NOVOS PARADIGMAS PARA O GERENCIAMENTO DO RISCO CANCERÍGENO15h10 – Modo de Ação e Avaliação do Risco – Dra. Rita Schoeny (USEPA, EUA)16h:10 – Modo de Ação cancerígena do Benzeno – Dr. Terrence J.Monks (Un. Arizona, EUA) Dr. João Lauro V. de Camargo UNESP – Faculdade de Medicina firstname.lastname@example.org Brasília, 5-6 dezembro 2012
Risk = Toxicity x Exposure (dose) No Exposure = No Risk
CARCINOGEN agent causally related to the induction of neoplasia IDENTIFICATION OF CARCINOGENS1. Human evidence (case reports, epidemiology, …)2. Laboratory animals evidence (harmonized assays,…)3. Supportive evidences: in vitro assays, structure-activity relationship,…
BENZENE CARCINOGENICITY“Suffice to say that there continues to be consensus that benzene is carcinogenicto humans and that it is a known cause of human leukemia.” Cogliano et al., Amer. J. Industr. Med., 2011(on the behalf of the IARC Monograph Programme Staff, 2009 IARC’s evaluation of benzene) In laboratory rats and mice of both sexes: epithelial tumors at multiple sites, also lymphomas in mice (National Toxicology Program, Report on Carcinogens, 12th Edition ) ARE LAB ANIMALS GOOD MODELS FOR STUDYING BENZENE CARCINOGENICITY ?
Clinical manifestationDNA damaging agent Initiation Promotion Progression Benign Cancer Normal cell Initiated cell neoplasia Cell Aneuploidy Mutation proliferation MULTISTAGE CARCINOGENESIS Harris CC. IN Molecular Dosimetry and Human Cancer, CRC Press, 1991
Chemical Humans and Tumors Exposure Lab. animals MODE OF ACTION (MoA) ??EVENTS PRECEEDING NEOPLASIA – USEFUL FO RISK ASSESSMENT ?
• COMPLETE CARCINOGENS • CARCINOGENS THAT DAMAGES GENOTOXIC DNA NOT DIRECTLY NON-GENOTOXICCARCINOGENS CARCINOGENS Direct DNA SUSTAINED CELL Citotoxicity, damage, PROLIFERATION mitogenesis, cell mutagenic UNDER EXPOSURE communication potential interference, endocrine disruption, etc. Genomic instability CANCER Mutator phenotype
SUMMARY – THE NEW PARADIGMS OR CARCINOGENIC RISK ASSESSMENT1. Mode of action/mechanims of chemical carcinogens2. Evaluation of the relevance of the MoA to humans (species extrapolation)3. Thresholds for non-genotoxic and genotoxicc carcinogens4. Ways of extrapolating carcinogenic levels to reference values : linear (no threshod) or non-linear (threshold).
Rita Schoeny, Ph.D.• Senior Science Advisor, USEPA Office of Research and Development• Dr. Schoeny has published on metabolism and mutagenicity of PCBs and PAHs, complexenvironmental mixtures; health and ecological effects of mercury; drinking water contaminants;and on human health risk assessment. She has been the chair of an USEPA working group on theuse of genetic toxicity data in determining mode of action for carcinogens.• Dr. Schoeny has delivered classes and speeches about risk assessment around the world.• She is the recipient of the USEPA Gold, Silver and Bronze Medals, USEPA’s Science AchievementAward for Health Sciences, the FDA Teamwork Award for national advice on mercury-contaminated fish. http://toxforum.org/participant/dr-rita-schoeny
Terrence J. Monks, Ph.D.• Head and Professor, Department of Pharmacology & Toxicology, Collee of Pharmacy, The University of Arizona• Dr. Monks received his PhD at St Mary’s Hospital Medical School, Un. of London, focusing on drug metabolism. His post-doc was at the NIH, Bethesda, on mechanisms of chemically- induced toxicities (bromobenzene & acetoaminophen).• Dr. Monks developed an academic carrier at The University of Texas at Austin, up to the Full Professor position. Research area: molecular stress response to reactive oxigen species and DNA damage, particularly mechanisms of cell death.• Currently, he maintains the same research interest at the University of Arizona, plus the mechanisms and then role of metabolism of ectasy-induced neurotoxicity.• More than 100 papers on peer-reviewed pharmacology/toxicology-related journals.
EXTRAPOLATION TO LOWER DOSES (Linear and non-linear, threshold)Incidenceof tumors;Mortality * * * POD, BMD NOAEL ? A B C D DOSES
KEY WORDS • HAZARD – the intrinsic toxicity of a chemical • RISK = exposure x toxicity (no exposure, no risk) • MODE OF ACTION – a sequence of successive measurable cellular key events leading to the development of preneoplasia and/or neoplasia • WEIGHT OF EVIDENCE – the overall data available about a chemical that support the assumption that it is a carcinogen (one study is not enough, unless it is scientifically robust ) • SUFFICIENT/LIMITED EVIDENCE – Depends on expert scientific judgment to assume whether the weight of evidence is sufficient or limited • MARGIN OF EXPOSURE - Ratio of the no-observed-adverse-effect level (NOAEL) or other reference dose for the critical effect to the theoretical, predicted, or estimated exposure dose or concentration.
HUMAN RELEVANCE McClellan RO, Inhal. Toxicol., 11:477-518,1999
ASSUMING CAUSALITY WHEN AN ASSOCIATION IS FOUND Proc. Royal. Soc. Med., 58:295-300, 1965. 1. Strength - intensity of effects 2. Consistency – repeated effects 3. Specificity – no other strong putative cause 4. Temporality – cause followed by effect 5. Biological gradient – dose-response relationship 6. Plausibility – does not confront what is known 7. Coherence – an acceptable natural history Austin Bradford Hill 8. Experiment – effectiveness of intervention2002 9. Analogy – relying on similar events 2006 2011