Threshold dose

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Threshold dose is the minimum dose of drug that triggers minimal detectable biological effect in an animal. [1] 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. [2] Several benchmarks have been established to describe the effects of a particular dose of drug in a particular species, such as NOEL(no-observed-effect-level), NOAEL(no-observed-adverse-effect-level) and LOAEL(lowest-observed-adverse-effect-level). [3] They are established by reviewing the available studies and animal studies. [1] 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. [4] 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. [5] In toxicology, there are some other safety factors including LD50, LC50 and EC50.

Contents

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. [3] Common responses are alterations in structures, growth, development and average lifespan of the treated group of organisms. [6] 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. [7]  

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 1L of air, for 6 hours per day). [8]

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. [3] In some literature, NOEL is the only dose level referred by the terminology ‘threshold dose’. [9]

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. [3]

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. [3] There is a biologically or statistically significant increase in the prevalence of adverse effect in the treated group above this level. [10]

Examples for NOAEL and LOAEL
SubstanceAnimalNOAELLOAELReference
Oxydemeton-methyl Rat0.5 mg/kg/day2.3 mg/kg/day [11]
Boron Rat55 mg/kg/day76 mg/kg/day [12]
Barium Rat0.21 mg/kg/day0.51 mg/kg/day [13]
Trifluoroiodomethane Rat20000 ppm for non-thyroid related effects20000 ppm for thyroid related effects [14]
Acetaminophen Human25 mg/kg/day75 mg/kg/day [15]

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. [3] 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. [16] 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. [1] The precursor of a biological effect can also be the response for assessment. [1] 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. [1] 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. [17] 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. [17]  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. [18] 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. [4] [18]

Animal Studies

Animal studies are conducted when the data collected from qualitative examination of available studies is scarce. It is for expanding the range of doses. [19] 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. [1] 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. [20]

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. [21] Within the same group, the same dose is given on a daily basis for a specified period, such as 28 days or 90 days. [22] 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. [21]

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. [23] 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 (RfD). [1]

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. [20] As a result, 10-fold uncertainty factors (UF) are applied to convert NOAEL to the reference dose. The UFinter and UFintra account for the inter- and intra-species variation respectively. [20]

[24]

Limitations

Inapplicability

For carcinogenic substances, theoretically NOAEL and LOAEL do not exist as there is no safe dose for the carcinogens. A linear no-threshold model is commonly used for illustrating the probability of cancer development from radiation. There is no threshold value at which stochastic health effects start emerging. [25] Only for non-cancer health outcomes, there is an assumption of the presence of a safety margin below which no negative biological effect is expected. [25]

Inconsistency

Most dose-response models are obtained from animal experiments out of ethical concerns. Therefore, the results might not be consistent with that of the human population. [5] Individual differences also arise among people in terms of age, weight, gender, health status, etc. [20] Thus, in most circumstances, the threshold dose serves as a reference to evaluate the probable outcome of a certain dosage of a substance for the general population, while great deviations might exist in special populations such as immunocompromised patients, pregnant women and young children. [26]

Incomprehensiveness

The threshold dose is only a measure of acute toxicity since the drug or toxic substance investigated is administered at once. The consequence of long-term administration remains unknown. [27] As the threshold dose is the measured minimal response, its accuracy heavily depends on the machinery used. It is possible that further refinement is needed. [28] Furthermore, the threshold dose only reflects the dose required for a minimum detectable response but it should not be misunderstood that health effects are absolutely absent in the doses below the threshold dose. [25]

Other safety factors

LD50, LC50

The median lethal dose (LD50) of a substance is defined as the dose that leads to death in 50% of the tested population. It is a significant parameter in toxicology study and indicates the acute toxicity of a particular substance. LD50 is usually expressed in the weight of the chemical administered in milligram per unit of body weight (mg/kg). [29] In the discussion of environmental toxins, as there is no direct administration of toxic materials, a similar parameter LC50 will be mentioned instead. LC50 is the concentration of substance in air that kills half of the tested population during the experimental period. [30]

EC50

The median effective concentration (EC50) is the concentration of a drug required to reach 50% of the maximal biological effect the drug can exert. It is a reflection of the potency of a drug and is expressed in molar units such as mol/L. [31] The value of EC50 greatly depends on the affinity of the drug for its receptor, as well as the efficacy of the drug, which conveys receptor occupancy and the ability of the drug to trigger a biological response. [32] EC50 is incorporated in the Hill’s Equation, a function that demonstrates the relationship between agonist concentration and ligand binding. EC50 is mathematically given as the inflection point of the equation. [33]

Related Research Articles

In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures of the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the dose required to kill half the members of a tested population after a specified test duration. LD50 figures are frequently used as a general indicator of a substance's acute toxicity. A lower LD50 is indicative of increased toxicity.

A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849–1919) and is derived from the word toxic.

Toxicology Study of substances harmful to living organisms

Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating exposures to toxins and toxicants. The relationship between dose and its effects on the exposed organism is of high significance in toxicology. Factors that influence chemical toxicity include the dosage, duration of exposure, route of exposure, species, age, sex, and environment. Toxicologists are experts on poisons and poisoning. There is a movement for evidence-based toxicology as part of the larger movement towards evidence-based practices. Toxicology is currently contributing to the field of cancer research, since some toxins can be used as drugs for killing tumor cells. One prime example of this is ribosome-inactivating proteins, tested in the treatment of leukemia.

Toxicity Degree of harmfulness of substances

Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell (cytotoxicity) or an organ such as the liver (hepatotoxicity). By extension, the word may be metaphorically used to describe toxic effects on larger and more complex groups, such as the family unit or society at large. Sometimes the word is more or less synonymous with poisoning in everyday usage.

The therapeutic index is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxicity. The related terms therapeutic window or safety window refer to a range of doses which optimize between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

Hormesis

Hormesis is a characteristic of many biological processes, namely a biphasic or triphasic response to exposure to increasing amounts of a substance or condition. Within the hormetic zone, the biological response to low exposures to toxins and other stressors is generally favorable. The term "hormesis" comes from Greek hórmēsis "rapid motion, eagerness", itself from ancient Greek hormáein "to set in motion, impel, urge on", the same Greek root as the word hormone. The term 'hormetics' has been proposed for the study and science of hormesis.

In toxicology, the lethal dose (LD) is an indication of the lethal toxicity of a given substance or type of radiation. Because resistance varies from one individual to another, the "lethal dose" represents a dose at which a given percentage of subjects will die. The lethal concentration is a lethal dose measurement used for gases or particulates. The LD may be based on the standard person concept, a theoretical individual that has perfectly "normal" characteristics, and thus not apply to all sub-populations.

A reference dose is the United States Environmental Protection Agency's maximum acceptable oral dose of a toxic substance.Reference doses are most commonly determined for pesticides. The EPA defines an oral reference dose as:

[A]n estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population that is likely to be without an appreciable risk of deleterious effects during a lifetime.

Acceptable daily intake or ADI is a measure of the amount of a specific substance in food or drinking water that can be ingested (orally) daily over a lifetime without an appreciable health risk. ADIs are expressed usually in milligrams per kilograms of body weight per day.

Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time. To be described as acute toxicity, the adverse effects should occur within 14 days of the administration of the substance.

Diphenylamine Chemical compound

Diphenylamine is an organic compound with the formula (C6H5)2NH. The compound is a derivative of aniline, consisting of an amine bound to two phenyl groups. The compound is a colorless solid, but commercial samples are often yellow due to oxidized impurities. Diphenylamine dissolves well in many common organic solvents, and is moderately soluble in water. It is used mainly for its antioxidant properties. Diphenylamine is widely used as an industrial antioxidant, dye mordant and reagent and is also employed in agriculture as a fungicide and antihelmintic.

Dose–response relationship Measure of organism response to stimulus

The dose–response relationship, or exposure–response relationship, describes the magnitude of the response of an organism, as a function of exposure to a stimulus or stressor after a certain exposure time. Dose–response relationships can be described by dose–response curves. This is explained further in the following sections. A stimulus response function or stimulus response curve is defined more broadly as the response from any type of stimulus, not limited to chemicals.

Phosmet Organophosphate non-systemic insecticide

Phosmet is a phthalimide-derived, non-systemic, organophosphate insecticide used on plants and animals. It is mainly used on apple trees for control of codling moth, though it is also used on a wide range of fruit crops, ornamentals, and vines for the control of aphids, suckers, mites, and fruit flies.

The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effects of the tested protocol. In drug development, the NOAEL of a new drug is assessed in laboratory animals, such as mice, prior to initiation of human trials in order to establish a safe clinical starting dose in humans. The OECD publishes guidelines for Preclinical Safety Assessments, in order to help scientists discover the NOAEL.

Safety pharmacology is a branch of pharmacology specialising in detecting and investigating potential undesirable pharmacodynamic effects of new chemical entities (NCEs) on physiological functions in relation to exposure in the therapeutic range and above.

Tolerable daily intake (TDI) refers to the daily amount of a chemical that has been assessed safe for human being on long-term basis. Originally acceptable daily intake (ADI) was introduced in 1961 to define the daily intake of a food additive which, during the entire lifetime, appears to be without appreciable risk. For contaminants and other foreign chemicals not used intentionally, the term TDI is often preferred. Both ADI and TDI are usually assessed based on animal experiments, and it is most often hundreds of times lower than the dose causing no observable adverse effect (NOAEL) in the most sensitive tested animal species. Because the confounding factors may vary depending on the quality of data and the type of adverse effect, TDI values are not good estimates of the harmfulness of chemicals, and must be considered administrative tools to set allowable limits for chemicals, rather than scientific measures. The threshold limit value (TLV) of a chemical substance is a level to which it is believed a worker can be exposed day after day for a working lifetime without adverse effects.

Ethoprophos Chemical compound

Ethoprophos (or ethoprop) is an organophosphate ester with the formula C8H19O2PS2. It is a clear yellow to colourless liquid that has a characteristic mercaptan-like odour. It is used as an insecticide and nematicide and it is an acetylcholinesterase inhibitor.

Tolerable weekly intake (TWI) estimates the amount per unit body weight of a potentially harmful substance or contaminant in food or water that can be ingested over a lifetime without risk of adverse health effects. TWI is generally preceded by "provisional" to indicate insufficient data exists, increasing uncertainty. The term TWI should be reserved for when there is a well-established and internationally accepted tolerance, backed by sound and uncontested data. Although similar in concept to tolerable daily intake (TDI), which is of the same derivation of acceptable daily intakes (ADIs), TWI accounts for contaminants that do not clear the body quickly and may accumulate within the body over a period of time. An example is heavy metals such as arsenic, cadmium, lead, and mercury. The concept of TWI takes into account daily variations in human consumption patterns.

Occupational toxicology is the application of toxicology to chemical hazards in the workplace. It focuses on substances and conditions that occur in workplaces, where inhalation exposure and dermal exposure are most important, there is often exposure to mixtures of chemicals whose interactions are complex, health effects are influenced or confounded by other environmental and individual factors, and there is a focus on identifying early adverse affects that are more subtle than those presented in clinical medicine.

Nivalenol Type of mycotoxin

Nivalenol (NIV) is a mycotoxin of the trichothecene group. In nature it is mainly found in fungi of the Fusarium species. The Fusarium species belongs to the most prevalent mycotoxin producing fungi in the temperate regions of the northern hemisphere, therefore making them a considerable risk for the food crop production industry.

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