NOVOS PARADIGMAS PARA OGERENCIAMENTO 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 CamargoUNESP – Faculdade de Medicina

decam@fmb.unesp.br

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 CARCINOGENS 1. Human evidence (case reports, epidemiology, …)2. Laboratory animals evidence (harmonized assays,…)3. Supportive evidences: in vitro assays, structure-activity

relationship,…

“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 )

BENZENE CARCINOGENICITY

ARE LAB ANIMALS GOOD MODELS FOR STUDYING BENZENE CARCINOGENICITY ?

MULTISTAGE CARCINOGENESIS

Harris CC. IN Molecular Dosimetry and Human Cancer, CRC Press, 1991

Clinical manifestation

Normal cell Initiated cellBenign

neoplasiaCancer

Initiation Promotion

Progression

DNA damaging agent

Cellproliferation

MutationAneuploidy

Humans andLab. animals

TumorsChemical Exposure

MODE OF ACTION (MoA) ??

EVENTS PRECEEDING NEOPLASIA – USEFUL FO RISKASSESSMENT ?

GENOTOXICCARCINOGENS

NON-GENOTOXICCARCINOGENS

SUSTAINED CELLPROLIFERATION

UNDER EXPOSURE

CANCER

Direct DNA damage,

mutagenic potential

Citotoxicity, mitogenesis, cell communication

interference, endocrine

disruption, etc.

Genomic instabilityMutator phenotype

• COMPLETE CARCINOGENS• CARCINOGENS THAT DAMAGES

DNA NOT DIRECTLY

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).

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

• 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.

Terrence J. Monks, Ph.D.

HAVE NICE SESSION!

EXTRAPOLATION TO LOWER DOSES (Linear and non-linear, threshold)

Incidenceof tumors;Mortality

?

*

*

*

DOSESA B C D

NOAEL

POD, BMD

• 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.

KEY WORDS

Exposure

Adverse Effect

Key event 2

Key event 3

Key event 1

MODE OF ACTION = INTEGRATED KEY EVENTS

D. WOLF, USEPA, 2008

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

HUMAN RELEVANCE

ASSUMING CAUSALITY WHEN AN ASSOCIATION IS FOUND

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

8. Experiment – effectiveness of intervention

9. Analogy – relying on similar events

Proc. Royal. Soc. Med., 58:295-300, 1965.

Austin Bradford Hill

2002

2006

2011