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 given substance. 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 higher toxicity.
The term LD50 is generally attributed to John William Trevan. The test was created by J. W. Trevan in 1927. The term semilethal 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 as laboratory mice. In 2011, the U.S. Food and Drug Administration approved alternative methods to LD50 for testing the cosmetic drug botox without animal tests.
Conventions 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, sometimes also stated as nanograms (suitable for botulinum toxin), micrograms, 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). 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.
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 within radiation health physics, for ionizing 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 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. 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 LD50s to some test animal. In biological 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).
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.Ernest Hodgson (2004). A Textbook of Modern Toxicology. Wiley-Interscience (3rd ed.).
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 on 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, such as humans, etc.
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.
The following examples are listed in reference to LD50 values, in descending order, and accompanied by LC50 values, {bracketed}, when appropriate.
Substance Animal, route LD50 {LC50} LD50 : g/kg {LC50 : g/L} standardised Reference Water () rat, oral >90,000 mg/kg >90 Sucrose (table sugar) rat, oral 29,700 mg/kg 29.7 Corn syrup rat, oral 25,800 mg/kg 25.8 Glucose (blood sugar) rat, oral 25,800 mg/kg 25.8 Monosodium glutamate (MSG) rat, oral 16,600 mg/kg 16.6 Stevioside (from stevia) mice and rats, oral 15,000 mg/kg 15 Gasoline (petrol) rat 14,063 mg/kg 14.0 Vitamin C (ascorbic acid) rat, oral 11,900 mg/kg 11.9 Glyphosate (isopropylamine salt) rat, oral 10,537 mg/kg 10.537 Lactose (milk sugar) rat, oral 10,000 mg/kg 10 Aspartame mice, oral 10,000 mg/kg 10 Urea () rat, oral 8,471 mg/kg 8.471 Cyanuric acid rat, oral 7,700 mg/kg 7.7 A.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. Cadmium sulfide (CdS) rat, oral 7,080 mg/kg 7.08 Advanced Search – Alfa Aesar – A Johnson Matthey Company . Alfa.com. Retrieved on 2013-07-17. Ethanol () rat, oral 7,060 mg/kg 7.06 Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) rat, oral 6,860 mg/kg 6.86 Melamine rat, oral 6,000 mg/kg 6 Taurine rat, oral 5,000 mg/kg 5 Melamine cyanurate rat, oral 4,100 mg/kg 4.1 Fructose (fruit sugar) rat, oral 4,000 mg/kg 4 Sodium molybdate () rat, oral 4,000 mg/kg 4 Sodium chloride (table salt) rat, oral 3,000 mg/kg 3 Paracetamol (acetaminophen) rat, oral 2000 mg/kg 2 Delta-9-tetrahydrocannabinol (THC) rat, oral 1,270 mg/kg 1.27 Cannabidiol (CBD) rat, oral 980 mg/kg 0.98 Methanol () human, oral 810 mg/kg 0.81 Trinitrotoluene (TNT)rat, oral790 mg/kg0.790 Arsenic (Elemental, As) rat, oral 763 mg/kg 0.763 Ibuprofen rat, oral 636 mg/kg 0.636 Formaldehyde () rat, oral 600–800 mg/kg 0.6 Solanine (main alkaloid in the several plants in Solanaceae amongst them Solanum tuberosum) rat, oral (2.8 mg/kg human, oral) 590 mg/kg 0.590 Atropine (from Atropa bella-donna, Datura stramonium, Mandragora officinarum and Brugmansia)rat, oral500 mg/kg0.500 Piperidine rat, oral 400 mg/kg 0.4 Alkyl dimethyl benzalkonium chloride (ADBAC) rat, oral fish, immersion aquatic invertebrates, immersion 304.5 mg/kg {0.28 mg/L} {0.059 mg/L} 0.3045 {0.00028} {0.000059} Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) rat, oral 293 mg/kg 0.293 Coumarin Material Safety Data Sheet (MSDS) Psilocybin (from psilocybin mushrooms) mouse, oral 280 mg/kg 0.280 Hydrochloric acid (HCl) rat, oral 238–277 mg/kg 0.238 Ketamine rat, intraperitoneal 229 mg/kg 0.229 Aspirin (acetylsalicylic acid) rat, oral 200 mg/kg 0.2 Toxicology of Drugs and Chemicals, Deichmann, W.B., New York, Academic Press, Inc., 1969, -(67), 1969 Caffeine rat, oral 192 mg/kg 0.192 Arsenic trisulfide () rat, oral 185–6,400 mg/kg 0.185–6.4 Sodium nitrite () rat, oral 180 mg/kg 0.18 Methylenedioxymethamphetamine (MDMA) rat, oral 160 mg/kg 0.16 Uranyl acetate dihydrate () mouse, oral 136 mg/kg 0.136 Dichlorodiphenyltrichloroethane (DDT) mouse, oral 135 mg/kg 0.135 Uranium (U) mice, oral 114 mg/kg (estimated) 0.114 Bisoprolol mouse, oral 100 mg/kg 0.1 Cocaine mouse, oral 96 mg/kg 0.096 Cobalt(II) chloride () rat, oral 80 mg/kg 0.08 Cadmium oxide (CdO) rat, oral 72 mg/kg 0.072 Safety (MSDS) data for cadmium oxide Thiopental sodium (used in lethal injection) rat, oral 64 mg/kg 0.064 Demeton-S-methyl rat, oral 60 mg/kg 0.060 Methamphetamine rat, intraperitoneal 57 mg/kg 0.057 Sodium fluoride (NaF) rat, oral 52 mg/kg 0.052 Nicotine mouse and rat, oral