In toxicology, the median lethal dose, LD₅₀ (abbreviation for “Lethal Dose, 50%”), LC₅₀ (Lethal Concentration, 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 after a specified test duration. 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, is still widely used. 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.

Contents 1 Conventions 2 Limitation 3 Examples 4 Animal rights concerns 5 See also 6 Other measures of toxicity 7 Related measures 8 References 9 External links

[edit] 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 (µg/kg) or nanograms per kilogram (ng/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.^[3]

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/m³. 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/m³ is equivalent to 10 minutes of 10 mg/m³ (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/m³).

[edit] Limitation

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, animal species tested, environmental factors and mode of administration.^[4] Another weakness is that it measures acute toxicity only (as opposed to chronic toxicity at lower doses), and does not take into account toxic effects that do not result in death but are nonetheless serious (e.g. brain damage). There can be wide variability between species as well; what is relatively safe for rats may very well be extremely toxic for humans, and vice versa. In other words, a relatively high LD₅₀ does not necessarily mean a substance is harmless, since its relative harmfulness depends on its usual dose, but a very low one is always a cause for concern.

[edit] Examples

NOTE: comparing substances (especially drugs) to each other by LD₅₀ can be misleading in many cases due (in part) to differences in effective dose (ED₅₀). Therefore, it is more useful to compare such substances by therapeutic index, which is simply the ratio of LD₅₀ to ED₅₀.

Substance	Animal, Route	LD50	Reference
Sucrose (table sugar)	rat, oral	29,700,000,000 ng/kg	[5]
Vitamin C (ascorbic acid)	rat, oral	11,900,000,000 ng/kg	[6]
Cyanuric acid	rat, oral	7,700,000,000 ng/kg
cadmium sulfide	rat, oral	7,080,000,000 ng/kg	[7]
Grain alcohol (ethanol)	rat, oral	7,060,000,000 ng/kg	[8]
Melamine	rat, oral	6,000,000,000 ng/kg
Melamine cyanurate	rat, oral	4,100,000,000 ng/kg
Sodium molybdate	rat, oral	4,000,000,000 ng/kg	[9]
Table Salt	rat, oral	3,000,000,000 ng/kg	[10]
Paracetamol (acetaminophen)	rat, oral	1,944,000,000 ng/kg	[11]
THC (main psychoactive substance in Cannabis)	rat, oral	1,270,000,000 ng/kg (males) 730,000,000 ng/kg (females)	[12]
Metallic Arsenic	rat, oral	763,000,000 ng/kg	[13]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants)	rat, oral	293,000,000 ng/kg	[14]
Aspirin (acetylsalicylic acid)	rat, oral	200,000,000 ng/kg	[15]
Caffeine	rat, oral	192,000,000 ng/kg	[16]
Arsenic trisulfide	rat, oral	185,000,000 - 6,400,000,000 ng/kg	[17]
Sodium nitrite	rat, oral	180,000,000 ng/kg	[18]
Cobalt(II) chloride	rat, oral	80,000,000 ng/kg	[19]
Cadmium oxide	rat, oral	72,000,000 ng/kg	[20]
Sodium fluoride	rat, oral	52,000,000 ng/kg	[21]
Nicotine	rat, oral	50,000,000 ng/kg	[22]
Lysergic acid diethylamide (LSD)	rat, intravenous	16,500,000 ng/kg	[23]
Strychnine	rat, oral	16,000,000 ng/kg	[24]
Arsenic trioxide	rat, oral	14,000,000 ng/kg	[25]
Metallic Arsenic	rat, intraperitoneal	13,000,000 ng/kg	[26]
Sodium cyanide	rat, oral	6,400,000 ng/kg	[27]
White phosphorus	rat, oral	3,030,000 ng/kg	[28]
Mercury(II) chloride	rat, oral	1,000,000 ng/kg	[29]
Beryllium oxide	rat, oral	500,000 ng/kg	[30]
Aflatoxin B1 (from Aspergillus flavus)	rat, oral	480,000 ng/kg	[31]
Venom of the Inland taipan (Australian snake)	rat, subcutaneous	25,000 ng/kg	[32]
Dioxin (TCDD)	rat, oral	20,000 ng/kg	[33]
VX (nerve agent)	human, oral, inhalation, absorption through skin/eyes	2,300 ng/kg (estimated)	[34]
Batrachotoxin (from poison dart frog)	human, sub-cutaneous injection	2,000-7,000 ng/kg (estimated)	[35]
Maitotoxin	mouse, intraperitoneal	130 ng/kg	[36]
Polonium-210	human, inhalation	10 ng/kg (estimated)	[37]
Botulinum toxin (Botox)	human, oral, injection, inhalation	1 ng/kg (estimated)	[38]
Ionizing radiation	human, irradiation	6 Gy
Substance	Animal, Route	LC50	Reference
Alkyl dimethyl benzalkonium chloride (ADBAC)	fish, immersion	280,000 ng/L	[39]

[edit] Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International,^[40] 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).

[edit] See also

• Animal testing
• Reed-Muench method

[edit] Other measures of toxicity

• Certain safety factor
• Therapeutic index
• Protective index
• Fixed Dose Procedure to estimate LD50
• Median toxic dose (TD50)
• Lowest published toxic concentration (TCLo)
• Lowest published lethal dose (LDLo)
• IC₅₀ (50% inhibitory concentration)
• Draize test
• Indicative limit value
• No Observable Adverse Effect Level (NOAEL)
• Lowest Observable Adverse Effect Level (LOAEL)
• Up-and-down procedure

[edit] Related measures

• TCID₅₀ Tissue Culture Infective Dosage
• EID₅₀ Egg Infective Dosage
• ELD₅₀ Egg Lethal Dosage
• Plaque forming units (pfu)

[edit] References

[edit] External links

• Canadian Centre for Occupational Health and Safety
• List of LD-50s for selected psychoactive substances
• "Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures." 1995

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