Threshold dose
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, no-observed-adverse-effect-level, and lowest-observed-adverse-effect-level. 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 or ppm, while the threshold dose of drugs by inhalation delivery has the unit of mg/L 6h/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
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
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.| Substance | Animal | NOAEL | LOAEL | Reference |
| Oxydemeton-methyl | Rat | 0.5 mg/kg/day | 2.3 mg/kg/day | |
| Boron | Rat | 55 mg/kg/day | 76 mg/kg/day | |
| Barium | Rat | 0.21 mg/kg/day | 0.51 mg/kg/day | |
| Trifluoroiodomethane | Rat | 20000 ppm for non-thyroid related effects | 20000 ppm for thyroid related effects | |
| Acetaminophen | Human | 25 mg/kg/day | 75 mg/kg/day |
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.Animal studies
are conducted when the data collected from qualitative examination of available studies is scarce. It is for expanding the range of doses. Also, animal studies allow the manipulation of the study design, such as the age and gender of treated animals. Animal study is therefore less susceptible to the influences of confounders than observational studies and therefore contributes to a more rigorous dose-response assessment. As the assessed animals exhibit variation in characteristics with humans such as body size, extrapolation should be carried out to estimate the dose-response relationship in humans.A common animal study is repeated dose toxicity testing. The participating species are divided into 4 groups, receiving placebo, low dose, mid-dose and high dose of the drugs respectively. Within the same group, the same dose is given on a daily basis for a specified period, such as 28 days or 90 days. Subsequent to the specified period, necropsy or tissue samples collection allows identification of the dose levels bring about certain effects and therefore establishment of NOAEL and LOAEL.
Significance
The threshold doses such as NOAEL, LOAEL and NOEL are essential values in risk assessment. The maximum safe starting doses of different drugs can be obtained from them prior to human clinical trials. Another application is to assess the safe dose for chronic exposure. They are utilized to estimate the daily exposure which does not induce detrimental effects in humans in their lifetime, which is also known as the reference dose.The variations between different species and the extrapolation of dose-response relationship generated from animal studies to that for humans introduce uncertainties into the analysis of dose-response. Humans also manifest intra-variation of sensitivity towards a particular substance among the population. As a result, 10-fold uncertainty factors are applied to convert NOAEL to the reference dose. The UFinter and UFintra account for the inter- and intra-species variation respectively.