Proportion of chemicals evaluated as carcinogenic Chemical Carcinogenesis 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 Chemicals tested in rats and or mice Chem in Carcinogen Potency Database Natural pesticides 37 71 52 Mold toxins 14 23 61 Chemicals in roasted coffee 21 30 70 17 34 50 Innes negative chemicals retested Physician s desk reference PDR Drugs with reported cancer tests FDA database of drug submissions 117 241 49 125 282 44 Ames and Gold Mutat Res 447 3447 3 13 2000 CANCER A multicausal multicausal multistage group of diseases the mechanisms of which are still only partially known known IARC Scientific Publications 1992 Cancer is a group of diseases characterized by uncontrolled growth growth and spread of abnormal cells that can result in death American Cancer Society 2002 Age adjusted Cancer Death Rates by Site US 1930 1998 Females Males Benign tissue 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 origin 1 WHAT MAY CAUSE CANCER Hereditary disorders Chemicals Viruses Chronic inflammation From http www cancersupportivecare com riskintro html 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 2 IARC 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 humans U S NTP 2002 Known to be a human carcinogen Reasonably anticipated to be a human carcinogen Cal EPA 2004 Known to the state to cause cancer Cogliano et al 2004 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 3 Exposures to Chemicals in the Workplace Agent Industries and Trades with Proved Excess Cancers and Exposure Primary Affected Site p Aminodiphenyl Chemical manufacturing Urinary bladder Asbestos Construction asbestos mining and milling production of friction products and cement Copper mining and smelting Pleura peritoneum bronchus Skin bronchus liver Chemical manufacturing Bronchus Chemical and rubber manufacturing petroleum refining Bone marrow Benzidine naphthylamine and derived dyes Dye and textile production Urinary bladder Chromium and chromates Tanning pigment making Nasal sinus bronchus Isopropyl alcohol manufacture Chemical manufacturing Nickel Polynuclear aromatic hydrocarbons from coke coal tar shale mineral oils and creosote Vinyl chloride monomer Nickel refining Steel making roofing chimney cleaning Cancer of paranasal sinuses Nasal sinus bronchus Skin scrotum bronchus Chemical manufacturing Liver Wood dust Cabinetmaking carpentry Nasal sinus Arsenic Alkylating agents mechloroethamine hydrochloride and bis chloromethyl ether Benzene Carcinogenic Risks of Chemical Agents Associated with Medical Therapy and Diagnosis Chemical or Drug Associated Neoplasms Evidence for Carcinogenicity Alkylating agents cyclophosphamide melphalan Inorganic arsenicals Bladder leukemia Sufficient Azathioprine an immunosuppressive drug Chlornaphazine Chloramphenicol Diethylstibesterol Skin liver Sufficient Lymphoma reticulum cell sarcoma skin Karposi s sarcoma Bladder Sufficient Leukemia Vagina clear cell carcinoma Limited Sufficient Sufficient Estrogens Premenopausal Postmenopausal Methoxypsoralen with ultaviolet light Oxymetholone Phenacetin Liver cell adenoma Endometrium Skin Sufficient Limited Sufficient Liver Renal pelvis carcinoma Limited Sufficient Phenytoin diphenyhydantoin Thorotrast Lymphoma neuroblastoma Liver angiosarcoma Limited Sufficient Modified from Cullen et al 1990 Carcinogenic Factors Associated with Lifestyle Associated Neoplasm Evidence for Carcinogenicity Esophagus liver oropharynx larynx Sufficient Aflatoxins Liver Sufficient Betel chewing Mouth Sufficient Dietary intake fat protein calories Reproductive history Late age at first pregnancy Zeo or low parity Tobacco smoking Breast colon Sufficient endometrium gallbladder Chemical Physiological Condition or Natural Process Alcoholic beverages Breast Ovary Mouth pharynx laryns lung esophagus bladder Sufficient Sufficent Sufficient 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 Modified from Pitot 1986a and Vainio et al 1991 4 Initiation Initiating Event Cell Proliferation clonal expansion ting uta M ond nt Sec Eve Promotion t Mu Eve Initiating event involves cellular genome MUTATIONS Target genes oncogenes tumor