Lec 14 & 15 (Toxicology & Poisoning) Flashcards
Therapuetic Index Equation
LD50/ED50
higher = safer
Standardized Safety Margin Equation
100x(LD1-ED99/ED99)
How close are LD1 and ED99?
more (+) = safer
more (-) = more toxic
Acute Toxicity
effects after a single, short term exposure, typically within 24 hours
Chronic Toxicity
- delayed poisonous effect from exposure
- measure in experimental conditions after 3 months of continuous or occasional exposure
(i. e. pesticides over time)
FDA (4)
Food & Drug Administration
- drugs
- food additives
- cosmetics
- medical devices
EPA (4)
Environmental Protection Agency
- pesticides
- industrial chemicals
- hazardous waste
- pollutants (in air, water, soil)
OSHA (1)
Occupational Health and Safety Administration
-chemicals in the workplace
TLV
Threshold Limit Value
- estimates of max exposure levels during work hours on a long term basis
- levels that won’t cause effects
- guideline for use
PEL
Permissible Exposure Value
- OSHA regulation
- protect workers during normal work duration
RFD
Reference Dose
- EPA regulation
- max oral dose for no human effect over lifetime
- based on animal studies of NOEL (no observable effect level)
Extrapolation Challenge
- extrapolate from animals to humans
- LOEL: lowest observed effect dose
Difficulties in Carcinogenic Risk Assessment in Humans (4)
- uncertainty of extrapolation of dose-response data from studies in animals to low doses
- species differences in carcinogenicity of chemicals
- lack of in-vivo with humans, monkeys
- expense of conducting lifetime exposure studies in rate (but the best way to study carcinogenic risk)
- uncertainty about role of minor metabolites in causing cancer
Protein Interaction (mechanism of toxicity)
binding to receptors or enzymes
i.e. AChE inhibitor or irreversible agonist
DNA (mechanism of toxicity)
interaction or binding
Oxidative Stress (mechanism of toxicity)
- leads to GSH (glutathione) depletion (prevents cell damage)
- formation of O2 radicals & lipid peroxidation
Increased Intracellular Ca2+ (mechanism of toxicity)
can over-activate pathways that lead to membrane and nuclear damage, decrease levels of ATP
Genotoxic vs. Epigenetic (mechanism of toxicity)
- paths to cell transformation
- Genotoxic: chemical agents that alter DNA causing activation of a proto-oncogene and/or inhibition of a tumor suppressor gene
- Epigenetic (non-genotoxic): increased DNA replication & clonal expansion of transformed cell, decreased cell death
Apoptosis (mechanism of toxicity)
- programmed cell death, signal transduction pathway
- apoptotic bodies are phagocytosed, no inflammation, intact cell membrane
- cell shrinkage and convolution
- pyknosis
- karyorrhexis
Necrosis (mechanism of toxicity)
- path to cell death that leads to swelling, membrane lysis and inflammation
- cytoplasm is released
- karyolysis
- pyknosis
- karyorrhesis
Karyorrhexis
nuclear fragmentation (following pyknosis)