticoagulant rodenticides. C&D 8th, p. 968
348
What widely used industrial chemical is classified by IARC as a probable human carcinogen because
high doses cause nasopharyngeal carcinoma in rats?
A. silica
B. formaldehyde
C. sulfur dioxide
D. nitrogen dioxide
Answer: B
Explanation and Reference:
Nasal carcinomas were induced in rats in a two-year bioassay. C&D 8th, p. 1264-1265
349
What product of dinoflagellates causes paralytic shellfish poisoning often observed during times of
algal bloom?
A. saxitoxin
B. ciguatoxin
C. tetrodotoxin
D. domoic acid
Answer: A
Explanation and Reference:
The etiological agent in dinoflagellate poisoning is saxitoxin or related compounds. C&D, 8th, p. 1341
350
What is the primary mechanism of action of ricin, a component of castor beans?
A. conversion in the liver of monocrotaline into an active pyrrolic metabolite and the resultant
production of cardiopulmonary toxicity
B. competitive antagonism of sphingosine in associated blocking of enzyme activity related to
sphingolipid biosynthesis
C. inactivation of the 60s ribosomal subunit leading to inhibition of protein synthesis
D. combination of the cyclic heptapeptide with actin in muscle cells to and resultant interference with
muscle function
Answer: C
Explanation and Reference:
This is the specific mechanism of action of the ricin amino acid lectin chain. C&D 8th, p. 1136
351
What substance has been linked to the oral toxicity of bitter almonds and peach kernels?
A. linamarin
B. carboxatractyloside
C. ptaquiloside
D. amygdalin
Answer: D
Explanation and Reference:
Amygdalin is a cyanogen present in bitter almond and peach kernels. C&D 8th, p. 1140
352
What creature's venomous bite can cause large lesions characterized by severe, invading, muscular
necrosis?
A. fire ant
B. black widow spider
C. brown recluse spider
D. Gila monster
Answer: C
Explanation and Reference:
This is characteristic of severe bites by the brown recluse spider. C&D 8th, 1149-1150
353
A patient comes to the emergency room with blurred vision, vomiting, abdominal cramps, salivation,
sweating, and muscle weakness, without significant CNS effects. Atropine and charcoal are
administered, and the patient improves in 2 hours without use of p
A. paraquat
B. aldicarb
C. diethyl parathion
D. aluminum phosphide
Answer: B
Explanation and Reference:
Inhibition of AChE by carbamates, such as aldicarb, is transient and use of 2-PAM is not
recommended. C&D 8th, p. 947
354
What is radon's primary respiratory effect in humans associated with its decay to the solid phase
daughter product Polonium-218?
A. mesothelioma
B. nasal tumors
C. chronic bronchitis
D. lung cancer
Answer: D
Explanation and Reference:
Numerous epidemiology studies have linked radon to lung cancer. C&D 8th, p. 394 (Table 8-1), 434
(Table 8-32), 741
354
Hypericin causes photosensitization in livestock following consumption of Hypericum perforatum.
What is the common name for this plant?
A. nettles
B. castor bean
C. mugwort
D. St. John's wort
Answer: D
Explanation and Reference:
St. John's wort is the common name for H. perforatum. C&D 8th, p. 1134
355
What is the primary source of reducing-type air pollution?
A. CO
B. oxides of nitrogen
C. ozone
D. SO2
Answer: D
Explanation and Reference:
SO2 is the classic reducing-type air pollutant which causes an acidic atmosphere with reductive
chemistry. C&D 8th, p. 1250-1253
356
What is the principal toxic effect of the mycotoxin citrinin from Penicillium citrinum?
A. neurotoxicity
B. cardiotoxicity
C. nephrotoxicity
D. hepatotoxicity
Answer: C
Explanation and Reference:
The kidney is the target for citrinin. C&D 8th, p. 1338, Table 31-26
357
What is the currently accepted mechanism for the toxic action of ricin?
A. selective antagonism of spinal inhibitory neurons
B. interference with the sodium/potassium-ATPase
C. blockage of mitotic spindle formation
D. reduced protein synthesis due to inactivation of 60s ribosomal subunits
Answer: D
Explanation and Reference:
The A-chain of the ricin molecule binds to the 60s robosomal subunit and directly inhibits protein
synthesis. C&D 8th, p. 1136
358
Cardiomyopathy has been observed in humans deficient in which essential metal?
A. selenium
B. magnesium
C. manganese
D. molybdenum
Answer: A
Explanation and Reference:
Endemic cardiomyopathy has been observed in humans with document selenium deficiency (Keshan
disease) C&D 8th p. 1007
359
What ocular condition has been associated with accidental exposure to naphthalene?
A. cataracts
B. glaucoma
C. conjunctival melanoma
D. exophthalmos
Answer: A
Explanation and Reference:
The lens is subject to cataract formation from exposure to naphthalene. C&D 8th, p. 780
360
Under what conditions is a substance considered to be GRAS (generally recognized as safe)?
A. thoroughly tested according to all regulatory guidelines established by the US Food and Drug
Administration
B. used at less than 1% of the diet for the average adult male
C. recognized as safe by experts based on currently available information published in the scientific
literature
D. used as a food in a foreign country for at least five years
Answer: C
Explanation and Reference:
GRAS designation is based on the opinion of scientific experts through experiments or experience
prior to 1958. FDA may make this designation but is not required to. Any food additive not
designated as GRAS becomes a regulated additive under the Food, D
361
Why are the sprouts and young leaves of pokeweed (Phytolacca Americana) safer to eat than mature
leaves?
A. Mature parts of the plant produce belladonna alkaloids.
B. Young leaves contain only the A-chain of a ribosomal inhibiting protein.
C. Mature leaves contain increased concentrations of a saponin, which can cause severe gastritis.
D. Mature leaves contain increased concentration of anemonin, which has marked irritant properties.
Answer: B
Explanation and Reference:
Pokeweed (Phytolacca americana) is one of several important plants in the Euphorbia family, which
include the Ricinus and Abrus genera, that produce ribosomal inhibitory proteins. The A-chain
cleaves purine bases from ribosomes but it is the B-chain tha
362
What organ system is most susceptible to lead poisoning in children?
A. hematopoietic system
B. nervous system
C. immune system
D. endocrine system
Answer: B
Explanation and Reference:
The brain and neurological system of children continues to develop for several years after birth. CD
8th p. 994
363
Pesticides often have adverse health effects for non-target species including humans. From a global
perspective, what is the major health and safety issue problem in humans?
A. endocrine disruption
B. low-level, chronic exposure through contaminated food
C. increased incidence of cancer
D. acute poisoning
Answer: D
Explanation and Reference:
Acute poisoning remains largest concern world-wide, especially in developing countries. Most
hospital admissions are related to intentional (suicidal) ingestion of these compounds. C&D 8th, pp.
936-37
364
What pulmonary effect is most likely to result from SO2 gas exposure?
A. decreased mucociliary clearance
B. bronchoconstriction via Type I hypersensitivity
C. local and centrally mediated bronchoconstriction via formation of sulfite
D. induction of pulmonary fibrosis following damage to epithelial cells
Answer: C
Explanation and Reference:
SO2 is a water soluble sensory irritant gas predominantly absorbed in the upper airways. C&D 8th p.
1250
365
What is the mode of action of the chemical warfare agent phosgene?
A. irritant induced Clara cell proliferation
B. autoimmune mediated tissue destruction
C. overt lipid peroxidation leading to lung toxicity and pulmonary edema
D. spindle poison-like suppression of immediate early gene activation
Answer: C
Explanation and Reference:
Phosgene can produce immediate alveolar damage leading to rapid death at high concentrations. At
lower levels, phosgene compromises alveolar barrier function that leads to pulmonary edema which
often can be fatal. C&D 8th, pg 712
366
What are the most common types of DNA damage caused by ultraviolet (UV) radiation?
A. intercalation and adducts
B. single and double-strand breaks
C. DNA protein cross-links abd 1,2-photo-radicals
D. cyclobutane pyrimidine dimers and 6,4-photoproducts
Answer: D
Explanation and Reference:
UV radiation causes cyclobutane-pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). Single
and double-strand breaks are associated with ionizing radiation (x-rays); and altered DNA bases are
most commonly associated with endogenous agents. DNA-prot
367
What is the toxin that makes castor beans poisonous?
A. ricin
B. cardiac glycosides
C. pyrrolizidine alkaloids
D. colchicine
Answer: A
Explanation and Reference:
The toxic agents of castor beans are two lectins: ricin I and ricin II of which ricin II is more toxic. C&D
8th, p 1136.
368
What is the source of a form of poisoning that causes soft tissue calcification in cattle?
A. eating feed supplemented with high levels of calcium
B. eating plants containing Vitamin D-like glycosides
C. eating plants contaminated by polychlorobiphenyls
D. eating feed contaminated by aflatoxin
Answer: B
Explanation and Reference:
Consumption of Cestrum spp, which include day-blooming jasmine, causes hypercalcemia and soft
tissue calcification in grazing cattle and chickens. Aflatoxins mostly affect the liver; polychlorinated
hydrocarbons are general toxins and probable carcinogens
369
Snake venoms are complex mixtures, however, their poisonous effects are most commonly due to
what substances?
A. enzymes and polypeptides
B. formic acids
C. toxic alkaloids
D. vasoactive amines
Answer: A
Explanation and Reference:
Proteins and peptides, enzymatic and non-enzymatic, make up over 90% of the dry weight of snake
venoms. C&D 8th p. 1155
370
The synthetic pyrethroids are a major class of insecticides modeled after a group of natural
insecticides extracted from what flowers?
A. chrysanthemum (Chrysanthemum spp.)
B. oleander (Nerium spp.)
C. milkweed (Asclepias spp.)
D. lily of the valley (Convallaria majalis)
Answer: A
Explanation and Reference:
Pyrethroids are insecticides developed from compounds found in chrysanthemums. C&D 8th p. 947.
371
Ergot alkaloids from a fungal parasite (Claviceps purpurea) on grains of rye can cause blackening of
limbs ("St. Anthony's fire") and, in pregnant women, abortion. These effects are due to what biological
activity of the alkaloids?
A. peripheral neurotoxicity
B. disruption of mitochondrial respiration
C. peripheral vasoconstriction
D. peripheral vasodilation
Answer: C
Explanation and Reference:
Ingestion of the fungus Claviceps purpurea (ergot), which grows on grains that are used for food,
causes vaoconstriction. C&D 8th, p. 1138.
372
Bisphenol A is a chemical of concern for what reason?
A. extensive use in plastic manufacturing and possible thyroid hormone disruption
B. bioaccumulation in the environment and potential as a chemical carcinogen
C. surfactant properties and potential for endocrine disruption
D. use in plastics and strong binding to the aryl hydrocarbon receptor
Answer: A
Explanation and Reference:
Possible leaching from polycarbonate-containing plastics makes this chemical a particular concern for
childhood exposure. C&D 8th p. 922
373
Which aflatoxin is the most toxicologically potent and commonly occurs in produce?
A. Aflatoxin G1
B. Aflatoxin B1
C. Aflatoxin B2
D. Aflatoxin G2
Answer: B
Explanation and Reference:
Occurs in corn, peanuts and a variety of grains and is acutely toxic in all species, inducing a variety of
types of hepatotoxicity. C&D 8th pp. 1338-39
374
What is an important class of chemicals that are formed during grilling or broiling of meat and is
associated with cancer in humans?
A. aliphatic amines
B. hydrazines
C. heterocyclic amines
D. ethyleneimines
Answer: C
Explanation and Reference:
They are formed as a result of high temperature cooking of proteins, especially those containing high
levels of creatinine and carbohydrates. C&D 9th p 1350-1351
375
For what therapeutic agent is the neurotoxicity associated with its use mediated by a disruption of
microtubule dissociation into tubulin subunits?
A. atropine
B. d-tubocurarine
C. procainamide
D. paclitaxel
Answer: D
Explanation and Reference:
Paclitaxel is the correct answer. It is a chemotherapeutic used to treat a variety of neoplasms.
Taxol's mechanism of action involves interference with the normal breakdown of microtubules during
cell division. C&D 9th p. 854, Table 16-3
376
Furanocoumarins in grapefruit juice can increase the systemic exposure to certain orally administered
drugs such as simvastatin (HMG-coA reductase inhibitor) and felodipine (calcium channel blocker)
through what mechanism?
A. inhibition of hepatic CYP3A4
B. inhibition of intestinal CYP3A4
C. inhibition of hepatic CYP1A1
D. induction of UDP-glucuronosyltransferase
Answer: B
Explanation and Reference:
Furanocoumarin derivatives initially inhibit intestinal enzyme cytochrome P450 isoform CYP3A4 and
are believed to be primarily responsible for the effects of grapefruit on the enzyme. Inhibition of
hepatic CYP3A4 occurs later. C&D 9th p 308
377
What factor most commonly accounts for the differential effects observed with isoniazid in some
people?
A. inhibition of the CYP3A isoform of cytochrome P450
B. genetic polymorphism of an N-acetyltransferase enzyme
C. competition for Phase I metabolism by phenytoin or phenobarbital
D. polymorphism of the CYP2D6 isoform of cytochrome P450
Answer: B
Explanation and Reference:
Isoniazid is metabolized by hepatic acrylamine N-acetyltransferase type 2 (gene, NAT2). Isoniazid
clearance in patients has been traditionally classified as one of two phenotypic groups (slow and fast)
but recently an intermediate group has also been identified
378
The shape of the dose-response curve has many important implications in toxicity assessment. For
example, essential nutrients can be potentially toxic at high doses. What phrase best describes the
shape of the dose-response curve for essential nutrients?
A. R step function (threshold dose response)
B. S shaped sigmoid curve
C. U shaped parabolic curve
D. / straight line (linear dose-response)
Answer: C
Explanation and Reference:
The U-shape of the dose-response curve (i.e., hormesis) is the result of physiological homeostatic
control. C&D 9th p 37-38
379
Gallium compounds, such as gallium arsenide and gallium nitrate, are used in electronics
manufacturing and medicine, both diagnostically and therapeutically. In humans, these compounds
can decrease DNA synthesis by initial binding to what plasma transport
A. metallothionein
B. transferrin
C. hemoglobin
D. albumin
Answer: B
Explanation and Reference:
The primary valence state of gallium is +3, resembling the ferric state of iron. Because of this, gallium
binds to transferrin and interacts with the iron -dependent ribonucleotide reductase resulting in a
decrease in DNA synthesis. C&D 9th p 1142
380
What is the International Conference on Harmonization of Technical Requirements for the
Registration of Pharmaceuticals for Human Use (ICH)?
A. ICH is a joint effort of the Food and Drug Administration (FDA), the Environmental Protection
Agency (EPA), and the Occupational Safety and Health Act (OSHA) to develop a common approach
to the safety assessment of chemicals.
B. ICH is a joint regulatory/industry project to improve, through harmonization, the efficiency of the
process for developing and registering new medicinal products in Europe, Japan, and the United
States, in order to make these products available to patient
C. The ICH process was completed in 1997 and the international standards for safety and efficacy of
pharmaceuticals recommended by the ICH have been adopted by Europe, Japan, and the United
States.
D. ICH is an Agency of the United Nations Food and Agricultural Organization that is intended to
establish international equivalents to the safety and efficacy standards of the US FDA and the
European Agency for the Evaluation of Medicinal Products (EMEA).
Answer: B
Explanation and Reference:
These are definitions (glossary) that an entry-level toxicologist should know. C&D 9th, p. 1583; Hayes
6th, p. 2091
381
What is the purpose of the US Food and Drug Administration's (FDA) Good Laboratory Practices
(GLP) regulation?
A. assure the quality and integrity of safety data file for products regulated by FDA
B. assure appropriate interpretation of product safety data submitted to FDA
C. assure the validation of all data submitted to the FDA in support of product registration
D. provide testing guidelines for nonclinical safety testing
Answer: A
Explanation and Reference:
The good laboratory practice (GLP) standards created by the Food and Drug Administration (FDA)
and Environmental Protection Agency (EPA) primarily establish requirements for the planning,
conduct, and reporting of research results used
382
According to Good Laboratory Practices (21 CFR 58) reagents must be labeled with what basic
information?
A. identity, titer or concentration, storage requirements, date opened and expiration date
B. identity, titer or concentration, date opened and expiration date
C. identity, titer or concentration, identity of person opening the bottle, and expiration date
D. identity, titer or concentration, storage requirements and expiration date
Answer: D
Explanation and Reference:
All reagents and solutions in the laboratory areas shall be labeled to indicate identity, titer or
concentration, storage requirements, and expiration date. Deteriorated or outdated reagents and
solutions shall not be used. This is from 21 CFR 58.105 su
383
What type of toxicology study is no longer required prior to filing an Investigational New Drug (IND)
application for a Phase I clinical trial in healthy volunteers?
A. single-dose toxicity studies by oral and/or intravenous routes in two rodent species
B. repeat-dose toxicity study in two species (one rodent and one nonrodent)
C. cardiovascular safety pharmacology
D. mutagenicity and genotoxicity
Answer: A
Explanation and Reference:
Acute toxicity is no longer required. The information can be obtained from appropriately conducted
dose-escalation studies or short-duration dose-ranging studies that define an MTD (Maximum
Tolerated Dose) in the general toxicity test species. Repeated-d
384
The United States Animal Welfare Act and Animal Welfare Regulations (Code of Federal Regulations,
Title 9, Chapter 1, Subchapter A) lists what membership requirement for the Institutional Animal Care
and Use Committee (IACUC)?
A. .IACUC members must serve at least three years of appointment
B. The IACUC must be comprised of a Chairman and at least three additional members.
C. At least one member of the IACUC must not be affiliated with the facility.
D. The Chairman of the IACUC appoints IACUC members.
Answer: C
Explanation and Reference:
IACUC committee has to have at least a chairman and two other members, one member must be a
veterinarian and one member must not be affiliated with the facility. Code of Federal Regulations,
Title 9, Chapter 1, Subchapter A, paragraph 2.31 section 3 item
385
According to the ICH Guidelines, a carcinogenicity study of a pharmaceutical compound is required
when the expected continuous clinical usage is expected for what period?
A. testing depends on the type of drug only and not the duration of usage
B. daily regardless of the expected duration of clinical usage
C. daily use of a period of at least 6 months
D. daily for a period of up to one month
Answer: C
Explanation and Reference:
Carcinogenicity studies should be performed for any pharmaceutical whose expected clinical use is
continuous for at least 6 months. ICH Guidelines - Safety: S1A The need for long-term rodent
carcinogenicity studies of pharmaceuticals, Issue Date 11/1995,
386
The use of dental amalgam fillings is an occupational health concern because it may expose workers
to what element at a level greater than recommended standards?
A. mercury
B. silver
C. gold
D. cadmium
Answer: A
Explanation and Reference:
Dental amalgam contains elemental mercury that can be released at levels high enough to cause
concern for dental workers. There is no scientific consensus regarding the adverse health effects of
this exposure. Hayes 6th, p.852.
387
Experimental fish screening assays for endocrine active substances are most likely to utilize what
specific indicator to demonstrate exogenous estrogen simulation effects?
A. induction of mixed function oxygenases
B. delta-aminolevulinic acid dehydratase inhibition
C. synthesis of vitellogenin (VTG)
D. induction of metallothionein
Answer: C
Explanation and Reference:
VTG is a good example of such a biomarker in that it provides an insight to the mode of action
(estrogenicity) that is vital to fish reproductive health. C&D 8th, p. 1279 & 1294
388
Sulfur dioxide is considered a component of outdoor ambient air pollution. How are the toxicological
properties of SO2 best characterized at environmentally-relevant concentrations?
A. Sulfur dioxide is an insoluble particulate absorbed predominantly in the upper airways and can
stimulate bronchoconstriction.
B. Sulfur dioxide is an insoluble particulate absorbed predominantly by swallowing particles trapped
in the respiratory mucous of the upper airways and typically causes erosion of the gastric mucosa.
C. Sulfur dioxide is a water-soluble irritant gas absorbed predominantly in the upper airways and can
stimulate bronchoconstriction.
D. Sulfur dioxide is a non-irritating water-soluble gas that is not absorbed in the airways or dermally
to any significant extent and stimulates bronchoconstriction only in individuals with existing asthmatic
or emphysematous conditions.
Answer: C
Explanation and Reference:
Sulfur dioxide is highly soluble in water and, therefore, is efficiently absorbed in the upper respiratory
tract as sulfurous acid. Greater than 90 percent of inhaled sulfur dioxide is absorbed in the
nasopharynx. However, mouth breathing (voluntary hyper
389
In the US, what is a legally enforceable standard related specifically to occupational exposure?
A. Biological Exposure Index
B. Threshold Limit Value
C. Time-Weighted-Average Exposure Limit
D. Permissible Exposure Limit
Answer: D
Explanation and Reference:
The permissible exposure limit (PEL or OSHA PEL) is a legal limit in the United States for exposure
of an employee to a chemical substance or physical agent. C&D 9th p 1554
390
What substance is recognized as an antidote for ethylene glycol poisoning by a mechanism involving
inhibition of alcohol dehydrogenase?
A. N-acetylcysteine
B. methanol
C. disulfiram
D. 4-methylpyrazole
Answer: D
Explanation and Reference:
A potent inhibitor of alcohol dehydrogenase, fomepizole (4-methylpyrazole) blocks the metabolic
bioactivation of ethylene glycol, thus minimizing the formation of toxic metabolites and allowing
ethylene glycol to be eliminated unchanged by the kidneys.
391
The American Conference of Governmental Industrial Hygienists (ACGIH) lists a ceiling limit (TLV-C)
of 1 ppm for ethylene chlorohydrin. What does this mean?
A. A worker can be safely exposed to this material at concentrations up to 1 ppm for 8 hours per day,
five days per week.
B. The general population can be safely exposed to 1 ppm for 30 minutes per day.
C. The 1 ppm concentration should never be exceeded in the work place.
D. Workers can be exposed to 1 ppm of this material for 15 minutes as long as there is 60 minutes
between exposures.
Answer: C
Explanation and Reference:
A Threshold Limit Value (Concentration) means the absolute exposure limit that should not be
exceeded for any time, in this case 1 ppm ethylene chloride. C&D 8th, p 1394
392
Prior to conducting a research study in the United States to assess the effects of an industrial
chemical's effect on reproductive function in laboratory animals, a university investigator will have to
get his study protocol approved by what entity?
A. ICCVAM
B. US EPA
C. IACUC
D. APHIS
Answer: C
Explanation and Reference:
No approval from the Regulatory Agencies are required before performing this study, however
IACUC approval is required before any animal study. Before animals can be used, the proposed
animal use must be reviewed and approved by an Institutional Animal
393
Measurement of abnormally high levels of vitellogenin in the blood of fish is an indication of exposure
to what class of compounds?
A. neurobehavioral compounds
B. alkylating agents
C. endocrine disruptors
D. sensitizers
Answer: C
Explanation and Reference:
Primary biomarker of effect in Fish EDSP assays. C&D 9th p 1438
394
Naloxone is an antidote for what type of poisoning?
A. opiates
B. ethylene glycol
C. digoxin
D. cyanide
Answer: A
Explanation and Reference:
Naloxone marketed under the trade name Narcan among others, is an opioid antagonist. Naloxone is
a medication used to counter the effects of opioids especially in overdose. C&D 8th, p.615
395
For what air pollutants were the U.S. National (Primary) Ambient Air Quality Standards established?
A. all priority toxic air contaminants
B. ozone, sulfur dioxide, carbon monoxide, and inhalable particulates (PM10)
C. benzene and gasoline
D. ammonia, diesel fuel, and polychlorinated biphenyls
Answer: B
Explanation and Reference:
EPA has set National Ambient Air Quality Standards for six principal pollutants, which are called
"criteria" pollutants. They are Carbon Monoxide; Lead; Nitrogen Dioxide; Ozone; Particle Pollution;
and Sulfur Dioxide. C&D 8th, p. 1234, Table 29-1
396
What product category falls under the regulatory authority of the U.S. Food and Drug Administration,
but does NOT require premarket approval?
A. veterinary drugs
B. medical devices
C. human drugs
D. cosmetics
Answer: D
Explanation and Reference:
With the exception of color additives, cosmetics are exempted from premarket approval under the
law. C&D 8th, p. 1416-1417.
397
What is the primary source of lead exposure for adults in the general population?
A. outdoor lead dust
B. lead-based paint
C. industrial emissions
D. food and water
Answer: D
Explanation and Reference:
While lead-based paint and contaminated dust are primary sources for children, food and water
represent primary sources for adults. C&D 8th, p. 993-994.
398
An arc welder works in a small enclosed area welding galvanized metal all day. She goes home at
5:00 PM feeling fine but at bedtime starts to experience breathing difficulty. Upon examination in the
emergency ward the attending physician diagnoses pulmon
A. chlorine
B. hydrogen sulfide
C. zinc oxide
D. nitrogen dioxide
Answer: C
Explanation and Reference:
Zinc fume fever or metal fume fever is particularly common among welders who work with galvanized
steel. C&D 8th, p. 1008-1009
399
Although a person registers a blood alcohol level of 0.3 percent, he/she can walk a straight line and
talk coherently. This is an example of what phenomenon?
A. cross-dependence
B. dispositional tolerance
C. abstinence syndrome
D. tissue tolerance
Answer: D
Explanation and Reference:
Upregulation of metabolic enzymes by frequent use of alcohol can affect the symptoms of exposure
to alcohol. C&D 8th, p. 1069-1072
400
How would you characterize a "class 2A" human carcinogen as defined by the International Agency
for Research on Cancer?
A. having limited human, but sufficient animal, evidence that it causes cancer
B. having limited human evidence or inadequate human, but sufficient animal, evidence that it
causes cancer
C. having sufficient human evidence that it causes cancer
D. demonstrating inadequate or absent human and animal evidence that it causes cancer
Answer: A
Explanation and Reference:
IARC has listed approximately 70 compounds in category 2A. Hayes 6th, pp. 56-57 Table 2.6.
401
The nuclear power station accident in Chernobyl in 1986 resulted in increased thyroid cancer in
exposed children. What agent is stockpiled for quick distribution in the event of a similar accident
elsewhere?
A. TSH
B. potassium iodide
C. iodine-131
D. EDTA
Answer: B
Explanation and Reference:
Potassium iodide blocks the thyroid from absorbing radioactive iodine. C&D 8th, p. 1125
402
Analgesics such as ibuprofen, aspirin, and cyclooxygenase-2 inhibitors exhibit both acute and chronic
renal toxicity. Analgesic nephropathy is often irreversible and is best characterized by necrotic
lesions where?
A. the distal tubule
B. the renal papilla
C. the proximal tubule
D. the glomerulus
Answer: B
Explanation and Reference:
Nephrotic injury from many analgesics occur in the renal papilla, initially occurring in the medullary
interstitial cells, followed by degeneration of cells in the medullary capillaries, loops of Henle, and
collecting ducts. C&D 8th, p. 683
403
A farmer came into the emergency department complaining of stomach pains, tingling in his
extremities and hair loss. He indicated that he had been using a chemical found in his barn to kill
rats. Exposure to what rodenticide is the likely cause of these
A. fluoroacetic acid
B. thallium
C. Coumadin©
D. nicotine
Answer: B
Explanation and Reference:
Exposure to Coumadin would be associated with hemorrhage. The main targets for fluoroacetic acid
(Compound 1080) are the CNS and the heart. Nicotine primarily acts on the CNS, and depending on
dose, can be either a stimulant or a depressant.
404
What pathological changes characterize chronic exposure to cadmium?
A. renal tubular dysfunction resulting in proteinuria
B. accumulation of cadmium-metallothionein complexes in liver mitochondria
C. hypotension secondary to calcium channel blockade
D. renal carcinoma originating in the glomeruli
Answer: A
Explanation and Reference:
Cadmium accumulation in the renal cortex causes tubular dysfunction resulting in proteinuria. C&D
8th, p. 991
405
Why does beryllium, a metal used in ceramic plants, the nuclear industry, and space vehicles, cause
a severe adverse reaction in some people?
A. because it initiates a cell-mediated immune response
B. because it can displace calcium in the bones, making them brittle and easy to break
C. because it binds to metallothionein and accumulates in the kidney
D. because it reacts with sunlight to cause skin lesions
Answer: A
Explanation and Reference:
Beryllium exposure may cause a delayed-type hypersensitivity reaction in skin which is a cellmediated
immune response. Skin testing and the lymphocyte proliferation test have been used to
identify berylium-sensitive individuals. C&D 8th, p. 989
406
What is the first line treatment of choice for organophosphate toxicity?
A. ethanol
B. vitamin K1
C. atropine
D. methylene blue
Answer: C
Explanation and Reference:
Atropine represents the cornerstone of the treatment for OP poisoning as it is a muscarinic receptor
antagonist and prevents the action of accumulating acetylcholine on these receptors. C&D 8th, p.
942-943
407
Carbon monoxide toxicity has been attributed to a reversible interaction with which critical protein?
A. cytochrome P450
B. methemoglobin
C. transferrin
D. hemoglobin
Answer: D
Explanation and Reference:
The toxic effects of CO have been attributed to the formation of carboxyhemoglobin, which decreases
the oxygen carrying capacity of the blood. C&D 8th, p. 832
408
Why is it difficult to predict the toxicity of engineered nanomaterials based on their chemical
composition?
A. They are very unstable and their properties change drastically over short periods of time .
B. Handling them requires specific techniques beyond most testing laboratories capabilities.
C. They are inert substances in vitro and require specialized in vivo assays to assess.
D. They have different physical and chemical properties than micro-scale products of the same
chemical composition.
Answer: D
Explanation and Reference:
Nanoparticles are known to react differently than larger particles of similar composition. C&D 8th, p.
1193-1197, Table 28-2
409
In the treatment of patients with cyanide poisoning, upon what critical step does the therapeutic
efficacy of sodium nitrite depend?
A. an increase in oxidative phosphorylation
B. the formation of methemoglobin
C. an increase in coronary arterial blood flow
D. relaxation of the nonvascular smooth muscle
Answer: B
Explanation and Reference:
Cyanide has a greater affinity for heme moieties with Fe3+, thus cyanide will bind to methemoglobin
more readily than hemoglobin. Consequently methemoglobin will compete with Cytochrome c oxidase
for binding to cyanide. Hayes 6th, p. 22
410
Consuming the leaves of the purple foxglove plant would be expected to cause what pathological
change(s)?
A. cardiac arrhythmias
B. renal toxicity
C. hepatic toxicity
D. CNS stimulation
Answer: A
Explanation and Reference:
The main toxin in foxglove, digitalis, is known as a cardiac glycoside, as it can cause cardiac
arrhythmias. C&D 8th, p. 1137
411
What source of contamination poses the greatest food-borne risk world-wide?
A. food additives
B. mycotoxins and food-borne molds
C. chemical contaminants/adulterants
D. microbial contamination
Answer: D
Explanation and Reference:
Of all the sources of food contamination and adulteration, microbial contamination is by far the most
prevalent cause of toxicological concern worldwide. C&D 8th, p. 1342.
412
What is the primary physiochemical property used in quantitative structure-activity relationship
(QSAR) models to predict bioconcentration in fish?
A. molecular weight
B. log octanol/water partition coefficient
C. affinity to organic carbon (Koc)
D. water solubility
Answer: B
Explanation and Reference:
Log octanol/water partition coefficient measures affinity to lipds, which has been correlated to a
reduction in metabolism and excretion and substances tend to be stored in lipid rich tissues. C&D
8th, p. 1277
413
Phthalates are often classified as endocrine disruptors or hormonally-active agents (HAAs). What is a
potential sauce if high-level exposure to phthalates in children?
A. mouthing of plastic toys
B. consumption of fruits and vegetables treated with pesticides
C. exposure to air emissions from coal-fired power plants
D. incidental ingestion of urban soils while playing outdoors
Answer: A
Explanation and Reference:
Phthalates are a class of plasticizers and until recently were used in pacifiers and other plastics
children have been exposed to. C&D 8th, p. 922
414
What specific information do biomarkers in ecotoxicology studies provide?
A. community structure and function
B. organismal exposure and effect
C. ecosystem stability and resilience
D. trophic relationships and energetics
Answer: B
Explanation and Reference:
Biomarker in ecotoxicity is largely relegated to understanding whether exposure has occurred and if
levels are sufficient to induce adverse effects in individuals. C&D 8th, p. 1293-1294
415
What route of exposure is the one of primary concern in the majority of work environments?
A. dermal
B. oral
C. ocular
D. respiratory
Answer: D
Explanation and Reference:
The respiratory system is most often the primary pathway of exposure to substances in occupational
settings. C&D 8th p 1394
416
1. Which of the following is NOT true:
A. The US EPA administers regulations intended to protect the environment and worker safety.
B. ICH guidelines recommend strategies for the safety assessment of drugs.
C. The FDA exercises premarketing authority over various products including medical devices.
D. TSCA empowers EPA to require safety testing of chemicals.
A
417
2. Regarding responsible use of laboratory animals in biomedical research, which of the following statements is TRUE:
A. The US Food and Drug Administration (FDA) administers the Animal Welfare Act (AWA), which requires research facilities to file an annual report.
B. The 3Rs refers to methods that require the use of animal testing to support drugs for human consumption.
C. The AWA requires each animal research facility to establish an Institutional Animal Care and Use Committee (IACUC).
D. The accreditation of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) is mandatory for laboratories using animals for biomedical research.
C
418
4. Which of the following is NOT a characteristic of anticholinesterase insecticide poisoning?
A. Miosis and blurred vision
B. Muscle twitching
C. Urinary retention and slowed gastrointestinal motility
D. Excessive bronchial secretions
C
418
3. Which of the following is NOT true concerning Good Laboratory Practices (GLPs)?
A. Are required for nonclinical hazard assessment studies submitted for regulatory review to support marketing and clinical testing.
B. Require that a testing facility employ a diverse laboratory staff.
C. Require appropriate training and expertise of study personnel.
D. Set standards for documentation and reporting of study procedures and data.
B
419
5. Paraquat undergoes a NADPH-mediated one-electron reduction to a species that reacts with molecular oxygen to generate which of these toxic reactive oxygen species?
A. Singlet oxygen
B. Superoxide anion radical
C. Hydroxyl radical
D. Hydrogen peroxide
C
420
6. Which of the following is a direct-acting alkylating carcinogen?
A. Ethylene oxide
B. Benzene
C. 1-Naphthylamine
D. Naphthalene
A
421
7. The adverse effects of acute ethylene glycol ingestion are related to which of the following?
A. Renal toxicity due to oxalic acid formation
B. Metabolic acidosis due to formic acid production
C. Metabolism to the mutagen acetaldehyde
D. Production of carbon monoxide
A
422
9. Which of the following endpoints is related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity?
A. Damage to hair cells of the chochlea
B. Inhibition of monoamine oxidase B
C. Toxicity to Schwann cells
D. Degeneration of dopaminergic neurons in substantia nigra
D
423
8. Benzene causes bone marrow toxicity by which of the following mechanisms?
A. Fragility of red blood cell membranes.
B. Destruction of megakaryocytes.
C. Formation of reactive metabolites.
D. Destruction of lymphocyte progenitors.
C
424
10. Which of the following is NOT related to glutamate signaling and toxicity?
A. Glutamate is considered an excitatory amino acid.
B. The cerebellum is the brain region most susceptible to glutamate toxicity.
C. Glutamate toxicity affects dendrites, but spares axons.
D. Glutamate receptor agonists include kainite and N-methyl-D-aspartate
B
425
11. Which of the following solvents is associated with anemia, leukopenia, and chronic myelogenous leukemia?
A. Carbon disulfide
B. Ethylene glycol
C. Xylene
D. Benzene
D
426
12. The use of ethanol or fomipazol to treat acute methanol ingestion is based on which of the following rationale?
A. Slowing rate of methanol absorption from the gastrointestinal tract.
B. Competing with alcohol dehydrogenase to prevent metabolite formation.
C. Producing nontoxic metabolites.
D. Enhancing renal clearance of methanol
D
427
13. Which of the following cytochrome P450 (CYP) enzymes is most susceptible to inhibition by furanocoumarins in grapefruit juice?
A. CYP2D6
B. CYP2El
C. CYP3A4
D. CYP4Fl
C
428
15. Which of the following is most applicable to aflatoxin toxicity?
A. Ketone moiety allows for direct binding to DNA.
B. Nongenotoxic inducer of peroxisome proliferation in the liver.
C. Secondary amine is converted to nitrosamine in the liver.
D. Converted by cytochrome P450 enzymes to toxic epoxide.
D
429
14. Which of the following mechanisms applies to mercury crossing the blood-brain barrier?
A. Diffusion across the myelin sheath.
B. Uptake by divalent metal transporters.
C. Transport by amino acid or organic anion transporters.
D. Competition for sulfate transport
C
430
16. Which of the following is required for acetaminophen biotransformation to a quinoneimine metabolite?
A. CYP2E1 activity
B. Sulfation
C. Hydroxylation
D. Glutathione S-transferase activity
A
431
ATP-binding cassette (ABC) transporters are transmembrane proteins that translocate various substrates across cell membranes including exogenous compounds such as drugs, drug conjugates, and metabolites and endogenous compounds such as lipids, sterols, and bilirubin. Which one of the following is NOT an example of a class of ABC transporters?
A. Multidrug-Associated Resistance Protein (MRP)
B. Breast Cancer Resistance Protein (BCRP)
C. Bile Salt Export Protein (BSEP)
D. Multidrug andToxicant Extrusion Proteins (MATE)
D
431
17. Which of the following solvents is associated with mutations in the von Hippel-Lindau tumor suppressor gene and kidney cancer in humans?
A. Benzene
B. Trichloroethylene
C. Ethyl benzene
D. Methylene chloride
B
432
19. Which of the following is NOT regarded as an advantage of compartmental toxicokinetic models?
A. Require information on tissue physiology or anatomic structure.
B. Useful in predicting toxicant concentration in blood at different doses.
C. Estimate time course of accumulation.
D. Define concentration-response relationships
A
433
20. Which of the following is TRUE concerning the impact of genetic alterations?
A. Proto-oncogenes have no role in normal growth and development.
B. Endogenous metabolic byproducts typically produce DNA single-and double-strand breaks.
C. Chemicals can alter DNA by forming DNA adducts or intercalating between DNA bases.
D. Mutation of both alleles of P53 is required for colorectal cancer development.
C
434
22. The in vitro micronucleus assay is a surrogate for chromosomal aberration analysis and can be used to assess the potential to induce:
A. Gene mutation
B. Gene duplication
C. Point mutations
D. Chromosomal breaks and aneuploidy
D
435
21. The Salmonella tester strains used in the bacterial mutation assay (OECD Test Guideline 471) are defective in which DNA repair pathway?
A. Recombinational repair
B. Excision repair
C. Error-prone repair
D. Nonhomologous end-joining
B
436
23. The in vitro genetic toxicology test battery uses a liver homogenate preparation referred to as S9 that contains added co-factors for:
A. Phase I and Phase II enzymes
B. Uridine-5'-diphospho-glucuronyltransferase (UDPGA)
C. Cytochrome P450 enzymes (CYP450s)
D. Glutathione-S-transferases (GSH transferases)
C
437
24. The alkaline (pH >13) Comet assay uses single gel electrophoresis to determine DNA damage that is quantified by:
A. Percent tail DNA
B. DNA repair
C. DNA adducts
D. Unscheduled DNA synthesis
A
438
25. Which of the following statements describes the promotion stage of carcinogenesis?
A. Stage in which irreversible, heritable changes occur in DNA, and are fixed by DNA replication and cell division.
B. Stage in which internal and/or external stimuli induce reversible clonal expansion of an initiated cell population.
C. Stage in which tumor growth occurs at a secondary site not adjacent to the primary site.
D. Stage in which preneoplastic cells acquire irreversible neoplastic structural and functional characteristics
B
439
26. Which of the following is an epigenetic, receptor-mediated mode of action associated with induction of cancer in rodent bioassays?
A. Agent-induced cytotoxicity and regenerative hyperplasia.
B. Binding of agent to alpha-2-microglobulin protein.
C. Binding of agent to PPAR-alpha protein.
D. Agent-induced changes in DNA methylation pattern
C
440
29. Which of the following insecticides or types of insecticides are NOT known for targeting sodium channels?
A. Diamides
B. Pyrethroids
C. DDT
D. Dihyrdropyrazoles
A
441
28. Which of the following statements is TRUE?
A. The Food Quality Protection Act (FQPA) of 1996 amended only the Federal Food, Drug, and Cosmetic Act (FFDCA}, but not the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).
B. The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) is a statute that provides for federal regulation of pesticide distribution, sale, and use.
* C. Pesticide residues are not regulated within the Federal Food, Drug, and Cosmetic Act (FFDCA) statute.
D. The Pesticide Registration Improvement Act (PRIA) of 2004 amended FIFRA to create a fee-for-service component to pesticide registration; however, PRIA was later rescinded.
B
441
Which of the following effects, observed in short to medium length exposure preclinical toxicity studies, would NOT be considered to be of high concern for potential risk for inducing carcinogenicity in a rodent carcinogenicity bioassay?
A. Biopersistenceof agent and/or metabolites in tissues.
B. Evidence of hormonal perturbation.
C. Chronic tissue inflammation.
D. Poor systemic absorption of agent by expected route of exposure.
D
442
30. Identify which pesticide or type of pesticide is NOT correctly matched with itstoxic effect(s) or syndrome(s).
A. Carbamates-delayed polyneuropathy
B. Paraquat-lung and kidney toxicity
C. Organophosphates-salivation, lacrimation, urination, and defecation (SLUD)
D. Nicotine-green tobacco sickness
A
443
31. Which of the following calculations is NOT correct?
A. RfD = LOAEL/UFs
B. Oral slope factor= BMR/BMDL
C. Risk specific dose= Dose x potency
D. Margin of exposure= NOAEL/Exposure
C
444
32. Which of the following is CORRECT regarding application of uncertainty factors in developing a dose-response assessment?
A. UFH address biological variability between the test species and humans.
B. UFS reflects the likelihood that a study of longer-duration often identifies a higher POD than a shorter duration study.
C. When dosimetric adjustments are applied to a NOAEL from an animal toxicology study this adjustment is often used to replace the toxicodynamic portion of UFA.
D. A factor of 1 is used for the UFL when a BMD(L) is used as the point of departure.
D
445
34. Which of the following is CORRECT relative to the IK,?
A. The IK, is a current mostly observed during Phase O {i.e., cardiac depolarization).
B. The IK, current originates from a channel assembled from the KVLQT1.
C. The IK, channel is a cardiac voltage gated sodium channel.
D. Along with IK,' the IK, is responsible for termination of the plateau phase of the action potential.
D
445
33. Which of the following statements is NOT correct?
A. In order to assess whether an observed effect is relevant to humans, we need to know the mode of action in the experimental animal species.
B. Evaluation of human relevance includes use of the IPCS MOA and Human Relevance Framework.
C. Mode-of-action evaluation is done only for cancer endpoints.
D. The result of the hazard characterization step for cancer assessments is a cancer classification or a Weight of Evidence Descriptor with supporting narrative to support cancer classification and to support a decision regarding the approach for doing the quantitative cancer dose-response assessment
C
446
35. Which statement relative to cardiac biomarkers is CORRECT?
A. Troponin T (cTnT) and I (cTnl) are expressed in various muscles including cardiomyocytes.
B. CRP is recognized as a selective biomarker of cardiac inflammation.
C. CK-BB is the predominant isoform of CK isoenzymes found in the myocardium.
D. B-Type Natriuretic Peptide (BNP) is secreted by the ventricular myocardium in response to volume and pressure overload
D
447
36. Which statement relative to the electrocardiogram (ECG) is CORRECT?
A. The ORS interval represents the conduction pathways through the atria.
B. The PR interval is the measure of time from onset of ventricular activation to end of repolarization.
C. The QT interval reflects the action potential duration of the ventricles.
D. Heart failure is associated with up-regulation of two potassium channels (IK, and IK,) and short QT syndrome
C
448
37. Increased blood concentration of which of the following is considered to be a reliable biomarker of carbon monoxide exposure?
A. Methemoglobin
B. Carboxyhemoglobin
C. Bilirubin
D. Hemin
B
449
38. The murine local lymph node assay is used to assess the ability of a test article to produce what type of reaction?
A. Anaphylaxis
B. Allergic contact dermatitis
C. Urticaria
D. Immune complex vasculitis
B
449
40. Anaphylaxis in humans treated with penicillin is mediated by which of the following?
A. Anti-hapten lgG
B. Anti-hapten CD8 T-cells
C. Anti-hapten complement activation
D. Anti-hapten lgE
D
450
39. Red blood cell basophilic stippling is a biomarker for exposure to which of the following metals?
A. Arsenic
B. Chromium
C. Lead
D. Copper
C
451
41. The Delaney clause of the US Food, Drug and Cosmetic Act (FD&C Act) applies to all substances EXCEPT:
A. Drugs used for food producing animals
B. Natural colorings used in foods
C. Pesticides
D. Flavoring substances that are also naturally occurring
C
452
46. The number of pregnant females divided by the number of females with confirmed mating, then multiplied by 100, is known as the:
A. Female mating index
B. Fecundity index
C. Female fertility index
D. Gestation index
B
452
42. Favism is associated with all of the following EXCEPT:
A. Occurs primarily in European Caucasians.
B. Is associated with glucose-6-phosphate dehydrogenase deficiency.
C. Release of pyrimidine aglycones such as divicine and isouramil from beans.
D. Results in red blood cell hemolysis
A
453
44. Which of the following potential male reproductive toxicants does NOT target spermatogenesis?
A. Cadmium
B. Vitamin A
C. CCl
D. a-Chlorohydrin
D
453
When looking at dose-response patterns for an agent that caused developmental toxicity in an animal study, the most concern from a human health perspective is:
A. Malformations occur at a dose level at the highest level tested.
B. Growth retardation occurs at a dose level less than those associated with embryo/fetal lethality.
C. Embryo/fetal lethality occurs at a dose level at the highest level tested.
D. Malformations occur at a dose level less than those associated with growth retardation.
D
454
43. Food hyper-reactivity (allergy):
A. Is primarily associated with lgA-mediated immune responses.
B. Is most often associated with low molecular weight (<5,000 daltons) proteins.
C. Does not occur as a cross-reactivity with other substances.
D. Is primarily associated with lgE and lgG immune reactions
D
455
47. Which of the following is TRUE about oxygen utilization in the liver?
A. Zone 1 has the lowest oxygen utilization (~4-5%).
B. Zone 2 has the highest oxygen utilization (~9%).
C. Similar oxygen utilization throughout the hepatic acinus.
D. Zone 1 has the highest oxygen utilization (~9-13%).
D
456
50. Cells associated with the liver that have an immune function include:
A. Kupffer and endothelial cells
B. Kupffer and stellate cells
C. Kupffer and Ito cells
D. Endothelial cells and stellate cells
A
456
48. For bile acids and bile acid transport, all of the following are correct EXCEPT:
A. Bile acid uptake into the hepatocytes occurs via NTCP transporter.
B. Conjugated bile acids are transported by BSEP, an efflux transporter.
C. BSEP is located at the sinusoidal aspect of the hepatocyte.
D. Inhibition of BSEP can be associated with drug-drug interactions.
C
457
49. Apoptosis, compared to necrosis, is best described as:
A. Characterized by cell swelling.
B. Is a single-cell event.
C. Involves the influx of inflammatory mediators and cellular infiltrates.
D. Results in the release of cellular constituents including alanine. aminotransferase(ALT) and damaged-associated molecular patterns (DAMPS).
B
458
52. All of the following characteristics are TRUE for idiosyncratic drug induced liver injury (iDILI) EXCEPT:
A. Idiosyncratic liver injury is observed with a diverse spectrum of xenobiotics.
B. Idiosyncratic liver injury is always dose-dependent.
C. Idiosyncratic liver injury is a rare occurrence and difficult to predict through pre-clinical testing.
D. Idiosyncratic liver injury has also been associated with consumption of herbal remedies and food supplements.
B
458
54. The apparent volume of distribution (V) can be described by all of the following EXCEPT:
A. Is defined as the ratio of volume to amount of the toxicant.
B. Does not correspond to a realistic anatomical volume.
C. In a one-compartment model, the toxicant instantaneously equilibrates between the blood (plasma) and tissue.
D. The Vdcan be greater than 1.0, particularly for highly lipophilic toxicants.
A
459
51. All of the following statements about hepatic steatosis are correct EXCEPT:
A. Valproic acid is a classic example of a drug that causes hepatic steatosis.
B. Drugs that cause steatosis accumulate in the mitochondria causing an inhibition of cellular respiration.
C. Steatosis may progress to non-alcoholic steatohepatitis (NASH) due to increased insulin resistance.
D. Is due to the accumulation of lipids and triglycerides in the hepatocyte.
C
460
55. Which of the following characteristics is NOT appropriate for an ideal metal chelator?
A. Greater affinity with low toxicity.
B. Rapid elimination of the toxic metal.
C. Different distribution as the metal.
D. High water solubility
C
461
56. With regard to arsenic toxicology, which of the next statements is NOT correct?
A. Causes neuronal injury and cardiotoxicity.
B. Can cause skin carcinomas in humans.
C. Mees' lines is an important biomarker of exposure.
D. Causes acute promyelocytic leukemia
D
462
57. Which of the following is TRUE with regards to the Minamata Bay poisoning?
A. It was caused by chronic mercury poisoning by mining wastes into Japanese rice paddies.
B. Led to the birth of many children with developmental disabilities such as cerebral palsy.
C. Caused by the ingestion offish and shellfish that bioaccumulated inorganic mercury.
D. Led to pregnant women giving birth to children with severe bone malformations.
B
463
59. Chemically induced alpha2u-globulin nephropathy isa male rat specific syndrome associated with a low incidence of renal tumors in male rats with chronic exposure to which of the following nephrotoxicants?
A. Cadmium
B. d-Limonene
C. Cisplatin
D. Acetaminopen
B
464
58. Which is the primary site of kidney damage resulting from acute exposure to inorganic mercury salts?
A. Glomerulus
B. Proximal tubule
C. Loop of Henle
D. Renal papilla
B
465
Vinyl chloride has been recognized as an occupational carcinogen since the early 1970s. Vinyl chloride metabolites are known to form DNA adducts, including etheno-guanine, etheno-cytosine, and etheno-adenine.The formation of these adducts is dependent on which of the following?
A. Reduction of chloroacetylaldehyde by aldehyde dehygrogenase.
B. Oxidation of vinyl chloride to chloroethyleneoxide by CYP2El.
C. Non-enzymatic rearrangement of vinyl chloride to chloroacetylaldehyde.
D. Formation of chlorethylene oxide by epoxide hydrolase
B
465
60. Which nephrotoxicant listed below is dependent on biotransformation to a reactive intermediate for cytotoxicity within the proximal tubule?
A. Aristolochic acid
B. Ibuprofen
C. Decalin
D. Chloroform
D
466
61. Benzoylecgonine is the primary urinary metabolite of which drug of abuse?
A. Opiates
B. Methamphetamine
C. Benzodiazepines
D. Cocaine
D
467
62. Because of their ease of use, low cost, high relative specificity, and accuracy, which of the following is frequently used in the initial screen to detect many drugs in the forensic urine drug testing (FUDT) laboratory?
A. Gas Chromatographic methods
B. lmmunochemical methods
C. Thin layer chromatographic methods
D. Liquid chromatographic methods
B
468
64. Over 3,000 garment workers presented with rapidly worsening dyspnea, fever, cough, and weight loss.There was a rapid progression to respiratory failure and death within 1-2 years. Most of these workers have been involved in the production of sand-blasted jeans and were typically short-term employees (i.e., a few months to years). Their symptoms and disease progression were typical of?
A. Acute silicosis
B. Chronic silicosis
C. Bronchiolitis obliterans
D. Acute bronchitis
A
469
65. Richard runs a landscaping company. The previous fall, he had a chronic cough and shortness of breath. His physician treated him with antibiotics and the symptoms resolved over the winter. On the first job the following spring, Richard removed old mulch from landscaping and noticed there was a lot of white mold and"smoke"when it was disturbed. That evening he presented to the emergency room with a cough, shortness of breath, fever, and chest pain, and felt like he was "coming down with the flu:' The treating physician noted "pop and squeak" lung sounds upon inspiration. The physician prescribed a steroid and recommended that Richard avoid handling moldy materials. Richard most likely suffered from which of the following?
A. Chronic fibrotic lung disease
B. Bronchitis pneumonitis
C. Acute hypersensitivity pneumonitis
D. Asthma
C
470
66. The most important factor in determining how deeply an inhaled gas penetrates into the respiratory tract is:
A. Concentration of the gas.
B. Molecular weight of the gas.
C. Water solubility of the gas.
D. Depth of airway mucus
C
471
67. Which of the following parameters is most commonly used to characterize the size distribution of an inhaled aerosol?
A. Aspect ratio
B. Geometric standard deviation
C. Terminal settling velocity
D. Mass median aerodynamic diameter
B
472
68. Which of the following BEST pairs an inhaled toxicant with a chronic pulmonary disease?
A. lsocynates-Lung cancer
B. Asbestos-Chronic bronchitis
C. Ozone-Emphysema
D. Beryllium-Granulomatous lung disease
D
473
Which of the following statement is TRUE about the US EPA’s Endocrine Disruption Screening Program (EDSP)?
A. Existing in vivo testing requirements for pesticides adequately address the identification of EDs
B. EDSP targets Estrogen, Androgen, and Thyroid (EAT) modalities
C. EPA’s EDSP focuses solely on assessing endocrine disruption in wildlife
D. In 1996, the Office Chemical Safety and Pollution Prevention successfully implemented Section 408(p)(3)(A) of the Federal Food, Drug, and Cosmetic Act to test all pesticides for endocrine-disruption activity
Correct Answer: B, EDSP targets Estrogen, Androgen, and Thyroid (EAT) modalities
Reference: https://www.epa.gov/system/files/documents/2021-07/_epaoig_20210728-21-e-0186.pdf
Rationale: Choice A is incorrect, as regulatory agencies have recognized that current standard test methods do not provide adequate data to identify potential endocrine disruptors (ED) or to assess risk to humans and wildlife. Hence the impetus for creation of the EDSP, or Endocrine Disruption Screening Program. https://www.epa.gov/endocrine-disruption/endocrine-disruptor-screening-program-edsp-policies-and-procedures. Choice C is incorrect, as endpoints evaluated include ecological and human health endpoints. https://www.epa.gov/endocrine-disruption/use-high-throughput-assays-and-computational-tools-endocrine-disruptor. Choice D is incorrect, as the Food Quality Protection Act was passed in 1996, and as of 2021, the aforementioned Section has not been implemented https://www.epa.gov/system/files/documents/2021-07/_epaoig_20210728-21-e-0186.pdf
474
Which of the following is a target of a major class of insecticides?
A. Inhibition of glutamine synthase
B. Inhibition of 5-enolpyruvyl shikimate 3- phosphate synthase
C. Mimicry of auxin growth hormone
D. Inhibition of mitochondrial complex I electron transport
Correct Answer: D, Inhibition of mitochondrial complex I electron transport is the target of rotenoid insecticides such as rotenone.
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1079, 1082, Table 22-8
Rationale: Choice A is incorrect, as this is a plant specific pathway that is targeted by herbicides such as glufosinate. (Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1088). Choice B is incorrect, as this is a plant specific pathway that is targeted by glyphosate. (Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1088). Choice C is incorrect, as this is a plant specific pathway that is targeted by analogues of auxin - chlorophenoxy herbicides such as 2,4-D or MCPA. (Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1082, 1083, Table 22-17).
475
Which of the following best describes pyrethrin and pyrethroid insecticides?
A. Pyrethrins are synthetic analogs of pyrethroids
B. Pyrethrins were originally developed from plants and were found to decompose rapidly in the environment
C. Type II pyrethroids target both voltage-gated sodium channels and GABA-gated calcium channels
D. The cyano group distinguishes Type II pyrethrins from Type I pyrethrins
Correct Answer: B, Pyrethrins were originally developed from plants and were found to decompose rapidly in the environment.
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1070.
Rationale: Choice A is incorrect, as pyrethroids are the synthetic analogs of pyrethrins. Choice C is not correct, as Type II pyrethroids target both voltage-gated sodium channels and GABA-gated chloride channels. Choice D is not correct, as the cyano group distinguishes Type II from Type I pyrethroids. (Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1070-1073).
476
Which of the following statements is correct about drug-drug interactions?
A. In vivo drug-drug interaction studies conducted in nonclinical species are predictive of the magnitude of a drug-drug interaction in humans
B. Direct CYP inhibition can result in a clinically relevant drug interaction by decreasing the concentration of the substrate drug and reducing its efficacy
C. Results of in vitro experiments conducted with human hepatocytes or liver microsomes can be used to predict the potential for a clinically relevant drug-drug interaction
D. PK-mediated drug interactions may occur due to the high expression drug-metabolizing enzymes in kidney, lung, and muscle
Correct answer: C, Results of in vitro experiments conducted with human hepatocytes or liver microsomes can be used to predict the potential for a clinically relevant drug-drug interaction
Reference: FDA Guidance for Industry: In Vitro Drug Interaction Studies – Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions. CDER, January 2020. page 2.
Rationale: In vitro data generated in CYP inhibition and induction studies using human hepatocytes or liver microsomes can be used to assess the potential and the magnitude of a potential drug interaction. Due to species differences, in vivo studies in nonclinical species are not predictive of a drug interaction in humans. CYP inhibition would result in an increase in drug concentrations and potentially toxicity of the substrate drug, not a reduction in concentration and loss of efficacy. Drug metabolism drug interactions occur primarily in liver and intestine.
477
Which statement is TRUE about the relationship of elimination half-life (t1/2) to clearance and volume of distribution?
A. The elimination t1/2 is dependent on the volume of distribution but is independent of clearance
B. The elimination t1/2 can be calculated from the volume of distribution and the clearance
C. The elimination t1/2 can be calculated as the Dose/AUC
D. If Vd is fixed, t1/2 increases as clearance increases
Correct answer: B, The elimination t1/2 can be calculated from the volume of distribution and the clearance
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education 373.
Rationale: Elimination half-life is calculated as: t1/2 = 0.693 * Vd/CL. t1/2 is dependent on both the Vd and the CL. t1/2 is inversely proportional to CL, so if Vd is fixed, t1/2 will decrease if CL is increased.
478
Which level of the ecological scale is first to combine the solely biotic and abiotic components?
A. Population
B. Community
C. Ecosystem
D. Landscape
Correct answer: C, Ecosystem
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1276.
Rational: An ecosystem is the first combination of the biotic and abiotic components. Choice A is incorrect, as a population is only biotic and is a set of multiple organisms of the same species. Choice B is incorrect, as a community is only biotic and is an assemblage of multiple species. Choice D is incorrect, as a landscape is a spatially expanded ecosystem.
479
Which of the following organism level impact presents the greatest ecotoxicological concern?
A. Lethality
B. Reproductive and developmental
C. Immune compromise
D. Behavior changes
Correct answer: B, Reproductive and developmental
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 1285.
Rational: Reproductive and developmental impacts present the greatest concern because of their direct impacts on population dynamics, a key ecological parameter. A is incorrect, as in most cases, environmental levels are not sufficient to outrightly kill wildlife. C is incorrect, as immune suppression can render organisms susceptible to diseases, but the impact is less than on population dynamics. D is incorrect, as behavior changes can have indirect impacts on population dynamics.
480
Which of the following best explains a Margin of Exposure (MOE) of 25?
A. The relevant NOAEL or BMD(L) is 25 times higher than the estimated human dose
B. The RfD is 25 times greater than the corresponding TD50
C. The exposure is 25 times lower for the patient in question than what is typical for the average individual
D. The relevant NOAEL or BMD(L) is 25 times lower than the estimated dose
Correct Answer: A, The relevant NOAEL or BMD(L) is 25 times higher than the estimated dose
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 134.
Rationale: The MOE is calculated as the NOAEL or BMD(L) divided by the exposure or dose.
481
Which of the following is true regarding Cramer classes and their associated threshold doses?
A. Cramer Class 1 represents chemicals of greatest toxicity
B. They provide a way of comparing the estimated toxicity of any type of chemical
C. The thresholds are based on a statistical analysis of NOAELs for a set of example chemicals
D. They provide data that are often used in adverse outcome pathway (AOP) analyses
Correct answer: C, The thresholds are based on a statistical analysis of NOAELs for a set of example chemicals.
Reference: EFSA Scientific Committee. "Guidance on the use of the Threshold of Toxicological Concern approach in food safety assessment" EFSA Journal 17(6). https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2019.5708
Rationale: Cramer Class 1 chemicals are assumed to be lowest toxicity. The Cramer classification scheme does not work for all chemicals (e.g., not for radionuclides). The thresholds were derived by a statistical evaluation of NOAELs for several hundred chemicals and the use of uncertainty factors. Although questions involved in assigning chemical class can relate to chemical structure, the Cramer class does not really provide useful information as input to an AOP.
482
Which of the following correctly identifies the traditional four components of risk assessment?
A. Chemical analysis, dose characterization, risk calculation and risk management
B. Hazard identification, dose response assessment, exposure assessment and risk characterization
C. Animal/in vitro studies, dose extrapolation, human intake assessment, risk communication
D. Data gathering, weight of evidence evaluation, dose metric selection, uncertainty, and sensitivity analysis
Correct answer: B. Hazard identification, dose response assessment, exposure assessment and risk characterization
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 128.
Rationale: The other answers listed are not elements of the traditional risk assessment paradigm.
483
Which of the following is an important issue with using a NOAEL approach (versus the benchmark dose [BMD] approach) for deriving toxicity criteria?
A. The number of uncertainty or assessment factors is too large when using a NOAEL
B. The NOAEL is based on animal study data that may not be particularly relevant for human health concerns
C. The NOAEL requires one to define a particular effect of interest whereas the benchmark dose approach does not
D. The value of the NOAEL can be strongly influenced by the number of doses and dose placement in the relevant study
Correct Answer: D. The value of the NOAEL can be strongly influenced by the number of doses and dose placement in the relevant study
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 140.
Rationale: The number of uncertainty and assessment factors would not differ when using a NOAEL vs. a BMD. Both the NOAEL and the BMD are typically based on animal study data (with some exceptions, e.g., methylmercury which uses human data) and in both cases the relevance to human health is evaluated. Both the NOAEL and BMD approach require selection of the effect of interest. The final choice is correct;the NOAEL is strongly influenced by the number of doses and where the doses are placed along the dose response curve.
484
Which statement relative to the ECG is correct? A. The QRS interval represents the conduction pathways through the atria B. The PR interval is the measure of time from onset of ventricular activation to end of repolarization C. The QT interval reflects the action potential duration of the ventricles D. Heart failure is associated with up-regulation of two potassium channels (IKs and IKr) and short QT syndrome
Correct answer: C, The QT interval reflects the action potential duration of the ventricles Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 802, 817.
Rationale: Answers A, B, and D are incorrect. The QRS interval represents the conduction pathway through the ventricles. The PR interval is a measure of the time from onset of atrial activation to the onset of ventricular activation. Dysfunction of IKs and IKr is associated with long QT syndrome.
485
From the Best Practice Considerations for the In vivo QT Studies as outlined in the ICH E14/S7B Implementation Working Group Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential Questions and Answers issued in 2022, which of the following statement is incorrect?
A. An assessment of exposure for in-vivo QT studies in different animals from the ones used for the pharmacodynamic assessment is encouraged.
B. It is preferable to use the same animal species in the safety pharmacology and non-rodent toxicity studies to facilitate understanding of the possible relationship between adverse cardiovascular pharmacodynamic effects and structural effects on the heart
C. It is customary to use conscious freely moving telemeterized animals for the in vivo QT studies but the choice of alternative model approaches (e.g., anesthetized or paced animals) might be justified in certain circumstances to achieve adequate exposures or to overcome specific compound-related challenges
D. The sponsor should demonstrate the independence of QTc to RR intervals observed in the study through QTc versus RR plots accompanied by additional information (e.g., number of matched QTc-RR pairs, correlation metric, 95% confidence intervals, p-values)
Correct Answer: A, An assessment of exposure for in-vivo QT studies in different animals from the ones used for the pharmacodynamic assessment is encouraged.
Reference: https://database.ich.org/sites/default/files/ICH_E14-S7B_TrainingMaterial_2022_0407.pdf
Rationale: The ICH Questions and Answers document recommends that exposure for in-vivo QT studies be conducted in the same animals as those used for the pharmacodynamic.
486
From the Best Practice Considerations for In vitro Studies as outlined in the ICH E14/S7B Implementation Working Group Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential Questions and Answers issued in 2022, which of the following statement is incorrect?
A. Patch clamp experiments on cells overexpressing cardiac ion channels, including hERG, CaV1.2, and NaV1.5, should be performed at near physiological temperature (35–37 °C).
B. The primary derived endpoints are inhibitory concentrations such as the IC50 value
C. If 50% current inhibition could not be achieved, a justification of the highest concentration tested should be provided together with the relation of this concentration to therapeutic free and total drug levels.
D. The concentration of test compound to which the cells were exposed should be verified by applying a validated analytical method to the solution collected from dose formulation aliquots.
Correct Answer: D. The concentration of test compound to which the cells were exposed should be verified by applying a validated analytical method to the solution collected from dose formulation aliquots.
Reference: https://database.ich.org/sites/default/files/ICH_E14-S7B_TrainingMaterial_2022_0407.pdf
Rationale: The ICH Questions and Answers document recommends that samples to confirm test compound concentration for in vitro hERG inhibition studies be collected.
487
What could be disadvantages of using the rat for juvenile toxicity studies?
A. For large molecules, the rodent may not be pharmacologically relevant for highly targeted therapies.
B. Well-studied species in juvenile animal studies with extensive historical control data
C. Body size allows most manipulations/administrations starting early preweaning
D. Compressed development allows for inclusion of additional endpoints which are difficult to perform using large animals (such as developmental neurotoxicity, immunotoxicity, fertility/breeding
Correct answer: A, For large molecules the rodent may not be pharmacologically relevant for highly targeted therapies.
Reference: ICH S11 Guideline: None Clinical Safety Testing in Support of Development of Pediatric Medicines. Attachment A, Table A6.
Rationale: Compared to humans, the ability of a rodent to absorb, distribute, metabolize, and excrete a small molecule is still developing for the first few weeks postnatally. For large molecules, the pharmacologic target for that molecule may not exist in the rodent. Answers B thorough D include some of the advantages of using rats for juvenile toxicity studies.
488
In 2021, the US Centers for Disease Control and Prevention (CDC) recommended which of the following action levels for children’s blood lead levels?
A. 0.7 micrograms/deciliter (dL)
B. 3.5 micrograms/dL
C. 5.0 micrograms/dL
D. 25 micrograms/dL
Correct answer: B, 3.5 micrograms/dL
Reference: https://ajph.aphapublications.org/doi/10.2105/AJPH.2021.306429#:~:text=In%202021%2C%20the%20CDC's%20Lead,to%203.5%20micrograms%20per%20deciliter. Rationale: Scientists and clinicians continue to find adverse impacts of childhood lead exposure as action levels are lowered. The prior action level of 5.0 micrograms per deciliter was reduced to 3.5 micrograms/dL.
489
What chemical was found to contaminate hand sanitizers during the COVID-19 pandemic and increase risk of blindness if accidentally ingested? A. Methanol B. Triclosan C. Isopropanol D. Ethanol
Correct answer: A, Methanol Reference: U.S. Food and Drug Administration, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-hand-sanitizers-consumers-should-not-use Rationale: Of the four choices, methanol is the only one well-known to cause blindness. Isopropanol and ethanol are common ingredients in hand sanitizers; triclosan is seldom used for this purpose.
490
With regard to the different cell types in the lung, which cell type works with endothelial cells in the alveolar region of the lung to facilitate gas exchange? A. Club cells B. Type 1 cells C. Type 2 cells D. Alveolar macrophages
Correct answer: B, Type 1 cells
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 698. Rationale: In healthy lungs, oxygen can diffuse across the very thin processes of pulmonary Type 1 cells into alveolar capillaries.
491
What amino acid in foods leads to acrylamide formation in carbohydrate-rich foods that are cooked at high temperatures? A. Alanine B. Arginine C. Aspartic acid D. Asparagine
Correct answer: D, Asparagine Reference: U.S. Food and Drug Administration, 2022. https://www.fda.gov/food/chemical-contaminants-food/acrylamide-questions-and-answers Rationale: Acrylamide forms from sugars and the amino acid asparagine during certain types of high-temperature cooking, such as frying, roasting, and baking.
492
Many heavy metals, including depleted uranium, are toxic to the kidney, and cause release of 2-microglobulin into the urine. Where do these metals primarily cause damage in the kidney? A. Papilla interstitium B. Glomerulus C. Proximal tubules D. Macula densa
Correct answer: C, Proximal tubules
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 676. Rationale: Urinary 2-microglobulin is associated with proximal tubular damage.
493
What size/shape feature BEST defines a nanomaterial? A. At least one dimension less than 100 nm in size B. All dimensions less than 100 nm in size
C. Spherical particles of the same size as a red blood cell D. Flat materials 1-10 nm in thickness
Correct answer: A, At least one dimension less than 100 nm in size Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 1189. Rationale: The National Nanotechnology Institute (NNI; http://www.nano.gov/) defines nanotechnology as the understanding and control of matter at the nanoscale at dimensions between approximately 1 nm and 100 nm.
494
What is the role of treatment with an oxime drug in a person who has been poisoned by an organophosphorus (OP) insecticide?
A. Restoration of the function of the catalytic site of acetylcholinesterase
B. Antagonism of muscarinic acetylcholine receptors
C. Agonism of all classes of acetylcholine receptors
D. Enhancement of the degradation of the insecticide
Correct answer: A, Restoration of the function of the catalytic site of acetylcholinesterase
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 941. Rationale: Atropine antagonizes (not agonizes) muscarinic acetylcholine receptors. OP insecticides are degraded by both cytochrome P450 enzymes and paraoxonases.
495
What class of pesticides may be based on the anti-coagulant warfarin? A. Insecticides B. Insect repellants C. Plant growth regulators D. Rodenticides
Correct answer: Rodenticides
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 968. Rationale: Coumarins, including warfarin, when used as an anticoagulant and a rodenticide, antagonize the Vitamin K pathway, leading to prolonged bleeding. Following the discovery of rats resistant to warfarin, second-generation “superwarfarins” were introduced as anticoagulant rodenticides.
496
In response to water shortages and poor water quality leading to diarrheal diseases in children, the World Bank drilled extremely deep wells to supply pathogen free water to residents of Bangladesh. Within 5-10 years, residents who drank water from these wells began to develop raised, darkly pigmented lesions on the bottoms of their feet, palm of their hands, and torso. To what metal did residents receiving excessively high exposures? A. Arsenic B. Beryllium C. Cadmium D. Chromium
Correct answer: A, Arsenic Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 988. Rationale: Orally ingested arsenic-induced skin lesions are unusual; in that they are most commonly located on non-sun-exposed parts of the body.
497
Which of the following is the second most common cause of adult lung cancer in the U.S.?
A. Cadmium
B. Vaping
C. Radon
D. Ozone
Correct answer: C, Radon
Reference: US Environmental Protection Agency, 2022. https://www.epa.gov/radon/health-risk-radon
Rationale: Radon is a radioactive gas and emits alpha particles, which can cause cytotoxicity and mutations when inhaled.
498
Which of the following statement about kidney toxicity is TRUE?
A. The main target organ for melamine toxicity is the kidney in humans.
B. Over-the-counter analgesics such as aspirin, cause toxicity to the glomerulus in the kidney.
C. The kidney selectively filters toxic molecules into the urine and retains valuable molecules such as glucose.
D. The glomerulus is the site of reabsorption of water in the kidney.
Correct answer: A, The main target organ for melamine toxicity is the kidney in humans.
Reference: Wen J. et al. Asia Pac J Clin Nutr 2016 25(4):697-705.
Rationale: Children who consumed milk adulterated with melamine to enhance the apparent protein concentration of the milk developed kidney stones; some progressed to kidney failure and death. The other statements are not true with regard to kidney function and toxicity
498
Which of the following statements about MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity in humans is TRUE?
A. Caused death of cells in the substantia nigra and symptoms similar to Parkinson's disease
B. Caused cirrhosis of the liver and liver failure.
C. Caused decreased glomerular filtration rate and chronic kidney disease.
D. Is mutagenic and is linked to liver cancer.
Correct answer: A, Caused death of cells in the substantia nigra and symptoms similar to Parkinson's disease
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 754-755
Rationale: MPTP is taken up into the cells of the substantia nigra of the brain via dopamine transporters. In these cells, MPTP causes inhibition of mitochondrial respiration. The other endpoints listed are not associated with MPTP toxicity.
499
What animal species is considered to be a reasonable surrogate for human skin in evaluating drug penetration across the skin and toxic responses? A. Mouse B. Rat C. Rabbit D. Mini-pig
Correct answer: D, mini pig
Reference: Sahota, Pritam S., James A. Popp, Jerry F. Hardisty, and Chirukandath Gopinath, eds. 2013. Toxicologic Pathology: Nonclinical Safety Assessment, 1st ed. Boca Raton, FL: CRC Press.
Rationale: The species that most closely resembles human skin in terms of stratum corneum thickness and epidermal thickness is the pig.
500
According to the World Health Organization, which of the following dietary deficiencies is associated with impaired cognitive development?
A. Selenium
B. Calcium
C. Iodine
D. Trivalent chromium (Cr+3)
Correct answer: C, Iodine
Reference: https://apps.who.int/nutrition/topics/idd/en/index.html
Rationale: Thyroid hormone, which contains iodine, is critical for late prenatal and early postnatal development. Iodine deficiency reduces available thyroid hormone, resulting in impaired cognitive development and potentially more severe mental retardation (cretinism).
501
Which of the following is true concerning perchlorate exposure and the thyroid gland?
A. Perchlorate decreases the synthesis of thyroid hormone by reducing the uptake of tyrosine.
B. Perchlorate decreases the uptake of iodine into the thyroid gland.
C. Perchlorate inhibits the enzyme thyroid peroxidase.
D. Perchlorate inhibits the enzyme 5’-monodeiodinase
Correct answer: B, Perchlorate decreases the uptake of iodine into the thyroid gland.
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 919-920.
Rationale: Perchlorate inhibits the sodium-iodine transporter and reduces the amount of iodine entering the thyroid.
502
Cells may contain influx and efflux transporters. Which of the following correctly pairs the transporter type with the known transporter? A. Efflux: Organic anion transporting polypeptides (OATP) B. Uptake: Bile salt export pump (BSEP)
C. Efflux: Breast cancer resistance protein (BCRP)
D. Uptake: p-Glycoprotein (Pgp)
Correct answer: C, Efflux: BCRP
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 725 (Figure 13-6).
Rationale: Knowledge of transporters and role of transporters in toxicity and elimination of xenobiotics is important for understanding liver function.
502
Which of the following is TRUE regarding the oxygen content of incoming blood flow via the hepatic artery and portal vein?
A. Zone 1 has the lowest oxygen utilization (~4-5%)
B. Zone 2 has the highest oxygen utilization (~9%)
C. Similar oxygen utilization throughout the hepatic acinus
D. Zone 1 has the highest oxygen utilization (~9-13%)
Correct answer: D, Zone 1 has the highest oxygen utilization in the liver
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 640.
Rationale: Knowledge of oxygen utilization within the hepatic acinus (zones) is important for understanding functional consequence of metabolism
503
Which of the following cell types in the liver that have an immune function?
A. Kupffer and endothelial cells
B. Kupffer and stellate cells
C. Kupffer and Ito cells
D. Endothelial cells and stellate cells
Correct answer: A, Kupffer and endothelial cells
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 721-724.
Rationale: Kupffer (resident liver macrophages) and endothelial cells are the immune cells of the liver responsible for immune-mediated responses, e.g., cytokine release.
503
Which of the following is correct about hepatic steatosis?
A. Aflatoxin an example of a xenobiotic that causes hepatic steatosis
B. Extra-hepatic transport of free fatty acids does not occur in steatosis
C. Non-alcoholic steatohepatitis (NASH) is primarily due to increased insulin resistance
D. Is due to the accumulation of lipids and triglycerides in the hepatocyte
Correct answer: C, Non-alcoholic steatohepatitis (NASH) is primarily due to increased insulin resistance
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 727-728; 1371-1372.
Rationale: Steatosis may progress to NASH (non-alcoholic fatty liver disease, NFLD) and is associated with accumulation of non-triglyceride fatty acids (FFAs) from extra-hepatic (adipose) and hepatic accumulation in the hepatocyte.
504
Which of the following describes apoptosis, compared to necrosis?
A. Apoptosis is characterized by cell swelling
B. Apoptosis is a single cell event
C. Apoptosis involves the influx of inflammatory mediators and cellular infiltrates
D. Apoptosis results in the release of cellular constituents including alanine aminotransferase (ALT) and damaged-associated molecular patterns (DAMPS)
Correct answer: B, Apoptosis is a single cell event
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 726.
Rationale: Apoptosis is a single cell event. All other answers described necrosis.
505
All of the following characteristic is TRUE for idiosyncratic drug induced liver injury (iDILI) EXCEPT:
A. Idiosyncratic liver injury is observed with a diverse spectrum of xenobiotics
B. Idiosyncratic liver injury is always dose-dependent
C. Idiosyncratic liver injury is a rare occurrence and difficult to predict through pre-clinical testing
D. Idiosyncratic liver injury has also been associated with consumption of herbal remedies and food supplements
Correct answer: B, Idiosyncratic liver injury is always dose-dependent
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 656-658.
Rationale: Idiosyncratic reactions are NOT always dose-dependent. Idiosyncratic drug hepatotoxicity is a rare but potentially serious adverse event, which is not clearly dose-dependent. iDILI is often unpredictable and has been observed consumption of herbal remedies and food supplements.
506
The apparent volume of distribution (Vd) can be described by the following EXCEPT:
A. Is defined as the ratio of volume to mg of the toxicant
B. Does not correspond to a realistic anatomical volume
C. In a one-compartment model, the toxicant instantaneously equilibrates between the blood (plasma) and tissue
D. The Vd can be greater than 1.0, particularly for highly lipophilic toxicants
Correct answer: C, For a one-compartment model, first order kinetics proceeds as a variable rate of elimination
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 368-369.
Rationale: As a log plasma concentration vs. time, a first order figures results in a linear plot compared to an exponential plot as a non-log vs. time plot. Because of the assumptions in a one-compartment model, elimination proceeds at a constant rate and the half-life of elimination is constant. Ethanol is the classic example of zero-order kinetics.
507
Dermal sensitization methods that utilize Freund’s Complete Adjuvant (FCA) include all of the following EXCEPT:
A. Guinea pig maximization test
B. Buehler method
C. Mouse ear swelling test
D. Optimization test
Correct answer: B, Buehler method
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 1352-1357.
Rationale: Knowledge of methods used for delayed hypersensitivity is needed to ensure study design optimization.
508
In the evaluation of ocular irritation, regulatory classification of an irritant is based on a score of 1-110 based on all of the following EXCEPT:
A. The rabbit is the preferred species
B. Scoring of the cornea
C. Scoring of the lens
D. Scoring for edema
Correct answer: C, Scoring of the lens
Reference: Hayes, A. Wallace, and Claire L. Kruger, eds. 2014. Hayes’ Principles and Methods of Toxicology, 6th ed. Boca Raton, FL: CRC Press. 1141. OECD TG 405, 2021. Test Guideline No. 405: In Vivo Eye Irritation/Serious Eye Damage (oecd-ilibrary.org)
Rationale: Knowledge of methods used for determining the ocular irritation scoring is needed to ensure study design optimization. Eye irritation is based on scoring of the cornea, conjunctiva and iris.
509
Skin penetration of a xenobiotic and resultant toxicity is determined by all of the following EXCEPT:
A. Presentation of the parent compound only to Langerhans cells resulting in Type IV hypersensitivity
B. Hydration of the skin
C. The pH of the xenobiotic and absorption into systemic blood supply
C. Skin contact site on the body
Correct answer: A, Presentation of the parent compound only to Langerhans cells resulting in Type IV hypersensitivity
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 842-843.
Hayes, A. Wallace, and Claire L. Kruger, eds. 2014. Hayes’ Principles and Methods of Toxicology, 6th ed. Boca Raton, FL: CRC Press. 347.
Rationale: Knowledge of ability of compounds to be metabolized in the skin is necessary for a complete safety evaluation of a topically applied compound.
510
A method for evaluating physiological retinal function of dark- and light-adaptation is:
A. Functional observational battery (FOB)
B. Angiography
C. Electroretinogram (ERG)
D. Optical coherence tomography (OCT)
Correct answer: C, Electroretinogram (ERG)
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 776.
Rationale: Knowledge of the available methods for nonclinical evaluation of ocular function is necessary for a complete safety evaluation of the eye.
511
All of the following are examples of ionizing radiation EXCEPT:
A. Ultraviolet (UV) radiation
B. Gamma rays
C. X-rays
D. Alpha particles
Correct answer: A, Ultraviolet (UV) radiation
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 1113.
Rationale: Knowledge of the different forms of radiation is necessary for a general toxicologist.
512
What is the toxic effect of tetrodotoxin, found in the puffer fish liver?
A. Paralyzes diaphragm muscles (skeletal) causing respiratory arrest
B. Degeneration of renal tubular epithelium
C. Causes severe hepatocyte degeneration
D. Aplastic anemia
Correct answer: A, Paralyzes diaphragm muscles (skeletal) causing respiratory arrest
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 50.
Rationale: Knowledge of the mechanism of action of natural toxins is necessary for a general toxicologist.
513
Which site of deposition is most likely for particles having a dimension of >10 μm in the human respiratory tract?
A. Nose and oral pharynx
B. Upper bronchi by impaction
C. Alveoli by Brownian movement
D. Sedimentation in the proximal airway
Correct answer: A, Nose and oral pharynx
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 804-805 (Figure 15-7).
Rationale: Knowledge of the mechanics of particle deposition and airflow into the respiratory system is critical to understanding regional toxicity
514
Hydrogen fluoride (hydrofluoric acid, HF) is a highly toxic substance with inhalation or dermal exposure in occupational settings. Which of the following statements about HF is correct?
A. Causes minimal lower respiratory irritation
B. Causes systemic hypocalcemia
C. Causes bone fluorosis with acute exposure
D. Causes liver cancer with long-term, high-level exposure
Correct answer: B, Causes systemic hypocalcemia
Reference: Dart’s Medical Toxicology, 2004. 1133, 1352-1357.
Rationale: Knowledge of the toxicology of inhaled HF is important for occupational settings to ensure controls are in place.
515
Which statement is correct about the deposition of fibers in the lung?
A. Fibers are deposited all along the respiratory tree regardless of size
B. Deposition of fibers is accounted for by fiber length and diameter only
C. Longer fibers (>10 μm) tend to be less toxic than shorter fibers (<5 μm)
D. Mesothelioma is associated with asbestosis fibers of <0.5 μm
Correct answer: D, Mesothelioma is associated with asbestosis fibers of <0.5 μm
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 823-824 (Table 15-7).
Rationale: Knowledge of the mechanics of fiber deposition, fiber aspect ratio and airflow into the respiratory system is critical to understanding regional toxicity.
516
The site of ototoxicity of agents is often associated with which of the following?
A. Vancomycin and disruption of fluid mechanics in the vestibule
B. Furosemide and disruption of tympanic membrane
C. Vancomycin and hair cell necrosis (Organ of Corti)
D. NSAIDs and systemic alkalosis
Correct answer: C, Vancomycin and hair cell necrosis (Organ of Corti) Reference: Bruniera FR, et al. The use of vancomycin with its therapeutic and adverse effects: a review. Eur Rev Med Pharmacol Sci. 2015 Feb;19(4):694-700.
Rationale: Knowledge of the side effects of therapeutics is a basic understanding of toxicity.
517
Which statement relative to the ICH S7A guideline is correct?
A. For in vitro studies, the upper limit of the concentration range may be influenced by physico-chemical properties of the test substance
B. Central nervous system assessment related to learning and memory is required as per Safety Pharmacology core battery.
C. Safety pharmacology is not required for novel biotechnology-derived products that do not achieve highly specific receptor targeting
D. Secondary pharmacodynamic studies generally need to be conducted in compliance
with GLP.
Correct answer: A, For in vitro studies, the upper limit of the concentration range may be influenced by physico-chemical properties of the test substance
Reference: ICH S7A approved guideline
Rationale: Knowledge of the specifics of ICH S7 is needed to determine when such studies are required or not required. Biotechnology derived products will generally require safety pharmacology studies but not always.
518
Which statement relative to cardiac biomarkers is correct? A. Troponin T (cTnT) and I (cTnI) are expressed in various muscles including cardiomyocytes B. C-Reactive Protein (CRP) is recognized as a selective biomarker of cardiac inflammation C. Creatine kinase BB (CK-BB) is the predominant isoform of CK isoenzymes found in the myocardium D. B-Type Natriuretic Peptide (BNP) is secreted by the ventricular myocardium in response to volume and pressure overload
Correct answer: D, B-Type Natriuretic Peptide (BNP) is secreted by the ventricular myocardium in response to volume and pressure overload. Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 818. Rationale: Answers A–C are incorrect. The troponins are expressed exclusively in cardiac myocytes. CRP is a biomarker of systemic and vascular inflammation. CK-BB is predominantly expressed in brain and kidney.
519
Which of the following is true of ICH M7?
A. Allows for the consideration of in silico predictions in place of in vitro studies
B. Specifies six strains of Salmonella that must be used in genotoxicity assays
C. Focuses on non-genotoxic impurities in pharmaceuticals
D. Eliminates the need for an expert rule-based predictive systems
Correct answer: A, Allows for the consideration of in silico predictions in place of in vitro studies. Reference: Barber C, Amberg A, Custer et al. Establishing best practice in the application of expert review of mutagenicity under ICH M7. Regul Toxicol Pharmacol. 2015 Oct;73(1):367-77.
Rationale: ICH M7 seeks to detect genotoxic impurities in pharmaceuticals, allows for consideration of in silico predictions, with two tiers of validation: an expert rule-based predictive system and a statistical predictive system.
520
Which statement relative to the ICH S7B guideline is correct?
A. The upstroke of the action potential is primarily a consequence of a rapid, transient influx of K+
B. A sub-maximally effective concentration of a positive control substance should be used to demonstrate the responsiveness of in vitro preparations for ion channel and action potential duration assays and should be included in every study
C. Laboratory animal species used for in vivo electrophysiology studies include rat, dog, monkey, swine, rabbit, ferret, and guinea pig
D. QT is considered to be a cardiac safety biomarker that is independent from heart rate
Correct answer: B, A sub-maximally effective concentration of a positive control substance should be used to demonstrate the responsiveness of in vitro preparations for ion channel and action
Reference: ICH S7B approved guideline
Rationale: Knowledge of the requirements for undertaking in vitro studies and the specifications of a protocol design are critical to determining a potential cardiac risk.
521
Methotrexate decreases pro-inflammatory signaling through which mechanism?
A. Inhibition of cyclooxygenase 1 and 2
B. Inhibition of dihydrofolate reductase
C. Inhibition of the glucocorticoid receptor
D. Inhibition of HMG-CoA reductase
Correct answer: B, Inhibition of dihydrofolate reductase
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 565.
Graffner-Nordberg, et al., Design and synthesis of dihydrofolate reductase inhibitors encompassing a bridging ester group. Evaluation in a mouse colitis model. J Med Chem. 2003;46(16):3455-62.
Rationale: Methotrexate decreases inflammation by dihydrofolate reductase, which decreases lymphocyte activation and translocation.
522
Which statement relative to the effects of Rapamycin and Tacrolimus is correct? A. Rapamycin and tacrolimus may produce adverse cardiovascular effects including hypotension B. Rapamycin and tacrolimus may produce adverse cardiovascular effects including hypermagnesemia C. Rapamycin and tacrolimus may produce adverse cardiovascular effects including hyperkalemia D. Rapamycin and tacrolimus interact with a protein that associates with ryanodine receptors (RyRs) which become destabilized resulting in Ca2+ leak from the sarcoplasmic reticulum
Correct answer: D, Rapamycin and tacrolimus interact with a protein that associates with ryanodine receptors (RyRs) which become destabilized resulting in Ca2+ leak from the sarcoplasmic reticulum Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 823, 824.
Rationale: Adverse cardiovascular effects of these two immunosuppressive drugs include hypertension, hypokalemia (low blood potassium), and hypomagnesemia
523
Which of the following official determinations gives the U.S. FDA the authority to have a food recalled?
A. Unfit
B. Adulterated
C. Nonnutritive
D. Contaminated
Correct answer: B, Adulterated Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1330, 1576.
Rationale: Basic knowledge of the FD&C Act is necessary for a general toxicologist that evaluate foods or any other xenobiotic that may appear in foods.
524
Food hypersensitivity could be due to which of the following?
A. Immune reactions
B. Pancreatic anomalies
C. Psychological preferences
D. Thyroid issues
Correct answer: A, Immune reactions Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 1352-1354.
Rationale: Basic knowledge of the occurrence of food allergy is necessary for a general toxicologist that evaluate foods or any other xenobiotic that may appear in foods
525
Which of the following types of biomarker is defined as one that is measured in a biological compartment of an individual?
A. Biomarker of effect
B. Biomarker of interaction
C. Biomarker of susceptibility
D. Biomarker of exposure
Correct answer: D, Biomarker of exposure Reference: Lowry LK. Role of biomarkers of exposure in the assessment of health risks. Toxicol Lett. 1995 May;77(1-3):31-8.
Rationale: Biomarker of exposure is the biomarker (e.g., parent chemical, metabolite(s), etc.) that is measured in a biological compartment (blood, urine, etc.). The others are defined differently; the biomarker of interaction is not a recognized biomarker.
526
Information required to be provided to employees under the OSHA Hazard Communication Standard (HCS) includes:
A. Understanding information on safety data sheets (SDSs) and labels and how OELs are derived
B. How to write safety data sheets (SDSs) for chemicals used in their workplace
C. Understanding information on safety data sheets (SDSs) and labels
D. Only information on the health hazards of chemicals used in their workplace
answer: C. Understanding information on safety data sheets (SDSs) and labels.
Reference: Hayes Principles and Methods (6th edition; 2014) pages 687 and 695.
Rationale: The OSHA HCS is specific in that both physical and health hazards of chemicals used in the workplace are covered (so D is not correct). The HCS also includes training on how to use/understand information contained in SDSs but not how to write them (so choice B is not correct). Choice A is not correct with regard to how OELs are derived.
527
In the Multistage Model of Carcinogenesis, which one of the following is correctly paired?
A. Initiation – considered to be a reversible event
B. Progression – considered to be a reversible event
C. Promotion – considered to be a reversible event
D. Promotion - considered to be an irreversible event
Correct answer: C, Promotion – considered to be a reversible event
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 398.
Rationale: In the Multistage Model of Carcinogenesis, initiation and progression are considered to be irreversible events; promotion is the only one of the three that is considered to be reversible.
528
Which of the following would be an example of a non-genotoxic (epigenetic) chemical carcinogen?
A. Carbon tetrachloride
B. Vinyl chloride
C. Acrylamide
D. Dimethyl sulfate
Correct answer: A, Carbon tetrachloride Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 1061.
Rationale: Choices B, C and D all are genotoxic carcinogens. Carbon tetrachloride is considered to be a nongenotoxic carcinogen (acts as a cytotoxicant).
529
What phase of the cell cycle is DNA considered to be most susceptible to damage by physical and chemical agents?
A. M-Phase (mitosis)
B. S-Phase
C. G2-Phase
D. G1-Phase
Correct answer: B, S-Phase Reference: Smart, Robert C, Hodgson E., eds. 2008. Molecular and Biochemical Toxicology, 4th ed. John Wiley & Sons, Inc. 442.
Rationale: The S-phase is when DNA replication occurs – DNA is unwound for replication and highly susceptible to electrophilic chemical/metabolite attack at its nucleophilic centers.
530
Which of the following is a characteristic of malignant neoplasms?
A. Relatively slow growing
B. Often encapsulated
C. Poorly-differentiated
D. Relatively few mitotic cells
Correct answer: C, Poorly-differentiated
Reference: Chapter 4. Neoplasia. In: Pathology: The Big Picture. McGraw-Hill; 2008.
Rationale: Choices A, B and D are characteristics of benign neoplasms
531
Superoxide dismutase, glutathione peroxidases, and peroxiredoxins are involved in the detoxification of what type of biotransformation products?
A. Nucleophiles
B. Free radicals
C. Electrophiles
D. Protein toxins
Correct answer: B, Free radicals
Reference: Klaassen, Curtis D., ed. 2013. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 8th ed. New York: McGraw-Hill Education. 57-58.
Rationale: Nucleophiles are generally detoxified by conjugation at the nucleophilic functional group. Electrophiles are often detoxified by conjugation with reduced glutathione. Thioredoxin and proteases detoxify many protein toxins.
532
According to the Gell and Coombs classification system, T cell-mediated sensitization reactions fall under which category?
A. Type I
B. Type II
C. Type III
D. Type IV
A68. Correct answer: D, Type IV
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 646-648.
Rationale: Type IV hypersensitivity reactions are mediated by T cells, rather than B cells/antibodies.
533
Which form of anemia may be attributed to a deficiency in hemoglobin production despite the presence of iron?
A. Hemolytic anemia
B. Aplastic anemia
C. Sideroblastic anemia
D. Megaloblastic anemia
Correct answer: C, Sideroblastic anemia
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 597-598.
Rationale: Sideroblastic anemia is caused by a deficiency of heme biosynthesis, which results in decreased hemoglobin formation, even in the presence of excess iron.
534
Which of the following drug classes are known to induce hypersensitivity reactions through the formation of a hapten-protein complex?
A. ACE inhibitors
B. β-lactam antibiotics
C. Local anesthetics
D. Sulfonamides
Correct answer: B, β-lactam antibiotics
Reference: Klaassen, Curtis D., ed. 2018. Casarett & Doull’s Toxicology: The Basic Science of Poisons, 9th ed. New York: McGraw-Hill Education. 76-77; 693-694.
Rationale: Haptens are peptides that are too small to be recognized as antigens by the immune system but become antigenic when they bind to other proteins such as carrier proteins. β-lactam antibiotics, such as penicillin, are known to induce hypersensitivity reactions through the hapten response.
535
What drug inhibits steroidogenesis causing ovarian histological changes?
Ketoconazole
536
What drug has mixed estrogen agonist-antagonist activities?
Tamoxifen
537
What drug is an estrogenic pesticide that is successfully detected by accelerated puberty?
Methoxychlor
538
What drug is used as a positive estrogenic control?
Ethinyl estradiol
539
What drug alters liver, hypothalamic, pituitary, and ovarian function and delays puberty?
Phenobarbital
540
What drug is a weak estrogenic plastic monomer with negative endocrine effects?
Bisphenol A
541
What drug is an anti-thyroid agent that lowers T4, increases TSH, and causes thyroid histological changes at low doses that slightly delays rat puberty?
Propylthiouracil
542
What drug is a fungicide that weakly inhibits aromatase, slightly delays puberty, and lowers T4 and retards growth?
Fenarimol
543
What drug is an herbicide that alters hypothalamic-pituitary function and delays puberty and growth?
Atrazine
544
What drug is an estrogenic pesticide that accelerates puberty?
Methoxychlor
545
What drug is an anti-thyroid toxicant that affects thyroid endpoints and delays puberty?
Polybrominated diphenyl ether
546
What drug is an aromatase inhibitor and delays puberty?
Fadrazole
547
What drug is a gonadotripin-releasing hormaone antagonist that delays puberty?
Antarelix
548
What drug is an estrogenic surfactant that accelerates female rat puberty?
Octylphenol
549
What drug is an estrogenic pharmaceutical that accelerates puberty?
DES
550
ICI 182, 780 and ZM 189,154 are estrogeneic receptor antagonists that delay puberty? True or False?
True
551
What chemical is an Alkylating drug that treats: chronic myelogenous leukemia, myeloproliferative dz, myelofibrosis, bone marrow transplant
In rodents: prenatal treatment inhibits germ cell development, delayed puberty, reduced fertility, and disrupted hormone development.
Busulfan
552
What chemical is a Flame retardants, flavors and fragrances, solvent
Destroys prenatal follicles
4-Vinylcyclohexene (VCH)
553
Chlorosugars and epichlorohydrin have what effect on sperm?
Inhibit energy metabolism
554
What chemical avoids the HPG axis and can have a testicular effect causing lesions?
m-Dinitrobenzene (DNB)
555
What chemical metabolizes to methoxyacetaldehyde and methoxyacetid acid (MAA) and affects spermatogenesis?
Ethylene Glycol Monomethyl Ether (EGME)
556
Exposure to this chemical causes chloracne.
Polychlorinated dibenzodioxins (PCDDs): 2,3,7,8- Tetrachlorodibenzo-p-dioxin
557
What Organotin is known to have profound but reversible thymic atrophy?
Tributylin oxide
558
