General principles and legality Flashcards
purpose of toxicological testing
to characterise the hazard info for bulk chemicals on environment and humans.
For pharmaceuticals to identify recommended starting doses, acceptable risks, and to identify the toxicology using biomarkers and physiological indicators.
Clinical trials needed as 30% of effects of drugs only observed in humans.
Lead optimisation timeline
early in vitro screens to identify potential molecular toxicological mechanisms.
Animal testings on rodent and non-rodent species.
Then early human volunteer studies and then phase 2 and 3 clinical trials.
Toxicology glossary/key terms
Hazard - potential for compound to cause harm
Risk - likelihood that harmful effects will occur.
TI = therapeutic index = TD50/ED50.
Biomarker is a biochemical or physiological measure to indicate toxicity or injury.
ICH aims to establish a uniform approach to toxicity testing internationally.
NOAEL - no observable adverse effects level
LOAEL lowest observable adverse effects level
MTD = maximum tolerated dose
FIH = 1st in human dose
LDLo lethal dose low
LD50 benefits and drawbacks
identifies a dose where 50% of population can be expected to die.
Does not account for toxicology from chronic exposure.
No longer always calculated in vivo, but normally done using estimations from sub-lethal toxicology indicators.
Different exposure protocols (time frames) used for animal studies and their purposes
acute - single dose - LD50 test or estimation
Sub-acute - <1 month. identifies MTD and NOAEL
Sub-chronic - 1-3 months. establish NOAEL and LOAEL as well as FIH dose.
chronic - 3 months-2 year. looks at organ toxicity, carcinogenicity, genotoxicity, mutagenicity, developmental toxicology, neurotoxicity, toxicokinetics, enivornmental impacts, etc…
Other factors that determine toxicity
ROA, e.g., intraperitoneal tubocurarine is 350x more toxic than oral in mice
Species differences - receptor differences and immunity, e.g., humans 200-400 fold more sensitive to digoxin toxicity vs rats. conversely rats cannot digest coumarin -> 7-OH coumarin - toxic
effect of metabolism on toxicity
Metabolic pathways, e.g., fast deactivation can reduce toxicity compared to in vitro, or metabolic activation can produce toxic metabolites (paracetamol) also, ethanol induces cyp2E1 - paracetamol toxicity
Population based modified kinetics, e.g., age, disease state, race, etc…
Drug accumulation examples of toxicity
Lead accumulates in bones, modifying D3 action.
The insecticide DDT accumulates in adipose and can be found years post-exposure
cadmium has t1/2 5-10y
Asbestos can remain in lungs for decades.
