Misc Flashcards
Saccharin causes bladder cancer in rats NOT humans. Why?
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.
Thalidomide drug repurposing
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
Requirements of STEPS (System for
Thalidomide Education and Prescribing Safety) program for Thalidomide
All women of childbearing age taking Thalidomide should:
use two forms of birth control
Mechanistic studies can help with
- drug repurposing
- understanding basic physiology, pharmacology, cell biology, and biochemistry.
PHARMACOGENOMICS
6-mercaptopurine, used in the treatment of some forms of leukemia.
Polymorphisms in some kids to detox 6-mercaptopurine resutls in toxicity
What statutes does EPA regualte/
- FIFRA
- TSCA
- SDWA
- RCRA
- Clean Air Act
- Comprehensive Environmental Response, Compensation and Liability Act [CERCLA- Superfund (clean up of waste sites with chemccals toxic to humans and environment)
Consumer Product Safety Commission (CPSC)
protecting consumers from hazardous household substances
Department of Transportation (DOT)
ensures materials shipped in interstate commerce are labeled and packaged appropiiately in accordance with their degree of hazard
Four principles of biomedical ethics ( dev after World War II)
- 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
Bradford Hill defined
criteria for determining causation (Hill, 1965).
- Strength of association (relationship between independent and
dependent variables) - Consistency of findings (replication of results by different studies)
- Biological gradient (strength of the dose-response relationship)
- Temporal sequence (“cause” before effect)
- Biologic or theoretical plausibility (mechanism of action)
- Coherence with established knowledge (no competing hypotheses)
- Specificity of association (cause is tightly linked to an outcome)
Evidence-based approach to determine causation ( in place of bradford hill criteria)
by Guzelian et al. (2005)
Does measure of acute tox (like LD50) accurately reflect all toxicity?
NO
some chemicals with low acute toxicity may have carcinogenic, teratogenic, or neurobehavioral
effects
zeralanone
toxin by mold
Can same chemcial have multiple, different toxic effects in same organism each with its own D-R curve
YES
Some low dose effects may not be evident at higher doses (due to masking at the higher doses)
Some low dose effects have ‘saturation’
Low dose effects different from high dose seen with ENDOCRINE DISRUPTORS
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.
How Ach esterase inhibitors (like oragnophospate insecticides, carbamates, nerve gases) block Ach esterase ?
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
How does antidote for Ach inhibitors (inhibitors like OPs, nerve gas, carbamates) work?
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.
