Mushroom poisoning

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Mushroom_poisoning 

 

Mushroom poisoning
Other names	Mycetism, mycetismus
Amanita phalloides accounts for the majority of fatal mushroom poisonings worldwide.
Specialty	Emergency medicine, toxicology

Mushroom poisoning refers to harmful effects from ingestion of toxic substances present in a mushroom. These symptoms can vary from slight gastrointestinal discomfort to death in about 10 days. The toxins present are secondary metabolites produced by the fungus. Mushroom poisoning is usually the result of ingestion of wild mushrooms after misidentification of a toxic mushroom as an edible species. The most common reason for this misidentification is close resemblance in terms of colour and general morphology of the toxic mushrooms species with edible species. To prevent mushroom poisoning, mushroom gatherers familiarize themselves with the mushrooms they intend to collect, as well as with any similar-looking toxic species. The safety of eating wild mushrooms may depend on methods of preparation for cooking.

Signs and symptoms

Poisonous mushrooms contain a variety of different toxins that can differ markedly in toxicity. Symptoms of mushroom poisoning may vary from gastric upset to organ failure resulting in death. Serious symptoms do not always occur immediately after eating, often not until the toxin attacks the kidney or liver, sometimes days or weeks later.

The most common consequence of mushroom poisoning is simply gastrointestinal upset. Most "poisonous" mushrooms contain gastrointestinal irritants that cause vomiting and diarrhea (sometimes requiring hospitalization), but usually no long-term damage. However, there are a number of recognized mushroom toxins with specific, and sometimes deadly, effects:

Toxin	Toxicity	Effects
Alpha-amanitin	Deadly	Causes often fatal liver damage 1–3 days after ingestion. Principal toxin in the death cap.
Phallotoxin	Non-lethal	Causes extreme gastrointestinal upset. Found in various mushrooms.
Orellanine	Deadly	Redox cycler similar to paraquat. Causes kidney failure within 3 weeks after ingestion. Principal toxin in genus Cortinarius.
Muscarine	Potentially deadly	Causes SLUDGE syndrome. Found in various mushrooms. Antidote is atropine
Monomethylhydrazine (MMH)	Deadly	Causes brain damage, seizures, gastrointestinal upset, and hemolysis. Metabolic poison. Principal toxin in genus Gyromitra. Antidote is large doses of intravenous pyridoxine hydrochloride[1]
Coprine	Non-lethal	Causes illness when consumed with alcohol. Principal toxin in genus Coprinus.
Ibotenic acid	Potentially deadly	Excitotoxin. Principal toxin in Amanita muscaria, A. pantherina, and A. gemmata.
Muscimol	Potentially deadly	Causes CNS depression and hallucinations. Principal toxin in Amanita muscaria, A. pantherina, and A. gemmata.
Arabitol	Non-lethal	Causes diarrhea in some people.
Bolesatine	Non-lethal	Causes gastrointestinal irritation, vomiting, nausea.
Ergotamine	Deadly	Affects the vascular system and can lead to loss of limbs and/or cardiac arrest. Found in genus Claviceps.

The period of time between ingestion and the onset of symptoms varies dramatically between toxins, some taking days to show symptoms identifiable as mushroom poisoning.

• Alpha-amanitin: For 6–12 hours, there are no symptoms. This is followed by a period of gastrointestinal upset (vomiting and profuse, watery diarrhea). This stage is caused primarily by the phallotoxins and typically lasts 24 hours. At the end of this second stage is when severe liver damage begins. The damage may continue for another 2–3 days. Kidney damage can also occur. Some patients will require a liver transplant. Amatoxins are found in some mushrooms in the genus Amanita, but are also found in some species of Galerina and Lepiota. Overall, mortality is between 10 and 15 percent. Recently, Silybum marianum or blessed milk thistle has been shown to protect the liver from amanita toxins and promote regrowth of damaged cells.
• Orellanine: This toxin causes no symptoms for 3–20 days after ingestion. Typically around day 11, the process of kidney failure begins, and is usually symptomatic by day 20. These symptoms can include pain in the area of the kidneys, thirst, vomiting, headache, and fatigue. A few species in the very large genus Cortinarius contain this toxin. People having eaten mushrooms containing orellanine may experience early symptoms as well, because the mushrooms often contain other toxins in addition to orellanine. A related toxin that causes similar symptoms but within 3–6 days has been isolated from Amanita smithiana and some other related toxic Amanitas.
• Muscarine: Muscarine stimulates the muscarinic receptors of the nerves and muscles. Symptoms include sweating, salivation, tears, blurred vision, palpitations, and, in high doses, respiratory failure. Muscarine is found in mushrooms of the genus Omphalotus, notably the jack o' Lantern mushrooms. It is also found in A. muscaria, although it is now known that the main effect of this mushroom is caused by ibotenic acid. Muscarine can also be found in some Inocybe species and Clitocybe species, in particular Clitocybe dealbata, and some red-pored Boletes.
• Gyromitrin: Stomach acids convert gyromitrin to monomethylhydrazine (MMH), a compound employed in rocket fuel. It affects multiple body systems. It blocks the important neurotransmitter GABA, leading to stupor, delirium, muscle cramps, loss of coordination, tremors, and/or seizures. It causes severe gastrointestinal irritation, leading to vomiting and diarrhea. In some cases, liver failure has been reported. It can also cause red blood cells to break down, leading to jaundice, kidney failure, and signs of anemia. It is found in mushrooms of the genus Gyromitra. A gyromitrin-like compound has also been identified in mushrooms of the genus Verpa.
• Coprine: Coprine is metabolized to a chemical that resembles disulfiram. It inhibits aldehyde dehydrogenase (ALDH), which, in general, causes no harm, unless the person has alcohol in their bloodstream while ALDH is inhibited. This can happen if alcohol is ingested shortly before or up to a few days after eating the mushrooms. In that case the alcohol cannot be completely metabolized, and the person will experience flushed skin, vomiting, headache, dizziness, weakness, apprehension, confusion, palpitations, and sometimes trouble breathing. Coprine is found mainly in mushrooms of the genus Coprinus, although similar effects have been noted after ingestion of Clitocybe clavipes.
• Ibotenic acid: Decarboxylates into muscimol upon ingestion. The effects of muscimol vary, but nausea and vomiting are common. Confusion, euphoria, or sleepiness are possible. Loss of muscular coordination, sweating, and chills are likely. Some people experience visual distortions, a feeling of strength, or delusions. Symptoms normally appear after 30 minutes to 2 hours and last for several hours. A. muscaria, the "Alice in Wonderland" mushroom, is known for the hallucinatory experiences caused by muscimol, but A. pantherina and A. gemmata also contain the same compound. While normally self-limiting, fatalities have been associated with A. pantherina, and consumption of a large number of any of these mushrooms is likely to be dangerous.
• Arabitol: A sugar alcohol, similar to mannitol, which causes no harm in most people but causes gastrointestinal irritation in some. It is found in small amounts in oyster mushrooms, and considerable amounts in Suillus species and Hygrophoropsis aurantiaca (the "false chanterelle").

Causes

New species of fungi are continuing to be discovered, with an estimated number of 800 new species registered annually. This, added to the fact that many investigations have recently reclassified some species of mushrooms from edible to poisonous has made older classifications insufficient at describing what now is known about the different species of fungi that are harmful to humans. Thus, contrary to what older registers state, it is now thought that of the approximately 100,000 known fungi species found worldwide, about 100 of them are poisonous to humans. However, by far the majority of mushroom poisonings are not fatal, and the majority of fatal poisonings are attributable to the Amanita phalloides mushroom.

Amanita spp., immature, possibly poisonous, Amanita mushrooms.

 

Edible shaggy mane Coprinus comatus mushrooms.

 

A majority of these cases are due to mistaken identity. This is a common occurrence with A. phalloides in particular, due to its resemblance to the Asian paddy-straw mushroom, Volvariella volvacea. Both are light-colored and covered with a universal veil when young.

Amanitas can be mistaken for other species, as well, in particular when immature. On at least one occasion they have been mistaken for Coprinus comatus. In this case, the victim had some limited experience in identifying mushrooms, but did not take the time to correctly identify these particular mushrooms until after he began to experience symptoms of mushroom poisoning.

Amanitas, two examples of immature Amanitas, one deadly and one edible.

 

Puffball, an edible puffball mushroom, which closely resembles the immature Amanitas.

 

The author of Mushrooms Demystified, David Arora cautions puffball-hunters to beware of Amanita "eggs", which are Amanitas still entirely encased in their universal veil. Amanitas at this stage are difficult to distinguish from puffballs. Foragers are encouraged to always cut the fruiting bodies of suspected puffballs in half, as this will reveal the outline of a developing Amanita should it be present within the structure.

A majority of mushroom poisonings in general are the result of small children, especially toddlers in the "grazing" stage, ingesting mushrooms found in the lawn. While this can happen with any mushroom, Chlorophyllum molybdites is often implicated due to its preference for growing in lawns. C. molybdites causes severe gastrointestinal upset but is not considered deadly poisonous.

A few poisonings are the result of misidentification while attempting to collect hallucinogenic mushrooms for recreational use. In 1981, one fatality and two hospitalizations occurred following consumption of Galerina autumnalis, mistaken for a Psilocybe species. Galerina and Psilocybe species are both small, brown, and sticky, and can be found growing together. However, Galerina contains amatoxins, the same poison found in the deadly Amanita species. Another case reports kidney failure following ingestion of Cortinarius orellanus, a mushroom containing orellanine.

It is natural that accidental ingestion of hallucinogenic species also occurs, but is rarely harmful when ingested in small quantities. Cases of serious toxicity have been reported in small children. Amanita pantherina, while containing the same hallucinogens as Amanita muscaria (e.g., ibotenic acid and muscimol), has been more commonly associated with severe gastrointestinal upset than its better-known counterpart.

Jack-O-Lantern, a poisonous mushroom sometimes mistaken for a chanterelle.

 

Chanterelle, edible.

 

Although usually not fatal, Omphalotus spp., "Jack-o-lantern mushrooms," are another cause of sometimes significant toxicity. They are sometimes mistaken for chanterelles. Both are bright-orange and fruit at the same time of year, although Omphalotus grows on wood and has true gills rather than the veins of a Cantharellus. They contain toxins known as illudins, which causes gastrointestinal symptoms. 

Bioluminescent species are generally inedible and often mildly toxic.

Clitocybe dealbata, which is occasionally mistaken for an oyster mushroom or other edible species contains muscarine.

Toxicities can also occur with collection of morels. Even true morels, if eaten raw, will cause gastrointestinal upset. Typically, morels are thoroughly cooked before eating. Verpa bohemica, although referred to as "thimble morels" or "early morels" by some, have caused toxic effects in some individuals. Gyromitra spp., "false morels", are deadly poisonous if eaten raw. They contain a toxin called gyromitrin, which can cause neurotoxicity, gastrointestinal toxicity, and destruction of the blood cells. The Finns consume Gyromitra esculenta after parboiling, but this may not render the mushroom entirely safe, resulting in its being called the "fugu of the Finnish cuisine".

A more unusual toxin is coprine, a disulfiram-like compound that is harmless unless ingested within a few days of ingesting alcohol. It inhibits aldehyde dehydrogenase, an enzyme required for breaking down alcohol. Thus, the symptoms of toxicity are similar to being hung over—flushing, headache, nausea, palpitations, and, in severe cases, trouble breathing. Coprinus species, including Coprinopsis atramentaria, contain coprine. Coprinus comatus does not, but it is best to avoid mixing alcohol with other members of this genus.

Recently, poisonings have also been associated with Amanita smithiana. These poisonings may be due to orellanine, but the onset of symptoms occurs in 4 to 11 hours, which is much quicker than the 3 to 20 days normally associated with orellanine.

Paxillus involutus is also inedible when raw, but is eaten in Europe after pickling or parboiling. However, after the death of the German mycologist Dr Julius Schäffer, it was discovered that the mushroom contains a toxin that can stimulate the immune system to attack its own red blood cells. This reaction is rare, but can occur even after safely eating the mushroom for many years. Similarly, Tricholoma equestre was widely considered edible and good, until it was connected with rare cases of rhabdomyolysis.

In the fall of 2004, thirteen deaths were associated with consumption of Pleurocybella porrigens or "angel's wings". In general, these mushrooms are considered edible. All the victims died of an acute brain disorder, and all had pre-existing kidney disease. The exact cause of the toxicity was not known at this time and the deaths cannot be definitively attributed to mushroom consumption.

However, mushroom poisoning is not always due to mistaken identity. For example, the highly toxic ergot Claviceps purpurea, which grows on rye, is sometimes ground up with rye, unnoticed, and later consumed. This can cause devastating, even fatal effects, which is called ergotism.

Cases of idiosyncratic or unusual reactions to fungi can also occur. Some are probably due to allergy, others to some other kind of sensitivity. It is not uncommon for an individual person to experience gastrointestinal upset associated with one particular mushroom species or genus.

Some mushrooms might concentrate toxins from their growth substrate, such as Chicken of the Woods growing on yew trees.

Poisonous mushrooms

Of the most lethal mushrooms, three—the death cap (A. phalloides), destroying angels (A. virosa and A. bisporigera), and the fool's mushroom (A. verna)—belong to the genus Amanita, and two more—the deadly webcap (C. rubellus), and the fool's webcap (C. orellanus)—are from the genus Cortinarius. Several species of Galerina, Lepiota, and Conocybe also contain lethal amounts of amatoxins. Deadly species are listed in the List of deadly fungi.

The following species may cause great discomfort, sometimes requiring hospitalization, but are not considered deadly.

• Amanita muscaria (fly agaric) – Contains the psychoactive muscimol and the neurotoxin ibotenic acid. Ibotenic acid decarboxylates into muscimol upon curing of the mushroom, rendering it relatively non-toxic, though death via respiratory depression is possible. Muscimol intoxication is often considered unpleasant and undesirable, however, and as such has seen little recreational use compared to the unrelated psilocybin mushroom, though it has been used as an entheogen by the native people of Siberia.
• Amanita pantherina (panther mushroom) – contains similar toxins as A. muscaria, but is associated with more fatalities than A. muscaria.
• Chlorophyllum molybdites (greengills) – causes intense gastrointestinal upset.
• Entoloma (pinkgills) – some species are highly poisonous, such as livid entoloma (Entoloma sinuatum), Entoloma rhodopolium, and Entoloma nidorosum. Symptoms of intense gastrointestinal upset appear after 20 minutes to 4 hours, caused by an unidentified gastrointestinal irritant.
• Many Inocybe species such as Inocybe fastigiata and Inocybe geophylla contain muscarine, while Inocybe erubescens is the only one known to have caused death.
• Some white Clitocybe species, including C. rivulosa and C. dealbata – contain muscarine.
• Tricholoma pardinum, Tricholoma tigrinum (tiger tricholoma) – gastrointestinal upset due to an unidentified toxin, begins in 15 minutes to 2 hours and lasts 4 to 6 days.
• Tricholoma equestre (man-on-horseback) – until recently thought edible and good, can lead to rhabdomyolysis after repeated consumption.
• Hypholoma fasciculare/Naematoloma fasciculare (sulfur tuft) – usually causes gastrointestinal upset, but the toxins fasciculol E and F could lead to paralysis and death.
• Paxillus involutus (brown roll-rim) – once thought edible, but now found to destroy red blood cells with regular or long-term consumption.
• Rubroboletus satanas (Devil's bolete), Suillellus luridus, Rubroboletus legaliae, Chalciporus piperatus, Neoboletus luridiformis, Rubroboletus pulcherrimus – gastrointestinal irritation. Of these, only R. pulcherrimus has been implicated in a death. Many books list N. luridiformis as edible, but Arora lists it as "to be avoided".
• Hebeloma crustuliniforme (known as poison pie or fairy cakes) – causes gastrointestinal symptoms such as nausea and vomiting.
• Russula emetica (the sickener) – as its name implies, causes rapid vomiting. Other Russulas with a peppery taste (Russula silvicola, Russula mairei) will likely do the same.
• Agaricus hondensis, Agaricus californicus, Agaricus praeclaresquamosus, Agaricus xanthodermus – cause vomiting and diarrhea in most people, although some people seem to be immune.
• Lactifluus piperatus, Lactarius torminosus, Lactarius rufus – these and other peppery-tasting milk-caps are pickled and eaten in Scandinavia, but are indigestible or poisonous unless correctly prepared.
• Lactarius vinaceorufescens, Lactarius uvidus – reported to be poisonous. Arora reports that all yellow- or purple-staining Lactarius are "best avoided".
• Ramaria gelatinosa – causes indigestion in many people, although some seem immune.
• Gomphus floccosus (the scaly chanterelle) – causes gastric upset in many people, although some eat it without problems. G. floccosus is sometimes confused with the chanterelle.

Prognosis and treatment

Some mushrooms contain less toxic compounds and, therefore, are not severely poisonous. Poisonings by these mushrooms may respond well to treatment. However, certain types of mushrooms contain very potent toxins and are very poisonous; so even if symptoms are treated promptly mortality is high. With some toxins, death can occur in a week or a few days. Although a liver or kidney transplant may save some patients with complete organ failure, in many cases there are no organs available. Patients hospitalized and given aggressive support therapy almost immediately after ingestion of amanitin-containing mushrooms have a mortality rate of only 10%, whereas those admitted 60 or more hours after ingestion have a 50–90% mortality rate.

Society and culture

Folk traditions

Many folk traditions concern the defining features of poisonous mushrooms. However, there are no general identifiers for poisonous mushrooms, so such traditions are unreliable. Guidelines to identify particular mushrooms exist, and will serve only if one knows which mushrooms are toxic.

Examples of erroneous folklore "rules" include:

• "Poisonous mushrooms are brightly colored." – Indeed, fly agaric, usually bright-red to orange or yellow, is narcotic and hallucinogenic, although no human deaths have been reported. The deadly destroying angel, in contrast, is an unremarkable white. The deadly Galerinas are brown. Some choice edible species (chanterelles, Amanita caesarea, Laetiporus sulphureus, etc.) are brightly colored, whereas most poisonous species are brown or white.
• "Insects/animals will avoid toxic mushrooms." – Fungi that are harmless to invertebrates can still be toxic to humans; the death cap, for instance, is often infested by insect larvae.
• "Poisonous mushrooms blacken silver." – None of the known mushroom toxins have a reaction with silver.
• "Poisonous mushrooms taste bad." – People who have eaten the deadly Amanitas and survived have reported that the mushrooms tasted quite good.
• "All mushrooms are safe if cooked/parboiled/dried/pickled/etc." – While it is true that some otherwise-inedible species can be rendered safe by special preparation, many toxic species cannot be made toxin-free. Many fungal toxins are not particularly sensitive to heat and so are not broken down during cooking; in particular, α-amanitin, the poison produced by the death cap (Amanita phalloides) and others of the genus, is not denatured by heat.
• "Poisonous mushrooms will turn rice red when boiled." – A number of Laotian refugees were hospitalized after eating mushrooms (probably toxic Russula species) deemed safe by this folklore rule and this misconception cost at least one person her life.
• "Poisonous mushrooms have a pointed cap. Edible ones have a flat, rounded cap." – The shape of the mushroom cap does not correlate with presence or absence of mushroom toxins, so this is not a reliable method to distinguish between edible and poisonous species. Death cap, for instance, has a rounded cap when mature.
• "Boletes are, in general, safe to eat." – It is true that, unlike a number of Amanita species in particular, in most parts of the world, there are no known deadly varieties of the genus Boletus, which reduces the risks associated with misidentification. However, mushrooms like the Devil's bolete are poisonous both raw and cooked and can lead to strong gastrointestinal symptoms, and other species like the lurid bolete require thorough cooking to break down toxins. As with other mushroom genera, proper caution is, therefore, advised in determining the correct species.

Notable cases

• Siddhartha Gautama (known as The Buddha), by some accounts, may have died of mushroom poisoning around ~479 BCE, though this claim has not been universally accepted.
• Roman Emperor Claudius is said to have been murdered by being fed the death cap mushroom. However, this story first appeared some two centuries after the events, and it is even debatable whether Claudius was murdered at all. Pope Clement VII is also rumored to have been murdered this way. However, it is similarly debated whether he died from any kind of poisoning at all.
• Holy Roman Emperor Charles VI and Tsaritsa Natalia Naryshkina are believed to have died from eating the death cap mushroom.
• The composer Johann Schobert died in Paris, along with his wife, one of his children, maidservant, and four acquaintances after insisting that certain poisonous mushrooms were edible.
• The best-selling author Nicholas Evans (The Horse Whisperer) was poisoned (but survived) after eating Cortinarius rubellus.
• The parents of the physicist Daniel Gabriel Fahrenheit, who created the Fahrenheit temperature scale, died in Danzig on 14 August 1701 from accidentally eating poisonous mushrooms.

In fiction

• In the civil war drama The Beguiled, Clint Eastwood's character John McBurney, an injured Union soldier at a boarding school for girls, was poisoned by a jealous, vengeful headmistress and her young female students. The headmistress was played by Geraldine Page.
• In Bollywood movie 7 Khoon Maaf, Modhusudhon Tarafdar (Naseeruddin Shah), a Bengali doctor who rescues Susanna from a suicide attempt and marries her, tries to poison Susanna with mushroom soup several years later for her inheritance.
• Linda Howard's action/romance novel Kiss Me While I Sleep has the anti-heroine use synthetic orellanine as a weapon.
• In Julius Streicher's Nazi propaganda children's book The Poisonous Mushroom, Jews are compared to deadly fungi.
• In "The Story of Babar" by Jean de Brunhoff, the King of the Elephants died from eating a poisonous mushroom.
• The 1993 Italian film Fiorile features a woman who takes revenge on her brother by feeding him poisonous mushrooms.
• In the 2006 Game Boy Advance video game title 'Mother 3' the main protagonists, Lucas and friends, ingest poisonous mushrooms and have a bad trip.
• In the 2017 film "Phantom Thread", Alma fed poisonous mushrooms to the renowned fashion designer Reynolds Woodcock.

Testing cosmetics on animals

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Testing_cosmetics_on_animals 

 

Worldwide laws regarding testing cosmetics on animals

	Nationwide ban on all cosmetic testing on animals		Partial ban on cosmetic testing on animals1
	Ban on the sale of cosmetics tested on animals		No ban on any cosmetic testing on animals
	Unknown

¹some methods of testing are excluded from the ban or the laws vary within the country

Cosmetic testing on animals is a type of animal testing used to test the safety and hypoallergenic properties of products for use by humans. Due to the harm done to the animal subjects, this testing is opposed by animal rights activists and others. Cosmetic animal testing is banned in the European Union, United Kingdom, India, Israel, and Norway.

Definition

Using animal testing in the development of cosmetics may involve testing either a finished product or the individual ingredients of a finished product on animals, often rabbits, as well as mice, rats, and other animals. Cosmetics can be defined as products applied to the body in various ways in order to enhance the body's appearance or to cleanse the body. This includes all hair products, makeup, nail products and soaps.

The United States Food and Drug Administration (FDA) continues to endorse animal testing methods.

Re-using existing test data obtained from previous animal testing is generally not considered to be cosmetic testing on animals; however, the acceptability of this to opponents of testing is inversely proportional to how recent the data is.

Methods

Methods of testing cosmetics on animals include many different tests that are categorized differently based on which areas the cosmetics will be used for. One new ingredient in any cosmetic product used in these tests could lead to the deaths of at least 1,400 animals.

 

Dermal penetration: Rats are mostly used in this method that analyzes moment of a chemical, and the penetration of the chemical in the bloodstream. Dermal penetration is a method that creates a better understanding of skin absorption.

Skin sensitisation: This is a method that determines if a chemical causes an allergic reaction. The chemical adjuvant is injected to boost the immune system. In the past it was performed on guinea pigs, and applied on a shaved patch of skin. Substances are assessed based on appearance of skin.

Acute toxicity: This test is used to determine danger of exposure to a chemical by mouth, skin, or inflammation. Rats and mice are injected in lethal dose 50% (LD50). This test can cause animal convulsions, loss of motor function, and seizures.

Draize test: This is a method of testing that may cause irritation or corrosion to the skin or eye on animals, dermal sensitization, airway sensitization, endocrine disruption, and LD₅₀ (which refers to the lethal dose which kills 50% of the treated animals).

Skin corrosivity or irritation: This method of test assesses the potential of a substance causing irreversible damage to the skin. It is typically performed on rabbits and involves putting chemicals on a shaved patch of skin. This determines the level of damage to the skin that includes itching, inflammation, swelling, etc.

Alternatives

Cosmetics manufacturers who do not test on animals may now use in vitro screens to test for endpoints which can determine potential risk to humans with a very high sensitivity and specificity. Companies such as CeeTox in the USA, recently acquired by Cyprotex, specialize in such testing and organizations like the Center for Alternatives to Animal Testing (CAAT), PETA and many other organizations advocate the use of in vitro and other non-animal tests in the development of consumer products. By using safe ingredients from a list of 5,000 which have already been tested in conjunction with modern methods of cosmetics testing, the need for tests using animals are negated.

EpiSkin™, EpiDerm™ and SkinEthic are each composed of artificial human skin as an option for alternative testing. Artificial skin can imitate the reaction actual human skin will have to a product and the chemicals it contains and can be altered to mimic different skin types and ages. For example, using UV light on EpiSkin can cause it to resemble older skin and adding melanocytes will turn the skin a darker color. This helped create a spectrum of different skin colors that are then used to compare the results of sunblock on a different variety of people. To address potential issues with other parts of the human body, research companies such as NOTOX have developed a synthetic model of the human liver, which is the main organ to detox the body, in order to test harmful ingredients and chemicals to see if the liver can detox those elements. Research companies can also use body parts and organs taken from animals slaughtered for the meat industry to perform tests such as the Bovine Corneal Opacity and Permeability Test and Isolated Chicken Eye Test.

History

In 1937, a mistake was made that ended up changing the pharmaceutical industry drastically. A company created a medicine (Elixir sulfanilamide) “to treat streptococcal infections”, and without any scientific research the medicine was out on shelves. This medicine turned out to be extremely poisonous to people, leading to large poisoning outbreaks followed by over 100 deaths. This epidemic led to a law being passed in 1938, called the U.S. Food, Drug, and Cosmetics Act, enforcing more rigorous guidelines on cosmetic products. After this law was passed companies looked to animals to test their products, in turn, creating the first encounters of cosmetic animal testing.

Non-profit organizations

This "Leaping Bunny" indicates that cosmetic products with this logo have not been tested on animals.

• Cruelty Free International: Cruelty Free International and its partners manage the certification of all the companies across the world looking to be cruelty free. Companies producing beauty and household products which do not test their products on animals for any market can request membership of The Leaping Bunny Program, which allows that company to feature Cruelty Free International's Leaping Bunny logo on their products. This program sets global standard of operations and sales. Companies headquartered internationally can obtain certification from Cruelty Free International. Companies headquartered in the United States and Canada can obtain certification from The Coalition for Consumer Information on Cosmetics (CCIC). In 2013, over 500 companies were certified. However, some company's certifications were revoked after it was discovered they continued to test on animals in Asia.
• Humane Society International: This is a global animal protection organization that works to help all animals—including animals in laboratories.

Procedures of animal testing

There is a strategy used in animal testing laboratories titled the 'Three R's:' Reduction, refinement, and replacement' (Doke, "Alternatives to Animal Testing: A Review").

• Reduction: This approach is built upon the ethics to have a minimal number of animal subjects being tested on for current and later tests.
• Refinement: This suggests that the planned distress and pain caused to an animal subject to be as little as possible. This approach focuses on making a home for the animals before entering testing grounds in order to elongate the life of laboratory animals. Discomfort to animals causes an imbalance in hormonal levels which create fluctuating results during testing.
• Replacement: This provides the opportunity to study the response of cellular models, but in other words, replacement searches for alternatives that could be done rather than testing on animal subjects.

Legal requirements and status

Due to the strong public backlash against cosmetic testing on animals, most cosmetic manufacturers say their products are not tested on animals. However, they are still required by trading standards and consumer protection laws in most countries to show their products are not toxic and not dangerous to public health, and that the ingredients are not dangerous in large quantities, such as when in transport or in the manufacturing plant. In some countries, it is possible to meet these requirements without any further tests on animals. In other countries, it may require animal testing to meet legal requirements. The United States and Japan are frequently criticized for their insistence on stringent safety measures, which often requires animal testing. Some retailers distinguish themselves in the marketplace by their stance on animal testing.

Legal requirements in Japan

Although Japanese law doesn’t require non-medicated cosmetics to be tested on animals, it doesn’t prohibit it either, leaving the decision to individual companies. Animal testing is required mainly when the product contains newly-developed tar colors, ultraviolet ray protective ingredients or preservatives, and when the amount of any ingredient regulated in terms of how much can be added is increased.

Japanese Brands such as Shiseido and Mandom have ended much, but not all, of their animal testing. However, most other leading cosmetics companies in Japan still test on animals.

Jurisdictions with bans

Brazil, São Paulo

São Paulo in Brazil, banned cosmetic animal testing in 2014.

European Union

The European Union (EU) followed suit, after it agreed to phase in a near-total ban on the sale of animal-tested cosmetics throughout the EU from 2009, and to ban cosmetics-related animal testing. Animal testing is regulated in EC Regulation 1223/2009 on cosmetics. Imported cosmetics ingredients tested on animals were phased out for EU consumer markets in 2013 by the ban, but can still be sold to outside of the EU. Norway banned cosmetics animal testing the same time as the EU. In May 2018 the European Parliament voted for the EU and its Member States to work towards a UN convention against the use of animal testing for cosmetics.

European Free Trade Association

The rest of the EFTA, including Norway, Liechtenstein, Switzerland, and Iceland also banned cosmetic testing.

Guatemala

In 2017, Guatemala banned cosmetic animal testing.

India

In early 2014, India announced a ban on testing cosmetics on animals in the country, thereby becoming the second country in Asia to do so. Later India banned import of cosmetics tested on animals in November 2014.

Israel

Israel banned "the import and marketing of cosmetics, toiletries or detergents that were tested on animals" in 2013.

New Zealand

In 2015, New Zealand also banned animal testing.

Turkey

Turkey "banned any animal testing for cosmetic products that have already been introduced to the market." 

UK

Animal testing on cosmetics or their ingredients was banned in the UK in 1998.

Jurisdictions where prohibitions are considered

Association of Southeast Asian Nations

The Association of Southeast Asian Nations (ASEAN) is potentially "making strides toward ending cosmetics testing on animals."

Australia

In Australia, the End Cruel Cosmetics Bill was introduced to Parliament in March 2014, which would ban local testing, which generally doesn't happen there, and importation of cosmetics tested on animals. In 2016 a bill was passed to ban the sale of cosmetics tested on animals, which came into effect in July 2017.

Brazil

Brazil's legislation will vote on a nationwide animal testing for cosmetics ban by the end of March 2014.

Canada

Canada has not banned animal testing for cosmetics. It got very close to instituting a ban in June 2019, but the bill ultimately failed. https://www.straight.com/news/1282096/v-victoria-shroff-canada-could-have-been-40th-country-ban-animal-testing-beauty by Vancouver Animal Law Lawyer and adjunct Professor of animal law, V. Victoria Shroff: Canada could have been the 40th country to ban animal testing for beauty products | Georgia Straight Vancouver's News & Entertainment Weekly.

United States

In March 2014, the Humane Cosmetics Act was introduced to the U.S. congress which would ban cosmetic testing on animals and eventually would ban the sale of cosmetics tested on animals. The bill did not advance.

South Korea

South Korea is also potentially "making strides toward ending cosmetics testing on animals."

Taiwan

In 2015, Taiwan launched a bill proposing a ban on cosmetic testing on animals. It passed in 2016 and goes into effect in 2019.

Other statuses

China

China passed a law on 30 June 2014 to eliminate the requirement for animal testing of cosmetics. Though domestically-produced ordinary cosmetic goods do not require testing, animal testing is still mandated by law for Chinese-made "cosmeceuticals" (cosmetic goods which make a functional claim) which are available for sale in China. Cosmetics intended solely for export are exempt from the animal testing requirement. As of March 2019, post-market testing (i.e. tests on cosmetics after they hit the market) for finished imported and domestically produced cosmetic products will no longer require animal testing. 

Russia

In 2013, the Russian Ministry of Health stated "Toxicological testing is performed by means of testing for skin allergic reaction or test on mucous tissue/eye area (with use of lab animals) or by use of alternative general toxicology methods (IN VITRO). In this manner the technical regulations include measures which provide an alternative to animal testing".

Wild animal suffering

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Wild_animal_suffering 

 

A juvenile red-tailed hawk eating a california vole

Wild animal suffering is the suffering experienced by nonhuman animals in nature through causes such as disease, injury, parasitism, starvation, natural disasters, and killings by other animals. Wild animal suffering has historically been discussed in the context of the philosophy of religion as an instance of the problem of evil. More recently, a number of academics have considered the suspected scope of the problem from a secular standpoint as a general moral issue, one that humans might be able to take actions toward preventing.

There is considerable disagreement around this latter point, as many believe that human interventions in nature, for this reason, would be either unethical, unfeasible, or both. Advocates of such interventions point out that humans intervene in nature all the time—sometimes in very substantial ways—for their own interests and to further environmentalist goals and that there are many ways that humans already successfully intervene to help wild animals such as vaccinating and healing injured and sick animals, rescuing animals in fires and natural disasters, feeding hungry animals, providing thirsty animals with water, and caring for orphaned animals. Advocates also argue that although wide-scale interventions may not be possible with current knowledge, they could become feasible in the future with increased knowledge and advanced technologies. For these reasons, they claim it is important to raise awareness about the issue of wild-animal suffering, spread the view that we should help animals suffering in these situations and encourage research into effective measures which can be taken to improve the welfare of wild animals without causing greater harms.

Extent of suffering in nature

In his autobiography, Charles Darwin acknowledged that the existence of extensive suffering in nature was fully compatible with the workings of natural selection, yet maintained that pleasure was the main driver of fitness-increasing behavior in organisms. Evolutionary biologist Richard Dawkins challenged Darwin's claim in his book River Out of Eden, wherein he argued that wild animal suffering must be extensive due to the interplay of the following evolutionary mechanisms:

• Selfish genes – genes are wholly indifferent to the well-being of individual organisms as long as DNA is passed on.
• The struggle for existence – competition over limited resources results in the majority of organisms dying before passing on their genes.
• Malthusian checks – even bountiful periods within a given ecosystem eventually lead to overpopulation and subsequent population crashes.

From this, Dawkins concludes that the natural world must necessarily contain enormous amounts of animal suffering as an inevitable consequence of Darwinian evolution. To illustrate this he wrote:

A litter of mice with their mother. The reproduction of mice follows an r-selection strategy, with many offspring, short gestation, less parental care, and a short time until sexual maturity.

The total amount of suffering per year in the natural world is beyond all decent contemplation. During the minute that it takes me to compose this sentence, thousands of animals are being eaten alive, many others are running for their lives, whimpering with fear, others are slowly being devoured from within by rasping parasites, thousands of all kinds are dying of starvation, thirst, and disease. It must be so. If there ever is a time of plenty, this very fact will automatically lead to an increase in the population until the natural state of starvation and misery is restored.

Building on this, others have argued that the prevalence of r-selected animals in the wild indicates that the average life of a wild animal is likely to be very short and end in a painful death. According to this view, the average life of a wild animal should thus contain more suffering than happiness, since a painful death would outweigh any short-lived moments of happiness in their short lives.

In "Bambi or Bessie: Are Wild Animals Happier?", Christie Wilcox argues that wild animals do not appear to be happier than domestic animals, based on findings of wild animals having greater levels of cortisol and elevated stress responses relative to domestic animals. Additionally, unlike domestic animals, animals in the wild do not have some of their needs provided for them by human caretakers. Welfare economist Yew-Kwang Ng has written that evolutionary dynamics can lead to animal welfare which is worse than necessary for a given population equilibrium.

Philosophical status

History of concern for wild animals

The idea that suffering is common in nature has been observed by several writers historically.

Italian polymath Leonardo da Vinci, in his notebooks (written between 1487–1505) lamented the suffering experienced by wild animals due to predation and reproduction, questioning: "Why did nature not ordain that one animal should not live by the death of another?"

Philosopher David Hume in his 1779 posthumous work Dialogues Concerning Natural Religion made reference to the antagonism experienced and inflicted by wild animals upon each other, observing: "The stronger prey upon the weaker, and keep them in perpetual terror and anxiety."

One expression commonly used to express suffering in nature comes from Alfred Tennyson's poem "In Memoriam A.H.H.": "Nature, red in tooth and claw", published in 1850.

In 1851, the German philosopher Arthur Schopenhauer also insisted on the extent of suffering in nature, drawing attention to the asymmetry between the pleasure experienced by a carnivorous animal and the suffering of the animal it consumes: "Whoever wants summarily to test the assertion that the pleasure in the world outweighs the pain, or at any rate that the two balance each other, should compare the feelings of an animal that is devouring another with those of that other".

In the 1874 posthumous essay "On Nature", utilitarian philosopher John Stuart Mill wrote about suffering in nature and the imperative of struggling against it:

In sober truth, nearly all the things which men are hanged or imprisoned for doing to one another, are nature's every day performances. [...] The phrases which ascribe perfection to the course of nature can only be considered as the exaggerations of poetic or devotional feeling, not intended to stand the test of a sober examination. No one, either religious or irreligious, believes that the hurtful agencies of nature, considered as a whole, promote good purposes, in any other way than by inciting human rational creatures to rise up and struggle against them. [...] Whatsoever, in nature, gives indication of beneficent design proves this beneficence to be armed only with limited power; and the duty of man is to cooperate with the beneficent powers, not by imitating, but by perpetually striving to amend, the course of nature - and bringing that part of it over which we can exercise control more nearly into conformity with a high standard of justice and goodness.

In his 1892 book Animals' Rights: Considered in Relation to Social Progress, the English writer and naturalist Henry Stephens Salt focused an entire chapter on the plight of wild animals, "The Case of Wild Animals". Salt wrote that:

It is of the utmost importance to emphasize the fact that, whatever the legal fiction may have been, or may still be, the rights of animals are not morally dependent on the so-called rights of property; it is not to owned animals merely that we must extend our sympathy and protection. [...] To take advantage of the sufferings of animals, whether wild or tame, for the gratification of sport, or gluttony, or fashion, is quite incompatible with any possible assertion of animals' rights.

Salt argued that humans are justified in killing wild animals in self-defense, but that "[...] we are not justified in unnecessarily killing—still less in torturing—any harmless beings whatsoever." English writer. In 1782, Member of Parliament Soame Jenyns argued that this should apply to insects as well: "We are unable to give life, and therefore ought not to take it away from the meanest insect without sufficient reason."

In his 1906 book The Universal Kinship, J. Howard Moore argued that the egoism of sentient beings—a product of natural selection—which leads them to exploit their sentient fellows, was the "most mournful and immense fact in the phenomena of conscious life", and speculated whether a sufficiently sympathetic human could significantly improve this situation if given the chance: "[One] cannot help wondering whether an ordinary human being with only common-sense and insight and an average concern for the welfare of the world would not make a great improvement in terrestrial affairs if he only had the opportunity for a while."

In 1991, the environmental philosopher Arne Næss critiqued what he termed the "cult of nature" of contemporary and historical attitudes of indifference towards suffering in nature. He argued that we should confront the reality of the wilderness and that we should be prepared to disturb natural processes—when feasible—to relieve suffering.

Ecology as intrinsically valuable

Holmes Rolston III argues that only unnatural animal suffering is a morally bad thing and that humans do not have a duty to intervene in natural cases. He celebrates carnivores in nature because of the significant ecological role they play. Others have argued that the reason that humans have a duty to protect other humans from predation is because humans are part of the cultural world rather than the natural world and so different rules apply to them in these situations. Others argue that prey animals are fulfilling their natural function, and thus flourishing, when they are preyed upon or otherwise die, since this allows natural selection to work. This can be seen by some as an appeal to nature.

Wild animal suffering as a reductio ad absurdum

That people would also be obliged to intervene in nature has been used as a reductio ad absurdum against the position that animals have rights. This is because if animals such as prey animals did have rights, people would be obliged to intervene in nature to protect them, but this is claimed to be absurd. An objection to this argument is that people do not see intervening in the natural world to save other people from predation as absurd and so this could be seen to involve treating non-human animals differently in this situation without justification, which is due to speciesism. However, this argument already grants the premise in question that animals should have rights, and that preferring human interests is wrong, and therefore it is begging the question.

Relevance to the theological problem of evil

The problem of evil has been extended beyond human troubles to include the suffering of animals over the course of evolution.

Interventions to reduce suffering

Arguments for intervention

Some theorists have reflected on whether we should accept the harms that animals suffer in nature or try to do something to mitigate them. The moral basis for interventions aimed at reducing wild animal suffering can be rights-based or welfare-based. From a rights-based perspective, if animals have a moral right to life or bodily integrity, intervention may be required to prevent such rights from being violated by other animals.

From a welfare-based perspective, a requirement to intervene may arise insofar as it is possible to prevent some of the suffering experienced by wild animals without causing even more suffering. Advocates of intervention in nature argue that nonintervention is inconsistent with either of these approaches. Some proposed courses of action include removing predators from wild areas, refraining from reintroducing predators, providing medical care to sick or injured animals, and rescuing wild animals from natural disasters.

Practicality of intervening in nature

A common objection to intervening in nature is that it would be impractical, either because of the amount of work involved, or because the complexity of ecosystems would make it difficult to know whether or not an intervention would be net beneficial on balance. Aaron Simmons argues that we should not intervene to save animals in nature because doing so would result in unintended consequences such as damaging the ecosystem, interfering with human projects, or resulting more animal deaths overall. Philosopher Peter Singer has argued that intervention in nature would be justified if one could be reasonably confident that this would greatly reduce wild animal suffering and death in the long run. In practice, however, Singer cautions against interfering with ecosystems because he fears that doing so would cause more harm than good.

Other authors dispute Singer's empirical claim about the likely consequences of intervening in the natural world, and argue that some types of intervention can be expected to produce good consequences overall. Economist Tyler Cowen cites examples of animal species whose extinction is not generally regarded as having been on balance bad for the world. Cowen also notes that insofar as humans are already intervening in nature, the relevant practical question is not whether we should intervene at all, but what particular forms of intervention we should favor. Philosopher Oscar Horta similarly writes that there are already many cases in which we intervene in nature for other reasons, such as for human interest in nature and environmental preservation as something valuable in their own rights. Horta has also proposed that courses of action aiming at helping wild animals should be carried out and adequately monitored first in urban, suburban, industrial, or agricultural areas. Likewise, moral philosopher Jeff McMahan argues that since humans "are already causing massive, precipitate changes in the natural world," we should favor those changes that would promote the survival "of herbivorous rather than carnivorous species."

Peter Vallentyne suggests that, while humans should not eliminate predators in nature, they can intervene to help prey in more limited ways. In the same way that we help humans in need when the cost to us is small, we might help some wild animals at least in limited circumstances.

Potential conflict between animal rights and environmentalism

It has been argued that the environmentalist goal of preserving certain abstract entities such as species and ecosystems and policy of non-interference in regard to natural processes is incompatible with animal rights views which place the welfare and interests of nonhuman animals at the center of concern. Examples include environmentalists supporting hunting for species population control, while animal rights advocates oppose it; animal rights advocates arguing for the extinction or reengineering of carnivores or r-strategist species, while deep ecologists defend their right to be and flourish as they are; animal rights advocates defending the reduction of wildlife habitats or arguing against their expansion out of concern that most animal suffering takes place within them, while environmentalists want to safeguard and expand them. Oscar Horta has argued that there are instances where environmentalists and animal rights advocates may both support approaches which would consequently reduce wild animal suffering.

Welfare biology

Welfare biology is a proposed research field for studying the welfare of nonhuman animals, with a particular focus on their relationship with natural ecosystems. It was first advanced in 1995 by Yew-Kwang Ng, who defined it as "the study of living things and their environment with respect to their welfare (defined as net happiness, or enjoyment minus suffering)". Such research is intended to promote concern for nonhuman animal suffering in the wild and to establish effective actions that can be undertaken to help these individuals.

History of interventions

In 2016, 350 starving hippos and buffaloes at Kruger National Park were killed by park rangers. One of the motives for the action was to prevent the animals from suffering as they died.

In 2018, a team of BBC filmmakers dug a ramp in the snow to allow a group of penguins to escape a ravine.

In 2019, 2000 baby flamingos were rescued after they were abandoned by their parents in a drought in South Africa.

Wildlife contraception has been used successfully to reduce and stabilize populations of wild horses, white-tailed deer, American bison and African elephants.

Cytokine release syndrome

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Cytokine_release_syndrome 

 

Cytokine release syndrome (CRS)
Other names	Infusion-related reaction (IRR), infusion reaction, cytokine storm
Specialty	Immunology

Cytokine release syndrome (CRS) is a form of systemic inflammatory response syndrome that can be triggered by a variety of factors such as infections and certain drugs. It occurs when large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. CRS is also an adverse effect of some monoclonal antibody drugs, as well as adoptive T-cell therapies. Severe cases have been called cytokine storms. When occurring as a result of drug administration, it is also known as an infusion reaction.

Signs and symptoms

Symptoms include fever, fatigue, loss of appetite, muscle and joint pain, nausea, vomiting, diarrhea, rashes, fast breathing, rapid heartbeat, low blood pressure, seizures, headache, confusion, delirium, hallucinations, tremor, and loss of coordination.

Lab tests and clinical monitoring show low blood oxygen, widened pulse pressure, increased cardiac output (early), potentially diminished cardiac output (late), high nitrogen levels in blood, elevated D-dimer, elevated transaminases, factor I deficiency and excessive bleeding, higher-than-normal level of bilirubin.

Cause

CRS occurs when large numbers of white blood cells, including B cells, T cells, natural killer cells, macrophages, dendritic cells, and monocytes are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. These cells are activated by infected cells that die by apoptosis or necrosis.

This can occur when the immune system is fighting pathogens, as cytokines signal immune cells such as T-cells and macrophages to travel to the site of infection. In addition, cytokines activate those cells, stimulating them to produce more cytokines.

CRS has also arisen with biotherapeutics intended to suppress or activate the immune system through receptors on white blood cells. Muromonab-CD3, an anti-CD3 monoclonal antibody intended to suppress the immune system to prevent rejection of organ transplants; alemtuzumab, which is anti-CD52 and used to treat blood cancers as well as multiple sclerosis and in organ transplants; and rituximab, which is anti-CD20 and used to treat blood cancers and auto-immune disorders, all cause CRS. Adoptive T-cell therapies with T-cells modified with chimeric antigen receptors (CAR-T) also causes CRS.

It appears that interleukin 6 is a key mediator of CRS.

Severe CRS or cytokine reactions can occur in a number of infectious and non-infectious diseases including graft-versus-host disease (GVHD), acute respiratory distress syndrome (ARDS), sepsis, Ebola, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS). Hemophagocytic lymphohistiocytosis and Epstein-Barr virus-related hemophagocytic lymphohistiocytosis are caused by extreme elevations in cytokines and can be regarded as one form of severe cytokine release syndrome. Cytokine reaction syndrome may also be induced by certain medications, such as the CD20 antibody rituximab and the CD19 CAR T cell tisagenlecleucel. The experimental drug TGN1412 - also known as Theralizumab - caused extremely serious symptoms when given to six participants in a Phase I trial. A controlled and limited CRS is triggered by active fever therapy with mixed bacterial vaccines (MBV) according to Coley; it is used for oncological and certain chronic diseases.

Diagnosis

CRS needs to be distinguished from symptoms of the disease itself and, in the case of drugs, from other adverse effects—for example tumor lysis syndrome requires different interventions. As of 2015, differential diagnoses depended on the judgement of doctor as there were no objective tests.

Classification

CRS is a form of systemic inflammatory response syndrome and is an adverse effect of some drugs.

The Common Terminology Criteria for Adverse Events classifications for CRS as of version 4.03 issued in 2010 were:

Grades	Toxicity
Grade 1	Mild reaction, infusion interruption not indicated; intervention not indicated
Grade 2	Therapy or infusion interruption indicated but responds promptly to symptomatic treatment (e.g., antihistamines, NSAIDS, narcotics, IV fluids); prophylactic medications indicated for <=24 hrs
Grade 3	Prolonged (e.g., not rapidly responsive to symptomatic medication or brief interruption of infusion); recurrence of symptoms following initial improvement; hospitalization indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates)
Grade 4	Life-threatening consequences; pressor or ventilatory support indicated
Grade 5	Death

Prevention

Severe CRS caused by some drugs can be prevented by using lower doses, infusing slowly, and administering anti-histamines or corticosteroids before and during administration of the drug.

In vitro assays have been developed to understand the risk that pre-clinical drug candidates might cause CRS and guide dosing for Phase I trials, and regulatory agencies expect to see results of such tests in investigational new drug applications.

A modified chandler loop model can be used as a preclinical tool to assess infusion reactions. 

Management

Treatment for less severe CRS is supportive, addressing the symptoms like fever, muscle pain, or fatigue. Moderate CRS requires oxygen therapy and giving fluids and antihypotensive agents to raise blood pressure. For moderate to severe CRS, the use of immunosuppressive agents like corticosteroids may be necessary, but judgement must be used to avoid negating the effect of drugs intended to activate the immune system.

Tocilizumab, an anti-IL6 monoclonal antibody, has been used in some medical centers to treat severe CRS.

Although frequently used to treat severe CRS in people with ARDS, corticosteroids and NSAIDs have been evaluated in clinical trials and have shown no effect on lung mechanics, gas exchange, or beneficial outcome in early established ARDS.

Epidemiology

Severe CRS is rare. Minor and moderate CRS are common side effects of immune-modulating antibody therapies and CAR-T therapies.

History

The first reference to the term cytokine storm in the published medical literature appears to be by Ferrara et al. in 1993 in a discussion of graft vs. host disease; a condition in which the role of excessive and self-perpetuating cytokine release had already been under discussion for many years. The term next appeared in a discussion of pancreatitis in 2002, and in 2003 it was first used in reference to a reaction to an infection.

It is believed that cytokine storms were responsible for the disproportionate number of healthy young adult deaths during the 1918 influenza pandemic, which killed 50 to 100 million people. In this case, a healthy immune system may have been a liability rather than an asset. Preliminary research results from Taiwan also indicated this as the probable reason for many deaths during the SARS epidemic in 2003. Human deaths from the bird flu H5N1 usually involve cytokine storms as well. Cytokine storm has also been implicated in hantavirus pulmonary syndrome.

In 2006, a medical study at Northwick Park Hospital in England resulted in all 6 of the volunteers given the drug TGN1412 becoming critically ill, with multiple organ failure, high fever, and a systemic inflammatory response. Parexel, a company conducting trials for pharmaceutical companies, in one of its own documents, wrote about the trial and said TGN1412 could cause a cytokine storm—the dangerous reaction the men experienced.

In the 2019–20 coronavirus pandemic, a number of deaths due to COVID-19 have been attributable to cytokine release storms.