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Thursday, December 7, 2023

DDT

From Wikipedia, the free encyclopedia

Dichlorodiphenyltrichloroethane
Chemical structure of DDT
Names
Preferred IUPAC name
1,1′-(2,2,2-Trichloroethane-1,1-diyl)bis(4-chlorobenzene)
Other names
Dichlorodiphenyltrichloroethane (DDT)
Clofenotane

Dichlorodiphenyltrichloroethane, commonly known as DDT, is a colorless, tasteless, and almost odorless crystalline chemical compound, an organochloride. Originally developed as an insecticide, it became infamous for its environmental impacts. DDT was first synthesized in 1874 by the Austrian chemist Othmar Zeidler. DDT's insecticidal action was discovered by the Swiss chemist Paul Hermann Müller in 1939. DDT was used in the second half of World War II to limit the spread of the insect-borne diseases malaria and typhus among civilians and troops. Müller was awarded the Nobel Prize in Physiology or Medicine in 1948 "for his discovery of the high efficiency of DDT as a contact poison against several arthropods". The WHO's anti-malaria campaign of the 1950s and 1960s relied heavily on DDT and the results were promising, though there was a resurgence in developing countries afterwards.

By October 1945, DDT was available for public sale in the United States. Although it was promoted by government and industry for use as an agricultural and household pesticide, there were also concerns about its use from the beginning. Opposition to DDT was focused by the 1962 publication of Rachel Carson's book Silent Spring. It talked about environmental impacts that correlated with the widespread use of DDT in agriculture in the United States, and it questioned the logic of broadcasting potentially dangerous chemicals into the environment with little prior investigation of their environmental and health effects. The book cited claims that DDT and other pesticides caused cancer and that their agricultural use was a threat to wildlife, particularly birds. Although Carson never directly called for an outright ban on the use of DDT, its publication was a seminal event for the environmental movement and resulted in a large public outcry that eventually led, in 1972, to a ban on DDT's agricultural use in the United States. Along with the passage of the Endangered Species Act, the United States ban on DDT is a major factor in the comeback of the bald eagle (the national bird of the United States) and the peregrine falcon from near-extinction in the contiguous United States.

The evolution of DDT resistance and the harm both to humans and the environment led many governments to curtail DDT use. A worldwide ban on agricultural use was formalized under the Stockholm Convention on Persistent Organic Pollutants, which has been in effect since 2004. Recognizing that total elimination in many malaria-prone countries is currently unfeasible in the absence of affordable/effective alternatives for disease control, the convention exempts public health use within World Health Organization (WHO) guidelines from the ban.

DDT still has limited use in disease vector control because of its effectiveness in killing mosquitos and thus reducing malarial infections, but that use is controversial due to environmental and health concerns. DDT is one of many tools to fight malaria, which remains the primary public health challenge in many countries. WHO guidelines require that absence of DDT resistance must be confirmed before using it. Resistance is largely due to agricultural use, in much greater quantities than required for disease prevention.

Properties and chemistry

DDT is similar in structure to the insecticide methoxychlor and the acaricide dicofol. It is highly hydrophobic and nearly insoluble in water but has good solubility in most organic solvents, fats and oils. DDT does not occur naturally and is synthesised by consecutive Friedel–Crafts reactions between chloral (CCl
3
CHO
) and two equivalents of chlorobenzene (C
6
H
5
Cl
), in the presence of an acidic catalyst. DDT has been marketed under trade names including Anofex, Cezarex, Chlorophenothane, Dicophane, Dinocide, Gesarol, Guesapon, Guesarol, Gyron, Ixodex, Neocid, Neocidol and Zerdane; INN is clofenotane.

Isomers and related compounds

Commercial DDT is a mixture of several closely related compounds. Due to the nature of the chemical reaction used to synthesize DDT, several combinations of ortho and para arene substitution patterns are formed. The major component (77%) is the desired p,p' isomer. The o,p' isomeric impurity is also present in significant amounts (15%). Dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD) make up the balance of impurities in commercial samples. DDE and DDD are also the major metabolites and environmental breakdown products. DDT, DDE and DDD are sometimes referred to collectively as DDX.

Production and use

DDT has been formulated in multiple forms, including solutions in xylene or petroleum distillates, emulsifiable concentrates, water-wettable powders, granules, aerosols, smoke candles and charges for vaporizers and lotions.

From 1950 to 1980, DDT was extensively used in agriculture – more than 40,000 tonnes each year worldwide – and it has been estimated that a total of 1.8 million tonnes have been produced globally since the 1940s. In the United States, it was manufactured by some 15 companies, including Monsanto, Ciba, Montrose Chemical Company, Pennwalt, and Velsicol Chemical Corporation. Production peaked in 1963 at 82,000 tonnes per year. More than 600,000 tonnes (1.35 billion pounds) were applied in the US before the 1972 ban. Usage peaked in 1959 at about 36,000 tonnes.

In 2009, 3,314 tonnes were produced for malaria control and visceral leishmaniasis. India is the only country still manufacturing DDT, and is the largest consumer. China ceased production in 2007.

Mechanism of insecticide action

In insects, DDT opens voltage-sensitive sodium ion channels in neurons, causing them to fire spontaneously, which leads to spasms and eventual death. Insects with certain mutations in their sodium channel gene are resistant to DDT and similar insecticides. DDT resistance is also conferred by up-regulation of genes expressing cytochrome P450 in some insect species, as greater quantities of some enzymes of this group accelerate the toxin's metabolism into inactive metabolites. Genomic studies in the model genetic organism Drosophila melanogaster revealed that high level DDT resistance is polygenic, involving multiple resistance mechanisms. In the absence of genetic adaptation, Roberts and Andre 1994 find behavioral avoidance nonetheless provides insects with some protection against DDT. The M918T mutation event produces dramatic kdr for pyrethroids but Usherwood et al. 2005 find it is entirely ineffective against DDT. Scott 2019 believes this test in Drosophila oocytes holds for oocytes in general.

History

Commercial product concentrate containing 50% DDT, circa 1960s
Commercial product of Ciba-Geigy Néocide (powder box, 50 g) containing 10% DDT, made in France.

DDT was first synthesized in 1874 by Othmar Zeidler under the supervision of Adolf von Baeyer. It was further described in 1929 in a dissertation by W. Bausch and in two subsequent publications in 1930.  The insecticide properties of "multiple chlorinated aliphatic or fat-aromatic alcohols with at least one trichloromethane group" were described in a patent in 1934 by Wolfgang von Leuthold. DDT's insecticidal properties were not, however, discovered until 1939 by the Swiss scientist Paul Hermann Müller, who was awarded the 1948 Nobel Prize in Physiology and Medicine for his efforts.

Use in the 1940s and 1950s

An airplane spraying DDT over Baker County, Oregon as part of a spruce budworm control project, 1955
DDT spray log in Bosa (Sardinia)

DDT is the best-known of several chlorine-containing pesticides used in the 1940s and 1950s. During this time, the use of DDT was driven by protecting American soldiers from diseases in tropical areas. Both British and American scientists hoped to use it to control spread of malaria, typhus, dysentery, and typhoid fever among overseas soldiers, especially considering that the pyrethrum was harder to access since it came mainly from Japan. Due to the potency of DDT, it was not long before America's War Production Board placed it on military supply lists in 1942 and 1943 and encouraged its production for overseas use. Enthusiasm regarding DDT became obvious through the American government's advertising campaigns of posters depicting Americans fighting the Axis powers and insects and through media publications celebrating its military uses. In the South Pacific, it was sprayed aerially for malaria and dengue fever control with spectacular effects. While DDT's chemical and insecticidal properties were important factors in these victories, advances in application equipment coupled with competent organization and sufficient manpower were also crucial to the success of these programs.

In 1945, DDT was made available to farmers as an agricultural insecticide and played a role in the elimination of malaria in Europe and North America. Despite concerns emerging in the scientific community, and lack of research, the FDA considered it safe up to 7 parts per million in food. There was a large economic incentive to push DDT into the market and sell it to farmers, governments, and individuals to control diseases and increase food production.

DDT was also a way for American influence to reach abroad through DDT-spraying campaigns. In the 1944 issue of Life magazine there was a feature regarding the Italian program showing pictures of American public health officials in uniforms spraying DDT on Italian families.

In 1955, the World Health Organization commenced a program to eradicate malaria in countries with low to moderate transmission rates worldwide, relying largely on DDT for mosquito control and rapid diagnosis and treatment to reduce transmission. The program eliminated the disease in "North America, Europe, the former Soviet Union", and in "Taiwan, much of the Caribbean, the Balkans, parts of northern Africa, the northern region of Australia, and a large swath of the South Pacific" and dramatically reduced mortality in Sri Lanka and India.

However, failure to sustain the program, increasing mosquito tolerance to DDT, and increasing parasite tolerance led to a resurgence. In many areas early successes partially or completely reversed, and in some cases rates of transmission increased. The program succeeded in eliminating malaria only in areas with "high socio-economic status, well-organized healthcare systems, and relatively less intensive or seasonal malaria transmission".

DDT was less effective in tropical regions due to the continuous life cycle of mosquitoes and poor infrastructure. It was applied in sub-Saharan Africa by various colonial states, but the 'global' WHO eradication program didn't include the region. Mortality rates in that area never declined to the same dramatic extent, and now constitute the bulk of malarial deaths worldwide, especially following the disease's resurgence as a result of resistance to drug treatments and the spread of the deadly malarial variant caused by Plasmodium falciparum. Eradication was abandoned in 1969 and attention instead focused on controlling and treating the disease. Spraying programs (especially using DDT) were curtailed due to concerns over safety and environmental effects, as well as problems in administrative, managerial and financial implementation. Efforts shifted from spraying to the use of bednets impregnated with insecticides and other interventions.

United States ban

By October 1945, DDT was available for public sale in the United States, used both as an agricultural pesticide and as a household insecticide. Although its use was promoted by government and the agricultural industry, US scientists such as FDA pharmacologist Herbert O. Calvery expressed concern over possible hazards associated with DDT as early as 1944. In 1947, Bradbury Robinson, a physician and nutritionist practicing in St. Louis, Michigan, warned of the dangers of using the pesticide DDT in agriculture. DDT had been researched and manufactured in St. Louis by the Michigan Chemical Corporation, later purchased by Velsicol Chemical Corporation, and had become an important part of the local economy. Citing research performed by Michigan State University in 1946, Robinson, a past president of the local Conservation Club, opined that:

perhaps the greatest danger from D.D.T. is that its extensive use in farm areas is most likely to upset the natural balances, not only killing beneficial insects in great number but by bringing about the death of fish, birds, and other forms of wild life either by their feeding on insects killed by D.D.T. or directly by ingesting the poison.

As its production and use increased, public response was mixed. At the same time that DDT was hailed as part of the "world of tomorrow", concerns were expressed about its potential to kill harmless and beneficial insects (particularly pollinators), birds, fish, and eventually humans. The issue of toxicity was complicated, partly because DDT's effects varied from species to species, and partly because consecutive exposures could accumulate, causing damage comparable to large doses. A number of states attempted to regulate DDT. In the 1950s the federal government began tightening regulations governing its use. These events received little attention. Women like Dorothy Colson and Mamie Ella Plyler of Claxton, Georgia gathered evidence about DDT's effects and wrote to the Georgia Department of Public Health, the National Health Council in New York City, and other organizations.

In 1957 The New York Times reported an unsuccessful struggle to restrict DDT use in Nassau County, New York, and the issue came to the attention of the popular naturalist-author Rachel Carson. William Shawn, editor of The New Yorker, urged her to write a piece on the subject, which developed into her 1962 book Silent Spring. The book argued that pesticides, including DDT, were poisoning both wildlife and the environment and were endangering human health. Silent Spring was a best seller, and public reaction to it launched the modern environmental movement in the United States. The year after it appeared, President John F. Kennedy ordered his Science Advisory Committee to investigate Carson's claims. The committee's report "add[ed] up to a fairly thorough-going vindication of Rachel Carson's Silent Spring thesis", in the words of the journal Science, and recommended a phaseout of "persistent toxic pesticides". In 1965, the U.S. military removed DDT from the military supply system due in part to the development of resistance by body lice to DDT; it was replaced by lindane.

DDT became a prime target of the growing anti-chemical and anti-pesticide movements, and in 1967 a group of scientists and lawyers founded Environmental Defense (later Environmental Defense Fund, EDF) with the specific goal of enacting a ban on DDT. Victor Yannacone, Charles Wurster, Art Cooley and others in the group had all witnessed bird kills or declines in bird populations and suspected that DDT was the cause. In their campaign against the chemical, the EDF petitioned the government for a ban and filed lawsuits. Around this time, toxicologist David Peakall was measuring DDE levels in the eggs of peregrine falcons and California condors and finding that increased levels corresponded with thinner shells.

In response to an EDF suit, the U.S. District Court of Appeals in 1971 ordered the EPA to begin the de-registration procedure for DDT. After an initial six-month review process, William Ruckelshaus, the Agency's first Administrator rejected an immediate suspension of DDT's registration, citing studies from the EPA's internal staff stating that DDT was not an imminent danger. However, these findings were criticized, as they were performed mostly by economic entomologists inherited from the United States Department of Agriculture, who many environmentalists felt were biased towards agribusiness and understated concerns about human health and wildlife. The decision thus created controversy.

The EPA held seven months of hearings in 1971–1972, with scientists giving evidence for and against DDT. In the summer of 1972, Ruckelshaus announced the cancellation of most uses of DDT – exempting public health uses under some conditions. Again, this caused controversy. Immediately after the announcement, both the EDF and the DDT manufacturers filed suit against EPA. Many in the agricultural community were concerned that food production would be severely impacted, while proponents of pesticides warned of increased breakouts of insect-borne diseases and questioned the accuracy of giving animals high amounts of pesticides for cancer potential. Industry sought to overturn the ban, while the EDF wanted a comprehensive ban. The cases were consolidated, and in 1973 the United States Court of Appeals for the District of Columbia Circuit ruled that the EPA had acted properly in banning DDT. During the late 1970s, the EPA also began banning organochlorines, pesticides that were chemically similar to DDT. These included aldrin, dieldrin, chlordane, heptachlor, texaphene, and mirex.

Some uses of DDT continued under the public health exemption. For example, in June 1979, the California Department of Health Services was permitted to use DDT to suppress flea vectors of bubonic plague. DDT continued to be produced in the United States for foreign markets until 1985, when over 300 tons were exported.

International usage restrictions

In the 1970s and 1980s, agricultural use was banned in most developed countries, beginning with Hungary in 1968 – although in practice it continued to be used through at least 1970. This was followed by Norway and Sweden in 1970, West Germany and the United States in 1972, but not in the United Kingdom until 1984.

In contrast to West Germany, in the German Democratic Republic DDT was used until 1988. Especially of relevance were large-scale applications in forestry in the years 1982–1984, with the aim to combat bark beetle and pine moth. As a consequence, DDT-concentrations in eastern German forest soils are still significantly higher compared to soils in the former western German states.

By 1991, total bans, including for disease control, were in place in at least 26 countries; for example, Cuba in 1970, the US in the 1980s, Singapore in 1984, Chile in 1985, and the Republic of Korea in 1986.

The Stockholm Convention on Persistent Organic Pollutants, which took effect in 2004, put a global ban on several persistent organic pollutants, and restricted DDT use to vector control. The convention was ratified by more than 170 countries. Recognizing that total elimination in many malaria-prone countries is currently unfeasible in the absence of affordable/effective alternatives, the convention exempts public health use within World Health Organization (WHO) guidelines from the ban. Resolution 60.18 of the World Health Assembly commits WHO to the Stockholm Convention's aim of reducing and ultimately eliminating DDT. Malaria Foundation International states, "The outcome of the treaty is arguably better than the status quo going into the negotiations. For the first time, there is now an insecticide which is restricted to vector control only, meaning that the selection of resistant mosquitoes will be slower than before."

Despite the worldwide ban, agricultural use continued in India, North Korea, and possibly elsewhere. As of 2013, an estimated 3,000 to 4,000 tons of DDT were produced for disease vector control, including 2,786 tons in India. DDT is applied to the inside walls of homes to kill or repel mosquitoes. This intervention, called indoor residual spraying (IRS), greatly reduces environmental damage. It also reduces the incidence of DDT resistance. For comparison, treating 40 hectares (99 acres) of cotton during a typical U.S. growing season requires the same amount of chemical to treat roughly 1,700 homes.

Environmental impact

Degradation of DDT to form DDE (by elimination of HCl, left) and DDD (by reductive dechlorination, right)

DDT is a persistent organic pollutant that is readily adsorbed to soils and sediments, which can act both as sinks and as long-term sources of exposure affecting organisms. Depending on environmental conditions, its soil half-life can range from 22 days to 30 years. Routes of loss and degradation include runoff, volatilization, photolysis and aerobic and anaerobic biodegradation. Due to hydrophobic properties, in aquatic ecosystems DDT and its metabolites are absorbed by aquatic organisms and adsorbed on suspended particles, leaving little DDT dissolved in the water (however, its half-life in aquatic environments is listed by the National Pesticide Information Center as 150 years). Its breakdown products and metabolites, DDE and DDD, are also persistent and have similar chemical and physical properties. DDT and its breakdown products are transported from warmer areas to the Arctic by the phenomenon of global distillation, where they then accumulate in the region's food web.

Medical researchers in 1974 found a measurable and significant difference in the presence of DDT in human milk between mothers who lived in New Brunswick and mothers who lived in Nova Scotia, "possibly because of the wider use of insecticide sprays in the past".

Because of its lipophilic properties, DDT can bioaccumulate, especially in predatory birds. DDT is toxic to a wide range of living organisms, including marine animals such as crayfish, daphnids, sea shrimp and many species of fish. DDT, DDE and DDD magnify through the food chain, with apex predators such as raptor birds concentrating more chemicals than other animals in the same environment. They are stored mainly in body fat. DDT and DDE are resistant to metabolism; in humans, their half-lives are 6 and up to 10 years, respectively. In the United States, these chemicals were detected in almost all human blood samples tested by the Centers for Disease Control in 2005, though their levels have sharply declined since most uses were banned. Estimated dietary intake has declined, although FDA food tests commonly detect it.

Despite being banned for many years, in 2018 research showed that DDT residues are still present in European soils and Spanish rivers.

Eggshell thinning

The chemical and its breakdown products DDE and DDD caused eggshell thinning and population declines in multiple North American and European bird of prey species. Both laboratory experiments and field studies confirmed this effect. The effect was first conclusively proven at Bellow Island in Lake Michigan during University of Michigan-funded studies on American herring gulls in the mid-1960s. DDE-related eggshell thinning is considered a major reason for the decline of the bald eagle, brown pelican, peregrine falcon and osprey. However, birds vary in their sensitivity to these chemicals, with birds of prey, waterfowl and song birds being more susceptible than chickens and related species. Even in 2010, California condors that feed on sea lions at Big Sur that in turn feed in the Palos Verdes Shelf area of the Montrose Chemical Superfund site exhibited continued thin-shell problems, though DDT's role in the decline of the California condor is disputed.

The biological thinning mechanism is not entirely understood, but DDE appears to be more potent than DDT, and strong evidence indicates that p,p'-DDE inhibits calcium ATPase in the membrane of the shell gland and reduces the transport of calcium carbonate from blood into the eggshell gland. This results in a dose-dependent thickness reduction. Other evidence indicates that o,p'-DDT disrupts female reproductive tract development, later impairing eggshell quality. Multiple mechanisms may be at work, or different mechanisms may operate in different species.

Human health

A U.S. soldier is demonstrating DDT hand-spraying equipment. DDT was used to control the spread of typhus-carrying lice.
Spraying hospital beds with DDT, PAIGC hospital of Ziguinchor, 1973
Biomagnification is the build up of toxins in a food chain. The DDT concentration is in parts per million. As the trophic level increases in a food chain, the amount of toxic build up also increases. The X's represent the amount of toxic build up accumulating as the trophic level increases. Toxins build up in organism's tissues and fat. Predators accumulate higher toxins than the prey.

DDT is an endocrine disruptor. It is considered likely to be a human carcinogen although the majority of studies suggest it is not directly genotoxic. DDE acts as a weak androgen receptor antagonist, but not as an estrogen. p,p'-DDT, DDT's main component, has little or no androgenic or estrogenic activity. The minor component o,p'-DDT has weak estrogenic activity.

Acute toxicity

DDT is classified as "moderately toxic" by the U.S. National Toxicology Program (NTP) and "moderately hazardous" by WHO, based on the rat oral LD50 of 113 mg/kg. Indirect exposure is considered relatively non-toxic for humans.

Chronic toxicity

Primarily through the tendency for DDT to build up in areas of the body with high lipid content, chronic exposure can affect reproductive capabilities and the embryo or fetus.

  • A review article in The Lancet states: "research has shown that exposure to DDT at amounts that would be needed in malaria control might cause preterm birth and early weaning ... toxicological evidence shows endocrine-disrupting properties; human data also indicate possible disruption in semen quality, menstruation, gestational length, and duration of lactation".
  • Other studies document decreases in semen quality among men with high exposures (generally from indoor residual spraying).
  • Studies are inconsistent on whether high blood DDT or DDE levels increase time to pregnancy. In mothers with high DDE blood serum levels, daughters may have up to a 32% increase in the probability of conceiving, but increased DDT levels have been associated with a 16% decrease in one study.
  • Indirect exposure of mothers through workers directly in contact with DDT is associated with an increase in spontaneous abortions.
  • Other studies found that DDT or DDE interfere with proper thyroid function in pregnancy and childhood.
  • Mothers with high levels of DDT circulating in their blood during pregnancy were found to be more likely to give birth to children who would go on to develop autism.

Carcinogenicity

In 2015, the International Agency for Research on Cancer classified DDT as Group 2A "probably carcinogenic to humans". Previous assessments by the U.S. National Toxicology Program classified it as "reasonably anticipated to be a carcinogen" and by the EPA classified DDT, DDE and DDD as class B2 "probable" carcinogens; these evaluations were based mainly on animal studies.

A 2005 Lancet review stated that occupational DDT exposure was associated with increased pancreatic cancer risk in 2 case control studies, but another study showed no DDE dose-effect association. Results regarding a possible association with liver cancer and biliary tract cancer are conflicting: workers who did not have direct occupational DDT contact showed increased risk. White men had an increased risk, but not white women or black men. Results about an association with multiple myeloma, prostate and testicular cancer, endometrial cancer and colorectal cancer have been inconclusive or generally do not support an association. A 2017 review of liver cancer studies concluded that "organochlorine pesticides, including DDT, may increase hepatocellular carcinoma risk".

A 2009 review, whose co-authors included persons engaged in DDT-related litigation, reached broadly similar conclusions, with an equivocal association with testicular cancer. Case–control studies did not support an association with leukemia or lymphoma.

Breast cancer

The question of whether DDT or DDE are risk factors in breast cancer has not been conclusively answered. Several meta analyses of observational studies have concluded that there is no overall relationship between DDT exposure and breast cancer risk. The United States Institute of Medicine reviewed data on the association of breast cancer with DDT exposure in 2012 and concluded that a causative relationship could neither be proven nor disproven.

A 2007 case-control study using archived blood samples found that breast cancer risk was increased 5-fold among women who were born prior to 1931 and who had high serum DDT levels in 1963. Reasoning that DDT use became widespread in 1945 and peaked around 1950, they concluded that the ages of 14–20 were a critical period in which DDT exposure leads to increased risk. This study, which suggests a connection between DDT exposure and breast cancer that would not be picked up by most studies, has received variable commentary in third-party reviews. One review suggested that "previous studies that measured exposure in older women may have missed the critical period". The National Toxicology Program notes that while the majority of studies have not found a relationship between DDT exposure and breast cancer that positive associations have been seen in a "few studies among women with higher levels of exposure and among certain subgroups of women".

A 2015 case control study identified a link (odds ratio 3.4) between in-utero exposure (as estimated from archived maternal blood samples) and breast cancer diagnosis in daughters. The findings "support classification of DDT as an endocrine disruptor, a predictor of breast cancer, and a marker of high risk".

Malaria control

Malaria remains the primary public health challenge in many countries. In 2015, there were 214 million cases of malaria worldwide resulting in an estimated 438,000 deaths, 90% of which occurred in Africa. DDT is one of many tools to fight the disease. Its use in this context has been called everything from a "miracle weapon [that is] like Kryptonite to the mosquitoes", to "toxic colonialism".

Before DDT, eliminating mosquito breeding grounds by drainage or poisoning with Paris green or pyrethrum was sometimes successful. In parts of the world with rising living standards, the elimination of malaria was often a collateral benefit of the introduction of window screens and improved sanitation. A variety of usually simultaneous interventions represents best practice. These include antimalarial drugs to prevent or treat infection; improvements in public health infrastructure to diagnose, sequester and treat infected individuals; bednets and other methods intended to keep mosquitoes from biting humans; and vector control strategies such as larvaciding with insecticides, ecological controls such as draining mosquito breeding grounds or introducing fish to eat larvae and indoor residual spraying (IRS) with insecticides, possibly including DDT. IRS involves the treatment of interior walls and ceilings with insecticides. It is particularly effective against mosquitoes, since many species rest on an indoor wall before or after feeding. DDT is one of 12 WHO–approved IRS insecticides.

The WHO's anti-malaria campaign of the 1950s and 1960s relied heavily on DDT and the results were promising, though temporary in developing countries. Experts tie malarial resurgence to multiple factors, including poor leadership, management and funding of malaria control programs; poverty; civil unrest; and increased irrigation. The evolution of resistance to first-generation drugs (e.g. chloroquine) and to insecticides exacerbated the situation. Resistance was largely fueled by unrestricted agricultural use. Resistance and the harm both to humans and the environment led many governments to curtail DDT use in vector control and agriculture. In 2006 WHO reversed a longstanding policy against DDT by recommending that it be used as an indoor pesticide in regions where malaria is a major problem.

Once the mainstay of anti-malaria campaigns, as of 2008 only 12 countries used DDT, including India and some southern African states, though the number was expected to rise.

Initial effectiveness

When it was introduced in World War II, DDT was effective in reducing malaria morbidity and mortality. WHO's anti-malaria campaign, which consisted mostly of spraying DDT and rapid treatment and diagnosis to break the transmission cycle, was initially successful as well. For example, in Sri Lanka, the program reduced cases from about one million per year before spraying to just 18 in 1963 and 29 in 1964. Thereafter the program was halted to save money and malaria rebounded to 600,000 cases in 1968 and the first quarter of 1969. The country resumed DDT vector control but the mosquitoes had evolved resistance in the interim, presumably because of continued agricultural use. The program switched to malathion, but despite initial successes, malaria continued its resurgence into the 1980s.

DDT remains on WHO's list of insecticides recommended for IRS. After the appointment of Arata Kochi as head of its anti-malaria division, WHO's policy shifted from recommending IRS only in areas of seasonal or episodic transmission of malaria, to advocating it in areas of continuous, intense transmission. WHO reaffirmed its commitment to phasing out DDT, aiming "to achieve a 30% cut in the application of DDT world-wide by 2014 and its total phase-out by the early 2020s if not sooner" while simultaneously combating malaria. WHO plans to implement alternatives to DDT to achieve this goal.

South Africa continues to use DDT under WHO guidelines. In 1996, the country switched to alternative insecticides and malaria incidence increased dramatically. Returning to DDT and introducing new drugs brought malaria back under control. Malaria cases increased in South America after countries in that continent stopped using DDT. Research data showed a strong negative relationship between DDT residual house sprayings and malaria. In a research from 1993 to 1995, Ecuador increased its use of DDT and achieved a 61% reduction in malaria rates, while each of the other countries that gradually decreased its DDT use had large increases.

Mosquito resistance

In some areas, resistance reduced DDT's effectiveness. WHO guidelines require that absence of resistance must be confirmed before using the chemical. Resistance is largely due to agricultural use, in much greater quantities than required for disease prevention.

Resistance was noted early in spray campaigns. Paul Russell, former head of the Allied Anti-Malaria campaign, observed in 1956 that "resistance has appeared after six or seven years". Resistance has been detected in Sri Lanka, Pakistan, Turkey and Central America and it has largely been replaced by organophosphate or carbamate insecticides, e.g. malathion or bendiocarb.

In many parts of India, DDT is ineffective. Agricultural uses were banned in 1989 and its anti-malarial use has been declining. Urban use ended. One study concluded that "DDT is still a viable insecticide in indoor residual spraying owing to its effectivity in well supervised spray operation and high excito-repellency factor."

Studies of malaria-vector mosquitoes in KwaZulu-Natal Province, South Africa found susceptibility to 4% DDT (WHO's susceptibility standard), in 63% of the samples, compared to the average of 87% in the same species caught in the open. The authors concluded that "Finding DDT resistance in the vector An. arabiensis, close to the area where we previously reported pyrethroid-resistance in the vector An. funestus Giles, indicates an urgent need to develop a strategy of insecticide resistance management for the malaria control programmes of southern Africa."

DDT can still be effective against resistant mosquitoes and the avoidance of DDT-sprayed walls by mosquitoes is an additional benefit of the chemical. For example, a 2007 study reported that resistant mosquitoes avoided treated huts. The researchers argued that DDT was the best pesticide for use in IRS (even though it did not afford the most protection from mosquitoes out of the three test chemicals) because the other pesticides worked primarily by killing or irritating mosquitoes – encouraging the development of resistance. Others argue that the avoidance behavior slows eradication. Unlike other insecticides such as pyrethroids, DDT requires long exposure to accumulate a lethal dose; however its irritant property shortens contact periods. "For these reasons, when comparisons have been made, better malaria control has generally been achieved with pyrethroids than with DDT." In India outdoor sleeping and night duties are common, implying that "the excito-repellent effect of DDT, often reported useful in other countries, actually promotes outdoor transmission".

Residents' concerns

IRS is effective if at least 80% of homes and barns in a residential area are sprayed. Lower coverage rates can jeopardize program effectiveness. Many residents resist DDT spraying, objecting to the lingering smell, stains on walls, and the potential exacerbation of problems with other insect pests. Pyrethroid insecticides (e.g. deltamethrin and lambda-cyhalothrin) can overcome some of these issues, increasing participation.

Human exposure

A 1994 study found that South Africans living in sprayed homes have levels that are several orders of magnitude greater than others. Breast milk from South African mothers contains high levels of DDT and DDE. It is unclear to what extent these levels arise from home spraying vs food residues. Evidence indicates that these levels are associated with infant neurological abnormalities.

Most studies of DDT's human health effects have been conducted in developed countries where DDT is not used and exposure is relatively low.

Illegal diversion to agriculture is also a concern as it is difficult to prevent and its subsequent use on crops is uncontrolled. For example, DDT use is widespread in Indian agriculture, particularly mango production and is reportedly used by librarians to protect books. Other examples include Ethiopia, where DDT intended for malaria control is reportedly used in coffee production, and Ghana where it is used for fishing. The residues in crops at levels unacceptable for export have been an important factor in bans in several tropical countries. Adding to this problem is a lack of skilled personnel and management.

Criticism of restrictions on DDT use

Restrictions on DDT usage have been criticized by some organizations opposed to the environmental movement, including Roger Bate of the pro-DDT advocacy group Africa Fighting Malaria and the libertarian think tank Competitive Enterprise Institute; these sources oppose restrictions on DDT and attribute large numbers of deaths to such restrictions, sometimes in the millions. These arguments were rejected as "outrageous" by former WHO scientist Socrates Litsios. May Berenbaum, University of Illinois entomologist, says, "to blame environmentalists who oppose DDT for more deaths than Hitler is worse than irresponsible". More recently, Michael Palmer, a professor of chemistry at the University of Waterloo, has pointed out that DDT is still used to prevent malaria, that its declining use is primarily due to increases in manufacturing costs, and that in Africa, efforts to control malaria have been regional or local, not comprehensive.

The question that ... malaria control experts must ask is not "Which is worse, malaria or DDT?" but rather "What are the best tools to deploy for malaria control in a given situation, taking into account the on-the-ground challenges and needs, efficacy, cost, and collateral effects – both positive and negative – to human health and the environment, as well as the uncertainties associated with all these considerations?"

Hans Herren & Charles Mbogo

Criticisms of a DDT "ban" often specifically reference the 1972 United States ban (with the erroneous implication that this constituted a worldwide ban and prohibited use of DDT in vector control). Reference is often made to Silent Spring, even though Carson never pushed for a DDT ban. John Quiggin and Tim Lambert wrote, "the most striking feature of the claim against Carson is the ease with which it can be refuted".

Investigative journalist Adam Sarvana and others characterize these notions as "myths" promoted principally by Roger Bate of the pro-DDT advocacy group Africa Fighting Malaria (AFM).

Alternatives

Insecticides

Organophosphate and carbamate insecticides, e.g. malathion and bendiocarb, respectively, are more expensive than DDT per kilogram and are applied at roughly the same dosage. Pyrethroids such as deltamethrin are also more expensive than DDT, but are applied more sparingly (0.02–0.3 g/m2 vs 1–2 g/m2), so the net cost per house per treatment is about the same. DDT has one of the longest residual efficacy periods of any IRS insecticide, lasting 6 to 12 months. Pyrethroids will remain active for only 4 to 6 months, and organophosphates and carbamates remain active for 2 to 6 months. In many malaria-endemic countries, malaria transmission occurs year-round, meaning that the high expense of conducting a spray campaign (including hiring spray operators, procuring insecticides, and conducting pre-spray outreach campaigns to encourage people to be home and to accept the intervention) will need to occur multiple times per year for these shorter-lasting insecticides.

In 2019, the related compound difluorodiphenyltrichloroethane (DFDT) was described as a potentially more effective and therefore potentially safer alternative to DDT.

Non-chemical vector control

Before DDT, malaria was successfully eliminated or curtailed in several tropical areas by removing or poisoning mosquito breeding grounds and larva habitats, for example by eliminating standing water. These methods have seen little application in Africa for more than half a century. According to CDC, such methods are not practical in Africa because "Anopheles gambiae, one of the primary vectors of malaria in Africa, breeds in numerous small pools of water that form due to rainfall ... It is difficult, if not impossible, to predict when and where the breeding sites will form, and to find and treat them before the adults emerge."

The relative effectiveness of IRS versus other malaria control techniques (e.g. bednets or prompt access to anti-malarial drugs) varies and is dependent on local conditions.

A WHO study released in January 2008 found that mass distribution of insecticide-treated mosquito nets and artemisinin–based drugs cut malaria deaths in half in malaria-burdened Rwanda and Ethiopia. IRS with DDT did not play an important role in mortality reduction in these countries.

Vietnam has enjoyed declining malaria cases and a 97% mortality reduction after switching in 1991 from a poorly funded DDT-based campaign to a program based on prompt treatment, bednets and pyrethroid group insecticides.

In Mexico, effective and affordable chemical and non-chemical strategies were so successful that the Mexican DDT manufacturing plant ceased production due to lack of demand.

A review of fourteen studies in sub-Saharan Africa, covering insecticide-treated nets, residual spraying, chemoprophylaxis for children, chemoprophylaxis or intermittent treatment for pregnant women, a hypothetical vaccine and changing front–line drug treatment, found decision making limited by the lack of information on the costs and effects of many interventions, the small number of cost-effectiveness analyses, the lack of evidence on the costs and effects of packages of measures and the problems in generalizing or comparing studies that relate to specific settings and use different methodologies and outcome measures. The two cost-effectiveness estimates of DDT residual spraying examined were not found to provide an accurate estimate of the cost-effectiveness of DDT spraying; the resulting estimates may not be good predictors of cost-effectiveness in current programs.

However, a study in Thailand found the cost per malaria case prevented of DDT spraying (US$1.87) to be 21% greater than the cost per case prevented of lambda-cyhalothrin–treated nets (US$1.54), casting some doubt on the assumption that DDT was the most cost-effective measure. The director of Mexico's malaria control program found similar results, declaring that it was 25% cheaper for Mexico to spray a house with synthetic pyrethroids than with DDT. However, another study in South Africa found generally lower costs for DDT spraying than for impregnated nets.

A more comprehensive approach to measuring the cost-effectiveness or efficacy of malarial control would not only measure the cost in dollars, as well as the number of people saved, but would also consider ecological damage and negative human health impacts. One preliminary study found that it is likely that the detriment to human health approaches or exceeds the beneficial reductions in malarial cases, except perhaps in epidemics. It is similar to the earlier study regarding estimated theoretical infant mortality caused by DDT and subject to the criticism also mentioned earlier.

A study in the Solomon Islands found that "although impregnated bed nets cannot entirely replace DDT spraying without substantial increase in incidence, their use permits reduced DDT spraying".

A comparison of four successful programs against malaria in Brazil, India, Eritrea and Vietnam does not endorse any single strategy but instead states, "Common success factors included conducive country conditions, a targeted technical approach using a package of effective tools, data-driven decision-making, active leadership at all levels of government, involvement of communities, decentralized implementation and control of finances, skilled technical and managerial capacity at national and sub-national levels, hands-on technical and programmatic support from partner agencies, and sufficient and flexible financing."

DDT resistant mosquitoes may be susceptible to pyrethroids in some countries. However, pyrethroid resistance in Anopheles mosquitoes is on the rise with resistant mosquitoes found in multiple countries.

Pollutant

From Wikipedia, the free encyclopedia
Surface runoff, also called nonpoint source pollution, from a farm field in Iowa, the United States during a rainstorm. Topsoil, as well as farm fertilizers and other potential pollutants, runoff unprotected farm fields when heavy rains occur.

A pollutant or novel entity is a substance or energy introduced into the environment that has undesired effects, or adversely affects the usefulness of a resource. These can be both naturally forming (i.e. minerals or extracted compounds like oil) or anthropogenic in origin (i.e. manufactured materials or byproducts). Pollutants result in environmental pollution or become public health concerns when they reach a concentration high enough to have significant negative impacts.

A pollutant may cause long- or short-term damage by changing the growth rate of plant or animal species, or by interfering with resources used by humans, human health or wellbeing, or property values. Some pollutants are biodegradable and therefore will not persist in the environment in the long term. However, the degradation products of some pollutants are themselves polluting such as the products DDE and DDD produced from the degradation of DDT.

Pollution has widespread negative impacts on the environment. When analyzed from a planetary boundaries perspective, human society has released novel entities that well exceed safe levels.

Different types of pollutants in the environment

Pollutants can be categorized in a variety of different ways. For example, it is sometimes useful to distinguish between stock pollutants and fund pollutants. Another way is to group them together according to more specific properties, such as organic, particulate, pharmaceutical, et cetera. The environment has some capacity to absorb many discharges without measurable harm, and this is called “assimilative capacity (or absorptive capacity); a pollutant actually causes pollution when the assimilative capacity is exceeded.

Stock pollutants

Pollutants, towards which the environment has low absorptive capacity are called stock pollutants. Examples include persistent organic pollutants like PCBs, non-biodegradable plastics and heavy metals. Stock pollutants accumulate in the environment over time. The damage they cause increases as more pollutant is emitted, and persists as the pollutant accumulates. Stock pollutants can create a burden for the future generations, bypassing on the damage that persists well after the benefits received from incurring that damage, have been forgotten. Scientists have officially deemed that the planetary boundaries safe chemical pollutant levels (novel entities) have been surpassed.

Fund pollutants

In contrast to stock pollutants, for which the environment has low absorptive capacity, fund pollutants are those for which the environment has a moderate absorptive capacity. Fund pollutants do not cause damage to the environment unless the emission rate exceeds the receiving environment's absorptive capacity (e.g. carbon dioxide, which is absorbed by plants and oceans). Fund pollutants are not destroyed, but rather converted into less harmful substances, or diluted/dispersed to non-harmful concentrations.

Specific groups of pollutants

Many pollutants are within the following notable groups:

Light pollutant

Light pollution is the impact that anthropogenic light has on the visibility of the night sky. It also encompasses ecological light pollution which describes the effect of artificial light on individual organisms and on the structure of ecosystems as a whole.

The night sky viewed from Luhasoo bog, Estonia with light pollution in the background

Zones of influence

Pollutants can also be defined by their zones of influence, both horizontally and vertically.

Horizontal zone

The horizontal zone refers to the area that is damaged by a pollutant. Local pollutants cause damage near the emission source. Regional pollutants cause damage further from the emission source.

Vertical zone

The vertical zone refers to whether the damage is ground-level or atmospheric. Surface pollutants cause damage by accumulating near the Earth's surface. Global pollutants cause damage by concentrating on the atmosphere.

Measuring concentration

Measures of pollutant concentration are used to determine risk assessment in public health.

Industry is continually synthesizing new chemicals, the regulation of which requires evaluation of the potential danger for human health and the environment. Risk assessment is nowadays considered essential for making these decisions on a scientifically sound basis.

Measures or defined limits include:

Regulation

International

Pollutants can cross international borders and therefore international regulations are needed for their control. The Stockholm Convention on Persistent Organic Pollutants, which entered into force in 2004, is an international legally binding agreement for the control of persistent organic pollutants. Pollutant Release and Transfer Registers (PRTR) are systems to collect and disseminate information on environmental releases and transfers of toxic chemicals from industrial and other facilities.

European Union

The European Pollutant Emission Register is a type of PRTR providing access to information on the annual emissions of industrial facilities in the Member States of the European Union, as well as Norway.

United States

Clean Air Act standards. Under the Clean Air Act, the National Ambient Air Quality Standards (NAAQS) are developed by the Environmental Protection Agency (EPA) for six common air pollutants, also called "criteria pollutants": particulates; smog and ground-level ozone; carbon monoxide; sulfur oxides; nitrogen oxides; and lead. The National Emissions Standards for Hazardous Air Pollutants are additional emission standards that are set by EPA for toxic air pollutants.

Clean Water Act standards. Under the Clean Water Act, EPA promulgated national standards for municipal sewage treatment plants, also called publicly owned treatment works, in the Secondary Treatment Regulation. National standards for industrial dischargers are called Effluent guidelines (for existing sources) and New Source Performance Standards, and currently cover over 50 industrial categories. In addition, the Act requires states to publish water quality standards for individual water bodies to provide additional protection where the national standards are insufficient.

RCRA standards. The Resource Conservation and Recovery Act (RCRA) regulates the management, transport and disposal of municipal solid waste, hazardous waste and underground storage tanks.

Wednesday, December 6, 2023

Robustness (evolution)

From Wikipedia, the free encyclopedia
https://en.wikipedia.org/wiki/Robustness_(evolution)

In evolutionary biology, robustness of a biological system (also called biological or genetic robustness) is the persistence of a certain characteristic or trait in a system under perturbations or conditions of uncertainty. Robustness in development is known as canalization. According to the kind of perturbation involved, robustness can be classified as mutational, environmental, recombinational, or behavioral robustness etc. Robustness is achieved through the combination of many genetic and molecular mechanisms and can evolve by either direct or indirect selection. Several model systems have been developed to experimentally study robustness and its evolutionary consequences.
A network of genotypes linked by mutations. Each genotype is made up of 3 genes: a, b & c. Each gene can be one of two alleles. Lines link different phenotypes by mutation. The phenotype is indicated by colour. Genotypes abc, Abc, aBc and abC lie on a neutral network since all have the same, dark phenotype. Genotype abc is robust since any single mutation retains the same phenotype. Other genotypes are less robust as mutations change the phenotype (e.g. ABc).

Classification

Mutational robustness

Mutational robustness (also called mutation tolerance) describes the extent to which an organism's phenotype remains constant in spite of mutation. Robustness can be empirically measured for several genomes and individual genes by inducing mutations and measuring what proportion of mutants retain the same phenotype, function or fitness. More generally robustness corresponds to the neutral band in the distribution of fitness effects of mutation (i.e. the frequencies of different fitnesses of mutants). Proteins so far investigated have shown a tolerance to mutations of roughly 66% (i.e. two thirds of mutations are neutral).

Conversely, measured mutational robustnesses of organisms vary widely. For example, >95% of point mutations in C. elegans have no detectable effect and even 90% of single gene knockouts in E. coli are non-lethal. Viruses, however, only tolerate 20-40% of mutations and hence are much more sensitive to mutation.

Robustness to stochasticity

Biological processes at the molecular scale are inherently stochastic. They emerge from a combination of stochastic events that happen given the physico-chemical properties of molecules. For instance, gene expression is intrinsically noisy. This means that two cells in exactly identical regulatory states will exhibit different mRNA contents. The cell population level log-normal distribution of mRNA content follows directly from the application of the Central Limit Theorem to the multi-step nature of gene expression regulation.

Environmental robustness

In varying environments, perfect adaptation to one condition may come at the expense of adaptation to another. Consequently, the total selection pressure on an organism is the average selection across all environments weighted by the percentage time spent in that environment. Variable environment can therefore select for environmental robustness where organisms can function across a wide range of conditions with little change in phenotype or fitness (biology). Some organisms show adaptations to tolerate large changes in temperature, water availability, salinity or food availability. Plants, in particular, are unable to move when the environment changes and so show a range of mechanisms for achieving environmental robustness. Similarly, this can be seen in proteins as tolerance to a wide range of solvents, ion concentrations or temperatures.

Genetic, molecular and cellular causes

Core eukaryotic metabolic network. Circles indicate metabolites and lines indicate conversions by enzymes. Many metabolites can be produced via more than one route, therefore the organism is robust to the loss of some metabolic enzymes

Genomes mutate by environmental damage and imperfect replication, yet they display remarkable tolerance. This comes from robustness both at many different levels.

Organism mutational robustness

There are many mechanisms that provide genome robustness. For example, genetic redundancy reduces the effect of mutations in any one copy of a multi-copy gene. Additionally the flux through a metabolic pathway is typically limited by only a few of the steps, meaning that changes in function of many of the enzymes have little effect on fitness. Similarly metabolic networks have multiple alternate pathways to produce many key metabolites.

Protein mutational robustness

Protein mutation tolerance is the product of two main features: the structure of the genetic code and protein structural robustness. Proteins are resistant to mutations because many sequences can fold into highly similar structural folds. A protein adopts a limited ensemble of native conformations because those conformers have lower energy than unfolded and mis-folded states (ΔΔG of folding). This is achieved by a distributed, internal network of cooperative interactions (hydrophobic, polar and covalent). Protein structural robustness results from few single mutations being sufficiently disruptive to compromise function. Proteins have also evolved to avoid aggregation as partially folded proteins can combine to form large, repeating, insoluble protein fibrils and masses. There is evidence that proteins show negative design features to reduce the exposure of aggregation-prone beta-sheet motifs in their structures. Additionally, there is some evidence that the genetic code itself may be optimised such that most point mutations lead to similar amino acids (conservative). Together these factors create a distribution of fitness effects of mutations that contains a high proportion of neutral and nearly-neutral mutations.

Gene expression robustness

During embryonic development, gene expression must be tightly controlled in time and space in order to give rise to fully functional organs. Developing organisms must therefore deal with the random perturbations resulting from gene expression stochasticity. In bilaterians, robustness of gene expression can be achieved via enhancer redundancy. This happens when the expression of a gene under the control of several enhancers encoding the same regulatory logic (ie. displaying binding sites for the same set of transcription factors). In Drosophila melanogaster such redundant enhancers are often called shadow enhancers.

Furthermore, in developmental contexts were timing of gene expression in important for the phenotypic outcome, diverse mechanisms exist to ensure proper gene expression in a timely manner. Poised promoters are transcriptionally inactive promoters that display RNA polymerase II binding, ready for rapid induction. In addition, because not all transcription factors can bind their target site in compacted heterochromatin, pioneer transcription factors (such as Zld or FoxA) are required to open chromatin and allow the binding of other transcription factors that can rapidly induce gene expression. Open inactive enhancers are call poised enhancers.

Cell competition is a phenomenon first described in Drosophila where mosaic Minute mutant cells (affecting ribosomal proteins) in a wild-type background would be eliminated. This phenomenon also happens in the early mouse embryo where cells expressing high levels of Myc actively kill their neighbors displaying low levels of Myc expression. This results in homogeneously high levels of Myc.

Developmental patterning robustness

Patterning mechanisms such as those described by the French flag model can be perturbed at many levels (production and stochasticity of the diffusion of the morphogen, production of the receptor, stochastic of the signaling cascade, etc). Patterning is therefore inherently noisy. Robustness against this noise and genetic perturbation is therefore necessary to ensure proper that cells measure accurately positional information. Studies of the zebrafish neural tube and antero-posterior patternings has shown that noisy signaling leads to imperfect cell differentiation that is later corrected by transdifferentiation, migration or cell death of the misplaced cells.

Additionally, the structure (or topology) of signaling pathways has been demonstrated to play an important role in robustness to genetic perturbations. Self-enhanced degradation has long been an example of robustness in System biology. Similarly, robustness of dorsoventral patterning in many species emerges from the balanced shuttling-degradation mechanisms involved in BMP signaling.

Evolutionary consequences

Since organisms are constantly exposed to genetic and non-genetic perturbations, robustness is important to ensure the stability of phenotypes. Also, under mutation-selection balance, mutational robustness can allow cryptic genetic variation to accumulate in a population. While phenotypically neutral in a stable environment, these genetic differences can be revealed as trait differences in an environment-dependent manner (see evolutionary capacitance), thereby allowing for the expression of a greater number of heritable phenotypes in populations exposed to a variable environment.

Being robust may even be a favoured at the expense of total fitness as an evolutionarily stable strategy (also called survival of the flattest). A high but narrow peak of a fitness landscape confers high fitness but low robustness as most mutations lead to massive loss of fitness. High mutation rates may favour population of lower, but broader fitness peaks. More critical biological systems may also have greater selection for robustness as reductions in function are more damaging to fitness. Mutational robustness is thought to be one driver for theoretical viral quasispecies formation.

Each circle represents a functional gene variant and lines represent point mutations between them. Light grid-regions have low fitness, dark regions have high fitness. (a) White circles have few neutral neighbours, black circles have many. Light grid-regions contain no circles because those sequences have low fitness. (b) Within a neutral network, the population is predicted to evolve towards the centre and away from 'fitness cliffs' (dark arrows).

Emergent mutational robustness

Natural selection can select directly or indirectly for robustness. When mutation rates are high and population sizes are large, populations are predicted to move to more densely connected regions of neutral network as less robust variants have fewer surviving mutant descendants. The conditions under which selection could act to directly increase mutational robustness in this way are restrictive, and therefore such selection is thought to be limited to only a few viruses and microbes having large population sizes and high mutation rates. Such emergent robustness has been observed in experimental evolution of cytochrome P450s and B-lactamase. Conversely, mutational robustness may evolve as a byproduct of natural selection for robustness to environmental perturbations.

Robustness and evolvability

Mutational robustness has been thought to have a negative impact on evolvability because it reduces the mutational accessibility of distinct heritable phenotypes for a single genotype and reduces selective differences within a genetically diverse population. Counter-intuitively however, it has been hypothesized that phenotypic robustness towards mutations may actually increase the pace of heritable phenotypic adaptation when viewed over longer periods of time.

One hypothesis for how robustness promotes evolvability in asexual populations is that connected networks of fitness-neutral genotypes result in mutational robustness which, while reducing accessibility of new heritable phenotypes over short timescales, over longer time periods, neutral mutation and genetic drift cause the population to spread out over a larger neutral network in genotype space. This genetic diversity gives the population mutational access to a greater number of distinct heritable phenotypes that can be reached from different points of the neutral network. However, this mechanism may be limited to phenotypes dependent on a single genetic locus; for polygenic traits, genetic diversity in asexual populations does not significantly increase evolvability.

In the case of proteins, robustness promotes evolvability in the form of an excess free energy of folding. Since most mutations reduce stability, an excess folding free energy allows toleration of mutations that are beneficial to activity but would otherwise destabilise the protein.

In sexual populations, robustness leads to the accumulation of cryptic genetic variation with high evolutionary potential.

Evolvability may be high when robustness is reversible, with evolutionary capacitance allowing a switch between high robustness in most circumstances and low robustness at times of stress.

Methods and model systems

There are many systems that have been used to study robustness. In silico models have been used to model promoters, RNA secondary structure, protein lattice models, or gene networks. Experimental systems for individual genes include enzyme activity of cytochrome P450, B-lactamase, RNA polymerase, and LacI have all been used. Whole organism robustness has been investigated in RNA virus fitness, bacterial chemotaxis, Drosophila fitness, segment polarity network, neurogenic network and bone morphogenetic protein gradient, C. elegans fitness and vulval development, and mammalian circadian clock.

Rydberg atom

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Rydberg_atom Figure 1: Electron orbi...