Median lethal dose
In toxicology, the median lethal dose, LD50, LC50 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. 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, 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. So, 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 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.
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 | |
| 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 | |
| Methanol | human, oral | 810 mg/kg | 0.81 | |
| 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 | 1,944 mg/kg | 1.944 | |
| Delta-9-tetrahydrocannabinol | rat, oral | 1,270 mg/kg | 1.27 | |
| Cannabidiol | rat, oral | 980 mg/kg | 0.98 | |
| Metallic 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 main alkaloid in the several plants in Solanaceae amongst them Solanum tuberosum | rat, oral | 590 mg/kg | 0.590 | |
| 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 | 0.18 | |
| 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 | rat, oral | 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 | |
| Piperidine | rat, oral | 30 mg/kg | 0.030 | |
| 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 | |
| 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 | |
| Strychnine | human, oral | 1–2 mg/kg | 0.001–0.002 | |
| Mercury chloride | rat, oral | 1 mg/kg | 0.001 | |
| Nicotine | human, oral | 0.8 mg/kg | 0.0008 | |
| 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 | |
| Amatoxin | rat | 300-700 µg/kg | 0.0007 | |
| Tetrodotoxin | mice, oral | 334 µg/kg | 0.000334 | |
| Fentanyl | monkey | 300 µg/kg | 0.0003 | |
| Bufotoxin | cat, intravenous | 300 µg/kg | 0.0003 | |
| Caesium-137 | mouse, parenternal | 21.5 µCi/g | 0.000245 | |
| 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 | |
| Aconitine main alkaloid in Aconitum napellus and related species | rat, intraveneous | 80 µg/kg | 0.000080 | |
| 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 | |
| CrTX-A | crayfish, intraperitoneal | 5 µg/kg | 0.000005 | |
| Latrotoxin | mice | 4.3 µg/kg | 0.0000043 | |
| 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 | |
| Maitotoxin | mouse, intraperitoneal | 130 ng/kg | 0.00000013 | |
| 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 | 5 Gy |
Poison Scale
The LD 50 values have a very wide range. The botulinum toxin as the most toxic substance known has an LD 50 value of 1 ng / kg, while the most non-toxic substance water has an LD 50 value of more than 90 g / kg. That's 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 LD 50 values, which is standardized in kg per kg body weight, is considered.
The dimensionless value found can be entered in a toxin scale. Water as the most important substance has the catchy value 1 in the toxin scale obtained in this way.
Animal rights concerns
and animal-welfare groups, such as Animal Rights International, 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 abolished the requirement for the oral test in 2001.Other measures of toxicity
- IDLH
- Certain safety factor
- Therapeutic index
- Protective index
- Fixed Dose Procedure to estimate LD50
- Median toxic dose
- Lowest published toxic concentration
- Lowest published lethal dose
- EC50
- IC50
- Draize test
- Indicative limit value
- No-observed-adverse-effect level
- Lowest-observed-adverse-effect level
- Up-and-down procedure
Related measures
- TCID50 Tissue Culture Infective Dosage
- EID50 Egg Infective Dosage
- ELD50 Egg Lethal Dosage
- Plaque forming units