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.

Nanomanufacturing

From Wikipedia, the free encyclopedia

Nanomanufacturing is both the production of nanoscaled materials, which can be powders or fluids, and the manufacturing of parts "bottom up" from nanoscaled materials or "top down" in smallest steps for high precision, used in several technologies such as laser ablation, etching and others. Nanomanufacturing differs from molecular manufacturing, which is the manufacture of complex, nanoscale structures by means of nonbiological mechanosynthesis (and subsequent assembly).^[1]

The term "nanomanufacturing" is widely used, e.g. by the European Technology Platform MINAM^[2] and the U.S. National Nanotechnology Initiative (NNI).^[3] The NNI refers to the sub-domain of nanotechnology as one of its five "priority areas."^[4] There is also a nanomanufacturing program at the U.S. National Science Foundation, through which the National Nanomanufacturing Network (NNN) has been established. The NNN is an organization that works to expedite the transition of nanotechnologies from laboratory research to production manufacturing and it does so through information exchange,^[5] strategic workshops, and roadmap development.

The NNI has defined nanotechnology very broadly,^[6] to include a wide range of tiny structures, including those created by large and imprecise tools. However, nanomanufacturing is not defined in the NNI's recent report, Instrumentation and Metrology for Nanotechnology. In contrast, another "priority area," nanofabrication, is defined as "the ability to fabricate, by directed or self-assembly methods, functional structures or devices at the atomic or molecular level" (p. 67).

Nanomanufacturing appears to be the near-term, industrial-scale manufacture of nanotechnology-based objects, with emphasis on low cost and reliability. Many professional societies have formed Nanotechnology technical groups. The Society of Manufacturing Engineers, for example, has formed a Nanomanufacturing Technical Group to both inform members of the developing technologies and to address the organizational and IP (intellectual property) legal issues that must be addressed for broader commercialization.

In 2014 the Government Accountability Office noted that America's leadership in nanotechnology was put at risk by a failure of the government to invest in preparing basic research for commercial application.^[7]

Background

The realization of the numerous applications and benefits of nano-scale systems in everyday materials, electronics, medicine, energy conservation, sustainability, and transportation has led to research in developing techniques to produce these nano-systems on a larger-scale and at higher rates.^[8] Programs and organizations like the NNI and NNN are currently funding research towards designing economic, sustainable and reliable industry-scale nanomanufacturing techniques.^[9][10]

An example of such technology is the Nanoscale Offset Printing System (NanoOps) which was developed by researchers at the Center of High-rate Nanomanufacturing (CHN) in Northeastern University.^[11] The NanoOps is a form of directed assembly which is faster and more economic than traditional 3D printing of nanosystems. Ahmed Busnaina, who was the head lead of the project and featured in the film From Lab to Fab: Pioneers in Nano-manufacturing describes the system as a printing press. An etched template with nano wires is dipped in a solution with nano particles which acts as the ink for the press.^[12] The nanoparticles adhere to the template when electricity is applied to the solution.^[11] The template with the attached nano particles can then be taken out of the solution and pressed onto any material of choice. According to Busnaina, the whole process only costs 1% of conventional manufacturing and can reduce manufacturing time from days to minutes.^[11]

General overview

Nanomanufacturing refers to manufacturing processes of objects or material with dimensions between one and one hundred nanometers.^[13] These processes results in nanotechnology, extremely devices, structures, features, and systems that have applications in organic chemistry, molecular biology, aerospace engineering, physics, and beyond.^[14] Nanomanufacturing enables the creation of new materials and products that have applications such as material removal processes, device assembly, medical devices, electrostatic coating and fibers, and lithography.^[14] Nanomanufacturing is a relatively recent branch of manufacturing that represents both a new field of science and also a new marketplace. Research in nanomanufacturing, unlike tradition manufacturing, requires collective effort across typical engineering divides, such as collaboration between mechanical engineers, physicists, biologists, chemists, and material scientists.^[14]

Nanomanufacturing can generally be broken down into two categories: top-down and bottom-up approaches.

Nanomanufacturing industry

In 2009, $91 billion was in US products that incorporate nanoscale components.^[15] More than 60 countries established nanomanufacturing industry related programs at a national level between 2001 and 2004.^[15] Cumulative funding since 2000 for National Nanotechnology Initiative (NNI) is more than $12 billion.^[15]

Table. 1 Nanotechnology Development in the Worlds and U.S.^[16]

 

Figure.1 Number of nanotechnology related and non-overlapping application patents.^[17]

For sustainability point of view, Atomic Layer Deposition (ALD) is a Nano-scale manufacturing technology using bottom-up and chemical vapor deposition (CVD) manufacturing method.^[17] ALD replaces SiO₂ dielectric film with Al₂O₃ dielectric film.^[17] ALD industry is already in use in Semiconductor industry and promising in solar cells, fuel cells, medical device, sensor, polymer industries.^[17] Nanomanufacturing technology allow improvements in food packaging.^[16] For example, improvement in plastic material barrier allow customers to identify relevant information.^[16] Longer food life and safer food is aimed with self repairing functions as well.^[16] Performance of traditional construction materials; steel and concrete improves with nanotechnology. Reinforcing concrete with metal oxide nanoparticle reduces permeability and increase strength.^[18] Property of high tensile strength and Young’s modulus of Nanocarbon additions such as Carbon nanotubes (CNTs) and Carbon nanofibers (CNFs), creates denser and less porous material.^[18]

Challenges of nanomanufacturing

The transitioning of nanotechnology from lab demonstrations to industrial-scale manufacturing a number has a number of challenges, some of which include:

• Developing production techniques that are economic and produce viable yield^[9]
• Controlling the precision of the assembly of nanostructures^[9][14]
• Testing reliability and establishing methods for defect control. Currently, defect control in the semiconductor industry is non-selective and takes 20-25% of the total manufacturing time. Removal of defects for nano-scale system is projected to take up much more time because it requires selective and careful removal of impurities.^[14]
• Maintaining nano-scale properties and quality of nano-system during high-rate and high volume production as well as during the lifetime of the product after production^[9][14]
• Assessing the environmental, ethical and social impacts^[19]