Part 3: Mechanistic Toxicology

Question 1

1. 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 1

Answer: D

Updated Explanation:
Increased water solubility of metals enhances their ability to dissolve in gastric fluids, increasing their absorption through the gastrointestinal tract. Therefore, metals with higher solubility profiles in the soil matrix are more bioavailable when ingested, making this the primary factor influencing oral bioavailability.

Why the other choices are incorrect:
• A. Increased fraction of metals tightly bound to the soil matrix – Metals that are tightly bound are less likely to be released, reducing their solubility and absorption potential.
• B. Increased ratio of soil lead:arsenic dissolving in gastric acid – The ratio of two metals doesn’t inherently affect the bioavailability of either, and this option is confusing and not mechanistically relevant.
• C. Increased age of the exposed individual – While age can influence absorption efficiency, it is a host factor, not a property of the soil matrix, and therefore not the primary determinant in this context.

Question 2

2. 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 2

Answer: B
Explanation and Reference:
Cadmium induces metallothionine with subsequestration of cadmium as Cd-MT complex. C&D 9th p. 783`

Question 3

3. What is the primary target organ for xylene and ethylbenzene toxicity?
   A. central nervous system
   B. lungs
   C. bone marrow
   D. reproductive organs

Answer 3

Answer: A
Explanation and Reference:
These compounds have limited capacity to adversely affect organs other than the CNS. C&D 9th p 1202

Question 4

4. 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 4

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

Question 5

5. Inhibition of what enzyme is involved in acute toxicity of organophosphate insecticides?
   A. carboxylesterase
   B. acetylcholinesterase
   C. neuropathy target esterase
   D. butyrylcholinesterase

Answer 5

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

Question 6

6. Paraquat is a herbicide associated with what mechanism of toxicity?
   A. alkylating DNA
   B. GABA Inhibition
   C. free radical formation
   D. anticholinesterase inhibition

Answer 6

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

Question 7

7. 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 7

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

Question 8

8. 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 8

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

Question 9

9. What type of radiation has the highest linear energy transfer (LET)?
   A. alpha particles
   B. beta particles
   C. gamma rays
   D. x-rays

Answer 9

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

Question 10

10. What elements are essential nutrients?
    A. iron, nickel, copper
    B. zinc, copper, cobalt
    C. vanadium, thallium, manganese
    D. copper, beryllium, selenium

Answer 10

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

Question 11

11. 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 11

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

Question 12

12. 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 12

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;

Question 13

13. Piperonyl butoxide inhibits CYP450 and increases the toxicity of which compounds
    A. mirex
    B. carbamates
    C. organophosphates
    D. pyrethroids

Answer 13

Answer: D
Explanation and Reference:
Inhibition of CYP450 by piperonyl butoxide increases the toxicity of pyrethroids. C&D 9th, p. 1071

Question 14

14. 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 14

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

Question 15

15. 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 15

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

Question 16

16. 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 16

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 FDA- approved GRAS substance and commonly found in soft drinks. It is essentially non-toxic. C&D 9th, p. 1093

Question 17

17. 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 17

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

Question 18

18. Fungistatic azole drugs block the synthesis of what critical cell membrane components?
    A. cholesterol
    B. usnic acid
    C. mevalonate
    D. ergosterol

Answer 18

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

Question 19

19. 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 19

Answer: D
Explanation and Reference:
Oxidative stress plays a significant role in Hg toxicity. C&D 9th p. 1129

Question 20

20. 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 20

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

Question 21

21. 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 21

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

Question 22

22. What enzyme is involved in organophosphate-induced delayed polyneuropathy?
    A. butyrylcholinesterase
    B. ATPase
    C. neuropathy target esterase
    D. acetylcholinesterase

Answer 22

Answer: C
Explanation and Reference:
NPTE causes digital sensorimotor axonopathy. C&D 9th, p. 1066

Question 23

23. 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 23

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

Question 24

24. 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 24

Answer: C
Explanation and Reference:
Pyrethroids act through disruption of sodium channels. C&D 9th, p. 1072

Question 25

25. 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 25

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

Question 26

26. What chemical asphyxiant forms carboxyhemoglobin and prevents oxygenation of blood? A. carbon monoxide B. natural gas C. kerosene D. carbon disulfide

Answer 26

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

Question 27

27. 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 27

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

Question 28

28. 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 28

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

Question 29

29. 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 29

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

Question 30

30. 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 30

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

Question 31

31. 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 31

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

Question 32

32. 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 32

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

Question 33

33. What is the most abundant hepatic cytochrome P450 sub-family in humans? A. CYP2A B. CYP2B C. CYP3A4 D. CYP1A

Answer 33

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

Question 34

34. 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 34

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

Question 35

35. 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 35

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

Question 36

36. 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 pro- inflammatory 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 36

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

Question 37

37. 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 37

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

Question 38

38. 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 38

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

Question 39

39. 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 ion- trapped in the stomach and largely non-ionized (diffusible) in the blood

Answer 39

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

Question 40

40. 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 40

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

Question 41

41. 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 41

Answer: D Explanation and Reference: In nonprimates, methanol is oxidized by the catalase-peroxidase system, whereas in primates (Non- human and human), the alcohol dehydrogenase system takes the main role in methanol oxidation. C&D 9th, p. 1207

Question 42

42. 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 42

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.

Question 43

43. 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 43

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

Question 44

44. 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 44

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.

Question 45

45. 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 45

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

Question 46

46. 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 46

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.

Question 47

47. 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 47

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

Question 48

48. 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 48

Answer: C Explanation and Reference: Produces a superoxide radical while reducing NADPH + H+ to NADP in pulmonary cells. C&D 9th, p. 1084-1085

Question 49

49. 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 49

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

Question 50

50. 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 50

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

Question 51

51. 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 51

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

Question 52

52. 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 52

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

Question 53

53. 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 53

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., TNF- alpha, IL-1B, IL-6, IL-10). C&D 9th, p. 729 Figure 13-9, 731

Question 54

54. 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 54

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.

Question 55

55. What cytochrome P450 (CYP) is the most abundant in the normal human liver? A. CYP2D6 B. CYP3A4 C. CYP2E1 D. CYP1A2

Answer 55

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.

Question 56

56. 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 56

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

Question 57

57. 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 57

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.

Question 58

58. 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 58

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

Question 59

59. 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 59

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

Question 60

60. 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 60

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

Question 61

61. 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 61

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.

Question 62

62. 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 62

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.

Question 63

63. 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 63

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

Question 64

64. 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 64

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

Question 65

65. 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 65

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

Question 66

66. 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 66

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

Question 67

67. 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 67

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

Question 68

68. 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 68

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.

Question 69

69. 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 69

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

Question 70

70. 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 70

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

Question 71

71. 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 71

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.

Question 72

72. 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 72

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

Question 73

73. 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 73

Answer: C Explanation and Reference: Excessive secretion of TSH can act in a proliferating manner. C&D 9th p. 454

Question 74

74. 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 74

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.

Question 75

75. 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 75

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

Question 76

76. What is considered an acute response of the lung to injury? A. emphysema B. interstitial granulomatosis C. pulmonary edema D. fibrosis

Answer 76

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

Question 77

77. 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 77

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.

Question 78

78. 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 78

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.

Question 79

79. 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 79

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

Question 80

80. 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 post- synaptic 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 80

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.

Question 81

81. 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 81

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

Question 82

82. 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 82

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

Question 83

83. 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 83

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

Question 84

84. 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 84

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

Question 85

85. What is the most common site of toxicant-induced renal injury? A. glomerulus B. connecting tubule C. proximal tubule D. loop of Henle

Answer 85

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

Question 86

86. 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 86

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

Question 87

87. 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 87

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

Question 88

88. 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 88

Answer: D Explanation and Reference: Metals may bind to sulfhydryl group of proteins important to tissue function and survival. C&D 9th, p. 781

Question 89

89. 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 89

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

Question 90

90. Alteration of normal microtubules function is the primary toxic effect for what compound? A. cuprizone B. carbon disulfide C. taxol D. atropine

Answer 90

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,

Question 91

91. 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 91

Answer: A Explanation and Reference: Type I Hypersensitivity involves the production of IgE which activate mast cells. C&D 9th, p. 646-649

Question 92

92. 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 92

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

Question 93

93. 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 93

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

Question 94

94. 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 94

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

Question 95

95. 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 95

Answer: C Explanation and Reference: Mutations occur from errors in DNA repair or replications. C&D 9th p 441-445

Question 96

96. 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 96

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

Question 97

97. 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 97

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

Question 98

98. 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 98

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.

Question 99

99. What toxic agent causes reproductive or developmental toxicity by damaging DNA directly? A. diethylstilbestrol B. thalidomide C. retinoic acid D. radiation

Answer 99

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.

Question 100

100. 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 100

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

Question 101

101. 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 101

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

Question 102

102. 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 102

Answer: C Explanation and Reference: CYP2F2 is specific to mice. C&D 9th, p. 824

Question 103

103. 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 103

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

Question 104

104. 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 104

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

Question 105

105. 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 105

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

Question 106

106. 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 106

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

Question 107

107. 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 107

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

Question 108

108. 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 108

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

Question 109

109. What immunoglobulin class is most commonly associated with immediate onset of allergic reactions in humans? A. IgE B. IgM C. IgA D. IgG

Answer 109

Answer: A Explanation and Reference: IgE is the primary immunoglobin responsible for allergic responses in humans. C&D 9th p 640

Question 110

110. Contact hypersensitivity reactions are commonly associated with direct and prolonged contact with what element? A. nickel B. lithium C. iron D. lead

Answer 110

Answer: A Explanation and Reference: Nickel has been reported to elicit contact urticaria C&D 9th p 966-967

Question 111

111. 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 111

Answer: B Explanation and Reference: Furocoumarins (lime juice) can cause increased dermal pigmentation. C&D 9th Fig 19-2f, p 968

Question 112

112. 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 112

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, ciliary body, and iris, and can cause the characteristic "bull's eye retina". C&D9th p 891

Question 113

113. 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 113

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

Question 114

114. 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 114

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

Question 115

115. 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 115

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

Question 116

116. 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 116

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

Question 117

117. 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 117

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

Question 118

118. 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 118

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

Question 119

119. Stimulation of what receptor type is responsible for the toxic action of carbamate insecticides? A. serotonergic B. glutamate C. muscarinic D. dopamine

Answer 119

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

Question 120

120. 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 120

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

Question 121

121. 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 121

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.

Question 122

122. 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 122

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.

Question 123

123. 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 123

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

Question 124

124. 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 124

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

Question 125

125. 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 125

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

Question 126

126. 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 126

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.

Question 127

127. 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 127

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.

Question 128

128. 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 128

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

Question 129

129. 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 129

Answer: C Explanation and Reference: Particle size determines depth of penetration. Larger particle impact earlier. C&D 9th, p. 795, Figure 15-1

Question 130

130. 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 130

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

Question 131

131. 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 131

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.

Question 132

132. 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 132

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

Question 133

133. 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 133

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

Question 134

134. 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 134

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

Question 135

135. 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 135

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

Question 136

136. Which ocular tissue is highly vulnerable to systemic, toxicant induced structural and/or functional damage? A. cornea B. retina C. lens D. iris

Answer 136

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.

Question 137

137. 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 137

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.

Question 138

138. 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 138

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

Question 139

139. 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 139

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.

Question 140

140. 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 140

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.

Question 141

141. 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 141

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

Question 142

142. 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 142

Answer: B Explanation and Reference: The zone 1 hepatocytes both preferentially accumulate iron and since they are closer to the oxygen- rich blood entering the sinusoid and the higher oxygen concentration faciliates lipid peroxidation. C&D 8th, p. 650, Table 13-3

Question 143

143. 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 143

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

Question 144

144. 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 144

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

Question 145

145. Which organ system is most susceptible to cisplatin toxicity? A. heart B. CNS C. liver D. kidney

Answer 145

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

Question 146

146. 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 146

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.

Question 147

147. 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 147

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.

Question 148

148. What metabolic reaction is associated with glutathione transferase? A. conjugation B. hydrolysis C. reduction D. oxidation

Answer 148

Answer: A Explanation and Reference: Glutathione transferase is required for conjugation reactions. C&D 9th, p. 201

Question 149

149. A 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 149

Answer: B Explanation and Reference: The apparent volume of distribution (Vd) of a xenobiotic is an estimate of the total blood and blood- equivalent 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.

Question 150

150. 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 150

Answer: D Explanation and Reference: Elimination half-life (T1/2) is proportional to volume of distribution and clearance. C&D 9th, p. 406

Question 151

151. 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 151

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

Question 152

152. 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 152

Answer: A Explanation and Reference: Peanut allergies illicit Type 1 hypersensitivity via increases in IgE and compliment. C&D 9th, p.1353, 646

Question 153

153. 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 153

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

Question 154

154. 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 154

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

Question 155

155. 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 155

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

Question 156

156. 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 156

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

Question 157

157. 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 157

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.

Question 158

158. 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 158

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

Question 159

159. 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 159

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

Question 160

160. What types of molecules are commonly identified using two-dimensional polyacrylamide gel electrophoresis? A. proteins B. DNA adducts C. nucleotide mutations D. cDNA

Answer 160

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

Question 161

161. 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 161

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

Question 162

162. 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 mediated by sensitized T lymphocytes

Answer 162

Answer: D Allergic contact dermatitis is a Type IV hypersensitivity reaction, also called a delayed-type hypersensitivity (DTH). It involves T-cell–mediated immune responses. The first exposure sensitizes the immune system, and the reaction typically occurs 24–72 hours after subsequent exposure.

Question 163

163. 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 163

Answer: B Explanation and Reference: Stellate cells preferentially extract and store this vitamin. C&D 8h, p. 650, Table 13-3

Question 164

164. What is the primary psychoactive analyte of marijuana? A. tetrahydrocannabinol B. hydroxycannabidiol C. trihydrocannabinol D. cannabidiol

Answer 164

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.

Question 165

165. By what action does the antineoplastic drug methotrexate cause ocular toxicity? A. anti-metabolite B. oxidative stress C. mitotic inhibitor D. alkylation

Answer 165

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).

Question 166

166. 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 166

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

Question 167

167. 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 167

Answer: C Explanation and Reference: Chronic beryllium disease involves antigen-stimulated, cell-mediated immune response. C&D 9th, p. 691,1118

Question 168

168. 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 168

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

Question 169

169. 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 169

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

Question 170

170. 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 170

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

Question 171

171. What is the antidote recommended for cyanide poisoning? A. fomepizole B. sodium nitrate/sodium thiosulfate C. N-acetylcysteine D. activated charcoal/water

Answer 171

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.

Question 172

172. What is the commonly used serum biomarker for nicotine exposure? A. cotinine B. cadmium C. norcotinine D. nicotine-N'-oxide

Answer 172

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.

Question 173

173. 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 173

Answer: D Explanation and Reference: This is how certain fibers are deposited in the respiratory tract. C&D 8th, p. 703

Question 174

174. 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 174

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

Question 175

175. 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 175

Answer: C Explanation and Reference: Sulfur dioxide is an irritant gas in the upper airways and causes bronchoconstriction. C&D 8th, p. 1250

Question 176

176. 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 176

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

Question 177

177. 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 177

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.

Question 178

178. 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 178

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.

Question 179

179. 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 179

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

Question 180

180. 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 180

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

Question 181

181. 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 181

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

Question 182

182. 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 182

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

Question 183

183. 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 183

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