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 lethal dose (LD) is an indication of the lethal
toxicity
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subst ...
of a given substance or type of
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 ...
. 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 The standard person or reference person is a theoretical individual that has perfectly "normal" characteristics. This model is used for much research into radiation safety. For many years, the standard person was called reference man because the w ...
concept, a theoretical individual that has perfectly "normal" characteristics, and thus not apply to all sub-populations.
Median lethal dose (LD50)
The median lethal dose, LD
50 (abbreviation for "lethal dose, 50%"), LC
50 (lethal concentration, 50%) or LCt
50 (lethal concentration and time) 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 ...
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.
History
The test was created by J.W. Trevan in 1927. 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
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 US
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.
Units and measurement
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, but stated as nanograms (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 ...
), micrograms, milligrams, or grams (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.
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 with
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 ...
, 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
Cell culture or tissue culture is the process by which cells are grown under controlled conditions, generally outside of their natural environment. The term "tissue culture" was coined by American pathologist Montrose Thomas Burrows. This te ...
s. One form of measuring LD is to use
model organism
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...
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
The Sydney funnel-web spider (''Atrax robustus'') is a species of venomous Mygalomorphae, mygalomorph spider native to eastern Australia, usually found within a radius of Sydney. It is a member of a group of spiders known as Australian funnel- ...
. The
square–cube law
The square–cube law (or cube–square law) is a mathematical principle, applied in a variety of scientific fields, which describes the relationship between the volume and the surface area as a shape's size increases or decreases. It was first ...
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.
Median infective dose
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
50's 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. Bio ...
infective dosage is the number of infective doses per minute for a cubic meter (e.g., ICt
50 is 100 medium doses - min/m
3).)
Lowest lethal dose
The lowest lethal dose (LD
Lo) is the least amount of drug that can produce death in a given animal species under controlled conditions. The dosage is given per unit of bodyweight (typically stated in
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 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 a substance known to have resulted in fatality in a particular species. When quoting an LD
Lo, the particular species and method of administration (''e.g.'' ingested, inhaled,
intravenous
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 ...
) are typically stated.
Median lethal concentration
For gases and aerosols, lethal concentration (given in mg/m
3 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
50 value that is independent of time.
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. LCt
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.
Lowest lethal concentration
The LC
Lo is the lowest concentration of a chemical, given over a period of time, that results in the fatality of an individual animal. LC
Lo is typically for an acute (<24 hour) exposure. It is related to the LC
50, the median lethal concentration. The LC
Lo is used for gases and aerosolized material.
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.
[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.''
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
snakes
Snakes are elongated, limbless, carnivorous reptiles of the suborder Serpentes . Like all other squamates, snakes are ectothermic, amniote vertebrates covered in overlapping scales. Many species of snakes have skulls with several more joi ...
, LD
50 results may be misleading due to the physiological differences between mice, rats, and humans. Many
venomous snakes
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 gr ...
are specialized predators of 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
mammals
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 ...
have a very similar physiology, LD
50 results may or may not have equal bearing upon every mammal species, including humans.
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, have campaigned against LD
50 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 LD
50, 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 also
References
{{DEFAULTSORT:Lethal Dose
Concentration indicators
Medical emergencies
Toxicology