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64-456: The term LD 50 is generally attributed to John William Trevan. 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 . In 2011, the U.S. Food and Drug Administration approved alternative methods to LD 50 for testing

128-506: A 2014 study from McGill University which suggests that mice handled by men rather than women showed higher stress levels. Another study in 2016 suggested that gut microbiomes in mice may have an impact upon scientific research. The worldwide market for gene-altered mice is predicted to grow to $ 1.59 billion by 2022, growing at a rate of 7.5 percent per year. Taxonomy Cf. The abbreviation cf. (short for either Latin confer or conferatur , both meaning 'compare')

192-550: 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

256-556: A dark brown, nearly black coat. They are more sensitive to noise and odours and are more likely to bite than the more docile laboratory strains such as BALB/c . Group-housed C57BL/6 mice (and other strains) display barbering behaviour, which used to be seen as a sign of dominance. However, it is now known that this is more of a stereotypical behaviour triggered by stress, comparable to trichotillomania in humans or feather plucking in parrots. Mice that have been barbered extensively can have large bald patches on their bodies, commonly around

320-469: 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 (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

384-447: A good model for early-stage AD because they show amyloidogenesis and working memory impairments linked to age but do not show neuronal degeneration. The absence of cell death suggests that changes in typical cellular signaling cascades involved in learning and synaptic plasticity are probably linked to the memory phenotype. Associative learning impairments are exacerbated when Tg2576 mice are crossed with PS1 transgenic animals that possess

448-463: A lower neutrophil enzymatic capacity, lower activity of the complement system , and a different set of pentraxins involved in the inflammatory process ; and lack genes for important components of the immune system, such as IL-8 , IL-37 , TLR10 , ICAM-3 , etc. Laboratory mice reared in specific-pathogen-free (SPF) conditions usually have a rather immature immune system with a deficit of memory T cells . These mice may have limited diversity of

512-405: A number of researchers. Regarding experiments on mice, some researchers have complained that "years and billions of dollars have been wasted following false leads" as a result of a preoccupation with the use of these animals in studies. Mice differ from humans in several immune properties: mice are more resistant to some toxins than humans; have a lower total neutrophil fraction in the blood ,

576-407: A possible identity, or at least a significant resemblance, such as between a newly observed specimen and a known species or taxon . Such a usage might suggest a specimen's membership of the same genus or possibly of a shared higher taxon. For example, in the note " Diptera: Tabanidae , cf. Tabanus ", the author is confident of the order and family ( Diptera : Tabanidae ) but can only suggest

640-535: A single breeding pair. Inbred mice have several traits that make them ideal for research purposes. They are isogenic , meaning that all animals are nearly genetically identical. Approximately 98.7% of the genetic loci in the genome are homozygous , so there are probably no "hidden" recessive traits that could cause problems. They also have very unified phenotypes due to this stability. Many inbred strains have well documented traits that make them ideal for specific types of research. The following table shows

704-634: A standard for their care and use. Compliance with the PHS is required for a research project to receive federal funding. PHS policy is administered by the Office of Laboratory Animal Welfare. Many academic research institutes seek accreditation voluntarily, often through the Association for Assessment and Accreditation of Laboratory Animal Care , which maintains the standards of care found within The Guide for

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768-525: A tunnel or cupped hands is advocated. In behavioural tests, tail-handled mice show less willingness to explore and to investigate test stimuli, as opposed to tunnel-handled mice which readily explore and show robust responses to test stimuli. In nature, mice are usually herbivores , consuming a wide range of fruit or grain. However, in laboratory studies it is usually necessary to avoid biological variation and to achieve this, laboratory mice are almost always fed only commercial pelleted mouse feed. Food intake

832-416: 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 has an LD 50 value of more than 90 g/kg; 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

896-632: Is 20 days. A fertile postpartum estrus occurs 14–24 hours following parturition , and simultaneous lactation and gestation prolongs gestation by 3–10 days owing to delayed implantation. The average litter size is 10–12 during optimum production, but is highly strain-dependent. As a general rule, inbred mice tend to have longer gestation periods and smaller litters than outbred and hybrid mice. The young are called pups and weigh 0.5–1.5 g (0.018–0.053 oz) at birth, are hairless, and have closed eyelids and ears. Pups are weaned at 3 weeks of age when they weigh about 10–12 g (0.35–0.42 oz). If

960-484: 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. 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 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

1024-430: Is a group in which all members are as nearly as possible genetically identical. In laboratory mice, this is accomplished through inbreeding . By having this type of population, it is possible to conduct experiments on the roles of genes, or conduct experiments that exclude genetic variation as a factor. In contrast, outbred populations are used when identical genotypes are unnecessary or a population with genetic variation

1088-526: 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 mammalian research model and are used for research in genetics , physiology , psychology , medicine and other scientific disciplines . Mice belong to the Euarchontoglires clade, which includes humans . This close relationship,

1152-410: Is also possible. Each route has a recommended injection site, approximate needle gauge and recommended maximum injected volume at a single time at one site, as given in the table below: To facilitate intravenous injection into the tail, laboratory mice can be carefully warmed under heat lamps to vasodilate the vessels. A common regimen for general anesthesia for the house mouse is ketamine (in

1216-531: Is an albino laboratory-bred strain from which a number of common substrains are derived. With over 200 generations bred since 1920, BALB/c mice are distributed globally and are among the most widely used inbred strains used in animal experimentation . BALB/c are noted for displaying high levels of anxiety and for being relatively resistant to diet-induced atherosclerosis , making them a useful model for cardiovascular research. Male BALB/c mice are aggressive and will fight other males if housed together. However,

1280-465: Is approximately 15 g (0.53 oz) per 100 g (3.5 oz) of body weight per day; water intake is approximately 15 ml (0.53 imp fl oz; 0.51 US fl oz) per 100 g of body weight per day. Routes of administration of injections in laboratory mice are mainly subcutaneous , intraperitoneal and intravenous . Intramuscular administration is not recommended due to small muscle mass. Intracerebral administration

1344-421: Is commonly placed between the genus name and the species name to describe a specimen that is hard to identify because of practical difficulties, such as poor preservation. For example, " Barbus cf. holotaenia " indicates that the specimen is in the genus Barbus and believed to be Barbus holotaenia , but the actual species-level identification cannot be certain. Cf. can also be used to express

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1408-496: Is more useful to compare such substances by therapeutic index , 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, {bracketed}, when appropriate. human, smoking human, inhalation human, oral 3.3 μg/kg 10–1000 μg/kg 0.0000033 0.00001–0.001 human, oral 5.7 μg/kg 0.0000057 2.3–31.5 μg/kg 0.0000023 The LD 50 values have

1472-608: Is required, and are usually referred to as stocks rather than strains . Over 400 standardized, inbred strains have been developed. Most laboratory mice are hybrids of different subspecies, most commonly of Mus musculus domesticus and Mus musculus musculus . Laboratory mice can have a variety of coat colours, including agouti, black and albino . Many (but not all) laboratory strains are inbred. The different strains are identified with specific letter-digit combinations; for example C57BL/6 and BALB/c . The first such inbred strains were produced in 1909 by Clarence Cook Little , who

1536-425: Is spontaneous. The duration of the estrous cycle is 4–5 days and lasts about 12 hours, occurring in the evening. Vaginal smears are useful in timed matings to determine the stage of the estrous cycle. Mating can be confirmed by the presence of a copulatory plug in the vagina up to 24 hours post-copulation. The presence of sperm on a vaginal smear is also a reliable indicator of mating. The average gestation period

1600-953: Is the Tg2576 strain of mice. The K670M and N671L double mutations seen in the human 695 splice-variant of the amyloid precursor protein (APP) are expressed by this strain. A hamster prion protein gene promoter , predominantly in neurons, drives the expression. When compared to non-transgenic littermates, Tg2576 mice show a five-fold rise in Aβ40 and a 10- to 15-fold increase in Aβ42/43. These mice develop senile plaques linked to cellular inflammatory responses because their brains have approximately five times as much transgenic mutant human APP than indigenous mouse APP. The mice exhibit main characteristics of Alzheimer's disease (AD), such as increased generation of amyloid fibrils with aging, plaque formation, and impaired hippocampus learning and memory. Tg2576 mice are

1664-498: Is unusually sensitive to pain and to cold, and analgesic medications are less effective in this strain. Unlike most laboratory mouse strains, the C57BL/6 drinks alcoholic beverages voluntarily. It is more susceptible than average to morphine addiction , atherosclerosis , and age-related hearing loss . When compared directly to BALB/c mice, C57BL/6 mice also express both a robust response to social rewards and empathy. BALB/c

1728-405: 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 only to suggest a comparison, and the words "see" or " vide " be used generally to point to a source of information. In Italian , the abbreviation "cfr." ( confronta , 'confront') is more common than "cf." is. In biological naming conventions, cf.

1792-681: The American Veterinary Medical Association issued new guidelines for CO 2 induction, stating that a flow rate of 10% to 30% volume/min is optimal for euthanasing laboratory mice. A recent study detected a murine astrovirus in laboratory mice held at more than half of the US and Japanese institutes investigated. Murine astrovirus was found in nine mice strains, including NSG , NOD-SCID , NSG-3GS , C57BL6 - Timp-3 , uPA-NOG , B6J , ICR, Bash2 , and BALB/C , with various degrees of prevalence. The pathogenicity of

1856-478: The microbiota , which directly affects the immune system and the development of pathological conditions. Moreover, persistent virus infections (for example, herpesviruses ) are activated in humans, but not in SPF mice with septic complications and may change the resistance to bacterial coinfections . "Dirty" mice are possibly better suitable for mimicking human pathologies. In addition, inbred mouse strains are used in

1920-544: The white-footed mouse ( Peromyscus leucopus ) and the North American deer mouse ( Peromyscus maniculatus ). Mice have been used in biomedical research since the 17th century when William Harvey used them for his studies on reproduction and blood circulation and Robert Hooke used them to investigate the biological consequences of an increase in air pressure. During the 18th century Joseph Priestley and Antoine Lavoisier both used mice to study respiration . In

1984-428: The 19th century Gregor Mendel carried out his early investigations of inheritance on mouse coat color but was asked by his superior to stop breeding in his cell "smelly creatures that, in addition, copulated and had sex". He then switched his investigations to peas but, as his observations were published in a somewhat obscure botanical journal, they were virtually ignored for over 35 years until they were rediscovered in

Median lethal dose - Misplaced Pages Continue

2048-662: The 20th and 21st Centuries. The Jackson Laboratory in Bar Harbor, Maine is currently one of the world's largest suppliers of laboratory mice, at around 3 million mice a year. The laboratory is also the world's source for more than 8,000 strains of genetically defined mice and is home of the Mouse Genome Informatics database. Breeding onset occurs at about 50 days of age in both females and males, although females may have their first estrus at 25–40 days. Mice are polyestrous and breed year round; ovulation

2112-507: The A246E FAD mutation. This crosses promotes the build-up of amyloid and plaque development in the CNS. This lends credence to the theory that AD pathogenesis is influenced by the interplay between APP and PS-1 gene products. Although Tg2576 mice do not perfectly replicate late-stage AD with cell death, they do offer a platform for researching the physiology and biochemistry of the illness.With

2176-456: The BALB/Lac substrain is much more docile. Most BALB/c mice substrains have a long reproductive life-span. There are noted differences between different BALB/c substrains, though these are thought to be due to mutation rather than genetic contamination. The BALB/cWt is unusual in that 3% of progeny display true hermaphroditism . A useful model for Alzheimer's disease (AD) in the lab

2240-607: The Care and Use of Laboratory Animals and the PHS policy. This accreditation is, however, not a prerequisite for federal funding, unlike the actual compliance. While mice are by far the most widely used animals in biomedical research, recent studies have highlighted their limitations. For example, the utility of rodents in testing for sepsis , burns , inflammation , stroke , ALS , Alzheimer's disease , diabetes , cancer , multiple sclerosis , Parkinson's disease , and other illnesses has been called into question by

2304-453: The LD 50 . The earliest was the 1927 "conventional" procedure by Trevan, which requires 40 or more animals. The fixed-dose procedure , proposed in 1984, estimates a level of toxicity by feeding at defined doses and looking for signs of toxicity (without requiring death). The up-and-down procedure , proposed in 1985, yields an LD 50 value while dosing only one animal at a time. Laboratory mouse The laboratory mouse or lab mouse

2368-744: The U.K. are published each year. In the U.K. in 2013, there were a total of 3,077,115 regulated procedures undertaken on mice in scientific procedure establishments, licensed under the Act. In the U.S., laboratory mice are not regulated under the Animal Welfare Act administered by the USDA APHIS . However, the Public Health Service Act (PHS) as administered by the National Institutes of Health does offer

2432-459: The ability to accurately extrapolate findings to humans. Researchers have also noted that many studies involving mice are poorly designed, leading to questionable findings. Some studies suggests that inadequate published data in animal testing may result in irreproducible research, with missing details about how experiments are done are omitted from published papers or differences in testing that may introduce bias. Examples of hidden bias include

2496-452: The associated high homology with humans, their ease of maintenance and handling, and their high reproduction rate, make mice particularly suitable models for human-oriented research. The laboratory mouse genome has been sequenced and many mouse genes have human homologues. Lab mice are sold at pet stores for snake food and can also be kept as pets . Other mouse species sometimes used in laboratory research include two American species,

2560-751: The baseline substance is neatly 1 in the negative logarithmic toxin scale. Animal-rights and animal-welfare groups, such as Animal Rights International, have campaigned against LD 50 testing on animals. Several countries, including the UK , have taken steps to ban the oral LD 50 , 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). A number of procedures have been defined to derive

2624-547: The closest non- primate relatives of humans along with lagomorphs , treeshrews , and flying lemurs . Rodentia (rodents) Lagomorpha (rabbits, hares, pikas) Scandentia (treeshrews) Dermoptera (flying lemurs) Primates († Plesiadapiformes , Strepsirrhini , Haplorrhini ) Laboratory mice are the same species as the house mouse ; however, they are often very different in behaviour and physiology . There are hundreds of established inbred , outbred , and transgenic strains. A strain , in reference to rodents,

Median lethal dose - Misplaced Pages Continue

2688-460: The cosmetic drug Botox without animal tests. The LD 50 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

2752-776: The design and execution of the tests themselves. In addition, the caging of laboratory animals may render them irrelevant models of human health because these animals lack day-to-day variations in experiences, agency, and challenges that they can overcome. The impoverished environments inside small mouse cages can have deleterious influences on biomedical results, especially with respect to studies of mental health and of systems that depend upon healthy psychological states. For example, researchers have found that many mice in laboratories are obese from excess food and minimal exercise, which alters their physiology and drug metabolism. Many laboratory animals, including mice, are chronically stressed, which can also negatively affect research outcomes and

2816-495: 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 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). As a measure of toxicity, LD 50 is somewhat unreliable and results may vary greatly between testing facilities due to factors such as

2880-438: The dose of 100 mg per kg body weight) plus xylazine (in the dose of 5–10 mg per kg), injected by the intraperitoneal route. It has a duration of effect of about 30 minutes. Approved procedures for euthanasia of laboratory mice include compressed CO 2 gas, injectable barbiturate anesthetics , inhalable anesthetics, such as Halothane, and physical methods, such as cervical dislocation and decapitation. In 2013,

2944-486: The early 20th century. In 1902 Lucien Cuénot published the results of his experiments using mice which showed that Mendel's laws of inheritance were also valid for animals — results that were soon confirmed and extended to other species. In the early part of the 20th century, Harvard undergraduate Clarence Cook Little was conducting studies on mouse genetics in the laboratory of William Ernest Castle . Little and Castle collaborated closely with Abbie Lathrop who

3008-457: The earthquake strength using the Richter scale , the pH value , as a measure for the acidic or basic character of an aqueous solution or of loudness in decibels . In this case, the negative decimal logarithm of the LD 50 values, which is standardized in kg per kg body weight, is considered −log 10 (LD 50 ) . The dimensionless value found can be entered in a toxin scale. Water as

3072-472: The female does not mate during the postpartum estrus, she resumes cycling 2–5 days post-weaning. Newborn males are distinguished from newborn females by noting the greater anogenital distance and larger genital papilla in the male. This is best accomplished by lifting the tails of littermates and comparing perinea . Mice are mammals of the clade (a group consisting of an ancestor and all its descendants) Euarchontoglires , which means they are amongst

3136-519: The genetic characteristics of the sample population, animal species tested, environmental factors and mode of administration. 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 , LD 50 results may be misleading due to

3200-413: The genus ( Tabanus ) and has no information favouring a particular species. Among numismatists (coin collector-research specialists), cf. may be used in references on the paper and/or online coin identification information meaning "compare to". It is common for abbreviations of listings in trusted coin catalogues or sales from certain online auctions to be cited when identifying a particular coin. If

3264-399: The head, snout, and shoulders, although barbering may appear anywhere on the body. Also self-barbering can occure. Both hair and vibrissae may be removed. Barbering is more frequently seen in female mice; male mice are more likely to display dominance through fighting. C57BL/6 has several unusual characteristics which make it useful for some research studies but inappropriate for others: It

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3328-506: The help of transgenic mouse models, researchers can make progress in AD research by understanding the intricate relationships between gene products that are involved in the production of Aβ peptide.e physiology and biochemistry of the illness. Traditionally, laboratory mice have been picked up by the base of the tail. However, recent research has shown that this type of handling increases anxiety and aversive behaviour. Instead, handling mice using

3392-399: The many available strains includes - Since 1998, it has been possible to clone mice from cells derived from adult animals. There are many strains of mice used in research, however, inbred strains are usually the animals of choice for most fields. Inbred mice are defined as being the product of at least 20 generations of brother X sister mating, with all individuals being derived from

3456-612: The method of administration ; for instance, many substances are less toxic when administered orally than when intravenously 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 , for ionizing radiation , as survival beyond 60 days usually results in recovery. A comparable measurement

3520-570: The murine astrovirus was not known. In the U.K., as with all other vertebrates and some invertebrates, any scientific procedure which is likely to cause "pain, suffering, distress or lasting harm" is regulated by the Home Office under the Animals (Scientific Procedures) Act 1986 . U.K. regulations are considered amongst the most comprehensive and rigorous in the world. Detailed data on the use of laboratory mice (and other species) in research in

3584-514: The overwhelming majority of studies, while the human population is heterogeneous, pointing to the importance of studies in interstrain hybrid, outbred , and nonlinear mice. An article in The Scientist notes, "The difficulties associated with using animal models for human disease result from the metabolic, anatomic, and cellular differences between humans and other creatures, but the problems go even deeper than that" including issues with

3648-409: The physical and behavioural characteristics of house mice; however, due to many generations of artificial selection, some of these characteristics now vary markedly. Due to the large number of strains of laboratory mice, it is impractical to comprehensively describe the appearance and behaviour of all of them; however, they are described below for two of the most commonly used strains. C57BL/6 mice have

3712-566: 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, LD 50 results may or may not have equal bearing upon every mammal species, such as humans, etc. 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

3776-408: The size of the human genome. Estimating the number of genes contained in the mouse genome is difficult, in part because the definition of a gene is still being debated and extended. The current count of primary coding genes in the laboratory mouse is 23,139. compared to an estimated 20,774 in humans. Various mutant strains of mice have been created by a number of methods. A small selection from

3840-640: The top 10 most popular strains according to Jackson Laboratories . The Jackson Labs DO ( Diversity Outbred ) project is a mouse breeding program using multiple inbred founder strains to create a genetically diverse population of mice for use in scientific research. These mice are designed for fine genetic mapping , and capture a large portion of the genetic diversity of the mouse genome. This project has resulted in over 1,000 genetically diverse mice which have been used to identify genetic factors for diseases such as obesity, cancer, diabetes, and alcohol use disorder. Laboratory mice have retained many of

3904-420: 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

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3968-495: Was a breeder of fancy mice and rats which she marketed to rodent hobbyists and keepers of exotic pets, and later began selling in large numbers to scientific researchers. Together they generated the DBA (Dilute, Brown and non-Agouti) inbred mouse strain and initiated the systematic generation of inbred strains. The mouse has since been used extensively as a model organism and is associated with many important biological discoveries of

4032-432: 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/m is equivalent to 10 minutes of 10 mg/m (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. In these cases, the lethal concentration may be given simply as LC 50 and qualified by

4096-512: Was influential in promoting the mouse as a laboratory organism. In 2011, an estimated 83% of laboratory rodents supplied in the U.S. were C57BL/6 laboratory mice. Sequencing of the laboratory mouse genome was completed in late 2002 using the C57BL/6 strain. This was only the second mammalian genome to be sequenced after humans. The haploid genome is about three billion base pairs long (3,000 Mb distributed over 19 autosomal chromosomes plus 1 respectively 2 sex chromosomes), therefore equal to

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