What dosing regime should be used and in which in vivo test

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Reference no: EM131501851

Assignment

QUESTION 1
Which DNA repair mechanism/s were used to show that low levels of ethyl methane sulfonate did not cause an increased risk to patients treated with the batch of Viracept contaminated with EMS?

a. BER

b. NER

c. MMR

d. MGMT and BER

e. NER and MPG

f. NER and MPG

g. MMR and MGMT

QUESTION 2
Provide the name of a new flow cytometric based in vivo test that can be used within genetic toxicology to assess the level of gene mutations induced by a compound.

a. Micronucleus assay

b. COMET assay

c. MutaMouse

d. Pig-a

e. Amest test

f. HPRT

g. MLA

h. All of the above

QUESTION 3
By using the attached TransGenic database, what was the lowest total dose to cause a positive increase in gene mutations in vivo for Tamoxifen?
TRAiD 7.0 Experimental Data with CAS Corrected GRD rev July 26, 2015 References Added Sept 23, 2015(1).xls

a. 420mg/kg

b. 441mg/kg

c. 840mg/kg

d. 1600mg/kg

e. 3000mg/kg

f. 3400mg/kg

g. None

QUESTION 4
Using TransGenicDB (TRAID) TRAiD 7.0 Experimental Data with CAS Corrected GRD rev July 26, 2015 References Added Sept 23, 2015.xls what is the lowest total dose of urethane shown to cause mutations in MutaMouse?

a. 100

b. 200

c. 300

d. 600

e. 900

f. 1400

g. 13650

QUESTION 5
What techniques are recommended by the OECD for differentiating between aneugens and clastogens when using the micronucleus assay?

a. FISH with pancentromeric DNA probes

b. Primed in situ labelling with pancentromeric specific primers together with appropriate DNA counterstaining,

c. Anti-kinetochore antibodies

d. All of the above.

QUESTION 6
When testing the genotoxic activity of a compound expected to require metabolic activation to become genotoxic, what is the proposed study design for the cytokinesis block in vitro micronucleus assay as advised by the OECD?

a. Treat for 3-6 hours in the presence of S9; remove the S9 and treatment medium; add fresh medium and cytochalasin B; harvest 1.5-2.0 normal cell cycles later.

b. Treat for 1.5-2.0 normal cell cycles in the presence of cytochalasin B and S9; harvest at the end of the exposure period

c. Treat for 1.5-2.0 normal cells cycles in the presence of S9; add fresh medium and cytochalasin B; harvest 1.5 ? 2.0 normal cell cyles later.

d. None of the above.

QUESTION 7
Why was Fexinidazole thought to be genotoxic to humans, and how was this proven to be incorrect by the drugs for neglected disease initiative?

a. It produced micronuclei in Chinese hamster cells but not in human lymphoblastoid cells.

b. The substance was metabolically deactivated in mammalian systems.

c. Used knockout bacterial strain to show it was a bacterial specific mutagen

d. It was an anti-microbial and therefore caused a misleading response.

e. It was within a class of substances known to be genotoxic to humans, but was shown to be non-genotoxic in itself.?

f. It was only genotoxic at very high levels in humans.?

QUESTION 8
Table 1 for MCQs.docx?
Using the data sets provided, please state whether NCE1 is a mutagen, and if so, what type of point mutations are induced following exposure to this substance?

a. No

b. Yes, frameshifts, transitions, transversions and/or small deletions

c. Yes, frameshifts base pair substitutions

d. Yes, base pare substitutions, transitions transversions and/or small deletions.?

e. Frameshifts

f. Equivocal

QUESTION 9
Table 1 for MCQs(1).docx?
Using the data provide, answer the following question.
Does the chemical require metabolic activation, and if so, what dosing regime should be used and in which in vivo test?

a. No

b. Yes, intraperitoneal administration transgenic endpoint

c. Yes, intravenously administered transgenic endpoint

d. Yes, orally administered transgenic endpoint

e. Yes, orally administered micronucleus endpoint

f. Yes, intravenously administered micronucleus endpoint

g. Yes, intraperitoneal administration micronucleus endpoint

h. Equivocal

QUESTION 10
What would a positive result in an in vivo mutation test mean for a drug if NCE1 were an impurity in a drug? See attached for the in vitro Ames data for NCE
Table 1 for MCQs_1_.docx

a. The drugs development should be discontinued, there is no other option.

b. A negative COMET assay in vivo would negate these results?

c. A safe level of exposure using a threshold argument could be derived using the in vivo dose response data.

d. A carcinogenicity bioassay should be used to disporive this misleading positive

e. This is an aneugenic substance and the drug should not be developed any further.?

f. The impurity is not an issue, continue with the human health risk assessment submission.?

g. This would be the first impurity seen in a drug and there is no presidence set which could be followed here.?

QUESTION 11
For questions 11-14 MCQs.doc
Explain the results found in example 1.?

a. A threshold dose response was observed.??

b. Equivocal because limit of cytotoxicity was not reached.

c. Equivocal because positive control was not suitable.

d. Equivocal because the negative control exceeded the global evaluation factor derived from compiled historical control data.

e. Decrease in mutagenic response shows clear evidence of hormesis

f. Not mutagenic when tested up to the limit of cytotoxicity.?

QUESTION 12
Explain the results found in example 2.?For questions 11-14 MCQs(3).docx?

a. Mutagenic under all three conditions ? MF exceeded the GEF at more than 1 concentration for all treatments and highly significant linear trend.

b. Mutagenic under all three conditions ? MF exceeded the GEF at more than 1 concentration for all treatments and highly significant linear trend, however precipitate at these positive concentrations lead to an equivocal result.

c. Mutagenic only following metabolic activation ? MF exceeded at more than 1 concentration for all treatments and highly significant linear trend.

d. Excessive toxicity seen with positive controls for all but 1 experiment, so the results are equivocal.

e. Non-mutagenic under all three condition ? MF only exceeded the GEF at doses with excessive toxicity.

QUESTION 13
For questions 11-14 MCQs(1).docx?
Explain the results found in example 3.

a. Mutagenic for 24h ?S-9 treatment only (at 1229 ?g/mL), with highly significant linear trend, however, mutagenicity seen only at cytotoxic doses.

b. Not mutagenic when tested up to the limit of cytotoxicity.

c. Mutagenic for 24h with -S-9 treatment only (at 1229 ?g/mL), with highly significant linear trend.

d. Mutagenic for 24h following metabolic activation only (at 1229 ?g/mL), with highly significant linear trend.

e. Equivocal due to negative control exceeding the GEF.

QUESTION 14
For questions 11-14 MCQs(2).docx?
Explain the results shown in example 4.?

a. Not mutagenic when tested up to the limit of cytotoxicity.

b. Clearly mutagenic following 3h -/+ S-9 treatments with highly significant linear trends. No further experimental work required.

c. Mutagenic for 24h ?S-9 treatment only, with highly significant linear trend.

d. Equivocal because positive control was too cytotoxic at the doses tested.

e. Equivocal because the negative control exceeded the global evaluation factor derived from compiled historical control data.

f. Decrease in mutagenic response shows clear evidence of hormesis.

Attachment:- Attachment.rar

Reference no: EM131501851

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