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NOVOS PARADIGMAS PARA O          GERENCIAMENTO DO RISCO CANCERÍGENO15h10 – Modo de Ação e Avaliação do Risco – Dra. Rita S...
Risk   =   Toxicity x Exposure (dose)       No Exposure = No Risk
CARCINOGEN    agent causally related to the induction of neoplasia             IDENTIFICATION OF CARCINOGENS1. Human evide...
BENZENE CARCINOGENICITY“Suffice to say that there continues to be consensus that benzene is carcinogenicto humans and that...
Clinical                                                                                                             manif...
Chemical   Humans and       Tumors    Exposure   Lab. animals          MODE OF ACTION (MoA) ??EVENTS PRECEEDING NEOPLASIA ...
• COMPLETE CARCINOGENS               • CARCINOGENS THAT DAMAGES GENOTOXIC            DNA NOT DIRECTLY      NON-GENOTOXICCA...
SUMMARY – THE NEW PARADIGMS                 OR CARCINOGENIC RISK ASSESSMENT1. Mode of action/mechanims of chemical carcino...
Rita Schoeny, Ph.D.• Senior Science Advisor, USEPA Office of Research and Development• Dr. Schoeny has published on metabo...
Terrence J. Monks, Ph.D.• Head and Professor, Department of Pharmacology & Toxicology, Collee of Pharmacy, The  University...
HAVE NICE SESSION!
EXTRAPOLATION TO LOWER DOSES                 (Linear and non-linear, threshold)Incidenceof tumors;Mortality               ...
KEY WORDS   • HAZARD – the intrinsic toxicity of a chemical   • RISK = exposure x toxicity (no exposure, no risk)   • MODE...
MODE OF ACTION = INTEGRATED KEY EVENTS                                      Exposure                     Key event 1      ...
HUMAN RELEVANCE                  McClellan RO, Inhal. Toxicol., 11:477-518,1999
ASSUMING CAUSALITY WHEN AN ASSOCIATION IS FOUND                                                           Proc. Royal. Soc...
07 joão lauro viana
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07 joão lauro viana

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Seminário Nacional do Benzeno (5 e 6 dez/12) - Derivação de Limites de Exposição Ocupacional para Substâncias Carcinogênicas e
Mutagênicas - Experiências Internacionais e Nacional

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07 joão lauro viana

  1. 1. 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 decam@fmb.unesp.br Brasília, 5-6 dezembro 2012
  2. 2. Risk = Toxicity x Exposure (dose) No Exposure = No Risk
  3. 3. 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,…
  4. 4. 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 ?
  5. 5. 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
  6. 6. Chemical Humans and Tumors Exposure Lab. animals MODE OF ACTION (MoA) ??EVENTS PRECEEDING NEOPLASIA – USEFUL FO RISK ASSESSMENT ?
  7. 7. • 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
  8. 8. 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).
  9. 9. 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
  10. 10. 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.
  11. 11. HAVE NICE SESSION!
  12. 12. EXTRAPOLATION TO LOWER DOSES (Linear and non-linear, threshold)Incidenceof tumors;Mortality * * * POD, BMD NOAEL ? A B C D DOSES
  13. 13. 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.
  14. 14. MODE OF ACTION = INTEGRATED KEY EVENTS Exposure Key event 1 Key event 2 Key event 3 Adverse Effect D. WOLF, USEPA, 2008
  15. 15. HUMAN RELEVANCE McClellan RO, Inhal. Toxicol., 11:477-518,1999
  16. 16. 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

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