Mutagen

From Wikipedia, the free encyclopedia

The international pictogram for chemicals that are sensitising, mutagenic, carcinogenic or toxic to reproduction.

In genetics, a mutagen is a physical or chemical agent that changes the genetic material, usually DNA, of an organism and thus increases the frequency of mutations above the natural background level. As many mutations can cause cancer, mutagens are therefore also likely to be carcinogens, although not always necessarily so. Some chemicals only become mutagenic through cellular processes. Not all mutations are caused by mutagens: so-called "spontaneous mutations" occur due to spontaneous hydrolysis, errors in DNA replication, repair and recombination.

Discovery

The first mutagens to be identified were carcinogens, substances that were shown to be linked to cancer. Tumors were described more than 2,000 years before the discovery of chromosomes and DNA; in 500 B.C., the Greek physician Hippocrates named tumors resembling a crab karkinos (from which the word "cancer" is derived via Latin), meaning crab.^[1] In 1567, Swiss physician Paracelsus suggested that an unidentified substance in mined ore (identified as radon gas in modern times) caused a wasting disease in miners,^[2] and in England, in 1761, John Hill made the first direct link of cancer to chemical substances by noting that excessive use of snuff may cause nasal cancer.^[3] In 1775, Sir Percivall Pott wrote a paper on the high incidence of scrotal cancer in chimney sweeps, and suggested chimney soot as the cause of scrotal cancer.^[4] In 1915, Yamagawa and Ichikawa showed that repeated application of coal tar to rabbit's ears produced malignant cancer.^[5] Subsequently, in the 1930s the carcinogen component in coal tar was identified as a polyaromatic hydrocarbon (PAH), benzo[a]pyrene.^[2][6] Polyaromatic hydrocarbons are also present in soot, which was suggested to be a causative agent of cancer over 150 years earlier.

The association of exposure to radiation and cancer had been observed as early as 1902, six years after the discovery of X-ray by Wilhelm Röntgen and radioactivy by Henri Becquerel.^[7] Georgii Nadson and German Filippov were the first who created fungi mutants under ionizing radiation in 1925.^[8][9] The mutagenic property of mutagens was first demonstrated in 1927, when Hermann Muller discovered that x-rays can cause genetic mutations in fruit flies, producing phenotypic mutants as well as observable changes to the chromosomes,^[10][11] visible due to presence of enlarged 'polytene' chromosomes in fruit fly salivary glands.^[12] His collaborator Edgar Altenburg also demonstrated the mutational effect of UV radiation in 1928.^[13] Muller went on to use x-rays to create Drosophila mutants that he used in his studies of genetics.^[14] He also found that X-rays not only mutate genes in fruit flies,^[10] but also have effects on the genetic makeup of humans. Similar work by Lewis Stadler also showed the mutational effect of X-rays on barley in 1928,^[16] and ultraviolet (UV) radiation on maize in 1936.^[17] The effect of sunlight had previously been noted in the nineteenth century where rural outdoor workers and sailors were found to be more prone to skin cancer.^[18]

Chemical mutagens were not demonstrated to cause mutation until the 1940s, when Charlotte Auerbach and J. M. Robson found that mustard gas can cause mutations in fruit flies.^[19] A large number of chemical mutagens have since been identified, especially after the development of the Ames test in the 1970s by Bruce Ames that screens for mutagens and allows for preliminary identification of carcinogens.^[20][21] Early studies by Ames showed around 90% of known carcinogens can be identified in Ames test as mutagenic (later studies however gave lower figures),^[22][23][24] and ~80% of the mutagens identified through Ames test may also be carcinogens. Mutagens are not necessarily carcinogens, and vice versa. Sodium azide for example may be mutagenic (and highly toxic), but it has not been shown to be carcinogenic.^[26]

Effects

Mutagens can cause changes to the DNA and are therefore genotoxic. They can affect the transcription and replication of the DNA, which in severe cases can lead to cell death. The mutagen produces mutations in the DNA, and deleterious mutation can result in aberrant, impaired or loss of function for a particular gene, and accumulation of mutations may lead to cancer. Mutagens may therefore be also carcinogens. However, some mutagens exert their mutagenic effect through their metabolites, and therefore whether such mutagens actually become carcinogenic may be dependent on the metabolic processes of an organism, and a compound shown to be mutagenic in one organism may not necessarily be carcinogenic in another.^[27]
Different mutagens act on the DNA differently. Powerful mutagens may result in chromosomal instability,^[28] causing chromosomal breakages and rearrangement of the chromosomes such as translocation, deletion, and inversion. Such mutagens are called clastogens.

Mutagens may also modify the DNA sequence; the changes in nucleic acid sequences by mutations include substitution of nucleotide base-pairs and insertions and deletions of one or more nucleotides in DNA sequences. Although some of these mutations are lethal or cause serious disease, many have minor effects as they do not result in residue changes that have significant effect on the structure and function of the proteins. Many mutations are silent mutations, causing no visible effects at all, either because they occur in non-coding or non-functional sequences, or they do not change the amino-acid sequence due to the redundancy of codons.

Some mutagens can cause aneuploidy and change the number of chromosomes in the cell. They are known as aneuploidogens.^[29]

In Ames test, where the varying concentrations of the chemical are used in the test, the dose response curve obtained is nearly always linear, suggesting that there may be no threshold for mutagenesis. Similar results are also obtained in studies with radiations, indicating that there may be no safe threshold for mutagens. However, the no-threshold model is disputed with some arguing for a dose rate dependent threshold for mutagenesis.^{[30] [10]} Some have proposed that low level of some mutagens may stimulate the DNA repair processes and therefore may not necessarily be harmful. More recent approaches with sensitive analytical methods have shown that there may be non-linear or bilinear dose-responses for genotoxic effects, and that the activation of DNA repair pathways can prevent the occurrence of mutation arising from a low dose of mutagen.^[31]

Types

Mutagens may be of physical, chemical or biological origin. They may act directly on the DNA, causing direct damage to the DNA, and most often result in replication error. Some however may act on the replication mechanism and chromosomal partition. Many mutagens are not mutagenic by themselves, but can form mutagenic metabolites through cellular processes, for example through the activity of the cytochrome P450 system and other oxygenases such as cyclooxygenase.^[32] Such mutagens are called promutagens.

Physical mutagens

• Ionizing radiations such as X-rays, gamma rays and alpha particles cause DNA breakage and other damages. The most common lab sources include cobalt-60 and cesium-137.
  
• Ultraviolet radiations with wavelength above 260 nm are absorbed strongly by bases, producing pyrimidine dimers, which can cause error in replication if left uncorrected.
  
• Radioactive decay, such as ¹⁴C in DNA which decays into nitrogen.

DNA reactive chemicals

A DNA adduct (at center) of the mutagenic metabolite of benzo[a]pyrene from tobacco smoke.

A large number of chemicals may interact directly with DNA. However, many such as PAHs, aromatic amines, benzene are not necessarily mutagenic by themselves, but through metabolic processes in cells they produce mutagenic compounds.

• Reactive oxygen species (ROS) – These may be superoxide, hydroxyl radicals and hydrogen peroxide, and large number of these highly reactive species are generated by normal cellular processes, for example as a by-products of mitochondrial electron transport, or lipid peroxidation. As an example of the latter, 15-hydroperoxyicosatetraenocic acid, a natural product of cellular cyclooxygenases and lipoxygenases, breaks down to form 4-hydroxy-2(E)-nonenal, 4-hydroperoxy-2(E)-nonenal, 4-oxo-2(E)-nonenal, and cis-4,5-epoxy-2(E)-decanal; these bifunctional electophils are mutagenic in mammalian cells and may contribute to the development and/or progression of human cancers (see 15-Hydroxyicosatetraenoic acid).^[33] A number of mutagens may also generate these ROS. These ROS may result in the production of many base adducts, as well as DNA strand breaks and crosslinks.
  
• Deaminating agents, for example nitrous acid which can cause transition mutations by converting cytosine to uracil.
  
• Polycyclic aromatic hydrocarbon (PAH), when activated to diol-epoxides can bind to DNA and form adducts.
  
• Alkylating agents such as ethylnitrosourea. The compounds transfer methyl or ethyl group to bases or the backbone phosphate groups. Guanine when alkylated may be mispaired with thymine. Some may cause DNA crosslinking and breakages. Nitrosamines are an important group of mutagens found in tobacco, and may also be formed in smoked meats and fish via the interaction of amines in food with nitrites added as preservatives. Other alkylating agents include mustard gas and vinyl chloride.
  
• Aromatic amines and amides have been associated with carcinogenesis since 1895 when German physician Ludwig Rehn observed high incidence of bladder cancer among workers in German synthetic aromatic amine dye industry. 2-Acetylaminofluorene, originally used as a pesticide but may also be found in cooked meat, may cause cancer of the bladder, liver, ear, intestine, thyroid and breast.
  
• Alkaloid from plants, such as those from Vinca species,^{[citation needed]} may be converted by metabolic processes into the active mutagen or carcinogen.
  
• Bromine and some compounds that contain bromine in their chemical structure.
  
• Sodium azide, an azide salt that is a common reagent in organic synthesis and a component in many car airbag systems.
  
• Psoralen combined with ultraviolet radiation causes DNA cross-linking and hence chromosome breakage.
  
• Benzene, an industrial solvent and precursor in the production of drugs, plastics, synthetic rubber and dyes.

Base analogs

• Base analog, which can substitute for DNA bases during replication and cause transition mutations.

Intercalating agents

• Intercalating agents, such as ethidium bromide and proflavine, are molecules that may insert between bases in DNA, causing frameshift mutation during replication. Some such as daunorubicin may block transcription and replication, making them highly toxic to proliferating cells.

Metals

Many metals, such as arsenic, cadmium, chromium, nickel and their compounds may be mutagenic, but they may act, however, via a number of different mechanisms.^[34] Arsenic, chromium, iron, and nickel may be associated with the production of ROS, and some of these may also alter the fidelity of DNA replication. Nickel may also be linked to DNA hypermethylation and histone deacetylation, while some metals such as cobalt, arsenic, nickel and cadmium may also affect DNA repair processes such as DNA mismatch repair, and base and nucleotide excision repair.^[35]

Biological agents

• Transposon, a section of DNA that undergoes autonomous fragment relocation/multiplication. Its insertion into chromosomal DNA disrupts functional elements of the genes.
  
• Virus – Virus DNA may be inserted into the genome and disrupts genetic function. Infectious agents have been suggested to cause cancer as early as 1908 by Vilhelm Ellermann and Oluf Bang,^[36] and 1911 by Peyton Rous who discovered the Rous sarcoma virus.
  
• Bacteria – some bacteria such as Helicobacter pylori cause inflammation during which oxidative species are produced, causing DNA damage and reducing efficiency of DNA repair systems, thereby increasing mutation.

Protection

Fruits and vegetables are rich in antioxidants.

Antioxidants are an important group of anticarcinogenic compounds that may help remove ROS or potentially harmful chemicals. These may be found naturally in fruits and vegetables.^[38] Examples of antioxidants are vitamin A and its carotenoid precursors, vitamin C, vitamin E, polyphenols, and various other compounds. β-Carotene is the red-orange colored compounds found in vegetables like carrots and tomatoes. Vitamin C may prevent some cancers by inhibiting the formation of mutagenic N-nitroso compounds (nitrosamine). Flavonoids, such as EGCG in green tea, have also been shown to be effective antioxidants and may have anti-cancer properties. Epidemiological studies indicate that a diet rich in fruits and vegetables is associated with lower incidence of some cancers and longer life expectancy,^[39] however, the effectiveness of antioxidant supplements in cancer prevention in general is still the subject of some debate.^[39][40]

Other chemicals may reduce mutagenesis or prevent cancer via other mechanisms, although for some the precise mechanism for their protective property may not be certain. Selenium, which is present as a micronutrient in vegetables, is a component of important antioxidant enzymes such as gluthathione peroxidase. Many phytonutrients may counter the effect of mutagens; for example, sulforaphane in vegetables such as broccoli has been shown to be protective against prostate cancer.^[41] Others that may be effective against cancer include indole-3-carbinol from cruciferous vegetables and resveratrol from red wine.^[42]

An effective precautionary measure an individual can undertake to protect themselves is by limiting exposure to mutagens such as UV radiations and tobacco smoke. In Australia, where people with pale skin are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.^[43][44]

In 1981, human epidemiological analysis by Richard Doll and Richard Peto indicated that smoking caused 30% of cancers in the US.^[45] Diet is also thought to cause a significant number of cancer, and it has been estimated that around 32% of cancer deaths may be avoidable by modification to the diet.^[46] Mutagens identified in food include mycotoxins from food contaminated with fungal growths, such as aflatoxins which may be present in contaminated peanuts and corn; heterocyclic amines generated in meat when cooked at high temperature; PAHs in charred meat and smoked fish, as well as in oils, fats, bread, and cereal;^[47] and nitrosamines generated from nitrites used as food preservatives in cured meat such as bacon (ascobate, which is added to cured meat, however, reduces nitrosamine formation).^[38] Overly-browned starchy food such as bread, biscuits and potatoes can generate acrylamide, a chemical shown to cause cancer in animal studies.^[48][49] Excessive alcohol consumption has also been linked to cancer; the possible mechanisms for its carcinogenicity include formation of the possible mutagen acetaldehyde, and the induction of the cytochrome P450 system which is known to produce mutagenic compounds from promutagens.^[50]

For certain mutagens, such as dangerous chemicals and radioactive materials, as well as infectious agents known to cause cancer, government legislations and regulatory bodies are necessary for their control.^[51]

Test systems

Many different systems for detecting mutagen have been developed.^[52][53] Animal systems may more accurately reflect the metabolism of human, however, they are expensive and time-consuming (may take around three years to complete), they are therefore not used as a first screen for mutagenicity or carcinogenicity.

Bacterial

• Ames test – This is the most commonly used test, and Salmonella typhimurium strains deficient in histidine biosynthesis are used in this test. The test checks for mutants that can revert to wild-type. It is an easy, inexpensive and convenient initial screen for mutagens.
  
• Resistance to 8-azaguanine in S. typhimurium – Similar to Ames test, but instead of reverse mutation, it checks for forward mutation that confer resistance to 8-Azaguanine in a histidine revertant strain.
  
• Escherichia coli systems – Both forward and reverse mutation detection system have been modified for use in E. coli. Tryptophan-deficient mutant is used for the reverse mutation, while galactose utility or resistance to 5-methyltryptophan may be used for forward mutation.
  
• DNA repair – E. coli and Bacillus subtilis strains deficient in DNA repair may be used to detect mutagens by their effect on the growth of these cells through DNA damage.

Yeast

Systems similar to Ames test have been developed in yeast. Saccharomyces cerevisiae is generally used. These systems can check for forward and reverse mutations, as well as recombinant events.

Drosophila

Sex-Linked Recessive Lethal Test – Males from a strain with yellow bodies are used in this test. The gene for the yellow body lies on the X-chromosome. The fruit flies are fed on a diet of test chemical, and progenies are separated by sex. The surviving males are crossed with the females of the same generation, and if no males with yellow bodies are detected in the second generation, it would indicate a lethal mutation on the X-chromosome has occurred.

Plant assays

Plants such as Zea mays, Arabidopsis thaliana and Tradescantia have been used in various test assays for mutagenecity of chemicals.

Cell culture assay

Mammalian cell lines such as Chinese hamster V79 cells, Chinese hamster ovary (CHO) cells or mouse lymphoma cells may be used to test for mutagenesis. Such systems include the HPRT assay for resistance to 8-azaguanine or 6-thioguanine, and ouabain-resistance (OUA) assay.

Rat primary hepatocytes may also be used to measure DNA repair following DNA damage. Mutagens may stimulate unscheduled DNA synthesis that results in more stained nuclear material in cells following exposure to mutagens.

Chromosome check systems

These systems check for large scale changes to the chromosomes and may be used with cell culture or in animal test. The chromosomes are stained and observed for any changes. Sister chromatid exchange is a symmetrical exchange of chromosome material between sister chromatids and may be correlated to the mutagenic or carcinogenic potential of a chemical. In micronucleus Test, cells are examined for micronuclei, which are fragments or chromosomes left behind at anaphase, and is therefore a test for clastogenic agents that cause chromosome breakages. Other tests may check for various chromosomal aberrations such as chromatid and chromosomal gaps and deletions, translocations, and ploidy.

Animal test systems

Rodents are usually used in animal test. The chemicals under test are usually administered in the food and in the drinking water, but sometimes by dermal application, by gavage, or by inhalation, and carried out over the major part of the life span for rodents. In tests that check for carcinogens, maximum tolerated dosage is first determined, then a range of doses are given to around 50 animals throughout the notional lifespan of the animal of two years. After death the animals are examined for sign of tumours. Differences in metabolism between rat and human however means that human may not respond in exactly the same way to mutagen, and dosages that produce tumours on the animal test may also be unreasonably high for a human, i.e. the equivalent amount required to produce tumours in human may far exceed what a person might encounter in real life.

Mice with recessive mutations for a visible phenotype may also be used to check for mutagens. Females with recessive mutation crossed with wild-type males would yield the same phenotype as the wild-type, and any observable change to the phenotype would indicate that a mutation induced by the mutagen has occurred.

Mice may also be used for dominant lethal assays where early embryonic deaths are monitored. Male mice are treated with chemicals under test, mated with females, and the females are then sacrificed before parturition and early fetal deaths are counted in the uterine horns.

Transgenic mouse assay using a mouse strain infected with a viral shuttle vector is another method for testing mutagens. Animals are first treated with suspected mutagen, the mouse DNA is then isolated and the phage segment recovered and used to infect E. coli. Using similar method as the blue-white screen, the plaque formed with DNA containing mutation are white, while those without are blue.

In anti-cancer therapy

Many mutagens are highly toxic to proliferating cells, and they are often used to destroy cancer cells. Alkylating agents such as cyclophosphamide and cisplatin, as well as intercalating agent such as daunorubicin and doxorubicin may be used in chemotherapy. However, due to their effect on other cells which are also rapidly dividing, they may have side effects such as hair loss and nausea. Research on better targeted therapies may reduce such side-effects. Ionizing radiations are used in radiation therapy.

In fiction

In science fiction, mutagens are often represented as substances that are capable of completely changing the form of the recipient or gaining them superpower. Powerful radiations are the agents of mutation for the superheroes in Marvel Comics's Fantastic Four, Daredevil, and Hulk, while in the Teenage Mutant Ninja Turtles franchise the mutagen is chemical agent also called "ooze", and for Inhumans the mutagen is the Terrigen Mist. Mutagens are also featured in television series, computer and video games, such as the Cyberia, The Witcher, Metroid Prime: Trilogy, Resistance: Fall of Man, Resident Evil, Infamous, Command & Conquer, Gears of War 3, BioShock, and Fallout.

Carcinogen

From Wikipedia, the free encyclopedia

The international pictogram for chemicals that are sensitising, mutagenic, carcinogenic or toxic to reproduction.

A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis, the formation of cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substances are considered carcinogens, but their carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins, and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is equally likely to arise in both natural and synthetic substances.^[1] Carcinogens are not necessarily immediately toxic; thus, their effect can be insidious.

Cancer is any disease in which normal cells are damaged and do not undergo programmed cell death as fast as they divide via mitosis. Carcinogens may increase the risk of cancer by altering cellular metabolism or damaging DNA directly in cells, which interferes with biological processes, and induces the uncontrolled, malignant division, ultimately leading to the formation of tumors. Usually, severe DNA damage leads to programmed cell death, but if the programmed cell death pathway is damaged, then the cell cannot prevent itself from becoming a cancer cell.

There are many natural carcinogens. Aflatoxin B₁, which is produced by the fungus Aspergillus flavus growing on stored grains, nuts and peanut butter, is an example of a potent, naturally occurring microbial carcinogen. Certain viruses such as hepatitis B and human papilloma virus have been found to cause cancer in humans. The first one shown to cause cancer in animals is Rous sarcoma virus, discovered in 1910 by Peyton Rous. Other infectious organisms which cause cancer in humans include some bacteria (e.g. Helicobacter pylori ^[2][3]) and helminths (e.g. Opisthorchis viverrini ^[4] and Clonorchis sinensis ^[5].

Dioxins and dioxin-like compounds, benzene, kepone, EDB, and asbestos have all been classified as carcinogenic.^[6] As far back as the 1930s, Industrial smoke and tobacco smoke were identified as sources of dozens of carcinogens, including benzo[a]pyrene, tobacco-specific nitrosamines such as nitrosonornicotine, and reactive aldehydes such as formaldehyde, which is also a hazard in embalming and making plastics. Vinyl chloride, from which PVC is manufactured, is a carcinogen and thus a hazard in PVC production.

Co-carcinogens are chemicals that do not necessarily cause cancer on their own, but promote the activity of other carcinogens in causing cancer.

After the carcinogen enters the body, the body makes an attempt to eliminate it through a process called biotransformation. The purpose of these reactions is to make the carcinogen more water-soluble so that it can be removed from the body. However, in some cases, these reactions can also convert a less toxic carcinogen into a more toxic carcinogen.

DNA is nucleophilic; therefore, soluble carbon electrophiles are carcinogenic, because DNA attacks them. For example, some alkenes are toxicated by human enzymes to produce an electrophilic epoxide. DNA attacks the epoxide, and is bound permanently to it. This is the mechanism behind the carcinogenicity of benzo[a]pyrene in tobacco smoke, other aromatics, aflatoxin and mustard gas.

Radiation

CERCLA identifies all radionuclides as carcinogens, although the nature of the emitted radiation (alpha, beta, gamma, or neutron and the radioactive strength), its consequent capacity to cause ionization in tissues, and the magnitude of radiation exposure, determine the potential hazard. Carcinogenicity of radiation depends on the type of radiation, type of exposure, and penetration. For example, alpha radiation has low penetration and is not a hazard outside the body, but emitters are carcinogenic when inhaled or ingested. For example, Thorotrast, a (incidentally radioactive) suspension previously used as a contrast medium in x-ray diagnostics, is a potent human carcinogen known because of its retention within various organs and persistent emission of alpha particles. Low-level ionizing radiation may induce irreparable DNA damage (leading to replicational and transcriptional errors needed for neoplasia or may trigger viral interactions) leading to pre-mature aging and cancer.^[8][9][10]

Not all types of electromagnetic radiation are carcinogenic. Low-energy waves on the electromagnetic spectrum including radio waves, microwaves, infrared radiation and visible light are thought not to be, because they have insufficient energy to break chemical bonds. Evidence for carcinogenic effects of non-ionizing radiation is generally inconclusive, though there are some documented cases of radar technicians with prolonged high exposure experiencing significantly higher cancer incidence.^[11]

Higher-energy radiation, including ultraviolet radiation (present in sunlight), x-rays, and gamma radiation, generally is carcinogenic, if received in sufficient doses. For most people, ultraviolet radiations from sunlight is the most common cause of skin cancer. In Australia, where people with pale skin are often exposed to strong sunlight, melanoma is the most common cancer diagnosed in people aged 15–44 years.^[12][13]

Substances or foods irradiated with electrons or electromagnetic radiation (such as microwave, X-ray or gamma) are not carcinogenic.^{[citation needed]} In contrast, non-electromagnetic neutron radiation produced inside nuclear reactors can produce secondary radiation through nuclear transmutation.

In prepared food

Chemicals used in processed and cured meat such as some brands of bacon, sausages and ham may or may not produce carcinogens.^[14] For example, nitrites used as food preservatives in cured meat such as bacon have also been noted as being carcinogenic with demographic links, but not causation, to colon cancer.^[15] Cooking food at high temperatures, for example grilling or barbecuing meats, can, or can not, also lead to the formation of minute quantities of many potent carcinogens that are comparable to those found in cigarette smoke (i.e., benzo[a]pyrene).^[16] Charring of food looks like coking and tobacco pyrolysis, and produces carcinogens. There are several carcinogenic pyrolysis products, such as polynuclear aromatic hydrocarbons, which are converted by human enzymes into epoxides, which attach permanently to DNA. Pre-cooking meats in a microwave oven for 2–3 minutes before grilling shortens the time on the hot pan, and removes heterocyclic amine (HCA) precursors, which can help minimize the formation of these carcinogens.^[17]

Reports from the Food Standards Agency have found that the known animal carcinogen acrylamide is generated in fried or overheated carbohydrate foods (such as french fries and potato chips).^[18] Studies are underway at the FDA and European regulatory agencies to assess its potential risk to humans.

In cigarettes

There is a strong association of smoking with lung cancer; the lifetime risk of developing lung cancer increases significantly in smokers.^[19] A large number of known carcinogens are found in cigarette smoke. Potent carcinogens found in cigarette smoke include polycyclic aromatic hydrocarbons (PAH, such as benzo[a]pyrene), Benzene, and Nitrosamine.^[20]

Mechanisms of carcinogenicity

Carcinogens can be classified as genotoxic or nongenotoxic. Genotoxins cause irreversible genetic damage or mutations by binding to DNA. Genotoxins include chemical agents like N-nitroso-N-methylurea (NMU) or non-chemical agents such as ultraviolet light and ionizing radiation. Certain viruses can also act as carcinogens by interacting with DNA.

Nongenotoxins do not directly affect DNA but act in other ways to promote growth. These include hormones and some organic compounds.^[21]

Classification

International Agency for Research on Cancer

The International Agency for Research on Cancer (IARC) is an intergovernmental agency established in 1965, which forms part of the World Health Organization of the United Nations. It is based in Lyon, France. Since 1971 it has published a series of Monographs on the Evaluation of Carcinogenic Risks to Humans^[22] that have been highly influential in the classification of possible carcinogens.

• Group 1: the agent (mixture) is definitely carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.
• Group 2A: the agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans.
• Group 2B: the agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans.
• Group 3: the agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans.
• Group 4: the agent (mixture) is probably not carcinogenic to humans.

Globally Harmonized System

The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) is a United Nations initiative to attempt to harmonize the different systems of assessing chemical risk which currently exist (as of March 2009) around the world. It classifies carcinogens into two categories, of which the first may be divided again into subcategories if so desired by the competent regulatory authority:

• Category 1: known or presumed to have carcinogenic potential for humans
  • Category 1A: the assessment is based primarily on human evidence
  • Category 1B: the assessment is based primarily on animal evidence
• Category 2: suspected human carcinogens

U.S. National Toxicology Program

The National Toxicology Program of the U.S. Department of Health and Human Services is mandated to produce a biennial Report on Carcinogens.^[23] As of June 2011, the latest edition was the 12th report (2011).^[6] It classifies carcinogens into two groups:

• Known to be a human carcinogen
• Reasonably anticipated being a human carcinogen

American Conference of Governmental Industrial Hygienists

The American Conference of Governmental Industrial Hygienists (ACGIH) is a private organization best known for its publication of threshold limit values (TLVs) for occupational exposure and monographs on workplace chemical hazards. It assesses carcinogenicity as part of a wider assessment of the occupational hazards of chemicals.

• Group A1: Confirmed human carcinogen
• Group A2: Suspected human carcinogen
• Group A3: Confirmed animal carcinogen with unknown relevance to humans
• Group A4: Not classifiable as a human carcinogen
• Group A5: Not suspected as a human carcinogen

European Union

The European Union classification of carcinogens is contained in the Dangerous Substances Directive and the Dangerous Preparations Directive. It consists of three categories:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances which should be regarded as if they are carcinogenic to humans.
• Category 3: Substances which cause concern for humans, owing to possible carcinogenic effects but in respect of which the available information is not adequate for making a satisfactory assessment.

This assessment scheme is being phased out in favor of the GHS scheme (see above), to which it is very close in category definitions.

Safe Work Australia

Under a previous name, the NOHSC, in 1999 Safe Work Australia published the Approved Criteria for Classifying Hazardous Substances [NOHSC:1008(1999)].^[24] Section 4.76 of this document outlines the criteria for classifying carcinogens as approved by the Australian government. This classification consists of three categories:

• Category 1: Substances known to be carcinogenic to humans.
• Category 2: Substances that should be regarded as if they were carcinogenic to humans.
• Category 3: Substances that have possible carcinogenic effects in humans but about which there is insufficient information to make an assessment.

Procarcinogen

A procarcinogen is a precursor to a carcinogen. One example is nitrites when taken in by the diet. They are not carcinogenic themselves, but turn into nitrosamines in the body, which can be carcinogenic.^[25]

Common carcinogens

Occupational carcinogens

Occupational carcinogens are agents that pose a risk of cancer in several specific work-locations:

Carcinogen	Associated cancer sites or types	Occupational uses or sources
Arsenic and its compounds	Lung Skin Hemangiosarcoma	Smelting byproduct Component of: Alloys Electrical and semiconductor devices Medications (e.g. melarsoprol) Herbicides Fungicides Animal dips Drinking water from contaminated aquifers.
Asbestos	Lungs Asbestosis Gastrointestinal tract Pleural Mesothelioma Peritoneal Mesothelioma	Not in widespread use, but found in: Constructions Roofing papers Floor tiles Fire-resistant textiles Friction linings (brake pads) (only outside Europe) Replacement friction linings for automobiles still may contain asbestos
Benzene	Leukemia Hodgkin's lymphoma	Light fuel oil Former use as solvent and fumigant Printing Lithography Paint Rubber Dry cleaning Adhesives Coatings Detergents
Beryllium and its compounds	Lung	Missile fuel Lightweight alloys Aerospace applications Nuclear reactors
Cadmium and its compounds[26]	Prostate	Yellow pigments Phosphors Solders Batteries Metal paintings and coatings
Hexavalent chromium(VI) compounds	Lung	Paints Pigments Preservatives
IC engine exhaust gas	Lung[27] Bladder[27]	Exhaust gas from engines
Ethylene oxide	Leukemia	Ripening agent for fruits and nuts Rocket propellant Fumigant for foodstuffs and textiles Sterilant for hospital equipment
Nickel	Nose Lung	Nickel plating Ferrous alloys Ceramics Batteries Stainless-steel welding byproduct
Radon and its decay products	Lung	Uranium decay Quarries and mines Cellars and poorly ventilated places
Vinyl chloride	Hemangiosarcoma Liver	Refrigerant Production of polyvinyl chloride Adhesive for plastics Former use in pressurized containers
Shift work that involves circadian disruption[28]	Breast
Involuntary smoking (Passive smoking)[29]	Lung
Radium-226, Radium-224, Plutonium-238, Plutonium-239[30] and other alpha particle emitters with high atomic weight	Bone (they are bone seekers) Liver	Nuclear fuel processing Radium dial manufacturing

Others

• Gasoline (contains aromatics)
• Lead and its compounds
• Alkylating antineoplastic agents (e.g. mechlorethamine)
• Other alkylating agents (e.g. dimethyl sulfate)
• Ultraviolet radiation from the sun and UV lamps
• Alcohol (causing head and neck cancers)
• Other ionizing radiation (X-rays, gamma rays, etc.)

Major carcinogens implicated in the four most common cancers worldwide

In this section, the carcinogens implicated as the main causative agents of the four most common cancers worldwide are briefly described. These four cancers are lung, breast, colon, and stomach cancers. Together they account for about 41% of worldwide cancer incidence and 42% of cancer deaths.

Lung cancer

Lung cancer (pulmonary carcinoma) is the most common cancer in the world, both in terms of cases (1.6 million cases; 12.7% of total cancer cases) and deaths (1.4 million deaths; 18.2% of total cancer deaths).^[34] Lung cancer is largely caused by tobacco smoke. Risk estimates for lung cancer in the United States indicate that tobacco smoke is responsible for 90% of lung cancers. Other factors are implicated in lung cancer, and these factors can interact synergistically with smoking so that total attributable risk adds up to more than 100%. These factors include occupational exposure to carcinogens (about 9-15%), radon (10%) and outdoor air pollution (1-2%).^[35] Tobacco smoke is a complex mixture of more than 5,300 identified chemicals. The most important carcinogens in tobacco smoke have been determined by a “Margin of Exposure” approach.^[36] Using this approach, the most important tumorigenic compounds in tobacco smoke were, in order of importance, acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, cadmium, acetaldehyde, ethylene oxide, and isoprene. Most of these compounds cause DNA damage by forming DNA adducts or by inducing other alterations in DNA.^[33] DNA damages are subject to error-prone DNA repair or can cause replication errors. Such errors in repair or replication can result in mutations in tumor suppressor genes or oncogenes leading to cancer.

Breast cancer

Breast cancer is the second most common cancer [(1.4 million cases, 10.9%), but ranks 5th as cause of death (458,000, 6.1%)].^[34] Increased risk of breast cancer is associated with persistently elevated blood levels of estrogen.^[37] Estrogen appears to contribute to breast carcinogenesis by three processes; (1) the metabolism of estrogen to genotoxic, mutagenic carcinogens, (2) the stimulation of tissue growth, and (3) the repression of phase II detoxification enzymes that metabolize ROS leading to increased oxidative DNA damage.^[38][39][40] The major estrogen in humans, estradiol, can be metabolized to quinone derivatives that form adducts with DNA.^[41] These derivatives can cause dupurination, the removal of bases from the phosphodiester backbone of DNA, followed by inaccurate repair or replication of the apurinic site leading to mutation and eventually cancer. This genotoxic mechanism may interact in synergy with estrogen receptor-mediated, persistent cell proliferation to ultimately cause breast cancer.^[41] Genetic background, dietary practices and environmental factors also likely contribute to the incidence of DNA damage and breast cancer risk.

Colon cancer

Colorectal cancer is the third most common cancer [1.2 million cases (9.4%), 608,000 deaths (8.0%)].^[34] Tobacco smoke may be responsible for up to 20% of colorectal cancers in the United States.^[42] In addition, substantial evidence implicates bile acids as an important factor in colon cancer. Twelve studies (summarized in Bernstein et al.^[43]) indicate that the bile acids deoxycholic acid (DCA) and/or lithocholic acid (LCA) induce production of DNA-damaging reactive oxygen species and/or reactive nitrogen species in human or animal colon cells. Furthermore, 14 studies showed that DCA and LCA induce DNA damage in colon cells. Also 27 studies reported that bile acids cause programmed cell death (apoptosis). Increased apoptosis can result in selective survival of cells that are resistant to induction of apoptosis.^[43] Colon cells with reduced ability to undergo apoptosis in response to DNA damage would tend to accumulate mutations, and such cells may give rise to colon cancer.^[43] Epidemiologic studies have found that fecal bile acid concentrations are increased in populations with a high incidence of colon cancer. Dietary increases in total fat or saturated fat result in elevated DCA and LCA in feces and elevated exposure of the colon epithelium to these bile acids. When the bile acid DCA was added to the standard diet of wild-type mice invasive colon cancer was induced in 56% of the mice after 8 to 10 months.^[44] Overall, the available evidence indicates that DCA and LCA are centrally important DNA-damaging carcinogens in colon cancer.

Stomach cancer

Stomach cancer is the fourth most common cancer [990,000 cases (7.8%), 738,000 deaths (9.7%)].^[34] Helicobacter pylori infection is the main causative factor in stomach cancer. Chronic gastritis (inflammation) caused by H. pylori is often long-standing if not treated. Infection of gastric epithelial cells with H. pylori results in increased production of reactive oxygen species (ROS).^[45][46] ROS cause oxidative DNA damage including the major base alteration 8-hydroxydeoxyguanosine (8-OHdG). 8-OHdG resulting from ROS is increased in chronic gastritis. The altered DNA base can cause errors during DNA replication that have mutagenic and carcinogenic potential. Thus H. pylori-induced ROS appear to be the major carcinogens in stomach cancer because they cause oxidative DNA damage leading to carcinogenic mutations. Diet is thought to be a contributing factor in stomach cancer - in Japan where very salty pickled foods are popular, the incidence of stomach cancer is high. Preserved meat such as bacon, sausages, and ham increases the risk while a diet high in fresh fruit and vegetables may reduce the risk. The risk also increases with age.^[47]

Organophosphate

From Wikipedia, the free encyclopedia

General chemical structure of the organophosphate functional group

Organophosphates (also known as phosphate esters) are a class of organophosphorus compounds with the general structure O=P(OR)₃. They can be considered as esters of phosphoric acid. Like most functional groups organophosphates occur in a diverse range of forms, with important examples including key biomolecules such as DNA, RNA and ATP, as well as many insecticides, herbicides, and nerve agents.

Chemistry

Synthesis

Various routes exist for the synthesis of organophosphates.

Esterification of phosphoric acid:

 

OP(OH)₃ + ROH → OP(OH)₂(OR) + H₂O

OP(OH)₂(OR) + R'OH → OP(OH)(OR)(OR') + H₂O

OP(OH)(OR)(OR') + R"OH → OP(OR)(OR')(OR") + H₂O

Alcohols can be detached from phosphate esters by hydrolysis, which is the reverse of the above reactions. For this reason, phosphate esters are common carriers of organic groups in biosynthesis.

Oxidation of phosphite esters.

Organophosphites can be readily oxidised to give organophosphates:

P(OR)₃ + [O] → OP(OR)₃

Alcoholysis of POCl_3.

Phosphorus oxychloride reacts readily with alcohols to give organophosphates:

O=PCl₃ + 3 ROH → O=P(OR)₃ + 3 HCl

Properties

The phosphate esters bearing OH groups are acidic and partially deprotonated in aqueous solution. For example, DNA and RNA are polymers of the type [PO₂(OR)(OR')⁻]_n. Polyphosphates also form esters; an important example of an ester of a polyphosphate is ATP, which is the monoester of triphosphoric acid (H₅P₃O₁₀).

In nature

Anatoxin-a(S)

Anatoxin-a(S) is a naturally occurring organophosphate produced by cyanobacteria.

Pesticides

The word "organophosphates", when appearing in communications (e.g., from the press or the government), in areas such as agriculture, the environment, and human and animal health, very often refers to a group of insecticides (pesticides) that act on the enzyme acetylcholinesterase^{[citation needed]} (see also carbamates).^{[citation needed]} Today, organophosphates make up about 50% of the killing agents in chemical pesticides.^[1]

Organophosphate pesticides (OPPs), like some nerve agents, inhibit this neuromuscular enzyme, which is broadly essential for normal function in insects, but also in humans and many other animals.^[2] OPPs affect this enzyme in varied ways, a principle one being through irreversible covalent inhibition,^[3] and so create potentials for poisoning that vary in degree. The brain sends out neurotransmitters to the nerve endings in the body; organophosphates disrupt this process from occurring.This chemical, organophosphate works by disrupting the enzyme, acetylcholinesterase. Acetylcholinesterase break down the acetylcholine neurotransmitter, which sends out signals to other nerve endings in the body. Without these neurotransmitters from the brain, the nerves in the human body cannot function properly.^[1]

For instance, parathion, one of the first OPPs commercialized, is many times more potent than malathion, an insecticide used in combating the Mediterranean fruit fly (Med-fly) and West Nile Virus-transmitting mosquitoes.^[4] Human and animal exposure to them can be through ingestion of foods containing them, or via absorption through the skin or lungs.^[2]

The human and animal toxicity of OPPs make them a societal health and environmental concern;^[2] the EPA banned most residential uses of organophosphates in 2001, but their agricultural use, as pesticides on fruits and vegetables, is still permitted, and they are as is their use in mosquito abatement in public spaces such as parks.^[2] For instance, the most commonly used OPP in the U.S., malathion,^[5] sees wide application in agriculture, residential landscaping, and pest control programs (including mosquito control in public recreation areas).^[6] As of 2010, forty such OPPs were registered for use in the U.S.,^[7] with at least 73 million pounds used in one time period^[which?] in agricultural and residential settings.^[7] Commonly used organophosphates have included:

• parathion
• malathion^[6][5]
• methyl parathion
• chlorpyrifos
• diazinon
• dichlorvos
• phosmet
• fenitrothion^[8]
• tetrachlorvinphos,
• azamethiphos
• azinphos-methyl
• Terbufos

Studies have shown that prolonged exposure to OPPs—e.g., in the case of farm workers—can lead to health problems, including increased risks for cardiovascular and respiratory disease, and cancer. In the case of pregnant women, exposure can result in premature births.^[9] In addition, permanent damage to the brain’s chemical make-up, and changes in human behavior and emotion can occur to the fetus in pregnant women.^[10]

Organophosphate pesticides degrade rapidly by hydrolysis on exposure to sunlight, air, and soil, although small amounts can be detected in food and drinking water. Organophosphates contaminate drinking water by moving through the soil to the ground water.^[11] When the pesticide degrades, it is broken down into several chemicals.^[11]Organophosphates degrade faster than the organochlorides,^{[citation needed]} the greater acute toxicity of OPPs result in the elevated risk associated with this class of compounds (see the Toxicity section below).

Nerve agents

History

Early pioneers in the field include Jean Louis Lassaigne (early 19th century) and Philippe de Clermont (1854). In 1932, German chemist Willy Lange and his graduate student, Gerde von Krueger, first described the cholinergic nervous system effects of organophosphates, noting a choking sensation and a dimming of vision after exposure on themselves, which they attributed to the esters themselves. ^[12] This discovery later inspired German chemist Gerhard Schrader at company IG Farben in the 1930s to experiment with these compounds as insecticides. Their potential use as chemical warfare agents soon became apparent, and the Nazi government put Schrader in charge of developing organophosphate (in the broader sense of the word) nerve gases. Schrader's laboratory discovered the G series of weapons, which included Sarin, Tabun, and Soman. The Nazis produced large quantities of these compounds, though did not use them during World War II. British scientists experimented with a cholinergic organophosphate of their own, called diisopropylfluorophosphate, during the war. The British later produced VX nerve agent, which was many times more potent than the G series, in the early 1950s, almost 20 years after the Germans had discovered the G series.

After World War II, American companies gained access to some information from Schrader's laboratory, and began synthesizing organophosphate pesticides in large quantities. Parathion was among the first marketed, followed by malathion and azinphosmethyl. The popularity of these insecticides increased after many of the organochlorine insecticides such as DDT, dieldrin, and heptachlor were banned in the 1970s.

Structural features

Effective organophosphates have the following structural features:

• A terminal oxygen connected to phosphorus by a double bond, i.e. a phosphoryl group
• Two lipophilic groups bonded to the phosphorus
• A leaving group bonded to the phosphorus, often a halide

Terminal oxygen vs. terminal sulfur

Thiophosphoryl compounds, those bearing the P=S functionality, are much less toxic than related phosphoryl derivatives. Thiophosphoryl compounds are not active inhibitors of acetylcholinesterase in either mammals or insects; in mammals, metabolism tends to remove lipophilic side groups from the phosphorus atom, while in insects it tends to oxidize the compound, thus removing the terminal sulfur and replacing it with a terminal oxygen, which allows the compound to more efficiently act as an acetylcholinesterase inhibitor.

Fine tuning

Within these requirements, a large number of different lipophilic and leaving groups have been used. The variation of these groups is one means of fine tuning the toxicity of the compound. A good example of this chemistry are the P-thiocyanate compounds which use an aryl (or alkyl) group and an alkylamino group as the lipophilic groups. The thiocyanate is the leaving group.

One of the products of the reaction of Fc₂P₂S₄ with dimethyl cyanamide

A German patent claimed that the reaction of 1,3,2,4-dithiadiphosphetane 2,4-disulfides with dialkyl cyanamides formed plant protection agents which contained six-membered (P-N=C-N=C-S-) rings. It has been proven in recent times by the reaction of diferrocenyl 1,3,2,4-dithiadiphosphetane 2,4-disulfide (and Lawesson's reagent) with dimethyl cyanamide that, in fact, a mixture of several different phosphorus-containing compounds is formed. Depending on the concentration of the dimethyl cyanamide in the reaction mixture, either a different six-membered ring compound (P-N=C-S-C=N-) or a nonheterocylic compound (FcP(S)(NR2)(NCS)) is formed as the major product; the other compound is formed as a minor product.

In addition, small traces of other compounds are also formed in the reaction. The ring compound (P-N=C-S-C=N-) {or its isomer} is unlikely to act as a plant protection agent, but (FcP(S)(NR2)(NCS)) compounds can act as nerve poisons in insects.

Health effects

Poisoning

Many "organophosphates" are potent nerve agents, functioning by inhibiting the action of acetylcholinesterase (AChE) in nerve cells. They are one of the most common causes of poisoning worldwide, and are frequently intentionally used in suicides in agricultural areas.

Organophosphosphate pesticides can be absorbed by all routes, including inhalation, ingestion, and dermal absorption. Their inhibitory effects on the acetylcholinesterase enzyme lead to a pathological excess of acetylcholine in the body. Their toxicity is not limited to the acute phase, however, and chronic effects have long been noted. Neurotransmitters such as acetylcholine (which is affected by organophosphate pesticides) are profoundly important in the brain's development, and many organophosphates have neurotoxic effects on developing organisms, even from low levels of exposure. Other organophosphates are not toxic, yet their main metabolites, such as their oxons, are. Treatment includes both a pralidoxime binder and an anticholinergic such as atropine.

Chronic toxicity

Repeated or prolonged exposure to organophosphates may result in the same effects as acute exposure including the delayed symptoms. Other effects reported in workers repeatedly exposed include impaired memory and concentration, disorientation, severe depressions, irritability, confusion, headache, speech difficulties, delayed reaction times, nightmares, sleepwalking, drowsiness, or insomnia. An influenza-like condition with headache, nausea, weakness, loss of appetite, and malaise has also been reported.^[13]

A recent study done by Madurai Kamaraj University in India have shown a direct correlation between usage of organophosphates and diabetes among Indian agricultural population.^[14]

Low-level exposure

Even at relatively low levels, organophosphates may be hazardous to human health. The pesticides act on acetylcholinesterase,^[15] an enzyme found in the brain chemicals closely related to those involved in ADHD, thus fetuses and young children, where brain development depends on a strict sequence of biological events, may be most at risk.^[16] They can be absorbed through the lungs or skin or by eating them on food. According to a 2008 report from the U.S. Department of Agriculture, ″detectable″ traces of organophosphate were found in a representative sample of produce tested by the agency, 28% of frozen blueberries, 20% of celery, 27% of green beans, 17% of peaches, 8% of broccoli, and 25% of strawberries.^[17]

The United States Environmental Protection Agency lists parathion as a possible human carcinogen.^[18]

An organic diet is an effective way to reduce exposure to the organophosphorus pesticides commonly used in agricultural production.^[19] Organophosphate metabolite levels rapidly drop, and for some metabolites, become undetectable in children's urine when an organic diet is consumed.^[19] This is speculative based on a short study of 23 children, in which only a few organophosphate compounds were potentially reduced, no effect was shown for the majority of them that were found in the samples.

Cancer

The International Agency for Research on Cancer (IARC), found that some organophosphates may increased cancer risk.^[20] Tetrachlorvinphos and parathion were classified as "possibly carcinogenic", whereas malathion and diazinon were classified as probably carcinogenic to humans.^[21]

Affected populations

According to the EPA, organophosphate use in 2004 accounts for 40% of all insecticide products used in the United States.^[22] Out of concerns for potential hazards of organophosphate exposure to child development, the EPA began phasing out forms of organophosphates used indoors in 2001.^[22] While it is used in forestry, urban, and public health spraying (mosquito abatement programs, etc.) as well, the general population has been observed to have low exposure .^[23] Thus, the primary affected population that faces exposure to organophosphates are farmworkers, especially those in countries that have fewer restrictions on its usage, such as in India.^[24]

Farmworkers in the United States

In the United States, migrant and seasonal farmworkers are the most susceptible to organophosphate exposure. Of the U.S. farmworker population, there are about 4.2 million seasonal or migrant men, women, and even children, 70% of which are born in Mexico and an overwhelming majority of 90% of all are Latino.^[25] This almost homogenous racial aspect of employment in farm work in the United States highly suggests social, economic, and political factors undercurrents that would explain their vulnerability.^[26] Half of the farmworker population in the United States do not have legal documentation and two thirds live in poverty, making it difficult to fully understand and document the characteristics of this population with relative certainty.^[27] Furthermore, the group faces linguistic barriers, with about 70% of the migrant seasonal farmworker population reporting that they cannot speak English well.^[28]

In the United States, poverty and lack of documentation status puts migrant farmworkers in housing situations that make them far more likely to contract infectious or parasitic diseases and to suffer from chemical related ailments than the general U.S. population.^[29] Field workers who are exposed to pesticides continue to further expose their families in their residences, especially through contaminated clothing in which the residue settles as house dust.^[29]

Economic, social, racial, and political barriers make passing policy and creating protective measures less likely to occur; in the context of their jobs, migrant seasonal farm workers are structurally vulnerable to exploitation and working conditions that are Occupational Factors not up to health standards if they are unable to find the necessary physical and social resources to protect themselves.^[30]   

The nature of their job may require constant exposure to toxins and pesticides and subjects them to increasingly extreme weather as climate change progresses. Thus, migrant farm work has been ranked conservatively as possibly the second most dangerous jobs in the country.^[31]

Regulatory Efforts

Organophosphates (OPs) were among the most widely used insecticides until the 21st century. ^[32] And until the mid 1990's, general pesticide regulation was dependent on the Federal Food, Drug and Cosmetic Act (FFDCA) and the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) passed in 1938 and 1947, respectively. ^[33] In 1993, the Environmental Protection Agency (EPA) was bound by a pledge made to Congress to significantly reduce the amount of pesticides used in the United States, and the U.S. Department of Agriculture, along with the Food and Drug Administration, joined the EPA in this commitment. ^[34] Then, in 1996, The Food Quality Protection Act (FQPA) was signed into law to strengthen the regulation of pesticide in food and make regulation practices more consistent. ^[33] One way that this strengthening was accomplished was through mandating aggregate and cumulative exposure risk assessments in derivative food tolerance levels. ^[33] The EPA selected OPs as the first class of pesticides for assessing food tolerances because of their specific toxicity behavior as acetylcholinesterase inhibitors. ^[33]

Between 1996 and 1999, the use of OPs actually increased (despite the passing of the FQPA) from 75 million to 91 million pounds per year. ^[33] However, this is mainly due to the cotton boll weevil eradication program through the U.S Department of Agriculture and the use of OPs eventually decreased to 46 million pounds per year by 2004. ^[33] The residential use of OP pesticides may have declined more quickly, when compared to commercial use, largely due to the voluntary cancellation of chlorpyrifos and diazinon as approved pesticides for home use. ^[33] The phaseout of both chlorpyrifos and diazinon for most residential uses was complete in 2005.^[33]

According to the nongovernmental organisation Pesticide Action Network, parathion is one of the most dangerous pesticides.^{[35][not in citation given]} In the US alone, more than 650 agricultural workers have been poisoned since 1966, of which 100 died. In underdeveloped countries, many more people have suffered fatal and nonfatal intoxications.^{[citation needed]} The World Health Organization, PAN, and numerous environmental organizations propose a general and global ban.^{[citation needed]} Its use is banned or restricted in 23 countries and its import is illegal in a total of 50 countries.^[36] Its use was banned in the U.S. in 2000 and it has not been used since 2003.^[36]

In 2001, the EPA placed new restrictions on the use of the organophosphates phosmet and azinphos-methyl to increase protection of agricultural workers.^{[citation needed]} The crop uses reported at that time as being phased out in four years included those for almonds, tart cherries, cotton, cranberries, peaches, pistachios, and walnuts.^{[citation needed]} The crops with time-limited registration included apples/crab apples, blueberries, sweet cherries, pears, pine seed orchards, brussels sprouts, cane berries, and the use of azinphos-methyl by nurseries for quarantine requirements.^[37] The labeled uses of phosmet include alfalfa, orchard crops (e.g. almonds, walnuts, apples, cherries), blueberries, citrus, grapes, ornamental trees (not for use in residential, park, or recreational areas) and nonbearing fruit trees, Christmas trees and conifers (tree farms), potatoes, and peas.^[38] Azinphos-methyl has been banned in Europe since 2006.^[39]

In May 2006, the Environmental Protection Agency (EPA) reviewed the use of dichlorvos and proposed its continued sale, despite concerns over its safety and considerable evidence suggesting it is carcinogenic and harmful to the brain and nervous system, especially in children. Environmentalists charge that the latest decision was the product of backroom deals with industry and political interference.^[40]

As of 2013, thirty-six types of organophosphates were registered for use in the United States. ^[32] Organophosphates are currently used in a variety of environments (e.g. agriculture, gardens and veterinary practices), however, several notable OPs have been discontinued for use. ^[32] This includes parathion, which is no longer registered for any use, and chlorpyrifos (as mentioned previously), which is no longer registered for home use. ^[32] And again, other than for agricultural use, the OP diazinon has been banned in the U.S.