Chemical Carcinogenesis CANCER A multicausal multistage group of diseases the mechanisms of which are still only partially known IARC Scientific Publications 1992 Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells that can result in death American Cancer Society 2006 Age adjusted Cancer Death Rates by Site US 1930 2002 Chemicals Viruses Chronic inflammation From http www cancersupportivecare com riskintro html WHAT MAY CAUSE CANCER Hereditary disorders History of Chemical Carcinogenesis Chemical carcinogenesis was first suggested by clinicians 200 years ago Scrotal cancer in chimney sweeps Potts Nasal cancer and snuff dipping Hill Today 50 chemicals are recognized as human carcinogens First experimental studies in animals were done 80 years ago History of Chemical Carcinogenesis Large numbers of chemicals were tested for carcinogenic potential in the 1970 1990s Maximum Tolerated Doses MTD were used 60 of rodent carcinogens were genotoxic 40 of rodent carcinogens were nongenotoxic Some chemicals were single site single species carcinogens Others were multisite multispecies carcinogens Dose response varies from 1 2 MTD to 1 1000 MTD Most regulations use straight mathematical extrapolation of high dose rodent data to predict risks Proportion of chemicals evaluated as carcinogenic Proportion Percentage Chemicals tested in both rats and mice 350 590 59 Naturally occurring chemicals 79 139 57 Synthetic chemicals 271 451 60 702 1348 52 Natural pesticides 37 71 52 Mold toxins 14 23 61 Chemicals in roasted coffee 21 30 70 17 34 50 117 241 49 125 282 44 Chemicals tested in rats and or mice Chem in Carcinogen Potency Database Innes negative chemicals retested Physician s desk reference PDR Drugs with reported cancer tests FDA database of drug submissions Ames and Gold Mutat Res 447 3 13 2000 IARC 2007 monographs iarc fr Carcinogenic to humans group 1 100 agents to date Probably carcinogenic to humans group 2A 68 Possibly carcinogenic to humans group 2B 246 Not classifiable as to its carcinogenicity to humans group 3 516 Probably not carcinogenic to humans group 4 1 U S EPA 2003 Carcinogenic to humans Likely to be carcinogenic to humans Suggestive evidence of carcinogenic potential Inadequate information to assess carcinogenic potential Not likely to be carcinogenic to humans U S NTP 2002 see NTP levels of evidence pdf Known to be a human carcinogen Reasonably anticipated to be a human carcinogen Cal EPA 2004 Known to the state to cause cancer WORLD HEALTH ORGANIZATION INTERNATIONAL AGENCY FOR RESEARCH ON CANCER IARC Monograph Evaluations LYON FRANCE Slide courtesy of V Cogliano IARC IARC Slide courtesy of V Cogliano IARC A tour of IARC s classifications Preamble Part B Section 6 d Slide courtesy of V Cogliano IARC Slide courtesy of V Cogliano IARC Cancer Cases Attributable to Environmental Carcinogens Worldwide 1990 Infections viruses parasites H pylori Tobacco smoked and smokeless Occupation Alcohol drinking 16 14 4 3 37 Diet and dietary components including contaminants Pollution Reproductive factors 25 2 2 29 IARC Group 1 Carcinogenic to humans Monographs Volumes 1 84 1972 2002 89 Agents and Exposures Medical drugs and treatments Industrial processes Infectious agents or processes Physical agents Industrial chemicals Inhaled particulates Metals and inorganic salts Lifestyle factors incl herbal remedies Other 24 13 10 10 7 5 5 7 8 Chemical Carcinogenesis in the 21st Century New perceptions of previously known carcinogens Combined effects of multiple exposures Examples o Alcohol drinking and aflatoxins o Alcohol drinking and HBV HBC o Alcohol drinking and tobacco smoking o Tobacco smoking and asbestos arsenic radon Stages of Carcinogenesis Initiation Initiating Event Cell Proliferation clonal expansion g n i t ta u M d n t o n c e e S Ev Cell Proliferation t n e v E g n i t ta u M N Cell Proliferation Promotion Progression Malignancy Cellular and Molecular Mechanisms in Multistage Carcinogenesis INITIATION Simple genetic changes From http newscenter cancer gov sciencebehind Initiating event involves cellular genome MUTATIONS Target genes oncogenes tumor suppressor genes signal transduction cell cycle apoptosis regulators SOURCES OF MUTATIONS ENDOGENOUS DNA DAMAGE EXOGENOUS DNA DAMAGE Free Polymerase Environmental Life Radicals Errors Styles Depurination Agents DNA REPAIR CELL REPLICATION MUTATION Chemical Exposure air water food etc Internal Exposure Metabolic Activation Macromolecular Binding DNA RNA Detoxication Protein Biomarker Biologically Effective Dose X Efficiency of Mispairing X Cell Proliferation Initiation Accumulation of mutations during tumor progression Loeb L A Cancer Res 61 3230 9 2001 Cellular and Molecular Mechanisms in Multistage Carcinogenesis PROMOTION From http newscenter cancer gov sciencebehind Reversible enhancement repression of gene expression increased cell proliferation inhibition of apoptosis No direct structural alteration in DNA by agent or its metabolites 1 X No Tumors 2 X Tumors 3 X Tumors 4 X No Tumors No Tumors 5 Time X Application of Initiator Application of Promoter Basophilic Focus N Adenoma Carcinoma MN M1 Promotion Regression Progression No Tumors Tumors Application of Promoter Adapted from Marsman and Popp Carcinogenesis 15 111 117 1994 Cellular and Molecular Mechanisms in Multistage Carcinogenesis PROGRESSION Irreversible enhancement repression of gene expression Complex genetic alterations chromosomal translocations deletions gene amplifications recombinations etc Complex genetic changes From http newscenter cancer gov sciencebehind Selection of neoplastic cells for optimal growth genotype phenotype in response to the cellular environment Phenotypic characteristics of cancer cells Immortalization Transformation Loss of contact growth inhibition Autonomy of proliferation Avoidance of apoptosis Aberrant differentiation Induction of angiogenesis Human Tumors and Stages of Carcinogenesis Multiple Stages of Human Colon Cancer It is estimated that by age 70 50 of the population at large have acquired precancerous adenomas in the colon 10 of this group will progress to malignancy in the following 10 years Familial Adenomatous Polyposis FAP is linked to the APC gene whose protein is involved in catenin signaling The gene acts as a tumor suppressor and the loss of function mutation causes development of hundreds to thousands of adenomas with a consequent high risk of progression to malignancy Hereditary Non
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