Editing Lethal dose

{{Short description|Sufficient amount to kill}}
In [[toxicology]], the '''lethal dose''' ('''LD''') is an indication of the lethal [[toxicity]] of a given substance or type of [[radiation]]. Because resistance varies from one individual to another, the "lethal dose" represents a dose (usually recorded as dose per kilogram of subject body weight) at which a given ''percentage'' of subjects will die. The lethal concentration is a lethal dose measurement used for gases or particulates. The LD may be based on the [[standard person]] concept, a theoretical individual that has perfectly "normal" characteristics, and thus not apply to all sub-populations.

==<span id="LD50"></span>Median lethal dose (LD<sub>50</sub>)==
{{Main article|Median lethal dose}}
The median lethal dose, LD<sub>50</sub> (abbreviation for "lethal dose, 50%"), LC<sub>50</sub> (lethal concentration, 50%) or LCt<sub>50</sub> (lethal concentration and time) of a [[toxin]], [[radiation]], or [[pathogen]] is the [[Dose (pharmacology)|dose]] required to kill half the members of a tested population after a specified test duration. LD<sub>50</sub> figures are frequently used as a general indicator of a substance's [[acute toxicity]].<ref>{{cite journal |vauthors=Gavanji S, Bakhtari A, Famurewa AC, Othman EM |title=Cytotoxic Activity of Herbal Medicines as Assessed in Vitro: A Review |journal=Chemistry & Biodiversity |volume=20 |pages=3–27 |date=January 2023 |issue=2 |pmid=36595710 |doi=10.1002/cbdv.202201098|s2cid=255473013 |doi-access=free }}</ref> A lower LD<sub>50</sub> is indicative of increased toxicity.

=== History ===
The test was created by J.W. Trevan in 1927.<ref>[http://www.ccohs.ca/oshanswers/chemicals/ld50.html What is an LD50 and LC50] {{webarchive|url=https://web.archive.org/web/20150626013647/http://www.ccohs.ca/oshanswers/chemicals/ld50.html |date=2015-06-26 }}</ref> 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 ''sub''lethal dose; because of this ambiguity, it is usually avoided. LD<sub>50</sub> is usually determined by tests on animals such as [[laboratory mice]]. In 2011 the US [[Food and Drug Administration]] approved alternative methods to LD<sub>50</sub> for testing the cosmetic drug [[Botox]] without animal tests.<ref>
{{cite news
 |date        = 12 April 2008
 |title       = In U.S., Few Alternatives To Testing On Animals
 |newspaper   = Washington Post
 |url         = https://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html
 |access-date  = 2011-06-26
 |url-status     = live
 |archive-url  = https://web.archive.org/web/20121112163835/http://www.washingtonpost.com/wp-dyn/content/article/2008/04/11/AR2008041103733.html
 |archive-date = 12 November 2012
}}</ref>

=== Units and measurement ===
The LD<sub>50</sub> is usually expressed as the mass of substance administered per unit mass of test subject, typically as [[milligram]]s of substance per [[kilogram]] of body mass, but stated as nanograms (suitable for [[botulinum]]), micrograms, milligrams, 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 LD<sub>50</sub> is ''not'' the lethal dose for all subjects; some may be killed by much less, while others survive doses far higher than the LD<sub>50</sub>. Measures such as "LD<sub>1</sub>" and "LD<sub>99</sub>" (dosage required to kill 1% or 99%, respectively, of the test population) are occasionally used for specific purposes.<ref>[https://www.cdc.gov/niosh/pdfs/97-119-a.pdf REGISTRY OF TOXIC EFFECTS OF CHEMICAL SUBSTANCES (RTECS)<br>COMPREHENSIVE GUIDE TO THE RTECS] {{webarchive|url=https://web.archive.org/web/20130516165953/http://www.cdc.gov/niosh/pdfs/97-119-a.pdf |date=2013-05-16 }}</ref>

Lethal dosage often varies depending on the method of [[Drug administration|administration]]; for instance, many substances are less toxic when administered orally than when [[Intravenous therapy|intravenously]] administered. For this reason, LD<sub>50</sub> figures are often qualified with the mode of administration, e.g., "LD<sub>50</sub> i.v."

The related quantities LD<sub>50</sub>/30 or LD<sub>50</sub>/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 with [[radiation]], as survival beyond 60 days usually results in recovery.

==== Estimation using model organisms ====
LD values for humans are best estimated by extrapolating results from human [[cell culture]]s. One form of measuring LD is to use [[model organism]]s, particularly animals like mice or rats, converting to dosage per kilogram of biomass, and extrapolating to human norms. The degree of error from animal-extrapolated LD values is large. The biology of test animals differs in important aspects to that of humans. For instance, mouse tissue is approximately fifty times less responsive than human tissue to the venom of the [[Sydney funnel-web spider]]{{Citation needed|date=April 2018}}. The [[square–cube law]] also complicates the scaling relationships involved. Researchers are shifting away from animal-based LD measurements in some instances. The U.S. Food and Drug Administration has begun to approve more non-animal methods in response to animal welfare concerns.<ref>{{Cite web
 |title       = Vision and Roadmap for the 21st Century
 |publisher   = [[National Toxicology Program]]
 |url         = http://ntp.niehs.nih.gov/go/vision
 |access-date  = 2011-10-29
 |url-status     = live
 |archive-url  = https://web.archive.org/web/20081012173524/http://ntp.niehs.nih.gov/go/vision
 |archive-date = 2008-10-12
}}</ref>

=== Median infective dose ===
The median infective dose (ID<sub>50</sub>) 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 LD<sub>50</sub>'s to some test animal. In [[biological warfare]] infective dosage is the number of infective doses per minute for a cubic meter (e.g., ICt<sub>50</sub> is 100 medium doses - min/m<sup>3</sup>).)

==<span id="LDLo"></span>Lowest lethal dose==
The lowest lethal dose (LD<sub>Lo</sub>) is the least amount of drug that can produce death in a given animal species under controlled conditions.<ref>[http://www.ccohs.ca/oshanswers/chemicals/ld50.html What is an LD50 and LC50] {{webarchive|url=https://web.archive.org/web/20150626013647/http://www.ccohs.ca/oshanswers/chemicals/ld50.html |date=2015-06-26 }}</ref><ref>{{cite web
 |date=24 June 2011 
 |title=Allergan Receives FDA Approval for First-of-Its-Kind, Fully in vitro, Cell-Based Assay for BOTOX® and BOTOX® Cosmetic (onabotulinumtoxinA) 
 |publisher=Allergan Web site 
 |url=http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 
 |access-date=2012-08-15 
 |url-status=dead 
 |archive-url=https://web.archive.org/web/20110626185759/http://agn.client.shareholder.com/releasedetail.cfm?ReleaseID=587234 
 |archive-date=26 June 2011 
}}</ref> The dosage is given per unit of bodyweight (typically stated in [[milligram]]s per [[kilogram]]) of a substance known to have resulted in fatality in a particular species. When quoting an LD<sub>Lo</sub>, the particular species and method of administration (''e.g.'' ingested, inhaled, [[intravenous]]) are typically stated.

==<span id="LC50"></span>Median lethal concentration==
For gases and aerosols, lethal concentration (given in mg/m<sup>3</sup> or ppm, parts per million) is the analogous concept, although this also depends on the duration of exposure, which has to be included in the definition. The term incipient lethal level is used to describe a LC<sub>50</sub> value that is independent of time.<ref>{{Cite book|title=Fish Physiology: Euryhaline Fishes, Volume 32|last=Schultz|first=Eric|publisher=Academic Press|year=2013|isbn=978-0-12-396951-4|pages=481–482}}</ref>

A comparable measurement is LCt<sub>50</sub>, which relates to lethal dosage from exposure, where C is concentration and t is time. It is often expressed in terms of mg-min/m<sup>3.</sup> LCt<span style="font-size:100%;"><sub>50</sub></span> 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&nbsp;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&nbsp;mg/m<sup>3</sup> is equivalent to 10 minutes of 10&nbsp;mg/m<sup>3</sup> (1 × 100 = 100, as does 10 × 10 = 100).{{Citation needed|reason=A citation for what? 
There is a Wikipedia article about Haber''s law clearly linked to on the paragraph - please elaborate or remove this citation needed somebody, as I am not sure which to do.   Thank you.  date=April 2016|date=June 2017}}

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 '''LC<sub>50</sub>''' and qualified by a duration of exposure (e.g., 10 minutes). The [[material safety data sheet]]s for toxic substances frequently use this form of the term even if the substance does follow Haber's Law.{{Citation needed|date=April 2016}}

==<span id="LCLo"></span>Lowest lethal concentration==
The LC<sub>Lo</sub> is the lowest concentration of a chemical, given over a period of time, that results in the fatality of an individual animal. LC<sub>Lo</sub> is typically for an acute (<24 hour) exposure.<ref>{{cite book |title = Encyclopedia of Genetics, Genomics, Proteomics and Informatics |url = https://archive.org/details/encyclopediagene12gred |url-access = limited |pages = [https://archive.org/details/encyclopediagene12gred/page/n772 1087] |year = 2008 |isbn = 978-1-4020-6754-9 |publisher = Springer |doi = 10.1007/978-1-4020-6754-9_9257|chapter = LCLo (lethal concentration low) }}</ref><ref>{{cite web |url=http://www.utexas.edu/safety/ehs/msds/glossary/?page=l |title=MSDS Glossary |access-date=2015-05-31 |url-status=dead |archive-url=https://web.archive.org/web/20150621230708/http://www.utexas.edu/safety/ehs/msds/glossary/?page=l |archive-date=2015-06-21 }}</ref> It is related to the LC<sub>50</sub>, the median lethal concentration. The LC<sub>Lo</sub> is used for gases and aerosolized material.<ref>{{cite web |url=http://www.ilpi.com/msds/ref/lclo.html |title=The MSDS HyperGlossary: LC-Lo, Lowest Lethal Concentration |access-date=2015-05-31 |url-status=dead |archive-url=https://web.archive.org/web/20150619091119/http://www.ilpi.com/msds/ref/lclo.html |archive-date=2015-06-19 }}</ref>

== Limitations ==
As a measure of toxicity, lethal dose 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.<ref name="ReferenceA">Ernest Hodgson (2004). ''A Textbook of Modern Toxicology''. Wiley-Interscience (3rd ed.).{{page needed|date=January 2014}}</ref>

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 [[Theobromine poisoning|toxic to many animals]]. When used to test [[venom]] from venomous creatures, such as [[snakes]], LD<sub>50</sub> results may be misleading due to the physiological differences between mice, rats, and humans. Many [[venomous snakes]] are specialized predators of mice, and their venom may be adapted specifically to incapacitate mice; and [[mongoose]]s may be exceptionally resistant. While most [[mammals]] have a very similar physiology, LD<sub>50</sub> results may or may not have equal bearing upon every mammal species, including humans.

== Animal rights concerns ==
[[Animal rights|Animal-rights]] and [[Animal welfare|animal-welfare]] groups, such as Animal Rights International,<ref>[http://www.ari-online.org/main.html Thirty-Two Years of Measurable Change] {{webarchive|url=https://web.archive.org/web/20070211201203/http://www.ari-online.org/main.html |date=2007-02-11 }}</ref> have campaigned against LD<sub>50</sub> testing on animals in particular as, in the case of some substances, causing the animals to die slow, painful deaths. Several countries, including the [[United Kingdom|UK]], have taken steps to ban the oral LD<sub>50</sub>, and the [[Organisation for Economic Co-operation and Development]] (OECD) abolished the requirement for the oral test in 2001.<ref>{{cite journal |title = Death of LD50 |journal = Trends in Pharmacological Sciences |volume = 22 |issue = 2 |pages = 62 |date = February 1, 2001 |first = David |last = Cutler |doi = 10.1016/S0165-6147(00)01627-8}}</ref>

==See also==
{{Columnslist|colwidth=30em|
* [[IDLH]]
* [[Certain safety factor]]
* [[Therapeutic index]]
* [[Protective index]]
* [[Fixed-dose procedure]] to estimate LD<sub>50</sub>
* [[Median lethal dose]], LD<sub>50</sub>
* [[Median toxic dose]] (TD<sub>50</sub>)
* [[Lowest published toxic concentration]] (TCLo)
* [[EC50|EC<sub>50</sub>]] (half maximal effective concentration)
* [[IC50|IC<sub>50</sub>]] (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]]
* [[TCID50|TCID<sub>50</sub>]] Tissue Culture Infective Dosage
* EID<sub>50</sub> Egg Infective Dosage
* ELD<sub>50</sub> Egg Lethal Dosage
* [[Plaque forming units]] (pfu)
}}

== References ==
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{{Toxicology}}

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[[Category:Causes of death]]
[[Category:Concentration indicators]]
[[Category:Medical emergencies]]
[[Category:Toxicology]]