Intoxicology, themedian lethal dose,LD50 (abbreviation for "lethal dose, 50%"),LC50 (lethal concentration, 50%) orLCt50 is atoxic unit that measures thelethal dose of a givensubstance.[1] The value of LD50 for a substance is thedose 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'sacute toxicity. A lower LD50 is indicative of higher toxicity.
The term LD50 is generally attributed to John William Trevan.[2] The test was created by J. W. Trevan in 1927.[3] The termsemilethal dose is occasionally used in the same sense, in particular with translations of foreign language text, but can also refer to a sublethal dose. LD50 is usually determined by tests on animals such aslaboratory mice. In 2011, the U.S.Food and Drug Administration approved alternative methods to LD50 for testing the cosmetic drugBotox without animal tests.[4][5]
The LD50 is usually expressed as the mass of substance administered per unit mass of test subject, typically asmilligrams of substance perkilogram of body mass, sometimes also stated asnanograms (suitable forbotulinum),micrograms, orgrams (suitable forparacetamol) 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). For substances in the environment, such as poisonous vapors or substances in water that are toxic to fish, the concentration in the environment (per cubic metre or per litre) is used, giving a value of LC50. But in this case, the exposure time is important (see below).
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.[6]
Lethal dosage often varies depending on the method ofadministration; for instance, many substances are less toxic when administered orally than whenintravenously 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 within radiationhealth physics, forionizing radiation, 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 that will cause incapacitation rather than death. These measures are commonly used to indicate the comparative efficacy ofchemical 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 byFritz Haber and is sometimes referred to asHaber'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 ashydrogen cyanide, are rapidly detoxified by the human body, and do not follow Haber's law. In these cases, the lethal concentration may be given simply as LC50 and qualified by a duration of exposure (e.g., 10 minutes). Thematerial 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 LD50s to some test animal. Inbiological warfare infective dosage is the number of infective doses per cubic metre of air times the number of minutes of exposure (e.g., ICt50 is 100 medium doses - min/m3).
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.[7]
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 betoxic to many animals. When used to testvenom from venomous creatures, such assnakes, LD50 results may be misleading due to the physiological differences between mice, rats, and humans. Manyvenomous snakes are specialized predators on mice, and their venom may be adapted specifically to incapacitate mice; andmongooses may be exceptionally resistant. While mostmammals have a very similar physiology, LD50 results may or may not have equal bearing upon every mammal species, such as humans, etc.
Note: Comparing substances (especially drugs) to each other by LD50 can be misleading in many cases due (in part) to differences ineffective dose (ED50). Therefore, it is more useful to compare such substances bytherapeutic index, which is simply the ratio of LD50 to ED50.[8]
The following examples are listed in reference to LD50 values, in descending order, and accompanied by LC50 values, {bracketed}, when appropriate.
Negative values of thedecimal logarithm of the median lethal dose LD50 (−log10(LD50)) on a linearized toxicity scale encompassing 11 orders of magnitude. Water occupies the lowest toxicity position (1) while the toxicity scale is dominated by thebotulinum toxin (12).[107]
The LD50 values have a very wide range. Thebotulinum toxin as the most toxic substance known has an LD50 value of 1 ng/kg, while the most non-toxic substancewater has an LD50 value of more than 90 g/kg; a difference of about 1 in 100 billion, or 11 orders of magnitude. As with all measured values that differ by many orders of magnitude, a logarithmic view is advisable. Well-known examples are the indication of the earthquake strength using theRichter scale, thepH value, as a measure for the acidic or basic character of an aqueous solution or ofloudness indecibels.In this case, the negative decimal logarithm of the LD50 values, which is standardized in kg per kg body weight, is considered−log10(LD50).
The dimensionless value found can be entered in a toxin scale. Water as the baseline substance is nearly 1 in the negative logarithmic toxin scale.
A number of procedures have been defined to derive the LD50. The earliest was the 1927 "conventional" procedure by Trevan, which requires 40 or more animals. Thefixed-dose procedure, proposed in 1984, estimates a level of toxicity by feeding at defined doses and looking for signs of toxicity (without requiring death).[108] Theup-and-down procedure, proposed in 1985, yields an LD50 value while dosing only one animal at a time.[109][110]
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^abcA.A. Babayan, A.V.Aleksandryan, "Toxicological characteristics of melamine cyanurate, melamine and cyanuric acid", Zhurnal Eksperimental'noi i Klinicheskoi Meditsiny, Vol.25, 345–9 (1985). Original article in Russian.
^Rosenkrantz H, Heyman IA, Braude MC (April 1974). "Inhalation, parenteral and oral LD50 values of delta 9-tetrahydrocannabinol in Fischer rats".Toxicology and Applied Pharmacology.28 (1):18–27.doi:10.1016/0041-008X(74)90126-4.PMID4852457.
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^Milbrath DS, Engel JL, Verkade JG, Casida JE (February 1979). "Structure--toxicity relationships of 1-substituted-4-alkyl-2,6,7-trioxabicyclo[2.2.2.]octanes".Toxicology and Applied Pharmacology.47 (2):287–293.Bibcode:1979ToxAP..47..287M.doi:10.1016/0041-008x(79)90323-5.PMID452023.
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^van den Heuvel MJ, Clark DG, Fielder RJ, Koundakjian PP, Oliver GJ, Pelling D, et al. (July 1990). "The international validation of a fixed-dose procedure as an alternative to the classical LD50 test".Food and Chemical Toxicology.28 (7):469–482.doi:10.1016/0278-6915(90)90117-6.PMID2210519.
^Lipnick RL, Cotruvo JA, Hill RN, Bruce RD, Stitzel KA, Walker AP, et al. (March 1995). "Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures".Food and Chemical Toxicology.33 (3):223–231.doi:10.1016/0278-6915(94)00136-c.PMID7896233.
^Lichtman AH (August 1998). "The up-and-down method substantially reduces the number of animals required to determine antinociceptive ED50 values".Journal of Pharmacological and Toxicological Methods.40 (2):81–85.doi:10.1016/s1056-8719(98)00041-0.PMID10100496.
Lipnick RL, Cotruvo JA, Hill RN, Bruce RD, Stitzel KA, Walker AP, et al. (March 1995). "Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures".Food and Chemical Toxicology.33 (3):223–231.doi:10.1016/0278-6915(94)00136-C.PMID7896233.
