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

1. NOVOS PARADIGMAS PARA O
GERENCIAMENTO DO RISCO CANCERÍGENO
15h10 – 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. Risk = Toxicity x Exposure (dose)
No Exposure = No Risk

3. CARCINOGEN
agent causally related to the induction of neoplasia
IDENTIFICATION OF CARCINOGENS
1. Human evidence (case reports, epidemiology, …)
2. Laboratory animals evidence (harmonized assays,…)
3. Supportive evidences: in vitro assays, structure-activity
relationship,…

4. BENZENE CARCINOGENICITY
“Suffice to say that there continues to be consensus that benzene is carcinogenic
to 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. Clinical
manifestation
DNA 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. Chemical Humans and Tumors
Exposure Lab. animals
MODE OF ACTION (MoA) ??
EVENTS PRECEEDING NEOPLASIA – USEFUL FO RISK
ASSESSMENT ?

7. • COMPLETE CARCINOGENS
• CARCINOGENS THAT DAMAGES
GENOTOXIC DNA NOT DIRECTLY NON-GENOTOXIC
CARCINOGENS 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. SUMMARY – THE NEW PARADIGMS
OR CARCINOGENIC RISK ASSESSMENT
1. Mode of action/mechanims of chemical carcinogens
2. Evaluation of the relevance of the MoA to humans (species extrapolation)
3. Thresholds for non-genotoxic and genotoxicc carcinogens
4. Ways of extrapolating carcinogenic levels to reference values : linear (no
threshod) or non-linear (threshold).

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, complex
environmental 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 the
use 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 Achievement
Award for Health Sciences, the FDA Teamwork Award for national advice on mercury-
contaminated fish.
http://toxforum.org/participant/dr-rita-schoeny

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. HAVE NICE SESSION!

13. EXTRAPOLATION TO LOWER DOSES
(Linear and non-linear, threshold)
Incidence
of tumors;
Mortality *
*
*
POD, BMD
NOAEL
?
A B C D DOSES

14. 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.

15. MODE OF ACTION = INTEGRATED KEY EVENTS
Exposure
Key event 1
Key event 2
Key event 3
Adverse Effect
D. WOLF, USEPA, 2008

16. HUMAN RELEVANCE
McClellan RO, Inhal. Toxicol., 11:477-518,1999

17. 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 intervention
2002 9. Analogy – relying on similar events
2006
2011