In toxicology, the median lethal dose, LD50 (abbreviation for “Lethal Dose, 50%”), LC50 (Lethal Concentration, 50%) or LCt50 (Lethal Concentration & Time) of a toxin, radiation, or pathogen 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. The test was created by J.W. Trevan in 1927.[1] It is being phased out in some jurisdictions in favor of tests such as the Fixed Dose Procedure;[2] however the concept, and calculation of the median lethal dose for comparison purposes, is still widely used. The term semilethal dose is occasionally used with the same meaning, in particular in translations from non-English-language texts, but can also refer to a sublethal dose; because of this ambiguity, it is usually avoided. The U.S. Food and Drug Administration has begun to approve alternative methods to LD50 in response to research, cruelty concerns, and the lack of validity/sensitivity of the test as it relates to humans. [3] [4]
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The LD50 is usually expressed as the mass of substance administered per unit mass of test subject, such as grams of substance per kilogram 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 LD50 of a substance is given in milligrams per kilogram of body weight. In the case of some neurotoxins such as batrachotoxin, one of the most deadly toxins known, the LD50 may be more conveniently expressed as micrograms per kilogram (µg/kg) or nanograms per kilogram (ng/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 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.[5]
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 an 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, 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. 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 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 LD50's to some test animal. In biological warfare infective dosage is the number of infective doses per minute for a cubic meter (e.g., ICt50 is 100 medium doses - min/m³).
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.[6] Another weakness is that it measures acute toxicity only (as opposed to chronic toxicity at lower doses), and does not take into account toxic effects that do not result in death but are nonetheless serious (e.g., brain damage). 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 LD50 does not necessarily mean a substance is harmless, since its relative harmfulness depends on its usual dose, but a very low one is always a cause for concern.
When used to test venom from venomous creatures, such as snakes, LD50 results may be misleading due to the physiological differences between mice and humans. Many venomous snakes are specialized predators on mice, their venom may be adapted specifically to incapacitate mice. While most mammals have a very similar physiology, LD50 results may or may not be directly relevant to humans.
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.
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} standardized |
Reference |
|---|---|---|---|---|
| Sucrose (table sugar) | rat, oral | 29,700 mg/kg | 29.7 | [7] |
| Vitamin C (ascorbic acid) | rat, oral | 11,900 mg/kg | 11.9 | [8] |
| Cyanuric acid | rat, oral | 7,700 mg/kg | 7.7 | [9] |
| cadmium sulfide | rat, oral | 7,080 mg/kg | 7.08 | [10] |
| Grain alcohol (ethanol) | rat, oral | 7,060 mg/kg | 7.06 | [11] |
| Melamine | rat, oral | 6,000 mg/kg | 6 | [9] |
| Melamine cyanurate | rat, oral | 4,100 mg/kg | 4.1 | [9] |
| Sodium molybdate | rat, oral | 4,000 mg/kg | 4 | [12] |
| Table Salt | rat, oral | 3,000 mg/kg | 3 | [13] |
| Paracetamol (acetaminophen) | rat, oral | 1,944 mg/kg | 1.944 | [14] |
| Delta-9-tetrahydrocannabinol (THC) | rat, oral | 1,270 mg/kg | 1.270 | [15] |
| Metallic Arsenic | rat, oral | 763 mg/kg | 0.763 | [16] |
| Alkyl dimethyl benzalkonium chloride (ADBAC) | rat, oral fish, immersion aq. invertebrates, imm. |
304.5 mg/kg {0.28 mg/L} {0.059 mg/L} |
0.3045 {0.00028} {0.000059} |
[17] |
| Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) | rat, oral | 293 mg/kg | 0.293 | [18] |
| Aspirin (acetylsalicylic acid) | rat, oral | 200 mg/kg | 0.2 | [19] |
| Caffeine | rat, oral | 192 mg/kg | 0.192 | [20] |
| Arsenic trisulfide | rat, oral | 185–6,400 mg/kg | 0.185 | [21] |
| Sodium nitrite | rat, oral | 180 mg/kg | 0.18 | [22] |
| Cobalt(II) chloride | rat, oral | 80 mg/kg | 0.08 | [23] |
| Cadmium oxide | rat, oral | 72 mg/kg | 0.072 | [24] |
| Sodium fluoride | rat, oral | 52 mg/kg | 0.052 | [25] |
| Nicotine | rat, oral | 50 mg/kg | 0.05 | [26] |
| Pentaborane | human, oral | <50 mg/kg | <0.05 | [27] |
| Lysergic acid diethylamide (LSD) | rat, intravenous | 16.5 mg/kg | 0.0165 | [28] |
| Arsenic trioxide | rat, oral | 14 mg/kg | 0.014 | [29] |
| Metallic Arsenic | rat, intraperitoneal | 13 mg/kg | 0.013 | [30] |
| Sodium cyanide | rat, oral | 6.4 mg/kg | 0.0064 | [31] |
| White phosphorus | rat, oral | 3.03 mg/kg | 0.00303 | [32] |
| Strychnine | human, oral | 1–2 mg/kg(estimated) | 0.001 | [33] |
| Mercury(II) chloride | rat, dermal | 41 mg/kg | 0.041 | [34] |
| Beryllium oxide | rat, oral | 0.5 mg/kg | 0.0005 | [35] |
| Aflatoxin B1 (from Aspergillus flavus) | rat, oral | 0.48 mg/kg | 0.00048 | [36] |
| Venom of the Inland Taipan (Australian snake) | rat, subcutaneous | 25 µg/kg | 0.000025 | [37] |
| Dioxin (TCDD) | rat, oral | 20 µg/kg | 0.00002 | [38] |
| VX (nerve agent) | human, oral, inhalation, absorption through skin/eyes | 2.3 µg/kg (estimated) | 0.0000023 | [39] |
| Batrachotoxin (from poison dart frog) | human, sub-cutaneous injection | 2-7 µg/kg (estimated) | 0.000002 | [40] |
| Venom of Hydrophis belcheri (Belcher's Sea Snake) | mouse, intraperitoneal | 0.25 µg/kg | 0.00000025 | [41] |
| Maitotoxin | mouse, intraperitoneal | 0.13 µg/kg | 0.00000013 | [42] |
| Polonium-210 | human, inhalation | 10 ng/kg (estimated) | 0.00000001 | [43] |
| Botulinum toxin (Botox) | human, oral, injection, inhalation | 1 ng/kg (estimated) | 0.000000001 | [44] |
| Ionizing radiation | human, irradiation | 3-6 Gy |
Animal-rights and animal-welfare groups, such as Animal Rights International,[45] have campaigned against LD50 testing on animals in particular as, in the case of some substances, causing the animals to die slow, painful deaths. Several countries, including the UK, have taken steps to ban the oral LD50, 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).
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