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] 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 U.S. Food and Drug Administration approved alternative methods to LD50 for testing the cosmetic drug BOTOX.[2][3]
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 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).
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, 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 be directly relevant to humans.
A low LD50 in animals is always a cause for concern for humans, but a high animal value does not guarantee that a substance is similarly harmful to humans.
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] |
| 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 | [13] |
| Table Salt | rat, oral | 3,000 mg/kg | 3 | [14] |
| Paracetamol (acetaminophen) | rat, oral | 1,944 mg/kg | 1.944 | [15] |
| Delta-9-tetrahydrocannabinol (THC) | rat, oral | 1,270 mg/kg | 1.270 | [16] |
| Metallic Arsenic | rat, oral | 763 mg/kg | 0.763 | [17] |
| 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} | [18] |
| Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) | rat, oral | 293 mg/kg | 0.293 | [19] |
| Aspirin (acetylsalicylic acid) | rat, oral | 200 mg/kg | 0.2 | [20] |
| Caffeine | rat, oral | 192 mg/kg | 0.192 | [21] |
| Arsenic trisulfide | rat, oral | 185–6,400 mg/kg | 0.185 | [22] |
| Sodium nitrite | rat, oral | 180 mg/kg | 0.18 | [23] |
| Bisoprolol | mouse, oral | 100 mg/kg | 0.1 | [24] |
| Cobalt(II) chloride | rat, oral | 80 mg/kg | 0.08 | [25] |
| Cadmium oxide | rat, oral | 72 mg/kg | 0.072 | [26] |
| Sodium fluoride | rat, oral | 52 mg/kg | 0.052 | [27] |
| Nicotine | rat, oral mice, oral | 50 mg/kg 3.3 mg/kg | 0.05 0.0033 | [28] [29] |
| Pentaborane | human, oral | <50 mg/kg | <0.05 | [30] |
| Capsaicin | mouse, oral | 47.2 mg/kg | 0.0472 | [31] |
| Mercury(II) chloride | rat, dermal | 41 mg/kg | 0.041 | [32] |
| Lysergic acid diethylamide (LSD) | rat, intravenous | 16.5 mg/kg | 0.0165 | [33] |
| Arsenic trioxide | rat, oral | 14 mg/kg | 0.014 | [34] |
| Metallic Arsenic | rat, intraperitoneal | 13 mg/kg | 0.013 | [35] |
| Sodium cyanide | rat, oral | 6.4 mg/kg | 0.0064 | [36] |
| White phosphorus | rat, oral | 3.03 mg/kg | 0.00303 | [37] |
| Strychnine | human, oral | 1–2 mg/kg(estimated) | 0.001 | [38] |
| Cantharidin | human, oral | 0.5 mg/kg | 0.0005 | |
| Aflatoxin B1 (from Aspergillus flavus) | rat, oral | 0.48 mg/kg | 0.00048 | [39] |
| Venom of the Inland Taipan (Australian snake) | rat, subcutaneous | 25 µg/kg | 0.000025 | [40] |
| Ricin | rat, intraperitoneal rat, oral | 22 μg/kg 20–30 mg/kg | 0.000022 0.02 | [41] |
| Dioxin (TCDD) | rat, oral | 20 µg/kg | 0.00002 | [42] |
| Sarin | mouse, subcutaneous injection | 17.23 µg/kg (estimated) | 0.0000172 | [43] |
| VX | human, oral, inhalation, absorption through skin/eyes | 2.3 µg/kg (estimated) | 0.0000023 | [44] |
| Batrachotoxin (from poison dart frog) | human, sub-cutaneous injection | 2-7 µg/kg (estimated) | 0.000002 | [45] |
| Venom of Hydrophis belcheri (Belcher's Sea Snake) | mouse, intraperitoneal | 0.25 µg/kg | 0.00000025 | [46] |
| Maitotoxin | mouse, intraperitoneal | 0.13 µg/kg | 0.00000013 | [47] |
| Polonium-210 | human, inhalation | 10 ng/kg (estimated) | 0.00000001 | [48] |
| Botulinum toxin (Botox) | human, oral, injection, inhalation | 1 ng/kg (estimated) | 0.000000001 | [49] |
| Ionizing radiation | human, irradiation | 3-6 Gy |
Animal rights concerns
Animal-rights and animal-welfare groups, such as Animal Rights International,[50] 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
- IDLH
- Certain safety factor
- Therapeutic index
- Protective index
- Fixed Dose Procedure to estimate LD50
- Median toxic dose (TD50)
- Lowest published toxic concentration (TCLo)
- 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)
- Up-and-down procedure
Related measures
- TCID50 Tissue Culture Infective Dosage
- EID50 Egg Infective Dosage
- ELD50 Egg Lethal Dosage
- Plaque forming units (pfu)
References
- ^ What is an LD50 and LC50
- ^ "Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX® and BOTOX® Cosmetic (onabotulinumtoxinA)". Allergan Web site. Page last updated 24 June 2011. Retrieved 2012-08-15.
- ^ "In U.S., Few Alternatives To Testing On Animals". Washington Post. Page last updated 12 April 2008. Retrieved 2011-06-26.
- ^ REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (RTECS)
COMPREHENSIVE GUIDE TO THE RTECS - ^ Ernest Hodgson - A Textbook of Modern Toxicology; Wiley-Interscience 2004 (3rd Edition)
- ^ [1] - see to Section 11: Toxicological Information for the LD50 verification
- ^ Safety (MSDS) data for sucrose
- ^ Walker R, Lupien JR (April 2000). "The safety evaluation of monosodium glutamate". Journal of Nutrition 130 (4S Suppl): 1049S–52S. PMID 10736380.
- ^ "Safety (MSDS) data for ascorbic acid". Oxford University. 2005-10-09. Retrieved 2007-02-21.
- ^ a b c A.A. Babayan, A.V.Aleksandryan, "Toxicological characteristics of melamine cyanurate, melamine and cyanuric acid", Zhurnal Eksperimental'noi i Klinicheskoi Meditsiny, Vol.25, 345-9 (1985). Original article in Russian.
- ^ Advanced Search - Alfa Aesar - A Johnson Matthey Company. Alfa.com. Retrieved on 2013-07-17.
- ^ Safety (MSDS) data for ethyl alcohol
- ^ Safety (MSDS) data for sodium molybdate
- ^ Safety (MSDS) data for sodium chloride
- ^ Safety (MSDS) data for 4-acetamidophenol
- ^ LD50 values of THC in fischer rats
- ^ [2]
- ^ Frank T. Sanders, ed. (August 2006). Reregistration Eligibility Decision for Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) (Report). U.S. Environmental Protection Agency Office of Prevention, Pesticides, and Toxic Substances. pp. 114. Retrieved 2009-03-31.
- ^ Coumarin Material Safety Data Sheet (MSDS)
- ^ Safety (MSDS) data for acetylsalicylic acid
- ^ Safety (MSDS) data for caffeine
- ^ [3]
- ^ Safety (MSDS) data for sodium nitrite
- ^ DrugBank data for bisoprolol
- ^ Safety (MSDS) data for cobalt (II) chloride
- ^ Safety (MSDS) data for cadmium oxide
- ^ Sodium Fluoride MSDS
- ^ Safety (MSDS) data for nicotine
- ^ IPCS INCHEM
- ^ Pentaborane chemical and safety data
- ^ "Capsaicin Material Safety Data Sheet" (PDF). sciencelab.com. 2007. Retrieved 2007-07-13.
- ^
- ^ Erowid LSD (Acid) Vault : Fatalities / Deaths. Erowid.org. Retrieved on 2013-07-17.
- ^ Safety (MSDS) data for arsenic trioxide
- ^ Safety (MSDS) data for metallic arsenic
- ^ Safety (MSDS) data for sodium cyanide
- ^
- ^ INCHEM: Chemical Safety Information from Intergovernmental Organizations:Strychnine.
- ^ Safety (MSDS) data for aflatoxin B1
- ^ LD50 for various snakes. Seanthomas.net. Retrieved on 2013-07-17.
- ^ 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.
- ^ U.S. National Toxicology Program acute toxicity studies for Dioxin (2,3,7,8-TCDD)
- ^ Histochemical Demonstration of Calcium Accumulation in Muscle Fibres after Experimental Organophosphate Poisoning. Het.sagepub.com (1990-07-01). Retrieved on 2013-07-17.
- ^ Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection
- ^ Brief Review of Natural Nonprotein Neurotoxins
- ^ The Deadliest Snakes in the World | The Steve Irwin Mosaic Tribute Project. Crikeymatemosaic.wordpress.com (2006-10-17). Retrieved on 2013-07-17.
- ^ Yokoyama, Akihiro; Murata, Michio; Oshima, Yasukatsu; Iwashita, Takashi; Yasumoto, Takeshi (1988). "Some Chemical Properties of Maitotoxin, a Putative Calcium Channel Agonist Isolated from a MarineDinoflagellate". J. Biochem. 104 (2): 184–187. PMID 3182760.
- ^ Topic 2 Toxic Chemicals and Toxic Effects
- ^ Fleming, Diane O.; Hunt, Debra Long (2000). Biological Safety: principles and practices. Washington, DC: ASM Press. p. 267. ISBN 1-55581-180-9.
- ^ Thirty-Two Years of Measurable Change
External links
- Canadian Centre for Occupational Health and Safety
- Lipnick, RL; Cotruvo, JA; Hill, RN; Bruce, RD; Stitzel, KA; Walker, AP; Chu, I; Goddard, M et al. (1995). "Comparison of the up-and-down, conventional LD50, and fixed-dose acute toxicity procedures". Food and chemical toxicology 33 (3): 223–31. doi:10.1016/0278-6915(94)00136-C. PMID 7896233.
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