Median lethal dose
Template:Short description Template:Redirect 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.<ref>Template:Cite web</ref> 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.<ref name="Biographical Memoirs of Fellows of the Royal Society 1957 pp. 273–288">Template:Cite journal</ref> The test was created by J. W. Trevan in 1927.<ref>Template:Cite web</ref> 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.<ref>Template:Cite web</ref><ref>Template:Cite news</ref>
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, 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.<ref>Template:Cite web</ref>
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
[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.<ref name="ReferenceA">Ernest Hodgson (2004). A Textbook of Modern Toxicology. Wiley-Interscience (3rd ed.).Template:Page needed</ref>
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
[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.<ref>Template:Cite web</ref>
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 | <ref>Template:Cite web</ref> |
| Sucrose (table sugar) | rat, oral | Template:Ntsh29,700 mg/kg | 29.7 | <ref>Template:Cite web</ref> |
| Corn syrup | rat, oral | Template:Ntsh25,800 mg/kg | 25.8 | <ref>Template:Cite web</ref> |
| Glucose (blood sugar) | rat, oral | Template:Ntsh25,800 mg/kg | 25.8 | <ref>Template:Cite web</ref> |
| Monosodium glutamate (MSG) | rat, oral | Template:Ntsh16,600 mg/kg | 16.6 | <ref name="Walker00">Template:Cite journal</ref> |
| Stevioside (from stevia) | mice and rats, oral | Template:Ntsh15,000 mg/kg | 15 | <ref>Template:Cite journal</ref> |
| Gasoline (petrol) | rat | Template:Ntsh14,063 mg/kg | 14.0 | <ref>Template:Cite web</ref> |
| Vitamin C (ascorbic acid) | rat, oral | Template:Ntsh11,900 mg/kg | 11.9 | <ref>Template:Cite web</ref> |
| Glyphosate (isopropylamine salt) | rat, oral | Template:Ntsh10,537 mg/kg | 10.537 | <ref>Template:Cite web</ref> |
| Lactose (milk sugar) | rat, oral | Template:Ntsh10,000 mg/kg | 10 | <ref>Template:Cite web</ref> |
| Aspartame | mice, oral | Template:Ntsh10,000 mg/kg | 10 | <ref>Template:Cite web</ref> |
| Urea (Template:Chem2) | rat, oral | Template:Ntsh8,471 mg/kg | 8.471 | <ref>Template:Cite web</ref> |
| Cyanuric acid | rat, oral | Template:Ntsh7,700 mg/kg | 7.7 | <ref name="Babayan">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.</ref> |
| Cadmium sulfide (CdS) | rat, oral | Template:Ntsh7,080 mg/kg | 7.08 | <ref>Advanced Search – Alfa Aesar – A Johnson Matthey Company Template:Webarchive. Alfa.com. Retrieved on 2013-07-17.</ref> |
| Ethanol (Template:Chem2) | rat, oral | Template:Ntsh7,060 mg/kg | 7.06 | <ref>Template:Cite web</ref> |
| Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) | rat, oral | Template:Ntsh6,860 mg/kg | 6.86 | <ref>Template:Cite report</ref> |
| Melamine | rat, oral | Template:Ntsh6,000 mg/kg | 6 | <ref name="Babayan" /> |
| Taurine | rat, oral | Template:Ntsh5,000 mg/kg | 5 | <ref>Template:Cite web</ref> |
| Melamine cyanurate | rat, oral | Template:Ntsh4,100 mg/kg | 4.1 | <ref name="Babayan" /> |
| Fructose (fruit sugar) | rat, oral | 4,000 mg/kg | 4 | <ref>Template:Cite web</ref> |
| Sodium molybdate (Template:Chem2) | rat, oral | 4,000 mg/kg | 4 | <ref>Template:Cite web</ref> |
| Sodium chloride (table salt) | rat, oral | 3,000 mg/kg | 3 | <ref>Template:Cite web</ref> |
| Paracetamol (acetaminophen) | rat, oral | 2000 mg/kg | 2 | <ref>Template:Cite web</ref> |
| Aspirin (acetylsalicylic acid) | rat, oral | 1,600 mg/kg | 1.6 | <ref>Template:Cite web</ref> |
| Delta-9-tetrahydrocannabinol (THC) | rat, oral | 1,270 mg/kg | 1.27 | <ref>Template:Cite journal</ref> |
| Cannabidiol (CBD) | rat, oral | 980 mg/kg | 0.98 | <ref>Template:Cite web</ref> |
| Methanol (Template:Chem2) | human, oral | Template:Ntsh810 mg/kg | 0.81 | <ref>Template:Cite web</ref> |
| Trinitrotoluene (TNT) | rat, oral | 790 mg/kg | 0.790 | |
| Arsenic (As) | rat, oral | 763 mg/kg | 0.763 | <ref>Template:Cite web</ref> |
| Ibuprofen | rat, oral | 636 mg/kg | 0.636 | <ref>Template:Cite web</ref> |
| Formaldehyde (Template:Chem2) | rat, oral | 600–800 mg/kg | 0.6 | <ref>Template:Cite web</ref> |
| 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 | <ref>Template:Cite web</ref> |
| 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} |
<ref name=epaRED>Template:Cite report</ref> |
| Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) | rat, oral | 293 mg/kg | 0.293 | <ref>Coumarin Material Safety Data Sheet (MSDS) Template:Webarchive</ref> |
| Psilocybin (from psilocybin mushrooms) | mouse, oral | 280 mg/kg | 0.280 | <ref>Template:Cite book</ref> |
| Hydrochloric acid (HCl) | rat, oral | 238–277 mg/kg | 0.238 | <ref>Template:Cite web</ref> |
| Ketamine | rat, intraperitoneal | 229 mg/kg | 0.229 | <ref>Template:Cite web</ref> |
| Caffeine | rat, oral | 192 mg/kg | 0.192 | <ref>Template:Cite journal</ref> |
| Arsenic trisulfide (Template:Chem2) | rat, oral | 185–6,400 mg/kg | 0.185–6.4 | <ref>Template:Cite web</ref> |
| Sodium nitrite (Template:Chem2) | rat, oral | 180 mg/kg | 0.18 | <ref>Template:Cite webTemplate:Dead link</ref> |
| Methylenedioxymethamphetamine (MDMA) | rat, oral | 160 mg/kg | 0.18 | <ref>Template:Cite journal</ref> |
| Uranyl acetate dihydrate (Template:Chem2) | mouse, oral | 136 mg/kg | 0.136 | <ref name=Depluranium4>Template:Cite web</ref> |
| Dichlorodiphenyltrichloroethane (DDT) | mouse, oral | 135 mg/kg | 0.135 | <ref>Template:Cite book</ref> |
| Uranium (U) | mice, oral | Template:Ntsh114 mg/kg (estimated) | 0.114 | <ref name=Depluranium4/> |
| Bisoprolol | mouse, oral | 100 mg/kg | 0.1 | <ref>Template:Cite web</ref> |
| Cocaine | mouse, oral | 96 mg/kg | 0.096 | <ref>Template:Cite web</ref> |
| Cobalt(II) chloride (Template:Chem2) | rat, oral | 80 mg/kg | 0.08 | <ref>Template:Cite web</ref> |
| Cadmium oxide (CdO) | rat, oral | 72 mg/kg | 0.072 | <ref>Safety (MSDS) data for cadmium oxideTemplate:Dead link</ref> |
| Thiopental sodium (used in lethal injection) | rat, oral | 64 mg/kg | 0.064 | <ref>Template:Cite web</ref> |
| Demeton-S-methyl | rat, oral | 60 mg/kg | 0.060 | <ref>Template:Cite web</ref> |
| Methamphetamine | rat, intraperitoneal | 57 mg/kg | 0.057 | <ref>Template:Cite book</ref> |
| Sodium fluoride (NaF) | rat, oral | 52 mg/kg | 0.052 | <ref>Template:Cite web</ref> |
| Nicotine | mouse and rat, oral
human, smoking |
50 mg/kg | 0.05 | <ref name=Mayer>Template:Cite journal</ref> |
| Pentaborane | human, oral | 50 mg/kg | 0.05 | <ref>Template:Cite web</ref> |
| Capsaicin | mouse, oral | 47.2 mg/kg | 0.0472 | <ref>Template:Cite web</ref> |
| Vitamin D3 (cholecalciferol) | rat, oral | 37 mg/kg | 0.037 | <ref>Template:Cite web</ref> |
| Piperidine (from black pepper) | rat, oral | 30 mg/kg | 0.030 | <ref>Template:Cite web</ref> |
| Heroin (diamorphine) | mouse, intravenous | 21.8 mg/kg | 0.0218 | <ref>Template:Cite web</ref> |
| Lysergic acid diethylamide (LSD) | rat, intravenous | 16.5 mg/kg | 0.0165 | <ref>Erowid LSD (Acid) Vault : Fatalities / Deaths Template:Webarchive. Erowid.org. Retrieved on 2013-07-17.</ref> |
| Arsenic trioxide (Template:Chem2) | rat, oral | 14 mg/kg | 0.014 | <ref>Template:Cite web</ref> |
| Metallic arsenic (As) | rat, intraperitoneal | 13 mg/kg | 0.013 | <ref>Template:Cite web</ref> |
| Sodium cyanide (NaCN) | rat, oral | 6.4 mg/kg | 0.0064 | <ref>Template:Cite web</ref> |
| Chlorotoxin (CTX, from scorpions) | mice | 4.3 mg/kg | 0.0043 | <ref>Template:Cite web</ref> |
| Hydrogen cyanide (HCN) | mouse, oral | 3.7 mg/kg | 0.0037 | <ref>Template:Cite web</ref> |
| Carfentanil | rat, intravenous | 3.39 mg/kg | 0.00339 | <ref>Template:Cite web</ref> |
| Nicotine (from various Solanaceae genera) | mice, oral | 3.3 mg/kg | 0.0033 | <ref name=Mayer/> |
| White phosphorus (P) | rat, oral | 3.03 mg/kg | 0.00303 | <ref>Template:Cite web</ref> |
| Strychnine (from Strychnos nux-vomica) | human, oral | 1–2 mg/kg (estimated) | 0.001–0.002 | <ref>INCHEM: Chemical Safety Information from Intergovernmental Organizations: Strychnine Template:Webarchive.</ref> |
| Aconitine (from Aconitum napellus and related species) | human, oral | Template:Ntsh1–2 mg/kg | 0.001–0.002 | <ref>Template:Cite journal</ref> |
| Mercury(II) chloride (Template:Chem2) | rat, oral | 1 mg/kg | 0.001 | <ref>Template:Cite web</ref> |
| Cantharidin (from blister beetles) | human, oral | 500 μg/kg | 0.0005 | <ref>Template:Cite book</ref> |
| Aflatoxin B1 (from Aspergillus flavus mold) | rat, oral | 480 μg/kg | 0.00048 | <ref>Template:Cite web</ref> |
| Plutonium (Pu) | dog, intravenous | 320 μg/kg | 0.00032 | <ref>Template:Cite journal</ref> |
| Bufotoxin (from Bufo toads) | cat, intravenous | Template:Ntsh300 μg/kg | 0.0003 | <ref>Template:Cite web</ref> |
| Brodifacoum | rat, oral | 270 μg/kg | 0.00027 | <ref>Template:Cite web</ref> |
| Caesium-137 (Template:Chem) | mouse, parenteral | Template:Ntsh21.5 μCi/g | 0.000245 | <ref>Template:Cite book [(21.5 μCi/g) × (1000 g/kg) × (0.0114 μg/μCi) = 245 μg/kg]</ref> |
| Sodium fluoroacetate (Template:Chem2) | rat, oral | 220 μg/kg | 0.00022 | <ref>Template:Cite book</ref> |
| Chlorine trifluoride (ClF3) | mouse, absorption through skin | 178 μg/kg | 0.000178 | <ref>Template:Cite web</ref> |
| Sarin | mouse, subcutaneous injection | Template:Ntsh172 μg/kg | 0.000172 | <ref>Template:Cite journal</ref> |
| Robustoxin (from Sydney funnel-web spider) | mice | Template:Ntsh150 μg/kg | 0.000150 | <ref>Template:Cite journal</ref> |
| VX | human, oral, inhalation, absorption through skin/eyes | Template:Ntsh140 μg/kg (estimated) | 0.00014 | <ref>Template:Cite journal</ref> |
| Venom of the Brazilian wandering spider | rat, subcutaneous | Template:Ntsh134 μg/kg | 0.000134 | <ref>Venomous Animals and their Venoms, vol. III, ed. Wolfgang Bücherl and Eleanor Buckley</ref> |
| Amatoxin (from Amanita phalloides mushrooms) | human, oral | 100 μg/kg | 0.0001 | <ref>Template:Cite journal</ref><ref>Template:Cite book</ref> |
| Dimethylmercury (Template:Chem2) | human, transdermal | Template:Ntsh50 μg/kg | 0.000050 | <ref>Template:Cite journal</ref> |
| TBPO (t-Butyl-bicyclophosphate) | mouse, intravenous | 36 μg/kg | 0.000036 | <ref name="pmid452023">Template:Cite journal</ref> |
| Fentanyl | monkey | 30 μg/kg | 0.00003 | <ref>Template:Cite web</ref> |
| Venom of the inland taipan | rat, subcutaneous | Template:Ntsh25 μg/kg | 0.000025 | <ref>LD50 for various snakes Template:Webarchive. Seanthomas.net. Retrieved on 2013-07-17.</ref> |
| Ricin (from castor oil plant) | rat, intraperitoneal rat, oral |
Template:Ntsh22 μg/kg 20–30 mg/kg |
0.000022 0.02 |
<ref>Template:Cite journal</ref> |
| 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 | <ref>Template:Cite journal</ref> |
| CrTX-A (from Carybdea rastonii box jellyfish venom) | crayfish, intraperitoneal | Template:Ntsh5 μg/kg | 0.000005 | <ref>Template:Cite journal</ref> |
| Latrotoxin (from widow spider venom) | mice | Template:Ntsh4.3 μg/kg | 0.0000043 | <ref>Template:Cite web</ref>Template:Self-published inline |
| Epibatidine (from Epipedobates anthonyi poison dart frog) | mouse, intravenous | 1.46-13.98 μg/kg | 0.00000146 | <ref>Template:Cite journal</ref> |
| Batrachotoxin (from poison dart frog) | human, sub-cutaneous injection | Template:Ntsh2–7 μg/kg (estimated) | 0.000002 | <ref name=":0">Template:Cite journal</ref> |
| 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 |
Template:Citation needed |
| Saxitoxin (from certain marine dinoflagellates) | human, intravenously human, oral |
0.6 μg/kg 5.7 μg/kg |
0.0000006 0.0000057 |
<ref name=":0" /> |
| Pacific ciguatoxin-1 (from ciguateric fish) | mice, intraperitoneal | 250 ngTemplate:Ntsh/kg | 0.00000025 | <ref>Template:Cite journal</ref> |
| Palytoxin (from Palythoa coral) | mouse, intravenous Template:Fix |
45 ng/kg 2.3–31.5 μg/kg |
0.000000045 0.0000023 |
<ref>Template:Cite journal</ref> |
| Maitotoxin (from ciguateric fish) | mouse, intraperitoneal | 50 ngTemplate:Ntsh/kg | 0.00000005 | <ref>Template:Cite web</ref> |
| Polonium-210 (Template:Chem) | human, inhalation | Template:Ntsh10 ng/kg (estimated) | 0.00000001 | <ref>Topic 2 Toxic Chemicals and Toxic Effects Template:Webarchive</ref> |
| Diphtheria toxin (from Corynebacterium) | mice | Template:Ntsh10 ng/kg | 0.00000001 | <ref name="biology.unm.edu">Template:Cite web</ref> |
| Shiga toxin (from Shigella bacteria) | mice | Template:Ntsh2 ng/kg | 0.000000002 | <ref name="biology.unm.edu"/> |
| Tetanospasmin (from Clostridium tetani) | mice | Template:Ntsh2 ng/kg | 0.000000002 | <ref name="biology.unm.edu"/> |
| Botulinum toxin (from Clostridium botulinum) | human, oral, injection, inhalation | Template:Ntsh1 ng/kg (estimated) | 0.000000001 | <ref>Template:Cite book</ref> |
| Ionizing radiation | human, irradiation | 3–5 Gy (Gray) | — | <ref>Template:Cite journal</ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref> |
Poison scale
[edit]
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 the Richter scale, 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
[edit]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).<ref>Template:Cite journal</ref> The up-and-down procedure, proposed in 1985, yields an LD50 value while dosing only one animal at a time.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
See also
[edit]- Animal testing
- Reed-Muench method
- The dose makes the poison – the toxicology adage that high quantities of any substance is lethal
Other measures of toxicity
[edit]- IDLH
- Certain safety factor
- Therapeutic index
- Protective index
- Median toxic dose (TD50)
- 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)
Related measures
[edit]- TCID50 Tissue Culture Infective Dosage
- Plaque forming units (pfu)