**3. Cancer risk — Carcinogens and co-carcinogens**

Currently we are aware that apart of inherited mutations, an important role in carcinogenesis play the factors connected with the expression to carcinogens [14]. This includes environmental factors (pollutions), lifestyle factors (tobacco smoking, diet, alcohol consumption, obesity, sedentary life), occupational factors (e.g. synthesis, dyes, fumes) and other factors (excessive exposure to sunlight, radiation, viruses, etc). Carcinogens (of chemical, physical or biological origin) include chemicals or non-chemical agents, which under certain conditions are able to induce cancer. Co-carcinogens, are not carcinogenic themselves but with other chemicals or non-chemical carcinogens, such as for example UV or ionizing radiation, promote the effects of a carcinogen in carcinogenesis. Carcinogens as well as co-carcinogens can be of natural or synthetic origins. In general, their carcinogenic action relay on direct or indirect action in the cellular DNA. Carcinogens acting directly can initiate the carcinogenesis by yielding highly reactive species that bind covalently to cellular DNA, while those acting indirectly can induce mutations to cellular DNA. Thus carcinogens are able to distort the conformation or function (replication/transcription) of DNA, which results not only in oncogene activation but also DNA amplification, gene transposition or chromosome translocation. Carcinogens may induce carcinogenesis directly by mutational activation of protooncogenes and/or inactivation of tumour suppression genes. Indirect action is realised through the mechanisms that generate chemical species (free radicals, reactive oxygen species, carcinogenic metabolites) which are capable of entering the nucleus of the cell.

Over 80% of carcinogenic substances are of environmental origins [15]. Restriction of the exposition to carcinogens can substantially reduce the risk of cancers also those of occupational type, which make approximately 4-5% of all human cancers. Thus evaluation and classification of the carcinogens is required from the cancer prevention point of view. Although there are many international and national organizations that classify carcinogens, but only a few are highly influential, the oldest and setting the standards, World Health Organization of the United Nations (WHO) International Agency for Research on Cancer (IARC) headquartered in Lyon, France, established in 1965; United Nations initiative from 1992 called Globally Harmonized System of Classification and Labelling of Chemicals (GHS), National Toxicology Program of the U.S. Department of Health and Human Services established in 1978, profes‐ sional organization American Conference of Governmental Industrial Hygienists, founded in 1938 in Washington and reorganized in 1946, European Union directives Dangerous Substan‐ ces Directive (67/548/EEC) and the Dangerous Preparations Directive (1999/45/EC) and Safe Work Australia (Independent Statutory Agency) which evolved from National Occupational Health and Safety Council (NOHSC) established in 1985. One of the prime roles of these organizations is to evaluate and classify the chemical, physical and biological carcinogens targeted to develop strategies for cancer prevention and control used by international and national health and regulatory agencies to protect public health. Since 1971 IARC evaluated the carcinogenicity of approximately 400 and collected data about 900 agents and published them in a series (101 till 2012) of Monographs on the Evaluation of Carcinogenic Risks to Humans [3]. Up to now IARC has identified 108 definitely, 66 probably, 284 possibly carcino‐ gens, 515 not classifiable as carcinogens and 1 probably not carcinogenic, Table 1. Alternative to IARC, a complex GSH classification system, collects data from tests, literature, and practical experience [16]. Since 2003 four editions of GHS have been published, but only most recent one, dated to 2011, has the form convenient for worldwide implementation. GSH delivers a global system of classification of chemicals (substances, alloys, mixtures) divided into three groups of hazards: physical (16 classes), health and environmental (12 and 2 classes, respec‐ tively) and a unique system of labelling and collecting the information in the form of safety data sheets (SDS). GSH requires the use of the harmonized classification scheme and the harmonized label elements for any carcinogenic chemical. Within the GSH system, the class of carcinogens was clearly separated as health hazard risk factor and divided to two categories: known and presumed carcinogens (subcategories 1A and 1B, respectively) and suspected carcinogens (category 2), Table 2. Irrespective of the classification system, the epidemiological evidence indicates that many drugs, including antineoplastic, sex hormones, antithyroid, antibacterial, antiparasitic, immunosuppressive ones used as single agents or in combinations as well as radiation (γ, X or UV) are known carcinogens.

synthetic aromatic amine dye in German industry, Ludwig Rehn (1849-1930) reported an increased incidence of bladder cancer in workers exposed to it. Many years later exact carcinogen, 2-naphthylamine, was recognized. In the 1930s the first company in American dye industry, DuPont, reported first cases of occupational cancer connected with the use of dyes, bladder cancer, at the Chambers Works plant. In 1935, Takaoki Sasaki and Tomizo Yoshida (1903-1973) induced malignant tumours (hepatoma) in a digestive organ by feeding rats by

**Effect Criteria No Agents and groups of**

sufficient evidence of carcinogenicity to humans, epidemiologic evidence,

occupational exposure, and animal studies; strong evidence that the agent acts through relevant mechanisms of carcinogenicity to

limited evidence of carcinogenicity to humans, but sufficient evidence of carcinogenicity in experimental animals; strong evidence that the carcinogenesis is mediated by mechanisms

that are also operate in humans

limited evidence in humans; less than sufficient evidence in experimental animals; inadequate evidence in humans but sufficient

or limited in experimental animals

or limited to experimental animals;

negative evidence of carcinogenicity,

not operate in humans.

not used

**Table 1.** Classification of carcinogens according to IARC, 2012

inadequate evidence in humans; inadequate

mechanisms of carcinogenesis in animals does

But the first chemical carcinogen - coal tar - was identified as early as in 1915 by Katsusaburo Yamagiwa (1863-1930) and Koichi Ichikawa (1888-1948) who induced cancer in laboratory

**agents/mixtures/ the exposure circumstance**

http://dx.doi.org/10.5772/52507

43

cyclophosphamide, chlornaphazine, melphalan, tamoxifen5, thiotepa, sulfur

ultraviolet radiation (UV-A, UV-B, UV-C), X-radiation, γ-radiation, radiation, radionuclides, neutron radiation, solar radiation

66 azacitidine, cisplatin, nitrogen mustard, doxorubicin

284 aziridine, dacarbazine, daunomycin, thiouracil,

515 ifosfamide, isophosphamide, actinomycin D

bleomycin

1 caprolactam

108 chlorambucil,

Anticancer Drug Discovery — From Serendipity to Rational Design

mustard

one of the azo dyes - *o*-aminoazotoluene.

carcinogenic

carcinogenic

carcinogenic

carcinogenic

carcinogenic

humans

**IARC classification**

Group 1 definitely

Group 2A probably

Group 2B possibly

Group 3 not classifiable as

Group 4 probably not

#### **3.1. Carcinogens of chemical/environmental origins**

As early as in 16th c. Phillippus Aureolus Theophratus Bombastus von Hohenheim (1493-1541) known as Paracelsus suggested that the "wasting disease of miners" might be linked to exposure to realgar (tetra-arsenic tetra-sulphide). Since the 17th c. cancer was associated with the presence of some chemicals. For example John Hill (1716-1775) linked tobacco use with nasal cancer, while Percivall Pot (1814-1788) described occupational risk of epithelial cancer of the scrotum connected with soot, in chimney sweepers. In 1795 Samuel Thomas von Soemmerring (1755-1830) cautioned that pipe smokers were excessively prone to cancer of the lip. Since then epidemiological evidence has been important in detecting carcinogens. In 1858, a Montpellier surgeon Etienne-Frédéric Bouisson (1813-1884) found that 63 of his 68 patients suffering from oral cancer were pipe smokers. Shortly after replacement of natural dyes by synthetic aromatic amine dye in German industry, Ludwig Rehn (1849-1930) reported an increased incidence of bladder cancer in workers exposed to it. Many years later exact carcinogen, 2-naphthylamine, was recognized. In the 1930s the first company in American dye industry, DuPont, reported first cases of occupational cancer connected with the use of dyes, bladder cancer, at the Chambers Works plant. In 1935, Takaoki Sasaki and Tomizo Yoshida (1903-1973) induced malignant tumours (hepatoma) in a digestive organ by feeding rats by one of the azo dyes - *o*-aminoazotoluene.

highly influential, the oldest and setting the standards, World Health Organization of the United Nations (WHO) International Agency for Research on Cancer (IARC) headquartered in Lyon, France, established in 1965; United Nations initiative from 1992 called Globally Harmonized System of Classification and Labelling of Chemicals (GHS), National Toxicology Program of the U.S. Department of Health and Human Services established in 1978, profes‐ sional organization American Conference of Governmental Industrial Hygienists, founded in 1938 in Washington and reorganized in 1946, European Union directives Dangerous Substan‐ ces Directive (67/548/EEC) and the Dangerous Preparations Directive (1999/45/EC) and Safe Work Australia (Independent Statutory Agency) which evolved from National Occupational Health and Safety Council (NOHSC) established in 1985. One of the prime roles of these organizations is to evaluate and classify the chemical, physical and biological carcinogens targeted to develop strategies for cancer prevention and control used by international and national health and regulatory agencies to protect public health. Since 1971 IARC evaluated the carcinogenicity of approximately 400 and collected data about 900 agents and published them in a series (101 till 2012) of Monographs on the Evaluation of Carcinogenic Risks to Humans [3]. Up to now IARC has identified 108 definitely, 66 probably, 284 possibly carcino‐ gens, 515 not classifiable as carcinogens and 1 probably not carcinogenic, Table 1. Alternative to IARC, a complex GSH classification system, collects data from tests, literature, and practical experience [16]. Since 2003 four editions of GHS have been published, but only most recent one, dated to 2011, has the form convenient for worldwide implementation. GSH delivers a global system of classification of chemicals (substances, alloys, mixtures) divided into three groups of hazards: physical (16 classes), health and environmental (12 and 2 classes, respec‐ tively) and a unique system of labelling and collecting the information in the form of safety data sheets (SDS). GSH requires the use of the harmonized classification scheme and the harmonized label elements for any carcinogenic chemical. Within the GSH system, the class of carcinogens was clearly separated as health hazard risk factor and divided to two categories: known and presumed carcinogens (subcategories 1A and 1B, respectively) and suspected carcinogens (category 2), Table 2. Irrespective of the classification system, the epidemiological evidence indicates that many drugs, including antineoplastic, sex hormones, antithyroid, antibacterial, antiparasitic, immunosuppressive ones used as single agents or in combinations

as well as radiation (γ, X or UV) are known carcinogens.

As early as in 16th c. Phillippus Aureolus Theophratus Bombastus von Hohenheim (1493-1541) known as Paracelsus suggested that the "wasting disease of miners" might be linked to exposure to realgar (tetra-arsenic tetra-sulphide). Since the 17th c. cancer was associated with the presence of some chemicals. For example John Hill (1716-1775) linked tobacco use with nasal cancer, while Percivall Pot (1814-1788) described occupational risk of epithelial cancer of the scrotum connected with soot, in chimney sweepers. In 1795 Samuel Thomas von Soemmerring (1755-1830) cautioned that pipe smokers were excessively prone to cancer of the lip. Since then epidemiological evidence has been important in detecting carcinogens. In 1858, a Montpellier surgeon Etienne-Frédéric Bouisson (1813-1884) found that 63 of his 68 patients suffering from oral cancer were pipe smokers. Shortly after replacement of natural dyes by

**3.1. Carcinogens of chemical/environmental origins**

42 Drug Discovery


**Table 1.** Classification of carcinogens according to IARC, 2012

But the first chemical carcinogen - coal tar - was identified as early as in 1915 by Katsusaburo Yamagiwa (1863-1930) and Koichi Ichikawa (1888-1948) who induced cancer in laboratory animals by prolonged application of coal tar to rabbit skin. Inflammation accompanying the coal tar application and cancer formation was in a good agreement with Virchow findings. The search for specific chemical carcinogens led to the discovery of pure carcinogenic chemi‐ cals including polycyclic aromatic hydrocarbons PAHs (e.g. benzo[a]pyrene, 1,2,5,6-diben‐ zanthracene) by Ernest Lawrence Kennaway (1881-1958) and Izrael Hieger (1901-1986), which were shown to be carcinogenic in mouse skin by Hieger et al. in 1933 [17]. Nowadays, we know that PAHs, mainly benzo[a]pyrene and heterocyclic amines (HCAs) belong to definite carcinogens which appear in smoke as a result of incomplete combustion [18] and thus are present not only in tobacco smoke but also in a fried/smoked meat as well as barbeque. PAHs often induce stomach cancer.

growing on stored grains, nuts and peanut butter and found worldwide as a contaminant in food. The discovery of Alfatoxin B1 followed upon "Turkey X Disease" (a liver disease) which killed over 100,000 turkeys in the UK in the early 1960s. The major metabolite of Aflatoxin B1, Aflatoxin B1-8,9-epoxide, exerts hepatotoxic effect, but synergistic interaction between Aflatoxin B1 and hepatitis B virus results in hepatocellular carcinoma. Another fungal contaminant is mycotic toxin Ochratoxin-A (OTA) produced by *Penicillium viridicatum* discovered during laboratory studies in the mid-1960s and encountered as a natural contam‐ inant in maize in 1969 in the USA [24]. Large group of carcinogens are tannins and tannic acid, which occur widely in plants (tea, coffee, and cocoa) but in concentrated doses reveal hepa‐ tocarcinogenic properties in both animals and humans. They have been found capable of causing liver tumours in experimental animals and oesophageal, throat & mouth cancers in humans. Cycads, important food sources in tropical regions, contain unique toxines cycasin and macrozamin that cause liver and kidney tumours in rats [25]. Safrole, 5-Allyl-1,3-benzo‐ dioxole found in sassafras tea, cinnamin, cocoa, nutmeg, black pepper, and other herbs and spices as well as isosafrole, 1,2-(Methylenedioxy)-4-propenylbenzene belong to liver carcino‐ gens in rats, they produce liver tumours following their oral administration [26]. Dihydrosa‐ frole is also carcinogenic in rats and mice, in which it produces tumours of the oesophagus, and liver tumours in males and lung tumours in both males and females, respectively. There is an evidence of the carcinogenic properties of estragole from anise, star anise, basil, bay, tarragon, fennel, marjoram or American wood turpentine oil, which proceeds through a genotoxic mechanism identical to that of safrole and also induce liver cancer in mice [27]. Black pepper (*Piper nigrum* L.), apart of tannic acid and safrole contains secondary amines pypera‐ dine and alpha-methylpyrroline, which can be nitrosated to N-nitroso-piperidine, a strong carcinogen, carcinogenic to experimental mice. It has been known since the 1960s that Comfrey (*Symphytum officinale* L.) contains carcinogenic hepatoxines belonging to pyrrolizidine alkaloids (PAs) e.g. lasiocarpine and symphatine, which can interfere with RNA and DNA

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45

synthesis within the liver cells and cause liver damage, cancer, and death [28].

Some chemical carcinogens have been discovered as a result of industrial or environmental accidents. For example in 1976, notoriety was gained by Seveso disaster - an explosion occurred in a TCP (2,4,5-trichlorophenol) reactor at the ICMESA chemical plant located about 20 km north of Milan, Italy. A mixture of different chemicals including dioxin was released into the atmosphere. This industrial accident caused the highest known exposure to 2,3,7,8-tetrachlor‐ odibenzo-p-dioxin (TCDD) in residential populations and linked dioxin exposure to chloracne, genetic impairments and excessive risk of lymphatic and hematopoietic tissue [29-32]. Another environmental disaster related to dioxines was contamination of a landfill of Love Canal in the Niagara Falls, New York, USA. This region was turned in 1920 to municipal and industrial chemical dumpsite by Hooker Chemica and in 1942-1953 it was contaminated by eleven highly toxic carcinogens including TCDD. In 1978 a record amount of rainfall in Love Canal resulted in leaching the chemicals from corroding waste-disposal drums in this area which caused environmental disaster, a drastic increase in birth defects, nervous disorders, high whiteblood-cell counts in residents, a possible precursor of leukaemia and cancers [33-35]. Many years later probable carcinogenic action of triclosan, an antibacterial agent added to soaps, toothpastes etc., has been linked to its degradation to TCDD in chlorinated water [36]. In the


**Table 2.** Classification of carcinogens according to GSH, 2011

Although cancer-causing substances are often considered to be exclusively synthetic, there are numerous natural carcinogens, chemical compounds that occur in environment, and in food plants [19]. Isaac Berenblum (1903-2000) discovered the potent inflammatory agent, croton oil extracted from *Croton Tiglium* L. native or cultivated in Asia (India, Ceylon, China), Malay Argipelago and Africa (Zanzibar, Tanzania), and its most active ingredient, 12-*O*-tetradeca‐ noylphorbol-13-acetate (TPA) in 1941 [20]. Both agents now belong to classic tumour promot‐ ers. In 1956, John Barnes (1913-1975) and Peter Magee, reported an example of synergistic interaction of chemical carcinogens with proinflammatory agents. i.e. liver tumors in rats induced by N-nitrosdimethylamine (NDMA) [21]. In 1972, another case, the influence of chronic respiratory infection with influenza virus on the development of lung cancer in rats induced by carcinogenic N-nitrosamine was reported [22], which occurs in some foodstuffs, latex, cosmetics. Since then about 90% of nitrosamine derivatives including hydrazines from raw mushrooms *Agaricus bisporus* (Lange) Imbach and *Gyromitra* (Pers.) Fr. have been deemed to be carcinogenic and promoters of benign hepatomas, liver cell carcinomas, angiomas and angiosarcomas of blood vessels, adenomas and adenocarcinomas of lungs.

One of the most potent naturally occurring microbial carcinogen is Aflatoxin B1, which is produced as secondary metabolite by the fungi *Aspergillus flavus* and *Aspergillus parasiticm* [23] growing on stored grains, nuts and peanut butter and found worldwide as a contaminant in food. The discovery of Alfatoxin B1 followed upon "Turkey X Disease" (a liver disease) which killed over 100,000 turkeys in the UK in the early 1960s. The major metabolite of Aflatoxin B1, Aflatoxin B1-8,9-epoxide, exerts hepatotoxic effect, but synergistic interaction between Aflatoxin B1 and hepatitis B virus results in hepatocellular carcinoma. Another fungal contaminant is mycotic toxin Ochratoxin-A (OTA) produced by *Penicillium viridicatum* discovered during laboratory studies in the mid-1960s and encountered as a natural contam‐ inant in maize in 1969 in the USA [24]. Large group of carcinogens are tannins and tannic acid, which occur widely in plants (tea, coffee, and cocoa) but in concentrated doses reveal hepa‐ tocarcinogenic properties in both animals and humans. They have been found capable of causing liver tumours in experimental animals and oesophageal, throat & mouth cancers in humans. Cycads, important food sources in tropical regions, contain unique toxines cycasin and macrozamin that cause liver and kidney tumours in rats [25]. Safrole, 5-Allyl-1,3-benzo‐ dioxole found in sassafras tea, cinnamin, cocoa, nutmeg, black pepper, and other herbs and spices as well as isosafrole, 1,2-(Methylenedioxy)-4-propenylbenzene belong to liver carcino‐ gens in rats, they produce liver tumours following their oral administration [26]. Dihydrosa‐ frole is also carcinogenic in rats and mice, in which it produces tumours of the oesophagus, and liver tumours in males and lung tumours in both males and females, respectively. There is an evidence of the carcinogenic properties of estragole from anise, star anise, basil, bay, tarragon, fennel, marjoram or American wood turpentine oil, which proceeds through a genotoxic mechanism identical to that of safrole and also induce liver cancer in mice [27]. Black pepper (*Piper nigrum* L.), apart of tannic acid and safrole contains secondary amines pypera‐ dine and alpha-methylpyrroline, which can be nitrosated to N-nitroso-piperidine, a strong carcinogen, carcinogenic to experimental mice. It has been known since the 1960s that Comfrey (*Symphytum officinale* L.) contains carcinogenic hepatoxines belonging to pyrrolizidine alkaloids (PAs) e.g. lasiocarpine and symphatine, which can interfere with RNA and DNA synthesis within the liver cells and cause liver damage, cancer, and death [28].

animals by prolonged application of coal tar to rabbit skin. Inflammation accompanying the coal tar application and cancer formation was in a good agreement with Virchow findings. The search for specific chemical carcinogens led to the discovery of pure carcinogenic chemi‐ cals including polycyclic aromatic hydrocarbons PAHs (e.g. benzo[a]pyrene, 1,2,5,6-diben‐ zanthracene) by Ernest Lawrence Kennaway (1881-1958) and Izrael Hieger (1901-1986), which were shown to be carcinogenic in mouse skin by Hieger et al. in 1933 [17]. Nowadays, we know that PAHs, mainly benzo[a]pyrene and heterocyclic amines (HCAs) belong to definite carcinogens which appear in smoke as a result of incomplete combustion [18] and thus are present not only in tobacco smoke but also in a fried/smoked meat as well as barbeque. PAHs

**word**

**Hazard statement**

Danger may cause cancer

Danger may cause cancer

Warning suspected

of causing cancer

**Symbol/Pictogram**

often induce stomach cancer.

human carcinogen

human carcinogen

human carcinogen is limited

**Table 2.** Classification of carcinogens according to GSH, 2011

1A known

44 Drug Discovery

1B presumed

2 suspected

**Category Effect Criteria Signal**

known to have carcinogenic potential for humans – largely based on human evidence

presumed to have carcinogenic potential for humans – largely based on animal evidence

evidence from animal and/or human studies

angiosarcomas of blood vessels, adenomas and adenocarcinomas of lungs.

Although cancer-causing substances are often considered to be exclusively synthetic, there are numerous natural carcinogens, chemical compounds that occur in environment, and in food plants [19]. Isaac Berenblum (1903-2000) discovered the potent inflammatory agent, croton oil extracted from *Croton Tiglium* L. native or cultivated in Asia (India, Ceylon, China), Malay Argipelago and Africa (Zanzibar, Tanzania), and its most active ingredient, 12-*O*-tetradeca‐ noylphorbol-13-acetate (TPA) in 1941 [20]. Both agents now belong to classic tumour promot‐ ers. In 1956, John Barnes (1913-1975) and Peter Magee, reported an example of synergistic interaction of chemical carcinogens with proinflammatory agents. i.e. liver tumors in rats induced by N-nitrosdimethylamine (NDMA) [21]. In 1972, another case, the influence of chronic respiratory infection with influenza virus on the development of lung cancer in rats induced by carcinogenic N-nitrosamine was reported [22], which occurs in some foodstuffs, latex, cosmetics. Since then about 90% of nitrosamine derivatives including hydrazines from raw mushrooms *Agaricus bisporus* (Lange) Imbach and *Gyromitra* (Pers.) Fr. have been deemed to be carcinogenic and promoters of benign hepatomas, liver cell carcinomas, angiomas and

One of the most potent naturally occurring microbial carcinogen is Aflatoxin B1, which is produced as secondary metabolite by the fungi *Aspergillus flavus* and *Aspergillus parasiticm* [23] Some chemical carcinogens have been discovered as a result of industrial or environmental accidents. For example in 1976, notoriety was gained by Seveso disaster - an explosion occurred in a TCP (2,4,5-trichlorophenol) reactor at the ICMESA chemical plant located about 20 km north of Milan, Italy. A mixture of different chemicals including dioxin was released into the atmosphere. This industrial accident caused the highest known exposure to 2,3,7,8-tetrachlor‐ odibenzo-p-dioxin (TCDD) in residential populations and linked dioxin exposure to chloracne, genetic impairments and excessive risk of lymphatic and hematopoietic tissue [29-32]. Another environmental disaster related to dioxines was contamination of a landfill of Love Canal in the Niagara Falls, New York, USA. This region was turned in 1920 to municipal and industrial chemical dumpsite by Hooker Chemica and in 1942-1953 it was contaminated by eleven highly toxic carcinogens including TCDD. In 1978 a record amount of rainfall in Love Canal resulted in leaching the chemicals from corroding waste-disposal drums in this area which caused environmental disaster, a drastic increase in birth defects, nervous disorders, high whiteblood-cell counts in residents, a possible precursor of leukaemia and cancers [33-35]. Many years later probable carcinogenic action of triclosan, an antibacterial agent added to soaps, toothpastes etc., has been linked to its degradation to TCDD in chlorinated water [36]. In the

early 1980s the high risk of lung, skin, kidney and bladder cancer due to chronic low level arsenic poisoning of water in different countries (Bangladesh, Vietnam, Cambodia, Tibet, Argentina, Chile, China, India, Mexico, Thailand, and US) caused by contamination of water by pesticides and various alloys containing arsenic, which resemble and thus substitute phosphorus in chemical reactions, was discovered [37]. In 1980 it was realized that exposure to formaldehyde (a hazard in embalming and production of plastics and vinyl chloride, from which PVC is manufactured) could cause nasal cancer in rats [38]. In the early 1970s, the carcinogenicity of vinyl chloride was linked to occupational angiosarcoma cancers in workers in industry. A few years later PVC was classified as a carcinogen [39-41]. Since then specific substances: aniline and benzidine, asbestos, wool/wood/leather dust have been linked to different types of cancer in humans bladder cancer, sinuses and lung cancer, mesothelioma, nasal sinuses, respectively [3]. Many drugs, including chemotherapeutic anticancer agents, diuretics, hormones have been recognized as a source of secondary cancers and thus classified as definite carcinogens. Most of anticancer drugs is classified as group 1 agents in IARC classification [3].

that the human papillomaviruses HPV16 and HPV18 were responsible for approximately 70% of cervical cancers, while Alan Storey, Kit Osborn and Lionel Crawford in 1990 indicated that HPV types 6 and 11 were responsible for 90% of genital warts. Valerie Beral, Thomas A. Peter‐ man, Harold W. Jaffe related Kaposi's sarcoma-associated herpesvirus (KSHV) with AIDS [49], which prompted Patrick S. Moore, Yuan Chang, Frank Lee and Ethel Cesarman to isolate Kapo‐ si sarcoma-associated herpesvirus (KSHV or HHV8) in 1994 [50]. Very recently in 2008, Chang and Moore developed a new method to identify oncoviruses called digital transcriptome sub‐ traction (DTS) and isolated DNA fragments of Merkel cell polyomavirus from a Merkel cell car‐

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There is also evidence of a link between the bacteria Helicobacter pylori (HP) responsible for development of gastric and duodenal ulcers and cancer risk [52,53]. The human oncogenic viruses, which include HBV, HCV, HIV, HPVs, EBV, KSHV, HTLV-I and HTLV-II and HP are associated with nearly 20% of the human cancer cases. The elimination of these pathogens would decrease by 23.6% the cases of cancer in developing countries and by 7.7% in developed countries [54]. The commonly omitted advantage of the discovery of oncoviruses was the possibility of transplantation of carcinogen-induced tumour systems in mice, which delivered

Rare source of cancer are also parasitic diseases caused by *Clonorchis sinensis* (Japan, Korea, Vietnam) and *Opisthorchis viverrini* (Thailand, Laos, and Malaysia) or *Schistosomas species* (Africa, Asia). All of them are known to be carcinogenic and linked with biliary tract cancer (cholangiocarcinoma) and bladder cancer, respectively [55]. Most of the biological carcinogens

Shortly after the discovery of chemical carcinogens, i.e. factors that suppress and activate the cell growth and division, the first physical carcinogens were identified. After discovery of Xrays by Wilhelm Roentgen (1845-1923) in 1895 and radioactive radiation by Henri Becquerel (1852-1908) in 1896, the exposure to radiation has been identified as one of the causes of can‐ cer. Working with early X-ray generators resulted in the acute skin reactions and the first radi‐ ation-induced cancer arising in an ulcerated area of the skin was reported in 1902. In 1910 to 1912, Pierre Marie, Jean Clunet and Gaston Raulot-Lapointe reported the induction of sarco‐ ma in rats by the application of X-irradiation. As early as in 1911 the first report of leukaemia in radiation workers appeared [56]. The 20th century pioneers in X-Ray/radium studies fell vic‐ tims to their work; surgeon Robert Abbe (1851-1928), physicist Marie Skłodowska-Curie (1867-1934) and physician Jean Bergonie (1857-1925) died due to leukaemia. The use of urani‐ um/plutonium based bombs against Hiroshima/Nagasaki during World War II revealed that ionising radiation irrespective of its origin is a cause of cancer [57]. Increased incidence of can‐ cer of bone marrow and essentially all organs was noted in Japan years to decades later. Some physical carcinogens have been discovered as a result of nuclear disasters. In 1957, the cooling system failed and the radioactive wastes chemical explosion of at Mayak nuclear fuel reproc‐ essing plant, Ozyorsk/Mayak, Russia caused radiation contamination which spread over hun‐ dred kilometres and pollution of the Techa River. This accident called Kyshtym disaster

cinoma, considered to be responsible for 70–80% of these cancers [51].

models for the studies on anticancer drugs.

are classified as group 1 agents in IARC classification [3].

**3.3. Carcinogens of physical origins (Radiation)**
