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 is a toxic unit that measures the lethal dose of a given substance. [1] 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.

Contents

The term LD50 is generally attributed to John William Trevan. [2] The test was created by J. W. Trevan in 1927. [3] 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. [4] [5]

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), 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. [6]

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. 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 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. [7]

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. [8]

The following examples are listed in reference to LD50 values, in descending order, and accompanied by LC50 values, {bracketed}, when appropriate.

SubstanceAnimal, routeLD50
{LC50}
LD50 : g/kg
{LC50 : g/L}
standardised		Reference
Water (H2O)rat, oral>>90 [9]
Sucrose (table sugar)rat, oral29.7 [10]
Corn Syrup rat, oral25.8 [11]
Glucose (blood sugar)rat, oral25.8 [12]
Monosodium glutamate (MSG)rat, oral16.6 [13]
Stevioside (from stevia)mice and rats, oral15 [14]
Gasoline (petrol)rat14.0 [15]
Vitamin C (ascorbic acid)rat, oral11.9 [16]
Glyphosate (isopropylamine salt of)rat, oral10.537 [17]
Lactose (milk sugar)rat, oral10 [18]
Aspartame mice, oral10 [19]
Urea (OC(NH2)2)rat, oral8.471 [20]
Cyanuric acid rat, oral7.7 [21]
Cadmium sulfide (CdS)rat, oral7.08 [22]
Ethanol (CH3CH2OH)rat, oral7.06 [23]
Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin)rat, oral6.86 [24]
Melamine rat, oral6 [21]
Taurine rat, oral5 [25]
Melamine cyanurate rat, oral4.1 [21]
Fructose (fruit sugar)rat, oral4,000 mg/kg4 [26]
Sodium molybdate (Na2MoO4)rat, oral4,000 mg/kg4 [27]
Sodium chloride (table salt)rat, oral3,000 mg/kg3 [28]
Aspirin (acetylsalicylic acid)rat, oral1,944 mg/kg1.944 [29]
Delta-9-tetrahydrocannabinol (THC)rat, oral1,270 mg/kg1.27 [30]
Cannabidiol (CBD)rat, oral980 mg/kg0.98 [31]
Methanol (CH3OH)human, oral0.81 [32]
Trinitrotoluene (TNT)rat, oral790 mg/kg0.790
Arsenic (As)rat, oral763 mg/kg0.763 [33]
Ibuprofen rat, oral636 mg/kg0.636 [34]
Formaldehyde (CH2O)rat, oral600–800 mg/kg0.6 [35]
Solanine (main alkaloid in the several plants in Solanaceae amongst them Solanum tuberosum )rat, oral (2.8 mg/kg human, oral)0.590 [36]
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}		 [37]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants)rat, oral293 mg/kg0.293 [38]
Psilocybin (from magic mushrooms)mouse, oral280 mg/kg0.280 [39]
Hydrochloric acid (HCl)rat, oral238–277 mg/kg0.238 [40]
Ketamine rat, intraperitoneal229 mg/kg0.229 [41]
Paracetamol (acetaminophen)rat, oral200 mg/kg0.2 [42]
Caffeine rat, oral192 mg/kg0.192 [43]
Arsenic trisulfide (AsS3)rat, oral185–6,400 mg/kg0.185–6.4 [44]
Sodium nitrite (NaNO2)rat, oral180 mg/kg0.18 [45]
Methylenedioxymethamphetamine (MDMA, ecstasy)rat, oral160 mg/kg0.18 [46]
Uranyl acetate dihydrate (UO2(CH3COO)2)mouse, oral136 mg/kg0.136 [47]
Dichlorodiphenyltrichloroethane (DDT)mouse, oral135 mg/kg0.135 [48]
Uranium (U)mice, oral0.114 [47]
Bisoprolol mouse, oral100 mg/kg0.1 [49]
Cocaine mouse, oral96 mg/kg0.096 [50]
Cobalt(II) chloride (CoCl2)rat, oral80 mg/kg0.08 [51]
Cadmium oxide (CdO)rat, oral72 mg/kg0.072 [52]
Thiopental sodium (used in lethal injection)rat, oral64 mg/kg0.064 [53]
Demeton-S-methyl rat, oral60 mg/kg0.060 [54]
Methamphetamine rat, intraperitoneal57 mg/kg0.057 [55]
Sodium fluoride (NaF)rat, oral52 mg/kg0.052 [56]
Nicotine mouse and rat, oral

human, smoking

50 mg/kg0.05 [57]
Pentaborane human, oral50 mg/kg0.05 [58]
Capsaicin mouse, oral47.2 mg/kg0.0472 [59]
Vitamin D3 (cholecalciferol)rat, oral37 mg/kg0.037 [60]
Piperidine (from black pepper)rat, oral30 mg/kg0.030 [61]
Heroin (diamorphine)mouse, intravenous21.8 mg/kg0.0218 [62]
Lysergic acid diethylamide (LSD)rat, intravenous16.5 mg/kg0.0165 [63]
Arsenic trioxide (As2O3)rat, oral14 mg/kg0.014 [64]
Metallic arsenic (As)rat, intraperitoneal 13 mg/kg0.013 [65]
Sodium cyanide (NaCN)rat, oral6.4 mg/kg0.0064 [66]
Chlorotoxin (CTX, from scorpions)mice4.3 mg/kg0.0043 [67]
Hydrogen cyanide (HCN)mouse, oral3.7 mg/kg0.0037 [68]
Carfentanil rat, intravenous3.39 mg/kg0.00339 [69]
Nicotine (from various Solanaceae genera)mice, oral3.3 mg/kg0.0033 [57]
White phosphorus (P)rat, oral3.03 mg/kg0.00303 [70]
Strychnine (from Strychnos nux-vomica )human, oral1–2 mg/kg (estimated)0.001–0.002 [71]
Aconitine (from Aconitum napellus and related species)human, oral0.001–0.002 [72]
Mercury(II) chloride (HgCl2)rat, oral1 mg/kg0.001 [73]
Cantharidin (from blister beetles)human, oral500 μg/kg0.0005 [74]
Aflatoxin B1 (from Aspergillus flavus mold)rat, oral480 μg/kg0.00048 [75]
Plutonium (Pu)dog, intravenous320 μg/kg0.00032 [76]
Bufotoxin (from Bufo toads)cat, intravenous0.0003 [77]
Brodifacoum rat, oral270 μg/kg0.00027 [78]
Caesium-137 (137
Cs)		mouse, parenteral0.000245 [79]
Sodium fluoroacetate (CH2FCOONa)rat, oral220 μg/kg0.00022 [80]
Chlorine trifluoride (ClF3)mouse, absorption through skin178 μg/kg0.000178 [81]
Sarin mouse, subcutaneous injection0.000172 [82]
Robustoxin (from Sydney funnel-web spider)mice0.000150 [83]
VX human, oral, inhalation, absorption through skin/eyes0.00014 [84]
Venom of the Brazilian wandering spider rat, subcutaneous0.000134 [85]
Amatoxin (from Amanita phalloides mushrooms)human, oral100 μg/kg0.0001 [86] [87]
Dimethylmercury (Hg(CH3)2)human, transdermal0.000050 [88]
TBPO (t-Butyl-bicyclophosphate)mouse, intravenous36 μg/kg0.000036 [89]
Fentanyl monkey30 μg/kg0.00003 [90]
Venom of the Inland Taipan (Australian snake)rat, subcutaneous0.000025 [91]
Ricin (from castor oil plant)rat, intraperitoneal
rat, oral		0.000022
0.02		 [92]
2,3,7,8-Tetrachlorodibenzodioxin (TCDD, in Agent Orange)rat, oral0.00002
Tetrodotoxin from the blue-ringed octopus intravenous0.0000082 [93]
CrTX-A (from Carybdea rastonii box jellyfish venom)crayfish, intraperitoneal0.000005 [94]
Latrotoxin (from widow spider venom)mice0.0000043 [95] [ self-published source? ]
Epibatidine (from Epipedobates anthonyi poison dart frog)mouse, intravenous1.46-13.98 μg/kg0.00000146 [96]
Batrachotoxin (from poison dart frog)human, sub-cutaneous injection0.000002 [97]
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

[ citation needed ]
Saxitoxin (from certain marine dinoflagellates)human, intravenously

human, oral

0.6 μg/kg

5.7 μg/kg

0.0000006

0.0000057

 [97]
Pacific Ciguatoxin-1 (from ciguateric fish)mice, intraperitoneal250 ng0.00000025 [98]
Palytoxin (from Palythoa coral)mouse, intravenous45 ng/kg

2.3–31.5 μg/kg

0.000000045

0.0000023

 [99]
Maitotoxin (from ciguateric fish)mouse, intraperitoneal 50 ng0.00000005 [100]
Polonium-210 (210
Po)		human, inhalation0.00000001 [101]
Diphtheria toxin (from Corynebacterium )mice0.00000001 [102]
Shiga toxin (from Shigella bacteria)mice0.000000002 [102]
Tetanospasmin (from Clostridium tetani )mice0.000000002 [102]
Botulinum toxin (from Clostridium botulinum )human, oral, injection, inhalation0.000000001 [103]
Ionizing radiation human, irradiation3–5  Gy (Gray)— [104] [105] [106]

Poison scale

Negative values of the decimal logarithm of the median lethal dose LD50 (-log10(LD50)) 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). Poison-Scale-long.jpg
Negative values of the decimal logarithm of the median lethal dose LD50 (−log10(LD50)) 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).

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 −log10(LD50).

The dimensionless value found can be entered in a toxin scale. Water as the baseline substance is neatly 1 in the negative logarithmic toxin scale.

Animal rights concerns

Animal-rights and animal-welfare groups, such as Animal Rights International, [108] 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 (OECD) abolished the requirement for the oral test in 2001 (see Test Guideline 401, Trends in Pharmacological Sciences Vol 22, February 22, 2001).

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). [109] The up-and-down procedure, proposed in 1985, yields an LD50 value while dosing only one animal at a time. [110] [111]

See also

Other measures of toxicity

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References

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  2. ↑ "John William Trevan, 1887-1956". Biographical Memoirs of Fellows of the Royal Society. 3: 273–288. 1957. doi:10.1098/rsbm.1957.0019. ISSN   0080-4606. Archived from the original on 2020-03-28. Retrieved 2024-03-31.
  3. ↑ "What is a LD50 and LC50?". OSH Answers Fact Sheets. Canadian Centre for Occupational Health and Safety. 5 October 2021. Archived from the original on 26 June 2015. Retrieved 15 July 2006.
  4. ↑ "Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX and BOTOX Cosmetic (onabotulinumtoxinA)". Allergan Web site. 24 June 2011. Archived from the original on 26 June 2011. Retrieved 2012-08-15.
  5. ↑ Gaul GM (12 April 2008). "In U.S., Few Alternatives To Testing On Animals". Washington Post . Archived from the original on 2012-11-12. Retrieved 2011-06-26.
  6. ↑ Doris V. Sweet, ed. (July 1997). "Registry of Toxic Effects of Chemical Substances (RTECS) / Comprehensive Guide to the RTECS" (PDF). U.S. Department of Health and Human Services. DHHS (NIOSH) Publication No. 97-119. Archived from the original (PDF) on 2013-05-16.
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  8. ↑ "Therapeutic index | CME at Pharmacology Corner". pharmacologycorner.com. 2011-01-26. Retrieved 2024-07-15.
  9. ↑ "Material Safety Data Sheet Water MSDS". Section 11: Toxicological Information for the LD50 verification. Archived from the original on 2012-09-02. Retrieved 2012-05-09.
  10. ↑ "Safety (MSDS) data for sucrose". ox.ac.uk. Archived from the original on 2011-06-12.
  11. ↑ "Safety (MSDS) data for Corn Syrup". fishersci.com. Archived from the original on 2022-09-21. Retrieved 2022-09-21.
  12. ↑ "Safety (MSDS) data for glucose" (PDF). utoronto.ca. Archived from the original (PDF) on 2017-01-01. Retrieved 2016-12-31.
  13. ↑ Walker R, Lupien JR (April 2000). "The safety evaluation of monosodium glutamate". The Journal of Nutrition. 130 (4S Suppl): 1049S–1052S. doi: 10.1093/jn/130.4.1049S . PMID   10736380.
  14. ↑ Toskulkao C, Chaturat L, Temcharoen P, Glinsukon T (1997). "Acute toxicity of stevioside, a natural sweetener, and its metabolite, steviol, in several animal species". Drug and Chemical Toxicology. 20 (1–2): 31–44. doi:10.3109/01480549709011077. PMID   9183561.
  15. ↑ "Toxicological profile for gasoline" (PDF). U.S. Department of Health and Human Services, Public Health Service Agency for Toxic Substances and Disease Registry. June 1995. p. 47. Archived from the original (PDF) on 2017-05-15. Retrieved 2020-01-05.
  16. ↑ "Safety (MSDS) data for ascorbic acid". Oxford University. 2005-10-09. Archived from the original on 2007-02-09. Retrieved 2007-02-21.
  17. ↑ "Glyphosate-isopropylammonium". PubChem. Archived from the original on 2021-03-02. Retrieved 2019-01-17.
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