1
Q
- 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
OSHA administers regulations regarding worker safety, not the EPA.
2
Q
- 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.
A
The AWA requires each animal research facility to establish an IACUC.
3
Q
- 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.
A
B, Require that a testing facility employ a diverse laboratory staff.
4
Q
- 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
A
C.
Anticholinesterase insecticides (e.g., organophosphates, carbamates) inhibit acetylcholinesterase, leading to accumulation of acetylcholine at synapses → overstimulation of muscarinic and nicotinic receptors.
Typical signs (cholinergic toxidrome):
Muscarinic: Miosis, blurred vision, bronchorrhea (excessive bronchial secretions), bronchospasm, bradycardia, increased GI motility → diarrhea, abdominal cramps, urinary frequency.
Nicotinic: Muscle twitching, fasciculations, weakness, paralysis.
CNS: Anxiety, confusion, convulsions, coma.
Therefore, urinary retention and slowed GI motility are not features—instead, you get urinary urgency/incontinence and diarrhea.
5
Q
- 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
A
C: Hydroxyl radicals are toxic species, and their formation is enhanced in the presence of oxygen, so oxygen
treatment of a paraquat-poisoned patient is counter-indicated, even in light of breathing difficulties.
6
Q
- Which of the following is a direct-acting alkylating carcinogen?
A. Ethylene oxide
B. Benzene
C. 1-Naphthylamine
D. Naphthalene
A
A.
Benzene, 1-naphthylamine, and naphthalene are biotransformed to toxic, carcinogenic metabolites; ethylene oxide is a direct-acting epoxide.
Direct-acting alkylating carcinogens = already electrophilic, don’t need metabolic bioactivation (e.g., ethylene oxide, β-propiolactone, bis(chloromethyl) ether).
Indirect (procarcinogens) = require metabolic activation (e.g., benzo[a]pyrene, benzene, vinyl chloride, aromatic amines).
7
Q
- 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
A, **Renal toxicity **due to oxalic acid formation.
8
Q
- 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.
A
C. CYP2E1 in the liver, as well as peroxidases and myeloperoxidases in bone marrow, generate toxic metabolites
of benzene, including catechol and hydroquinone, which can rearrange to extremely reactive metabolites such as o- and
p-benzoquinone.
9
Q
- 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 cochlea
B. Inhibition of monoamine oxidase B
C. Toxicity to Schwann cells
D. Degeneration of dopaminergic neurons in substantia nigra
A
D. MPTP is biotransformed to MPP+ by monoamine oxidase B; MPP+ is a substrate for the** dopamine transporter,
which is localized on dopamine neurons, including those in the substantia nigra**
MPTP → تبدیل به MPP⁺ → تخریب نورونهای دوپامینرژیک جسم سیاه → علائم پارکینسون.
10
Q
- 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.
A
glutamate is referred to as an “excitotoxin,”and memory loss can be a symptom of exposure to glutamate receptor
agonists, such as domoic acid, with brain lesions found in the hippocampus.
گلوتامات = مهمترین انتقالدهنده تحریکی مغز؛ برای یادگیری/حافظه ضروری اس
11
Q
- Which of the following solvents is associated with anemia, leukopenia, and chronic myelogenous leukemia?
A. Carbon disulfide
B. Ethylene glycol
C. Xylene
D. Benzene
A
Benzene is a bone marrow toxicant; the stated symptoms are not observed with carbon disulfide, ethylene glycol,
or xylene.
12
Q
- 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.
A
B.
, Competing with alcohol dehydrogenase to prevent metabolite formation.
Ethanol or fomipazol prevent formation of** formaldehyde and formate**, which lead to acidosis and
potential blindness
13
Q
- Which of the following cytochrome P450 (CYP) enzymes is most susceptible to inhibition by furanocoumarins in grapefruit juice?
A. CYP2D6
B. CYP2E1
C. CYP3A4
D. CYP4F1
A
c
Drugs that are extensively metabolized by CYP3A4 often carry a warning label, advising against consumption of
grapefruit or grapefruit juice, as this can inhibit preabsorption drug inactivation and enhanced gastrointestinal absorption,
leading to higher-than-expected blood concentrations of the drug.
14
Q
- 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.
A
C.
Mercury binds to cysteine and becomes a substrate for the organic anion transporter, and to a lesser extent, amino acid transporters.
—————
Hg⁰ (elemental vapor): crosses by passive diffusion (lipid-soluble).
Methylmercury: crosses via LAT1 transporter as a cysteine conjugate (mimics methionine).
Hg²⁺ (inorganic): does not cross BBB significantly.
15
Q
- 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.
A
d.
the hallmark of aflatoxin toxicity is** P450 bioactivation → epoxide → DNA adducts** →** hepatocellular carcinoma.**
16
Q
- 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
a. ulfation and glutathione conjugation are detoxification mechanisms for acetaminophen. Sulfation and
glucuronidation occur at the hydroxyl group that is inherent to the structure of acetaminophen.The quinoneimine
metabolite is formed when the amount of acetaminophen present saturates conjugation capacity, and formation of this toxic
metabolite is due to CYP2E1 activity.
17
Q
- 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
A
B, Trichloroethylene
18
Q
- 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 and Toxicant Extrusion Proteins (MATE)
A
d.
ATP-binding cassette (ABC) transporters:
Use ATP hydrolysis to transport substrates across membranes.**
Examples:
ABC = ATP-powered efflux.
**MRPs **(ABCC family) → efflux of drug conjugates
BCRP (ABCG2) → breast cancer resistance protein
BSEP (ABCB11) → bile salt export |
SLC = solute carriers, gradient-driven (influx & efflux).
OATs (Organic Anion Transporters, SLC22) → uptake of drug anions
**OCTs **(Organic Cation Transporters, SLC22) → uptake of drug cations
MATEs (Multidrug and Toxicant Extrusion, SLC47) → drug efflux using H⁺/Na⁺ gradient
GLUTs (SLC2) → glucose transport |
19
Q
- 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
a.
One of the advantages of compartmental modeling is that tissue physiology or anatomic structure is not required.
20
Q
- 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.
A
c.hemicals can cause DNA alterations by forming DNA adducts or intercalating between DNA
base pairs.
21
Q
- 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
A
The Salmonella tester strains used in the bacterial mutation assay (OECD 471) were developed by Bruce Ames
(UC Berkley) and are defected in the UvrABC genes involved in excision repair.
22
Q
- 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
A
D. The micronucleus assay has been validated as a replacement for the chromosomal aberration assay in the Genetic
Toxicology test battery.
23
Q
- 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)
A
C. The liver homogenate preparation used for in vitro genetic toxicology test includes cofactors for the synthesis of
NADPH, a co-factor required for the CYP450 enzyme family.
24
Q
- 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
A. : The Comet assay uses a single cell gel electrophoresis technique to quantify DNA from the nuclei of cells
embedded in agarose on a slide. The images of the nuclear DNA are quantified by validated software systems that quantify
the amount of DNA in the nucleus and the amount of DNA electrophoresed away from the nucleus to form a tail. Percent Tail
DNA is the preferred reporting parameter for the Comet assay that quantifies the total DNA and the amount present in the
tail to determine percent Tail DNA.
25
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. Stage in which internal and/or external stimuli induce reversible clonal expansion of an initiated
cell population.
26
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.
Epigenetic is used more broadly = any non-genotoxic mechanism of carcinogenesis.
“Non-genotoxic” = does not directly damage DNA sequence.
Includes receptor-mediated signaling, protein accumulation, cell death + compensatory proliferation.
B (α2u-globulin): تجمع پروتئین → آسیب فیزیکی به سلول → غیر گیرندهمحور.
C (PPAR-α): فعالسازی گیرنده هستهای → تغییر بیان ژن → گیرندهمحور.
27
27. 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. Biopersistence of 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.
Alternatives to rodent bioassays for carcinogenicity assessment of pharmaceuticals are being explored, including
submission of a carcinogenicity assessment document (CAD) to support a waiver of bioassay testing. The incorrect answers
are some of the effects observed in preclinical testing that are indicative of carcinogenic potential. Poor absorption would
minimize the systemic exposure to the agent and thus not be considered a likely predictive high-risk factor.
28
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.
FIFRA = use & sale of pesticides.
FFDCA = residues in food.
FQPA = modern safety reform, amends both laws, adds child protection.
PRIA = fee system for pesticide registration (still in force).
## Footnote
The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) regulates the registration, distribution, sale, and use of pesticides, requiring EPA approval based on an “unreasonable adverse effects” standard. The Federal Food, Drug, and Cosmetic Act (FFDCA) governs pesticide residues in food and feed, with EPA setting tolerance levels that FDA and USDA enforce. The Food Quality Protection Act (FQPA) of 1996 amended both FIFRA and FFDCA, unifying pesticide residue regulation under a single health-based standard, adding special child safety protections, and requiring regular tolerance reassessment. Finally, the Pesticide Registration Improvement Act (PRIA) of 2004 amended FIFRA to create a fee-for-service system that funds EPA’s pesticide registration reviews and has been reauthorized multiple times.
29
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.
The molecular target for **diamide** insecticides is ryanodine receptors (**calcium channels)**, not sodium channels.
Pyrethroids → Classic sodium channel modulators (keep channels open → hyperexcitation).
DDT → Also a sodium channel modulator, prolongs channel opening → tremors/seizures.
Dihydropyrazoles → Also target sodium channels, similar mode of action.
Diamides → Different! They act on **ryanodine receptors (RyR) in muscle cells**, releasing stored Ca²⁺ → muscle contraction, paralysis. Not sodium channel–targeting.
30
30. Identify which pesticide or type of pesticide is NOT correctly matched with its toxic 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
## Footnote
****Carbamates
**Short-lived **AChE inhibition (**reversible carbamylation)**.
Cause acute cholinergic crisis (SLUD, DUMBBELSS).
**Do NOT cause delayed polyneuropath**y.
Atropine works, **pralidoxime (2-PAM) usually unnecessary**.
Organophosphates
**Long-lasting **AChE inhibition **(irreversible phosphorylation, **unless treated quickly with 2-PAM).
Cause acute cholinergic crisis (SLUD/DUMBBELSS) plus possible **delayed polyneuropathy ****(OPIDP) after high or repeated exposure.
**Both atropine + pralidoxime (2-PAM) are used in treatment.**
31
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. Risk-specific dose (RSD) = the exposure level corresponding to a given cancer risk
RSD= Target Risk / Slope Factor (Potency)
Slope factor (SF) = potency, usually in (risk per mg/kg-day).
Target risk = typically 10⁻⁶ or 10⁻⁵
## Footnote
The OSF represents the upper bound of the lifetime cancer risk per unit of lifetime average daily dose (in mg/kg-day) and is used to estimate the cancer risk of a specific chemical by multiplying it by the exposure dose.
32
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.
UFH (human variability, intraspecies): protects sensitive subgroups like children, elderly, or genetically susceptible people. Default = 10.
UFA (animal to human, interspecies): adjusts for differences between test animals and humans, split into toxicokinetic and toxicodynamic parts. Default = 10.
UFS (subchronic to chronic): applied if only a subchronic study is available, since chronic studies might reveal more severe effects. Default = 10.
UFL (LOAEL to NOAEL): applied if only a LOAEL is available. Not needed if a BMD or BMDL is used (then UFL = 1). Default = 10.
UFD (database deficiency): applied if the toxicology database is incomplete (e.g., missing developmental or reproductive studies). Usually 3 or 10.
33
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. mode-of-action evaluation should be part of any chemical assessment, at least in the broad sense. Consideration
of human relevance requires knowledge of the mode of action in the experimental animal, and is done using the** ILSI/
IPCS mode of action/human relevance framework.** Hazard characterization for a carcinogen results in a descriptor or
cancer narrative.
34
34. Which of the following is CORRECT relative to the I kr?
A. The I kr is a current mostly observed during Phase 0 (i.e., cardiac depolarization).
B. The Ikr current originates from a channel assembled from the KVLQT1.
C. The Ikr channel is a cardiac voltage gated sodium channel.
D. Along with I_Ks, the Ikr is responsible for termination of the plateau phase of the action potential.
****D.
Cardiac muscle cells (ventricular myocytes) generate an electrical signal that has 5 phases (0–4):
Phase 0 – Rapid Depolarization
Triggered by Na⁺ influx through fast sodium channels.
This is the steep “upstroke” of the action potential.
NOT where I_Kr acts.
Phase 1 – Early Repolarization
A small, brief outward K⁺ current (I_to) brings voltage slightly down.
Phase 2 – Plateau Phase
**A balance between Ca²⁺ influx (L-type calcium channels) and K⁺ efflux.**
This plateau is crucial for contraction.
Phase 3 – Repolarization
**K⁺ currents dominate.**
**
I_Kr (rapid delayed rectifier K⁺ current) and I_Ks (slow delayed rectifier K⁺ current) push the membrane potential back down**.
This is where I_Kr plays its main role.
Phase 4 – Resting Membrane Potential
Stable potential, maintained by inward rectifier K⁺ channels (I_K1).
35
35. Which statement relative to cardiac biomarkers is CORRECT?
A. Troponin T (cTnT) and I (cTnI) 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
36
36. Which statement relative to the electrocardiogram (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 (I_Kr and I_Ks) and short QT syndrome.
C
37
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
Carbon monoxide binds with hemoglobin to form carboxyhemoglobin. Methemoglobin results from increased
oxidation of hemoglobin unrelated to carbon monoxide exposure. Bilirubin is a catabolic product of hemoglobin not
associated with carbon monoxide exposure. Hemin results from hemolysis unrelated to carbon monoxide exposure.
38
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. The Murine Local Lymph Node Assay (LLNA) is an in vivo test in mice.
It measures lymphocyte proliferation in the draining lymph nodes after topical application of a chemical.
Purpose: to determine if a substance can act as a skin sensitizer → leading to allergic contact dermatitis (Type IV hypersensitivity, T-cell mediated).
39
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.
**Basophilic stippling** = presence of **small, dark-blue granules **(aggregates of ribosomal RNA) in red blood cells.
It occurs when heme synthesis is disrupted.
**Lead** poisoning inhibits δ-aminolevulinic acid dehydratase (**ALAD) and ferrochelatase**, key enzymes in heme biosynthesis.
Result → **defective hemoglobin synthesis + ribosomal RNA clumping → basophilic stippling on a blood smear.**
40
40. Anaphylaxis in humans treated with penicillin is mediated by which of the following?
A. Anti-hapten IgG
B. Anti-hapten CD8 T-cells
C. Anti-hapten complement activation
D. Anti-hapten IgE
D.
Human anaphylaxis is IgE-mediated. Penicillin binds to proteins in vivo to form immunogenic hapten-protein
complexes. Neither hapten specific IgG nor CD8 T-cells are associated with anaphylaxis in humans. Penicillin hapten does not
activate complement.
41
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.
The Delaney Clause (1958 amendment to the US FD&C Act) states:
“**No additive shall be deemed safe if it is found to induce cancer when ingested by humans or animals.**”
It applies to:
Food additives
Color additives (including natural colorings)
Animal drugs used in food-producing animals
Flavoring substances (even if naturally occurring)
**But NOT pesticides**.
42
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.
Favism = a**cute hemolytic anemia** triggered by eating fava beans (broad beans) in individuals with **G6PD deficiency.**
Key features:
B. ✅ Associated with G6PD deficiency → reduced ability to handle oxidative stress.
C. ✅ Fava beans contain vicine and convicine, which are hydrolyzed to** divicine and isourami**l → strong oxidants that damage RBCs.
D. ✅ Leads to oxidative hemolysis of RBCs → jaundice, dark urine, anemia.
A. ❌ Incorrect, because favism occurs mostly in people of Mediterranean, African, and Middle Eastern descent, not primarily in European Caucasians.
43
43. Food hyper-reactivity (allergy):
A. Is primarily associated with IgA-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 IgE and IgG immune reactions.
d.
Food allergy (hyper-reactivity):
Most are IgE-mediated (Type I hypersensitivity). → Rapid reactions: hives, anaphylaxis, etc.
Some are IgG-mediated (delayed-type or mixed responses).
44
44. Which of the following potential male reproductive toxicants does NOT target spermatogenesis?
A. Cadmium
B. Vitamin A
C. CCl4
D. α-Chlorohydrin
D.
Some toxicants (like **α-chlorohydrin**) don’t kill sperm or stop spermatogenesis.
Instead, they temporarily interfere with epididymal functions (e.g., sperm energy metabolism).
If exposure stops, the next batch of sperm coming from the testis → can still mature normally.
Therefore, the infertility effect is reversible.
45
45. 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
46
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
C:
Female mating index
= (Number of females with confirmed mating ÷ Number of females paired) × 100
→ Measures efficiency of mating.
Fecundity index
= (Number of pregnant females ÷ Number of females mated) × 100
→ Sometimes used more broadly for reproductive success.-- broader, includes failures to mate properly)
Female fertility index
= (Number of pregnant females ÷ Number of females with confirmed mating) × 100
→ Tells us** how many matings actually resulted in pregnancy**.
**Gestation** index
= (Number of females with live** litters** ÷ Number of pregnant females) × 100
→ Measures success of carrying pregnancy to term.
47
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
48
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.
NTCP = uptake bile acids from blood.
BSEP = excrete bile acids into bile canaliculi.
MRP2 = drug conjugates & bilirubin to bile.
MRP3/4 = relief valves, send bile acids back to blood.
Transporter dysfunction → cholestasis, jaundice, hepatotoxicity.
49
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
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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 Tio cells
D. Endothelial cells and stellate cells
A
51
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.
**Valproic acid** is a well-known drug that induces microvesicular steatosis.
The mechanism is usually **impaired mitochondrial β-oxidation of fatty acids**, or increased** lipid synthesis.**
While mitochondrial dysfunction plays a role in drug-induced steatosis, the mechanism is not simply due to drug accumulation in mitochondria inhibiting cellular respiration. Instead, d**rugs like valproic acid disrupt mitochondrial β-oxidation and other metabolic pathways, leading to lipid accumulation**. The inhibition of respiration is a consequence of broader mitochondrial dysfunction, not direct accumulation of the drug.
52
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.
, idiosyncratic DILI is not dose-dependent. It can occur at therapeutic doses, often in a small susceptible population
53
53. Elimination pharmacokinetics for a one-compartment model may proceed via zero-order (A) or first-order (B) kinetics as shown in the figures below.
Based on the figures, all of the following are correct EXCEPT:
A. For first-order kinetics, elimination can be expressed as exponential.
B. Ethanol elimination is a classic example of zero-order kinetics.
C. For a one-compartment model, first-order kinetics proceeds as a variable rate of elimination.
D. Tissue concentrations of the xenobiotic are expected to decline by same elimination rate constant or half-life.
C
54
54. The apparent volume of distribution (Vd) 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 Vd can be greater than 1.0, particularly for highly lipophilic toxicants.
A
55
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:
An ideal chelator should:
Have high solubility in water.
Resist biotransformation.
Reach the sites of metal storage (same distribution as the metal).
Retain chelating ability at the pH of body fluids.
Form metal complexes that are less toxic than the free metal.
56
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.
Arsenic → neuro, cardiac, skin cancer, Mees’ lines.
Not APL-causing — instead, arsenic trioxide is an APL drug
57
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 of fish and shellfish that bioaccumulated inorganic mercury.
D. Led to pregnant women giving birth to children with severe bone malformations.
B.
Minamata Disease (Methylmercury)
Location: Minamata Bay, Japan (1950s).; Cause: Industrial d**ischarge of methylmercury from a chemical plan**t.
Exposure route: Eating contaminated fish and shellfish; Target organ: **Nervous system (especially developing fetal brain).**
Key symptoms: A**dults: sensory loss, ataxia, hearing and vision impairment**. Fetuses/newborns: **severe neurodevelopmental disabilities (resembled cerebral palsy).**
Pathology: Neurotoxicity due to organic mercury crossing the blood–brain and placental barriers.
--------------------------------------------------------
**Itai-Itai Disease (Cadmium)**
Location: Toyama Prefecture, Japan (early 20th century, reported in 1950s).; Cause: Mining and smelting → release of **cadmium into rivers → contamination of rice paddie**s; Exposure route:** Eating cadmium-contaminated rice**.; Target organ: Kidney (renal tubular damage) and bone.; Key symptoms: Severe osteomalacia and osteoporosis.
Intense bone pain → hence the name “itai-itai” = “ouch-ouch”. Pathology: **Cadmium-induced renal tubular dysfunction → calcium/phosphate loss → bone demineralization.**
58
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
59
59. Chemically induced alpha2u-globulin nephropathy is a 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. Acetaminophen
α2u-Globulin nephropathy:
A male rat–specific kidney lesion. Caused by accumulation of a male rat urinary protein (α2u-globulin) in proximal tubules after binding certain chemicals. Leads to hyaline droplet accumulation, tubular damage, and sometimes a low incidence of renal tumors in chronic studies. Important: This mechanism is not relevant to humans, so it has low human risk significance.
Chemicals associated: **d-Limonene, unleaded gasoline, some halogenated hydrocarbons.**
Why others are wrong:
A. Cadmium → nephrotoxic, but via accumulation in proximal tubular cells → causes renal failure, not α2u-globulinopathy.
C. Cisplatin → nephrotoxic due to DNA crosslinking and oxidative stress.
D. Acetaminophen → causes centrilobular hepatic necrosis (mainly hepatotoxicity), nephrotoxicity is secondary and not via α2u-globulin.
## Footnote
d-لیمونن → نفروپاتی α2u-گلوبولین → تومور کلیوی در موشهای نر (اما بیاهمیت برای انسان).
60
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.
Chloroform
A nephrotoxicant and hepatotoxicant.
Requires biotransformation by cytochrome P450 (mainly CYP2E1) to generate phosgene, a highly reactive metabolite.
This metabolite causes proximal tubular cytotoxicity in the kidney and centrilobular necrosis in the liver.
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61. Benzoylecgonine is the primary urinary metabolite of which drug of abuse?
A. Opiates
B. Methamphetamine
C. Benzodiazepines
D. Cocaine
D:
In the body, cocaine is rapidly hydrolyzed (mainly by esterases).
The primary urinary metabolite is benzoylecgonine.
This metabolite is used as the most reliable biomarker in urine drug screens for cocaine use (detectable for 2–3 days after single use, longer in heavy users).
## Footnote
کوکائین = محرک قوی عصبی → سریع متابولیزه میشود → بنزوئیلاکگونین در ادرار = مهمترین شاخص آزمایشگاهی برای شناسایی مصرف.
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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. Immunochemical methods
C. Thin layer chromatographic methods
D. Liquid chromatographic methods
B
63
63. 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 dehydrogenases.
B. Oxidation of vinyl chloride to chloroethylene oxide by CYP2E1.
C. Non-enzymatic rearrangement of vinyl chloride to chloroacetylaldehyde.
D. Formation of chloroethylene oxide by epoxide hydrolase.
B.
Vinyl chloride → CYP2E1 → chloroethylene oxide → DNA adducts (etheno-bases) → liver cancer.
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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
65
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.
An immune-mediated reaction (Type III/IV hypersensitivity) to inhaled organic antigens.
Manifests as acute febrile illness with cough, dyspnea, chest tightness
66
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
67
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
68
68. Which of the following BEST pairs an inhaled toxicant with a chronic pulmonary disease?
A. Isocyanates—Lung cancer
B. Asbestos—Chronic bronchitis
C. Ozone—Emphysema
D. Beryllium—Granulomatous lung disease
Beryllium is the classic example of an inhaled toxicant that causes chronic granulomatous lung disease, sometimes referred to as berylliosis or chronic beryllium disease. In its relatively insoluble forms, beryllium particles can have long residence times in the lung, and it can function as a hapten to stimulate the immune system and cause an influx of Be-specific CD4+ T cells into the lungs. The other agents listed are also pulmonary toxicants, but are incorrectly paired with resulting chronic outcomes. Correct pairings would include isocyanates–asthma, asbestos–fibrosis/lung cancer/mesothelioma, and ozone–fibrosis.
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