In
toxicologyToxicology is the study of the adverse effects of chemicals on living organisms. It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people.-History:...
, the
median lethal dose,
LD50 (abbreviation for “Lethal Dose, 50%”),
LC50 (Lethal Concentration, 50%) or
LCt50 (Lethal Concentration & Time) of a toxic substance or radiation is the dose required to kill half the members of a tested population. LD
50 figures are frequently used as a general indicator of a substance's
acute toxicityAcute toxicity describes the adverse effects of a substance which result either from a single exposure or from multiple exposures in a short space of time...
. The test was created by J.W. Trevan in 1927. It is being phased out in some jurisdictions in favor of tests such as the
Fixed Dose ProcedureFixed Dose Procedure , proposed in 1984, is a method to assess a substance's acute oral toxicity. In comparison to older LD50 test developed in 1927, this procedure produces accurate, reproducible results using fewer animals and causing less pain and suffering...
, however the concept, and calculation of the median lethal dose for comparison purposes, is still widely used.
As a measure of toxicity, LD
50 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. Another weakness is that it measures acute toxicity only (as opposed to
chronic toxicityChronic toxicity is a property of a substance that has toxic effects on a living organism, when that organism is exposed to the substance continuously or repeatedly. Compared with acute toxicity.Two distinct situations need to be considered:...
at lower doses), and does not take into account toxic effects that do not result in death but are nonetheless serious (e.g.
brain damageBrain damage, or acquired brain injury, is the destruction or degeneration of brain cells.-Causes:Brain damage may occur due to a wide range of conditions, illnesses, injuries, and as a result of iatrogenesis...
). There can be wide variability between species as well; what is relatively safe for rats may very well be extremely toxic for humans, and vice versa. In other words, a relatively high LD
50 does not necessarily mean a substance is harmless, but a very low one is always a cause for concern.
The term
semilethal dose is occasionally used with the same meaning, particularly in translations from non-English-language texts, but can also refer to a
sublethal dose; because of this ambiguity, it is usually avoided.
Conventions
The LD
50 is usually expressed as the mass of substance administered per unit mass of test subject, such as
gramThe gram , ; symbol g, is a unit of mass.Originally defined as "the absolute weight of a volume of pure water equal to the cube of the hundredth part of a metre, and at the temperature of melting ice" , a gram is now defined as one one-thousandth of the SI base unit, the kilogram, or...
s of substance per
kilogramThe kilogram is the base unit of mass in the International System of Units .[The spelling kilogram is the modern spelling used by the International Bureau of Weights and Measures , the U.S...]
of body mass. 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). Typically, the LD
50 of a substance is given in milligrams per kilogram of body weight. In the case of some
neurotoxinA neurotoxin is a toxin that acts specifically on nerve cells , usually by interacting with membrane proteins such as ion channels.Some sources are more general, and define the effect of neurotoxins as occurring at nerve tissue...
s such as
batrachotoxinBatrachotoxins are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in certain species of frogs , Melyridae beetles, and birds .- Chemistry :...
, one of the most deadly toxins known, the LD
50 may be more conveniently expressed as micrograms per kilogram (µg/kg)of 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 LD
50 is
not the lethal dose for all subjects; some may be killed by much less, while others survive doses far higher than the LD
50. Measures such as 'LD
1' and 'LD
99' (dosage required to kill 1% or 99% respectively of the test population) are occasionally used for specific purposes.
Lethal dosage often varies depending on the method of administration; for instance, many substances are less toxic when administered orally than when
intravenouslyIntravenous therapy or IV therapy is the giving of liquid substances directly into a vein. It can be intermittent or continuous; continuous administration is called an intravenous drip. The word intravenous simply means "within a vein", but is most commonly used to refer to IV therapy...
administered. For this reason, LD
50 figures are often qualified with the mode of administration, e.g. "LD
50 i.v."
The related quantities LD
50/30 or an LD
50/60 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. ICt
50 is the dose which will cause incapacitation rather than death. These measures are commonly used to indicate the comparative efficacy of
chemical warfareChemical warfare involves using the toxic properties of chemical substances as weapons to kill, injure, or incapacitate an enemy....
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 HaberFritz Haber was a German chemist, who received the Nobel Prize in Chemistry in 1918 for his development for synthesizing ammonia, important for fertilizers and explosives. Haber, along with Max Born, proposed the Born–Haber cycle as a method for evaluating the lattice energy of an ionic solid...
, and is sometimes referred to as
Haber's LawHaber's Law makes equivalent any two groupings of dose concentration and exposure time that have equivalent mathematical products. For instance, if we assign dose concentration the symbol C, and time the classic t, then for any two dose schema, if...
, 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 cyanideHydrogen cyanide is a chemical compound with chemical formula HCN. A solution of hydrogen cyanide in water is called hydrocyanic acid. Hydrogen cyanide is a colorless, extremely poisonous, and highly volatile liquid that boils slightly above room temperature at 26 °C...
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 SheetA material safety data sheet is a form containing data regarding the properties of a particular substance. An important component of product stewardship and workplace safety, it is intended to provide workers and emergency personnel with procedures for handling or working with that substance in a...
s 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 (ID
50) 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 LD
50's to some test animal. In
biological warfareBiological warfare , also known as germ warfare, is the use of pathogens such as viruses, bacteria, other disease-causing biological agents, or the toxins produced by them as biological weapons ....
infective dosage is the number of infective doses per minute for a cubic meter (e.g., ICt
50 is 100 medium doses - min/m³).
Animal rights concerns
Animal-rightsAnimal rights, also referred to as animal liberation, is the idea that the most basic interests of animals should be afforded the same consideration as the similar interests of humans...
and
animal-welfareAnimal welfare, the health and well-being of animals, represents a systematic concern for people who believe that nonhuman animals are sentient beings that deserve consideration, respect, and care...
groups, such as Animal Rights International, have campaigned against LD
50 testing on animals in particular as, in the case of some substances, causing the animals to die slow, painful deaths. Several countries, including the
UKThe United Kingdom of Great Britain and Northern Ireland is a sovereign state located off the northwestern coast of continental Europe. It is an island country, spanning an archipelago including Great Britain, the northeastern part of Ireland, and many small islands...
, have taken steps to ban the oral LD
50, and the Organization 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).
LD
50 still remains popular, despite its general weakness in providing a useful measure of toxicity.
Examples
| Substance |
Animal, Route |
LD50 |
Reference |
| Sucrose Sucrose, commonly called table sugar, is a moosaccharide of glucose and fructose with the molecular formula C12H22O11. This white, odorless, crystalline powder has a pleasing, sweet taste. It is best known for its role in human nutrition...
(table sugar) |
rat, oral |
29,700 mg/kg |
|
Vitamin CVitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate is required for a range of essential metabolic reactions in all animals and plants...
(ascorbic acid) |
rat, oral |
11,900 mg/kg |
|
Grain alcoholEthanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug, best known as the type of alcohol found in alcoholic beverages and in modern thermometers. Ethanol is one of the oldest recreational drugs...
(ethanol) |
rat, oral |
7,060 mg/kg |
|
Table SaltSodium chloride, also known as salt, common salt, table salt, or halite, is an ionic compound with the formula NaCl. Sodium chloride is the salt most responsible for the salinity of the ocean and of the extracellular fluid of many multicellular organisms...
|
rat, oral |
3,000 mg/kg |
|
ParacetamolParacetamol or acetaminophen is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of fever, headaches, and other minor aches and pains, and is a major ingredient in numerous cold and flu remedies...
(acetaminophen) |
rat, oral |
1,944 mg/kg |
|
THCTetrahydrocannabinol , also known as delta-9-tetrahydrocannabinol , Δ 1-THC , or dronabinol, is the main psychoactive substance found in the Cannabis plant....
(main psychoactive substance in CannabisCannabis is a genus of flowering plants that includes three putative species, Cannabis sativa L., Cannabis indica Lam., and Cannabis ruderalis Janisch. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for medicinal purposes, and as a...
) |
rat, oral |
1,270 mg/kg males; 730 mg/kg females |
|
CoumarinCoumarin is a chemical compound found in many plants, notably in high concentration in the tonka bean , vanilla grass , woodruff , mullein , and sweet grass...
(benzopyroneBenzopyrone may refer to either of two ketone derivatives of benzopyran which constitute the core skeleton of many flavonoid compounds:*Chromone *Coumarin...
, from Cinnamomum aromaticum and other plants) |
rat, oral |
293 mg/kg |
|
AspirinAspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication....
(acetylsalicylic acid) |
rat, oral |
200 mg/kg |
|
CaffeineCaffeine is a bitter, white crystalline xanthine alkaloid that is a psychoactive stimulant drug. Caffeine was discovered by a German chemist, Friedrich Ferdinand Runge, in 1819. He coined the term kaffein, a chemical compound in coffee, which in English became caffeine...
|
rat, oral |
192 mg/kg |
|
| Sodium nitrite Sodium nitrite, with chemical formula NaNO2, is used as a color fixative and preservative in meats and fish.When pure, it is a white to slight yellowish crystalline powder. It is very soluble in water and is hygroscopic. It is also slowly oxidized by oxygen in the air to sodium nitrate,...
|
rat, oral |
180 mg/kg |
|
NicotineNicotine is an alkaloid found in the nightshade family of plants which constitutes approximately 0.6–3.0% of dry weight of tobacco, with biosynthesis taking place in the roots, and accumulating in the leaves...
|
rat, oral |
50 mg/kg |
|
StrychnineStrychnine is a very toxic , colorless crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine causes muscular convulsions and eventually death through asphyxia or sheer exhaustion. The most common source is from the seeds of the...
|
rat, oral |
16 mg/kg |
|
| Sodium cyanide Sodium cyanide is an inorganic compound with the formula NaCN. This highly toxic colourless salt is used mainly in gold mining but has other niche applications...
|
rat, oral |
6.4 mg/kg |
|
Aflatoxin B1Aflatoxins are naturally occurring mycotoxins that are produced by many species of Aspergillus, a fungus, most notably Aspergillus flavus and Aspergillus parasiticus. Aflatoxins are toxic and among the most carcinogenic substances known...
(from Aspergillus flavus) |
rat, oral |
0.048 mg/kg |
|
| Venom of the Inland taipan (Australian snake) |
rat, subcutaneous |
0.025 mg/kg |
|
| Dioxin (TCDD) |
rat, oral |
0.020 mg/kg |
|
BatrachotoxinBatrachotoxins are extremely potent cardiotoxic and neurotoxic steroidal alkaloids found in certain species of frogs , Melyridae beetles, and birds .- Chemistry :...
(from poison dart frog) |
human, sub-cutaneous injection |
0.002-0.007 mg/kg (estimated) |
|
PoloniumPolonium is a chemical element with the symbol Po and atomic number 84, discovered in 1898 by Marie and Pierre Curie. A rare and highly radioactive metalloid, polonium is chemically similar to bismuth and tellurium, and it occurs in uranium ores. Polonium has been studied for possible use in...
210 |
human, inhalation |
0.00001 mg/kg (estimated) |
|
Botulinum toxinBotulinum toxin is a medication and a neurotoxic protein produced by the bacterium Clostridium botulinum, and is held to be the most toxic substance known to mankind with an LD50 of roughly 0.005-0.05 µg/kg...
(Botox) |
human, oral, injection |
0.000001 mg/kg (estimated) |
|
| Substance |
Animal, Route |
LC50 |
Reference |
| Alkyl dimethyl benzalkonium chloride (ADBAC) |
fish, immersion |
280 μg/L |
|
Other measures of toxicity
- Certain safety factor
The Certain Safety Factor is the ratio of the lethal dose to 1% of population to the effective dose to 99% of the population . This is a better safety index than the LD50 for materials that have both desirable and undesirable effects, because it factors in the ends of the spectrum where...
- Fixed Dose Procedure
Fixed Dose Procedure , proposed in 1984, is a method to assess a substance's acute oral toxicity. In comparison to older LD50 test developed in 1927, this procedure produces accurate, reproducible results using fewer animals and causing less pain and suffering...
- Lowest published toxic concentration (TCLo)
- Lowest published lethal dose
In toxicology, the LDLo is the lowest dosage per unit of bodyweight of a substance known to have resulted in fatality in a particular animal species...
(LDLo)
- IC50
The half maximal inhibitory concentration is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. Often, the compound in question is a drug candidate. This quantitative measure indicates how much of a particular drug or other substance is needed to...
(50% inhibitory concentration)
- Draize test
The Draize Test is an acute toxicity test devised in 1944 by Food and Drug Administration toxicologist John H. Draize. Initially used for testing cosmetics, the procedure involves applying 0.5mL or 0.5g of a test substance to the eye or skin of a restrained, conscious animal, and leaving it for...
- Indicative limit value
In the law of the European Union, indicative limit values, more exactly indicative occupational exposure limit values , are human exposure limits to hazardous substances specified by the Council of the European Union based on expert research and advice.They are not binding on member states but must...
- No Observable Adverse Effect Level (NOAEL)
- Lowest Observable Adverse Effect Level (LOAEL)
Related measures
- TCID50 Tissue Culture Infective Dosage
- EID50 Egg Infective Dosage
- ELD50 Egg Lethal Dosage
- Plaque forming units (pfu)
External links