Median lethal dose

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"LD50" redirects here. For other uses, see LD50 (disambiguation).

In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 (lethal concentration and time) of a toxin, radiation, or pathogen 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. 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 US Food and Drug Administration approved alternative methods to LD50 for testing the cosmetic drug BOTOX without animal tests.[2][3]

Conventions[edit]

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, but stated as nanograms (suitable for botulinum), micrograms, milligrams, or grams (suitable for paracetamol) per kilogram as toxicity decreases. 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).

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. LCt50 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 minute for a cubic meter (e.g., ICt50 is 100 medium doses - min/m3).

Limitation[edit]

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, 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[edit]

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]
Monosodium glutamate (MSG) rat, oral 16,600 mg/kg 16.6 [8]
Vitamin C (ascorbic acid) rat, oral 11,900 mg/kg 11.9 [9]
Cyanuric acid rat, oral 7,700 mg/kg 7.7 [10]
cadmium sulfide rat, oral 7,080 mg/kg 7.08 [11]
Grain alcohol (ethanol) rat, oral 7,060 mg/kg 7.06 [12]
sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) rat, oral 6,860 mg/kg 6.86 [13]
Melamine rat, oral 6,000 mg/kg 6 [10]
Melamine cyanurate rat, oral 4,100 mg/kg 4.1 [10]
Sodium molybdate rat, oral 4,000 mg/kg 4 [14]
Table Salt rat, oral 3,000 mg/kg 3 [15]
Paracetamol (acetaminophen) rat, oral 1,944 mg/kg 1.944 [16]
Delta-9-tetrahydrocannabinol (THC) rat, oral 1,270 mg/kg 1.270 [17]
Metallic Arsenic rat, oral 763 mg/kg 0.763 [18]
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}
[19]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) rat, oral 293 mg/kg 0.293 [20]
Aspirin (acetylsalicylic acid) rat, oral 200 mg/kg 0.2 [21]
Caffeine rat, oral 192 mg/kg 0.192 [22]
Arsenic trisulfide rat, oral 185–6,400 mg/kg 0.185 [23]
Sodium nitrite rat, oral 180 mg/kg 0.18 [24]
uranyl acetate dihydrate mouse, oral 136 mg/kg 0.136 [25]
Bisoprolol mouse, oral 100 mg/kg 0.1 [26]
Cobalt(II) chloride rat, oral 80 mg/kg 0.08 [27]
Cadmium oxide rat, oral 72 mg/kg 0.072 [28]
Sodium fluoride rat, oral 52 mg/kg 0.052 [29]
Nicotine rat, oral
mice, oral
50 mg/kg
3.3 mg/kg
0.05
0.0033
[30]
[31]
Pentaborane human, oral <50 mg/kg <0.05 [32]
Capsaicin mouse, oral 47.2 mg/kg 0.0472 [33]
Mercury(II) chloride rat, dermal 41 mg/kg 0.041 [34]
Lysergic acid diethylamide (LSD) rat, intravenous 16.5 mg/kg 0.0165 [35]
Arsenic trioxide rat, oral 14 mg/kg 0.014 [36]
Metallic Arsenic rat, intraperitoneal 13 mg/kg 0.013 [37]
Sodium cyanide rat, oral 6.4 mg/kg 0.0064 [38]
White phosphorus rat, oral 3.03 mg/kg 0.00303 [39]
Strychnine human, oral 1–2 mg/kg(estimated) 0.001 [40]
Cantharidin human, oral 0.5 mg/kg 0.0005
Aflatoxin B1 (from Aspergillus flavus) rat, oral 0.48 mg/kg 0.00048 [41]
Venom of the Brazilian wandering spider rat, subcutaneous 134 µg/kg 0.000134 [42]
Venom of the Inland Taipan (Australian snake) rat, subcutaneous 25 µg/kg 0.000025 [43]
Ricin rat, intraperitoneal
rat, oral
22 μg/kg
20–30 mg/kg
0.000022
0.02
[44]
Dioxin (TCDD) rat, oral 20 µg/kg 0.00002 [45]
Sarin mouse, subcutaneous injection 17.23 µg/kg (estimated) 0.0000172 [46]
VX human, oral, inhalation, absorption through skin/eyes 2.3 µg/kg (estimated) 0.0000023 [47]
Batrachotoxin (from poison dart frog) human, sub-cutaneous injection 2-7 µg/kg (estimated) 0.000002 [48]
Maitotoxin mouse, intraperitoneal 0.13 µg/kg 0.00000013 [49]
Polonium-210 human, inhalation 10 ng/kg (estimated) 0.00000001 [50]
Botulinum toxin (Botox) human, oral, injection, inhalation 1 ng/kg (estimated) 0.000000001 [51]
Ionizing radiation human, irradiation 6 Gy

Animal rights concerns[edit]

Animal-rights and animal-welfare groups, such as Animal Rights International,[52] have campaigned against LD50 testing on animals in particular as, in the case of some substances, causing the animals to die slow, painful deaths. 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[edit]

Other measures of toxicity[edit]

Related measures[edit]

References[edit]

  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. 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
  5. ^ Ernest Hodgson (2004). A Textbook of Modern Toxicology. Wiley-Interscience (3rd ed.).[page needed]
  6. ^ "Material Safety Data Sheet Water MSDS". Section 11: Toxicological Information for the LD50 verification. 
  7. ^ Safety (MSDS) data for sucrose
  8. ^ Walker R, Lupien JR (April 2000). "The safety evaluation of monosodium glutamate". Journal of Nutrition 130 (4S Suppl): 1049S–52S. PMID 10736380. 
  9. ^ "Safety (MSDS) data for ascorbic acid". Oxford University. 2005-10-09. Retrieved 2007-02-21. 
  10. ^ a b c 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.
  11. ^ Advanced Search - Alfa Aesar - A Johnson Matthey Company. Alfa.com. Retrieved on 2013-07-17.
  12. ^ Safety (MSDS) data for ethyl alcohol
  13. ^ 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." 
  14. ^ Safety (MSDS) data for sodium molybdate
  15. ^ Safety (MSDS) data for sodium chloride
  16. ^ Safety (MSDS) data for 4-acetamidophenol
  17. ^ LD50 values of THC in fischer rats
  18. ^ [1][dead link]
  19. ^ Frank T. Sanders, ed. (August 2006). Reregistration Eligibility Decision for Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) (Report). U.S. Environmental Protection Agency Office of Prevention, Pesticides, and Toxic Substances. pp. 114. http://www.epa.gov/oppsrrd1/REDs/adbac_red.pdf. Retrieved 2009-03-31.
  20. ^ Coumarin Material Safety Data Sheet (MSDS)
  21. ^ Safety (MSDS) data for acetylsalicylic acid
  22. ^ Safety (MSDS) data for caffeine
  23. ^ "MATERIAL SAFETY DATA SHEET - Spent Metal Catalyst". Archived from the original on 2011-09-28. 
  24. ^ Safety (MSDS) data for sodium nitrite
  25. ^ Chemical toxicity of uranium
  26. ^ DrugBank data for bisoprolol
  27. ^ Safety (MSDS) data for cobalt (II) chloride
  28. ^ Safety (MSDS) data for cadmium oxide
  29. ^ Sodium Fluoride MSDS
  30. ^ Safety (MSDS) data for nicotine
  31. ^ IPCS INCHEM
  32. ^ Pentaborane chemical and safety data
  33. ^ "Capsaicin Material Safety Data Sheet" (PDF). sciencelab.com. 2007. Retrieved 2007-07-13. 
  34. ^ http://www.sigmaaldrich.com/catalog/DisplayMSDSContent.doc
  35. ^ Erowid LSD (Acid) Vault : Fatalities / Deaths. Erowid.org. Retrieved on 2013-07-17.
  36. ^ Safety (MSDS) data for arsenic trioxide
  37. ^ Safety (MSDS) data for metallic arsenic
  38. ^ Safety (MSDS) data for sodium cyanide
  39. ^ "Hexachloroethane". Retrieved 2014-01-03. 
  40. ^ INCHEM: Chemical Safety Information from Intergovernmental Organizations: Strychnine.
  41. ^ Safety (MSDS) data for aflatoxin B1
  42. ^ Venomous Animals and their Venoms, vol. III, ed. Wolfgang Bücherl and Eleanor Buckley
  43. ^ LD50 for various snakes. Seanthomas.net. Retrieved on 2013-07-17.
  44. ^ 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.
  45. ^ U.S. National Toxicology Program acute toxicity studies for Dioxin (2,3,7,8-TCDD)
  46. ^ Histochemical Demonstration of Calcium Accumulation in Muscle Fibres after Experimental Organophosphate Poisoning. Het.sagepub.com (1990-07-01). Retrieved on 2013-07-17.
  47. ^ Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection
  48. ^ Brief Review of Natural Nonprotein Neurotoxins
  49. ^ Yokoyama, Akihiro; Murata, Michio; Oshima, Yasukatsu; Iwashita, Takashi; Yasumoto, Takeshi (1988). "Some Chemical Properties of Maitotoxin, a Putative Calcium Channel Agonist Isolated from a MarineDinoflagellate". J. Biochem. 104 (2): 184–187. PMID 3182760. 
  50. ^ Topic 2 Toxic Chemicals and Toxic Effects
  51. ^ Fleming, Diane O.; Hunt, Debra Long (2000). Biological Safety: principles and practices. Washington, DC: ASM Press. p. 267. ISBN 1-55581-180-9. 
  52. ^ Thirty-Two Years of Measurable Change

External links[edit]