Median lethal dose

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Template:Short description Script error: No such module "redirect hatnote". Template:Cs1 config 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.[1] 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.[2] The test was created by J. W. Trevan in 1927.[3] 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.[4][5]

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.[6]

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.[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 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.[8]

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 (Template:Chem2) rat, oral >Template:Ntsh90,000 mg/kg >90 [9]
Sucrose (table sugar) rat, oral Template:Ntsh29,700 mg/kg 29.7 [10]
Corn syrup rat, oral Template:Ntsh25,800 mg/kg 25.8 [11]
Glucose (blood sugar) rat, oral Template:Ntsh25,800 mg/kg 25.8 [12]
Monosodium glutamate (MSG) rat, oral Template:Ntsh16,600 mg/kg 16.6 [13]
Stevioside (from stevia) mice and rats, oral Template:Ntsh15,000 mg/kg 15 [14]
Gasoline (petrol) rat Template:Ntsh14,063 mg/kg 14.0 [15]
Vitamin C (ascorbic acid) rat, oral Template:Ntsh11,900 mg/kg 11.9 [16]
Glyphosate (isopropylamine salt) rat, oral Template:Ntsh10,537 mg/kg 10.537 [17]
Lactose (milk sugar) rat, oral Template:Ntsh10,000 mg/kg 10 [18]
Aspartame mice, oral Template:Ntsh10,000 mg/kg 10 [19]
Urea (Template:Chem2) rat, oral Template:Ntsh8,471 mg/kg 8.471 [20]
Cyanuric acid rat, oral Template:Ntsh7,700 mg/kg 7.7 [21]
Cadmium sulfide (CdS) rat, oral Template:Ntsh7,080 mg/kg 7.08 [22]
Ethanol (Template:Chem2) rat, oral Template:Ntsh7,060 mg/kg 7.06 [23]
Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) rat, oral Template:Ntsh6,860 mg/kg 6.86 [24]
Melamine rat, oral Template:Ntsh6,000 mg/kg 6 [21]
Taurine rat, oral Template:Ntsh5,000 mg/kg 5 [25]
Melamine cyanurate rat, oral Template:Ntsh4,100 mg/kg 4.1 [21]
Fructose (fruit sugar) rat, oral 4,000 mg/kg 4 [26]
Sodium molybdate (Template:Chem2) rat, oral 4,000 mg/kg 4 [27]
Sodium chloride (table salt) rat, oral 3,000 mg/kg 3 [28]
Paracetamol (acetaminophen) rat, oral 2000 mg/kg 2 [29]
Aspirin (acetylsalicylic acid) rat, oral 1,600 mg/kg 1.6 [30]
Delta-9-tetrahydrocannabinol (THC) rat, oral 1,270 mg/kg 1.27 [31]
Cannabidiol (CBD) rat, oral 980 mg/kg 0.98 [32]
Methanol (Template:Chem2) human, oral Template:Ntsh810 mg/kg 0.81 [33]
Trinitrotoluene (TNT) rat, oral 790 mg/kg 0.790
Arsenic (As) rat, oral 763 mg/kg 0.763 [34]
Ibuprofen rat, oral 636 mg/kg 0.636 [35]
Formaldehyde (Template:Chem2) rat, oral 600–800 mg/kg 0.6 [36]
Solanine (main alkaloid in the several plants in Solanaceae amongst them Solanum tuberosum) rat, oral (2.8 mg/kg human, oral) Template:Ntsh590 mg/kg 0.590 [37]
Atropine (from Atropa bella-donna, Datura stramonium, Mandragora officinarum and Brugmansia) rat, oral 500 mg/kg 0.500 [38]
Piperidine rat, oral 400 mg/kg 0.030 [39]
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}
[40]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) rat, oral 293 mg/kg 0.293 [41]
Psilocybin (from psilocybin mushrooms) mouse, oral 280 mg/kg 0.280 [42]
Hydrochloric acid (HCl) rat, oral 238–277 mg/kg 0.238 [43]
Ketamine rat, intraperitoneal 229 mg/kg 0.229 [44]
Caffeine rat, oral 192 mg/kg 0.192 [45]
Arsenic trisulfide (Template:Chem2) rat, oral 185–6,400 mg/kg 0.185–6.4 [46]
Sodium nitrite (Template:Chem2) rat, oral 180 mg/kg 0.18 [47]
Methylenedioxymethamphetamine (MDMA) rat, oral 160 mg/kg 0.18 [48]
Uranyl acetate dihydrate (Template:Chem2) mouse, oral 136 mg/kg 0.136 [49]
Dichlorodiphenyltrichloroethane (DDT) mouse, oral 135 mg/kg 0.135 [50]
Uranium (U) mice, oral Template:Ntsh114 mg/kg (estimated) 0.114 [49]
Bisoprolol mouse, oral 100 mg/kg 0.1 [51]
Cocaine mouse, oral 96 mg/kg 0.096 [52]
Cobalt(II) chloride (Template:Chem2) rat, oral 80 mg/kg 0.08 [53]
Cadmium oxide (CdO) rat, oral 72 mg/kg 0.072 [54]
Thiopental sodium (used in lethal injection) rat, oral 64 mg/kg 0.064 [55]
Demeton-S-methyl rat, oral 60 mg/kg 0.060 [56]
Methamphetamine rat, intraperitoneal 57 mg/kg 0.057 [57]
Sodium fluoride (NaF) rat, oral 52 mg/kg 0.052 [58]
Nicotine mouse and rat, oral

human, smoking

50 mg/kg 0.05 [59]
Pentaborane human, oral 50 mg/kg 0.05 [60]
Capsaicin mouse, oral 47.2 mg/kg 0.0472 [61]
Vitamin D3 (cholecalciferol) rat, oral 37 mg/kg 0.037 [62]
Heroin (diamorphine) mouse, intravenous 21.8 mg/kg 0.0218 [63]
Lysergic acid diethylamide (LSD) rat, intravenous 16.5 mg/kg 0.0165 [64]
Arsenic trioxide (Template:Chem2) rat, oral 14 mg/kg 0.014 [65]
Metallic arsenic (As) rat, intraperitoneal 13 mg/kg 0.013 [66]
Coniine (from Conium maculatum) mouse, intravenous 8 mg/kg 0.008 [67]
Sodium cyanide (NaCN) rat, oral 6.4 mg/kg 0.0064 [68]
Chlorotoxin (CTX, from scorpions) mice 4.3 mg/kg 0.0043 [69]
Hydrogen cyanide (HCN) mouse, oral 3.7 mg/kg 0.0037 [70]
Carfentanil rat, intravenous 3.39 mg/kg 0.00339 [71]
Nicotine (from various Solanaceae genera) mice, oral 3.3 mg/kg 0.0033 [59]
White phosphorus (P) rat, oral 3.03 mg/kg 0.00303 [72]
Strychnine (from Strychnos nux-vomica) human, oral 1–2 mg/kg (estimated) 0.001–0.002 [73]
Aconitine (from Aconitum napellus and related species) human, oral Template:Ntsh1–2 mg/kg 0.001–0.002 [74]
Mercury(II) chloride (Template:Chem2) rat, oral 1 mg/kg 0.001 [75]
Cantharidin (from blister beetles) human, oral 500 μg/kg 0.0005 [76]
Aflatoxin B1 (from Aspergillus flavus mold) rat, oral 480 μg/kg 0.00048 [77]
Plutonium (Pu) dog, intravenous 320 μg/kg 0.00032 [78]
Bufotoxin (from Bufo toads) cat, intravenous Template:Ntsh300 μg/kg 0.0003 [79]
Brodifacoum rat, oral 270 μg/kg 0.00027 [80]
Caesium-137 (Template:Chem) mouse, parenteral Template:Ntsh21.5 μCi/g 0.000245 [81]
Sodium fluoroacetate (Template:Chem2) rat, oral 220 μg/kg 0.00022 [82]
Chlorine trifluoride (ClF3) mouse, absorption through skin 178 μg/kg 0.000178 [83]
Sarin mouse, subcutaneous injection Template:Ntsh172 μg/kg 0.000172 [84]
Robustoxin (from Sydney funnel-web spider) mice Template:Ntsh150 μg/kg 0.000150 [85]
VX human, oral, inhalation, absorption through skin/eyes Template:Ntsh140 μg/kg (estimated) 0.00014 [86]
Venom of the Brazilian wandering spider rat, subcutaneous Template:Ntsh134 μg/kg 0.000134 [87]
Amatoxin (from Amanita phalloides mushrooms) human, oral 100 μg/kg 0.0001 [88][89]
Dimethylmercury (Template:Chem2) human, transdermal Template:Ntsh50 μg/kg 0.000050 [90]
TBPO (t-Butyl-bicyclophosphate) mouse, intravenous 36 μg/kg 0.000036 [91]
Fentanyl monkey 30 μg/kg 0.00003 [92]
Venom of the inland taipan rat, subcutaneous Template:Ntsh25 μg/kg 0.000025 [93]
Ricin (from castor oil plant) rat, intraperitoneal
rat, oral
Template:Ntsh22 μg/kg
20–30 mg/kg
0.000022
0.02
[94]
2,3,7,8-Tetrachlorodibenzodioxin (TCDD, in Agent Orange) rat, oral Template:Ntsh20 μg/kg 0.00002
Tetrodotoxin from the blue-ringed octopus intravenous Template:Ntsh8.2 μg/kg 0.0000082 [95]
CrTX-A (from Carybdea rastonii box jellyfish venom) crayfish, intraperitoneal Template:Ntsh5 μg/kg 0.000005 [96]
Latrotoxin (from widow spider venom) mice Template:Ntsh4.3 μg/kg 0.0000043 [97]Template:Self-published inline
Epibatidine (from Epipedobates anthonyi poison dart frog) mouse, intravenous 1.46-13.98 μg/kg 0.00000146 [98]
Batrachotoxin (from poison dart frog) human, sub-cutaneous injection Template:Ntsh2–7 μg/kg (estimated) 0.000002 [99]
Abrin (from rosary pea) mice, intravenously
human, inhalation
human, oral
0.7 μg/kg
3.3 μg/kg
10–1000 μg/kg
0.0000007
0.0000033
0.00001–0.001
Script error: No such module "Unsubst".
Saxitoxin (from certain marine dinoflagellates) human, intravenously
human, oral
0.6 μg/kg
5.7 μg/kg
0.0000006
0.0000057
[99]
Pacific ciguatoxin-1 (from ciguateric fish) mice, intraperitoneal 250 ngTemplate:Ntsh/kg 0.00000025 [100]
Palytoxin (from Palythoa coral) mouse, intravenous
Template:Category handlerTemplate:Category handler[<span title="Script error: No such module "string".">What do the 2 different figures represent?]Script error: No such module "Check for unknown parameters".
45 ng/kg
2.3–31.5 μg/kg
0.000000045
0.0000023
[101]
Maitotoxin (from ciguateric fish) mouse, intraperitoneal 50 ngTemplate:Ntsh/kg 0.00000005 [102]
Polonium-210 (Template:Chem) human, inhalation Template:Ntsh10 ng/kg (estimated) 0.00000001 [103]
Diphtheria toxin (from Corynebacterium) mice Template:Ntsh10 ng/kg 0.00000001 [104]
Shiga toxin (from Shigella bacteria) mice Template:Ntsh2 ng/kg 0.000000002 [104]
Tetanospasmin (from Clostridium tetani) mice Template:Ntsh2 ng/kg 0.000000002 [104]
Botulinum toxin (from Clostridium botulinum) human, oral, injection, inhalation Template:Ntsh1 ng/kg (estimated) 0.000000001 [105]
Ionizing radiation human, irradiation 3–5 Gy (Gray) [106][107][108]

Poison scale

File:Poison-Scale-long.jpg
Negative values of the decimal logarithm of the median lethal dose LD50 (Template:Math) on a linearized toxicity scale encompassing 11 orders of magnitude. Water occupies the lowest toxicity position (1) while the toxicity scale is dominated by the botulinum toxin (12).[109]

The LD50 values have a very wide range. The botulinum toxin as the most toxic substance known has an LD50 value of 1 ng/kg, while the most non-toxic substance water 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 magnitude scales, the pH value, as a measure for the acidic or basic character of an aqueous solution or of loudness in decibels. In this case, the negative decimal logarithm of the LD50 values, which is standardized in kg per kg body weight, is considered Template:Math.

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.

Procedures

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. The fixed-dose procedure, proposed in 1984, estimates a level of toxicity by feeding at defined doses and looking for signs of toxicity (without requiring death).[110] The up-and-down procedure, proposed in 1985, yields an LD50 value while dosing only one animal at a time.[111][112]

See also

Other measures of toxicity

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Related measures

References

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Further reading

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External links

Template:Pharmacology Template:Toxicology

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