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 with the same meaning, in particular in translations from non-English-language texts, but can also refer to a sublethal dose; because of this ambiguity, it is usually avoided. 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 ml/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 10.0 [12]
Aspartame mice, oral >10,000 mg/kg 10.0 [13]
Urea rat, oral 8,471 mg/kg 8.471 [14]
Cyanuric acid rat, oral 7,700 mg/kg 7.7 [15]
Cadmium sulfide rat, oral 7,080 mg/kg 7.08 [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 5.0 [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) rat, oral 1,944 mg/kg 1.944 [24]
Delta-9-tetrahydrocannabinol (THC) rat, oral 1,270 mg/kg 1.27 [25]
Cannabidiol (CBD) rat, oral 980 mg/kg 0.98 [26]
Methamphetamine rat, intraperitoneal 57 mg/kg 0.057 [27]
Metallic Arsenic rat, oral 763 mg/kg 0.763 [28]
Ibuprofen rat, oral 636 mg/kg 0.636 [29]
Formaldehyde rat, oral 600–800 mg/kg 0.600 [30]
Alkyl dimethyl benzalkonium chloride (ADBAC) rat, oral
fish, immersion
aq. invertebrates, imm.		 304.5 mg/kg
{0.28 mg/L}
{0.059 mg/L}		 0.3045
{0.00028}
{0.000059}		 [31]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) rat, oral 293 mg/kg 0.293 [32]
Psilocybin (from magic mushrooms) mouse, oral 280 mg/kg 0.280 [33]
Hydrochloric acid rat, oral 238–277 mg/kg 0.238 [34]
Ketamine rat, intraperitoneal 229 mg/kg 0.229 [35]
Aspirin (acetylsalicylic acid) rat, oral 200 mg/kg 0.2 [36]
Caffeine rat, oral 192 mg/kg 0.192 [37]
Arsenic trisulfide rat, oral 185–6,400 mg/kg 0.185–6.4 [38]
Sodium nitrite rat, oral 180 mg/kg 0.18 [39]
Methylenedioxymethamphetamine (MDMA, ecstasy) rat, oral 160 mg/kg 0.18 [40]
Uranyl acetate dihydrate mouse, oral 136 mg/kg 0.136 [41]
Dichlorodiphenyltrichloroethane (DDT) mouse, oral 135 mg/kg 0.135 [42]
Uranium mice, oral 114 mg/kg (estimated) 0.114 [43]
Bisoprolol mouse, oral 100 mg/kg 0.1 [44]
Cocaine mouse, oral 96 mg/kg 0.096 [45]
Cobalt(II) chloride rat, oral 80 mg/kg 0.08 [46]
Cadmium oxide rat, oral 72 mg/kg 0.072 [47]
Thiopental sodium (used in lethal injection) rat, oral 64 mg/kg 0.064 [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

 6.5–13.0 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 [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]
Bufotoxin (from Bufo toads) cat, intravenous 300 µg/kg 0.000300 [70]
Sarin mouse, subcutaneous injection 172 µg/kg 0.000172 [71]
Robustoxin (from Sydney funnel-web spider) mice 150 µg/kg 0.000150 [72]
VX human, oral, inhalation, absorption through skin/eyes 140 µg/kg (estimated) 0.00014 [73]
Venom of the Brazilian wandering spider rat, subcutaneous 134 µg/kg 0.000134 [74]
Venom of the Inland Taipan (Australian snake) rat, subcutaneous 25 µg/kg 0.000025 [75]
Ricin (from castor oil plant) rat, intraperitoneal
rat, oral		 22 μg/kg
20–30 mg/kg		 0.000022
0.02		 [76]
2,3,7,8-Tetrachlorodibenzodioxin (TCDD, in Agent Orange) rat, oral 20 µg/kg 0.00002 [77]
CrTX-A (from box jellyfish venom) crayfish, intraperitoneal 5 µg/kg 0.000005 [78]
Latrotoxin (from widow spider venom) mice 4.3 µg/kg 0.0000043 [79]
Batrachotoxin (from poison dart frog) human, sub-cutaneous injection 2–7 µg/kg (estimated) 0.000002 [80]
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 0.13 µg/kg 0.00000013 [81]
Polonium-210 human, inhalation 10 ng/kg (estimated) 0.00000001 [82]
Diphtheria toxin mice 10 ng/kg 0.00000001 [83]
Shiga toxin (from dysentery) mice 2 ng/kg 0.000000002 [83]
Tetanospasmin (tetanus toxin) mice 2 ng/kg 0.000000002 [83]
Botulinum toxin (Botox) human, oral, injection, inhalation 1 ng/kg (estimated) 0.000000001 [84]
Ionizing radiation human, irradiation 5 Gy [85]

Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International,[86] 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. ↑ What is an LD50 and LC50
  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.
  3. ↑ "In U.S., Few Alternatives To Testing On Animals". Washington Post. 12 April 2008. Retrieved 2011-06-26.
  4. ↑ REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (RTECS)
    COMPREHENSIVE GUIDE TO THE RTECS     Archived 2013-05-16 at the Wayback Machine.
  5. ↑ Ernest Hodgson (2004). A Textbook of Modern Toxicology. Wiley-Interscience (3rd ed.).
  6. ↑ "Material Safety Data Sheet Water MSDS". Section 11: Toxicological Information for the LD50 verification.
  7. ↑ Safety (MSDS) data for sucrose
  8. ↑ Safety (MSDS) data for glucose
  9. ↑ Walker R, Lupien JR (April 2000). "The safety evaluation of monosodium glutamate". The Journal of Nutrition. 130 (4S Suppl): 1049S–52S. PMID 10736380.
  10. ↑ Toskulkao C, Chaturat L, Temcharoen P, Glinsukon T (1997). "Acute toxicity of stevioside, a natural sweetener, and its metabolite, steviol, in several animal species". Drug and Chemical Toxicology. 20 (1–2): 31–44. PMID 9183561. doi:10.3109/01480549709011077.
  11. ↑ "Safety (MSDS) data for ascorbic acid". Oxford University. 2005-10-09. Archived from the original on 2007-02-09. Retrieved 2007-02-21.
  12. ↑ "Safety (MSDS) data for Lactose" (PDF).
  13. ↑ https://www.spectrumchemical.com/MSDS/A6051.pdf
  14. ↑ "Safety (MSDS) data for urea". 2015-03-06. Section 11: Toxicological Information for the LD50 verification. Retrieved 2015-03-06.
  15. 1 2 3 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.
  16. ↑ Advanced Search – Alfa Aesar – A Johnson Matthey Company. Alfa.com. Retrieved on 2013-07-17.
  17. ↑ Safety (MSDS) data for ethyl alcohol
  18. ↑ Mecler, Francis J. (May 1981). Mammalian Toxological Evaluation of DIMP and DCBP (Phase 3 – IMPA) (Final report ed.). Litton Bionetics, Inc. The oral LD50 values for the test material, IMPA, were 7650 and 6070 mg/kg for male and female rats, respectively.
  19. ↑ Safety (MSDS) data for methanol
  20. ↑ Safety data for taurine
  21. ↑ Safety (MSDS) data for fructose
  22. ↑ Safety (MSDS) data for sodium molybdate
  23. ↑ Safety (MSDS) data for sodium chloride
  24. ↑ Safety (MSDS) data for 4-acetamidophenol
  25. ↑ "Inhalation, parenteral and oral LD50 values of Δ9-tetrahydrocannabinol in Fischer rats". Toxicology and Applied Pharmacology. 28: 18–27. doi:10.1016/0041-008X(74)90126-4.
  26. ↑ MSDS of CBD
  27. ↑ Kiyatkin EA, Sharma HS. "Acute methamphetamine intoxication: brain hyperthermia, blood-brain barrier, brain edema, and morphological cell abnormalities". Int Rev Neurobiol. 88: 65–100. PMC 3145326 Freely accessible. PMID 19897075. doi:10.1016/S0074-7742(09)88004-5.
  28. ↑
  29. ↑ MSDS of Ibuprofen
  30. ↑ Formaldehyde SIDS Initial Assessment Report
  31. ↑ Frank T. Sanders, ed. (August 2006). Reregistration Eligibility Decision for Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) (PDF) (Report). U.S. Environmental Protection Agency Office of Prevention, Pesticides, and Toxic Substances. p. 114. Archived from the original (PDF) on 2009-10-24. Retrieved 2009-03-31.
  32. ↑ Coumarin Material Safety Data Sheet (MSDS) Archived 2011-09-27 at the Wayback Machine.
  33. ↑ Handbook of Mushroom Poisoning
  34. ↑ Safety (MSDS) data for hydrochloric acid
  35. ↑ Ketamine
  36. ↑ Safety (MSDS) data for acetylsalicylic acid
  37. ↑ Safety (MSDS) data for caffeine
  38. ↑ "Material Safety Data Sheet – Spent Metal Catalyst" (PDF). Archived from the original (PDF) on 2011-09-28.
  39. ↑ Safety (MSDS) data for sodium nitrite
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  41. ↑ Chemical toxicity of uranium
  42. ↑ Hayes WJ (21 December 2013) [1959]. "Pharmacology and toxicology of DDT". In Müller P, Simmons SW. DDT: The Insecticide Dichlorodiphenyltrichloroethane and Its Significance / Das Insektizid Dichlordiphenyltrichloräthan und Seine Bedeutung: Human and Veterinary Medicine. 2. Springer-Verlag. pp. 9–247. ISBN 978-3-0348-6809-9.
  43. ↑ http://www.who.int/ionizing_radiation/pub_meet/en/Depluranium4.pdf
  44. ↑ DrugBank data for bisoprolol
  45. ↑ DrugBank data for Cocaine
  46. ↑ Safety (MSDS) data for cobalt (II) chloride
  47. ↑ Safety (MSDS) data for cadmium oxide
  48. ↑ Thiopental sodium MSDS
  49. ↑ Sodium Fluoride MSDS
  50. ↑ Pentaborane chemical and safety data
  51. ↑ "Capsaicin Material Safety Data Sheet" (PDF). sciencelab.com. 2007. Retrieved 2007-07-13.
  52. ↑ http://www.sigmaaldrich.com/catalog/DisplayMSDSContent.doc
  53. ↑ MSDS for cholecalciferol crystalline
  54. ↑ MSDS for piperidine (pepper)
  55. ↑ MSDS for diamorphine
  56. ↑ Erowid LSD (Acid) Vault : Fatalities / Deaths. Erowid.org. Retrieved on 2013-07-17.
  57. ↑ Safety (MSDS) data for arsenic trioxide
  58. ↑ Safety (MSDS) data for metallic arsenic
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  61. ↑ Safety (MSDS) data for sodium cyanide
  62. ↑ Safety (MSDS) data for hydrogen cyanide
  63. ↑ "Chlorotoxin: A Helpful Natural Scorpion Peptide to Diagnose Glioma and Fight Tumor Invasion".
  64. ↑ "Hexachloroethane" (PDF). Retrieved 2014-01-03.
  65. ↑ INCHEM: Chemical Safety Information from Intergovernmental Organizations: Strychnine.
  66. ↑ Safety (MSDS) data for aflatoxin B1
  67. ↑ Los Alamos Science article for Plutonium toxicity
  68. ↑ Handbook of Biologically Active Peptides
  69. ↑ "Material Safety Data Sheet Tetrodotoxin ACC# 01139". Acros Organics N.V.
  70. ↑ "nih.gov Datasheet for Bufotoxin".
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  76. ↑ EFSA – Scientific Opinion of the CONTAM Panel: Ricin (from Ricinus communis) as undesirable substances in animal feed [1] - Scientific Opinion of the Panel on Contaminants in the Food Chain. Efsa.europa.eu. Retrieved on 2013-07-17.
  77. ↑ U.S. National Toxicology Program acute toxicity studies for Dioxin (2,3,7,8-TCDD)
  78. ↑ Nagai H (2003). "Recent Progress in Jellyfish Toxin Study". Journal of Health Science. 49 (5): 337–340. ISSN 1344-9702. doi:10.1248/jhs.49.337.
  79. ↑ http://biology.unm.edu/toolson/biotox/presentations_2013/ALPHA-LATROTOXIN%20POWERPOINT.pptx
  80. ↑ Brief Review of Natural Nonprotein Neurotoxins
  81. ↑ Yokoyama A, Murata M, Oshima Y, Iwashita T, Yasumoto T (August 1988). "Some chemical properties of maitotoxin, a putative calcium channel agonist isolated from a marine dinoflagellate". Journal of Biochemistry. 104 (2): 184–7. PMID 3182760. doi:10.1093/oxfordjournals.jbchem.a122438.
  82. ↑ Topic 2 Toxic Chemicals and Toxic Effects Archived 2007-09-29 at the Wayback Machine.
  83. 1 2 3 http://biology.unm.edu/toolson/biotox/representative_LD50_values.pdf
  84. ↑ Fleming DO, Hunt DL (2000). Biological Safety: principles and practices. Washington, DC: ASM Press. p. 267. ISBN 1-55581-180-9.
  85. ↑ European Nuclear Society
  86. ↑ Thirty-Two Years of Measurable Change Archived 2007-02-11 at the Wayback Machine.
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