Part IV: Risk Assessment Flashcards by Bonnie Blalock

For the safety determination of a Food Contact Substance (FCS), the US Food and Drug Administration (FDA) recommends the submission of a food additive petition for an estimated exposure greater than what concentration?
A. 0.5 ppm
B. 0.05 ppm
C. 1 ppm
D. 0.1 ppm

Answer: C
Explanation and Reference:
FDA recommends submission of a food additive petition for estimated exposure greater than 1 ppm. C&D 9th p 1334

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Hepatotoxicity has been associated with ingestion of high doses of what metal?
A. zinc
B. mercury
C. copper
D. selenium

Answer: C
Explanation and Reference:
Ingestion of copper salts, most frequently copper sulfate, may produce hepatic necrosis and death C&D 9th p 1133. Acute selenium toxicity can result in pulmonary edema and cardiovascular collapse (C&D p 1138). Ingestion of high doses of zinc can result in gastrointestinal distress and diarrhea (C&D 9th p 1139). Ingestion of mercury targets the brain and kidneys (C&D 9th p 1128).

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What has been identified as a toxicological endpoint associated with ethylene glycol and methanol intoxication?
A. damage of peripheral axons
B. retinal formation of oxalate crystals
C. hemorrhagic gastritis
D. metabolic acidosis

Answer: D
Explanation and Reference:
Only metabolic acidosis is common to both compounds. C&D 9th p 1206-1211

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Exposure to what solvent has been associated with elevated blood carboxyhemoglobin levels?
A. methylene chloride
B. chloroform
C. benzene
D. toluene

Answer: A
Explanation and Reference:
Methylene chloride is metabolized to carbon monoxide in the mixed function oxidase pathway. Carbon monoxide binds to hemoglobin forming carboxyhemoglobin. C&D 9th p 1191-1192 Fig 24-7

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What pesticide class has a primary adverse effect of paresthesia following dermal occupational exposure(characterized by burning, tingling, and stinging sensations)?
A. avermectins
B. organophosphates
C. pyrethroids
D. organochlorines

Answer: C
Explanation and Reference:
This is the primary effect from occupational exposure to pyrethroids. C&D 9th p 1073

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What exposure pathway provided the high concentrations of radioactive iodine to children following the Chernobyl disaster?
A. consumption of contaminated green leafy vegetables
B. exposure to precipitation fallout from rain and snow
C. consumption of fish and shellfish that bioconcentrated iodine
D. consumption of milk from cows grazing on contaminated pastures

Answer: D
Explanation and Reference:
Radioactive Plutonium 239, Strontium 90, Cesium 134 and 137, and Iodine 131 were released from the accident. Because iodine is taken up by the thyroid, there was a dose response relationship observed between Iodine 131 dose to the thyroid received in childhood within 15 years after the accident, and thyroid cancer risk. The primary source of the radioactive iodine was milk from cows grazing on contaminated pastures. C&D 9th p 1269, Hayes 6th p. 898

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What is the primary target organ for toxicity following exposure to ochratoxin A?
A. the brain
B. the spleen
C. the heart
D. the kidney

Answer: D
Explanation and Reference:
Ochratoxin A mainly causes endemic nephropathy and carcinogenesis by inhibiting the enzymes involved in phenylalanine metabolism, including phenylalanine-tRNA synthetase. It also inhibits mitohondrial ATP production and stimulates lipid peroxidation. C&D 9th p 1350

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Measurement of what metal in hair can be used as a reliable indicator of exposure?
A. lead
B. selenium
C. cadmium
D. mercury

Answer: D
Explanation and Reference:
Hair levels of mercury have been found to be a reliable measure of exposure to methylmercury. For most other metals, hair is not a reliable tissue for measuring exposure due to concerns with external contamination that complicate analysis. C&D 8th, p. 985.

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What is the primary target organ or system of toluene toxicity?
A. kidney
B. liver
C. central nervous system
D. hematopoietic system

Answer: C
Explanation and Reference:
The CNS is the primary target organ of toluene and other alkylbenzenes, due to its lipophilicity. It is commonly misused due to alcohol-like effects of euphoria and excitation. Toluene intoxication can lead to motor incoordination, dizziness, relaxation, lightheadedness, and hallucinations. Prolonged abuse (“huffing”) can lead to apathy, memory dysfunction and dimished visuospatial skills. Cardiac, renal and hepatic toxicities as well a getal alcohol-like syndrome have occasionally been reported. C&D 9th p 1201

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What is the primary mammalian target organ system adversely affected by the most commonly used insecticides?
A. endocrine system
B. respiratory system
C. cardiovascular system
D. nervous system

Answer: D
Explanation and Reference:
The CNS is the primary target for the most commonly used classes of pesticides (organophosphates and carbamates). The CNS of insects is highliy developed and not unlike that of mammaels, and there are similarities. C&D 9th p 1061, Table 22-8

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What rodenticide gets hydrolyzed in the stomach and produces a gas that causes necrosis of the gastrointestinal tract and injury to the liver and kidney?
A. warfarin
B. zinc phosphide
C. sodium fluroacetate
D. strychnine

Answer: B
Explanation and Reference:
Zinc phosphide ingestion leads to formation of phosphine gas (PH3) upon readtions with water or acids. C&D 9th p 1093

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What toxicological consequence has been reported following sub chronic exposure to DEET (N, N- Diethyl-m-toluamide)?
A. alpha 2µ-globulin induced nephropathy in male rats
B. chloracne on the face and upper back in humans
C. reproductive toxicity of failure for midline and palate closure in rabbits
D. paralysis in rodents

Answer: A
Explanation and Reference:
DEET does not pose a significant health concern to humans when used as directed. Subchronic toxicity studies in various species did not reveal major toxic effects, with the exception of renal lesions in male rats, which are considred to be unique to male rat physiology (α2µ-globulin induced nephropathy). C&D 9th p 1082

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Terrestrial environmental exposure to organic tin compounds is associated with the use of what?
A. paint
B. feed additives
C. machinery grease
D. fungicides

Answer: D
Explanation and Reference:
The key phrase is “terrestrial envrionment.” Triphenyltin is used as a fungicide. Tributyl tin was used as an antifouling agent in marine paints. C&D 9th p 1091

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How is the dose response relationship of a vitamin or trace element described?
A. Both low and high doses exhibit adverse effects.
B. Deficiency and excessive doses always demonstrate the same toxicities.
C. At very low doses, there are no adverse effects on living organisms.
D. Each vitamin and trace element has a unique dose response curve.

Answer: A
Explanation and Reference:
Hormesis is the characteristic dose-response curve of vitamins and trace minerals. This is a “U- shaped” curve where too little or too much of the compound in question may lead to toxicity.Example of a U-shaped curve with Vitamins and minerals. C&D 9th p 40 Fig 2-11

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What are the four key steps in the risk assessment process?
A. research, dose-response assessment, exposure assessment, risk communication
B. hazard identification, dose-response assessment, exposure assessment, risk characterization
C. research, hazard assessment, exposure calculation, risk characterization
D. hazard identification, exposure assessment, risk characterization, risk management

Answer: B
Explanation and Reference:
Only the correct answer contains the four defined steps of risk assessment. C&D 9th p 128 Fig 4-1

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What electrocardiogram (ECG) change identifies a risk of chemical-induced torsades de pointes?
A. prolonged QT interval
B. inverted T wave
C. P wave notching
D. elevated R wave amplitude

Answer: A
Explanation and Reference:
Torsades de Pointes occurs with an average increase in QT interval by 200 msec. This can be a life threatening ventricular arrhythmia and has been the focus of drug discovery and development in the last 2 decades. C&D 9th p 927

What is a chemotherapeutic compound commonly associated with myocardial toxicity?
A. doxorubicin
B. arabic gum
C. calcium acetate
D. carbon disulfide

Answer: A
Explanation and Reference:
Doxorubicin has high affinity for cardiolipin, a phospholipid found on the inner mitochondrial membrane, where NADH dehydrogenase converts the drug to a semiquinone radical. In the presence of oxygen, this radical is responsible for the generation of ROS, which then may peroxidize unsaturated membrane lipids and initiate myocardial cell injury. C&D 9th p 935

What is the most common initial adverse hepatic effect of valproic acid?
A. canalicular cholestasis
B. fatty liver
C. hepatocyte necrosis
D. hepatoma

Answer: B
Explanation and Reference:
Valproic acid effects fatty acid metabolism in liver mitochondria, via the depletion of L-carnitine. C&D 9th p 1547

Co-exposure to what compound or element would enhance the hepatotoxic potential of high therapeutic doses of the analgesic agent, acetaminophen?
A. mercury
B. ozone
C. ethanol
D. lead

Answer: C
Explanation and Reference:
Metabolism of acetaminophen by CYP2E1 results in a potentially toxic metabolite that is normally detoxified by conjugation with glutathione and excreted as a mercapturate. Ethanol also induces CYP2E1, and concurrent use may result in hepatotoxicity. C&D 9th p 1544

What is the mechanism of ocular toxicity associated with digitoxin attributed to?
A. formation of reactive intermediates
B. lipid peroxidation
C. inhibition of Na+/K+/-ATPase
D. inhibition of P-glycoprotein

Answer: C
Explanation and Reference:
The retina has the highest concentration of Na+/K+/-ATPase anywhere in the eye and inhibition of this enzyme is the primary target of digitalis. C&D 9th p 891

Exposure to benzene has been causally linked with development of what myeloid leukemia type?
A. acute myelogenous leukemia
B. chronic myelogenous leukemia
C. chronic lymphocytic leukemia
D. non-Hodgkin’s lymphoma

Answer: A
Explanation and Reference:
There is strong evidence from epidemiological studies that high-level benzene exposures result in an increased risk of acute myelogenous leukemia. C&D, 8th ed., pp 1063.

Liver damage through lipid peroxidation been reported following exposure to what environmental compound?
A. carbon monoxide
B. sulfur dioxide
C. natural gas
D. 1,2-dichlorobenzene

Answer: D
Explanation and Reference:
A primary target for lipid peroxidation by dichlorobenzene is the liver cell membrane. Hayes 6th p 1463

How is the nephrotoxicity associated with amino glycoside antibiotics characterized?
A. renal papillary necrosis with interstitial nephritis
B. glomerular sclerosis with interstitial fibrosis
C. renal proximal tubular degeneration/necrosis
D. increased medullary fibrosis

Answer: C
Explanation and Reference:
Nephrotoxicity occurs in 10-50% of patients treated with aminoglycoside antibiotics. Histologically, the target is the proximal renal tubular cell leading to necrosis. C&D 9th p 787

What has been characterized as the ultimate carcinogen formed from the polycyclic aromatic hydrocarbon, benzo(a)pyrene?
A. benzo(a)pyrene-7,8-epoxide
B. benzo(a)pyrene-9,10-diol
C. benzo(a)pyrene-7,8-diol-9,10-epoxide
D. benzo(a)pyrene-7,8-diol

Answer: C
Explanation and Reference:
The ultimate carcinogen is the benzo(a)pyrene-7,8-diol-9,10-epoxide, formed following 3 separate reactions, two involving CYP450 and one requiring epoxide hydrolase. The other compounds are not important metabolistes of benzo(a)pyrene. C&D 9th p 447, Fig 8-10b

25. In the context of environmental studies, to what does a trophic level transfer of contaminants refer? A. exposure through food web B. a traditional method used to assess changes in tissue concentrations C. chemical transport through different geological strata D. the bioavailability of a chemical

Answer: A Explanation and Reference: A trophic system is a food web, where individuals in a community can feed on different species depending on their life stage, seasons and relative abundancies of prey species. C&D 9th p 1451

26. The adrenal cortex has been shown to be particularly sensitive to the toxic effects of many xenobiotics. What does this sensitivity primarily result from? A. Adrenal cortical cells having impaired DNA repair enzyme pathways which result in higher accumulations of mutations than other tissues as the animal/person ages. B. Levels of metabolic enzymes within the adrenal cortical cells are lower than most other cells types, making the tissue more susceptible to the toxic effects of xenobiotics. C. The high lipid content of adrenal cortical cells with high levels of unsaturated fatty acids results in greater accumulation of lipophilic xenobiotic compounds and thus higher tissue exposures than many organs. D. Dendritic cells present in this region of the adrenal gland have particularly tight connections to the adrenal cortical cells, resulting in elevated hypersensitivity reactions.

Answer: C Explanation and Reference: Primary sensitivity results from high lipid content and high levels of unsaturated fatty acids. C&D 9th p 981

27. When describing wildlife exposure to contaminants, what is meant by "biologically effective dose"? A. the difference between external dose and internal dose B. the amount that actually reaches cells, sites or membranes where adverse effects occur C. the external dose due to direct contact D. the total dose that has been effectively biotransformed

Answer: B Explanation and Reference: The biologically effective dose is the amount of a compound that actually reaches cells, sites, or membranes where adverse effects occur. This definition is not limited to wildlife exposure. Hayes 6th, p. 458.

28. It is generally recognized that there are three categories of biomarkers: biomarkers of exposure, biomarkers of response or effect, and biomarkers of susceptibility. What would be a biomarker of exposure for benzene? A. elevated hemeoxygenase in blood B. phenyl mercapturic acid in urine C. decreased erythrocyte cholinesterase D. elevated serum ALT

Answer: B Explanation and Reference: Phenyl mercapturic acid in urine is a biomarker for Benzene exposure. C&D, 8th, pp 1066.

29. What is the advantage of applying the Benchmark Dose (BMD) approach instead of the NOAEL approach, in deriving a U.S. EPA Reference Dose (RfD)? A. It may be influenced by the choice of experimental doses. B. It eliminates consideration of variability in the dose-response data. C. It takes into account all the dose-response curve, includes confidence limit and uses a consistent Benchmark Response level for RfD calculations across studies. D. It eliminates the need for uncertainty factors.

Answer: C Explanation and Reference: The BMD provides a point of departure from which to then consider extrapolation of study data to chronic human general population applications. C&D 9th, pp. 138-141

30. When a sigmoid dose-response curve of cumulative percent response versus log dose is replotted as probit versus log dose, what probit value corresponds to a cumulative percent response of 50%? A. 1 B. 0.5 C. 3.33 D. 5

Answer: D Explanation and Reference: Probit values (probability units) are used to plot a dose response in a way that avoids negative numbers. Since quantal-dose responses are usually normally distributed, percent response can be converted to units of deviation from the mean or normal equivalent deviation (NED). The probit is then by definition the NED +5, and a 50% response would be a probit value of 5.0. C&D 9th p. 23, Fig. 2-4

31. The therapeutic index of a drug is an approximate statement about the relative safety of a drug expressed as which of the following? What expression is frequently used to designate the therapeutic index of a drug? A. (LD50-ED50)/ED50 B. TD50/ED50 C. TD01/ED99 D. ED50/LD50

Answer: B Explanation and Reference: The ratio of the toxic dose to the effective or therapeutic dose at the 50th percentile. C&D 9th p. 29.

32. According to the US Interagency Staff Group on Carcinogens, what key feature distinguishes the maximum tolerated dose (MTD) from other dose classifications? A. not a non-toxic dose, but rather produces some level of toxicity to indicate the animals were satisfactorily challenged B. estimated from the results of acute toxicity studies C. expected to produce at least some degree of life shortening in the test animals lifespan D. selected as the maximum dose not producing toxic effects

Answer: A Explanation and Reference: The US Interagency Staff Group on Carcinogens has defined the MTD as follows: "The highest dose currently recommended is that which, when given for the duration of the chronic study, is just high enough to elicit signs of minimal toxicity without significantly altering the animal's normal lifespan due to effects other than carcinogenicity. This dose, sometimes called the maximum tolerated dose (MTD), is determined in a subchronic study (usually 90 days duration) primarily on the basis of mortality, toxicity and pathology criteria. The MTD should not produce morphologic evidence of toxicity of a severity that would interfere with the interpretation of the study. Nor should it comprise so large a fraction of the animal's diet that the nutritional composition of the diet is altered, leading to nutritional imbalance.” DOSE SELECTION FOR CARCINOGENICITY STUDIES OF PHARMACEUTICALS, S1C(R2) 2008; Hayes, 4th ed. p. 37

33. If the total daily intake of a specific chemical agent via drinking water is 0.1 mg/kg/day, and the NOAEL (no observed adverse effect level) for neurotoxicity is 100 mg/kg/day, what is the MOE (margin of exposure) for neurotoxicity via the oral route? A. 10 B. 0.001 C. 1000 D. MOE cannot be calculated without an uncertainty factor (UF)

Answer: C Explanation and Reference: The MOE is the ratio of the NOAEL determined in animals compared with the level to which a human may be exposed [(100 mg/kg/day)/(0.1 mg/kg/day) = 1000]. C&D 9th p 29-30, 134

34. What are the intrinsic factors that determine the rate of absorption of a substance applied to the surface of the skin of a test animal? A. sex of test animal, anatomical site of application, pH of the dosing solution, temperature B. age of test animal, anatomical site of application, concentration of the dosing solution, condition of the skin (disease state) C. age of test animal, weight of the test animal, anatomical site of application D. age of test animal, weight of the test animal, concentration of the dosing solution

Answer: B Explanation and Reference: Skin thickness affects penetration, which varies according to age and location; aduvants (vehicles) can greatly affect absorption as well as disease state/condition of the skin. Hayes 6th, 1348-1349