In
toxicology
Toxicology is a scientific discipline, overlapping with biology, chemistry, pharmacology, and medicine, that involves the study of the adverse effects of chemical substances on living organisms and the practice of diagnosing and treating expo ...
, the median lethal dose, LD
50 (abbreviation for "
lethal dose
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 kilog ...
, 50%"), LC
50 (lethal concentration, 50%) or LCt
50 is a
toxic unit Toxic units (TU) are used in the field of toxicology to quantify the interactions of toxicants in binary mixtures of chemicals. A toxic unit for a given compound is based on the concentration at which there is a 50% effect (ex. EC50) for a certain b ...
that measures the
lethal dose
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 kilog ...
of a
toxin
A toxin is a naturally occurring organic poison produced by metabolic activities of living cells or organisms. Toxins occur especially as a protein or conjugated protein. The term toxin was first used by organic chemist Ludwig Brieger (1849– ...
,
radiation
In physics, radiation is the emission or transmission of energy in the form of waves or particles through space or through a material medium. This includes:
* ''electromagnetic radiation'', such as radio waves, microwaves, infrared, visi ...
, or
pathogen
In biology, a pathogen ( el, πάθος, "suffering", "passion" and , "producer of") in the oldest and broadest sense, is any organism or agent that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ ...
. The value of LD
50 for a substance is the
dose required to kill half the members of a tested population after a specified test duration. LD
50 figures are frequently used as a general indicator of a substance's
acute toxicity
Acute toxicity describes the adverse effects of a substance that result either from a single exposure or from multiple exposures in a short period of time (usually less than 24 hours). To be described as ''acute'' toxicity, the adverse effect ...
. A lower LD
50 is indicative of increased toxicity.
The test was created by J.W. Trevan in 1927. 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. LD
50 is usually determined by tests on animals such as
laboratory mice
The laboratory mouse or lab mouse is a small mammal of the order Rodentia which is bred and used for scientific research or feeders for certain pets. Laboratory mice are usually of the species ''Mus musculus''. They are the most commonly used ...
. In 2011, the U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
approved alternative methods to LD
50 for testing the cosmetic drug
Botox
Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium '' Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromus ...
without animal tests.
Conventions
The LD
50 is usually expressed as the mass of substance administered per unit mass of test subject, typically as
milligram
The kilogram (also kilogramme) is the unit of mass in the International System of Units (SI), having the unit symbol kg. It is a widely used measure in science, engineering and commerce worldwide, and is often simply called a kilo colloquially. ...
s of substance per
kilogram
The kilogram (also kilogramme) is the unit of mass in the International System of Units (SI), having the unit symbol kg. It is a widely used measure in science, engineering and commerce worldwide, and is often simply called a kilo colloquially ...
of body mass, sometimes also stated as
nanogram
To help compare different orders of magnitude, the following lists describe various mass levels between 10−59 kg and 1052 kg. The least massive thing listed here is a graviton, and the most massive thing is the observable universe ...
s (suitable for
botulinum
Botulinum toxin, or botulinum neurotoxin (BoNT), is a neurotoxic protein produced by the bacterium ''Clostridium botulinum'' and related species. It prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromusc ...
),
microgram
In the metric system, a microgram or microgramme is a unit of mass equal to one millionth () of a gram. The unit symbol is μg according to the International System of Units (SI); the recommended symbol in the United States and United Kingdom whe ...
s, or
gram
The gram (originally gramme; SI unit symbol g) is a Physical unit, unit of mass in the International System of Units (SI) equal to one one thousandth of a kilogram.
Originally defined as of 1795 as "the absolute weight of a volume of pure wate ...
s (suitable for
paracetamol
Paracetamol, also known as acetaminophen, is a medication used to treat fever and mild to moderate pain. Common brand names include Tylenol and Panadol.
At a standard dose, paracetamol only slightly decreases body temperature; it is inferior ...
) 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 LC
50. 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 LD
50 is not the lethal dose for all subjects; some may be killed by much less, while others survive doses far higher than the LD
50. Measures such as "LD
1" and "LD
99" (dosage required to kill 1% or 99%, respectively, of the test population) are occasionally used for specific purposes.
Lethal dosage often varies depending on the method of
administration
Administration may refer to:
Management of organizations
* Management, the act of directing people towards accomplishing a goal
** Administrative assistant, Administrative Assistant, traditionally known as a Secretary, or also known as an admini ...
; for instance, many substances are less toxic when administered orally than when
intravenously
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
administered. For this reason, LD
50 figures are often qualified with the mode of administration, e.g., "LD
50 i.v."
The related quantities LD
50/30 or LD
50/60 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
Health physics, also referred to as the science of radiation protection, is the profession devoted to protecting people and their environment from potential radiation hazards, while making it possible to enjoy the beneficial uses of radiation. H ...
, as survival beyond 60 days usually results in recovery.
A comparable measurement is LCt
50, 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
3. 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
Chemical warfare (CW) involves using the toxic properties of chemical substances as weapons. This type of warfare is distinct from nuclear warfare, biological warfare and radiological warfare, which together make up CBRN, the military acronym ...
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
Fritz Haber (; 9 December 186829 January 1934) was a German chemist who received the Nobel Prize in Chemistry in 1918 for his invention of the Haber–Bosch process, a method used in industry to synthesize ammonia from nitrogen gas and hydroge ...
and is sometimes referred to as
Haber's law
In toxicology, Haber's rule or Haber's law is a mathematical statement of the relationship between the concentration of a poisonous gas and how long the gas must be breathed to produce death, or other toxic effect. The rule was formulated by Germa ...
, which assumes that exposure to 1 minute of 100 mg/m
3 is equivalent to 10 minutes of 10 mg/m
3 (1 × 100 = 100, as does 10 × 10 = 100).
Some chemicals, such as
hydrogen cyanide
Hydrogen cyanide, sometimes called prussic acid, is a chemical compound with the formula HCN and structure . It is a colorless, extremely poisonous, and flammable liquid that boils slightly above room temperature, at . HCN is produced on an ...
, 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
50 and qualified by a duration of exposure (e.g., 10 minutes). The
Material Safety Data Sheet
A safety data sheet (SDS), material safety data sheet (MSDS), or product safety data sheet (PSDS) is a document that lists information relating to occupational safety and health for the use of various substances and products. SDSs are a widel ...
s 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 (ID
50) 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
50s to some test animal. In
biological warfare
Biological warfare, also known as germ warfare, is the use of biological toxins or infectious agents such as bacteria, viruses, insects, and fungi with the intent to kill, harm or incapacitate humans, animals or plants as an act of war. ...
infective dosage is the number of infective doses per cubic metre of air times the number of minutes of exposure (e.g., ICt
50 is 100 medium doses - min/m
3).
Limitation
As a measure of toxicity, LD
50 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.
[Ernest Hodgson (2004). ''A Textbook of Modern Toxicology''. Wiley-Interscience (3rd ed.).]
There can be wide variability between species as well; what is relatively safe for rats may very well be extremely toxic for humans (''
cf.
The abbreviation ''cf.'' (short for the la, confer/conferatur, both meaning "compare") is used in writing to refer the reader to other material to make a comparison with the topic being discussed. Style guides recommend that ''cf.'' be used onl ...
''
paracetamol toxicity
Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These include f ...
), and vice versa. For example, chocolate, comparatively harmless to humans, is known to be
toxic to many animals. When used to test
venom
Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...
from venomous creatures, such as
snake
Snakes are elongated, Limbless vertebrate, limbless, carnivore, carnivorous reptiles of the suborder Serpentes . Like all other Squamata, squamates, snakes are ectothermic, amniote vertebrates covered in overlapping Scale (zoology), scales. Ma ...
s, LD
50 results may be misleading due to the physiological differences between mice, rats, and humans. Many
venomous snake
Venomous snakes are species of the suborder Serpentes that are capable of producing venom, which they use for killing prey, for defense, and to assist with digestion of their prey. The venom is typically delivered by injection using hollow or g ...
s are specialized predators on mice, and their venom may be adapted specifically to incapacitate mice; and
mongoose
A mongoose is a small terrestrial carnivorous mammal belonging to the family Herpestidae. This family is currently split into two subfamilies, the Herpestinae and the Mungotinae. The Herpestinae comprises 23 living species that are native to so ...
s may be exceptionally resistant. While most
mammal
Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...
s have a very similar physiology, LD
50 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 LD
50 can be misleading in many cases due (in part) to differences in
effective dose (ED
50). Therefore, it is more useful to compare such substances by
therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
, which is simply the ratio of LD
50 to ED
50.
The following examples are listed in reference to LD
50 values, in descending order, and accompanied by LC
50 values, , when appropriate.
Poison scale
![Poison-Scale-long](https://upload.wikimedia.org/wikipedia/commons/2/29/Poison-Scale-long.jpg)
The LD
50 values have a very wide range. The
botulinum toxin as the most toxic substance known has an LD
50 value of 1 ng/kg, while the most non-toxic substance
water
Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a ...
has an LD
50 value of more than 90 g/kg. That's 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 Richter scale —also called the Richter magnitude scale, Richter's magnitude scale, and the Gutenberg–Richter scale—is a measure of the strength of earthquakes, developed by Charles Francis Richter and presented in his landmark 1935 ...
, the
pH value
In chemistry, pH (), historically denoting "potential of hydrogen" (or "power of hydrogen"), is a scale used to specify the acidity or basicity of an aqueous solution. Acidic solutions (solutions with higher concentrations of ions) are ...
, as a measure for the acidic or basic character of an aqueous solution or of
loudness
In acoustics, loudness is the subjectivity, subjective perception of sound pressure. More formally, it is defined as, "That attribute of auditory sensation in terms of which sounds can be ordered on a scale extending from quiet to loud". The rel ...
in
decibel
The decibel (symbol: dB) is a relative unit of measurement equal to one tenth of a bel (B). It expresses the ratio of two values of a power or root-power quantity on a logarithmic scale. Two signals whose levels differ by one decibel have a po ...
s.
In this case, the negative decimal logarithm of the LD
50 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
Animal rights is the philosophy according to which many or all sentient animals have moral worth that is independent of their utility for humans, and that their most basic interests—such as avoiding suffering—should be afforded the sa ...
and
animal-welfare groups, such as Animal Rights International,
Thirty-Two Years of Measurable Change
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
The Organisation for Economic Co-operation and Development (OECD; french: Organisation de coopération et de développement économiques, ''OCDE'') is an intergovernmental organization, intergovernmental organisation with 38 member countries ...
(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
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
* Reed-Muench method
* The dose makes the poison
"The dose makes the poison" ( la, dosis sola facit venenum 'only the dose makes the poison') is an adage intended to indicate a basic principle of toxicology. It is credited to Paracelsus who expressed the classic toxicology maxim "All things a ...
– the toxicology adage that high quantities of any substance is lethal
Other measures of toxicity
* IDLH
The term immediately dangerous to life or health (IDLH) is defined by the US National Institute for Occupational Safety and Health (NIOSH) as exposure to airborne contaminants that is "likely to cause death or immediate or delayed permanent advers ...
* Certain safety factor
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
* Therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
* Protective index
* Fixed Dose Procedure The fixed-dose procedure (FDP), proposed in 1992 by the British Toxicology Society, is a method to assess a substance's acute oral toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can dama ...
to estimate LD50
* Median toxic dose In toxicology, the median toxic dose (TD50) of a drug or toxin is the dose at which toxicity occurs in 50% of cases. The ''type'' of toxicity should be specified for this value to have meaning for practical purposes. The median toxic dose encompasse ...
(TD50)
* Lowest published lethal dose (LDLo)
* EC50 (half maximal effective concentration)
* IC50 (half maximal inhibitory concentration)
* Draize test
The Draize test is an acute toxicity test devised in 1944 by Food and Drug Administration (FDA) toxicologists John H. Draize and Jacob M. Spines. Initially used for testing cosmetics, the procedure involves applying 0.5 mL or 0.5 g of ...
* Indicative limit value
* No-observed-adverse-effect level The no-observed-adverse-effect level (NOAEL) denotes the level of exposure of an organism, found by experiment or observation, at which there is no biologically or statistically significant increase in the frequency or severity of any adverse effe ...
(NOAEL)
* Lowest-observed-adverse-effect level
The lowest-observed-adverse-effect level (LOAEL), or the lowest-observed-adverse-effect concentration (LOAEC), is the lowest concentration or amount of a substance found by experiment or observation that causes an adverse alteration of morphology, ...
(LOAEL)
* Up-and-down procedure Up-and-down procedure (or method) for toxicology tests in medicine is an alternative to the test, in which animals are used for acute toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can d ...
Related measures
* TCID50 Tissue Culture Infective Dosage
* Plaque forming units
A plaque-forming unit (PFU) is a measure used in virology to describe the number of virus particles capable of forming plaques per unit volume. It is a proxy measurement rather than a measurement of the absolute quantity of particles: viral part ...
(pfu)
References
External links
Canadian Centre for Occupational Health and Safety
*
{{DEFAULTSORT:Median Lethal Dose
Animal testing
Concentration indicators
Mathematics in medicine
Toxicology