Median lethal dose explained

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.

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, 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. ICt

₅₀ 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,, when appropriate.

Substance	Animal, route	class=unsortable	LD50	data-sort-type="number"	LD50 : g/kg standardised	class=unsortable	Reference
Water	rat, oral	>90,000 mg/kg	>90	^[9]
Sucrose (table sugar)	rat, oral	29,700 mg/kg	29.7	^[10]
Corn Syrup	rat, oral	25,800 mg/kg	25.8	^[11]
Glucose (blood sugar)	rat, oral	25,800 mg/kg	25.8	^[12]
Monosodium glutamate (MSG)	rat, oral	16,600 mg/kg	16.6	^[13]
Stevioside (from stevia)	mice and rats, oral	15,000 mg/kg	15	^[14]
Gasoline (petrol)	rat	14,063 mg/kg	14.0	^[15]
Vitamin C (ascorbic acid)	rat, oral	11,900 mg/kg	11.9	^[16]
Glyphosate (isopropylamine salt of)	rat, oral	10,537 mg/kg	10.537	^[17]
Lactose (milk sugar)	rat, oral	10,000 mg/kg	10	^[18]
Aspartame	mice, oral	10,000 mg/kg	10	^[19]
Urea	rat, oral	8,471 mg/kg	8.471	^[20]
Cyanuric acid	rat, oral	7,700 mg/kg	7.7	^[21]
Cadmium sulfide (CdS)	rat, oral	7,080 mg/kg	7.08	^[22]
Ethanol	rat, oral	7,060 mg/kg	7.06	^[23]
Sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin)	rat, oral	6,860 mg/kg	6.86	^[24]
Melamine	rat, oral	6,000 mg/kg	6
Taurine	rat, oral	5,000 mg/kg	5	^[25]
Melamine cyanurate	rat, oral	4,100 mg/kg	4.1
Fructose (fruit sugar)	rat, oral	4,000 mg/kg	4	^[26]
Sodium molybdate	rat, oral	4,000 mg/kg	4	^[27]
Sodium chloride (table salt)	rat, oral	3,000 mg/kg	3	^[28]
Paracetamol (acetaminophen)	rat, oral	1,944 mg/kg	1.944	^[29]
Delta-9-tetrahydrocannabinol (THC)	rat, oral	1,270 mg/kg	1.27	^[30]
Cannabidiol (CBD)	rat, oral	980 mg/kg	0.98	^[31]
Methanol	human, oral	810 mg/kg	0.81	^[32]
Arsenic (As)	rat, oral	763 mg/kg	0.763	^[33]
Ibuprofen	rat, oral	636 mg/kg	0.636	^[34]
Formaldehyde	rat, oral	600–800 mg/kg	0.6	^[35]
Solanine (main alkaloid in the several plants in Solanaceae amongst them Solanum tuberosum)	rat, oral (2.8 mg/kg human, oral)	590 mg/kg	0.590	^[36]
Alkyl dimethyl benzalkonium chloride (ADBAC)	rat, oral fish, immersion aquatic invertebrates, immersion	304.5 mg/kg	0.3045	^[37]
Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants)	rat, oral	293 mg/kg	0.293	^[38]
Psilocybin (from magic mushrooms)	mouse, oral	280 mg/kg	0.280	^[39]
Hydrochloric acid (HCl)	rat, oral	238–277 mg/kg	0.238	^[40]
Ketamine	rat, intraperitoneal	229 mg/kg	0.229	^[41]
Aspirin (acetylsalicylic acid)	rat, oral	200 mg/kg	0.2	^[42]
Caffeine	rat, oral	192 mg/kg	0.192	^[43]
Arsenic trisulfide	rat, oral	185–6,400 mg/kg	0.185–6.4	^[44]
Sodium nitrite	rat, oral	180 mg/kg	0.18	^[45]
Methylenedioxymethamphetamine (MDMA, ecstasy)	rat, oral	160 mg/kg	0.18	^[46]
Uranyl acetate dihydrate	mouse, oral	136 mg/kg	0.136	^[47]
Dichlorodiphenyltrichloroethane (DDT)	mouse, oral	135 mg/kg	0.135	^[48]
Uranium (U)	mice, oral	114 mg/kg (estimated)	0.114
Bisoprolol	mouse, oral	100 mg/kg	0.1	^[49]
Cocaine	mouse, oral	96 mg/kg	0.096	^[50]
Cobalt(II) chloride	rat, oral	80 mg/kg	0.08	^[51]
Cadmium oxide (CdO)	rat, oral	72 mg/kg	0.072	^[52]
Thiopental sodium (used in lethal injection)	rat, oral	64 mg/kg	0.064	^[53]
Demeton-S-methyl	rat, oral	60 mg/kg	0.060	^[54]
Methamphetamine	rat, intraperitoneal	57 mg/kg	0.057	^[55]
Sodium fluoride (NaF)	rat, oral	52 mg/kg	0.052	^[56]
Nicotine	mouse and rat, oralhuman, smoking	50 mg/kg	0.05	^[57]
Pentaborane	human, oral	50 mg/kg	0.05	^[58]
Capsaicin	mouse, oral	47.2 mg/kg	0.0472	^[59]
Vitamin D3 (cholecalciferol)	rat, oral	37 mg/kg	0.037	^[60]
Piperidine (from black pepper)	rat, oral	30 mg/kg	0.030	^[61]
Heroin (diamorphine)	mouse, intravenous	21.8 mg/kg	0.0218	^[62]
Lysergic acid diethylamide (LSD)	rat, intravenous	16.5 mg/kg	0.0165	^[63]
Arsenic trioxide	rat, oral	14 mg/kg	0.014	^[64]
Metallic arsenic (As)	rat, intraperitoneal	13 mg/kg	0.013	^[65]
Sodium cyanide (NaCN)	rat, oral	6.4 mg/kg	0.0064	^[66]
Chlorotoxin (CTX, from scorpions)	mice	4.3 mg/kg	0.0043	^[67]
Hydrogen cyanide (HCN)	mouse, oral	3.7 mg/kg	0.0037	^[68]
Carfentanil	rat, intravenous	3.39 mg/kg	0.00339	^[69]
Nicotine (from various Solanaceae genera)	mice, oral	3.3 mg/kg	0.0033
White phosphorus (P)	rat, oral	3.03 mg/kg	0.00303	^[70]
Strychnine (from Strychnos nux-vomica)	human, oral	1–2 mg/kg (estimated)	0.001–0.002	^[71]
Aconitine (from Aconitum napellus and related species)	human, oral	1–2 mg/kg	0.001–0.002	^[72]
Mercury(II) chloride	rat, oral	1 mg/kg	0.001	^[73]
Cantharidin (from blister beetles)	human, oral	500 μg/kg	0.0005	^[74]
Aflatoxin B1 (from Aspergillus flavus mold)	rat, oral	480 μg/kg	0.00048	^[75]
Plutonium (Pu)	dog, intravenous	320 μg/kg	0.00032	^[76]
Bufotoxin (from Bufo toads)	cat, intravenous	300 μg/kg	0.0003	^[77]
Brodifacoum	rat, oral	270 μg/kg	0.00027	^[78]
Caesium-137	mouse, parenteral	21.5 μCi/g	0.000245	^[79]
Sodium fluoroacetate	rat, oral	220 μg/kg	0.00022	^[80]
Chlorine trifluoride (ClF3)	mouse, absorption through skin	178 μg/kg	0.000178	^[81]
Sarin	mouse, subcutaneous injection	172 μg/kg	0.000172	^[82]
Robustoxin (from Sydney funnel-web spider)	mice	150 μg/kg	0.000150	^[83]
VX	human, oral, inhalation, absorption through skin/eyes	140 μg/kg (estimated)	0.00014	^[84]
Venom of the Brazilian wandering spider	rat, subcutaneous	134 μg/kg	0.000134	^[85]
Amatoxin (from Amanita phalloides mushrooms)	human, oral	100 μg/kg	0.0001	^[86] ^[87]
Dimethylmercury	human, transdermal	50 μg/kg	0.000050	^[88]
TBPO (t-Butyl-bicyclophosphate)	mouse, intravenous	36 μg/kg	0.000036	^[89]
Fentanyl	monkey	30 μg/kg	0.00003	^[90]
Venom of the Inland Taipan (Australian snake)	rat, subcutaneous	25 μg/kg	0.000025	^[91]
Ricin (from castor oil plant)	rat, intraperitoneal rat, oral	22 μg/kg 20–30 mg/kg	0.000022 0.02	^[92]
2,3,7,8-Tetrachlorodibenzodioxin (TCDD, in Agent Orange)	rat, oral	20 μg/kg	0.00002
Tetrodotoxin from the blue-ringed octopus	intravenous	8.2 μg/kg	0.0000082	^[93]
CrTX-A (from Carybdea rastonii box jellyfish venom)	crayfish, intraperitoneal	5 μg/kg	0.000005	^[94]
Latrotoxin (from widow spider venom)	mice	4.3 μg/kg	0.0000043	^[95]
Epibatidine (from Epipedobates anthonyi poison dart frog)	mouse, intravenous	1.46-13.98 μg/kg	0.00000146	^[96]
Batrachotoxin (from poison dart frog)	human, sub-cutaneous injection	2–7 μg/kg (estimated)	0.000002	^[97]
Abrin (from rosary pea)	mice, intravenouslyhuman, inhalation human, oral	0.7 μg/kg3.3 μg/kg 10–1000 μg/kg	0.00000070.0000033 0.00001–0.001
Saxitoxin (from certain marine dinoflagellates)	human, intravenouslyhuman, oral	0.6 μg/kg5.7 μg/kg	0.00000060.0000057
Pacific Ciguatoxin-1 (from ciguateric fish)	mice, intraperitoneal	250 ng/kg	0.00000025	^[98]
Palytoxin (from Palythoa coral)	mouse, intravenous	45 ng/kg2.3–31.5 μg/kg	0.0000000450.0000023	^[99]
Maitotoxin (from ciguateric fish)	mouse, intraperitoneal	50 ng/kg	0.00000005	^[100]
Polonium-210	human, inhalation	10 ng/kg (estimated)	0.00000001	^[101]
Diphtheria toxin (from Corynebacterium)	mice	10 ng/kg	0.00000001	^[102]
Shiga toxin (from Shigella bacteria)	mice	2 ng/kg	0.000000002
Tetanospasmin (from Clostridium tetani)	mice	2 ng/kg	0.000000002
Botulinum toxin (from Clostridium botulinum)	human, oral, injection, inhalation	1 ng/kg (estimated)	0.000000001	^[103]
Ionizing radiation	human, irradiation	3–5 Gy (Gray)	—	^[104] ^[105] ^[106]

Poison scale

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 .

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,^[107] 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).^[108] The up-and-down procedure, proposed in 1985, yields an LD50 value while dosing only one animal at a time.^{[109] [110]}

See also

• Animal testing
• Reed-Muench method
• The dose makes the poison – the toxicology adage that high quantities of any substance is lethal

Other measures of toxicity

• IDLH
• Certain safety factor
• Therapeutic index
• Protective index
• Median toxic dose (TD50)
• Lowest published lethal dose (LDLo)
• EC₅₀ (half maximal effective concentration)
• IC₅₀ (half maximal inhibitory concentration)
• Draize test
• Indicative limit value
• No-observed-adverse-effect level (NOAEL)
• Lowest-observed-adverse-effect level (LOAEL)

Related measures

• TCID₅₀ Tissue Culture Infective Dosage
• Plaque forming units (pfu)

Further reading

• Lipnick RL, Cotruvo JA, Hill RN, Bruce RD, Stitzel KA, Walker AP, Chu I, Goddard M, Segal L, Springer JA . Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures . Food and Chemical Toxicology . 33 . 3 . 223–231 . March 1995 . 7896233 . 10.1016/0278-6915(94)00136-C .

External links

• Canadian Centre for Occupational Health and Safety

Notes and References

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