Threshold dose is the minimum dose of drug that triggers minimal detectable biological effect in an animal. At extremely low doses, biological responses are absent for some of the drugs. The increase in dose above threshold dose induces an increase in the percentage of biological responses. Several benchmarks have been established to describe the effects of a particular dose of drug in a particular species, such as no-observed-effect-level (NOEL), no-observed-adverse-effect-level (NOAEL), and lowest-observed-adverse-effect-level (LOAEL). They are established by reviewing the available studies and animal studies. The application of threshold dose in risk assessment safeguards the participants in human clinical trials and evaluates the risks of chronic exposure to certain substances. However, the nature of animal studies also limits the applicability of experimental results in the human population and its significance in evaluating potential risk of certain substances. In toxicology, there are some other safety factors including LD50, LC50, and EC50.
Dose levels Threshold dose is a dose of drug barely adequate to produce a biological effect in an animal. In dose-response assessment, the term ‘threshold dose’ is refined into several terminologies, such as NOEL, NOAEL, and LOAEL. They define the limits of doses resulting in biological responses or toxic effects. Common responses are alterations in structures, growth, development and average lifespan of the treated group of organisms. The changes are found by comparing the observations between the treated and control groups. Both groups are of the same species and have the same environment of exposure in the trial. The only difference is that the treated group receives the experimental substance while the control group does not. For the drugs administered by oral and dermal route, the units of threshold dose are mg/kg body-weight/day (dose of the drug in mg per body weight in kg per day) or ppm (parts per million), while the threshold dose of drugs by inhalation delivery has the unit of mg/L 6h/day (amount of drug in mg in 1 L of air, for 6 hours per day).
NOEL NOEL is no-observed-effect-level. It is the maximum dose of a substance that has no observable effect on the treated group in human clinical trials or animal experimental trials. In some literature, NOEL is the only dose level referred by the terminology ‘threshold dose’.
NOAEL NOAEL is no-observed-adverse-effect-level. It is the maximum dose of a substance that has no observable adverse effect on the treated group in human clinical trials or animal experimental trials.
LOAEL LOAEL is lowest-observed-adverse-effect-level. It is the minimum dose of a substance that produces an observable adverse effect on the treated group in human clinical trials or animal experimental trials. There is a biologically or statistically significant increase in the prevalence of adverse effect in the treated group above this level.
Establishment of dose levels
Factors affecting threshold dose The dose-response relationship is dependent on various factors. They include the physicochemical properties of the drug, route of administration or exposure, duration of exposure, population size, and the characteristics of the studied organism such as their species, sex, ages, etc. The type of biological responses is also a significant factor for the variations of a dose-response relationship. Each response corresponds to one unique relationship. As it is not practical to establish the dose-response relationships for all possible responses, the studies usually narrow down the scopes to a few responses. All available studies examining the correlation between the target drug and its biological responses will be reviewed. The selection criteria for the critical responses for assessment is that the dose required to produce that particular response is the lowest. The precursor of a biological effect can also be the response for assessment. For instance, the risk factors of a disease may eventually precipitate the disease. In the study of the relationship between a drug and the development of a particular cardiovascular disease, the risk factors of the disease can be considered as the responses for measurement as well.
Process to evaluate threshold dose A two-step process is adopted to evaluate the specific dose levels, NOAEL and LOAEL. The first step is to carry out reviews of available studies or animal studies to obtain data on the effect of different doses of the target drug. They allow the establishment of dose-response relationships over the range of doses reported in the data collected. Often the data collected is inadequate to produce a range wide enough to observe the dose in which biological responses are not induced in humans. The dose which is sufficiently low to prevent the occurrence of the response in humans cannot be evaluated and therefore paves the way to the second step, extrapolation of the dose-response relationship. The results beyond the range covered by the available data are estimated. It attempts to make inferences of the region that the critical dose levels such as NOAEL and LOAEL fell within. Thus the doses starting to trigger adverse effects in humans can be evaluated. For step one, the two common approaches for evaluating threshold doses are qualitative examination of available studies and animal studies.
Qualitative examination of available studies The effects of the target drug at different doses are obtained from available studies. The dose-response relationship will be identified and extrapolation is often required to make inferences about the dose levels below the range of data collected.
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