ABT

13. Gentamicin-induced nephrotoxicity results from selective uptake into proximal tubule cells by megalin-mediated endocytosis, accumulation within lysosomes and inhibition of lysosomal enzymes. Which of the following is NOT an expected consequence of these effects on renal endocytic processes? A) increased urinary excretion of retinol B) altered gentamicin clearance resulting in increased serum levels with chronic dosing C) increased urinary excretion of low molecular weight protein D) decreased polycyclic aromatic hydrocarbon clearance due to interference with tubular transport processes E) increased urinary N-acetyl-glucosaminidase (NAG)

Answer I chose D because it didn't make much sense----Para-amino-Hippurate is the PAH that is most relevant for renal physiology. spent 45 minutes and moved on... http://aac.asm.org/content/43/5/1003.long A is likely correct (because of C), assuming retinol is bound to retinol binding protein B is correct because tubular uptake is saturable C is correct because of decreased protein reabsorbtion (damage to brush border)

1. Which of the following metals are causally linked to human cancer? A) arsenic and manganese B) vanadium and zinc C) cadmium and chromium D) arsenic and cobalt E) mercury and tin

1. Correct Answer = C, Cadmium and chromium Arsenic (As): Is a toxic and carcinogenic metalloid. (C&Ds, Pp. 936). The carcinogenic potential of arsenic was recognized over 110 years ago by Hutchinson, who observed an unusual number of skin cancers occurring in patients treated for various diseases with medicinal arsenicals. IARC (2004) has classified arsenic as a known human carcinogen, associated with tumors of the skin, lung, and urinary bladder, and possibly kidney, liver, and prostate. (C&Ds, Pp. 938). Cobalt (Co): Although the data linking cobalt exposure to cancer in humans is considered inadequate, in rodents, inhalation of cobalt sulfate induces lung tumors, including carcinoma, in rats and mice. Repository injections or implantation of various cobalt compounds can produce local sarcomas in rodents. The mechanism by which cobalt produces cancer is not defined. (C&Ds, Pp. 952) Cadmium (Cd): Cadmium compounds are considered to be human carcinogens. In humans, occupational respiratory exposure to cadmium has been most clearly associated with lung cancer. Early human studies also indicated a possible link to cancer of the prostate, which has not been confirmed by more recent work, despite evidence that the prostate can be a target of cadmium carcinogenesis in rats. Both the kidney and pancreas accumulate high concentrations of cadmium and exposure to cadmium may also be associated with human renal and pancreatic cancer. (C&Ds, Pp. 942) Chromium (Cr): Occupational exposure to hexavalent chromium compounds, particularly in the chrome production and pigment industries, is associated with increased risk of lung cancer, and hexavalent chromium-containing compounds are considered to be human carcinogens. Inhaled chromium compounds can penetrate to many tissues in the body, and thus have the potential to cause cancer at sites other than the lung. Accumulating evidence indicates an association between cancers of the bone, prostate, hematopoietic system, stomach, kidney, and urinary bladder and hexavalent chromium exposure. Furthermore, exposure of hexavalent chromium compounds through the drinking water enhances UV-induced skin cancer in the hairless mouse model. An association of hexavalent chromium in the drinking water with stomach cancer has also been reported. (C&Ds, Pp. 943) Manganese (Mn): Available data indicate that inorganic manganese is not carcinogenic in humans or rodents, and negative in Ames test, but may cause DNA damage and chromosome aberrations in vitro in mammalian cells. (C&Ds, Pp. 956). Mercury (Hg): No reference to mercury and cancer in C&Ds. Tin (Sn): Experimental studies have failed to find convincing evidence of carcinogenicity, mutagenicity, or teratogenicity of inorganic tin compounds. There is inadequate information to assess carcinogenic potential of organotin compounds in animals, and they are considered not classifiable as to human carcinogenicity. (C&Ds, Pp. 970) Vanadium (V): There are no data indicating a carcinogenic potential for vanadium compounds in animals or man, and vanadium compounds are only weakly mutagenic. (C&Ds, Pp. 972) Zinc (Zn): Epidemiological studies of workers in electrolytic zinc and copper refining industries have not found an increased incidence of cancer associated with occupational zinc inhalation. Oral zinc supplementation does not appear to have a significant effect on cancer incidence. In addition, zinc deficiency may be associated with increased risk of cancer in humans. Zinc supplementation could decrease oxidative stress and improve immune function, which may be a possible mechanism for its cancer preventive activity. In experimental animals, zinc prevents cadmium induced testicular cancer, but facilitates cadmium-induced prostate tumors. (C&Ds, Pp. 959-60)

36. In general, most allergens in food are A) carbohydrates B) proteins C) amino acids D) vitamins E) unintentional food additives

I chose B Did not find a reference saying that, but most allergenic foods (milk, egg, etc) are protein rich and most immunogenic compounds are proteins.

7. Phase I1 biotransformation of xenobiotics includes all of the following conjugations EXCEPT A) glucuronidation B) phosphorylation C) sulfation D) acetylation E) glutathione conjugation

Answer is: B A) Glucuronidation is a major pathway of xenobiotic biotransformation in mammalian species except for members of the cat family (lions, lynxes, civets, and domestic cats) (Tukey and Strassburg, 2000). Glucuronidation requires primarily the cofactor UDPGA, but can also use UDP-glucose, UDP-xylose, and UDP-galactose. The reaction is catalyzed by UDP-glucuronosyltransferases (UGTs), which are located predominantly in the endoplasmic reticulum of liver and other tissues, such as the kidney, gastrointestinal tract, lungs, prostate, mammary glands, skin, brain, spleen, and nasal mucosa (Fig. 6-50)277 B) Why Not? First, if xenobiotics could be phosphorylated, high intracellular levels of a xenobiotic might consume so much ATP as to jeopardize cell viability, whereas UDPGA and PAPS can be depleted without killing cells. Second, phosphorylation of endogenous substrates, such as glucose, is a mechanism for trapping endogenous substrates inside a cell. This works because the plasma membrane of all cells is a barrier to the passage of polar compounds by virtue of its hydrophobic properties (lipid bilayer) and its general lack of transporters that pump phosphorylated compounds outof the cell. The same is true for the phosphorylated metabolites of zidovudine and related antiviral drugs; they are retained inside the cell that forms them. A lipid bilayer is also a physical barrier to other water-soluble conjugates, such as glucuronides and sulfonates, but these are transported out of the cell by various transporters. Third, phosphorylation of both small molecules (such as inositol) and proteins (such as membrane-bound receptors and various transcription factors) plays an important role in intracellular and intranuclear signaling. It is possible that some xenobiotics, if theywere phosphorylated, might interfere with these regulatory systems and thereby disrupt cellular homeostasis. Fourth, even if xenobiotics were phosphorylated in the liver and excreted in bile, they would be rapidly hydrolyzed by high levels of alkaline phosphatase lining the surface of enterocytes in the small intestine, which would promote reabsorption of the xenobiotic (by the very process exploited in the design of phosphorylated prodrugs like fosamprenavir). Whatever the reason, there appears to be strong evolutionary pressure against the conjugation of xenobiotics with phosphoric acid.295 C) Many of the xenobiotics and endogenous substrates that undergo Oglucuronidation also undergo sulfonation, as illustrated in Fig. 6-34 for acetaminophen. D )N-Acetylation is a major route of biotransformation for xenobiotics containing an aromatic amine (R-NH group (R-NH-NH(R-NH-COCH(Evans, 1992).2) or a hydrazine2), which are converted to aromatic amides3) and hydrazides (R-NH-NH-COCH3), respectively. E) Conjugation of xenobiotics with the tripeptide glutathione (GSH), which is composed of glycine, cysteine, and glutamic acid (the latter being linked to cysteine via the γ -carboxyl group, not the usual α-carboxyl group, as shown in Fig. 6-49).285

25. Which of the following is MOST predictive of how deeply a given gas will penetrate into the respiratory tract in obligate nose breathers? A) regional blood flow B) water solubility C) molecular weight D) antigenicity of particle E) ventilation rate

Answer is:B Many species, particularly small laboratory rodents, are obligate nose breathers in which air passes almost exclusively through the nasal passages. Other species, including humans, monkeys, and dogs can inhale air through both the nose and the mouth (oronasal breathers). Air is warmed and humidified while passing through the nose. The nasal passages function as a filter for particles, which may be collected by diffusion or impaction on the nasal mucosa. Highly water soluble gases are absorbed efficiently in the nasal passages, which reach from the nostril to the pharynx.610

6. About 2% of Caucasians are deficient in the normal form of serum carboxylesterase. This is an important clinical consideration for treatment with A) phenobarbital B) succinylcholine C) aspirin D) hyperbaric oxygen E) thyroxin

Answer is:B B) stoichiometric binding of OP compounds to carboxylesterases is an important determinant of OP toxicity, as outlined in the following section on cholinesterases.Succinylcholine is a muscle relaxant whose duration of action is determined by serum BChE. In some individuals (causes prolonged muscular relaxation and apnea, which led to thediscovery of a genetic variant of BChE (Asp1992; Lockridge, 1992).∼2% of Caucasians), succinylcholine70 → Gly70) 179

27. Which of the following cancers was associated with radium exposure in watch dial painters? A) breast B) lung C) stomach D) bone E) leukemia

Answer is:D The paint was applied to the numerals with a small brush. As the brush became flattened, the women pointed the brushes on their tongues between applications, and thereby ingested a small quantity of radium each time.Radium is an alphaparticle emitter that is chemically similar to calcium, and is therefore a 'bone seeker'. 226Ra accumulated in the long bones irradiated osteoblasts and other nearby cells in the bone marrow with high-energy, short-distance alpha radiation, and produced bone cancer and other genetic damage.WIKI

39. For which of the following compounds does hepatic NOT contribute to toxicity? A) aflatoxin B1 B) methanol C) urethane D) 2,6-dinitrotoluene E) parathion

Answer: For which of the following compounds does hepatic biotransformation NOT contribute to toxicity? A) metabolized to AFB1 epoxide, covalent binding B) metabolized to formic acid, toxic C) urethane (ethyl carbamate) metabolized to vinyl carbamate epoxide, covalent binding D) metabolized to nitrobenzyl alohol, covalent binding E) metabolized to paraoxon and p-nitrophenol

14. Which of the following is TRUE about the metabolism and toxicity of benzene? A) the mouse has a higher rate of metabolism and is therefore more resistant to hematotoxicity B) bioactivation is required for carcinogenicity but not for myelotoxicity C) metabolism in the bone marrow plays an important role in myelotoxicity D) benzene oxide is detoxified by conjugation with sulfate E) phosphodiesterases oxidize benzene in bone marrow

Answer is C page 1008 Metabolism of benzene occurs primarily in the liver, though metabolism in bone marrow is believed by many authorities to play the key role in myelotoxicity A--is not true, CYP 2E1 transgenic mouse is B is false,, bioactivation is required for both D is false, Benzene oxide is (a) conjugated to gluthathione, or (b) nonenzymatically rearranged to phenol and (c) hydrated by epoxide hydrolase E is false, Myeloperoxidase oxidizes benzene to quinone in bone marrow

3. Which of the following statements regarding uranium toxicity is TRUE? A) direct evidence exists that uranium is carcinogenic to humans and animals B) the toxicity is not dependent on oxidation state C) long-term, low-level exposure is associated with BZ microglobulinuria D) uranium miners do not display an elevated risk of lung cancer E) radon decays to produce uranium, which is associated with renal tumors in highly exposed humans

Answer = A a. TRUE. Intakes of uranium exceeding EPA standards can lead to increased cancer risk, liver damage, or both. Long term chronic intakes of uranium isotopes in food, water, or air can lead to internal irradiation and/or chemical toxicity. (www.epa.gov) b. FALSE, Uranium has five oxidation states but only the 4+ and 6+ forms are stable enough to be of practical importance. (C&D's, Pp. 970) c. Microglobulinuria = The presence of microglobulins in the urine. (Wiki) d. FALSE. A higher incidence of lung cancer has been found in uranium miners and is probably due to radon and its daughter products, but not to uranium itself. (C&D's, Pp. 971). e. FALSE, Radon is a product of uranium as it (uranium) decays to lead. (C&D's, PP. 1070).

10. Factors leading to the increased use of physiologically-based models over classical pharmacokinetic models include all of the folIowing EXCEPT A) advances in computational power B) prediction of time-course changes in tissue distribution C) prediction of kinetics across species using allometric scaling D) need for less information to develop the physiologically-based model E) prediction of effects of altered physioIogical states on kinetics

10. Answer is D (D is is a disadvantage) p 317 Advantages of physiologically based models compared with classic models are that (1) these models can describe the time course of distribution of toxicants to any organ or tissue, (2) they allow estimation of the effects of changing physiologic parameters on tissue concentrations, (3) the same model can predict the toxicokinetics of chemicals across species by allometric scaling, and (4) complex dosing regimes and saturable processes such as metabolism and binding are easily accommodated (Gargas and Andersen, 1988). The disadvantages are that (1) much more information is needed to implement these models compared with classic models, (2) the mathematics can be difficult for many toxicologists to handle, and (3) values for parameters are often ill defined in various species, strains, and disease states. Nevertheless, physiologically based toxicokinetic models are conceptually sound and are potentially useful tools for gaining rich insight into the kinetics of toxicants beyond what classic toxicokinetic models can provide.

11. Which of the following pairs is MOST relevant for human risk evaluation? A) unleaded gasoline: renal tumors in male rats B) nitrilotriacetic acid: bladder tumors in rodents C) ethylacrylate: forestomach tumors in rodents D) ethylene bisdithiocarbamate : thyroid gland tumors in rodents E) dimethylnitrosamine: liver tumors in rodents

11. Answer is E, A-D FALSE, see table 4-4 p 113 A) unleaded gasoline: renal tumors in male rat FALSE due to alpha 2 microglobulin neophropathy and chronic injury leading to tumors by nongenotoxic mechanisms B) nitrilotriacetic acid: bladder tumors in rodents FALSE Reactive hyperplasia from cytotoxic precipitated chemicals C) ethylacrylate: forestomach tumors in rodents FALSE Direct oral gavage Local cytotoxicity Hyperplasia D) ethylene bisdithiocarbamate : thyroid gland tumors in rodents FALSE Lack of thyroid-binding protein in rodents versus humans Decreased t1/2 for T4; increased TSH levels in rodents E) dimethylnitrosamine: liver tumors in rodents TRUE p566 Repeated treatment with carbon tetrachloride, thioacetamide, dimethylnitrosamine, aflatoxin, or other chemicals has been associated with hepatic fibrosis in experimental animals and humans (Zimmerman, 1999).

12. Which of the following is NOT a characteristic of saturation toxicokinetics? A) the decline in drug/chemical levels in the body is not exponential B) the area under the curve (AUC) is not proportional to the dose administered C) volume of distribution (Vd), clearance (CI), elimination (K,, or beta), or half-life does not change with increasing dose administered D) the composition of excreted products changes quantitatively or qualitatively with the dose E) the dose-response curve shows a nonproportional change in response with an increasing dose

12. Answer is p 314 A) the decline in drug/chemical levels in the body is not exponential TRUE B) the area under the curve (AUC) is not proportional to the dose administered TRUE C) volume of distribution (Vd), clearance (CI), elimination (K,, or beta), or half-life does not change with increasing dose administered FALSE, they do change D) the composition of excreted products changes quantitatively or qualitatively with the dose TRUE E) the dose-response curve shows a nonproportional change in response with an increasing dose TRUE, show an abruptly steeper change in response with an increasing dose, starting at the dose at which saturation effects become evident.

2. Which of the following is TRUE regarding retinoblastoma? A) is induced by teratogenic retinoids such as Accutane B) is caused by the activation of an oncogene C) is only found in albinos D) is caused by the loss of a tumor suppressor gene E) is induced by loss of T4 helper cells

2. Correct Answer = D Retinoblastoma is a largely inherited form of cancer that arises because of the presence of two copies of a defective tumor suppressor gene. (C&Ds, Pp. 28)

24. Which of the following drugs was NOT withdrawn from the market due to a drug-induced increase in the cardiac action potential duration? A) astemizole B) grepafloxacin C) cisapride D) troglitazone E) terfenadine

24. Correct Answer = D, troglitazone a. FALSE = As a result of cardiotoxicity, both astemizole and terfenadine have been removed from the United States market. Terfenadine and astemizole cause altered repolarization, notched inverted T waves, prominent TU waves, prolonged QT interval, first- and second-degree AV block, ventricular tachycardia or fibrillation, and torsades de pointes. (C&Ds, Pp. 723) b. FALSE = Fluoroquinolone antibacterial drugs include ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin (levo-rotatory isomer of ofloxacin), lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, sparfloxacin, and trovafloxacin (Pickerill et al., 2000). Grepafloxacin, moxifloxacin, and sparfloxacin are associated with QT prolongation in perhaps a higher incidence than macrolides. In fact, grepafloxacin was voluntarily removed from the U.S. market because of the relatively high incidence of QT prolongation and risk of torsades de pointes. c. FALSE = Cisapride is a chemical that has been used as a prokinetic drug for gastrointestinal hypomotility. However, cisapride has been removed from the U.S. market because of risk of potentially lifethreatening arrhythmias (torsades de pointes) associated with its use. Like astemizole and terfenadine, cisapride inhibits delayed rectifier K+ current, prolongs action potential duration, prolongs the QT interval, and predisposes the heart to ventricular arrhythmias. (C&Ds, Pp. 724) d. TRUE = The antidiabetic drug troglitazone (Rezulin) was withdrawn from the market due to idiosyncratic hepatotoxicity. (C&Ds, Pp. 576) e. FALSE = As a result of cardiotoxicity, both astemizole and terfenadine have been removed from the United States market. Terfenadine and astemizole cause altered repolarization, notched inverted T waves, prominent TU waves, prolonged QT interval, first- and second-degree AV block, ventricular tachycardia or fibrillation, and torsades de pointes. (C&Ds, Pp. 723)

29. What is the MOST COMMON toxic effect of ephedra alkaloids in high doses? A) tachycardia B) bronchoconstriction C) methemoglobinemia D) oliguria E) hepatocellular necrosis

29. Answer is A pp 720-721 Of particular interest is the high concentration of ephedra alkaloids that may be present in some herbal remedies or "neutraceuticals," especially in products containing ma huang (Gurley et al., 1998). Tachycardia may occur from the consumption of large amounts of ephedra alkaloids, which may predispose the myocardium to ventricular arrhythmias.

1. Which of the following is the major site of accumulation for polybrominated biphenyls? A) adipose tissue B) bone C) liver D) kidney E) plasma proteins

Answer = A, adipose tissue There are many organic compounds that are highly stable and lipophilic, leading to their accumulation in the environment. The lipophilic nature of these compounds also permits rapid penetration of cell membranes and uptake by tissues, and it is not surprising that highly lipophilic toxicants are distributed and concentrated in body fat. The environmental accumulation and potential toxicological significance of long-term storage of numerous compounds including the pesticides aldrin, chlordane, DDT, dieldrin, endrin, heptachlor, mirex, and toxaphene, along with polychlorinated and polybrominated biphenyls, dioxins, and furans has led to international treaties controlling the use of these persistent organic pollutants. The potential for these compounds to produce toxicity, including carcinogenic, developmental, and endocrine effects is related to their accumulation and storage in body fat. (C&Ds, Pp. 147)

3. Which of the following BEST pairs a neurotoxicant with its mode of action? A) acrylamide: inhibition of fast anterograde axonal transport B) taxol: impaired dissociation of microtubules into tubulin subunits C) colchicine: decreased transcription of myelin basic protein mRNA D) nicotine: agonism of glutamate receptors E) cocaine: suppression of catecholaminergic neurotransmission

3. Correct Answer = ? A, B, E a. Acrylamide = decrease in the number of synaptic vesicles and mitochondria at the nerve terminal is also characteristic, probably due to inhibition of retrograde and anterograde axonal transport. (C&Ds, 644) b. Taxol = Like colchicine and the vinca alkaloids, paclitaxel binds to tubulin; however, instead of leading to depolymerization, it promotes the formation of microtubules. Once formed, these microtubules remain stabilized by paclitaxel even in conditions that normally lead to dissociation of tubulin subunits, including cold temperatures or the presence of calcium. When paclitaxel is injected directly into the sciatic nerve of rats, microtubules aggregate along the axon, causing axonal degeneration, demyelination, and impairment of regeneration. (C&Ds, Pp. 647) c. False, Colchicine = A number of plant alkaloids alter the assembly and depolymerization of microtubules in nerve axons, causing neurotoxicity. The oldest known of these are colchicine and the vinca alkaloids, which bind to tubulin and cause depolymerization of microtubules. (C&Ds, Pp. 646) d. False, Nicotine = Nicotine exerts its effects by binding to a subset of cholinergic receptors, the nicotinic receptors. C7Ds, Pp. 651). Binds nicotinic receptors (cholinergic) low-dose stimulation; high-dose blocking. (C&Ds, Pp. 649, Table 16-4) e. Cocaine = Cocaine blocks the reuptake of dopamine, norepinephrine, and serotonin at the nerve terminal in the CNS, and also causes release of dopamine from storage vesicles. (C7Ds, Pp. 652) Infarcts and hemorrhages; alteration in striatal dopamine Neurotransmission. (C&Ds, Pp. 649, Table 16-4)

30. Which of the following is the toxic principle in castor bean seeds? A) tetrodotoxin B) digitonin C) saxitoxin D) ricin E) bungarotoxin

30. Answer is D ricin A) tetrodotoxin - Puffer Fish Poisoning, blocks voltage-gated Na+ channels to cause paralysis. B) digitonin (digitoxin?) - From oleander (Nerium oleander and N. indicum), where honey made from the flowers, meat roasted on oleander sticks, or milk from a cow that eats the foliage can produce prostrating symptoms. The oleander toxin consists of a series of cardiac glycosides: thevetin, convallarin, steroidal, helleborein, ouabain, and digitoxin. Sympathetic nerves are paralyzed; the cardiotoxin stimulates the heart muscles similar to the action of digitalis, and gastric distress ensues C) saxitoxin - Dinoflagellate Poisoning (Paralytic Shellfish Poisoning or PSP; Saxitoxin) In contrast to other seafood toxins, there is a tolerance set for PSP. The etiologic agent in this type of poisoning is saxitoxin or related compounds and is found in mussels, cockles, clams, soft shell clams, butter clams, scallops, and shellfish broth. D) ricin - castor beans, blocks protein synthesis E) bungarotoxin - are a group of closely related neurotoxic proteins derived from the venom of kraits including Bungarus multicinctus, α-Bungarotoxin inhibits the binding of acetylcholine (ACh) to nicotinic acetylcholine receptors;

4. Which of the following causes toxicity due to inhibition of vitamin K reductase and vitamin K epoxide reductase? A) trichothecene mycotoxins B) carbamate insecticides C) nonsteroidal anti-inflammatory drugs D) anticoagulant rodenticides E) amphetamine-like stimulants

4. Correct Answer = D, anticoagulant The super rodenticides are another cause of acquired vitamin K deficiency. These chemicals have a very prolonged half-life in vivo; thus the coagulation defect may persist for weeks or months following exposure. (C&Ds, Pp. 473) Oral anticoagulants (warfarin) interfere with vitamin K metabolism by preventing the reduction of vitamin K epoxide, resulting in a functional deficiency of reduced vitamin K. (C&Ds, Pp. 474)

9. Which of the following can be used to calculate the half-life of a drug in the blood? A) volume of distribution and total bodyclearance B) first-order elimination and creatinine clearance C) plasma protein binding and drug receptor density in a given tissue D) metabolism of the drug and plasma concentration E) plasma concentration

9. Answer is A p 311 Elimination half-life is dependent upon both volume of distribution and clearance. T1/2 can be calculated from Vd and Cl: T1/2 = (0.693 × Vd) / Cl

4. Which of the following is TRUE regarding carbon disulfide neurotoxicity? A) is characterized by sensory and motor symptoms, initially in a stocking-and-glove distribution B) results fiom crosslinking of microtubule proteins C) is associated with ototoxicity and tinnitus D) is a neuronopathy affecting the entire neuron E) is identical pathologically to that caused by B,Br-iminodiproprionitrile (IDPN)

Answer = A a. TRUE The clinical effects of exposure to CS2 in the chronic setting are very similar to those of hexane exposure, with the development of sensory and motor symptoms occurring initially in a stocking and-glove distribution. In ddition to this chronic axonopathy, CS2 can also lead to aberrations in mood and signs of diffuse encephalopathic disease. (C&Ds, Pp. 643) b. FALSE, is capable of cross-linking proteins c. Could not find d. FALSE The neurotoxicity of CS2 is well known and involves damage to the peripheral and central nervous systems as well as profound effects on vision. The peripheral neuropathy results from a distal axonal degeneration of the large-caliber and long axons of the peripheral nerves and spinal cord, probably through the reactions with the sulfhydryl groups of axonal neurofilament proteins, yielding covalent cross linkages that lead to filamentous tangles and axonal swellings. (C&Ds, 685). e. FALSE These neurofilament swellings are similar to those observed in carbon disulfide or γ-diketones toxicity. (C&Ds, Pp. 644). CS2 to cause a distal axonopathy that is identical pathologically to that caused by n-hexane. (C&Ds, Pp. 642)

31. Sodium saccharin has been shown to induce bladder tumors A) through a genotoxic mechanism B) following a single oral exposure to neonatal female rats C) in male rats after very high life-time exposure D) in the untreated offspring of female rats treated with very high doses E) with a shallow dose response and no clear threshold

Answer is C pp 1201

22. Which of the following is responsible for tetrodotoxin poisoning? A) puffer fish B) Alaskan butter clam C) moray eel D) sea snail E) sandfish

Answer = A, puffer fish a. CORRECT, Tetrodon or puffer fish poisoning is caused by the improper preparation and consumption of any of about 90 species of puffer fish (fugu, blowfish, globefish, porcupine fish, molas, burrfish, balloonfish, toadfish, etc.); although the toxin has also been reported present in newts, frogs, octopus, starfish, flatworms, various crabs, and gastropods. Pufferfish are found in subtropical and tropical marine waters in the Atlantic (including off the coast of Florida), Pacific, and Indian Oceans. Some puffers live in brackish and fresh water. The toxin (tetrodotoxin) is located in nearly all the tissues, but the ovaries, roe, liver, intestines, and skin are the most toxic. (C&D's, PP. 1244). b. Alaskan butter clam = Saxitoxin, originally isolated from toxic Alaskan butter clams (Saxidomus giganticus) is actually a family of neurotoxins and includes neosaxitin and gonyautoxins 1 through 4. (C&D's Pp. 1222). c. Moray eel = Although the moray eel (Gymnothorax javanicus) and other carnivorous fishes may accumulate ciguatoxin as the result of eating other contaminated fish, the Indo-Pacific moray eel (Lycodontis nudivomer) has been shown to possess a mucous skin secretion with hemolytic, toxic and hemagglutinating properties, unrelated to ciguatoxin. The hemolytic properties can be separated from the hemagglutinating properties. The hemolytic property is lost upon treatment with trypsin and is unstable in the presence of heat, acidic or alkaline media. The skin mucous of other species of eels, the common European eel (Anguilla anguilla) and pike eel (Muraenesox cinereus) were found to have proteinaceous toxins, immunologically similar to that of the skin mucous toxin from the Japanese eel (Anguilla japonica). (C&D's, Pp. 1224) d. Sea snail = Ciguatera Poisoning The "cigua" in ciguatera toxin is derived from the Spanish name for the sea snail Turbo pica in which the symptoms were first reported. Ciguatera and related toxins (scaritoxin and maitotoxin) are ichthyosarcotoxic neurotoxins (anticholinesterase) and are found in 11 orders, 57 families, and over 400 species of fish as well as in oysters and clams. (C&D's, Pp. 1224). e. Sandfish = Not in C&D's

3. Which of the following is characteristic of silicosis? A) can be caused equally by crystalline or amorphous silica B) is associated with the inhalation of fibrogenic particles sized at 10 to 20 microns C) is initiated by the phagocytosis of inhaled silica by pulmonary macrophages D) usually has a latency period of less than 10 years E) can be completely reversed upon cessation of Exposure

Answer = C a. FALSE, Amorphous forms of silica such as kieselguhr and vitreous silica have very low fibrogenic potential. b. FALSE, usually less than 5 microns (um) c. TRUE The role of pulmonary alveolar macrophages in the ingestion of silica as an initiating event has been established. d. FALSE, chronic silicosis has a long latency period, usually more than 10 years. Although acute silicosis is much shorter. e. FALSE, No known treatment modality influences the relentless course of acute silicosis.

23. Silicosis is best described by which of the following? A) acute and chronic forms have the same pathological consequences B) recovery from the acute form of the disease generally occurs within one or two years C) the chronic form has a short latency period D) the fibrogenic response in the lung is not related to silica dust particle size E) the cytotoxic response of alveolar macrophages initiates pulmonary fibrosis

Answer = E (see C&Ds, Pp. 624-625) a. FALSE = The disease may be acute or chronic; this distinction is important conceptually because the pathological consequences are manifested quite differently. b. FALSE = patients have worsening dyspnea, fever, cough, and weight loss. There is rapid progression of respiratory failure, usually ending in death within a year or two. No known treatment modality influences the relentless course of acute silicosis. c. FALSE = Chronic silicosis has a long latency period, usually more than 10 years. d. FALSE = The main factors that affect the pathogenicity of silica both in vivo and in vitro, in addition to its structure, are particle size and concentration are particle size and concentration. Many studies have examined the relationship of silica particle size to fibrogenicity. In studies with humans, the most fibrogenic particle size appears to be about 1 μm (range 0.5-3 μm). In animal experiments (rats, hamsters), the comparable values appear to be 1-2 μm (range 0.5-5 μm). In animal models, there appears to be a direct relationship between the concentration of silica dust to which an animal is exposed and the intensity and rapidity of the histological reaction in the lung. e. TRUE = The role of pulmonary alveolar macrophages in the ingestion of silica as an initiating event has been established. Apparently, as part of the cytotoxic response of a macrophage to silica ingestion, the macrophage may release cytokines and other substances that cause fibroblasts to replicate and/or increase their rate of collagen biosynthesis.

2. Elimination following oral administration is a function of which of the following? A) area under the curve (AUCoral) and plasma half-life B) oral dose and plasma clearance C) AUCoraI and plasma clearance D) plasma clearance and bioavailability E) oral dose and plasma half-life

Answer =B Not directly in C&D...this is the only explanation that is close to useful For most drugs, absorption and elimination follow first order kinetics because the drug concentration is not sufficient to saturate the mechanism for absorption or elimination. If the process saturates, then zero order kinetics apply. For some drugs, elimination kinetics are dose-dependent (or more correctly, concentration dependent). As the plasma level increases, the value of t1/2e increases; the plasma concentration increases disproportionately with increases in dose, and finally, elimination rate becomes independent of plasma concentration http://www.columbia.edu/itc/gsas/g9600/2004/GrazianoReadings/Drugabs.pdf Basically in first order processes, clearance is the sole determinant of elimination, while in second order processes clearance and dose determine elimination.

37. Which of the following nephrotoxicants is correctly matched with its renal target? A) indomethacin: intercalated cells of outer medullary collecting duct B) cyclosporin: glomerular endothelial cell C) acetaminophen: thick ascending limb of Henle's loop D) lithium: distal tubule cell E) tetrafluoroethylene: S 1 segment of the proximal tubule

Answer B A) indomethacin (NSAID): papillary necrosis (initially medullary interstitial cells followed by degenerate changes to medullary loops of henle and capillaries. B) cyclosporin: arteriolopathy global, segmental glomerular sclerosis, striped interstitial fibrosis, and tubular atrophy. C) acetaminophen: proximal tubular necrosis with increases in BUN and serum creatinine D) lithium: Agents, such as lithium, cyclosporine, NSAIDs, lead, and cadmium, may produce chronic tubulointerstitial nephropathy with progressive loss of renal function E) tetrafluoroethylene (TFEC): The nephrotoxicity produced by haloalkenes is characterized morphologically by proximal tubular necrosis, primarily affecting the S3 segment, and functionally by increases in urinary glucose, protein, cellular enzymes, and BUN.

29. Which ofthe following tests would NOT be useful in assessing contact allergenicity of a chemical? A) Buehler assay B) guinea pig maximization test C) micronucIeus assay D) mouse ear swelling test E) murine local lymph node assay

Answer C&D p511-512 Answer is ( is NOT useful in assessing contact allergenicity) A) Buehler assay USEFUL, one of top two tests B) guinea pig maximization test USEFUL, one of top two tests C) micronucIeus assay Not useful, this is a short term in vivo test for of chromosomal alterations D) mouse ear swelling test USEFUL E) murine local lymph node assay USEFUL

40. Which of the following serum enzymes is the MOST specific indicator of biliary tract injury or cholestasis? A) alanine aminotransferase B) gamma-glutamyl transferase C) sorbitol dehydrogenase D) N-acetyl glucosamidase E) lactate dehydrogenase

Answer GGT A) alanine aminotransferase - necrosis B) gamma-glutamyl transferase C) sorbitol dehydrogenase D) N-acetyl glucosamidase E) lactate dehydrogenase - generic

14. All of the following can be evaluated from a multi-generation reproductive toxicity study EXCEPT A) mating index B) male fertility index C) female fertility index D) preimplantation loss E) postimplantation loss

Answer chose D....but am not sure of E These multigeneration studies normally encompass detailed measurements of reproductive performance (number of pregnant females from number of pairs mated, number of females producing a litter, litter size, number of live pups with their birth weights and sex). Measurement of growth and analysis of the reproductive organs in the F0 parental generation is conducted (including specific evaluations of ovarian follicles, estrous cyclicity, and sperm parameters). Similar measurements to those undertaken for the F0 are made on the F1 parents, but in addition offspring are normally carefully examined at birth (and sexually dimorphic end points may be collected such as AGD), at weaning, and at puberty (particularly the assessment of VO and time of first estrus in females and belanopreputial separation in males) in addition to the adult measurements of reproductive performance, organ weights, histology etc

38. For which of the following compound groups is fatty liver the primary toxic effect? A) carbon tetrachloride, ethanol, valproic acid B) acetaminophen, carbon tetrachloride, valproic acid C) carbon tetrachloride, ethanol, arsenic D) acetaminophen, carbon tetrachloride, ethanol E) ethanol, chlorpromazine, valproic acid

Answer is A A) carbon tetrachloride (true), ethanol (true), valproic acid (true) B) acetaminophen (maybe-not primary), carbon tetrachloride (true), valproic acid (false- reduces liver fat accumulation) C) carbon tetrachloride (true), ethanol (true), arsenic (false) D) acetaminophen (maybe-not primary), carbon tetrachloride (true), ethanol (true) E) ethanol (true), chlorpromazine (false), valproic acid (false)

40. Antineoplastic alkylating agents MOST commonly cause toxicity to which of the following? A) bone marrow and gastrointestinal mucosal cells B) bone marrow and cardiac myocytes C) gastrointestinaI mucosal cells and islets of Langerhans D) gonads and skeletomuscular system E) bone marrow and eyes

Answer is A An alkylating antineoplastic agent is an alkylating agent used in cancer treatment that attaches an alkyl group (CnH2n+1) to DNA. Since cancer cells, in general, proliferate faster and with less error-correcting than healthy cells, cancer cells are more sensitive to DNA damage — such as being alkylated. Alkylating agents are used to treat several cancers. However, they are also toxic to normal cells (cytotoxic), leading to damage, in particular in cells that divide frequently, as those in the gastrointestinal tract, bone marrow, testicles and ovaries, which can cause loss of fertility. Most of the alkylating agents are also carcinogenic. Hyperthermia is especially effective at enhancing the effects of alkylating agents A) bone marrow and gastrointestinal mucosal cells B) bone marrow and cardiac myocytes C) gastrointestinaI mucosal cells and islets of Langerhans D) gonads and skeletomuscular system E) bone marrow and eyes

5. Pulmonary edema in toxic lung injury typically represents A) an acute, exudative phase of lung injury B) the defining characteristic of interstitial fibrosis in the lung C) the infiltration of neutrophil elastase in emphysema D) a major contributor to the increased prevalence of asthma E) a reaction requiring a long latency period

Answer is A Toxic pulmonary edema represents an acute, exudative phase of lung injury that generally produces a thickening of the alveolar-capillary barrier. Edema fluid alters ventilation-perfusion relationships and limits diffusive transfer ofO2 andCO2 even in otherwise structurally normal alveoli. (P619)

32. Lidocaine, methylene blue and nitrates are associated with which of the following? A) methemoglobinemia B) aplastic anemia C) aldehyde dehydrogenase activation D) anesthesia E) alopecia

Answer is A Table 11-5 p 461 The most common cause of methemoglobinemia is exposure to an oxidizing xenobiotic that overwhelms the NADH-diaphorase system. A large number of chemicals and therapeutic chemicals may cause methemoglobinemia (Table 11-5). Nitrites appear to be able to interact directly with heme to facilitate oxidation of heme iron, but the precise mechanism that leads to methemoglobin formation is unknown for many of the other substances listed in Table 11-5.

12. Which of the following agents enters hepatocytes via carrier-mediated membrane transport? A) microcystin B) acetaminophen (paracetamol) C) carbon tetrachloride D) ethanol E) 2,3,7,8-tetrachlorodibenzo-p-dioxin

Answer is A microcystin pp 560 OATPs transport numerous drugs and also some hepatotoxins, e.g., phalloidin, microcystin, and amanitin

14. Which of the following is CORRECT regarding elimination of toxicants? A) toxicants excreted in the sweat may produce dermatitis B) toxicants conjugated to sulfate in dogs may be subject to enterohepatic circulation C) active transport of toxicants from the cerebrospinal fluid does not occur D) no specialized transport systems have been described for toxicant excretion by the lungs E) lead is not likely to be excreted into milk since plasma is more acidic than milk

Answer is A or D---page 156 B-is incorrect, glucuronidated toxicants undergo enterohepatic circulation C is incorrect, toxicants also can be removed from the CSF by active transport, using the transport systems present in the BCSFB D likely correct, No specialized transport systems have been described for the excretion of toxic substances by the lungs. Some xenobiotic transporters, including Mrp1 and P-gp, have been identified in the lung, but overall, compounds excreted via exhalation in the lung are most likely to be eliminated by simple diffusion E is incorrect, Metals chemically similar to calcium, such as lead, and chelating agents that form complexes with calcium also can be excreted into milk to a considerable extent.

9. Which of the following is cleared from extracellular fluid space by intravenous calcium disodium edetate (calcium EDTA)? A) lead B) mercury C) antimony D) beryllium E) thallium

Answer is A, lead, p 946

19. Which activity of atropine is MOST important when treating organophosphate poisoning? A) activation of acetylcholinesterase B) antagonism of acetylcholine at muscarinic receptors C) competition with acetylcholine binding at nicotinic receptors D) acceleration of the detoxification of organophosphates E) prevention of phosphorylated acetylcholinesterase from undergoing the aging process

Answer is B A) No B) antagonism of acetylcholine at muscarinic receptors (atropine) C) atropine does not act on nicotinic receptors D) no E) Not most important

26. Which of the following is TRUE concerning skin? A) human skin is a relatively inert barrier to chemical substances B) the stratum corneum actively transports many chemical substances into the blood C) most chemicals are absorbed across the stratum corneum by passive diffusion D) the outermost layer of the skin is the dermis E) human skin does not vary in thickness or cellular composition across the entire body

Answer is C, Toxicants move across the stratum corneum by passive diffusion.

33. Which of the following is NOT TRUE of nongenotoxic carcinogens? A) increased cell proliferation is not observed in target tissues as assessed by BrdU labeling index B) agents that induce peroxisome proliferation in rodent liver are generally nongenotoxic C) some nongenotoxic carcinogens act via receptor-mediated pathways D) saccharin-induced bladder tumors in rats form via a nongenotoxic mechanism E) examples include 2,3,718-tetrachlorodibenzop-dioxin and polychlorinated biphenyls

Answer is A----page 101 In summary, nongenotoxic carcinogens appear to act by enhancing cell division and/or inhibiting apoptosis B,C,E are true----page 98--xenobiotics that are nongenotoxic carcinogens in rodents but not in humans, such as phenobarbital, DDT, TCDD and peroxisomal proliferators (e.g., fibrates, WI-14643, di- and trihalogenated acetic acids) C is true---page 28 for example, it has been shown that bladder tumors observed in rats fed very high doses of saccharin will not occur at the much lower doses of saccharin encountered in the human diet. At the high concentrations fed to rats, saccharin forms an insoluble precipitate in the bladder that subsequently results in chronic irritation of bladder epithelium, enhanced cell proliferation, and ultimately bladder tumors

35. Which of the following will serve to maximally increase absorption of an inhaled gas with a low solubility ratio? A) increase the rate of pulmonary blood flow B) decrease the respiration rate C) increase the concentration of the solvent in the inspired air D) administer a metabolic inducer prior to exposure E) increase the ambient humidity

Answer is A----page 141----an increase in the rate of blood flow increases the rate of uptake of a compound with a low solubility ratio because of more rapid removal from the site of equilibrium, that is, the alveolar membranes B--respiratory rate influences alveolar concentration but does not solve the solubility problem Ethylene has a low solubility ration (0.14) while Chloroform has a high blood to gas partition coefficient (20). These two are the same thing.

2. Which of the following is used clinically as a chelating agent for acute iron poisoning? A) desferrioxamine B) dimercaprol C) calcium disodium edetate D) cholestyramine E) dithiocarbamate

Answer is A. A) Desferrioxamine is the chelator of choice for the treatment of acute iron intoxication and chronic iron overload. Iron chelators have also been proposed for the treatment of cancers with iron overload (Page 955) Also, deferoxamine works. Acute iron poisoning from accidental ingestion of iron containing dietary supplements is the most common cause of acute toxicity. It most often occurs in children. A decrease in occurrence of this type of poisoning followed the introduction of childproof lids on prescription medicines and vitamin supplements. Severe toxicity occurs after the ingestion of more than 0.5 g of iron or 2.5 g of ferrous sulfate. Toxicity occurs about 1-6 hours after ingestion. Symptoms include abdominal pain, diarrhea, and vomiting. Of particular concern are pallor or cyanosis, metabolic acidosis, and cardiac collapse. Death may occur in severely poisoned children within 24 hours. Supportive therapy and iron chelation with deferoxamine should be used as soon as possible. Inhalation of iron oxide fumes or dust may cause pneumoconiosis in occupational settings. (C&D's, Pp. 954) B) The most effective treatment of bismuth toxicity is to discontinue bismuth intake. Chelation therapy using dimercaprol (BAL), 2,3-dimercaptoduccinic acid (DMSA), and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) reduces the bismuth concentration in most organs (especially kidney and liver) and increase elimination in urine. (Page 961) C) Calcium disodium edetate (EDTA) is used for chelation in lead poisoning. (P947) D) Cholestyramine, an anion-exchange resin, has been shown effective both in animals and humans as a means to increase fecal excretion of the insecticide chlordecone, probably by sequestering the unmetabolized compound that is secreted into the intestinal lumen via biliary excretion; this interrupts enterohepatic circulation and shortens the biological half-life. E) Dithiocarbamates are fungicides used on crops that have low acute toxicity but can result in adverse effects with chronic exposure (that may be due to the dithiocarbamates acid or the metal moiety). (P966). Some water soluble forms of dithiocarbamates are effective antidotes for acute mercury poisoning and show promise as potential antidotes for lead poisoning (found in reference articles; couldn't find in C&D).

8. Retinoic acid can cause a variety of malformations in animals depending on the timing of exposure during the period of organogenesis. Which malformation would be MOST likely to occur with exposure early in this period? A) absence or short tail B) spina bifida C) absent or short limbs D) microphthalmia E) cleft palate

Answer is A. Short or absent tail. Refer to Table 10-1 (Page 423)

2. Which of the following is used clinically as achelating agent for acute iron poisoning? A) desferrioxamine B) dimercaprol C) calcium disodium edetate D) cholestyramine E) dithiocarbamate

Answer is A.A) Desferrioxamine is the chelator of choice for the treatment of acute iron intoxication and chronic iron overload. Iron chelatorshave also been proposed for the treatment of cancers with iron overload (Page 955) Also, deferoxamine works. Acute iron poisoning from accidental ingestion of iron containing dietary supplements is the most common cause of acute toxicity. It most often occurs in children. A decrease in occurrence of this type of poisoning followed the introduction of childproof lids on prescription medicines and vitamin supplements. Severe toxicity occurs after the ingestion of more than 0.5 g of iron or 2.5 g of ferrous sulfate. Toxicity occurs about 1-6 hours after ingestion. Symptoms include abdominal pain, diarrhea, and vomiting. Of particular concern are pallor or cyanosis, metabolic acidosis, and cardiac collapse. Death may occur in severely poisoned children within 24 hours. Supportive therapy and iron chelation with deferoxamine should be used as soon as possible. Inhalation of iron oxide fumes or dust may cause pneumoconiosis in occupational settings. (C&D's, Pp. 954)B) The most effective treatment of bismuth toxicity is to discontinue bismuth intake. Chelation therapy using dimercaprol (BAL), 2,3-dimercaptoduccinic acid (DMSA), and 2,3-dimercaptopropane-1-sulfonic acid (DMPS) reduces the bismuth concentration in most organs (especially kidney and liver) and increase elimination in urine. (Page 961)C) Calcium disodium edetate (EDTA) is used for chelation in lead poisoning. (P947)D) Cholestyramine, an anion-exchange resin, has been shown effective both in animals and humans as a means to increase fecal excretion of the insecticide chlordecone, probably by sequestering the unmetabolized compound that is secreted into the intestinal lumen via biliary excretion; this interrupts enterohepatic circulation and shortens the biological half-life.E) Dithiocarbamates are fungicides used on crops that have low acute toxicity but can result in adverse effects with chronic exposure (that may be due to the dithiocarbamates acid or the metal moiety). (P966). Some water soluble forms of dithiocarbamates are effective antidotes for acute mercury poisoning and show promise as potential antidotes for lead poisoning (found in reference articles; couldn't find in C&D).

37. Which of the following statements is NOT TRUE about statins? A) inhibit the cholesterol biosynthesis enzyme 3- hydroxy-3-methyl-glutaryl-CoA reductase B) increase the degradation of cholesterol within the blood stream C) can cause an increase in hepatic uptake of plasma LDL with a resulting reduction in circulating LDL levels D) have been associated with rhabdomyolysis E) are used to treat dyslipidemia

Answer is B A) TRUE - The statins occupy a portion of the binding site of HMG-CoA, thus blocking access of this substrate to the active site B) False - could not find this. C) TRUE - In rabbits, hepatocytes (liver cells) sense the reduced levels of liver cholesterol and seek to compensate by synthesizing LDL receptors to draw cholesterol out of the circulation. D) TRUE - Cerivastatin was withdrawn from the market in August, 2001 due to risk of serious rhabdomyolysis E) True

15. All of the following are correctly paired as xenobiotic and toxic metabolite EXCEPT A) amygdalin: HCN B) hexane: 2,5-hexanedione C) ethylene glycol: oxalic acid D) acetaminophen (paracetamol): N-acetyl-pbenzoquinoneimine E) methylisocyanate: methylamine

Answer is E----Table 3-1, methylisocyanate is NOT bioactivated The rest are correct pairs

12. Which of the following is TRUE about dichlorodiphenyltrichloroethane (DDT) insecticides? A) death following acute exposure is due to cardiac arrest in mammals B) motor neurons are more sensitive to their effects compared to sensory neurons C) they cause liver tumors in rats and monkeys D) they cause hypothyroidism in avian species E) tumor promotion has not been reported in experimental animals

Answer is B A) death following acute exposure is due to cardiac arrest in mammals FALSE, death due to respiratory failure B) motor neurons are more sensitive to their effects compared to sensory neurons TRUE, Sensory neurons not mentioned much. Acute exposure to high doses of DDT causes motor unrest, increased frequency of spontaneous movements, tremors, convulsions. Could not find exact quote about sensory being less sensitive though. C) they cause liver tumors in rats and monkeys FALSE, liver tumors in mice and rats, inconclusive in other species D) they cause hypothyroidism in avian species (not found) E) tumor promotion has not been reported in experimental animals FALSE, unlikely since not genotoxic but carcinogenic, no direct reference to exact mechanism, p 902

2 1. Over-production of tumor necrosis factor alpha can produce A) immunosuppression B) inflammation C) infection D) neutropenia E) phocomelia

Answer is B B) Alteration of the microcirculation and accumulation of inflammatory cells are the hallmarks of inflammation. These processes are largely initiated by resident macrophages secreting cytokines, such as TNF-α and interleukin-1. (P85) Response E is not related to this question but this comes up a lot...E) False. In the mid-to-late 1950s, mainly in Europe, thalidomide was prescribed to pregnant women in the first trimester to treat morning sickness. Unfortunately, whereas (R)-thalidomide is an effective sedative, the (S)-enantiomer is a teratogen that produces phocomelia (limb shortening). Thalidomide blocks the release of tissue necrosis factor alpha (TNFα) (173)

28. Which of the following is used as a serum biomarker to assess drug-induced cardiac toxicity? A) beta-glutamyltranspeptidase B) troponins C) creatinine isoenzyme D) sorbitol dehydrogenase E) alkaline phosphatase

Answer is B B) Cardiac troponin T (cTnT) and I (cTnI) are constituents of the myofilaments and expressed exclusively in cardiomyocytes. It is thus of absolute myocardial tissue specificity. In healthy persons, serum cTnT or cTnI are rarely detectable. Therefore, any measurable concentrations of serum cTnT or cTnI reflect irreversible myocardial injury such as myocardial infarction. The clinical experience has arrived at a recommendation that cTn measurement becomes the "gold standard" for diagnosis of acute myocardial infarction. (P718) C) There are three major CK isoenzymes identified; CK-MM is the principal form in skeletal muscle, CK-MB presents in myocardium in which CK-MM is also found, and CK-BB is the predominant form in brain and kidney. Elevation of serum CKMB is considered a reasonably specific marker of acute myocardial infarction. (P718)

25. Which of the following is the primary target for chloroform-induced nephrotoxicity? A) glomerulus B) proximal tubule C) distal tubule D) Bowman's capsule E) peritubular capillaries

Answer is B Chloroform produces nephrotoxicity in a variety of species, with some species being more sensitive than others. The primary cellular target is the proximal tubule, with no primary damage to the glomerulus or the distal tubule. (P601)

30. Which of the following substances cause megaloblastic anemia due to folate deficiency? A) gentamicin B) phenytoin C) ciprofl oxacin D) chloramphenicol E) primaquine

Answer is B Hematopoiesis requires active DNA synthesis and frequent mitoses. Folate and vitamin B12 are necessary to maintain synthesis of thymidine for incorporation into DNA (Fig. 11-3). Deficiency of folate and/or vitamin B12 results in megaloblastic anemia, with its characteristic morphologic and biochemical changes (Table 11-2, p 459), which commonly affect erythroid, myeloid, and megakaryocytic lineages. A number of xenobiotics may contribute to a deficiency of vitamin B12 and/or folate (Table 11-3), leading to megaloblastic anemia (Babior, 2006). Xenobiotics that cause folate deficiency megaloblastic anemia include: Phenytoin, Primidone, Carbamazepine, Phenobarbital, Sulfasalazine, Cholestyramine, Triamterine, Malabsorption syndromes, Antimetabolites Xenobiotics that cause b12 deficiency megaloblastic anemia include: Paraminosalicylic acid, Colchicine, Neomycin, Ethanol, Omeprazole, Hemodialysis, Zidovudine, Fish tapeworm

20. Which of the following is associated with spina bifida in offspring of epileptic women? A) excess foIate supplementation B) valproic acid C) phenytoin D) mephenytoin E) excess choline supplementation

Answer is B Pg. 420...Valproic acid, or 2-propylpentanoic acid, is an anticonvulsant first marketed in Europe in 1967 and in the United States in 1978. In 1982, Elizabeth Robert reported that of 146 cases of spina bifida aperta recorded in a birth defects surveillance system in Lyon, France, nine of the mothers had taken valproate during the first trimester.

7. Which of the following is NOT TRUE for methylene chloride metabolism and toxicity? A) metabolism by glutathione transferase theta is a low-affinity, high-capacity pathway B) the systemic toxic potential is high C) formaldehyde is thought to be a reactive metabolite in mice D) can cause cardiovascular disease from occupational exposures E) polymorphisms in CYP2EI contribute to the differential susceptibility to hepatotoxicity observed in humans

Answer is B MC has only a limited systemic toxicity potential review page 1003-4 for additional info A is true C is true D yes, Table 33-3 E is likely, did not find the specific infor but 2E1 is responsible for the reactive metabolite

15. Which of the following is the initial adverse effect of a rattlesnake bite? A) Type 1 hypersensitivity reaction B) hypotension leading to shock C) a precipitous decrease in vascular permeability D) tissue necrosis at the site of envenomation E) respiratory distress due to bronchoconstriction

Answer is B page 1098 Hypotension or shock is the major therapeutic problem in North American crotalid (rattle snake is (Crotalus viridis) bites A--antivenom can cause type 1 hypersensitivity C--WASP kinins cause INCRESE in vascular permeability D---not myonecrosis, The specific agent crotamine from Crotalus durissus terrificus venom induces skeletal muscle spasms and paralysis by changing the inactivation process of sodium channels E--venoms do not cause bronchoconstriction, organophosphates could

9. Which of the following describes a proximate carcinogen? A) it is the final form that interacts with cellular constituents B) requires one or more metabolic steps to interact with cellular constituents C) requires no further metabolism to interact with cellular constituents D) is inactive E) cannot be deactivated by enzymes

Answer is B pp 166 Point 11 Cytochrome P450 is particularly effective at converting proximate carcinogens to ultimate carcinogens by converting the former to electrophilic metabolites that bind to and mutate DNA, thereby leading to mutations and tumor initiation. The Ames' bacterial mutagenicity assay, which is representative of several mutagenicity tests, is performed in the absence and presence of cytochrome P450 (i.e., liver microsomes) to evaluate the mutagenic potential of both the parent compound and any electrophilic metabolites, respectively. Polycyclic aromatic hydrocarbons (combustion pollutants and components of tobacco smoke), aromatic amines (industrial chemicals), aflatoxin (a mycotoxin), cooked-food pyrolysis products, and tobacco-specific nitrosamines are all examples of proximate carcinogens that require metabolic activation to form electrophilic, DNA-binding metabolites (ultimate carcinogens).

11. A fiber with a diameter of 1 micron and a length of 200 microns will be deposited in the bronchial tree primarily by A) sedimentation B) interception C) infusion D) diffusion E) impaction

Answer is B pp 616 Interception occurs when the trajectory of a particle brings it near enough to a surface so that an edge of the particle contacts the airway surface. Interception is important for the deposition of fibers. Whereas fiber diameter determines the probability of deposition by impaction and sedimentation, interception is dependent on fiber length. Thus, a fiber with a diameter of 1 μm and a length of 200 μm will be deposited in the bronchial tree primarily by interception rather than impaction.

10. Chronic poisoning with which of the following metals causes peripheral neuropathy in adult humans but primarily encephalopathy in children? A) arsenic B) lead C) mercury D) chromium E) beryllium

Answer is B, lead, p 944

34. Which of the following pairs of tests are considered the MOST appropriate for initial assessment of genotoxicity? A) dominant lethal assay and the comet assay B) gene mutation assay (Ames assay) and mammalian assay for chromosome damage in vivo (micronucIeus assay in rat bone marrow) C) Drosophila sex-linked recessive lethal and gene mutation assay (Ames assay) D) chromosome aberration in CHO cells and sister chromatid exchange E) cytogenetic analysis for aneuploidy and mammalian assay for chromosome damage in vivo (micronucleus assay in mice)

Answer is B----page 403 ....a sensitive assay for gene mutations (e.g., the Ames assay) and an assay for clastogenic effects in mammals pivotal in the evaluation of genotoxicity, and this is the basis for our highlighting these assays in Table 9-1. The Ames assay has performed reliably with hundreds of compounds in laboratories throughout the world. Beyond gene mutations, one should evaluate damage at the chromosomal level with a mammalian in vitro or in vivo cytogenetic assay. Cytogenetic assays in rodents are especially useful for this purpose because they combine a well-validated genetic assay with mammalian pharmacodynamics and metabolism.

16. Which of the following CYP450 forms are responsible for the bioactivation of acetaminophen (paracetamol)? A) CYP1Al and CYP2D6 B) CYP1A2 and CYP2E1 C) CYP2A6 and CYP2C6 D) CYP2C9 and CYP2C19 E) CYP2D6 and CYP2E1

Answer is B---page 234

13. A worker in a metal fabricating plant is grinding a metal and develops tremors, difficulty in walking and compulsive behavior. What is the most likely cause? A) lead B) mercury C) magnesium D) aluminum E) manganese

Answer is B. C&D page 949 Inhalation of mercury vapor at extremely high concentrations may produce an acute, corrosive bronchitis and interstitial pneumonitis and, if not fatal, may be associated with central nervous system effects such as tremor or increased excitability A lead produces different CNS signs Symptoms of lead encephalopathy begin with lethargy, vomiting, irritability, loss of appetite, and dizziness, progressing to obvious ataxia, and a reduced level of consciousness, which may progress to coma and death C Magnesium does not cause ill effects but inhaled magnesium OXIDE, similar to ZINC OXIDE may cause metal fume fever D Aluminum Acute aluminum toxicity is rare. Most cases of aluminum toxicity in humans are observed in patients with chronic renal failure, or in persons exposed to aluminum in the workplace, with the lung, bone, and central nervous system as major target organs E Manganese can cause hand tremor later Early manifestations of manganese neurotoxicity include headache, insomnia, memory loss, muscle cramps, and emotional instability. Initial outward symptoms progress gradually and are mainly psychiatric. As exposure continues and the disease progresses, patients may develop prolonged muscle contractions (dystonia), decreased muscle movement (hypokinesia), rigidity, hand tremor, speech disturbances, and festinating cock-walk gait

16. Sodium nitrite is administered as an antidote for poisoning by which of the following gases? A) carbon monoxide B) cyanide C) nitrogen dioxide D) nitrous oxide E) sulfur dioxide

Answer is B.....page 1266 sodium nitrite is given to patients poisoned with cyanide to cause formation of methemoglobin, which serves as an alternative binding site for the cyanide ion thereby making it less toxic to the body A---Antidote for CO is hyperbaric oxygen C and D--No known antidote for nitrogen oxides E--no known antidote

4. Which of the following is TRUE about dichlorodiphenyltrichloroethane (DDT), dieldrin, and toxaphene? A) they are co-planar congeners with dioxin-like toxicity B) they are acetylcholinesterase inhibitors C) they induce neuroexcitatory effects and are environmentally persistent D) they are rapidly metabolized E) their toxicity is similar to that produced by nitrogen mustards

Answer is C A) False. Polychlorinated biphenyls (PCBs) are congeners with dioxin-like toxicity (P110). DDT dieldrin, and toxaphene are organochlorines. B) False. Organophosphates and carbamates are acetylcholinesterase inhibitors. (P526 and P528) C) True. Acute exposure to high doses of DDT causes motor unrest, increased frequency of spontaneous movements, abnormal susceptibility to fear and hypersusceptibility to external stimuli (light, touch, sound). This is followed by the development of fine tremors, progressing to coarse tremors, and eventually tonic-clonic convulsions. (P901) The primary target for Lindane and cyclodiene (chlordane, dieldrin, aldrin) toxicity is the central nervous system. Unlike DDT, tremor is essentially absent, but convulsions are a prominent aspect of poisoning. They bind to a specific site (the picrotoxin site) on the chloride channel, thereby blocking its opening and thus antagonizing the inhibitory action of GABA. As with DDT, they are extremely persistent in the environment, and some have endocrine disrupting properties. (P905) D) False. As with DDT, lindane and cyclodienes (chlordane, dieldrin, aldrin) are slowly metabolized, and have a tendency to bioaccumulate in adipose tissue; they are also excreted in milk. (P904)

39. Which of the following is a human toxicant produced by marine algae? A) ibotenic acid B) kojic acid C) domoic acid D) ellagic acid E) cyclopiazonic acid

Answer is C A) ibotenic acid - found in the mushrooms Amanita muscaria and Amanita pantherina, among others. Ibotenic acid is a powerful neurotoxin B) kojic acid - a chelation agent produced by several species of fungi, especially Aspergillus oryzae, which has the Japanese common name koji.Kojic acid is a by-product in the fermentation process of malting rice, for use in the manufacturing of sake, C) domoic acid - is the neurotoxin that causes amnesic shellfish poisoning (ASP), is associated with certain harmful algal blooms D) ellagic acid - is a natural phenol antioxidant found in numerous fruits and vegetables. The antiproliferative and antioxidant properties of ellagic acid have spurred preliminary research into the potential health benefits of ellagic acid consumption. E) cyclopiazonic acid - is a toxic fungal secondary metabolite. Chemically, it is an indole tetramic acid. CPA was originally isolated from Penicillium cyclopium and subsequently from other fungi including Penicillium griseofulvum, Penicillium camemberti, Aspergillus flavus, and Aspergillus versicolor. CPA only appears to be toxic in high concentrations. Biologically, CPA is a specific inhibitor of Ca2+-ATPase in the intracellular Ca2+ storage sites.

17. Which of the following is a specific pulmonary toxicant? A) 2,4,5-tnchlorophenoxyacetic acid (2,4,5-T) B) 2,4-dich1orophenoxyacetic acid (2,4-D) C) paraquat D) glyphosate E) diquat

Answer is C A)2,4,5-T - a synthetic auxin, is a herbicide used to defoliate broad-leafed plants. It was developed in the late 1940s and was widely used in the agricultural industry until being phased out, starting in the late 1970s due to toxicity concerns. Agent Orange, a defoliant used by the British in the Malayan Emergency and the U.S. in the Vietnam War, was equal parts 2,4,5-T and 2,4-D. 2,4,5-T itself is toxic with a NOAEL of 3 mg/kg/day and a LOAEL of 10 mg/kg/day B)2,4-D - is a common systemic pesticide/herbicide used in the control of broadleaf weeds. It is one of the most widely used herbicides in the world, and is the third most commonly used herbicide in North America. It was a major ingredient in Agent Orange alongside its chemically similar relative, 2,4,5-T (2,4,5-trichlorophenoxyacetic acid).The LD50 determined in an acute toxicity rat study is 639 mg/kg. Single oral doses of 5 and 30 mg/kg body weight did not cause any acute toxic effects in human volunteers. This chemical has been associated with the risk of amyotrophic lateral sclerosis. C) paraquat - Even a single swig, immediately spat out, can cause death from fibrous tissue developing in the lungs, leading to asphyxiation. Pure paraquat, when ingested, is highly toxic to mammals, including humans; potentially leading to acute respiratory distress syndrome (ARDS). Although there are no specific antidotes, fuller's earth or activated charcoal is an effective treatment if taken in time. There were also some successful cases of using cyclophosphamide (Endoxan) to treat Paraquat poisoning. Death may occur up to 30 days after ingestion. Diluted paraquat used for spraying is less toxic; thus, the greatest risk of accidental poisoning is during mixing and loading paraquat for use. D) glyphosate - is a broad-spectrum systemic herbicide used to kill weeds, especially annual broadleaf weeds and grasses known to compete with commercial crops grown around the globe. Monsanto brought it to market in the 1970s under the trade name Roundup. Human acute toxicity is dose related. Acute fatal toxicity has been reported in deliberate overdose. Epidemiological studies have not found associations between long term low level exposure to glyphosate and any disease. The EPA considers glyphosate to be noncarcinogenic and relatively low in dermal and oral acute toxicity. The EPA considered a worst case dietary risk model of an individual eating a lifetime of food derived entirely from glyphosate-sprayed fields with residues at their maximum levels. This model indicated that no adverse health effects would be expected under such conditions. E) diquat - is a contact herbicide that produces desiccation and defoliation. In humans, severe congestion and ulceration of the stomach and bowel are produced by the herbicide. After large doses of diquat are given, there is evidence of stretching and irritation of the GIT and thickening of the walls of the alveoli, or air cells of the lungs.

22. Which of the following immunopathies is NOT mediated by antibodies? A) food allergy B) systemic anaphylaxis C) dermal sensitization D) inhalation allergenicity E) allergic rhinitis

Answer is C Allergic contact dermatitis is a delayed (T-cell mediated) hypersensitive reaction. To induce sensitization through the skin, chemical haptens generally penetrate the lipid barrier and, to be detected by the immune system, become attached to carrier proteins. (P746)

24. Which of the following represents the most sensitive indicator of a toxicant-induced decrease in proximal tubule function? A) increased serum cystatin C B) increased urine lactate dehydrogenase C) increased urinary levels of low molecular weight protein D) decreased urine specific gravity E) increased serum potassium

Answer is C Cystatin C, is specific for glomerular a 13-kDa endogenous protein that inhibits cysteine proteases, is a viable candidate to replace creatinine in the measurement of GFR. It is produced at a constant rate by all tissues, freely filtered by the glomerulus and catabolized by the tubular epithelial cells; thus, its use is limited to serum levels and not urinary levels. Serum cystain C levels appear to be independent of height, gender, age, muscle mass, and coexisting diseases, and are more sensitive than creatinine in mildly impaired GFR. (P594, also 8th edition has a nice figure Figure 14-10)

18. Which of the following is associated with drug induced pulmonary phospholipidosis? A) alveolar accumulation of proteinaceous material B) proliferation of fibroblasts without inflammation C) alveolar macrophages containing concentric membranous structures D) alveolar and interstitial edema E) congestion and disruption of normal lung architecture

Answer is C Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies, most likely from an impaired phospholipid metabolism of the lysosome. Organs affected by phospholipidosis exhibit inflammatory reactions and histopathological changes.

6. What effect is associated with gestational exposure to an anti-androgen in rats? A) increased anogenital distance in female offspring B) increased incidence of reproductive tract malformations in female offspring C) decreased anogenital distance in male offspring D) decreased number of nipples andlor areolae in female offspring E) reduced survival of male offspring

Answer is C Vinclozolin and procymidone (dicarboximide fungicides), the herbicide linuron, Phthalates (Plasticizers), and p,p -DDE (Pesticide Metabolite) are examples of AR antagonists. For example, administration of vinclozolin during sexual differentiation demasculinizes and feminizes the male rat offspring such that treated males display female-like AGD at birth, retained nipples, hypospadias, suprainguinal ectopic testes, a blind vaginal pouch, and small to absent sex accessory glands. Procymidone administered from day 14 of pregnancy to day 3 after birth: AGD is shortened in male pups, and the males display retained nipples, hypospadias, cryptorchidism, cleft phallus, a vaginal pouch, and reduced sex accessory gland size. (P789)

19. Which of the following neurotoxic agents is best known for causing degeneration of dorsal root ganglia? A) aluminum B) trimethyltin C) doxorubicin D) kainate E) manganese

Answer is C pg. 637... In addition to its cardiac toxicity that limits the quantity of doxorubicin that can be given to cancer patients, doxorubicin also injures neurons in the PNS, specifically those of the dorsal root ganglia and autonomic ganglia (Spencer, 2000).

38. Chronic oral administration of corticosteroids can result in which of the following adverse effects? A) asthma B) skin thickening C) osteoporosis D) cardiac arrhythmias E) peripheral neuropathy

Answer is C A) asthma (FALSE) - inhaled steroids treat asthma by reducing inflammation in airways. B) skin thickening (FALSE) - can cause skin thinning C) osteoporosis (TRUE) - Steroid-induced osteoporosis may be a side-effect of long-term corticosteroid use. D) cardiac arrhythmias (FALSE) - Corticosteroids can cause sodium retention through a direct action on the kidney, in a manner analogous to the mineralocorticoid aldosterone. This can result in fluid retention and hypertension. E) peripheral neuropathy (FALSE) - oral corticosteriods given to treat peripheral neuropathy

32. Toxicity due to Amanita phalloides ingestion is associated with which organ system? A) renal B) central nervous system C) hepatic D) cardiovascular E) skeletal muscle

Answer is C (death cap mushroon) pp 1107-1108

16. All of the following neurotoxicants act primarily on the axon EXCEPT A) acrylamide B) carbon disulfide C) domoic acid D) hexane E) tri-ortho-cresyl phosphate

Answer is C ...domoic acid causes neuronal loss.....the rest cause axonopathies...Table 16-2 A--Acrylamide causes axonal degeneration B--Carbon disulfide causes axonal degeneration D--N-hexane is metabolized to gamma di ketone which causes distal axonopathy E--TOCP causes distal axonopathy

34. Which of the following agents is MOST LIKELY to lead to the formation of oxalic acid following ingestion? A) methanol B) ethanol C) ethylene glycol D) propylene glycol E) calcium gluconate

Answer is C Table 3.1----there was an earlier question by by Dan D is incorrect, remember that it is really safe E Calcium gluconate is used to treat DDT induced tremors

5. Which of the following statements is TRUE regarding metallothioneins? A) they are involved in metal homeostasis but do not provide protection against metal toxicity B) they are proteins having high molecular weights (over 10,000 Da) C) they are rich in thiol binding sites D) they have high affinity binding sites for essential metals but not nonessential metals E) they are generally not inducible

Answer is C... A page 147 metallothionein (MT), .....sequesters both essential and toxic metals including zinc and cadmium (Cd) with high affinities in the kidney and liver. In liver, Cd bound to MT serves to concentrate and sequester the heavy metal while preventing its excretion into bile. In the kidney, however, the Cd-MT complex is very toxic and is mechanistically involved in the chronic toxicity of Cd B is incorrect---page 936 They are small (6000 Da) C D is incorrect, it is thiol-rich because of cysteine and binds divalent cations (essential and nonessential) ...page 529 cysteine-rich protein that complexes normally with divalent cations, such as copper E is incorrect, page 432 Metallothionein synthesis is inducible by a wide variety of chemical and physical agents including metals, alcohols, urethane, endotoxin, alkylating agents, hyper- or hypothermia, and ionizing radiation additional info page 432 Because of its high affinity for Zn, MT may sequester Zn in the placenta, impeding transfer to the conceptus (induction of maternal hepatic MT by Cd or other agents can also induce fetal Zn deficiency

6. Which of the following BEST explains the greater susceptibility of humans and non-human primates to methanol toxicity, compared to rats? A) greater capacity for intraretinal metabolism in rats B) increased metabolism of formic acid C) limited capacity to oxidize formic acid D) pronounced metabolic acidosis E) accelerated oxidative phosphorylation

Answer is C...page 682 Human and nonhuman primates are highly sensitive to methanol-induced neurotoxicity due to their limited capacity to oxidize formic acid A is incorrect, Rats seem to have greater folate capacity, which helps metabolism B is correct, its because of decreased formic acid oxidation D is made up E is made up Additional info , Formic and oxalic acids are considerably more toxic than acetic acid. For this reason, methanol and ethylene glycol poisoning are commonly treated with ethanol, which competitively inhibits the oxidation of methanol and ethylene glycol by ADH and ALDH. The potent inhibitor of ADH, 4-methylpyrazole (fomepizole), is also used to treat methanol and ethylene glycol poisoning.

11. Which of the following mechanisms is shared by dichlorodiphenylethane (DDT) and chlordane? A) activity primarily directed against the peripheral nervous system B) inhibition of GABAA receptors C) enhanced release of neuro+t;ansmitters due to increased intracellular Ca levels D) inhibition of Na-K'-ATPase E) efficient absorption through the skin

Answer is D A) activity primarily directed against the peripheral nervous system FALSE for chlordane as primarily central activity B) inhibition of GABAA receptors FALSE, GABA inhibited for chlordane, GABA not mentioned for DDT C) enhanced release of neuro+t;ansmitters due to increased intracellular Ca levels FALSE D) inhibition of Na-K-ATPase TRUE for both E) efficient absorption through the skin FALSE DDT dermal absorption very limited, true for chlordane

2 1. Which of the following is the MOST plausible mechanism of carcinogenicity of inhaled formaldehyde in rats? A) induction of aneuploidy B) alkylation of nasal epithelial DNA C) high blood formaldehyde levels D) nasal epithelial cytotoxicity and proliferation E) a non-threshold dose-response curve

Answer is D The carcinogenicity and non-carcinogenicity effects of formaldehyde are a much debated topic. Page 1149 briefly describes formaldehyde effects and debates; there are also many literature articles. Nasal cancer had been induced empirically with formaldehyde vapor in a 2-year study where rats were exposed to 2, 6, or 14 ppm 6 hours per day, 5 days per week. The incidence of nasal squamous cell carcinomas was zero in the control and 2-ppm groups, 1% at 6-ppm, and 44% at 14-ppm. Exposure-related induction of squamous metaplasia occurred in the respiratory epithelium of the anterior nasal passages in all exposed groups. A 20-fold increase in cell proliferation in the nasal epithelium occurred after 5 days to 14 ppm. Mice were much less sensitive; one carcinoma at 14 ppm. The detection of DNA adducts in the two species paralleled the difference in the incidence of tumors as well as regional dosimetry. Note that formaldehyde nasal tumor induction in rats is one example of how larger species respond differently and extrapolation of rat tumor data to humans on the basis of formaldehyde concentration may overestimate doses of formaldehyde to humans.

27. Given equal exposure conditions of two agents to healthy skin, percutaneous permeability A) will be greater for the more hydrophilic agent B) will be directly proportional to their molecular weight (MW) if both agents are hydrophilic C) will be dominated by their hydrophobicity regardless of MW D) will be directly proportional to their hydrophobicity, but inversely proportional to their MW E) will be directly proportional to both their hydrophobicity and MW

Answer is D The degree of uptake depends upon the details of exposure conditions, being proportional to solute concentration (assuming it is dilute), time, and the amount of skin surface exposed. In addition, two intrinsic factors contribute to the absorption rate of a given compound: its hydrophobicity, which affects its ability to partition into epidermal lipid, and its rate of diffusion through this barrier. Although it is true for small molecules that hydrophobicity is a dominant factor in penetration, very hydrophobic compounds, once in the stratum corneum, may diffuse only very slowly into less hydrophobic regions below, so there is an inverse function of molecular weight (MW) or molecular volume as compounds get larger. Thus, hydrophobic agents of low MW permeate the skin better than those of high MW or those that are hydrophilic. Relations can be obtained for skin penetration (Pcw) using empirically derived constants (C1, C2, C3) that have the form shown below (P743): log Pcw = C1 − C2(MW) + C3 logKow

10. Which of the following is NOT TRUE for initiation of carcinogenesis? A) is an irreversible cellular change B) requires one or more cell division for fixation C) spontaneous initiation of cells is a common occurrence D) initiated cell is morphologically identifiable E) high efficiency of DNA repair can alter the process

Answer is D Tumor formation steps are: initiation (mutation), transformation, and progression. Initiation includes: DNA modification, Mutation, Genotoxic, One cell division necessary to lock in mutation, Modification is not enough to produce cancer, Nonreversible, Single treatment can induce mutation A) is an irreversible cellular change TRUE B) requires one or more cell division for fixation TRUE C) spontaneous initiation of cells is a common occurrence TRUE, unsure how common D) initiated cell is morphologically identifiable FALSE E) high efficiency of DNA repair can alter the process TRUE

18. Which of the following should be used to treat a symptomatic patient intoxicated by carbaryl within the preceding 12 hours? A) diazepam B) 2-PAM C) theophylline D) atropine E) saline

Answer is D carbaryl (Sevin) insecticide ... slowly reversible inhibitors of acetylcholinesterase A) diazepam acts on GABA B) 2-PAM - shown to make things worse when given with atropine C) theophylline competitive nonselective phosphodiesterase inhibitor, which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and inhibits leukotriene synthesis, and reduces inflammation and innate immunity D) atropine - atropine is a competitive antagonist of the muscarinic acetylcholine receptors E) saline ? - there is rapid reactivation of the carbamylated enzyme in the presence of water

20. Which of the following is NOT TRUE of pyrethrum? A) it was originally extracted from a species of Chrysanthemum B) it is a mixture of several esters C) it has insecticidal properties D) it causes little, if any, skin inflammation in humans upon direct contact E) it provides the structural basis for synthetic pyrethroids

Answer is D - can cause, itching, or blisters A) True - it was originally extracted from a species of Chrysanthemum B) True - it is a mixture of several esters (pyrethrin) C) True - it has insecticidal properties D) False - it causes little, if any, skin inflammation in humans upon direct contact E) True - it provides the structural basis for synthetic pyrethroids

33. Which of the following is TRUE of gammadiketone neurotoxicity? A) neurofilament proteins are selectively derivatized by the metabolite 2,5-hexanedione B) neurofilament filled swellings are preferentially located distal to nodes of Ranvier C) n-hexane neurotoxicity progresses at a more rapid rate than that induced by an equimolar concentration of methyl n-butyl ketone D) pyrrole formation and oxidation are necessary in the pathogenesis of the neuropathy E) nerve damage and muscle weakness progresses in a proximal to distal pattern

Answer is D page 641 N-hexane and methyl-n-butyl ketone cause similar damage by their metabolism to gammadiketones and pyrrole oxidation and cross-linking is a necessary step in the development of axonopathy. Neurofilaments accumulate in the distal axon, usually just proximal to a node of Ranvier, and form massive axonal swellings leading to retraction of myelin from the nodes. In addition to swelling, axonal atrophy is also a pathological feature of γ-diketone neurotoxicity. A& C are just distractors B is incorrect, locata in the distal axon, PROXIMAL to node of Rainvier E is incorrect axonopathies are usually distal to proximal

1. Which of the following forms of mercury is most likely to be found in fish? A) mercury bichloride B) mercuric chloride C) metallic mercury D) methylmercury E) tetraethylmercury

Answer is D. Typically, environmental exposure to mercury occurs via the food chain due to accumulation of MeHg in fish. (P639)

1. Which of the following forms of mercury is mostlikely to be found in fish? A) mercury bichloride B) mercuric chloride C) metallic mercury D) methylmercury E) tetraethylmercury

Answer is D. Typically, environmental exposure to mercury occurs via the food chain due to accumulation of MeHg in fish. (P639)

15. Which of the following is TRUE regarding micronuclei? A) nuclei found only in microorganisms such as viruses B) small nuclei generally seen in lower organisms like algae, bacteria, earthworm or hydra C) insoIuble Iysosomal inclusions that accumulate around the nucleus D) chromosomal fragments or whole chromosomes that were not incorporated into a nucleus during mitosis E) only seen using electron microscopy

Answer is D......page 1167 Micronuclei are chromosomal fragments that are not incorporated into the nucleus at cell division, and chemical exposures can markedly increase their frequency.

7. When evaluating results of reproductive toxicology studies, all of the following are valid assumptions EXCEPT A) an agent that produces an adverse developmental effect in experimental animals potentially poses a hazard to humans if sufficient exposure occurs during development B) all four manifestations of developmental toxicity (death, structural abnormaIities, growth alterations, and functional deficits) are of concern C) the types of developmental effects seen in animal studies are not necessarily the same as those that may be produced in humans D) there is no threshold dose for agents that produce developmental toxicity E) increases in dose can result in qualitative as well as quantitative differences in conceptus outcome

Answer is D; in general a threshold is assumed. (P439) Risk assessment for noncancer endpoints (e.g., developmental toxicity) generally defines the dose, route, timing, and duration of exposure that induces effects at the lowest level in the most relevant laboratory animal model (US EPA, 1991a,b). The exposure associated with this critical effect is then subjected to safety or uncertainty factors to derive a relatively safe human exposure level. The principal uncertainty factors (1. interspecies extrapolation and 2. variability in the human population) each have a default value of 10. In the absence of firm evidence upon which to base decisions on whether or not to extrapolate animal test data, the following default assumptions are generally made: (1) an agent that produces an adverse developmental effect in experimental animals will potentially pose a hazard to humans following sufficient exposure during development; (2) all four manifestations of developmental toxicity (death, structural abnormalities, growth alterations, and functional deficits) are of concern; (3) the specific types of developmental effects seen in animal studies are not necessarily the same as those that may be produced in humans; (4) the most appropriate species is used to estimate human risk when data are available (in the absence of such data, the most sensitive species is appropriate); and (5) in general, a threshold is assumed for the dose-response curve for agents that produce developmental toxicity.

17. Screening batteries to further evaluate neurobehavioral toxicity currently include A) histopathologic examination of brain, spinal cord and selected peripheral nerves B) evaluation of olfactory discrimination C) recording of clinical signs of toxicity during acute toxicity studies D) evaluation of various biochemical markers of neurological effects E) a functional observation battery and an evaluation of motor activity

Answer is E Did not spend a lot of time on this one.

8. All of the following are essential metals EXCEPT A) cobalt B) chromium C) molybdenum D) manganese E) lithium

Answer is E Metals generally regarded as essential for human health in trace amounts include iron, zinc, copper, manganese, chromium, molybdenum and selenium. They are essential because they form an integral part of one or more enzymes involved in a metabolic or biochemical process http://www.eurometaux.org/MetalsToday/MetalsFAQs/Metalsessentialforhumanhealth.aspx

31. Examples of Phase 1 metabolizing reactions in the liver include all of the following EXCEPT A) epoxidation B) deamination C) dealkylation D) aromatic hydroxylation E) methylation

Answer is E, methylation is a phase II reaction Types of Phase 2 (conjugation) Metabolism Reactions include: 1. Glucuronic acid conjugation 2. Sulfate conjugation 3. Amino acid conjugation 4. Glutathione conjugation 5. Acetylation 6. Methylation

23. Which of the following assays would be LEAST useful in understanding the immunotoxic potential of a chemical at doses that do not produce overt toxicity? A) hematologic assessment of circulating blood B) organ weights at necropsy C) bone marrow cellularity D) in vivo plaque forming cell assay E) serum creatinine concentrations

Answer is E: Refer to Table 12-9 Tier Approach for Immunotoxicology Testing (P520) Tier I Hematology, Body weight, Organ weights (spleen, thymus, kidney, liver), Spleen cellularity, Bone marrow cellularity and CFU, Immunopathology, PFC assay, Proliferative responses, NK assay Tier II Surface marker analysis, Secondary (IgG) PFC assay, CTL assay, DTH response Host-resistance studies

13. Which of the following BEST characterizes dental fluorosis? A) is observed in adults following acute exposure to excess fluoride B) is observed in adults chronically exposed to excess fluoride C) is observed in children chronically exposed to excess fluoride D) is observed in children following acute exposure to excess fluoride E) results from a stimulation of enamel-forming cells to lay-down excessive enamel

Answer is...C--page 965..doesnt explicitly say chronic but could be deduced from the scenario A is incorrect.....observed in Children B is incorrect observed in children D is incorrect..chronic E--incorrect, there is hypomineralized enamel, leading to enamel loss over time

5. Which of the following BEST describes P-glycoprotein? A) a plasma protein present only in male rats B) expressed mainly in the sinusoidaI membrane of hepatocytes C) excreted into urine in renal proximal tubular injury D) a primary active transporter contributing to the blood brain barrier E) a transporter that facilitates the intestinal absorption of some xenobiotics

Answer is: D A) α2u-Globulin is synthesized in the liver of male rats and is under androgen control.621 B) Phalloidin and microcystin are illustrative examples of hepatotoxins that target the liver as a consequence of extensive uptake into hepatocytes by sinusoidal transporters.588 C) D)The blood-brain barrier also contains transporters, such as the multidrug-resistant protein, which transport some xenobiotics that have diffused through endothelial cells back into the blood.632 E) Cyclosporine is returned from the enterocyte into the intestinal lumen by P-glycoprotein (an ATP-dependent xenobiotic transporter)

8. Which of the following statements is NOT CORRECT regarding apoptosis? A) can be initiated by cell injury B) is a more likely event than necrosis if ATP is depleted in a cell C) is a process that occurs during normal embryogenesis of the handlpaw D) is programmed cell death E) may prevent neoplasia by eliminating cells with DNA damage

Answer is:B A) Apoptosis initiated by cell injury can be regarded as tissue repair for two reasons, the first of which is that it may intercept the process leading to necrosis, as discussed earlier (see Fig. 3-17)82 B) Figure 18-13. Interchange between apoptotic and necrotic cell death pathways regulated by mitochondrial MPTP C) Apoptosis is necessary for sculpting the digits from the hand plate, for instance, and for assuring appropriate functional connectivity between the central nervous system and distal structures.425 D) The term programmed cell death(pcd) refers to a specific type of cell death, apoptosis, under genetic control in the embryo E) An overall imbalance between stimulation of proliferation and inhibition of apoptosis in the liver leads to the survival and expansion of these preneoplastic cells

28. Which of the following produces cardiovascular toxicity upon ingestion? A) bracken fern (Pteridium aquilinum) B) foxglove (Digitalis purpurea) C) dumb cane (Dieffenbachia) D) autumn crocus (Colchicum autumnale) E) ragwort (Senecio species)

Answer is:B A)Different portions of the plant may contain different concentrations of a chemical. An example of localization of bioactive compounds is found in the bracken fern ( in which the carcinogenic terpene, ptaquiloside, is found in high concentrations in the fronds compared with the roots (Rasmussen Pteridium aquilinum)1103 B)Several different families of plants contain species with cardioactive glycosides, the best known of which is Digitalis purpurea (foxglove, Scrophulariaceae).1106 C)Examples are hay fever (rhinitis) from exposure to airborne plant pollen and oral irritation, especially in children, from biting on a leaf of a plant such as dumb cane (Diffenbachia).1125 D)Colchicine is best known in western medicine for its antimitotic effect, resulting from block of formation of microtubules and failure of the mitotic spindle, for which it is useful in attacks of gout. Colchicine is the major alkaloid in the bulbs of Colchicum(autumn crocus, Liliaceae), native to Asia Minor. Severe autumnale gastroenteritis (nausea, vomiting, diarrhea, and dehydration) follows ingestion of the bulbs that may be mistaken for wild garlic. Systemic effects (confusion, hematuria, neuropathy, and renal failure) may develop in severe poisoning.1105 E)Other contaminations include contamination of milk with pyrrolizidine and other alkaloids after a cow has fed on tansy ragwort (white snakeroot (Senecio jacobaea) and tremetol contamination of milk fromEupatorium rugusum)Genotoxic Carcinogens334.

26. Which of the following forms of ionizing radiation would penetrate the least if the source is deposited on the skin? A) gamma rays B) alpha particles C) beta particles D) positron E) ultraviolet

Answer is:B A)Gamma rays and neutrons are more penetrating, causing diffuse damage throughout the body (e.g. radiation sickness, cell's DNA damage, cell death due to damaged DNA, increasing incidence of cancer) rather than burns. External radiation exposure should also be distinguished from internal exposure, due to ingested or inhaled radioactive substances, which, depending on the substance's chemical nature, can produce both diffuse and localized internal damage. B) Because of the short range of absorption, alphas are not, in general, dangerous to life unless the source is ingested or inhaled, in which case they become extremely dangerous. C) Beta particle(electrons and Positrons) are able to penetrate living matter to a certain extent and can change the structure of struck molecules. In most cases such change can be considered as damage with results possibly as severe as cancer and death. If the struck molecule is DNA it can show a spontaneous mutation. D) Beta particle E) An overexposure to UVB radiation can cause sunburn and some forms of skin cancer. However, the most deadly form - malignant melanoma - is mostly caused by the indirect DNA damage (free radicals and oxidative stress).

35. A change in the dependence on which of the following nutrients is used as an indicator of reverse mutation in the Ames assay? A) tryptophan B) histidine C) lysine D) arginine E) glucose

answer is B---page 395 In the Ames assay one measures the frequency of histidine-independent bacteria that arise in a histidine-requiring strain in the presence or absence of the chemical being tested A Tryptophan reversion assay is done in E.coli while Ames is done in Salmonella, both assays ask similar questions C,D,E---not used in mutation assays

36. Which of the following is NOT TRUE regarding chronic analgesic nephropathy? A) primary lesion is papillary necrosis B) likely results from ischemia secondary to renal vasoconstriction C) is generally reversible following withdrawal of the drug(s) D) can be caused by chronic non-steroidal anti-inflammatory drug abuse E) can be caused by chronic acetaminophen (paracetamol) abuse

answer is C----page 603 chronic consumption of combinations of NSAIDs and/or APAP (>3 years) results in an often irreversible form of nephrotoxicity known as analgesic nephropathy Acute Renal Failure may occur within hours of a large dose of a NSAID, is usually reversible upon withdrawal of the drug, and is characterized by.