34 Carcinogens in Air

Dr. Anita Lakhani

Contents

Introduction
Cancer and Mechanism of Carcinogenesis
Natural Carcinogens

Photocarcinogens and Photocarcinogenesis

Carcinogenic Mycotoxins Produced from Toxigenic Fungi

Carcinogens in Food Stuffs and Diet
Chronic Infection and Inflammation
Heavy Metals
Polycyclic Aromatic Hydrocarbons
Organochlorine Compounds
References

Introduction

Ambient air, particularly in densely populated urban environments, contains a variety of known human carcinogens, including organic compounds such as benzo[a]pyrene (B[a]P) and benzene, inorganic compounds such as arsenic and chromium, and radionuclides. These substances are present as components of complex mixtures, which may include carbon-based particles that absorb organic compounds; oxidants such as ozone; and sulfuric acid in aerosol form. The combustion of fossil fuels for power generation or transportation is the primary source of many organic and inorganic compounds, oxidants, and acids, and contributes heavily to particulate air pollution in most urban settings. Given below is a description of some of the anthropogenic carcinogens including arsenic, radon, nickel, chromium, cadmium, polycyclic aromatic hydrocarbons, organo-chlorine compounds.

Cancer and Mechanism of Carcinogenesis

Cancer is a group of diseases in which genetically damaged cells proliferate autonomously. Such cells are unable to respond to normal regulatory mechanisms and proliferate as a result the nearby normal cells are deprived of nutrients and eventually crowd surrounding healthy tissue. These cells may form either benign or malignant tumors depending on the damage they have sustained. Benign tumors are limited to a specific location and grow slowly. They are not considered cancerous and rarely cause death. In contrast, malignant tumors are often fatal because they can undergo metastasis, they migrate through blood or lymph vessels to distant locations throughout the body and interfere with normal functions and cause death due to failure of life-sustaining processes.

Carcinogenesis is characterized by three separate stages: initiation, promotion and progression. Initiation is the first stage of carcinogenesis and represents the occurrence of an irreversible change in a cell. This change is probably a genetic change or a mutation that results in a neoplastic cell and is caused by an initiating agent (e.g. chemical substance) that causes damage to DNA. Promotion is the second stage of carcinogenesis and is characterized by a clonic expansion of the initiated (mutated) cell to a benign tumor. The clonic expansion of initiated cells is not autonomous and is dependent on the repeated exposure to the promoter. Promoter may be an exogenous or an endogenous chemical substance, such as a hormone. Progression is the third stage of carcinogenesis and is characterized by the autonomous clonic expansion of mutated cells, even when the promoter is not present. Progression describes the irreversible transition from a benign to a malignant tumor. Chemicals that act as initiators and directly damage DNA are known as genotoxic. Chemicals that act as promoters are not able to produce mutations on their own but can increase the risk of cancer by increasing and stimulating the growth rate of mutated cells. Carcinogenic agents are often genotoxic, or able to damage DNA. Initiation involves genotoxicity, whereas promotion involves stimulation of cell proliferation.

Cancers are classified by the tissues affected. The vast majority of cancerous tumors are carcinomas (tumors derived from epithelial tissue cells such as skin, various glands, breasts, and the lining of most internal organs). In the leukemias, which are cancers of the bone marrow, excessive leukocytes are produced. Similarly, the lymphocytes produced in the lymph nodes and spleens proliferate.

Cancer and Mechanism of Carcinogenesis

Source : en.wikipedia.org Adapted from Vogelstein and K. Kinzler, 1993, Trends Genet. 9:101.

Figure1. Mechanism of Carcinogenesis

The International Agency for Research on Cancer has categorized agents, mixtures and exposures to five categories: carcinogenic to humans (Class 1), probably carcinogens to humans (Class 2A), possibly carcinogenic to humans (Class 2B), not classifiable as to carcinogenicity in humans (Class 3), probably not carcinogenic to humans ( Class 4).

Cancer therapy involves enormous cost and is associated with limited success. Hence it has now been increasingly recognized that cancer prevention is cost-effective. Recent research indicates that the majority of cases of cancer are preventable. For example, over one-third of cancer mortality is directly caused by tobacco use, and another one-third of cancer deaths have been linked to inadequate diets. Tobacco smoke, which contains thousands of chemicals, many of which are either carcinogens or tumor promoters, is responsible for most cases of lung cancer and contributes to cancers of the pancreas, bladder, and kidneys, among others. Diets that are high in fat and low in fiber content have been associated with increased incidence of cancers of the large bowel, breast, pancreas, and prostate. Other dietary risk factors include low consumption of fresh vegetables and fruit. In addition to providing sufficient antioxidant vitamins, many vegetables (and fruits to a lesser extent) contain numerous nonnutritive components that actively inhibit carcinogenesis. Some carcinogenesis inhibitors (e.g., organosulfides), referred to as blocking agents, prevent carcinogens from reacting with DNA or inhibit the activity of tumor promoters. Other inhibitors, referred to as suppressing agents (e.g., inositol hexaphosphate), prevent the further development of neoplastic processes that are already in progress. Many nonnutritive food components (e.g., tannins and protease inhibitors) possess both blocking and suppressing effects. In general, these molecules very effectively protect against cancer because many of them inhibit the arachidonic acid cascade and oxidative damage. Apparently low-fat, high-fiber diets that are rich in raw or fresh vegetables that are leafy green (e.g., spinach), cruciferous (e.g., broccoli), and members of the allium family (e.g., onions), as well as fresh fruits, are a prudent choice for individuals seeking to reduce their risk of cancer.

Natural Carcinogens

Naturally occurring carcinogens are made by living cells. Some of these are metabolites of green plants, fungi and bacteria. In addition a few products found in animal cells like the metabolites of tryptophan are also carcinogenic.

Photocarcinogens and Photocarcinogenesis

Ultraviolet radiation is a natural and variable component of our environment; it stimulates the production of vitamin D in our body. However, ultraviolet radiation causes several types of skin damage including the production of skin tumors, skin cancer and melanoma. Skin cancer and melanoma is a major public health problem in countries with a significant population of fair-skinned people. Exposure to the sun is the major cause of skin cancer and melanoma is of utmost importance. Exposure during the early decades of life, particularly if it causes burns is the dominant factor. Ultraviolet radiation is composed of three wavelengths: UVA, UVB and UVC. While UVC isn’t a concern for skin cancer, UVA and UVB cause tanning, burning, and photoaging. The World Health Organization has identified broad spectrum UV as a human carcinogen. UVA is long wavelength (320-400 nm) UV and accounts for up to 95 % of the solar UV radiation reaching the Earth’s surface. It can penetrate into the deeper layers of the skin causing skin aging and wrinkling. Recent studies suggest that it may also initiate and exacerbate the development of skin cancers. UVA rays are present during all daylight hours and they are present all year round and depending upon the time of the year, can be 30 to 50 times more prevalent than UVB rays. Furthermore, UVA radiation can penetrate glass and clouds. Thus, we are exposed to large doses of UVA throughout our lifetime. New research suggests that UVA exposure may be as damaging to the skin as UVB. Although scientists have known for several years that UVA penetrates more deeply into the skin than UVB, they believed that less of it was absorbed by DNA, causing fewer dangerous mutations. However an Australian-US study shows that UVA causes more genetic damage than UVB in skin cells where most skin cancers arise – the keratinocytes in the basal layer of the epidermis. UVB tends to cause damage in more superficial epidermal layers.

UVB is the middle-range of UV with wavelengths between 290-320 nm. It is responsible for burning, tanning, acceleration of skin aging and plays a very key role in the development of skin cancer. The intensity of UVB varies by season, location and time of day. They are more intense than UV A rays they do not penetrate glass. While the differences between UVB and UVA need to be explored further, it’s proven that exposure to the combination of UVB and UVA is a powerful attack on the skin. It can create irreversible damage that ranges from sunburn to premature aging to skin cancer. Protection from these rays is the only way to avoid these problems.

UVC is the shortest and highest energy UV with wavelengths less than 290 nm. However, since it is filtered by the ozone, these wavelengths do not reach the earth’s surface and do not contribute to skin damage in humans.

Carcinogenic Mycotoxins Produced from Toxigenic Fungi

Aflatoxins

Commonly occurring fungi growing in foods and feeds may produce toxins called as mycotoxins. Mycotoxins are secondary metabolites, they do not have any role in the normal metabolism involving the growth of the fungus. They have four kinds of toxicity: acute, chronic, mutagenic and teratogenic. The prime chronic effect of many mycotoxins is the induction of cancer, especially the liver. Some toxins affect DNA replication and hence can produce mutagenic and teratogenic effects. Many of the toxic fungi are ubiquitous and have a strong link with human food supplies. Aspergillus flavus and Aspergillus parasiticus, Fusarium and Penicillium are the common fungal molds that produce aflatoxin, ochratoxin, patulin and fumonism. Aflatoxins is the most potent human carcinogen, inducing aflotoxicosis and liver cancer within several months. It comprises of a group of closely related difuranocoumarin compounds produced in nature only by Aspergillus flavus, A. parasiticus and a recently described species A. nomius. A. flavus is ubiquitous. A. flavus and A. parasiticus have a particular affinity for nuts and oilseeds. Peanuts, maize and cotton seed are the three most important crops affected. Aflatoxins are a major health problem in developing countries, where long term food storage is often inadequate due to high heat and humidity, which encourages the growth of the mold. Mycotoxic fungi infect both grains and fruit; their growth is encouraged by poor storage conditions. Pre-harvest pest or mechanical damage to cereal grains, cobs and fruits enables fungal spores to enter the plant tissues and these spores germinate when the crop is moist. Post-harvest fungicide treatments are used to control fungal infection but penetration may limit the effectiveness of these treatments. Contamination of peanuts by aflatoxin is encouraged by severe drought followed by heat stress during fruit development. Fungal contamination of peanuts may also result during the preparation of peanut products and in other nuts such as walnuts, hazelnuts that are poorly dried during harvest. Cereals are a common substrate for growth of A. flavus, spices sometimes contain A. flavus with high levels of aflatoxin.

Aflatoxins are both acutely and chronically toxic to animals, including man, causing acute liver damage, liver cirrhosis, induction of tumours and teratogenic effects. The four naturally produced aflatoxins are known as aflatoxins B1, B2, G1 and G2. B and G refer to the blue green fluorescent colors produced by these compounds under UV light on thin layer chromatography plates, while the subscript numbers 1 and 2 indicate major and minor compounds respectively.

Aflatoxin B1 and B2 may be ingested by cows; in lactating cows, a proportion is hydroxylated and excreted in the milk as aflatoxins M1 and M2 which are of lower toxicity than the parent molecules, but significant because of widespread consumption of cow’s milk by infants. In 1974, an outbreak of hepatitis affected 400 Indian people killing almost a 100 people resulted from consumption of maize heavily contaminated with A. flavus, and containing up to 15 mg/kg of aflatoxins. Consumption of toxin by some of the affected adults was calculated to be 2-6 mg in a single day which showed that the acute lethal dose for adult humans is of the order of 10-20 mg. Because of their high toxicity, low limits for aflatoxins in foods and feeds have been set by many countries. Maximum level permitted for aflatoxins in all food commodities is15 ug/kg of total aflatoxins. Aflatoxin B1, is considered to be a class 1human carcinogen. It is believed that aflatoxin B1 are metabolized to highly reactive epoxides that form adducts primarily by reaction at N-7 position of guanine residues in liver DNA. Aflatoxins are also immunosuppressive, have an influence on protein energy metabolism, haemoglobin levels and effectiveness of vaccines. In industrialised countries, stringent sorting and clean up procedures are used to reduce aflatoxins to low levels in foods with a perceived risk.

Ochratoxin A

Ochratoxins are a group of mycotoxins produced as secondary metabolites by several fungi of the Aspergillus or Penicillium families. They are weak organic acids consisting of a derivative of an isocoumarin . The family of ochratoxins consists of three members, A, B, and C which differ slightly from each other in chemical structures and possess different toxic potentials. Ochratoxin A is the most abundant and hence the most commonly detected member but is also the most toxic. Ochratoxin A is found mainly in cereal and cereal products. It is also found in a range of other food commodities, including coffee, cocoa, wine, beer, pulses, spices, dried fruits, grape juice, pig kidney and other meat and meat products of non-ruminant animals exposed to feedstuffs contaminated with this mycotoxin. Ochratoxin A was originally described as a metabolite of A.ochraceus, a species with natural habitats in drying or decaying vegetation, seeds, nuts and fruits. A. ochraceus and closely related species are widely distributed in dried foods of various kinds. Nuts are also a major source. Ochratoxin A was also reported to be produced by Penicillium verrucosum a fungus found almost exclusively in grain from temperate zones. It is associated with northern European barley and wheat, and has also been isolated from meat products in Germany and other European countries. Aspergillus niger and A. carbonarius also produce ochratoxin A. These species are widespread in tropical foods, and survive sun drying. A. carbonarius is an important source of ochratoxin A in dried vine fruits, wines and probably coffee. Ochratoxin A is a moderately stable molecule and is partly destroyed during cooking and baking. The extent to which it is destroyed depends on pH, temperature and the other ingredients present.

Dietary intake represents the main source of ochratoxin A in humans. Human exposure to ochratoxin A occurs mainly through consumption of contaminated crops or food derived from animals exposed to contaminated feedstuffs. A second source is bread made from barley or wheat containing the toxin. Ochratoxin A is absorbed from the gastrointestinal tract. In most species, ochratoxin A is absorbed from the stomach as a result of its acidic properties. Absorption also takes place in the small intestine particularly in the proximal jejunum. In non-ruminant species such as pigs, chickens, rabbits and rats, around half of the ingested ochratoxin A may be absorbed. The absorbed ochratoxin A is distributed via blood, mainly to the kidneys, and at lower concentrations to the liver, muscle and fat, with a proportion metabolised into the non-toxic metabolite ochratoxin alpha and other less toxic minor metabolites at various sites in different species, and a significant proportion excreted unchanged. Ochratoxin A is an acute nephrotoxin, with oral LD50 values of 20 mg/kg in young rats and 3.6 mg/kg in day-old chicks. It is also lethal to mice, trout, dogs and pigs. Necroses of the renal tubules and periportal liver cells have been the main pathological changes observed after fatal doses. Ochratoxin A has immunosuppressive, embryonic, and also carcinogenic effects. Ochratoxin A plays a major role in the etiology of nephritis (kidney disease) in pigs in Scandinavia, and indeed in much of northern Europe. This is a serious animal health problem. Because ochratoxin A is fat soluble and not readily excreted, it accumulates in the depot fat of affected animals, and from there is ingested by humans eating pork. Ochratoxin A has been found in human blood over wide areas of Europe. In 1993, the International Agency for Research on Cancer (IARC) classified Ochratoxin A as possible human carcinogen (Group 2B) and concluded that there was sufficient evidence in experimental animals for the carcinogenicity of Ochratoxin A and inadequate evidence in humans for the carcinogenicity of Ochratoxin A.

Fumonisins

Fumonisins are mycotoxins produced by fungi of the genus Fusarium. Fumonisins consist of a 20 carbon aliphatic chain with two ester linked hydrophilic side chains, resembling sphingosine, an essential phospholipid in cell membranes. Fumonisin B1 is the diester of propane-1,2,3-tricarboxylic acid and 2S-amino-12S,16R-dimethyl-3S,5R,10R,14S,15R-pentahydroxyeicosane in which the C-14 and C-15 hydroxy groups are esterified with terminal carboxy group of propane-1,2,3-tricarboxylic acid. Fumonisin B2 is the C-10 deoxy analogue of Fumonisin B1 in which the corresponding stereogenic units of the eicosane backbone possess the same configuration. The major producer of Fumonisins are Fusanum monilifornte and closely related species, which are endemic in maize throughout the world. Maize is the only significant source of these compounds. The toxic action of Fumonisins appears to result from competition with sphingosine in sphingolipid metabolism. Symptoms of Fumonisin toxicity vary widely with animal type, dosage and toxigenic fungal isolate. The best defined disease, LEM, is characterized by liquefactive necrotic lesions in the white matter of the cerebral hemispheres of horses and other equine species. Marked neurotoxicity is evident, with aimless walking and loss of muscle control followed by death, which usually occurs about 2 weeks after toxin ingestion. The effect of fumonisins on humans has not been fully established, but much evidence suggests a role in human oesophageal cancer. Maize is the major staple food in areas of the Transkei in southern Africa where oesophageal cancer is endemic, and the most striking difference between areas of low and high incidence was the much greater infection of maize by F. momliforme in the high incidence areas. A similar situation occurs in parts of China with an exceptional incidence of oesophageal cancer. The International Agency for Research on Cancer found that Fumonisin B1 was a possible human carcinogen, but was neither mutagenic nor genotoxic. It alters the capacity of cells to proliferate.

Trichothecene Toxins: Deoxynivalenol and Nivalenol

The trichothecenes are the largest group of mycotoxins, consisting of more than 150 chemically-related toxic compounds. These mycotoxins are produced by several species of Fusarium, Stachybotrys, Trichoderma and Trichothecium. The most important trichothecene mycotoxins are deoxynivalenol (DON) and nivalenol, common contaminants of wheat, barley, and maize. DON is sometimes called vomitoxin because of its deleterious effects on the digestive system of monogastric animals. Humans consuming flour made from wheat contaminated with DON often demonstrate symptoms of nausea, fever, headaches, and vomiting. It was responsible for a large-scale human toxicosis in India in 1988, and human toxicosis have also been reported from China, Japan and Korea. Symptoms of toxicosis include anorexia, nausea, vomiting, headache, abdominal pain, diarrhoea, chills, giddiness and convulsions. DON causes vomiting and feed refusal in pigs at levels near 8 mg/kg of feed. Deoxynivalenol and Nivalenol cause a variety of immunological effects in laboratory animals, leading to increased susceptibility to all kinds of microbial diseases. These toxins do not appear to be carcinogenic, but may act synergistically with aflatoxins.

Cycasin

Cycasin are naturally occurring glucosides including cycasein (methylazoxymethanol-0-D–glucoside and its metabolite methylazoxymethanol (MAM) extractable from seeds and roots of cycad plants (plants intermediate between angiosperms and flowering plants). Cycasin is a general carcinogen and has profound effects on the central nervous system during embryonic and fetal development

Carcinogens in Food Stuffs and Diet

Man’s food is derived almost entirely from living systems and constitutes by far the major daily source of non-nutritive chemicals, which may include compounds that could increase or decrease the incidence of cancers in humans. In addition to the strong associations of tobacco, alcoholic drinks and ultraviolet radiation with the genesis of specific cancers, the probability of formation of cancers in the last third of the life span in an individual may reflect in part long-term dietary intakes of agents that increase cancer formation and/or of agents that inhibit the process. Animal fat and red meat is reported to increase the incidence of cancers of the breast, colon and prostate. These dietary fats affect the endogenous hormone levels, exert proliferative effects on bile acids on the colonic mucosa, effects of rodent carcinogen produced in the cooking of meat and excessive iron intake. Chinese –styled salted fish, particularly if consumed in childhood, is associated with nasopharyngeal cancer. Cooking of food is a common contributor to cancer. A wide variety of chemicals are formed during cooking. Four groups of chemical compounds present in food stuffs that cause tumours in rodents have attracted attention because of their mutagenicity, potency and concentration. (i) Nitrosamines, formed from nitrogen oxides present in gas flame or through burning (ii) heterocyclic amines, formed from heating amino acids or proteins. (iii) polycyclic aromatic hydrocarbons, formed from charring meat (iv) Furfural and similar furans, formed from heating sugars. In addition heating of fat generates mutagenic epoxides, hydroperoxides and unsaturated aldehydes that may also be of importance. Alcoholic beverages cause inflammation and cirrhosis of the liver, liver cancer, oral and oesophaegal cancer.

Ethyl carbamate

Fermented foods such as bread, yogurt, beer and wine produce ethyl carbamate at levels of 1-6 µg kg-1 and have been known to induce lung adenomas, hepatomas, mammary carcinomas, thymic lymphomas and haemangiomas in mice and other rodents. It is formed in ethanolic fermentations by the ethanolysis of carbamyl phosphate. The risks to humans of daily intakes of a few micrograms of ethyl carbamate from food sources appear to be very low. Previously ethyl carbamate was sometimes used as sedatives in humans. In the 1950-1975 period exposures of humans to ethyl carbamate occurred in Japan from the use of ethyl carbamate used as co-solvent for barbiturate drugs. Small structural changes in ethyl carbamate tend to reduce the carcinogenic activity of ethyl carbamate. For example methyl carbamate is inactive and n-propyl and iso-propyl carbamates have only weak activity in the mouse suggesting that only the ethyl carbons of ethyl carbamate covalently bind to the DNA in the mouse liver in vivo. Vinyl carbamate, a derivative of ethyl carbamate (CH2=CHOCONH2) is several to many-folds more active than ethyl carbamate.

Saffrole, Estragole and alkenylbenzenes

Plants and certain essential oils contain about 30 alkenylbenzene derivatives ranging from simple allyl- or propenylbenzenes with methoxy and/or methylenedioxy ring substituents. These compounds occur in a variety of foods, but they are especially prominent as active components of many spices. Safrole (1-allyl-3,4-methylenedioxybenzene also known as 5-(2-propenyl)-1,3-benzodioxide) alongwith estragole (1-allyl-4-methoxybenzene), isosafrole (1-propenyl-3,4-methylenedioxybenzene) and methyleugenol (9-allyl-3,4-dimethoxybenzene) have been identified to be hepatocarcinogenic for rats and mice. β-asarone (cis-1-propenyl-2,4,5-trimethoxybenzene) has been found to induce mesenchymal tumours of the small intestine in rats. Safrole is a derivative of aromatic phenol ether 1,3-benzodioxole is a major component of oil of sassafras and a minor constituent of oil of sweet basil and cinnamon. Commercially it is produced by distillation of oils rich in safrole. At room temperature it exists as colorless or pale-yellow with an odour of sassafras. It is practically insoluble in water and glycerine and slightly soluble in propylene glycol, soluble in alcohol and miscible with chloroform and ether. Safrole has been used as a flavouring agent in drugs and in the manufacture of heliotropin, perfumes, soaps and piperonyl butoxide. It has also been used as a preservative in mucilage and library paste and as a floatation frother and in the production of the drug 3,4-methylenedioxymethamphetamine (MDMA).

Humans may be exposed to safrole through inhalation, ingestion and dermal contact. Safrole may be ingested in edible spices including sassafras, cinnamon, nutmeg, mace, star anise, ginger, black and white pepper and from chewing betel quid. Safrole is also present in some herbal products derived from the sassafras tree and in bidi cigarettes. Safrole is present at low levels in these food stuffs and its concentration is further lowered during cooking. Based on common ingestion patterns, the estimated daily intake of safrole is 0.3 mg. Small amounts of safrole have been reported to be released to the environment as air emissions from on-site hazardous waste landfills or off-site non-hazardous waste landfills. Occupational exposure to safrole may occur by inhalation or dermal contact particularly to health professionals like pharmacists, physicians and nurses during formulation, preparation, administration or clean-up of drugs containing safrole or sassafras.

Estragole

Estragole is a principal component of oil of tarragon and is found in lower concentrations in oils of sweet basil and anise and other essential oils. Studies have indicated that it acts as a hepatocarcinogen for mice fed with high doses for long periods while on administration of small doses during the preweaning periods cause initiation of hepatocarcinogenesis in mice.

Tobacco-specific Nitrosamines

Tobacco is the most important global cause of cancer and is preventable. Smoking contributes to about one third of cancer, and one quarter of heart disease and premature deaths. Tobacco causes cancer of the lung, bladder, mouth, pharynx, pancreas, oesophagus and also colon. Tobacco contains more than 2500 compounds and tobacco smoke more than 3800 including tumor initiators such as the polynuclear aromatic hydrocarbons, tumor promoters, co-carcinogens, and organ-specific carcinogens. Tobacco smoke contains a wide variety of mutagens and rodent carcinogens. The oxidants in cigarette smoke contain mainly oxides of nitrogen which deplete the body’s antioxidants.

Tobacco contains an alkaloid nicotine, which is the main reason for the continued use of tobacco inspite of its known adverse health effects. Nicotine comprises 1-2% of unburned tobacco, its levels in mainstream cigarette smoke range from 0.5 to 2 mg/cigarette. Several alkaloids such as normicotine, anabasine and anatabine which are structurally similar to nicotine are also present in tobacco; their concentrations are less than that of nicotine. Nicotine is a tertiary amine, while normicotine, anabasine and anatabine are secondary amines. Secondary and tertiary amines react with nitrosating agents to form stable compounds called N-nitrosamines. In the case of a secondary amine nitrosation is a rapid reaction and, results in the replacement of N-H by N-N=O. For tertiary amines, the carbon-nitrogen bond is cleaved oxidatively, any of the alkyl groups attached to nitrogen is usually detached as a ketone or aldehyde and replaced by the -NO group. Thus, nitrosation of the secondary amines nomicotine, anabasine, and anatabine gives the corresponding nitrosamines NNN (N’-nitrosonornicotine, N’ refers to the nitrogen of the saturated ring, as opposed to the nitrogen of the pyridine ring which cannot be nitrosated), NAB (W’-nitrosoanabasine) and NAT (W’-nitrosoanatabine). Nitrosation of the tertiary amine, nicotine, gives NNN by cleavage of the N-CH3 bond with loss of formaldehyde or yields NNK (4-(methy1nitrosamino)-1-(3-pyndyl)-1-butanone (the origin of the term NNK is nicotine-derived nitrosaminoketone) or NNA by cleavage of either the 2′-N or 5′-N bond, respectively. The formation of NNN, NNK, and NNA from nicotine and of NNN, NAB, and NAT from nomicotine, anabasine, and anatabine has been confirmed in model studies. These alkaloid-derived nitrosamines are called “tobacco-specific nitrosamines.” All of the tobacco-specific nitrosamines, except NNA, have been detected in cigarette, cigar, and snuff tobacco and in mainstream and sidestream tobacco smoke. Their presence in tobacco results from nitrosation of the alkaloids during curing and processing. In cigarette smoke, 25 to 45% of the tobacco-specific nitrosamines originate by transfer from the tobacco and the remainder is pyrosynthesized, probably by reaction of the alkaloids with nitrogen oxides. The ribs and stems of the tobacco leaf contain the greatest proportion of nitrate, they have a profound influence on the levels of nitrosamines in tobacco products and in smoke. Tobacco-specific nitrosamines are also endogenously formed in smokers and snuff dippers. Snuff dipping is the practice of extracting juices from a pinch of moist fine-cut chewing tobacco, placed between the cheek and the gum. NNN and NNK are strong carcinogens and thus, they provide a link between nicotine, the habituating factor in tobacco, and tobacco-related cancers.

Humans may be exposed to tobacco-specific nitrosamines: by inhaling mainstream smoke and/or environmental tobacco smoke, by chewing tobacco and by snuff dipping or by endogenous formation of such compounds upon uptake of alkaloids and nitrogen oxides or nitrite. Tobacco products also contain small amounts of volatile nitrosamines and NDELA (N’-nitrosodiethanolamine). Generally, nitrate content of a tobacco product is proportionally related to the yields of nitrosamines. The main stream smoke yields of cigarettes are greatly influenced by the efficiency of filter tips, and filtration reduces levels of tobacco specific nitrosamines in proportion to the reduction of tar.

Exposure to nitrosamines from tobacco smoke affects not only the tobacco consumer but, in environments polluted by tobacco smoke, also the nonsmoker. Occupational exposure to the extent of a few µg/worker/day to nitrosamines can occur in limited areas in the chemical, rubber, steel industry and in leather tanneries. Estimates indicate that a snuff dipper who consumes 10 g of fine-cut tobacco per day ingests 10 to 20 mg of nitrite, 100 to 200 mg of nitrate, and 100 to 200 mg of nicotine. Microorganisms in the oral cavity can reduce nitrate to nitrite. Smoking of 20 cigarettes daily provides up to 12 mg of NOX and 30 mg of nicotine as well as other nitrosatable amines. The nitrosation potential of cigarette smoke has been demonstrated by the fact that urinary excretion of N-nitrosoproline by cigarette smokers is increased (5.9 ng/24 hr) compared to that of nonsmokers (3.6 ng/24 hr) who were on an identical diet. Ascorbic acid at levels of 1000 mg/day in the diet acts as notrosation inhibitor.

NNK is the most potent carcinogen among the tobacco-specific nitrosamines. It induces lung tumors in mice; nasal cavity, trachea, and lung tumors in hamsters; and nasal cavity, lung, and liver tumors in rats. Carcinogenic effects of NNN are organo-specific in nature the effect depends on the route of administration. The carcinogenic properties of NNK and NNN are partially due to their metabolic

conversion to electrophilic intermediates. Among these, methyldiazohydroxide formed from NNK leads to o-methylguanine in DNA. The metabolic activation of NNK and NNN occurs in tissues of laboratory animals and humans. These data on the occurrence, carcinogenicity, and metabolic activation of nicotine-derived nitrosamines strongly suggest that these compounds are important in the development of tobacco-related cancers in humans. Epidemiological evidence has indicated that the combination of alcohol and tobacco consumption represents a major composite risk factor for cancer of the upper digestive tract, presumably because tobacco smoke is the source of the carcinogenic stimuli and alcohol facilitates the activation of tobacco-associated carcinogens. Similarly, synergistic effects are observed in the induction of lung cancer in cigarette smokers working in uranium mines or who were asbestos workers. The surface of asbestos particles enhances nitrosamine formation from nicotine and nitrogen dioxide enhancing the endogenous formation of tobacco-specific nitrosamines in the lungs of cigarette smokers.

Chronic Infection and Inflammation

Chronic infections contribute to about one-third of the world’s cancer. Hepatitis B and C viruses are a major cause of chronic inflammation leading to liver cancer. It is the most common cancers observed in Asia and Africa. Leucocytes and other phagocytic cells combat bacteria, parasites and other virus-infected cells by destroying them with nitrogen oxide and superoxide. These react to form peroxynitrite, hypochlorite and hydrogen peroxide all of which are powerful mutagenic oxidizing agents. Human papilloma virus spread through sexual contact is a major cause for cervical cancer.

Infection of Schistosomiasis has been reported to cause inflammation and cancer of the colon in Asia and bladder cancer in Egypt. Similarly, infection of Opisthorchis viverrini, a liver fluke lodge in bile-ducts and increase the risk of cholangiocarcinoma, has been particularly observed in Malaysia. Infection by Chlonrchis sisensis in Chinese has shown an increase in the risk of cancer of the biliary tract while Helicobacter pylori infecting the stomach of people all over the globe is known to cause stomach cancer, ulcers and gastritis.

Heavy Metals

Arsenic

Arsenic is a metalloid placed in Group VA of the Periodic Table of Elements. It is the 20th most abundant element in the earth’s crust. Arsenic is found naturally,

its concentration in air in remote areas range from 1 to 3 ng m-3 whereas in urban areas concentrations may range from 20 to 100 ng m-3. Arsenic is also found in many foods at concentrations ranging from 20 to 140 ng kg-1.

Volcanic eruptions and other natural processes are the major sources of arsenic in the environment. As2O3, arsenolite an important arsenic compound is a by-product during smelting of ores of Cu, Pb, Co, Ni, Zn, and Au. Burning of fossil fuels in the power plants and households are other anthropogenic sources of As in the environment. Burning of coal leads to the volatilization of As4O6 which condenses in the flue gases, hence fly ash from thermal power plants may cause contamination of the soil. It is estimated that 17150t of arsenic are emitted to the atmosphere by volcanoes, 27t by the oceans, and between 125 to 3345t by combustion of wood, oil and by naturally occurring forest fires. In unpolluted areas arsenic concentrations have been reported to be a few ng m-3.

Arsenic compounds are also used in tanneries, it is an essential constituent in many coloring agents such as Scheele’s green (CuHAsO3), Paris Green (Cu(AsO2)2Cu(C2H3O2)2) and is also a by-product in the production of sulphuric acid. The use of arsenical fungicides, herbicides, and insecticides in agriculture and wood industry are other important sources of Arsenic. Until the introduction of DDT in 1947 and other organic pesticides, inorganic compounds of arsenic such as lead arsenate, sodium arsenate, calcium arsenate, zinc arsenite and zinc arsenate were used by wine and fruit growers. Monosodium methylarsonate, disodium methylarsonate, and dimethylarsinic acid were used as herbicides especially in cotton production. Organically boun arsenic compounds like diphenylchloroarsine, diphenylcyanoarsine, phenyldichloroarsine were used in World War I. Likewise dimethylarsinic acid was used during the Vietnam War for defoliation for military purposes. Moreover, until the discovery of antibiotics arsenic compounds were widely used in medicine for the treatment of a variety of illnesses. A solution containing 1% of potassium arsenite (Fowler’s solution) was used for the treatment of leukaemia and psoriasis or for fortifying. Donovan’s solution (arsenic iodide) and Valagin’s solution (arsenic trichloride) were recommended for the treatment of rheumatism, arthritis, asthma, malaria, trypanosomiasis, tuberculosis, and diabetes. Sodium arsenate was used for the treatment of chronic skin diseases, some parasitic diseases, and anaemia. An organically bound arsenic compound with 32 % arsenic (Salvarsan, Arsphenamin) was used for the treatment of syphilis. Recently arsenic has been used as an anticancer agent in the treatment of acute promeylocytic leukemia. Arsenic compounds are also used in the manufacturing of glass and is also added to some alloys to make them hard and corrosion resistant. Arsenic is used in the production of catalysts and in the form of GaAs also finds application in the semiconductor industry.

Arsenic is predominantly found in nature in the +5 (arsenate), +3 (arsenite), 0 (arsenic) and -3 (arsine) oxidation states. In the aqueous state the +5 and +3 oxidation states are predominant where it exists as arsenic and arsenous acid or their salts. Bacteria, fungi and yeasts can methylate inorganic compounds of As into organic compounds such as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and gaseous derivatives of arsine.

Exposure to arsenic occurs through ingestion, inhalation, dermal contact and to some extent through the parenteral route. The intake of arsenic from air, water and soil is usually much lower, but exposure may be significant for workers producing or using arsenic compounds in vineyards, ceramics, glass manufacturing, smelting, pharmaceuticals, refining of ores or semiconductor industries or at hazardous waste sites. The largest exposure to arsenic occurs through the diet with an average intake of about 50 µg d-1 from food.

Although Arsenic is an essential element many of its compounds are toxic. The toxicity of arsenic is different in its inorganic and organic compounds and also varies according to its oxidation states and solubility. The toxicity also depends on the exposure dose, frequency and duration, the biological species, age, gender and nutritional and genetic factors. Arsine gas (AsH3) is the most toxic compound with a fatal dose of 250 mg m-3 at an exposure time of 30 minutes. Most cases of human toxicity from arsenic have been associated with exposure to inorganic arsenic. Trivalent arsenic (As (III)) is 2-10 times more toxic than pentavalent arsenate (As(V)). Table 1 lists the lethal dose (LD50) for different inorganic compounds of Arsenic.

Compound	Lethal Dose (LD50 )
Arsenic trioxide	34.5 mg kg-1
Sodium arsenite,	4.5 mg kg-1
Sodium arsenate,	4 to 18 mg kg-1
Monomethylarsonic acid	1800 mg kg-1
Dimethylarsinic acid	1200 mg kg-1
Trimethylarsine.	8000 mg kg-1

Arsenic can cause a number of human health effects, including cancer. It can cause both acute and chronic poisoning. Acute arsenic poisoning may cause vomiting, dryness of the mouth and throat, muscle cramps, abdominal pain, tingling of the hands and feet, circulatory disorders and nervous weakness. Often cold and clammy skin, hallucinations, delirium and diarrhea appear. Fatal shock can develop due to renal failure, death can occur within 24 h or may result in irreversible organ disorders followed by death in the next few days due to hepatic failure, renal failure or heart attack. Chronic poisoning involves non-specific symptoms, such as chronic weakness, loss of reflexes, weariness, gastritis, colitis, anorexia, weight loss and hair loss. Long term exposure results in hyperkeratosis, hyperpigmentation, cardiovascular and peripheral vascular diseases, neurologic and neuro-behavioral disorders, developmental anomalies, diabetes, hearing loss, portal fibrosis, hematologic disorders, carcinoma, skin cancer, loose nails with transverse white bands across the nails called Mees lines, eczema, liver and kidney disorders. Arsenic is also deposited in the hair, skin, nails and bones. Large populations in West Bengal, Bangladesh, Thailand, Inner Mongolia, Taiwan, China, Mexico, Argentina, Chile, Finland and Hungary have been exposed to high concentrations of arsenic in their drinking water and are displaying various clinico-pathological conditions.

Both trivalent and pentavalent arsenic are absorbed in biological systems with the trivalent state exhibiting greater sorption characteristics. Both these oxidation states inhibit the functions of the mitochondria by inhibiting the various mitochondrial enzymes thus impairing the overall cellular respiration. As (III) compounds have a high affinity to sulfhydryl groups in proteins and enzymes such as dihydrolipoyl dehydrogenase and thiolase causing their deactivation and thereby producing inhibited oxidation of pyruvate and betaoxidation of fatty acids. As (V) on the other hand competes with phosphate in various cell reactions and can uncouple oxidative phosphorylation so that the high energy bonds of adenosine triphosphate are not conserved. AAAAA

Mechanism of Methylation of inorganic arsenic by bacteria, fungi and yeast

Genotoxicity tests have revealed that arsenic compounds inhibit DNA repair and induces chromosomal aberrations, sister-chromatid exchanges, and micronuclei formation in both human and rodent cells in culture and in cells of exposed humans. The mechanism of genotoxicity is not known, but is postulated to be due to the ability of arsenate to act as a phosphate analog. Arsenic trioxide induces DNA damage in human lymphocytes. Arsenic compounds can also induce gene amplification, arrest cells during mitosis, inhibit DNA repair and induce expression of the c-fox gene and the oxidative stress protein hemeoxygenase in mammalian cells. They act as promoters and co-mutagens for many toxic agents.

Inorganic arsenic (As (III) and As(IV)) is metabolized in humans through methylation to monomethyl arsenic acid [MMA(V)] and dimethyl arsenic acid [DMA(V)] which are finally excreted in urine. In the past the methylation process was widely accepted as a mechanism that minimzed the toxicity/carcinogenicity of arsenic. The present view is that the methylation process may be a toxification and not a detoxification pathway. Although several epidemiological studies have documented the sources of exposure and the impact of arsenic contamination, the mechanism by which arsenic induces health effects are not well characterized.

Radon

Radon (Rn222) discovered by Rutherford in 1899 is a noble gas produced by the decay of radium-226 in the uranium chain. Radon with a half life of 3.8 days decays to produce isotopes of polonium, bismuth and lead which are also short lived. These isotopes tend to attach to surfaces and aerosol particles such as dust and cigarette smoke. Hence through inhalation of the radon daughters as well as some radon the epithelium is radiated. Radon daughters emit alpha, beta and gamma radiation, the alpha radiation has significant effects on the tracheal and bronchial epithelium. The basal stem cells of the respiratory epithelium are predominantly at risk after the inhalation.

Radium in the ground is the major source of radon outdoors, but sources like natural gas, building materials and ground water, especially from deep wells contribute both outdoors and indoors. Radon is also carried into the mines through deep underground water streams and can also diffuse out of the rocks and from crushed ore. In this way miners are exposed by breathing the mine atmosphere. The general population may be exposed from indoor radon concentrations built up from the leakage of radon into houses from the geological materials in the ground and walls. The concentration of radon and its daughter elements indoors are influenced by ventilation and aerosols. Low ventilation rates in modern homes tend to build up the concentrations of radon and its daughters.

Exposure to radon and its daughters is known to induce lung tumors, both benign and malignant. Various epidemiological studies have revealed that the relative risk are between 4 and 21, suggesting that about 70-90% of the lung cancers among underground miners might be due to occupational exposure to radon and its daughters. In view of the risk of lung cancer, the presence of radon and its daughters in houses has become a matter of concern in several countries. Further a multiplicative interaction between radon daughter exposure and smoking among miners is known. However under certain conditions smoking is also believed to influence mucous secretion causing hyperplasia of the epithelium in the respiratory tract and thus, reducing the ability of the short range alpha particles to penetrate the basal cells of the epithelium and hence less carcinogenic change is induced. Although radon is toxic at high concentrations, radon can also exert a beneficial effect on immune system when it generates low radiation doses in man. Inhalation of radon probably significantly increases the activity of the antioxidant superoxide dismutase in the liver and kidney after exposure.

Nickel

Nickel is the 24th most abundant element in the earth’s crust. It is a hard, ductile transition metal with a silvery white lustre. It is not found in freestate and is primarily found naturally in the earth’s crust combined with oxygen or sulphur as oxides or sulphides. In the combined form it exists with sulphur and iron in pentlandite, with sulphur in millerite, with arsenic in nickeline and with sulphur and arsenic in nickel glance. It is also present in soil, in meteorites and is emitted from volcanoes. Nickel is one of the five ferromagnetic substances and is naturally magnetostrictive i.e. in the presence of a magnetic field undergoes a small change in length. It is resistant to corrosion by air, water and alkali, but dissolves readily in dilute oxidizing acids. It can exist in different oxidation states (-1, +1, +3, and +4), under environmental conditions the +2 state is the most prevalent. Nickel is used in many metallurgical processes such as electroplatiing and alloy production such as stainless steel and other nickel alloys with high corrosion and temperature resistance as well as nickel-cadmium batteries. Nickel metal and its alloys are also used as catalysts and pigments. Nickel salts such as nickel chloride, sulphate, nitrate, carbonate, hydroxide, acetate and oxide find several commercial applications.

Ni is widely distributed in the environment. It is released from both natural and anthropogenic sources. It is present in the air, water, soil and biological materials. Natural sources of atmospheric nickel include wind-blown dust derived from weathering of rocks and soils, volcanic emissions, forest fires and vegetation. Combustion of coal, diesel oil and fuel oil, waste incineration are the major anthropogenic sources. Low levels of Ni emissions may take place from tobacco, dental or orthopaedic implants, stainless steel utensils and inexpensive jewellery. Cigarettte smoke is another important source. Each cigarette contains 1.1 to 3.1µg of Ni and 10-20% of the inhaled Ni is in the gaseous phase. Ni concentrations vary considerably in ambient air; highest values reported from highly industrialized regions. Average levels of Ni reported from remote areas is 0.00001-0.003 µg m-3; 0.003-0.03 µg m-3 in urban areas with no metallurgical industries and 0.07-0.77 µg m-3 in Ni processing areas. Occupational exposure to nickel compounds can occur through inhalation or dermal contact and the magnitude of exposure depends on the industrial process.

The adverse health effects of nickel depend on the route of exposure and include systemic, immunologic, neurologic, reproductive, developmental or carcinogenic effects. All nickel compounds, except metallic nickel have been classified as human carcinogens by IARC. Nickel is absorbed through lungs, gastrointestinal tract and skin. The most common harmful effect of nickel in humans is an allergic skin reaction in individuals sensitive to nickel. Nickel dermatitis produces erythema, eczema and lichefication of the hands and other areas of the skin that contact nickel. Nickel metal dusts and some nickel compounds are potent carcinogens after inhalation, but the carcinogenic risk is governed by the conditions of occupational exposure. The bioavailability of nickel and the presence of constituents that promote oxygen-free radicals reactions influence the carcinogenicity of nickel compounds. The carcinogenic potency of individual compounds depends on their ability to enter cells. Water insoluble compounds exhibit potent carcinogenic activity while the highly water soluble compounds exhibit less potency. The nickel ions (Ni2+) from the water insoluble compounds readily enter the cells through phagocytic processes due to their bioavailability. Ni2+ ions can initiate carcinogenesis by mutagenesis, chromosome damage, formation of Z-DNA, inhibition of DNA excision-repair or epigenetic mechanisms. Another possible mode of cell death caused by Ni involves nickel induced lipid peroxidation. It is presumed that the nickel induced accumulation of iron is directly responsible for the formation of reactive oxygen species and the enhancement of lipid peroxidation. Antioxidants play an important role in abating hazards of nickel. Exogenous antioxidants interact with the free radicals by terminating the chain reactions. Ascorbic acid (Vitamin C) is a dietary antioxidant that inactivates oxygen free radicals serving as a scavenger of free radicals.

Cadmium

Cadmium is a heavy metal belonging to group IIB of the periodic table. It is naturally found in ores along with zinc, copper and lead. Volcanic activity is an important natural source of cadmium. It is widely used in industrial processes as an anticorrosive agent, stabilizer in PVC products, as a color pigment, a neutron absorber in nuclear power plants and in nickel cadmium batteries. Some phosphate fertilizers also contain cadmium. Cadmium is a ubiquitous environmental pollutant of increasing concern. Exposure via ambient air is usually low as cadmium concentrations in rural areas are about 1 ng m-3 or less, and in urban areas without major cadmium emitting industries, the average concentrations are generally less than 10 ng m-3. Average concentrations in air near cadmium emitting industries may be between 0.1 and 0.5µg m-3. The major source of inhalativ cadmium intoxication is cigarette smoke. The lungs resorb 40-60% of cadmium in tobacco smoke. Smokers generally have cadmium blood levels 4-5 times those of non-smokers. Cadmium absorbed from the lungs or the gut is initially stored in the liver, where it binds to metallothionein. Cd-metallothionein complexes are washed into sinusoidal blood, thus it is slowly released from the liver and eventually appears in the kidneys. The kidney is the main organ for long term accumulation of cadmium. Cd disappears very slowly from the kidneys. The half life period for cadmium in the human body may be up to 30 years. A life long intake can therefore lead to a cadmium accumulation in the kidney consequently resulting in tubulus cell necrosis.Inhalation of Cd containing air affects the respiratory system resulting in shortness of breath, lung edema and destruction of mucous membranes. In-vitro studies indicate that Cd compounds have mutagenic potential. They have been shown to induce chromosome damage and DNA strand breaks. Cd has been classified as a category 1 carcinogen. Inhalation of cadmium increases the risk of lung cancer. It exerts its genotoxicity through the production of reactive oxygen species and by inhibiting DNA repair. Cadmium concentrations increase in the testes and prostate during heavy exposure. It has been shown that testosterone synthesis decreases in Cd-exposed animals. Excessive exposure may interfere with the zinc/hormone relationship in the prostate, leading to prostatic cancers.

Chromium

Chromium rarely occurs naturally as chromium metal or elemental Cr, Cr(0). In the earth’s crust it is predominantly present in the trivalent form,Cr (III) with a worldwide mean value of 200 mg kg-1. It is also ubiquitous in air, water, soil and biological materials as hexavalent chromium [Cr (VI)] mainly contributed by human activities. The major anthropogenic sources of Cr (VI) emissions are chrome plating, production of chromates and bichromates, stainless steel, welding, ferrochrome alloys and chrome pigment production, material tanning and evaporative cooling towers. Combustion of coal and oil, cement works and waste incineration also release large quantities of Cr. Almost 35% of Cr released from all anthropogenic sources is Cr (VI), however the ratio of Cr (III)/Cr(VI) in the natural environment varies from 0.3 to 1.5 depending on oxidation/reduction and acid/base conditions. The releases of Cr (VI) from any source are reduced via biotic and abiotic processes to Cr (III) in most situations in the environment. The impact of Cr (VI) is therefore limited to the area around an exposure source. In biological systems, the oxidation of Cr (III) to Cr (VI) never occurs. In foodstuffs, Cr is generally considered to be present as Cr (III).

The general population may be exposed to chromium by inhaling ambient air, or ingesting food and drinking water that contain Chromium. Daily exposure from food sources is estimated at about 0.1 mg. Exposure may also occur through skin contact with certain consumer products containing Cr for example wood preservatives, cement, cleaning materials, textiles and leather tanned using Cr and via cigarette smoke. Chromium (III) is regarded as an essential element and has an important role in the maintenance of normal carbohydrate, lipid and protein metabolism. Almost all of the chromium in food is present as Cr (III) and about 0.5-1% of Cr (III) present in normal diet is absorbed. Absorption of ingested Cr (VI) compounds is greater than for Cr (III) compounds, ranging from 2-8%. Most of the ingested Cr (VI) is reduced to Cr (III) in the stomach prior to absorption. Cr (VI) is more efficiently absorbed through skin than Cr (III) compounds. In the blood, 95% of Cr (III) is bound to high molecular mass proteins like transferring while a small proportion binds with the low molecular mass oligopeptides. Cr (VI) is unstable in the body and is reduced to Cr (V), Cr (IV) and ultimately to Cr(III) by endogenous substances such as ascorbate and glutathione. It is believed that toxicity of Cr may result from damage to cellular components during this process.

The toxicity of Cr depends on the oxidation state, Cr (VI) is more toxic and more readily absorbed both by inhalation and ingestion. Acute exposure through inhalation affects the respiratory tract while effects on the kidney, gastrointestinal tract and liver are also observed. Ingestion of high doses of Cr (VI) compounds results in fatal effects in the respiratory, cardiovascular, gastrointestinal, hepatic, renal and neurological systems. Dermal exposure can lead to dermal ulcers as Cr (VI) compounds are corrosive in nature. Occupational exposure to inhaled Cr (VI) can cause nasal septal ulceration and perforation, respiratory irritation and inflammation, dyspnoea, cyanosis, gastrointestinal, hepatic, renal, haematological effects and lung cancer. Chronic exposure to Cr (III) can lead to weight loss, anaemia, liver dysfunction and renal failure.

(VI) has been classified as a Group 1 known human carcinogen while chromium metal and Cr (III) compounds are not classifiable as to their carcinogenicity to humans (Group 3) due to inadequate evidence in humans. Cr (VI) compounds may cause chromosomal aberrations and sister chromatid exchanges in humans. The genotoxicity of Cr (VI) is result of sequential reduction of Cr (VI) within the cells to Cr (III) and the binding of Cr (III) to macromolecules, including DNA. Cr (III) is not considered to be mutagenic in cellular systems. Studies have not shown Cr (III) to be carcinogenic.

Polycyclic Aromatic Hydrocarbons

Polycyclic aromatic hydrocarbons (PAH) belong to the group of Persistent organic pollutants. They are multi-aromatic ring systems composed of carbon and hydrogen atoms arranged in the form of fused aromatic rings with linear, cluster or angular arrangement. The PAH family includes 660 substances indexed by the National Institute of Standards and Technology and approximately 30 to 50 of them commonly occur in the environment. They are generally produced in incomplete combustion processes.

PAH originate from both natural and anthropogenic sources through incomplete combustion or high temperature pyrolytic processes involving fossil fuels or more generally materials containing C and H. PAH produced from combustion are initially generated at source in the gaseous state, a proportion of which then adsorb onto existing particles upon cooling of the emission. At the higher temperatures of combustion sources, larger proportions are present in the vapor phase. Emissions of PAH vary with combustion systems. Different types of combustion yield different distributions of PAH, thus those produced from coal burning are different than those produced by motor-fuel combustion, which differ from those produced by forest fires. The large-scale combustion, e.g., industrial with a burning rate of hundreds kilograms per hour, is normally better controlled, more complete, and results in lower formation of PAH than small-scale combustion such as domestic cook stoves with a burning rate of a few hundred grams to a few kilograms per hour. Natural sources of PAH include combustion (forest fires and volcanoes) and biosynthesis (sediment diagenesis, tar pits and biological conversion of biogenic precursors). Anthropogenic sources are the major contributors of the more hazardous PAH species and include mobile as well as stationary categories. Mobile categories are mainly vehicular (petrol and diesel engines) and tobacco smoking. Stationary categories include domestic heating, refuse burning and industrial activities such as metallurgical enterprises, foundries, timber treatment plants, as well as industries focusing on the carbonization, distillation and gasification of coal, coke and Aluminium production plants.

The physico-chemical properties of PAH are correlated to the number of rings, while minor differences within each ring-homologue can be attributed to the arrangement of the rings. The PAH have wide range of molecular weights from 128 to 276 with boiling points ranging from 218 to 525ºC, while some of the isomers have small differences in the boiling points. Vapor pressure generally tends to decrease with the increase in molecular weight. Low molecular weight (LMW) PAH, containing two or three fused rings are more volatile than high molecular weight (HMW) PAH containing >3 fused rings, which are primarily associated with particles. PAH are sparingly soluble or practically insoluble in water and soluble in many organic solvents; benzene, acetone, hexane and tetrahydrofuran readily dissolve PAH. Most of the PAH are fluorescent in ultra violet light and are photosensitive, forming endoperoxides which then undergo ring cleavage and dealkylation. They undergo two types of reactions i.e. electrophilic substitution and addition reaction. The former is preferred since it does not destroy the aromatic character of PAH, while addition is often followed by elimination resulting in a net substitution. PAH compounds undergo chemical transformation by gas-particle interactions in emission plumes, exhaust systems and even during atmospheric transport. PAH on reaction with other atmospheric pollutants such as O3, NO2, SO2, HNO3, Per-oxy Acetyl Nitrate (PAN) are concurrently exposed to sunlight and molecular oxygen and may form hetero-PAH like oxy, hydroxy, nitro and hydroxylnitro PAH. Nitro and oxy PAH reaction products may be present in the gas phase as well as particulate. The carcinogenicity and mutagenicity of many of these hetero-PAH compounds is greater than their parent compounds.

PAH are hydrophobic compounds and their persistence in the environment is mainly due to their low water solubility and electro-chemical stability. Evidence suggests that the lipophilicity, environmental persistence and genotoxicity of PAH increase upto four or five fused benzene rings. The extent to which humans are exposed to PAH is a function of dose, duration, pathway of exposure (breathing, eating, drinking, skin contact) and individual characteristics such as age, nutritional status, family traits including the concentration in ambient air, the prevailing atmospheric conditions, their distribution between the gaseous and particulate phases and the size of the particle with which the particulate fraction are associated. Smoking is an important contributor to PAH exposure. Smoking one cigarette cause intake of 20-40 ng of benzo(a)pyrene. PAH concentrations in air vary from a few ng m-3 to several hundred ng m-3; in urban areas the concentration can be tenfold higher than in rural areas. Occupational exposure from aluminium production plants, coke ovens and foundries can be considerably higher.

PAH are highly lipid-soluble and are absorbed from the lung, gut and skin of mammals. Inhaled PAH are predominantly adsorbed on soot particles. After deposition in the airways, the particles can be eliminated by bronchial clearance. PAH might be partly removed from the particles during transport on the ciliated mucosa and may penetrate into the bronchial epithelium cells where metabolism takes place. BaP and other PAH are readily adsorbed from the gastrointestinal tract when present as solutes in various dietary lipids. Their adsorption is facilitated by the presence of bile salts in the intestinal lumen. Irrespective of the route of administration, PAH are rapidly and widely distributed in the organism.

Not all PAHs are of equal toxicity. The toxicity is determined by the structure and the presence of substituents. Many PAHs belong to the group of carcinogens including both the unsubstituted and the substituted ones particularly the nitro, oxy and methylated derivatives and those containing carboxylic groups. PAHs present in the environment are not active and are unable to cause carcinogenesis. Only after entering the body of an organism they are metabolically transformed to carcinogenic forms. BaP and other PAH stimulate their own metabolism by inducing microsomal cytochrome P-450 monooxygenases and epoxide hydrolases. PAH exert their mutagenic and carcinogenic activity through biotransformation to chemically reactive intermediates, which bind covalently to cellular macromolecules (inter alia DNA). Extensive and systematic studies on the tumorigenicity of individual PAH metabolites in animals have led to the conclusion that vicinal or so called bay-region diol epoxides are the ultimate mutagenic and carcinogenic species of alternant PAH, although not necessarily the only ones . These diol epoxides are easily converted by epoxide ring opening into electrophilic carbonium ions, which are alkylating agents that covalently bind to nucleophilic sites in the DNA bases and in proteins. There is now ample evidence to suggest that the metabolically activated intermediates of carcinogenic hydrocarbons initiate carcinogenesis by binding covalently to DNA in the target tissues and form protein adducts and activate aryl hydrocarbon receptor (AhR)-mediated activity, and may interfere with estrogen receptor (ER)–mediated signaling. Subsequent DNA replication results in mutations leading to carcinogenesis. Covalent binding of carcinogenic hydrocarbons to DNA has been demonstrated under both in vitro and in vivo conditions.

BaP for example, is initially oxidized to several arene oxides and phenols. The arene oxides may rearrange spontaneously to phenols (3-OH-, 6-OH-, 7-OH, and 9-OH-BaP), undergo hydration (catalysed by microsomal epoxide hydrolases) to the corresponding trans-dihydrodiols (4,5-, 7,8- or 9,10- dihydrodiol), or react covalently with glutathione, either spontaneously or catalysed by cytosolic glutathione-S-transferases. The 7,8-dihydrdiol is the main product which may form 7,8-dihydroxy,9,10-epoxy 7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE), the most carcinogenic of four possible isomers. BPDE is the carcinogenic form of benzo(a)pyrene. It’s half life is 8 minutes which is long enough for its binding to nucleophilic parts of proteins and DNA. BPDE binds covalently to oxygen or nitrogen atoms of purine bases (guanine and adenine or pyrimidine bases (cytosine and thymidine). The half life of other forms is too short to bind to DNA or protein. The formation of such adducts initiates carcinogenesis. During the repair process, the PAH-DNA adduct is cut out from the DNA strand and replaced by the complementary base. When the repairing system makes a mistake, the sequence of nucleotides can be altered, and in place of the damaged DNA anew helix with incorrect order of bases is created. Such mutation can initiate carcinogenesis and further a neoplastic disease. The phenols can be further oxidized to quinones (1,6-, 3,6-, or 6,12-quinone). In addition, secondary epoxides derived from the phenols and the dihydrodiols (resulting in diol epoxides) are formed following further oxidation by the cytochrome P-450 monooxygenase system.

Concerning carcinogenicity, International Agency for Research on Cancer (IARC) has classified carcinogenic PAH into ‘probably carcinogenic’ and ‘possibly carcinogenic’ PAH. The carcinogenicity of PAH is about 1/103 – 1/104of that of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) on the other hand, the PAH concentration in the atmosphere is about 104 -106 times higher than that of TCDD.

Several PAH have potential to accumulate in fatty tissues and in other organic material. These attributes complicate their removal from human body. They tend to be stored mostly in kidney, liver and fat. Smaller amounts are stored in spleen, adrenal glands and ovaries. Their metabolites bind to DNA in cells and have a mutagenic or carcinogenic impact.

Organochlorine Compounds

Organochlorine compounds are compounds that contain chlorine. They are prepared by direct chlorination of aliphatic and aromatic hydrocarbons. Aliphatic compounds can be easily chlorinated while chlorination of aromatic compounds is comparatively difficult and proceeds through an ionic mechanism. The aliphatic organochlorine compounds are generally more reactive and undergo both substitution and elimination reactions. These compounds are quite stable and do not decompose or degrade by normal physical or biochemical processes because of their strong carbon-chloride bond. They are sparingly soluble in water but are highly lipophilic. Due to these properties they have been used as plasticizers, solvents, lubricants, dielectric fluids and pesticides. About 15,000 organochlorine substances are known and manufactured but few are also formed naturally in the environment at low levels. Approximately 2000 compounds are known to be produced by living organisms.

Organochlorines are a group of synthetic chemicals that include polychlorinated biphenyls (PCBs), dibenzo- p- dioxins/ polychlorinated dibenzofurans (PCDDs/ PCDFs or dioxins) and organochlorine pesticides, such as dichlorodiphenyl-trichloroethane (DDT), lindane, aldrin and dieldrin. The most abundant of these man-made organochlorine compounds are the PCBs and the pesticide DDT

Human exposure to organochlorine substances may occur through inhalation of air, ingestion of food and water and absorption by skin. However the major route of exposure to these substances is via food particularly contaminated fish and other animals because of the bioaccumulation of organochlorines in fish and other animals that humans consume. Organochlorines are absorbed from the gut, by the lungs and across the skin in varying degrees. Fat and organic solvents enhance gastrointestinal and dermal absorption of organochlorines. Most of the solid organochlorines are not highly volatile, pesticide- laden aerosols or dust particles trapped in respiratory mucous and subsequently swallowed may be vehicles leading to significant gastrointestinal absorption. Most organochlorines are dechlorinated to some extent, oxidized and then conjugated. The chief route of excretion is biliary, although nearly all organochlorines yield measurable urinary metabolites. Many of the unmetabolized pesticides are efficiently reabsorbed by the intestine, substantially retarding fecal excretion.

Organochlorine compounds have the ability to alter the levels of certain hormones, enzymes, growth factors and neurotransmitters and exert toxic effects disorders in the female and male reproductive system and infertility, carcinogenicity, developmental toxicity, neurotoxicity and immunotoxicity. Dioxins and particularly TCDD is a known human carcinogen. Organochlorines disturb the balance of endocrine system and therefore are known as hormone disrupting chemicals or as endocrine disrupters also called as environmental hormones, synthetic hormonally active agents (HAAs) and xenoestrogens.

Structures of some Organochlorine Compounds

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References:

Rehman M. Arsenic and Contamination of Drinking-water in Bangladesh: A Public-health Perspective. J Health Popul Nutr. 2002, 20(3):193-197.
Guertin J. Toxicity and health effects of chromium (All Oxidation states) In: Chromium (VI) Handbook, CRC Press.2004; 216-232.
Edling C. Radon daughter exposure and lung cancer. British Journal of Industrial Medicine. . 1985; 42:721-722.
Godt J, Scheidig F, Grosse-Siestrup C, Esche V, Bradenburg P, Reich A, Groneberg D.A. The toxicity of Cadmium and resulting hazards for human health. Journal of Occupational Medicine and Toxicology, 2006; 1: 22.
Abernathy CO, Liu YP, Longfellow D, Aposhian HV, Beck B, Fowler B, et al. Arsenic: health effects, mechanisms of actions, and research issues. Environ Health Perspect. 1999;107:593–597.
Anetor JI, Wanibuchi H, Fukushima S. Arsenic exposure and its health effects and risk of cancer in developing countries: micronutrients as host defence. Asian Pac J Cancer Prev. 2007;8(1):13–23.
ATSDR. Toxicological Profile for Cadmium (update) Atlanta, Georgia: Agency for Toxic Substances and Disease Registry; 1999. pp. 1–397.
Klaassen CD, Liu J, Diwan BA. Metallothionein Protection of Cadmium Toxicity Toxicol Appl Pharmacol. 2009, 238(3): 215–220.
Costa M, Davidson TL, Chen H, et al. Nickel carcinogenesis: epigenetics and hypoxia signaling. Mutat. Res. 2005; 592:79–88. doi: 10.1016/j.mrfmmm.2005.06.008.
Lu H, Shi X, Costa M, et al. Carcinogenic effect of nickel compounds. Mol Cell Biochem. 2005; 79:45–67. doi: 10.1007/s11010-005-8215-2.
Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile for Chromium. U.S. Department of Health and Human Services, Public Health Service. Agency for Toxic Substances and Disease Registry; 2000.
Chad M, Thompson, Haws LC, Harris MA, Gatto NM, Deborah M. Proctor Application of the U.S. EPA Mode of Action Framework for Purposes of Guiding Future Research: A Case Study Involving the Oral Carcinogenicity of Hexavalent Chromium. Toxicological Sciences 2011; 119(1), 20–40. doi:10.1093/toxsci/kfq32.
Boffetta P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control. 1997, 8, 442-472.
Andrysik Z, Vondracek J, Marvanova S, Ciganek M, Neca J, Pencikova K, Mahadevan B, Topinka J, Baird W.M, Kozubik A, Machala M. Activation of the aryl hydrocarbon receptor is the major toxic mode of action of an organic extract of a reference urban dust particulate matter mixture: the role of polycyclic aromatic hydrocarbons. Mutat. Res. 2011, 714, 53–62.
Baird W.M., Hooven L.A., Mahadevan B. Carcinogenic polycyclic aromatic hydrocarbon-DNA adducts and mechanism of action. Environ. Mol. Mutagen.2005, 45, 106–114.
Lewtas J. Air pollution combustion emissions: characterization of causative agents and mechanisms associated with cancer, reproductive, and cardiovascular effects. Mutat. Res. 2007, 636, 95–133.
Pesatori A.C., Consonni D., Rubagotti M., Grillo P., and Bertazzi P.A. Cancer incidence in the population exposed to dioxin after the Seveso accident: twenty years of follow-up. Environ. Health. 2009, 8:39-48
Van Den Berg M., Birnbaum L.S., and Denison M. The 2005 World Health Organization re-evaluation of human and mammalian toxic equivalency factors for dioxins and dioxin-like compounds,Toxicological Sciences,2006, 93(2):223-241.
Morsy F.A.M.E., El-Sadaawy M.M., Ahdy H.H.H, Fattah L.M.A, Sikaily A.M.E, Khaled. A, Tayel F.M.T. Potential human health risks from toxic metals, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, and organochlorine pesticides via canned fish consumption: Estimation of target hazard quotients, Journal of Environmental Science and Health, Part A: Toxic/Hazardous Substances and Environmental Engineering, 2013, 48(12) DOI:10.1080/10934529.2013.796782

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