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]
Contents
1 Conventions
2 Limitation
3 Examples
4 Animal rights concerns
5 See also
5.1 Other measures of toxicity
5.2 Related measures
6 References
7 External links
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.[citation needed]
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 and rats, oral | >15,000 mg/kg | >15 | [10] |
Vitamin C (ascorbic acid) | rat, oral | 11,900 mg/kg | 11.9 | [11] |
Glyphosate (isopropylamine salt of) | rat, oral | 10,537 mg/kg | 10.537 | [12] |
Lactose (milk sugar) | rat, oral | >10,000 mg/kg | >10 | [13] |
Aspartame | mice, oral | >10,000 mg/kg | >10 | [14] |
Urea | rat, oral | 8,471 mg/kg | 8.471 | [15] |
Cyanuric acid | rat, oral | 7,700 mg/kg | 7.7 | [16] |
Cadmium sulfide | rat, oral | 7,080 mg/kg | 7.08 | [17] |
Ethanol (Grain alcohol) | rat, oral | 7,060 mg/kg | 7.06 | [18] |
| Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) | rat, oral | 6,860 mg/kg | 6.86 | [19] |
Melamine | rat, oral | 6,000 mg/kg | 6 | [16] |
Methanol | rat, oral | 5,628 mg/kg | 5.628 | [20] |
Taurine | rat, oral | >5,000 mg/kg | >5 | [21] |
Melamine cyanurate | rat, oral | 4,100 mg/kg | 4.1 | [16] |
Fructose (fruit sugar) | rat, oral | 4,000 mg/kg | 4 | [22] |
Sodium molybdate | rat, oral | 4,000 mg/kg | 4 | [23] |
Sodium chloride (table salt) | rat, oral | 3,000 mg/kg | 3 | [24] |
Paracetamol (acetaminophen) | mouse, oral | 338 mg/kg | 0.338 | [25] |
Delta-9-tetrahydrocannabinol (THC) | rat, oral | 1270 mg/kg | 1.27 | [26] |
Cannabidiol (CBD) | rat, oral | 980 mg/kg | 0.98 | [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 | 0.6 | [30] |
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 | [31] |
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} | [32] |
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) | rat, oral | 293 mg/kg | 0.293 | [33] |
Psilocybin (from magic mushrooms) | mouse, oral | 280 mg/kg | 0.280 | [34] |
Hydrochloric acid | rat, oral | 238–277 mg/kg | 0.238 | [35] |
Ketamine | rat, intraperitoneal | 229 mg/kg | 0.229 | [36] |
Aspirin (acetylsalicylic acid) | rat, oral | 200 mg/kg | 0.2 | [37] |
Caffeine | rat, oral | 192 mg/kg | 0.192 | [38] |
Arsenic trisulfide | rat, oral | 185–6,400 mg/kg | 0.185–6.4 | [39] |
Sodium nitrite | rat, oral | 180 mg/kg | 0.18 | [40] |
Methylenedioxymethamphetamine (MDMA, ecstasy) | rat, oral | 160 mg/kg | 0.18 | [41] |
Uranyl acetate dihydrate | mouse, oral | 136 mg/kg | 0.136 | [42] |
Dichlorodiphenyltrichloroethane (DDT) | mouse, oral | 135 mg/kg | 0.135 | [43] |
Uranium | mice, oral | 114 mg/kg (estimated) | 0.114 | [44] |
Bisoprolol | mouse, oral | 100 mg/kg | 0.1 | [45] |
Cocaine | mouse, oral | 96 mg/kg | 0.096 | [46] |
Cobalt(II) chloride | rat, oral | 80 mg/kg | 0.08 | [47] |
Cadmium oxide | rat, oral | 72 mg/kg | 0.072 | [48] |
Thiopental sodium (used in lethal injection) | rat, oral | 64 mg/kg | 0.064 | [49] |
Methamphetamine | rat, intraperitoneal | 57 mg/kg | 0.057 | [50] |
Sodium fluoride | rat, oral | 52 mg/kg | 0.052 | [51] |
Pentaborane | human, oral | <50 mg/kg | <0.05 | [52] |
Capsaicin | mouse, oral | 47.2 mg/kg | 0.0472 | [53] |
Mercury(II) chloride | rat, dermal | 41 mg/kg | 0.041 | [54] |
Vitamin D3 (cholecalciferol) | rat, oral | 37 mg/kg | 0.037 | [55] |
Piperidine (from black pepper) | rat, oral | 30 mg/kg | 0.030 | [56] |
Heroin (diamorphine) | mouse, intravenous | 21.8 mg/kg | 0.0218 | [57] |
Lysergic acid diethylamide (LSD) | rat, intravenous | 16.5 mg/kg | 0.0165 | [58] |
Arsenic trioxide | rat, oral | 14 mg/kg | 0.014 | [59] |
| Metallic Arsenic | rat, intraperitoneal | 13 mg/kg | 0.013 | [60] |
Nicotine | human, oral mice, oral | 6.5–13 mg/kg (estimated) 3.34 mg/kg | 0.0065–0.013 0.0034 | [61] [62] |
Sodium cyanide | rat, oral | 6.4 mg/kg | 0.0064 | [63] |
Hydrogen cyanide | mouse, oral | 3.7 mg/kg | 0.0037 | [64] |
Chlorotoxin (CTX, from scorpions) | mice | 4.3 mg/kg | 0.0043 | [65] |
White phosphorus | rat, oral | 3.03 mg/kg | 0.00303 | [66] |
Strychnine | human, oral | 1–2 mg/kg (estimated) | 0.001–0.002 | [67] |
Cantharidin (from blister beetles) | human, oral | 500 µg/kg | 0.0005 | |
Aflatoxin B1 (from Aspergillus flavus mold) | rat, oral | 480 µg/kg | 0.00048 | [68] |
Plutonium | dog, intravenous | 320 µg/kg | 0.00032 | [69] |
Amatoxin (from Amanita phalloides mushrooms) | rat | 300-700 µg/kg | 0.0007 | [70] |
Tetrodotoxin (TTX, from blue-ringed octopus) | mice, oral | 334 µg/kg | 0.000334 | [71] |
Fentanyl | monkey | 300 µg/kg | 0.0003 | [72] |
Bufotoxin (from Bufo toads) | cat, intravenous | 300 µg/kg | 0.0003 | [73] |
Sarin | mouse, subcutaneous injection | 172 µg/kg | 0.000172 | [74] |
Robustoxin (from Sydney funnel-web spider) | mice | 150 µg/kg | 0.000150 | [75] |
VX | human, oral, inhalation, absorption through skin/eyes | 140 µg/kg (estimated) | 0.00014 | [76] |
| Venom of the Brazilian wandering spider | rat, subcutaneous | 134 µg/kg | 0.000134 | [77] |
Aconitine main alkaloid in Aconitum napellus and related species | rat, intraveneous | 80 µg/kg | 0.000080 | [78] |
| Venom of the Inland Taipan (Australian snake) | rat, subcutaneous | 25 µg/kg | 0.000025 | [79] |
Ricin (from castor oil plant) | rat, intraperitoneal rat, oral | 22 μg/kg 20–30 mg/kg | 0.000022 0.02 | [80] |
Carfentanil | human, oral | 20 µg/kg | 0.00002 | [81] |
2,3,7,8-Tetrachlorodibenzodioxin (TCDD, in Agent Orange) | rat, oral | 20 µg/kg | 0.00002 | [82] |
| CrTX-A (from box jellyfish venom) | crayfish, intraperitoneal | 5 µg/kg | 0.000005 | [83] |
Latrotoxin (from widow spider venom) | mice | 4.3 µg/kg | 0.0000043 | [84] |
Batrachotoxin (from poison dart frog) | human, sub-cutaneous injection | 2–7 µg/kg (estimated) | 0.000002 | [85] |
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 | [86] |
Polonium-210 | human, inhalation | 10 ng/kg (estimated) | 0.00000001 | [87] |
Diphtheria toxin | mice | 10 ng/kg | 0.00000001 | [88] |
Shiga toxin (from dysentery) | mice | 2 ng/kg | 0.000000002 | [88] |
Tetanospasmin (tetanus toxin) | mice | 2 ng/kg | 0.000000002 | [88] |
Botulinum toxin (Botox) | human, oral, injection, inhalation | 1 ng/kg (estimated) | 0.000000001 | [89] |
Ionizing radiation | human, irradiation | 5 Gy | [90] |
Animal rights concerns
Animal-rights and animal-welfare groups, such as Animal Rights International,[91] 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
- Animal testing
- Reed-Muench method
Other measures of toxicity
- IDLH
- Certain safety factor
- Therapeutic index
- Protective index
Fixed Dose Procedure to estimate LD50
Median toxic dose (TD50)- Lowest published toxic concentration (TCLo)
Lowest published lethal dose (LDLo)
EC50 (half maximal effective concentration)
IC50 (half maximal inhibitory concentration)- Draize test
- Indicative limit value
No-observed-adverse-effect level (NOAEL)
Lowest-observed-adverse-effect level (LOAEL)- Up-and-down procedure
Related measures
TCID50 Tissue Culture Infective Dosage- EID50 Egg Infective Dosage
- ELD50 Egg Lethal Dosage
Plaque forming units (pfu)
References
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^ "Brief Review of Natural Nonprotein Neurotoxins". asanltr.com.
^ 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. doi:10.1093/oxfordjournals.jbchem.a122438. PMID 3182760.
^ Topic 2 Toxic Chemicals and Toxic Effects Archived 2007-09-29 at the Wayback Machine.
^ abc http://biology.unm.edu/toolson/biotox/representative_LD50_values.pdf
^ Fleming DO, Hunt DL (2000). Biological Safety: principles and practices. Washington, DC: ASM Press. p. 267. ISBN 978-1-55581-180-8.
^ Koelzer, Winfried (2013). "Lethal dose". www.euronuclear.org. Retrieved 2018-09-15.
^ Thirty-Two Years of Measurable Change Archived 2007-02-11 at the Wayback Machine.
External links
- Canadian Centre for Occupational Health and Safety
Lipnick RL, Cotruvo JA, Hill RN, Bruce RD, Stitzel KA, Walker AP, Chu I, Goddard M, Segal L, Springer JA (March 1995). "Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures". Food and Chemical Toxicology. 33 (3): 223–31. doi:10.1016/0278-6915(94)00136-C. PMID 7896233.
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