Toxicology review Flashcards
(26 cards)
Toxin
toxic substance that are produced by biological systems such as plants, animals, funig and bateria
what are toxicants
any toxic substances produced by or a by-product of anthropogenic activities or naturally occuring substances
hazard
something that causes harm
risk
the proability or changes that a hazard will actually cause harm
what is risk assessment
identify hazards, assess exposure, examine dose-response relationships
what are the steps in risk charaterization
hazard idenitifcation, exposure assessment, dose-response assessment
Gathering toxicity data - in vitro tests
ames assay - gene mutation test
mammalian assays for chromosomal damage
cytogenetic assays- chromosomal aberrations, micronuclei, aneuploidy
MTT assays (cell growth) for cell metabolic activity and viability
apoptosis assays for programmed cell death
gathering toxicity data- in vivo studies
acute toxicity, skin and eye irritation corrosion, skins and respiratory sensitization, subcute studies, subchornic, chronic and carcinogeneticty, reproductive and developemtnal studies (extendended one generation studies)
Tox mechanisms
receptor mediated toxicity, bioactivation, or free radical toxicity
Implications of receptor mediated toxicity
effects should be reversible
toxicity is dose related
there is a threshold in which no measurable response occurs
responses should be tissue-specific
all compounds that bind to and activate the receptor should produce qualitative similar effects
in vivo exposure assessment study types
animal studies - acute, subacute (repated exposure 1 month or less), subchronic - (1-3 months), chornic (>3 months)
Assumptions made about the dose-response relationship
observed response is due to the chemical
degree of response is realted to the magtnitude of the dose
response in question is precielty defined and quanitifiable
NOAEL
The highest dose tested with no observed adverse effects.
threshold dose
The dose below which there is no detectable biological response or adverse effect.
Above the threshold dose, effects increase in severity or frequency with increasing dose.
LOAEL
The lowest dose tested with observed adverse effects.
linearized multistage model
graded dose-response curve vs. quantal dose response curve
graded – reporting on individuals – y axis is the degree of response (%)
quantal – reporting on populations – y axis is the frequency of the population with the defined response ie. 50% of the population vs. 100% of the population
therapeutic index
measure of a relative drug safety bases on quantal dose=response data
compares the dose that is therapeutic with the dose that causes toxicity and gives a numerical infication of the relative safety of a drug
sage to have a high therapeutic index ie. a wide window
number will not tell you the shape of the cruve
Thearuputix index calculation
TI = LD50 / ED 50 or TD50 / ED 50
certain safety factor (margin of safety)
CSF = LD1 (or TD1) / ED99
Compares extreme toxic and effective doses.
Ensures safety for nearly all individuals.
More conservative, accounts for variability.
reference dose
replaced the accepted daily intake estimate of the daily exposire to a chemical without an adverse impact
derived from a NOAEL + safety factors
RfD = MOAEL / (UF X MF)
uncertanitngty safety factor and modifying factor
assumes a threshold for a toxic response – non cancer endpoints
margin of exposure
NOAEL / acutal human exposure (moving towards using benchmark dose)
aiming for a margin of exposure of >100
bench mark dose
robust method to determine toxicity and safety
uses dose-response modeling and confidence limits – alternative to NOAEL
Reference dose – benchmark dose methods
RfD = BMDLx / safety factors
x is the % of pre-defined benchmark response
