Chemical-Induced CarcinogenesisSlide 2Slide 3History of Chemical CarcinogenesisSlide 5Slide 6Slide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Cancer Cases Attributable to Environmental Carcinogens (Worldwide, 1990)IARC Group 1 – Carcinogenic to humans Monographs Volumes 1-84 (1972-2002): 89 Agents and ExposuresChemical Carcinogenesis in the 21st CenturySlide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Classification of Carcinogens According to the Mode of ActionSlide 34Mechanism of Carcinogenesis: Genotoxic CarcinogensSchematic diagram showing the mechanism through which exposure to polycyclic aromatic hydrocarbons is thought to cause cancerSlide 37Slide 38Non-Genotoxic CarcinogensSlide 40Mechanism of Carcinogenesis: Non-Genotoxic CarcinogensSlide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53Slide 54Slide 55Slide 56Chemical-Induced Chemical-Induced CarcinogenesisCarcinogenesisCANCER:CANCER:““A multicausal, multistage group of diseases the mechanisms of which are still only A multicausal, multistage group of diseases the mechanisms of which are still only partially knownpartially known” (IARC Scientific Publications, 1992)” (IARC Scientific Publications, 1992)““Cancer is a group of diseases characterized by uncontrolled growth and spread of Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells […] that can result in death”abnormal cells […] that can result in death” (American Cancer Society, 2006) (American Cancer Society, 2006)Age-adjusted Cancer Death Rates, by Site, US, 1930-2005http://apps.nccd.cdc.gov/uscs/WHAT MAY CAUSE CANCER ?WHAT MAY CAUSE CANCER ? Hereditary Hereditary disordersdisorders ChemicalsChemicals VirusesViruses Chronic inflammationChronic inflammation ??????From http://www.cancersupportivecare.com/riskintro.htmlHistory 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•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 risksHistory of Chemical CarcinogenesisProportion PercentageChemicals tested in both rats and mice 350/590 59%Naturally occurring chemicals 79/139 57%Synthetic chemicals 271/451 60%Chemicals tested in rats and/or mice Chem. in Carcinogen. Potency Database 702/1348 52%Natural pesticides 37/71 52%Mold toxins 14/23 61%Chemicals in roasted coffee 21/30 70%Innes negative chemicals retested 17/34 50%Physician’s desk reference PDR Drugs with reported cancer tests 117/241 49%FDA database of drug submissions 125/282 44%Proportion of chemicals evaluated as Proportion of chemicals evaluated as carcinogeniccarcinogenic Ames and Gold Ames and Gold Mutat ResMutat Res 447:3-13, 2000 447:3-13, 2000IARC (2009) - monographs.iarc.fr•Carcinogenic to humans (group 1) – 108 agents to date•Probably carcinogenic to humans (group 2A) – 66•Possibly carcinogenic to humans (group 2B) – 248•Not classifiable as to its carcinogenicity to humans (group 3) – 515 •Probably not carcinogenic to humans (group 4) – 1U.S. EPA (2005 Guidelines, a.k.a. the “Red Book”) •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 cancerhttp://tools.niehs.nih.gov/srp/1/Resources/Arzuaga_IRIS_presentation.pdfwww.epa.gov/irisWORLD HEALTH ORGANIZATIONINTERNATIONAL AGENCY FOR RESEARCH ON CANCERIARC Monograph EvaluationsLYON, FRANCESlide courtesy of V. Cogliano (IARC)IARC:Slide courtesy of V. Cogliano (IARC)A tour of IARC’s classificationsPreamble, 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) 16%Tobacco (smoked and smokeless) 14%Occupation 4%Alcohol drinking 3% 37%Diet and dietary components including contaminants 25%Pollution 2%Reproductive factors 2% 29%IARC Group 1 – Carcinogenic to humansMonographs Volumes 1-84 (1972-2002): 89 Agents and ExposuresMedical drugs and treatments 24Industrial processes 13Infectious agents or processes 10Physical agents10Industrial chemicals 7Inhaled particulates 5Metals and inorganic salts 5Lifestyle factors (incl. herbal remedies) 7Other 8Chemical Carcinogenesis in the 21st CenturyNew perceptions of previously known carcinogens: Combined effects of multiple exposuresExamples:oAlcohol drinking and aflatoxinsoAlcohol drinking and HBV/HBCoAlcohol drinking and tobacco smokingoTobacco smoking and asbestos/arsenic/radonInitiatingEventCell Proliferation(clonal expansion)ProgressionCell ProliferationCell ProliferationMalignancySecond Mutating Event"N" Mutating EventInitiationPromotionStages of CarcinogenesisStages of CarcinogenesisCellular and Molecular Mechanisms in Multistage Carcinogenesis: INITIATIONInitiating event involves cellular genome – MUTATIONSTarget genes: - oncogenes/tumor suppressor genes- signal transduction- cell cycle/apoptosis regulatorsFrom http://newscenter.cancer.gov/sciencebehind/“Simple” genetic changesSOURCES OF SOURCES OF MUTATIONSMUTATIONSENDOGENOUS DNA DAMAGEENDOGENOUS DNA DAMAGEEXOGENOUS DNA DAMAGEEXOGENOUS DNA DAMAGEDepurinatioDepurinationnDNA REPAIRDNA REPAIRMUTATIONMUTATIONLifLifeeStyleStylessEnvironmentaEnvironmentallAgentAgentssFreeFreeRadicalsRadicalsPolymerasPolymeraseeErrorsErrorsCELL REPLICATIONCELL REPLICATIONChemical ExposureChemical Exposure (air, water, food, etc.)
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