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UNC-Chapel Hill ENVR 132 - Chemical Carcinogenesis

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Chemical CarcinogenesisChemical 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 miceChem. 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 PDRDrugs with reported cancer tests 117/241 49%FDA database of drug submissions 125/282 44%Proportion of chemicals evaluated as carcinogenicProportion of chemicals evaluated as carcinogenicAmes and Gold Ames and Gold MutatMutatResRes447:3447:3--13, 200013, 2000CANCER:CANCER:““A A multicausalmulticausal, multistage group of diseases the mechanisms of which are still, multistage group of diseases the mechanisms of which are stillonly only partially knownpartially known” (IARC Scientific Publications, 1992)” (IARC Scientific Publications, 1992)“Cancer is a group of diseases characterized by uncontrolled gro“Cancer is a group of diseases characterized by uncontrolled growth and spread of wth and spread of abnormal cells […] that can result in death”abnormal cells […] that can result in death”(American Cancer Society, 2002)(American Cancer Society, 2002)Age adjusted Cancer Death Rates, by Site, US, 1930-1998Females Males•Benigntissue is not cancer. Although the cell growth is moderately increased, the cells do not invade nearby tissue or spread to other parts of the body• Malignant tissue is cancer. The cancer cells divide out of control. They can invade and destroy nearby healthy tissue. Also, cancer cells can break away from the tumor they form and enter the bloodstream and lymphatic system•Metastasis: the spread of cancer beyond the organ of originWHAT MAY CAUSE CANCER ?WHAT MAY CAUSE CANCER ?¾¾Hereditary disordersHereditary disorders¾¾ChemicalsChemicals¾¾VirusesViruses¾¾Chronic inflammationChronic inflammation¾¾??????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 CarcinogenesisIARC (2004) •Carcinogenic to humans (group 1) •Probably carcinogenic to humans (group 2A) •Possibly carcinogenic to humans (group 2B) •Not classifiable as to its carcinogenicity to humans (group 3) •Probably not carcinogenic to humans (group 4) 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 humansU.S. NTP (2002)•Known to be a human carcinogen •Reasonably anticipated to be a human carcinogenCal/EPA (2004) •Known to the state to cause cancerCogliano et al, 2004Cancer 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 agents 10Industrial chemicals 7Inhaled particulates 5Metals and inorganic salts 5Lifestyle factors (incl. herbal remedies) 7Other 8Exposures to Chemicals in the WorkplaceAgentIndustries and Trades withProved Excess Cancers andExposure Primary Affected Sitep-Aminodiphenyl Chemical manufacturing Urinary bladderAsbestos Construction, asbestos mining andmilling, production of friction productsand cementPleura, peritoneum,bronchusArsenic Copper mining and smelting Skin, bronchus, liverAlkylating agents (mechloroethaminehydrochloride andbis[chloromethyl]ether)Chemical manufacturing BronchusBenzene Chemical and rubber manufacturing,petroleum refiningBone marrowBenzidine, β-naphthylamine, andderived dyesDye and textile production Urinary bladderChromium and chromates Tanning, pigment making Nasal sinus, bronchusIsopropyl alcohol manufacture Chemical manufacturing Cancer of paranasalsinusesNickel Nickel refining Nasal sinus, bronchusPolynuclear aromatic hydrocarbonsfrom coke, coal tar, shale, mineral oils,and creosoteSteel making, roofing, chimneycleaningSkin, scrotum, bronchusVinyl chloride monomer Chemical manufacturing LiverWood dust Cabinetmaking, carpentry Nasal sinusModified from Cullen et al. (1990).Chemical or Drug Associated Neoplasms Evidence for CarcinogenicityAlkylating agents(cyclophosphamide,melphalan)Bladder, leukemia SufficientInorganic arsenicals Skin, liver SufficientAzathioprine (animmunosuppressive drug)Lymphoma, reticulumcell sarcoma, skin,Karposi’s sarcoma (?)SufficientChlornaphazine Bladder SufficientChloramphenicol Leukemia LimitedDiethylstibesterol Vagina (clear cellcarcinoma)SufficientEstrogens Premenopausal PostmenopausalLiver cell adenomaEndometriumSufficientLimitedMethoxypsoralen withultaviolet lightSkin SufficientOxymetholone Liver LimitedPhenacetin Renal pelvis (carcinoma) SufficientPhenytoin(diphenyhydantoin)Lymphoma,neuroblastomaLimitedThorotrast Liver (angiosarcoma) SufficientCarcinogenic Risks of Chemical Agents Associated with Medical Therapy and DiagnosisChemical, PhysiologicalCondition or NaturalProcessAssociated Neoplasm Evidence forCarcinogenicityAlcoholic beverages Esophagus, liver,oropharynx, larynxSufficientAflatoxins Liver SufficientBetel chewing Mouth SufficientDietary intake (fat, protein,calories)Breast, colon,endometrium, gallbladderSufficientReproductive history Late age at first pregnancy Zeo or low parityBreastOvarySufficientSufficentTobacco smoking


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UNC-Chapel Hill ENVR 132 - Chemical Carcinogenesis

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