Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis Martyn Smith Director, Superfund Research Program [email protected] School of Public Health University of California, http://superfund.berkeley.edu Berkeley Mechanistic data - Problems to address • There is no broadly accepted, systematic method for identifying, organizing, and summarizing mechanistic data for the purpose of decision- making in cancer hazard identification • Many human carcinogens act via multiple mechanisms causing various biological changes in the multistage process of carcinogenesis – How to capture these diverse effects that lead to cancer and other adverse outcomes for all types of agents? MT Smith, UCB Dec 2015 2 Human Tumors and Stages of Carcinogenesis 3 Hussainet al., Oncogene, 2007 IARC Monographs Volume 100: The known causes of human cancer by organ site Eye Human immunodeficiency virus type 1 Ultraviolet-emitting tanning devices Brain and central X-radiation, gamma- Welding nervous system radiation Lung Aluminium production Arsenic and inorganic arsenic compounds Oral cavity Alcoholic beverages Pharynx Alcoholic beverages Asbestos (all forms) Betel quid with tobacco Betel quid with tobacco Beryllium and beryllium compounds Betel quid without tobacco Human papillomavirus type 16 Bis(chloromethyl)ether; chloromethyl methyl ether Human papillomavirus type 16 Tobacco smoking Nasal cavity Isopropyl alcohol manufacture using (technical grade) Smokeless tobacco and strong acids Cadmium and cadmium compounds Tobacco smoking Nasopharynx Epstein-Barr virus paranasal Leather dust Chromium (VI) compounds Formaldehyde sinus Nickel compounds Coal, indoor emissions from household combustion Tonsil Human papillomavirus type 16 Salted fish, Chinese-style Radium-226 and its decay products Coal gasification Wood dust Radium-228 and its decay products Coal-tar pitch Salivary gland X-radiation, gamma-radiation Tobacco smoking Coke production Wood dust Haematite mining (underground) Iron and steel founding Radioiodines, including iodine-131 Larynx Acid mists, strong inorganic MOPP (vincristine-prednisone-nitrogen mustard-procarbazine (exposure during childhood and Alcoholic beverages mixture) Thyroid adolescence) Asbestos (all forms) Nickel compounds X-radiation, gamma-radiation Tobacco smoking Painter (occupational exposure as) Plutonium Stomach Helicobacter pylori Mesothelioma Asbestos (all forms) Radon-222 and its decay products Rubber production industry (pleura or Erionite Rubber production industry Tobacco smoking peritoneum) Painter (occupational Silica dust, crystalline X-radiation, gamma-radiation exposure as) Soot Sulfur mustard Upper aerodigestive tract Acetaldehyde associated with consumption of Tobacco smoke, secondhand alcoholic beverages Tobacco smoking X-radiation, gamma-radiation Liver Aflatoxins Oesophagus Acetaldehyde associated with Breast Alcoholic beverages (hepatocytes) Alcoholic beverages consumption of alcoholic Diethylstilbestrol Estrogen-progestogen contraceptives beverages Estrogen-progestogen Hepatitis B virus Alcoholic beverages contraceptives Hepatitis C virus Betel quid with tobacco Estrogen-progestogen Plutonium Betel quid without tobacco menopausal TTVhoinobyrali cuccmhol-o 2ssr3mimd2oeo akkniendrgs i ’t( sicn hd sielmdcraoeykn e)prrso adnudct sin STXo-mrbaoadkcieacltoeio ssnsm, tgooakbmiancgmcoa-radiation X-radiation, gtahmermapay-radiation Urinary bladder A4A-lrAusmemniininciou abmnipd ph rienonodyruglcatinoinc arsenic compounds Gall bladder Thorium-232 and its decay Kidney Tobacco smoking Auramine production Biliary tract Chlonorchis sinensis products X-radiation, gamma-radiation BCehnlozrindainpehazine Opisthorchis viverrini Cyclophosphamide Colon and rectum ATXo-lcrbaoadhcioacltoiico sbnme, gvoaekmirnagmgeas-radiation Pancreas STomboakcecloe sssm tookbiancgco aRnedn aulr epteelrvis APrhiestnoaloccehtiinc apccoliadnn,t atsi ning MPR2-auaNibgnabetpeenhrrt t a(pho rypcolrcadoumudpcuiantciteotiionon nianld euxsptroysure as) Phenacetin, analgesic Schistosoma haematobium Anus Human immunodeficiency virus type 1 mixtures Tobacco smoking Human papillomavirus type 16 containing ortho-Toluidine Tobacco smoking X-radiation, gamma-radiation Bone Plutonium Leukaemia/ Azathioprine Endometrium EETassttmrroooggxeeifnne -nmpreongoepsatougseanl tmheernaoppyausal therapy RRRX-aaardddaiiiduuuimmmat---io222n222,468 g aaaannnmddd miiitttsssa -dddraeeedccciaaaayyyti opppnrrroooddduuuccctttsss lymphoma BB1C,euh3nsl-ouBzrleaufanmtanedbiuecnile Vagina Diethylstilbestrol (exposure in utero) Multiple sites Cyclosporine Cyclophosphamide Uterine cervix DEHHsiuuetmmrtohaagynnles niptmi-alpbmpreioluslgotnremoosdla t(eovefgixirceupineso nsctycuopyrnee vt rsiianr 1uc u6set ,pte y1trip8ove,e) 3s11, 33, 35, VulvOavaHruyHmuamn Aapnsa bppeialslpotiomllsoa m(vaiarlluv fsior utrymsp tsey) p1e6 16 (unspecified) FXi-srasidoinaS( etpitxorropnono,d tgsuiuuacmrmtes-, m9i nin0a cu-rltuaeddroiina)gtio n E(sKanardcpoootmhsiea l)ium HKaupmoasni simarmcoumnoad heefircpieens cvyi rvuisru s type 1 CEEFiptysocssptlioeoosinsnpi d-poBerroai nwdreriu tvhcit rcsu,iss ipnlcalutind ianngd S btrloenotmiuymc-in90 39, 45, 51, 52, 56, 58, 59 Estrogen menopausal therapy All cancers 2,3,7,8-Tetrachlorodibenzo- Formaldehyde Tobacco smoking Tobacco smoking combin para-dioxin Helicobacter Pylori ed Hepatitis C virus Penis Human papillomavirus type 16 2,3,4,7,8-Pentachlorodibenzofuran Skin Solar radiation Human immunodeficiency virus type 1 3,4,5,3’,4’-Pentachlorobiphenyl (PCB-126) (melanoma) Ultraviolet-emitting tanning devices Human T-cell lymphotropic virus type 1 4,4’-Methylenebis(2-chloroaniline) (MOCA) Kaposi sarcoma herpes virus Alpha-and beta-particle emitters Skin (other Arsenic and inorganic arsenic compounds Melphalan Areca nut malignant Azathioprine MOPP (vincristine-prednisone-nitrogen Aristolochic acid neoplasms) Coal-tar distillation mustard-procarbazine mixture) Section of the IARC Monographs (IMO) Benzidine, dyes metabolised to Coal-tar pitch Phosphorus-32, as phosphate Group 1 agents with Benzo[a]pyrene Cyclosporine Rubber production industry Two meetings held at IARC in elevsisd ethnacne sinu fhfuicmieannts EEtthhaylneonle in o xaildcoeh olic beverages MMeintehroaxls oaillse,n upnlturse autletrda voiro mletil Adly treated Semusmtineeth [y1lc-(y2c-lCohheloxryole)-t1h-ynl)it-r3o-s(4o-urea, or Etoposide Shale oils methyl-CCNU] 2012 on concordance and Ionizing radiation (all types) Solar radiation Thiotepa Neutron radiation Soot Thorium-232 and its decay products N′-Nitrosonornicotine (NNN) and 4-(N-nitroso- X-radiation, gamma-radiation Tobacco smoking mechanisms methylamino)-1-(3-pyridyl)-1-butanone Treosulfan (NNK) X-radiation, gamma-radiation Ult ilt diti HALLMARKS OF CANCER 1. Sustaining proliferative signaling 2. Evading growth suppressors 3. Resisting cell death 4. Enabling replicative immortality 5. Inducing aberrant angiogenesis 6. Activating invasion & metastasis Emerging Hallmarks • Reprogramming energy metabolism • Evading immune destruction Enabling Characteristics • Genomic instability and mutation • Inflammation 5 Hanahan and Weinberg 2011 MT Smith, UCB Dec 2015 Chemicals and other stressors act at different points on the disease continuum “Considering the multistep nature of cancer and the acquired capabilities implied by each of these hallmarks, it is therefore a very small step to envision how a series of complementary exposures acting in concert might prove to be far more carcinogenic than predictions related to any single exposure might suggest. Interacting contributors need not act simultaneously or continuously, they might act sequentially...” Goodson et al. Carcinogenesis. 2015 Jun; 36(Suppl 1): S254–S296. 6 MT Smith, UCB Dec2015 Disruptive action on key Low-dose effect (LDE, mechanism/pat LLDE, NLDE, threshold, Review team Chemical name hway unknown) Vascular cell adhesion Threshold (H-PC) (36 Diniconazole molecule and =TOXCAST) cytokine signaling Angiogenesis Thrombomodulin, vascular Unknown (H-PC) (36), Chlorothalonil proliferation and NLDE (A-in vivo) (38 in cytokine Amphibians) signaling Chemokine Unknown (H-CL, H-PC, A-CL) Immune system signaling, TGF-β, Pyridaben (36,139,140), threshold (A-I) evasion FAK, HIF-1a, IL- (141) 1a pathways Threshold (H-CL, H-PC, A-I) Chemokine (36,142–144), LDE (A-I, H-CL) signaling, TGF-β, Triclosan (145,146) None of these FAK, IL-1a papers (142-146) show pathways immune evasion Examples of endpoints used to support conclusions of Goodson et al. -- MT Smith, UCB Dec 2015 Problem is that assay endpoints don’t match hallmarks 7 Dilemma: Cancer or Carcinogens • Hallmarks are the biological characteristics of cancer cells and tumors in general, NOT the characteristic properties of human carcinogens • Need to identify the key characteristics of human carcinogens • IARC Working Group did this in 2012 and subsequently scientists at EPA, IARC and elsewhere determined how these characteristics could be searched for systematically MT Smith, UCB Dec 2015 8 Multiple Mechanisms of IARC Group 1 Carcinogens [KZ Guyton….MT Smith, Mut Res 681; 230, 2009] Carcinogen Mechanisms AFB1 As+3 Asbestos Benzene DNA damage + + - + Gene mutation + - + - Chrom mutation + + + + Aneuploidy - + + + Epigenetic + + + Receptor signaling - + + Other signaling - + + Immune effects + + + + Inflammation + + + + Cytotoxicity + + + + Mitogenic - + - Gap junction + + + Key Characteristics of Human Carcinogens Evidence that these Key characteristic: characteristics are observed, 1. Is Electrophilic or can be metabolically activated especially in humans or as 2. Is Genotoxic intermediate biomarkers in 3. Alters DNA repair or causes human specimens can genomic instability provide biological plausibility 4. Induces Epigenetic Alterations for epidemiological findings 5. Induces Oxidative Stress 6. Induces chronic inflammation and/or early warning if no 7. Is Immunosuppressive epidemiology exists 8. Modulates receptor-mediated effects Smith MT, Guyton KZ, Gibbons CF, Fritz JM, 9. Causes Immortalization Portier CJ, Rusyn I, DeMarini DM, Caldwell JC, Kavlock RJ, Lambert P, Hecht SS, Bucher 10. Alters cell proliferation, cell death, JR, Stewart BW, Baan R, Cogliano VJ and K or nutrient supply Straif. Env Health Persp., in press, http://ehp.niehs.nih.gov/15-09912/ 10 MT Smith, UCB Dec 2015