Median lethal dose

In toxicology, the median lethal dose, LD₅₀ (abbreviation for ?Lethal Dose, 50%?), or LCt₅₀ (Lethal Concentration & Time) of a toxic substance or radiation is the dose required to kill half the members of a tested population. LD₅₀ figures are frequently used as a general indicator of a substance's acute toxicity. The test was created by J.W. Trevan in 1927.^[1] It is being phased out in some jurisdictions in favor of tests such as the Fixed Dose Procedure,^[2] however the concept, and calculation of the median lethal dose for comparison purposes, continues in wide use. As a measure of toxicity, LD₅₀ is somewhat unreliable and results may vary greatly between testing facilities due to factors such as the genetic characteristics of the sample population, environmental factors and mode of administration.^[3]

The term semilethal dose is occasionally used with the same meaning, particularly in translations from non-English-language texts, but can also refer to a sublethal dose; because of this ambiguity, it is usually avoided.

Conventions

The LD₅₀ is usually expressed as the mass of substance administered per unit mass of test subject, such as grams of substance per kilogram of body mass. 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). Typically, the LD₅₀ of a substance is given in milligrams per kilogram of body weight. In the case of some neurotoxins such as batrachotoxin, one of the most deadly toxins known, the LD₅₀ may be more conveniently expressed as micrograms per kilogram (ľg/kg)of 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 an 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 within Radiation Health Physics, as survival beyond 60 days usually results in recovery.

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/mł. ICt₅₀ is the dose which 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/mł is equivalent to 10 minutes of 10 mg/mł (1 × 100 = 100, as does 10 × 10 = 100).

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.

For disease-causing organisms, there is also a measure known as the median infective dose and dosage. 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/mł).

Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International,^[5] 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 Organization for Economic Co-operation and Development (OECD) abolished the requirement for the oral test in 2001 (see Test Guideline 401, Trends in Pharmacological Sciences Vol 22, February 22, 2001).

LD₅₀ is often criticised for being needlessly cruel, as more modern methods of classifying toxicity, such as the use of computer generated molecular models or testing on cell cultures, are available. LD₅₀ still remains popular, despite its general weakness in providing a useful measure of toxicity.^[6]

Examples

Substance	Animal, Route	LD₅₀	Reference
Vitamin C (ascorbic acid)	rat, oral	11,900 mg/kg	^[7]
Grain alcohol	young rat, oral	10,600 mg/kg	^[8]
Table Salt	rat, oral	3,000 mg/kg	^[9]
THC (main psychoactive substance in Cannabis)	rat, oral	1,270 mg/kg males; 730 mg/kg females	^[10]
Caffeine	rat, oral	192 mg/kg	^[11]
Nicotine	rat, oral	50 mg/kg	^[12]
Strychnine	rat, oral	16 mg/kg	^[13]
Aflatoxin B1 (from Aspergillus flavus)	rat, oral	0.048 mg/kg	^[14]
Batrachotoxin (from poison dart frog)	human, sub-cutaneous injection	0.002-0.007 mg/kg (estimated)	^[15]
Polonium 210	human, inhalation	0.00001 mg/kg (estimated)	^[16]
Botulinum toxin (Botox)	human, oral, injection	0.000001 mg/kg (estimated)	^[17]