Median lethal dose

In toxicology, the median lethal dose, LD₅₀, LC₅₀ or LCt₅₀ is a toxic unit that measures the lethal dose of a given substance. 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. The test was created by J. W. Trevan in 1927. 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.

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, micrograms, or grams 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. For substances in the environment, such as poisonous vapors or substances in water that are toxic to fish, the concentration in the environment is used, giving a value of LC₅₀. But in this case, the exposure time is important.
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" 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 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 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 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.
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. 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 is the number of organisms received by a person or test animal qualified by the route of administration. 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.

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.
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. 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 to each other by LD₅₀ can be misleading in many cases due to differences in effective dose. 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,, when appropriate.

Substance	Animal, route	LD₅₀	LD₅₀ : g/kg standardised	Reference
Water	rat, oral	>90,000 mg/kg	>90
Sucrose	rat, oral	29,700 mg/kg	29.7
Corn syrup	rat, oral	25,800 mg/kg	25.8
Glucose	rat, oral	25,800 mg/kg	25.8
Monosodium glutamate	rat, oral	16,600 mg/kg	16.6
Stevioside	mice and rats, oral	15,000 mg/kg	15
Gasoline	rat	14,063 mg/kg	14.0
Vitamin C	rat, oral	11,900 mg/kg	11.9
Glyphosate	rat, oral	10,537 mg/kg	10.537
Lactose	rat, oral	10,000 mg/kg	10
Aspartame	mice, oral	10,000 mg/kg	10
Urea	rat, oral	8,471 mg/kg	8.471
Cyanuric acid	rat, oral	7,700 mg/kg	7.7
Cadmium sulfide	rat, oral	7,080 mg/kg	7.08
Ethanol	rat, oral	7,060 mg/kg	7.06
Sodium isopropyl methylphosphonic acid	rat, oral	6,860 mg/kg	6.86
Melamine	rat, oral	6,000 mg/kg	6
Taurine	rat, oral	5,000 mg/kg	5
Melamine cyanurate	rat, oral	4,100 mg/kg	4.1
Fructose	rat, oral	4,000 mg/kg	4
Sodium molybdate	rat, oral	4,000 mg/kg	4
Sodium chloride	rat, oral	3,000 mg/kg	3
Paracetamol	rat, oral	2000 mg/kg	2
Delta-9-tetrahydrocannabinol	rat, oral	1,270 mg/kg	1.27
Cannabidiol	rat, oral	980 mg/kg	0.98
Methanol	human, oral	810 mg/kg	0.81
Trinitrotoluene	rat, oral	790 mg/kg	0.790
Arsenic	rat, oral	763 mg/kg	0.763
Ibuprofen	rat, oral	636 mg/kg	0.636
Formaldehyde	rat, oral	600–800 mg/kg	0.6
Solanine	rat, oral	590 mg/kg	0.590
Atropine	rat, oral	500 mg/kg	0.500
Piperidine	rat, oral	400 mg/kg	0.030
Alkyl dimethyl benzalkonium chloride	rat, oral fish, immersion aquatic invertebrates, immersion	304.5 mg/kg	0.3045
Coumarin	rat, oral	293 mg/kg	0.293
Psilocybin	mouse, oral	280 mg/kg	0.280
Hydrochloric acid	rat, oral	238–277 mg/kg	0.238
Ketamine	rat, intraperitoneal	229 mg/kg	0.229
Aspirin	rat, oral	200 mg/kg	0.2
Caffeine	rat, oral	192 mg/kg	0.192
Arsenic trisulfide	rat, oral	185–6,400 mg/kg	0.185–6.4
Sodium nitrite	rat, oral	180 mg/kg	0.18
Methylenedioxymethamphetamine	rat, oral	160 mg/kg	0.16
Uranyl acetate dihydrate	mouse, oral	136 mg/kg	0.136
Dichlorodiphenyltrichloroethane	mouse, oral	135 mg/kg	0.135
Uranium	mice, oral	114 mg/kg	0.114
Bisoprolol	mouse, oral	100 mg/kg	0.1
Cocaine	mouse, oral	96 mg/kg	0.096
Cobalt chloride	rat, oral	80 mg/kg	0.08
Cadmium oxide	rat, oral	72 mg/kg	0.072
Thiopental sodium	rat, oral	64 mg/kg	0.064
Demeton-S-methyl	rat, oral	60 mg/kg	0.060
Methamphetamine	rat, intraperitoneal	57 mg/kg	0.057
Sodium fluoride	rat, oral	52 mg/kg	0.052
Nicotine	mouse and rat, oral human, smoking	50 mg/kg	0.05
Pentaborane	human, oral	50 mg/kg	0.05
Capsaicin	mouse, oral	47.2 mg/kg	0.0472
Vitamin D3	rat, oral	37 mg/kg	0.037
Heroin	mouse, intravenous	21.8 mg/kg	0.0218
Lysergic acid diethylamide	rat, intravenous	16.5 mg/kg	0.0165
Arsenic trioxide	rat, oral	14 mg/kg	0.014
Metallic arsenic	rat, intraperitoneal	13 mg/kg	0.013
Coniine	mouse, intravenous	8 mg/kg	0.008
Sodium cyanide	rat, oral	6.4 mg/kg	0.0064
Chlorotoxin	mice	4.3 mg/kg	0.0043
Hydrogen cyanide	mouse, oral	3.7 mg/kg	0.0037
Carfentanil	rat, intravenous	3.39 mg/kg	0.00339
Nicotine	mice, oral	3.3 mg/kg	0.0033
White phosphorus	rat, oral	3.03 mg/kg	0.00303
Phenylthiocarbamide	rat, oral	3 mg/kg	0.003
Strychnine	human, oral	1–2 mg/kg	0.001–0.002
Aconitine	human, oral	1–2 mg/kg	0.001–0.002
Mercury chloride	rat, oral	1 mg/kg	0.001
Aldicarb	rat, oral	650 μg/kg	0.00065
Cantharidin	human, oral	500 μg/kg	0.0005
Aflatoxin B1	rat, oral	480 μg/kg	0.00048
Plutonium	dog, intravenous	320 μg/kg	0.00032
Bufotoxin	cat, intravenous	300 μg/kg	0.0003
Brodifacoum	rat, oral	270 μg/kg	0.00027
Caesium-137	mouse, parenteral	21.5 μCi/g	0.000245
Sodium fluoroacetate	rat, oral	220 μg/kg	0.00022
Chlorine trifluoride	mouse, absorption through skin	178 μg/kg	0.000178
Sarin	mouse, subcutaneous injection	172 μg/kg	0.000172
Robustoxin	mice	150 μg/kg	0.000150
VX	human, oral, inhalation, absorption through skin/eyes	140 μg/kg	0.00014
Venom of the Brazilian wandering spider	rat, subcutaneous	134 μg/kg	0.000134
Amatoxin	human, oral	100 μg/kg	0.0001
Dimethylmercury	human, transdermal	50 μg/kg	0.000050
TBPO	mouse, intravenous	36 μg/kg	0.000036
Fentanyl	monkey	30 μg/kg	0.00003
Venom of the inland taipan	rat, subcutaneous	25 μg/kg	0.000025
Ricin	rat, intraperitoneal rat, oral	22 μg/kg 20–30 mg/kg	0.000022 0.02
2,3,7,8-Tetrachlorodibenzodioxin	rat, oral	20 μg/kg	0.00002
Tetrodotoxin from the blue-ringed octopus	intravenous	8.2 μg/kg	0.0000082
CrTX-A	crayfish, intraperitoneal	5 μg/kg	0.000005
Latrotoxin	mice	4.3 μg/kg	0.0000043
Epibatidine	mouse, intravenous	1.46-13.98 μg/kg	0.00000146
Batrachotoxin	human, sub-cutaneous injection	2–7 μg/kg	0.000002
Abrin	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
Saxitoxin	human, intravenously human, oral	0.6 μg/kg 5.7 μg/kg	0.0000006 0.0000057
Pacific ciguatoxin-1	mice, intraperitoneal	250 ng/kg	0.00000025
Palytoxin	mouse, intravenous human, oral	45 ng/kg 2.3–31.5 μg/kg	0.000000045 0.0000023
Maitotoxin	mouse, intraperitoneal	50 ng/kg	0.00000005
Polonium-210	human, inhalation	10 ng/kg	0.00000001
Diphtheria toxin	mice	10 ng/kg	0.00000001
Shiga toxin	mice	2 ng/kg	0.000000002
Tetanospasmin	mice	2 ng/kg	0.000000002
Botulinum toxin	human, oral, injection, inhalation	1 ng/kg	0.000000001
Ionizing radiation	human, irradiation	3–5 Gy	—