ICH Questions

1. ICH S1A covers the conditions of patient exposure and preclinical and in vitro test results (i.e., genotoxicity) which support requiring carcinogenicity testing prior to approving a new drug for use in human patients. What threshold of exposure duration is given that supports requiring carcinogenicity testing?

A. Intermittent

B. 3 months

C. 6 months

D. 12 months

2.  ICH S1B gives the following factors for determining which species to use for carcinogenicity testing.

Pharmacology

Repeated-dose toxicology. 

Metabolism

Toxicokinetics

Route of administration

In the absence of clear evidence favoring one species what is the recommended species?

A. Monkey

B. Mouse

C. Rabbit

D. Rat

3. ICH S1B covers the testing of pharmaceuticals for carcinogenicity. It contains an addendum meant to be used for it and the other ICH S1 guidelines. This addendum provides a weight of evidence approach where the available evidence can be used to classify a compound as likely, unlikely or uncertain with respect to its potential to cause cancer in patients at clinically relevant doses. Under this approach the compounds with uncertain carcinogenic potential would be the ones directed to 2-year rodent assays while the others directed to consult regulatory authorities about not conducting the assays. Using this weight of evidence approach, what evidence would most support performing a 2-year rodent assay to test for carcinogenicity potential in patients?

A. Genotoxicity potential found for parent drug in multiple species/assays

B. High selectivity (i.e., no off-target activity)

C. Low selectivity (i.e., off-target activity)

D. No genotoxicity potential found for parent drug or major human metabolites.

4. ICH S2C gives guidance on how to select maximum doses for carcinogenicity. One method involves calculating the AUC ratio and keeping doses at or below a point above which it is not considered likely to reflect a relative risk to humans. What is the ratio (i.e., fold difference)?

A. 2

B. 5

C. 25

D. 250

5. ICH S3A defines the primary objective of toxicokinetic studies as relating dose to systemic exposure. This is typically done by collecting plasma or whole blood. What would be most likely to lead to an overestimation of systemic exposure based on blood or plasma levels of the parent compound?

A. Albumin binding is high

B. Bioavailability is high

C. Half-life is relatively long (i.e., > 12 hours)

D. Distribution volume is relatively large (i.e., >5 liters)

6. ICH 3A states that the analytical methods used in toxicokinetic studies should be specific for the entity being measured and of adequate accuracy and precision. What does it say should be adequate for the measurement of the range of concentrations anticipated to occur in the generation of the toxicokinetic data?

a) Limit of blank

b) Limit of detection

c) Limit of quantitation

d) Minimum detection value

7. ICH S3A defines the primary objective of toxicokinetic studies as relating dose to systemic exposure. This is typically done by collecting plasma or whole blood. What would be most likely to lead to an overestimation of systemic exposure based on blood or plasma levels of the parent compound?

A. Albumin binding is high

B. Bioavailability is high

C. Half-life is relatively long (i.e., > 12 hours)

D. Distribution volume is relatively large (i.e., >5 liters)

8. ICH S3B gives guidance on when repeated dose tissue distribution studies might be warranted. What would most suggest such studies should be considered?

A. The apparent half-life of test compound (and/or metabolites) in tissues is significantly shorter than the apparent half-life of the elimination phase in plasma and is also more than twice the dosing interval in the toxicity studies.

B. The apparent half-life of test compound (and/or metabolites) in tissues is significantly shorter than the apparent half-life of the elimination phase in plasma and is less than half the dosing interval in the toxicity studies.

C. The apparent half-life of test compound (and/or metabolites) in tissues significantly exceeds the apparent half-life of the elimination phase in plasma and is less than half the dosing interval in the toxicity studies.

D. The apparent half-life of test compound (and/or metabolites) in tissues significantly exceeds the apparent half-life of the elimination phase in plasma and is also more than twice the dosing interval in the toxicity studies.

9. ICH S4 gives the guidance of the duration for chronic toxicity testing based on the animal model. Which of the following is correct?

A. Rodent study of 6 months and non-rodent study of 6 months

B. Rodent study of 6 months and non-rodent study of 9 months

C. Rodent study of 9 months and non-rodent study of 6 months

D. Rodent study of 9 months and non-rodent study of 9 months

10. ICH S5 gives guidance on DART studies with the aim to address the whole life cycle of an organism going from conception to conception. How many generations (hint think genetics) are involved in this type of approach?

A. 1

B. 2

C. 3

D. 4

11. In ICH S6 for Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals they give the guidance to use two relevant species for safety evaluation. What reasons did they give for only using one species?

A. It is cheaper to use just one species

B. Per the guideline humans are the only relevant species

C. There is no reason

D. Two relevant species were used for short-term studies already and their toxicity profiles were close enough to justify using just one species for long-term studies

12. ICH S7A provides guidance on safety pharmacology and associated studies. Per this guideline, what organ systems are part of the core battery?

A. Cardiovascular, Central Nervous System, and Gastrointestinal

B. Cardiovascular, Central Nervous System and Immune System

C. Cardiovascular, Central Nervous System and Renal

D. Cardiovascular, Central Nervous System, and Respiratory

13. ICH S7B Covers the evaluation of the potential for QT prolongation in a new pharmaceutical. What is the main concern with QT prolongation?

a) Atherosclerosis leading to sudden cardiac arrest

b) Bradycardia leading to sudden cardiac arrest

c) Cardiac arrest suddenly happening due to tachycardia

d) Defibrillation leading to sudden cardiac arrest

14. ICH S8 covers drug-induced immunotoxicity studies. What does it say is a generally acceptable study design?

A. Daily dosing for 3 days

B. Daily dosing for 7 days

C. Daily dosing for 28 days

D. Daily dosing for 90 days

15. ICH S9 covers the nonclinical evaluation of anticancer pharmaceuticals. When developing drugs for patients with advanced cancer and limited life-expectancy there's a shift in the risk-reward ratio that prioritizes getting treatments into trials sooner rather than later. Because of this some toxicity testing is required to be done before marketing but not before clinical trial. But patient safety is still a concern what is an example of a kind of toxicity that should be evaluated and evidence supplied before Phase I gets started?

A. Absorption of wavelengths by the pharmaceutical and other phototoxicity testing

B. Base-pair changes and other genotoxicity testing

C. Carcinogenicity

D. Developmental toxicity

16. What would be an example of a chemical (i.e., in chemico) assay as referenced in ICH S10 as something that should be tried before moving on to the next level of testing?

A. Animal is given a test chemical to see if there is a response to a given dose

B. Blood is given a test chemical to see if there is a response to a given dose

C. Chemical is given a test chemical to see if there is a response to a given dose

D. Data about a test chemical is put into a simulation to see if there is a response to a given dose

17. ICH S10 covers photosafety evaluation of pharmaceuticals. It recommends a ROS assay as an earlier screening assay. Data supports this assay under proper conditions (e.g., adequate solubility of test compound to reach high doses) as having high sensitivity but low specificity with respect to predicting in vivo phototoxicity. What does all this mean with respect to how results should be interpreted and what would be the best answer below?

A. Low dose (e.g., ~2 micromolar) negative results are probably true negatives and suggest a low probability of phototoxicity.

B. High dose (i.e., ~200 micromolar) negative results are probably true negatives and suggest a low probability of phototoxicity.

C. Low dose (e.g., ~2 micromolar) positive results are probably true positives and suggest a high probability of phototoxicity.

D. High dose (e.g., ~200 micromolar) positive results are probably false positives and suggest a low probability of phototoxicity.

18. ICH S10 covers photosafety testing of pharmaceuticals. What is true about how and why reactive oxygen species (ROS) are tested for?

A. They are the only phototoxic product formed from phototoxic pharmaceuticals, so they are the only test required

B. They do not normally form from phototoxic pharmaceuticals, but in vitro reporter assays exist that produce ROSs in large quantities so they can be tested for as an addition to the normal in vitro toxicity assays

C. Even when another form of phototoxic product forms from a phototoxic pharmaceutics, ROS seem to also form making them a useful initial screening tool that does not require cells, animals, or people

D. They are not tested for because they do not form from phototoxic pharmaceuticals

19. ICH S11 gives guidance on nonclinical testing for the development of pediatric pharmaceuticals. All other things being equal what would make further studies most likely to be needed based on the weight of the following evidence?

a) Adolescents will be treated with a high specificity pharmaceutical for acute use.

b) Babies (i.e., neonates and infants being treated with a low specificity pharmaceutical for chronic use.

c) Chronic use of a high specificity pharmaceutical for adolescents.

d) Duration of use is acute, specificity is low and children 2-11 years of age are the population being treated.

20. ICH S12 (Draft) Guideline covers nonclinical biodistribution considerations for gene therapy products. What is within the scope of this guideline?

A. Assessment of genomic integration and germline integration of gene therapy products

B. Body waste-based excretion of gene therapy product (i.e., shedding)

C. COVID-19 or other prophylactic vaccines

D. Distribution, persistence, and clearance of a gene therapy product at the site of administration and in target and non-target tissues

21. ICH Q3D R(2) lists permissible daily exposures (PDEs) for metals (e.g., cadmium, thallium). However, the metal calcium is left out of the appendix. What is the best reason for why this particular metal was left out?

A. It’s highly toxic so there is no permissible level

B. It’s moderately toxic so there are regional differences about what is permissible

C. It’s essentially non-toxic so there are no limitations needed

D. It’s an essential nutrient so recommended daily allowances are generally used instead

22. ICH M7 is not intended to be applied retrospectively to already approved products but is meant to be applied to products being developed. What would require reassessment of the potential risk of mutagenic impurities for an approved drug?

A. Altering the route of synthesis

B. Buying a raw material from a new supplier

C. Changing the manufacturing site

D. Demonstrating the purity, potency and identity of the API remains the same

23. ICH M4 describes the Common Technical Document which since it has largely become electronic is generally referred to as the eCTD. It is structured into five modules. What is true about the first module?

a) Animal (i.e., nonclinical) summary reports are required

b) Basic summary of quality is required

c) Clinical study reports are required

d) Documents specific to each region are required

24. ICH M3(R2) provides guidance on nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. It refers to microdose trials. What clinical trial phase is limited to microdoses designed to result in sub-therapeutic doses that do not have a whole-body effect and generally has the smallest number of clinical trial participants?

A. 0

B. I

C. II

D. III

25. ICH S10 provides guidance on Phototoxicity testing. It describes both in chemico (e.g., Reactive Oxygen Species (ROS)) and in vitro assays (e.g., 3T3 Neutral Red Uptake). What is generally true about these assays?

a) They have both high false positive and false negative rates and are not very reliable.

b) They have both low false negative and false positive rates and either a positive or negative result is enough to preclude further study.

c) They have low false positive but high false negative rates, so a negative result is reliable, but a positive result is only an indication for follow-up studies.

d) They have low false negative but high false positive rates, so a negative result is reliable, but a positive result is only an indication for follow-up studies.

26. (ICH S2) A new compound was tested in a 2-year rodent assay. Tumors were found in the thyroid glands of some of the treated animals. However, in the final report thyroid tumors were not listed as one of the toxicities associated with the compound at any dose. Why were these tumors not seen as toxicologically relevant?

A. Animals get thyroid tumors but humans do not

B. Bioactivation was involved in a way that is not relevant for humans

C. Controls (positive) had a higher thyroid tumor incidence

D. Dose was much higher for the animals that would be used in human patients

OECD Questions

1. OECD 202, Daphnia acute immobilization test guideline provides what threshold of immobilization as a reason to reject a limit test? 

a) 1 percent

b) 2 percent

c) 10 percent

d) 20 percent

2. The OECD 203 Fish Acute Toxicity Test provides guidance on how long to allow fish taken from larger pools to adjust to their new environment before testing can begin. What is this period called?

a) Acclimatization

b) Baseline

c) Conditioning

d) Detention

3. OECD 203 Gives guidance on how to perform acute fish toxicity testing with a goal to reduce the number of animals used. QSAR and other predictive methods are encouraged. If based on these methods acute toxicity is not anticipated for a given chemical at relevant concentrations what is recommended?

a) Acute toxicity testing is to be conducted but just at the highest concentration.

b) Both acute and chronic toxicity testing should be conducted using the same animals.

c) Consult with the relevant regulatory authorities to see if they prefer to omit acute toxicity testing in favor of chronic toxicity testing.

d) Drop the acute toxicity testing and only do chronic toxicity testing.

4. OECD 203 Gives guidance on how to perform acute fish toxicity testing. It requires what type of concentration information must be reported (i.e., is compulsory) for the test to be considered valid?

a) Difference between nominal and measured.

b) Nominal

c) Measured (analytical)

d) Theoretical

5. OECD 203 gives guidance on how to perform acute fish toxicity testing.What mortality rate threshold in the control group makes this test invalid?

a) 5 percent or 1 fish if fewer than 10 fish

b) 10 percent or 1 fish if fewer than 10 fish

c) 20 percent or 2 fish if fewer than 10 fish

d) 30 percent or 3 fish if fewer than 10 fish

6. The OECD 202 acute immobilization toxicology test states that in addition to the test compound which ideally has a minimum of five doses, for each test being run what must also be concomitantly run as a series?

a) A positive control (e.g., Potassium dichromate)

b) A negative control (e.g., dilution water)

c) A solvent control (e.g., DMSO)

d) All of the above

7. The OECD 492 reconstituted human cornea-like epithelium test method covers different in vitro tests. In addition to have good inter-laboratory and intra-laboratory reproducibility. They also had significantly lower (e.g., 1%, 4%, 9%) false negative than false positive (>20%) rates. These in vitro tests are now recognized as being acceptable screening tools for identification of chemicals not requiring classification for eye irritation or serious eye damage. Part of this acceptance had to do with how the false positive rates for the in vitro assays compared to the in vivo Draize eye test within-test variability. What is the within-test variability reported for the Draize rabbit eye test?

A. 1%

B. 2%

C. 12%

D. 120%

8. The OECD 471 guideline on the bacterial reverse mutation test recommends at least five strains of bacteria. The first four have GC base pairs as the primary reversion site. What does the other strain have as the primary reversion site?

a) AAATTT

b) AT

c) GC

d) GGGCCC

9. The OECD 443 Extended One Generation Reproductive Toxicity Study guideline is another guideline that allows for a limit-test option to reduce the number of animals tested for chemicals that are anticipated to have low toxicity. What is true about the limit test design for every study using a limit-test?

A. A low dose (no more than 10 mg/kg/day) group is needed

B. A medium dose (around 100 mg/kg/day) group is needed

C. A high dose (at least 1000 mg/kg/day group is needed

D. Both a low (no more than 10 mg/kg/day) and a high dose (at least 1000 mg/kg/day group are needed

10. OECD 442C In Chemico Skin Sensitization Test Guideline is based on what is known about the Adverse Outcome Pathway (AOP) of in vivo skin sensitization. The test is focused on the initial step, the covalent binding of chemical to amino acid (e.g., cysteine). What is the next step in this four-part AOP?

A. Dendritic cell activation

B. Fibroblast migration

C. Keratinocyte inflammatory response

D. T-cell proliferation

11. OECD 442A and 442B both involve in vivo sensitization assays looking for local lymph node changes. The methods differ (e.g., luciferase vs BRDU) but they share the same species. What species is used?

A. Guinea pig

B. Mouse

C. Rabbit

D. Rat



12. The OECD 438 Isolated Chicken Eye guidelines provides information on how to use ex vivo eyes to classify chemicals based on their potential to cause ocular damage. What is a dye used in vivo to stain corneal tissue on slides for use with fluorescent slit lamp microscopy?

A. Eosin

B. Fluorescein

C. Gram stain

D. Neutral Red

13. OECD 437 is an ex vivo test where freshly collected bovine eyes are prepared to isolate the part of the eyeballs (aside from the conjunctiva) that is most immediately exposed to the external environment. After isolation and preparation this part is tested to identify chemicals capable of causing serious eye damage without requiring application of these chemicals to the eyes of a live animal (i.e., rabbit). What ocular toxicity is this in vitro assay is designed to detect?

A. Cataract formation

B. Color vision disturbance

C. Constriction of pupil

D. Corneal opacity

14. OECD 432 In Vitro 3T3 Neutral Red Update (NRU) Phototoxicity Test needs to include what to be considered valid?

A. Activation by a metabolic system

B. Blanks which contain no cell culture media

C. Co-culturing with mycoplasma

D. Dosimetry check of the light source

15. OECD 420 Acute Oral Toxicity - Fixed Dose Procedure has a limit test which can be used in cases where it is expected for a chemical to classified as nontoxic at a regulatory limit. What is a likely limit dose for this procedure?

A. 5 mg/kg

B. 50 mg/kg

C. 300 mg/kg

D. 2000 mg/kg

16. The OECD 414 guideline on prenatal developmental toxicity studies recommends what two standard species be evaluated unless a change can be justified?

A. Rat and dog

B. Rat and monkey

C. Rat and mouse

D. Rat and rabbit

17. OECD 413 covers repeated dose inhalation toxicity testing to be given over a 90-day period. What is the recommended species?

A. Dog

B. Monkey

C. Rabbit

D. Rat

18. OECD 408 repeated dose 90-day rodent oral toxicity study guideline describes both how studies could be performed using smaller rodent species (e.g., mouse) with justification and how test animals can gain in weight over the time of the study. So, dosing can be kept relatively constant by tying it to animal weight. For a non-aqueous test compound given by gavage what is stated as the allowable dose volume?

A. 0.01 ml/100 g

B. 0.1 ml/100g

C. 1ml/100g

D. 10ml/100g

19. OECD 207 Acute Earthworm Toxicity Testing gives guidance on how to test their susceptibility towards new chemicals. What is unusual about this test species compared to almost all others that are tested routinely for toxicity either for pesticide or pharmaceutical development?

A. Oxygen can burn their skin so they cannot be kept in chambers exposed to normal room air as they need largely anaerobic conditions

B. Lighting needs to be controlled to provide a daily cycle of light and dark as opposed to being kept in the dark or light the whole time

C. They need to be kept moist as opposed either dry or submerged in water

D. They are remarkably robust so in general this is strictly a mortality test as any other signs of acute toxicity rarely happen to earthworms

20. OECD 202 gives what reason to not check the mobility of the Daphia at 48 hours?

A. It’s an optional time point

B. There is no reason

C. They should be checked at 72 hrs instead

D. They were already immobilized at 24 hours 

Mechanisms Questions

1. Steatohepatitis can be caused by excessive alcohol consumption but can have other causes. Either way it involves the accumulation of lipids in the liver. This could be studied in a very targeted way with lipidomics. The increase in the fat composition of a liver would be best captured under what type of general "omics" study?

A. Genomics

B. Metabolomics

C. Proteomics

D. Transcriptomics

2. Which of the following is an example of bioactivation?

A. Acetaldehyde being transformed into acetic acid by the enzyme aldehyde dehydrogenase

B. Bromine reacting with byproducts of disinfection chemicals (i.e., chlorine) forming bromodichloromethane in drinking water

C. Chlorpyrifos being transformed into chlorpyrifos oxon by the enzyme CYP2B6

D. Digitalis being conjugated with digibind in the digestive tract

3. Beta-carotene is not teratogenic even in doses high enough to start turning the mother orange herself. This has to do with how the enzymatic conversion of beta-carotene into vitamin A is regulated where the product inhibits its production past a particular point. This type of regulation is best described as what toxicity avoiding mechanism?

A. Chemical antagonism

B. Negative feedback

C. Physiological antagonism

D. Positive feedback

4. C&D Ch. 3 9th table 3 describes many different ultimate toxicants and their sources. Oxalic acid forms calcium oxalate which precipitates and damages the kidneys. Where does it come from?

A. Acetaminophen

B. Amygdalin

C. Ethanol

D. Ethylene glycol

Liver Toxicity Questions

1. A peanut butter sandwich contains two potential sources of a mycotoxin that can cause liver cancer as it gets bioactivated into an intercalating and adduct-forming ultimate carcinogen. To protect human health allowable limits are set for this toxin in a variety of nuts and grains.  What is this toxin called? 

A. Aflatoxin B1

B. Brevetoxin 

C. Cholera toxin

D. Digitoxin

2. Hepatotoxicants can be divided into intrinsic and idiosyncratic. With intrinsic hepatotoxicants like carbon tetrachloride, they are characterized by having characteristic to the chemical lesions and dose (often high) related responses tied to a direct effect of the chemical or metabolite.  Intrinsic hepatotoxicant injury happens reproducibly in both exposed individuals and in animal models. With idiosyncratic hepatotoxicants they are characterized by variable pathology, dosing, and the intersection of a variety of factors to cause toxicity. This means their toxicity is often limited to susceptible individuals and this toxicity may be missed during routine preclinical testing. Which of the following is an example of an idiosyncratic hepatotoxicant? 

A. Acetaminophen (aka paracetamol)

B. Alcohol (i.e., ethanol) 

C. Alpha amanitin (e.g., from Amanita phalloides) 

D. Anesthetic halothane. Note: The “halo” hints at how it was the first halogenated anesthetic 

3. There can be significant differences between species with respect to both the liver metabolites produced from the same chemical and the associated toxicity even at similar doses. While humanized animal models are available for some studies, there are other methods to study human specific metabolite production. To create both metabolites and to have signs of toxicity to assess what would be the better in vitro model? 

A. Expressed isoforms (e.g., CYP3A4)

B. Hepatocytes

C. Human liver nuclear pellets 

D. Microsomes

4. A patient comes in and has yellow sclera and a yellowish tinge to their nails and skin. What organ has most likely been damaged and what is building up in their body as a result of that injury to cause these color changes? 

A. Gall bladder and globin

B. Kidney and urea

C. Liver and bilirubin

D. Pancreas and lipase 

5. C&D 9th Chapter 13 table list different toxic responses of the liver (e.g., cancer) and associated toxicants (e.g., aflatoxin, arsenic). One chemical was listed as an example for inflammation, steatosis, hepatocyte death, liver regeneration, and fibrosis and cirrhosis. Which was that hepatotoxicant? 

A. Acetaminophen

B. Bacterial endotoxins

C. Ethanol 

D. Vinyl chloride 

Kidney Toxicity Questions

1. The kidneys are designed to filter the blood removing much of some wastes (e.g., urea) while retaining much of some key nutrients (e.g., sodium chloride, water). At the same time the red blood cells in the blood being filtered are also designed to generally stay in the blood and out of the urine. When blood does appear in the urine what is the most likely cause?

A. Dehydration

B. Glomerulus has been damaged

C. Nothing this is perfectly normal

D. Proximal tubule damage

2. The kidney is particularly susceptible to some toxicants at doses which if not safe are at least less toxic to other organs. What puts the kidneys at risk for the hydrophilic toxicants/metabolites that wind up in the kidneys?

A. Area is the highest

B. Bioactivation is the highest

C. Concentration is the highest

D. Damage repair is the lowest

3. What is the most common site of toxicant induced kidney damage?

A. Glomerulus

B. Loop of Henle/distal tubule

C. Papilla

D. Proximal tubule

4. The U.S. Preventative Services Task Forces has in progress a chronic kidney disease draft research plan. While the kidneys have greater repair capacity than some organs (e.g., heart, brain) chronic kidney damage is often irreversible. Earlier detection and interventions could preserve significant kidney function for some at risk patients. Chronic kidney disease is classified by increased amount of protein in the urine and decreased glomerular filtration rate. Part of the draft research plan involves exploring the risks and benefits of increased screening using biomarkers of glomerular function in asymptomatic individuals. What biomarkers are currently part of this draft research plan?

A. Albumin and creatine kinase

B. Alanine aminotransferase (ALT) and CK-18

C. Amounts of Brain Natriuretic Peptide (BNP) and cardiac troponins

D. Autoantibodies and C-Reactive Protein (CRP)