Median lethal dose

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In toxicology, the median lethal dose, LD50 (abbreviation for “lethal dose, 50%”), LC50 (lethal concentration, 50%) or LCt50 (lethal concentration and 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 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. LD50 is usually determined by tests on animals such as laboratory mice. In 2011 the US Food and Drug Administration approved alternative methods to LD50 for testing the cosmetic drug BOTOX without animal tests.23

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, but stated as nanograms (suitable for botulinum), micrograms, milligrams, or grams (suitable for paracetamol) per kilogram as toxicity decreases. 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).

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.4

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, 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. LCt50 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).

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.5

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, 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.

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
Water rat, oral >90,000 mg/kg >90 6
Sucrose (table sugar) rat, oral 29,700 mg/kg 29.7 7
Monosodium glutamate (MSG) rat, oral 16,600 mg/kg 16.6 8
Vitamin C (ascorbic acid) rat, oral 11,900 mg/kg 11.9 9
Cyanuric acid rat, oral 7,700 mg/kg 7.7 10
cadmium sulfide rat, oral 7,080 mg/kg 7.08 11
Grain alcohol (ethanol) rat, oral 7,060 mg/kg 7.06 12
sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) rat, oral 6,860 mg/kg 6.86 13
Melamine rat, oral 6,000 mg/kg 6 10
Melamine cyanurate rat, oral 4,100 mg/kg 4.1 10
Sodium molybdate rat, oral 4,000 mg/kg 4 14
Table Salt rat, oral 3,000 mg/kg 3 15
Paracetamol (acetaminophen) rat, oral 1,944 mg/kg 1.944 16
Delta-9-tetrahydrocannabinol (THC) rat, oral 1,270 mg/kg 1.270 17
Metallic Arsenic rat, oral 763 mg/kg 0.763 18
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}
19
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) rat, oral 293 mg/kg 0.293 20
Aspirin (acetylsalicylic acid) rat, oral 200 mg/kg 0.2 21
Caffeine rat, oral 192 mg/kg 0.192 22
Arsenic trisulfide rat, oral 185–6,400 mg/kg 0.185 23
Sodium nitrite rat, oral 180 mg/kg 0.18 24
Bisoprolol mouse, oral 100 mg/kg 0.1 25
Cobalt(II) chloride rat, oral 80 mg/kg 0.08 26
Cadmium oxide rat, oral 72 mg/kg 0.072 27
Sodium fluoride rat, oral 52 mg/kg 0.052 28
Nicotine rat, oral
mice, oral
50 mg/kg
3.3 mg/kg
0.05
0.0033
29
30
Pentaborane human, oral <50 mg/kg <0.05 31
Capsaicin mouse, oral 47.2 mg/kg 0.0472 32
Mercury(II) chloride rat, dermal 41 mg/kg 0.041 33
Lysergic acid diethylamide (LSD) rat, intravenous 16.5 mg/kg 0.0165 34
Arsenic trioxide rat, oral 14 mg/kg 0.014 35
Metallic Arsenic rat, intraperitoneal 13 mg/kg 0.013 36
Sodium cyanide rat, oral 6.4 mg/kg 0.0064 37
White phosphorus rat, oral 3.03 mg/kg 0.00303 38
Strychnine human, oral 1–2 mg/kg(estimated) 0.001 39
Cantharidin human, oral 0.5 mg/kg 0.0005
Aflatoxin B1 (from Aspergillus flavus) rat, oral 0.48 mg/kg 0.00048 40
Venom of the Brazilian wandering spider rat, subcutaneous 134 µg/kg 0.000134 41
Venom of the Inland Taipan (Australian snake) rat, subcutaneous 25 µg/kg 0.000025 42
Ricin rat, intraperitoneal
rat, oral
22 μg/kg
20–30 mg/kg
0.000022
0.02
43
Dioxin (TCDD) rat, oral 20 µg/kg 0.00002 44
Sarin mouse, subcutaneous injection 17.23 µg/kg (estimated) 0.0000172 45
VX human, oral, inhalation, absorption through skin/eyes 2.3 µg/kg (estimated) 0.0000023 46
Batrachotoxin (from poison dart frog) human, sub-cutaneous injection 2-7 µg/kg (estimated) 0.000002 47
Maitotoxin mouse, intraperitoneal 0.13 µg/kg 0.00000013 48
Polonium-210 human, inhalation 10 ng/kg (estimated) 0.00000001 49
Botulinum toxin (Botox) human, oral, injection, inhalation 1 ng/kg (estimated) 0.000000001 50
Ionizing radiation human, irradiation 3-6 Gy

Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International,51 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).

See also

Other measures of toxicity

Related measures

References

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  3. ^ "In U.S., Few Alternatives To Testing On Animals". Washington Post. 12 April 2008. Retrieved 2011-06-26. 
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    COMPREHENSIVE GUIDE TO THE RTECS
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  28. ^ Sodium Fluoride MSDS
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  43. ^ EFSA - Scientific Opinion of the CONTAM Panel: Ricin (from Ricinus communis) as undesirable substances in animal feed [1] - Scientific Opinion of the Panel on Contaminants in the Food Chain. Efsa.europa.eu. Retrieved on 2013-07-17.
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  51. ^ Thirty-Two Years of Measurable Change

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