Key characteristics of carcinogens as a basis for organizing data on mechanisms of carcinogenesis

17 Pages·2015·0.92 MB·English

by  Martyn Smith

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