Misc

Question 1

Saccharin causes bladder cancer in rats NOT humans. Why?

Answer 1

forms a crystalline precipitate at high concentrations in rats (does not occur in humans)

This precipitate can cause chronic irritation of bladder epithelium,
enhanced cell proliferation, and ultimately bladder tumor.

Question 2

Thalidomide drug repurposing

Answer 2

Eg: Thalidomine - originally sedative drug for pregnant women. Birth defects caused its ban (1962)

New Purpose: reintroduced in 1998

prevent angiogenesis in cancers, inflammatory diseases, leprosy, AIDS

Question 3

Requirements of STEPS (System for
Thalidomide Education and Prescribing Safety) program for Thalidomide

Answer 3

All women of childbearing age taking Thalidomide should:

use two forms of birth control

Question 4

Mechanistic studies can help with

Answer 4

1. drug repurposing
2. understanding basic physiology, pharmacology, cell biology, and biochemistry.

Question 5

PHARMACOGENOMICS

6-mercaptopurine, used in the treatment of some forms of leukemia.

Answer 5

Polymorphisms in some kids to detox 6-mercaptopurine resutls in toxicity

Question 6

What statutes does EPA regualte/

Answer 6

1. FIFRA
2. TSCA
3. SDWA
4. RCRA
5. Clean Air Act
6. Comprehensive Environmental Response, Compensation and Liability Act [CERCLA- Superfund (clean up of waste sites with chemccals toxic to humans and environment)

Question 7

Consumer Product Safety Commission (CPSC)

Answer 7

protecting consumers from hazardous household substances

Question 8

Department of Transportation (DOT)

Answer 8

ensures materials shipped in interstate commerce are labeled and packaged appropiiately in accordance with their degree of hazard

Question 9

Four principles of biomedical ethics ( dev after World War II)

Answer 9

• respect for autonomy,
• beneficence (do good),
• non-maleficence (do no harm),
• justice (be fair)

—became well established as a basis for decision-making in health care settings

Question 10

Bradford Hill defined
criteria for determining causation (Hill, 1965).

Answer 10

1. Strength of association (relationship between independent and
   dependent variables)
2. Consistency of findings (replication of results by different studies)
3. Biological gradient (strength of the dose-response relationship)
4. Temporal sequence (“cause” before effect)
5. Biologic or theoretical plausibility (mechanism of action)
6. Coherence with established knowledge (no competing hypotheses)
7. Specificity of association (cause is tightly linked to an outcome)

Question 11

Evidence-based approach to determine causation ( in place of bradford hill criteria)

Answer 11

by Guzelian et al. (2005)

Question 12

Does measure of acute tox (like LD50) accurately reflect all toxicity?

Answer 12

NO

some chemicals with low acute toxicity may have carcinogenic, teratogenic, or neurobehavioral
effects

Question 13

zeralanone

Answer 13

toxin by mold

Question 14

Can same chemcial have multiple, different toxic effects in same organism each with its own D-R curve

Answer 14

YES

Question 15

Some low dose effects may not be evident at higher doses (due to masking at the higher doses)

Some low dose effects have ‘saturation’

Answer 15

Low dose effects different from high dose seen with ENDOCRINE DISRUPTORS

Question 16

How AcH esterase breaks down Ach (NORMAL FUNCTIONING)

positively charged nitrogen in the acetylcholine molecule is attracted to the ionic site on acetylcholinesterase, and hydrolysis is catalyzed at the esteric site to form choline and acetic acid.

Answer 16

Question 17

How Ach esterase inhibitors (like oragnophospate insecticides, carbamates, nerve gases) block Ach esterase ?

Answer 17

a cholinesterase inhibitor (in this case, a nerve agent) attaches to the serine hydroxyl group on acetylcholinesterase. This prevents acetylcholine from interacting with the cholinesterase

Question 18

How does antidote for Ach inhibitors (inhibitors like OPs, nerve gas, carbamates) work?

Answer 18

The positively charged quaternary nitrogen on 2-PAM is attracted to the anionic site of acetylcholinesterase. 2-PAM then reacts with and removes the cholinesterase inhibitor. However, this cannot occur after aging has occurred.

Question 19

What is differnece b/w organophosphate mediated AcH esteraste inhibition vs.

carbamate induced AcH esterase inhibition?

Answer 19

carbamate-cholinesterase bond spontaneously hydrolyzes with a half-life of 1-2 hours. Hence recovery occurs (NO Aging)

with OPs, the longer the asscociation and inhibition, aging occurs

Question 20

EXCEPTION to the rule

For which carmate does administration of antidote (pralidoxime) worsen symptoms?

Answer 20

CARBARYL

Question 21

pralidoxime

Answer 21

2-pyridine aldoxime methyl chloride (oxime)

Question 22

How should 2-PAM be used for carmate poisoning?

Answer 22

1. initial dose of 1-2 g (20-40 mg/kg in children to a maximum of 1 g)
2. followed by a continuous infusion at 500 mg/hr

Give for 24h after symptoms resolve

Question 23

D-limonene which is regrded as a GRAS substance is spefically nephrocarcinogenic (causes hyaline droplet nephropathy and renal tumors) only in MALE rats NOT female rats or male or female mice or in humans.

D-limonene or it s metabolite [cis-d-limonene-1,2-oxide -the major metabolite involved in this toxicity) is also non genotixc in genotoxicity tests

So what is reaposnsible for the selective toxicity only in male rat kideneys?

Answer 23

Presence of rat specific α2u-globulin; through non genotoxic mechanisms promotes renal cell proliferation