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>{{#invoke:citation/CS1|citation |CitationClass=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>{{#invoke:citation/CS1|citation |CitationClass=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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite news</ref>

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 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>{{#invoke:citation/CS1|citation |CitationClass=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

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

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>{{#invoke:citation/CS1|citation |CitationClass=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	citation	CitationClass=web }}</ref>
Sucrose (table sugar)	rat, oral	Template:Ntsh29,700 mg/kg	29.7	citation	CitationClass=web }}</ref>
Corn syrup	rat, oral	Template:Ntsh25,800 mg/kg	25.8	citation	CitationClass=web }}</ref>
Glucose (blood sugar)	rat, oral	Template:Ntsh25,800 mg/kg	25.8	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Vitamin C (ascorbic acid)	rat, oral	Template:Ntsh11,900 mg/kg	11.9	citation	CitationClass=web }}</ref>
Glyphosate (isopropylamine salt)	rat, oral	Template:Ntsh10,537 mg/kg	10.537	citation	CitationClass=web }}</ref>
Lactose (milk sugar)	rat, oral	Template:Ntsh10,000 mg/kg	10	citation	CitationClass=web }}</ref>
Aspartame	mice, oral	Template:Ntsh10,000 mg/kg	10	citation	CitationClass=web }}</ref>
Urea (Template:Chem2)	rat, oral	Template:Ntsh8,471 mg/kg	8.471	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Sodium molybdate (Template:Chem2)	rat, oral	4,000 mg/kg	4	citation	CitationClass=web }}</ref>
Sodium chloride (table salt)	rat, oral	3,000 mg/kg	3	citation	CitationClass=web }}</ref>
Paracetamol (acetaminophen)	rat, oral	2000 mg/kg	2	citation	CitationClass=web }}</ref>
Aspirin (acetylsalicylic acid)	rat, oral	1,600 mg/kg	1.6	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Methanol (Template:Chem2)	human, oral	Template:Ntsh810 mg/kg	0.81	citation	CitationClass=web }}</ref>
Trinitrotoluene (TNT)	rat, oral	790 mg/kg	0.790
Arsenic (As)	rat, oral	763 mg/kg	0.763	citation	CitationClass=web }}</ref>
Ibuprofen	rat, oral	636 mg/kg	0.636	citation	CitationClass=web }}</ref>
Formaldehyde (Template:Chem2)	rat, oral	600–800 mg/kg	0.6	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Ketamine	rat, intraperitoneal	229 mg/kg	0.229	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Sodium nitrite (Template:Chem2)	rat, oral	180 mg/kg	0.18	citation	CitationClass=web }}Template: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	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Cocaine	mouse, oral	96 mg/kg	0.096	citation	CitationClass=web }}</ref>
Cobalt(II) chloride (Template:Chem2)	rat, oral	80 mg/kg	0.08	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Demeton-S-methyl	rat, oral	60 mg/kg	0.060	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Capsaicin	mouse, oral	47.2 mg/kg	0.0472	citation	CitationClass=web }}</ref>
Vitamin D3 (cholecalciferol)	rat, oral	37 mg/kg	0.037	citation	CitationClass=web }}</ref>
Piperidine (from black pepper)	rat, oral	30 mg/kg	0.030	citation	CitationClass=web }}</ref>
Heroin (diamorphine)	mouse, intravenous	21.8 mg/kg	0.0218	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Metallic arsenic (As)	rat, intraperitoneal	13 mg/kg	0.013	citation	CitationClass=web }}</ref>
Sodium cyanide (NaCN)	rat, oral	6.4 mg/kg	0.0064	citation	CitationClass=web }}</ref>
Chlorotoxin (CTX, from scorpions)	mice	4.3 mg/kg	0.0043	citation	CitationClass=web }}</ref>
Hydrogen cyanide (HCN)	mouse, oral	3.7 mg/kg	0.0037	citation	CitationClass=web }}</ref>
Carfentanil	rat, intravenous	3.39 mg/kg	0.00339	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=web }}</ref>
Brodifacoum	rat, oral	270 μg/kg	0.00027	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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	citation	CitationClass=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>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation	CitationClass=web }}</ref>

Poison scale

File:Poison-Scale-long.jpg

Negative values of the decimal logarithm of the median lethal dose LD₅₀ (Template:Math) on a linearized toxicity scale encompassing 11 orders of magnitude. Water occupies the lowest toxicity position (1) while the toxicity scale is dominated by the botulinum toxin (12).<ref>Template:Cite journal</ref>

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

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

• 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

• 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

• TCID₅₀ Tissue Culture Infective Dosage
• Plaque forming units (pfu)

Further reading

• Template:Cite journal

External links

• Canadian Centre for Occupational Health and Safety Template:Webarchive