21 Dose Toxicity Relationship Flashcards
Acute toxicity studies
-Most commonly performed studies for obtaining information on effects of chemical exposure
-Short-term, relatively inexpensive tests with death of test animal being the useful observed effect
-Information obtained can be used to:
Determine the relative toxicity of different chemicals - Done by comparing the respective LD50 values
Identify the target organs (heart, liver, kidneys, etc.) affected due to exposure, and
Determine appropriate doses for chronic studies
Chronic toxicity studies
-Performed over a period of months, years, or the lifetime of the test animal
-Doses of toxic substance are selected to assure that most of the animals will survive the entire time the study
-Different species of test animals may be more or less sensitive to the same toxic chemical
Males and females of the same species may respond differently to the same substance
Main purpose of performing acute and chronic toxicity studies is to establish
-Cause-effect relationship between exposure to a toxic substance and
-Observed effect in order to determine a safe exposure level
Dose-Response Curves
A curve is drawn to illustrates relationship between dose administered and observed response
This curve is referred to as dose-response curve
From these curves threshold level and relative toxicity of chemicals is obtained to establish safe levels of chemical exposure
Threshold dose
The threshold is the dose below which no effect is detected or above which an effect is first observed
The threshold information is useful in
Extrapolating animal data to humans and
Calculating what may be considered a safe human dose for a given toxic substance
The threshold dose (ThD0.0) is measured as mg/kg/day
It is assumed that humans are as sensitive as test animal
Equivalent dose in man is calculated by multiplying ThD0.0 by 70 kg (average weight of a man)
The calculation used to determine the safe human dose (SHD) is as follows:
SHD = (ThD_0.0 ×70)/SF = amount mg/day of toxic substance
Where,
SHD = Safe Human Dose
ThD0.0 = Threshold dose at which no effect is observed
70 = Average weight of a man
SF = Safety factor (ranges from 10 to 1000, which varies according to the type of test and data used to obtain the ThD0.0)
No observed effect level (NOEL)
The highest tested dose of a substance that has been reported to have no biologically significant effect on people or animals
(The highest concentration or amount of a substance, found by experiment or observation, that causes no biologically significant alteration of morphology, functional capacity, growth, development, or lifespan of the target organism distinguishable from those observed in normal (control) organisms of the same species and strain under the same defined conditions of exposure)
No observed adverse effect level (NOAEL)
The highest concentration or amount of a substance, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects in the exposed population when compared to its appropriate control
Adverse effects: e.g. alteration of morphology, functional capacity, growth, development or life span
Lowest-observed-effect-level (LOEL)
Lowest concentration or amount of a substance, that has been reported to cause biologically significant effect on people or animals
(The lowest concentration or amount of a substance, found by experiment or observation, that causes biologically significant alteration of morphology, functional capacity, growth, development, or lifespan of the target organism distinguishable from those observed in normal (control) organisms of the same species and strain under the same defined conditions of exposure)
Lowest-observed-adverse-effect-level (LOAEL)
Lowest concentration or amount of a substance found by experiment or observation that causes an adverse alteration of morphology, function, capacity, growth, development, or lifespan of a target organism distinguished from normal organisms of the same species under defined conditions of exposure
Adverse effects: e.g. alteration of morphology, functional capacity, growth, development or life span
Frank-effect level (FEL)
Level of exposure that produces unmistakable and irreversible effects (such as impairment or mortality) at statistically significant increased severity or frequency
The level where overt effects are observed is referred to as the Frank-effect level
Four types of dose response curves
Threshold
There is a level below which the response is not seen
Threshold dose is approximated by a NOAEL
Non-threshold
There is no safe level because all dose levels regardless to how small is potentially harmful
In some cases thresholds are assumed not to exist
E.g. There is no safe dose for the ingestion of cyanide
Linear
Response is directly related to dose
Nonlinear
Dose is not proportionate to response but varies according to mathematical shape of curve
Acceptable Daily Intake (ADI)
-Also called TDI, tolerable daily intake
-Estimated (maximum) amount of an agent to which a subject may be exposed daily for lifetime without risk
-Derived from NOAEL using UFs or SFs
ADI = NOAEL/SF
Reference Dose (RfD)
RfD is an estimate of the daily exposure that is likely to be without appreciable health effect even if continued exposure occurs over a lifetime
The RfD is determined by use of the following equation:
RfD = NOAEL (or LOAEL)/(UF1 × MF)
Benchmark Dose Approach
NOAEL approach uses only single points; shape of dose-response is ignored
Benchmark dose (BMD) is calculated from the curve fitted to the dose-response data, so all information is used
BMD can only be used when available data are suitable for modelling
Not replacement for NOAEL, but additional tool
A mathematical model is applied to the experimental data to produce a dose-response curve of best fit
By statistical calculation an upper 95% confidence limit of the curve is determined
Benchmark Response is defined as 10% (or 5% or 1%)
The Benchmark Dose corresponds to
Bench mark response on the upper confidence limit curve, or
Statistical 95th percent lower bound of ED (LED)
BMD can be expressed as ED01, ED05, ED10, or LED01, LED05, LED10
