半数致死量（はんすうちしりょう、median lethal dose）とは、物質の急性毒性の指標、致死量の一種としてしばしば使われる数値で、投与した動物の半数が死亡する用量をいう。"Lethal Dose, 50%"を略してLD50と書く。
概要
通常は動物の体重1kg当たりの投与重量mg（mg/kg）で表示する。また水生動物やガス・粉塵の吸入による投与の場合には濃度（単位はppmなど）で表示し、LC50（半数致死濃度 "Lethal Concentration, 50%"の略）と書く。当然ながら投与経路（経口、経皮、場合によっては静脈注射など）により数値は大きく異なる。
LC50はppmまたはmg/m3であらわされる。シアン化水素などのように蒸気密度が空気に近い気体であれば両者の数値はほぼ同値であるが、蒸気密度の大きな気体の場合、mg/m3の方が大きな数値を取る。LD50と異なり、LC50は吸入時間が分からなければその物質の毒性を知る上で重要な情報が欠けていることになる。情報源によっては毒性試験の際の吸入時間を明記せずに濃度のみを記載しているが、10分値と4時間値では（自然に解毒されない蓄積性の物質の場合）24倍の差があることになる。
注射・吸入の両方で同様に毒性が発現する物質であっても、LD50とLC50の換算には固定的な値はない。この理由としてはLC50は呼吸量によって大きく左右されることが挙げられる。動物種によっても呼吸量は異なり（大きい動物ほど体重あたりの呼吸量は少ない傾向がある）、同じ動物種でも安静時と興奮時では数倍の差がある。このため、測定値のぶれが大きいが、LD50の1 mg/kg当たりのLC50は10～500 mg/m3/1時間に収まることが多い。ただし一部の化学物質では、経口・注射ではそれほど強い毒性がないが、吸入した場合は肺水腫など呼吸器障害を起こす作用が強い場合があるため、LD50から予測される割にLC50が低い値をとることもある。
毒物及び劇物取締法における毒物・劇物の指定は半数致死量を基準としており、例えば経口投与の場合はLD50=50 mg/kg以下程度を毒物、LD50=300 mg/kg以下程度を劇物としている。
半数致死量を求めるには、1用量当たり数頭の動物を用いて数用量で試験し、ロジスティック回帰などの統計的方法により算出するが、誤差が大きいので信頼区間などとともに表示する必要がある。また供試動物数を少なくして上下法（1頭ずつ投与し、その結果に応じて次の動物に上または下の用量で投与していく）でおよその数値を求めることもある。
現在では、半数致死量を正確に求めることは科学的に意味がないこと、また供試動物をなるべく削減する動物福祉の観点から、半数致死量を求めずに、ある用量より上か下かだけを見る方法（固定用量法）が多くの毒性試験ガイドラインで採られている。
関連項目
- 致死量
- 動物実験
- 毒性学
- 毒
- 急性毒性試験
- TLm
- ICt50
- 動物実験代替法
"LD50" redirects here. For other uses, see LD50 (disambiguation).
In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a measure of the lethal dose of a toxin, radiation, or pathogen. 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 increased 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.[2][3]
Contents
- 1 Conventions
- 2 Limitation
- 3 Examples
- 4 Animal rights concerns
- 5 See also
- 5.1 Other measures of toxicity
- 5.2 Related measures
- 6 References
- 7 External links
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).
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, 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.
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 |
>7004900000000000000♠90g/kg |
>90 |
[6] |
| Sucrose (table sugar) |
rat, oral |
7004297000000000000♠29,700 mg/kg |
29.7 |
[7] |
| Monosodium glutamate (MSG) |
rat, oral |
7004166000000000000♠16,600 mg/kg |
16.6 |
[8] |
| Vitamin C (ascorbic acid) |
rat, oral |
7004119000000000000♠11,900 mg/kg |
11.9 |
[9] |
| Urea |
rat, oral |
7003847100000000000♠8,471 mg/kg |
11.5 |
[10] |
| Cyanuric acid |
rat, oral |
7003770000000000000♠7,700 mg/kg |
7.7 |
[11] |
| cadmium sulfide |
rat, oral |
7003708000000000000♠7,080 mg/kg |
7.08 |
[12] |
| Grain alcohol (ethanol) |
rat, oral |
7003706000000000000♠7,060 mg/kg |
7.06 |
[13] |
| sodium isopropyl methylphosphonic acid (IMPA, metabolite of sarin) |
rat, oral |
7003686000000000000♠6,860 mg/kg |
6.86 |
[14] |
| Melamine |
rat, oral |
7003600000000000000♠6,000 mg/kg |
6 |
[11] |
| Melamine cyanurate |
rat, oral |
7003410000000000000♠4,100 mg/kg |
4.1 |
[11] |
| Sodium molybdate |
rat, oral |
4,000 mg/kg |
4 |
[15] |
| Table Salt |
rat, oral |
3,000 mg/kg |
3 |
[16] |
| Paracetamol (acetaminophen) |
rat, oral |
1,944 mg/kg |
1.944 |
[17] |
| Delta-9-tetrahydrocannabinol (THC) |
rat, oral |
1,270 mg/kg |
1.27 |
[18] |
| Metallic Arsenic |
rat, oral |
763 mg/kg |
0.763 |
[19] |
| 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} |
[20] |
| Coumarin (benzopyrone, from Cinnamomum aromaticum and other plants) |
rat, oral |
293 mg/kg |
0.293 |
[21] |
| Aspirin (acetylsalicylic acid) |
rat, oral |
200 mg/kg |
0.2 |
[22] |
| Caffeine |
rat, oral |
192 mg/kg |
0.192 |
[23] |
| Arsenic trisulfide |
rat, oral |
185–6,400 mg/kg |
0.185-6.4 |
[24] |
| Sodium nitrite |
rat, oral |
180 mg/kg |
0.18 |
[25] |
| uranyl acetate dihydrate |
mouse, oral |
136 mg/kg |
0.136 |
[26] |
| Bisoprolol |
mouse, oral |
100 mg/kg |
0.1 |
[27] |
| Cobalt(II) chloride |
rat, oral |
80 mg/kg |
0.08 |
[28] |
| Cadmium oxide |
rat, oral |
72 mg/kg |
0.072 |
[29] |
| Sodium fluoride |
rat, oral |
52 mg/kg |
0.052 |
[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] |
| Nicotine |
human, oral |
6.5-13.0 mg/kg (estimated) |
0.0065-0.013 |
[37] |
| Sodium cyanide |
rat, oral |
6.4 mg/kg |
0.0064 |
[38] |
| White phosphorus |
rat, oral |
3.03 mg/kg |
0.00303 |
[39] |
| Strychnine |
human, oral |
1–2 mg/kg (estimated) |
0.001 |
[40] |
| Cantharidin |
human, oral |
0.5 mg/kg |
0.0005 |
|
| Aflatoxin B1 (from Aspergillus flavus) |
rat, oral |
0.48 mg/kg |
0.00048 |
[41] |
| Venom of the Brazilian wandering spider |
rat, subcutaneous |
6999134000000000000♠134 µg/kg |
0.000134 |
[42] |
| Venom of the Inland Taipan (Australian snake) |
rat, subcutaneous |
6998250000000000000♠25 µg/kg |
0.000025 |
[43] |
| Ricin |
rat, intraperitoneal
rat, oral |
6998220000000000000♠22 μg/kg
20–30 mg/kg |
0.000022
0.02 |
[44] |
| 2,3,7,8-Tetrachlorodibenzodioxin (TCDD, a dioxin) |
rat, oral |
6998200000000000000♠20 µg/kg |
0.00002 |
[45] |
| Sarin |
mouse, subcutaneous injection |
6998172309999900000♠17.23 µg/kg (estimated) |
0.0000172 |
[46] |
| VX |
human, oral, inhalation, absorption through skin/eyes |
6997230000000000000♠2.3 µg/kg (estimated) |
0.0000023 |
[47] |
| Batrachotoxin (from poison dart frog) |
human, sub-cutaneous injection |
6997200000000000000♠2-7 µg/kg (estimated) |
0.000002 |
[48] |
| Abrin |
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
|
|
| Maitotoxin |
mouse, intraperitoneal |
6996129990000099999♠0.13 µg/kg |
0.00000013 |
[49] |
| Polonium-210 |
human, inhalation |
6995100000000000000♠10 ng/kg (estimated) |
0.00000001 |
[50] |
| Botulinum toxin (Botox) |
human, oral, injection, inhalation |
6994100000000000000♠1 ng/kg (estimated) |
0.000000001 |
[51] |
| Ionizing radiation |
human, irradiation |
6 Gy |
|
[citation needed] |
Animal rights concerns
Animal-rights and animal-welfare groups, such as Animal Rights International,[52] 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 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).
See also
- Animal testing
- Reed-Muench method
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. 24 June 2011. Retrieved 2012-08-15.
- ^ "In U.S., Few Alternatives To Testing On Animals". Washington Post. 12 April 2008. Retrieved 2011-06-26.
- ^ REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (RTECS)
COMPREHENSIVE GUIDE TO THE RTECS
- ^ Ernest Hodgson (2004). A Textbook of Modern Toxicology. Wiley-Interscience (3rd ed.).[page needed]
- ^ "Material Safety Data Sheet Water MSDS". 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. [dead link]
- ^ "Safety (MSDS) data for urea". 2015-03-06. Section 11: Toxicological Information for the LD50 verification. Retrieved 2015-03-06.
- ^ 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
- ^ Mecler, Francis J. (May 1981). Mammalian Toxological Evaluation of DIMP and DCBP (Phase 3 - IMPA) (Final report ed.). Litton Bionetics, Inc.
The oral LD50 values for the test material, IMPA, were 7650 and 6070 mg/kg for male and female rats, respectively.
- ^ 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
- ^ [1][dead link]
- ^ Frank T. Sanders, ed. (August 2006). Reregistration Eligibility Decision for Alkyl Dimethyl Benzyl Ammonium Chloride (ADBAC) (PDF) (Report). U.S. Environmental Protection Agency Office of Prevention, Pesticides, and Toxic Substances. p. 114. Retrieved 2009-03-31.
- ^ Coumarin Material Safety Data Sheet (MSDS)
- ^ Safety (MSDS) data for acetylsalicylic acid
- ^ Safety (MSDS) data for caffeine
- ^ "MATERIAL SAFETY DATA SHEET - Spent Metal Catalyst" (PDF). Archived from the original (PDF) on 2011-09-28.
- ^ Safety (MSDS) data for sodium nitrite
- ^ Chemical toxicity of uranium
- ^ DrugBank data for bisoprolol
- ^ Safety (MSDS) data for cobalt (II) chloride
- ^ Safety (MSDS) data for cadmium oxide
- ^ Sodium Fluoride MSDS
- ^ Pentaborane chemical and safety data
- ^ "Capsaicin Material Safety Data Sheet" (PDF). sciencelab.com. 2007. Retrieved 2007-07-13.
- ^ http://www.sigmaaldrich.com/catalog/DisplayMSDSContent.doc
- ^ 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
- ^ Mayer B (January 2014). "How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century". Archives of Toxicology 88 (1): 5–7. doi:10.1007/s00204-013-1127-0. PMC 3880486. PMID 24091634.
- ^ Safety (MSDS) data for sodium cyanide
- ^ "Hexachloroethane" (PDF). Retrieved 2014-01-03.
- ^ INCHEM: Chemical Safety Information from Intergovernmental Organizations: Strychnine.
- ^ Safety (MSDS) data for aflatoxin B1
- ^ Venomous Animals and their Venoms, vol. III, ed. Wolfgang Bücherl and Eleanor Buckley
- ^ 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
- ^ 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; Segal, L; Springer, J.A.; Myers, R.C. (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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Concepts in pharmacology
|
|
| Pharmacokinetics |
- (L)ADME: (Liberation)
- Absorption
- Distribution
- Metabolism
- Excretion (Clearance)
- Loading dose
- Volume of distribution (Initial)
- Rate of infusion
- Compartment
- Bioequivalence
- Bioavailability
- Onset of action
- Biological half-life
- Plasma protein binding
- Therapeutic index (Median lethal dose, Effective dose)
|
|
| Pharmacodynamics |
- Toxicity (Neurotoxicology)
- Dose–response relationship (Efficacy, Potency)
- Antimicrobial pharmacodynamics: Minimum inhibitory concentration (Bacteriostatic)
- Minimum bactericidal concentration (Bactericide)
|
|
Agonism and
antagonism |
- Agonist: Inverse agonist
- Irreversible agonist
- Partial agonist
- Superagonist
- Physiological agonist
- Antagonist: Competitive antagonist
- Irreversible antagonist
- Physiological antagonist
- Other: Binding
- Affinity
- Binding selectivity
- Functional selectivity
|
|
| Other |
- Drug tolerance: Tachyphylaxis
- Drug resistance: Antibiotic resistance
- Multiple drug resistance
|
|
Drug discovery
strategies |
|
|
Related
fields/subfields |
- Pharmacogenetics
- Pharmacogenomics
- Neuropsychopharmacology (Neuropharmacology, Psychopharmacology)
|
|
|
Toxicology
|
|
- History of poison
- Toxinology
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| Fields |
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- Ecotoxicology
- Occupational toxicology
- Entomotoxicology
- Environmental toxicology
- Forensic toxicology
- Medical toxicology
- In vitro toxicology
- Toxicogenomics
|
|
| Concepts |
- Acceptable daily intake
- Acute toxicity
- Bioaccumulation
- Biomagnification
- Fixed Dose Procedure
- Lethal dose
- Poison
- Toxic capacity
- Toxicant
- Toxicity Class
- Venom
|
|
| Treatments |
- Activated carbon
- Antidote
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- Hemodialysis
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- Whole bowel irrigation
|
|
| Incidents |
- 1858 Bradford sweets poisoning
- 2007 pet food recalls
- Bhopal disaster
- Minamata disease
- Niigata Minamata disease
- Poisoning of Alexander Litvinenko
- Seveso disaster
- List of poisonings
|
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