Median lethal dose

In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a measure of the lethal dose of a toxin, radiation, or pathogen. 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 increased toxicity.

The test was created by J.W. Trevan in 1927.[1] 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.[2][3]

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), 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.[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 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 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. 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 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.[5]

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}
standardized		 Reference
Water rat, oral >90,000 mg/kg >90 [6]
Sucrose (table sugar) rat, oral 29,700 mg/kg 29.7 [7]
Glucose (blood sugar) rat, oral 25,800 mg/kg 25.8 [8]
Monosodium glutamate (MSG) rat, oral 16,600 mg/kg 16.6 [9]
Stevioside (from stevia) mice & rats, oral >15,000 mg/kg >15 [10]
Vitamin C (ascorbic acid) rat, oral 11,900 mg/kg 11.9 [11]
Lactose (milk sugar) rat, oral >10,000 mg/kg >10 [12]
Aspartame mice, oral >10,000 mg/kg >10 [13]
Urea rat, oral 8,471 mg/kg 8.471 [14]
Cyanuric acid rat, oral 7,700 mg/kg 7.7 [15]
Cadmium sulfiderat, oral7,080 mg/kg7.08[16]
Ethanol (Grain alcohol) rat, oral 7,060 mg/kg 7.06 [17]
Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) rat, oral 6,860 mg/kg 6.86 [18]
Melamine rat, oral 6,000 mg/kg 6 [15]
Methanol rat, oral 5,628 mg/kg 5.628 [19]
Taurine rat, oral >5,000 mg/kg >5 [20]
Melamine cyanurate rat, oral 4,100 mg/kg 4.1 [15]
Fructose (fruit sugar) rat, oral 4,000 mg/kg 4 [21]
Sodium molybdate rat, oral 4,000 mg/kg 4 [22]
Sodium chloride (table salt) rat, oral 3,000 mg/kg 3 [23]
Paracetamol (acetaminophen) mouse, oral 338 mg/kg 0.338 [24]
Delta-9-tetrahydrocannabinol (THC) rat, oral 1270 mg/kg 1.27 [25]
Cannabidiol (CBD) rat, oral 980 mg/kg 0.98 [26]
Metallic Arsenicrat, oral763 mg/kg0.763[27]
Ibuprofen rat, oral 636 mg/kg 0.636 [28]
Formaldehyde rat, oral 600–800 mg/kg 0.6 [29]
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}		 [30]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) rat, oral 293 mg/kg 0.293 [31]
Psilocybin (from magic mushrooms) mouse, oral 280 mg/kg 0.280 [32]
Hydrochloric acid rat, oral 238–277 mg/kg 0.238 [33]
Ketamine rat, intraperitoneal 229 mg/kg 0.229 [34]
Aspirin (acetylsalicylic acid) rat, oral 200 mg/kg 0.2 [35]
Caffeine rat, oral 192 mg/kg 0.192 [36]
Arsenic trisulfide rat, oral 185–6,400 mg/kg 0.185–6.4 [37]
Sodium nitrite rat, oral 180 mg/kg 0.18 [38]
Methylenedioxymethamphetamine (MDMA, ecstasy) rat, oral 160 mg/kg 0.18 [39]
Uranyl acetate dihydrate mouse, oral 136 mg/kg 0.136 [40]
Dichlorodiphenyltrichloroethane (DDT) mouse, oral 135 mg/kg 0.135 [41]
Uranium mice, oral 114 mg/kg (estimated) 0.114 [42]
Bisoprolol mouse, oral 100 mg/kg 0.1 [43]
Cocaine mouse, oral 96 mg/kg 0.096 [44]
Cobalt(II) chloride rat, oral 80 mg/kg 0.08 [45]
Cadmium oxide rat, oral 72 mg/kg 0.072 [46]
Thiopental sodium (used in lethal injection) rat, oral 64 mg/kg 0.064 [47]
Methamphetamine rat, intraperitoneal 57 mg/kg 0.057 [48]
Sodium fluoride rat, oral 52 mg/kg 0.052 [49]
Pentaborane human, oral <50 mg/kg <0.05 [50]
Capsaicin mouse, oral 47.2 mg/kg 0.0472 [51]
Mercury(II) chloride rat, dermal 41 mg/kg 0.041 [52]
Vitamin D3 (cholecalciferol) rat, oral 37 mg/kg 0.037 [53]
Piperidine (from black pepper) rat, oral 30 mg/kg 0.030 [54]
Heroin (diamorphine) mouse, intravenous 21.8 mg/kg 0.0218 [55]
Lysergic acid diethylamide (LSD) rat, intravenous 16.5 mg/kg 0.0165 [56]
Arsenic trioxide rat, oral 14 mg/kg 0.014 [57]
Metallic Arsenic rat, intraperitoneal 13 mg/kg 0.013 [58]
Nicotine human, oral

mice, oral

 6.5–13 mg/kg (estimated)

3.34 mg/kg

 0.0065–0.013

0.0034

 [59]

[60]

Sodium cyanide rat, oral 6.4 mg/kg 0.0064 [61]
Hydrogen cyanide mouse, oral 3.7 mg/kg 0.0037 [62]
Chlorotoxin (CTX, from scorpions) mice 4.3 mg/kg 0.0043 [63]
White phosphorus rat, oral 3.03 mg/kg 0.00303 [64]
Strychnine human, oral 1–2 mg/kg (estimated) 0.001–0.002 [65]
Cantharidin (from blister beetles) human, oral 500 µg/kg 0.0005
Aflatoxin B1 (from Aspergillus flavus mold) rat, oral 480 µg/kg 0.00048 [66]
Plutonium dog, intravenous 320 µg/kg 0.00032 [67]
Amatoxin (from Amanita phalloides mushrooms) rat 300-700 µg/kg 0.0007 [68]
Tetrodotoxin (TTX, from blue-ringed octopus) mice, oral 334 µg/kg 0.000334 [69]
Fentanyl monkey 300 µg/kg 0.0003 [70]
Bufotoxin (from Bufo toads) cat, intravenous 300 µg/kg 0.0003 [71]
Sarin mouse, subcutaneous injection 172 µg/kg 0.000172 [72]
Robustoxin (from Sydney funnel-web spider) mice 150 µg/kg 0.000150 [73]
VX human, oral, inhalation, absorption through skin/eyes 140 µg/kg (estimated) 0.00014 [74]
Venom of the Brazilian wandering spider rat, subcutaneous 134 µg/kg 0.000134 [75]
Venom of the Inland Taipan (Australian snake) rat, subcutaneous 25 µg/kg 0.000025 [76]
Ricin (from castor oil plant) rat, intraperitoneal
rat, oral		 22 μg/kg
20–30 mg/kg		 0.000022
0.02		 [77]
Carfentanil human, oral 20 µg/kg 0.00002 [78]
2,3,7,8-Tetrachlorodibenzodioxin (TCDD, in Agent Orange) rat, oral 20 µg/kg 0.00002 [79]
CrTX-A (from box jellyfish venom) crayfish, intraperitoneal 5 µg/kg 0.000005 [80]
Latrotoxin (from widow spider venom) mice 4.3 µg/kg 0.0000043 [81]
Batrachotoxin (from poison dart frog) human, sub-cutaneous injection 2–7 µg/kg (estimated) 0.000002 [82]
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
Maitotoxin (from ciguateric fish) mouse, intraperitoneal 130 ng/kg 0.00000013 [83]
Polonium-210 human, inhalation 10 ng/kg (estimated) 0.00000001 [84]
Diphtheria toxin mice 10 ng/kg 0.00000001 [85]
Shiga toxin (from dysentery) mice 2 ng/kg 0.000000002 [85]
Tetanospasmin (tetanus toxin) mice 2 ng/kg 0.000000002 [85]
Botulinum toxin (Botox) human, oral, injection, inhalation 1 ng/kg (estimated) 0.000000001 [86]
Ionizing radiation human, irradiation 5 Gy [87]

Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International,[88] have campaigned against LD50 testing on animals. Several countries, including the UK, have taken steps to ban the oral LD50, and the Organisation 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).

See also

Other measures of toxicity

References

  1. ↑ Safety, Government of Canada, Canadian Centre for Occupational Health and. "What is a LD50 and LC50? : OSH Answers". www.ccohs.ca.
  2. ↑ "Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX® and BOTOX® Cosmetic (onabotulinumtoxinA)". Allergan Web site. 24 June 2011. Archived from the original on 26 June 2011. Retrieved 2012-08-15.
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  4. ↑ REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (RTECS)
    COMPREHENSIVE GUIDE TO THE RTECS     Archived 2013-05-16 at the Wayback Machine.
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