Lethal dose

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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 (usually recorded as dose per kilogram of subject body weight) 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.

Contents

Median lethal dose (LD50)

The median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 (lethal concentration and time) of a toxin, radiation, or pathogen 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. [1] A lower LD50 is indicative of increased toxicity.

History

The test was created by J.W. Trevan in 1927. [2] The term "semilethal dose" is occasionally used with the same meaning, in particular in translations from non-English-language texts, but can also refer to a sublethal dose; because of this ambiguity, it is usually avoided. LD50 is usually determined by tests on animals such as laboratory mice. In 2011 the US Food and Drug Administration approved alternative methods to LD50 for testing the cosmetic drug Botox without animal tests. [3]

Units and measurement

The LD50 is usually expressed as the mass of substance administered per unit mass of test subject, typically as milligrams of substance per kilogram of body mass, but stated as nanograms (suitable for botulinum), micrograms, milligrams, or grams (suitable for paracetamol) per kilogram. Stating it this way allows the relative toxicity of different substances to be compared, and normalizes for the variation in the size of the animals exposed, although toxicity does not always scale simply with body mass.

The choice of 50% lethality as a benchmark avoids the potential for ambiguity of making measurements in the extremes and reduces the amount of testing required. However, this also means that LD50 is not the lethal dose for all subjects; some may be killed by much less, while others survive doses far higher than the LD50. Measures such as "LD1" and "LD99" (dosage required to kill 1% or 99%, respectively, of the test population) are occasionally used for specific purposes. [4]

Lethal dosage often varies depending on the method of administration; for instance, many substances are less toxic when administered orally than when intravenously administered. For this reason, LD50 figures are often qualified with the mode of administration, e.g., "LD50 i.v."

The related quantities LD50/30 or LD50/60 are used to refer to a dose that without treatment will be lethal to 50% of the population within (respectively) 30 or 60 days. These measures are used more commonly with radiation, as survival beyond 60 days usually results in recovery.

Estimation using model organisms

LD values for humans are best estimated by extrapolating results from human cell cultures. One form of measuring LD is to use model organisms, particularly animals like mice or rats, converting to dosage per kilogram of biomass, and extrapolating to human norms. The degree of error from animal-extrapolated LD values is large. The biology of test animals differs in important aspects to that of humans. For instance, mouse tissue is approximately fifty times less responsive than human tissue to the venom of the Sydney funnel-web spider [ citation needed ]. The square–cube law also complicates the scaling relationships involved. Researchers are shifting away from animal-based LD measurements in some instances. The U.S. Food and Drug Administration has begun to approve more non-animal methods in response to animal welfare concerns. [5]

Median infective dose

The median infective dose (ID50) is the number of organisms received by a person or test animal qualified by the route of administration (e.g., 1,200 org/man per oral). Because of the difficulties in counting actual organisms in a dose, infective doses may be expressed in terms of biological assay, such as the number of LD50's to some test animal. In biological warfare infective dosage is the number of infective doses per minute for a cubic meter (e.g., ICt50 is 100 medium doses - min/m3).)

Lowest lethal dose

The lowest lethal dose (LDLo) is the least amount of drug that can produce death in a given animal species under controlled conditions. [6] [7] The dosage is given per unit of bodyweight (typically stated in milligrams per kilogram) of a substance known to have resulted in fatality in a particular species. When quoting an LDLo, the particular species and method of administration (e.g. ingested, inhaled, intravenous) are typically stated.

Median lethal concentration

For gases and aerosols, lethal concentration (given in mg/m3 or ppm, parts per million) is the analogous concept, although this also depends on the duration of exposure, which has to be included in the definition. The term incipient lethal level is used to describe a LC50 value that is independent of time. [8]

A comparable measurement is LCt50, which relates to lethal dosage from exposure, where C is concentration and t is time. It is often expressed in terms of mg-min/m3. LCt50 is the dose that will cause incapacitation rather than death. These measures are commonly used to indicate the comparative efficacy of chemical warfare agents, and dosages are typically qualified by rates of breathing (e.g., resting = 10 L/min) for inhalation, or degree of clothing for skin penetration. The concept of Ct was first proposed by Fritz Haber and is sometimes referred to as Haber's law, which assumes that exposure to 1 minute of 100 mg/m3 is equivalent to 10 minutes of 10 mg/m3 (1 × 100 = 100, as does 10 × 10 = 100).[ citation needed ]

Some chemicals, such as hydrogen cyanide, are rapidly detoxified by the human body, and do not follow Haber's Law. So, in these cases, the lethal concentration may be given simply as LC50 and qualified by a duration of exposure (e.g., 10 minutes). The material safety data sheets for toxic substances frequently use this form of the term even if the substance does follow Haber's Law.[ citation needed ]

Lowest lethal concentration

The LCLo is the lowest concentration of a chemical, given over a period of time, that results in the fatality of an individual animal. LCLo is typically for an acute (<24 hour) exposure. [9] [10] It is related to the LC50, the median lethal concentration. The LCLo is used for gases and aerosolized material. [11] How

Limitations

As a measure of toxicity, lethal dose is somewhat unreliable and results may vary greatly between testing facilities due to factors such as the genetic characteristics of the sample population, animal species tested, environmental factors and mode of administration. [12]

There can be wide variability between species as well; what is relatively safe for rats may very well be extremely toxic for humans (cf. paracetamol toxicity), and vice versa. For example, chocolate, comparatively harmless to humans, is known to be toxic to many animals. When used to test venom from venomous creatures, such as snakes, LD50 results may be misleading due to the physiological differences between mice, rats, and humans. Many venomous snakes are specialized predators of mice, and their venom may be adapted specifically to incapacitate mice; and mongooses may be exceptionally resistant. While most mammals have a very similar physiology, LD50 results may or may not have equal bearing upon every mammal species, including humans.

Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International, [13] have campaigned against LD50 testing on animals in particular as, in the case of some substances, causing the animals to die slow, painful deaths. Several countries, including the UK, have taken steps to ban the oral LD50, and the Organisation for Economic Co-operation and Development (OECD) abolished the requirement for the oral test in 2001. [14]

See also

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 the lethal dose of a toxin, radiation, or pathogens. 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.

<span class="mw-page-title-main">Toxicity</span> 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.

<span class="mw-page-title-main">Propylene glycol</span> Chemical compound

Propylene glycol (IUPAC name: propane-1,2-diol) is a viscous, colorless liquid, which is nearly odorless but possesses a faintly sweet taste. Its chemical formula is CH3CH(OH)CH2OH. As it contains two alcohol groups, it is classed as a diol. It is miscible with a broad range of solvents, including water, acetone, and chloroform. In general, glycols are non-irritating and have very low volatility.

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 optimized between efficacy and toxicity, achieving the greatest therapeutic benefit without resulting in unacceptable side-effects or toxicity.

<span class="mw-page-title-main">Ethion</span> Chemical compound

Ethion (C9H22O4P2S4) is an organophosphate insecticide. Ethion is known to affect a neural enzyme called acetylcholinesterase and prevent it from working.

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.

<span class="mw-page-title-main">Abrin</span> Chemical compound

Abrin is an extremely toxic toxalbumin found in the seeds of the rosary pea, Abrus precatorius. It has a median lethal dose of 0.7 micrograms per kilogram of body mass when given to mice intravenously. The median toxic dose for humans ranges from 10 to 1000 micrograms per kilogram when ingested and is 3.3 micrograms per kilogram when inhaled.

In toxicology, the lowest published toxic dose is the lowest dosage per unit of bodyweight of a substance known to have produced signs of toxicity in a particular animal species. When quoting a TDLo, the particular species and method of administration are typically stated.

<span class="mw-page-title-main">Dose–response relationship</span> 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.

<span class="mw-page-title-main">Venomous snake</span> Species of the suborder Pikmin that produce poison

Venomous snakes are species of the suborder Serpentes that are capable of producing venom, which they use for killing prey, for defense, and to assist with digestion of their prey. The poison is typically delivered by injection using hollow or grooved fangs, although some poisonous snakes lack well-developed fangs. Common venomous snakes include the families Elapidae, Viperidae, Atractaspididae, and some of the Colubridae. The toxicity of venom is mainly indicated by murine LD50, while multiple factors are considered to judge the potential danger to humans. Other important factors for risk assessment include the likelihood that a snake will bite, the quantity of poison delivered with the bite, the efficiency of the delivery mechanism, and the location of a bite on the body of the victim. Snake poison may have both neurotoxic and hemotoxic or cytotoxic properties. There are about 600 venomous snake species in the world.

"The dose makes the poison" is an adage intended to indicate a basic principle of toxicology. It is credited to Paracelsus who expressed the classic toxicology maxim "All things are poison, and nothing is without poison; the dosage alone makes it so a thing is not a poison." This is often condensed to: "The dose makes the poison" or in Latin, "Sola dosis facit venenum". It means that a substance can produce the harmful effect associated with its toxic properties only if it reaches a susceptible biological system within the body in a high enough concentration.

The fixed-dose procedure (FDP), proposed in 1992 by the British Toxicology Society, is a method to assess a substance's acute oral toxicity.

<span class="mw-page-title-main">Benzotrichloride</span> Chemical compound

Benzotrichloride (BTC), also known as α,α,α-trichlorotoluene, phenyl chloroform or (trichloromethyl)benzene, is an organic compound with the formula C6H5CCl3. Benzotrichloride is an unstable, colorless or somewhat yellowish, viscous, chlorinated hydrocarbon with a penetrating odor. Benzotrichloride is used extensively as a chemical intermediate for products of various classes, i.e. dyes and antimicrobial agents.

A dose is a measured quantity of a medicine, nutrient, or pathogen which is delivered as a unit. The greater the quantity delivered, the larger the dose. Doses are most commonly measured for compounds in medicine. The term is usually applied to the quantity of a drug or other agent administered for therapeutic purposes, but may be used to describe any case where a substance is introduced to the body. In nutrition, the term is usually applied to how much of a specific nutrient is in a person's diet or in a particular food, meal, or dietary supplement. For bacterial or viral agents, dose typically refers to the amount of the pathogen required to infect a host. For information on dosage of toxic substances, see Toxicology. For information on excessive intake of pharmaceutical agents, see Drug overdose.

Poisonous material is a material, other than a gas, known to be so toxic to humans that it presents a health hazard during transportation.

Methacrylonitrile, MeAN in short, is a chemical compound that is an unsaturated aliphatic nitrile, widely used in the preparation of homopolymers, copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. MeAN is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer. It is a clear and colorless liquid, that has a bitter almond smell.

<span class="mw-page-title-main">EPN (insecticide)</span> Chemical compound

EPN is an insecticide of the phosphonothioate class. It is used against pests such as European corn borer, rice stem borer, bollworm, tobacco budworm, and boll weevil.

<span class="mw-page-title-main">Nivalenol</span> 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.

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 NOEL(no-observed-effect-level), NOAEL(no-observed-adverse-effect-level) and LOAEL(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.

References

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