Slide 1TerminologyTermsHistoryChemical CarcinogenesisSlide 6GenesCategories of CarcinogensBenzo[a]pyrene metabolismCategories (cont.)Carcinogenic StagesPromotersCategories (Cont.)Epigenetic AgentsCommon Human CarcinogensAflatoxinMutationsSlide 18Slide 19Slide 20Slide 21Slide 22Slide 23Short-term testsLimited Carcinogenicity TestsLong-term Carcinogenicity TestsLong-term Carcinogenicity Tests (cont.)Long-term Carcinogenicity Tests (cont.)Tumor incidenceTumor incidence (cont.)Evaluation of RiskCarcinogenesis / MutagenesisDavid Shubert Ph.D. [email protected] Sherman AnnexTerminology•Cancer - cancer is credited to the Greek physician Hippocrates (460-370 B.C.), considered the "Father of Medicine." Hippocrates used the terms carcinos and carcinoma to describe non-ulcer forming and ulcer-forming tumors.•Carcinogen – a physical (radiation) or chemical agent that increases the risk of cancer•Chemical carcinogenesis – indicates the induction or enhancement of neoplasia by chemicals•Mutagen – a physical (radiation) or chemical agent that modifies genetic material.Terms•Neoplasm – heritably altered, relatively autonomous growth of tissue•Benign•Malignant•Metastases – secondary growths of cells from the primary neoplasm•Cancer – malignant neoplasms•Tumor – space occupying lesions that may or may not be neoplasticHistory•1761 John Hill found users of tobacco snuff had a high rate of nasal cancer•1775 Sir Percival Pott observed that exposure to soot and coal tar by chimney sweeps induced cancer of the scrotum•1895 Rehn discovered bladder tumors among workers in aniline dye factories•1918 first time cancer was induced by a chemical. Multiple applications of coal tar to rabbit ears at Tokyo University by Yamagiwa and Ichikawa.•Coal tar: phenols, polycyclic aromatic hydrocarbons (PAHs). And heterocyclic.Chemical Carcinogenesis•James and Elizabeth Miller laid the groundwork for the field of chemical carcinogenesis•In 1947, the Millers became the first researchers to demonstrate that a foreign chemical, an aminoazo dye caused cancer in rats, by binding with proteins in the liver in a process referred to as covalent binding. In tissues that were not sensitive to the carcinogenic effect of the azo dye, there was no binding.•Proposed that chemicals require metabolic activation to electrophilic reactive intermediates•Bind to nucleophilic centers on proteins, RNA, or DNANucleophile – electron pair donorElectrophile – electron pair acceptorGenes•Oncogenes are mutated forms of genes that cause normal cells to grow out of control and become cancer cells. They are mutations of certain normal genes of the cell called proto-oncogenes, genes that normally control how often a cell divides and differentiates.(1970 discovered SRC gene)•Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die (a process known as apoptosis or programmed cell death). When tumor suppressor genes don’t work properly, cells can grow out of control, which can lead to cancer. (BRCA1 & BRCA2) mutations increase risk.Categories of Carcinogens•Direct Acting – ultimate carcinogens, electrophilic and bind to DNA and other macromolecules•Nitrosamides•Nitrosoureas•Alkyl and aryl epoxides•Precarcinogens – need conversion through bioactivation•Polycyclic aromatic hydrocarbons (PAHs)•Alflatoxin B•Safrole: weak carcinogen in rats found in basil, cinnamon nutmeg and pepper •Nitrosamines cured meats (Vitamin C will inhibit formation)Benzo[a]pyrene metabolismCategories (cont.)•Nongenotoxic carcionogens – do not damage DNA but enhance the growth of tumors by genotoxic carcinogens or induce tumors through other mechanisms•Cocarcinogens – increase the concentration of the initiator•Tobacco smoke small amounts of genotoxic carcinogens marked carcinogenic effects attributed to catechols which act as cocarcinogens•Promoters – increase effects of initiators•Phorbal esters•Demonstrate the two-stage process of carcinogenesis•Stimulation of cell proliferatin through cytotoxicity or hormonal effects•Inhibition of intercellular communication (restraint from surrounding cells)•ImmunosuppressionCarcinogenic Stages•Initiation – genotoxic events•Irreversible in the sense that the genotype and phenotype of the initiated cell is established•However not all cells survive (programmed cell death apoptosis) •Requires cell division for fixation•No threshold for dose•Promotion – clonal expansion of the initiated cell•Reversible promoted cell population existence dependent on continued administration of the promoting agent•Dose response evident and maximal effect•Phorbal esters & TCDD (Dioxin) most effective promoting of rat liver carcinogenesis•Progression – development of a maligmant tumorPromoters•Sub-threshold dose of initiator alone produces few tumorsI______________ few tumors•Sub-threshold dose followed by a promoter will produce many tumorsI____P________ many tumors•Treatment with a promoter only will produce very few tumorsP____________ Few tumors•Order of treatment is criticalCategories (Cont.)•Solid state carcinogens –foreign body reaction•Asbestos•Implanted materials plastics, metal , glass •Metals and metalloids – •Arsenic (carcinogenic in humans but not animals)•Cadmium ( pulmonary, prostate)•Chromium ( pulmonary, gastrointestinal)Epigenetic Agents•Not related to changed in DNA sequence •Immunosuppressive xenobiotics•Asbestos•Hormones•Promoters•Phorbal esters•TCDD (Dioxin)•Phenobarbital (rats)Common Human CarcinogensAgent Target organAflatoxin LiverAlcoholic beverages Pharynx, esophagus, liver, larynxTobacco smoke Lung, larynx, oral cavity, esophagusArsenic Skin, bronchus, liverAsbestos lungBenzene Bone marrowCadmium Lung, prostateAflatoxin•Fungal toxin (Aspergillus flavus & aspergillus parasiticus) commonly contaminated maize, cereals, oilseeds, tree nuts, ground nuts (peanuts) and other crops•Known to cause chronic and acute hepatocellular injury•Potent carcinogen and mutagen in many animals (epoxide intermediate)•Developed countries test commercial crops and regulate limits•Homegrown crops are not routinely testedMutations•Involve addition or deletions of base pairs or substitution of the incorrect base pair in DNA•Transitions•Switching purine for purine (A G) or pyrimidine for pyrimidine (C