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Mouse Lung Tumor Workshop

EPA conducted a State-of-the-Science Workshop on Chemically-induced Mouse Lung Tumors: Applications to Human Health Assessments. The purpose of this workshop was to discuss the available data and interpretation of results from studies of mouse bronchiolar-alveolar adenomas and carcinomas (lung tumors) following exposure to chemical agents, and the relevance of such tumors in mice to human cancer risk. Several lines of research have investigated whether or not these types of lung tumors are formed by a mode of action (MOA) which is specific to mice and are relevant to tumor formation or other toxicity in humans.

State-of-the-Science Workshop on
Chemically-induced Mouse Lung Tumors:
Applications to Human Health Assessments

January 7-8, 2014
8:30am-5:00pm

U.S. EPA Auditorium C111
109 T.W. Alexander Drive
Research Triangle Park, NC 27711

 

Final Agenda

Links to individual slide sets or a more detailed abstract for a presentation are provided; click on the title of a presentation to open the link.


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Tuesday, January 7, 2013

Opening and Overview

8:30 amRegistration
9:00 amWelcome and Introductory Remarks - John Vandenberg, PhD; NCEA RTP Division Director
9:20 amGoals and Scope of the Workshop (PDF) (24 pp, 294K) - George Woodall, PhD; Workshop Chair and Project Leader
9:50 amWorkshop Logistics (On-site and On-line Interactions) - Channa Keshava, PhD; Project Co-Leader

Session 1: Human Cancer Epidemiology and Pathophysiology

Co-Chairs:
Jason Fritz | US EPA
Eric Garshick | Harvard Medical School/VA Boston Healthcare System
Panelists:
James Collins, PhD | Dow Chemical Company
Brigitte Gomperts, MD | University of California, Los Angeles
Daniel Krewski, PhD | University of Ottawa
10:00 amSession Overview (PDF) (4 pp, 304K)
Jason Fritz and Eric Garshick
  • Brief statement of session goals, presentation/discussion format
  • Introduction of co-chairs, panel members
  • Listing of discussion topics
10:05 amApproaches to Determining Carcinogenic Risks in Humans (PDF) (19 pp, 477K)
Eric Garshick | Harvard Medical School/VA Boston Healthcare System
  • IARC criteria for assessment of human carcinogenicity
  • Approach to epidemiologic study design for lung cancer
  • Exposure assessment
  • Outcome assessment - level of pathological/histological detail available in epidemiologic studies
  • Confounding in the assessment of lung cancer risk
10:20 amGuided discussion
10:30 amEpidemiological Studies of Human Lung Cancer (PDF) (22 pp, 1.13M)
Dan Krewski | University of Ottawa
  • Known IARC Group 1 carcinogens/lung carcinogens
  • Causes of human lung cancer with attributable fractions
  • Concordance between human lung cancer with rodent and mouse models; note of mechanisms - to be further discussed during session 2
  • Specific examples of human lung cancer studies highlighting approaches to exposure and outcome assessment
  • Highlight examples where specific histological data impacted on epidemiologic study interpretation
10:45 amGuided discussion
10:55 amLung Cancer Mortality: Worker Exposed to Styrene, Ethylbenzene, or Naphthalene (PDF) (32 pp, 1.23M)
Jim Collins | Dow Chemical Company
  • Discuss human epidemiologic cancer data for the chemicals of interest - including evidence for immunological effects in styrene-exposed workers
  • Limitations of current studies, including approach to exposure assessment, biomonitoring, effects at the molecular level
  • Limitations of human epidemiologic database - are data sufficient to draw conclusions?
11:10 amGuided discussion
11:20 amHuman Lung Cancer Pathology and Cellular Biology (PDF) (18 pg, 1.12M)
Brigitte Gomperts | University of California, Los Angeles
  • Lung cancer pathology, histopathology
  • Biology of the origins of lung cancer, including state of knowledge regarding cell types of origin for lung cancer
  • Molecular biology of lung cancer, introduction to inflammation, genetics & epigenetics – to be further discussed during session 4 "Molecular Toxicity, Epigenetics, genetic polymorphisms"
  • Discussion of immune-related effects relevant to/found in workers exposed to Styrene – for further discussion during session 4
  • Relevant mutations/polymorphisms regarding chemicals of interest - for further discussion during sessions 2-4.
11:35 amGuided discussion
11:45 amSession Summary Discussion
12:00 pmLunch

Session 2: Comparative Pathology

Co-Chairs:
Charles Wood | US EPA
Mark Miller | Wake Forest University
Panelists:
Gary A. Boorman | Covance, Inc.
Laura Van Winkle | University of California, Davis
Arun Pandiri | Experimental Pathology Laboratories, Inc.
1:00 pmSession Overview (PDF) (19 pp, 1.89M)
Charles Wood and Mark Miller
1:15 pmComparative lung pathology (PDF) (16 pp, 1.01M)
Gary Boorman | Covance, Inc.
1:30 pmGuided discussion
1:45 pmMouse lung tumor model considerations (PDF) (22 pp, 4.87M)
Mark Miller | Wake Forest University
  • Discuss strain differences for wild-type mice as well as
  • Genetically Engineered Mouse Models (GEMMs) in lung cancer research
  • Use of mouse models to study mode of action (MOA): initiation and promotion - to be further discussed during session 3
2:00 pmGuided discussion
2:15 pmRodent lung tumors in NTP studies (PDF) (25 pp, 2.33M)
Arun Pandiri | Experimental Pathology Laboratories, Inc.
2:30 pmGuided discussion
2:45 pmBreak
3:00 pmSpecies Difference in Response and Cell of Origin (PDF) (25 pp, 9.41M)
Laura Van Winkle | University of California, Davis
3:15 pmGuided discussion
3:30 pmAnimal and Human Tumour Site Concordance (PDF) (30 pp, 2.34M)
Dan Krewski | University of Ottawa
3:45 pmGuided discussion
4:00 pmSession Summary Discussion
5:00 pmAdjourn for the Day

Wednesday, January 8, 2013

Session 3: Biological Mechanisms

Co-Chairs:
Paul Schlosser | US EPA
Ron Melnick | Ron Melnick Consulting
Panelists:
Tim Fennell | Research Triangle Institute
Kathy Burns | ScienceCorps LLC
Ernest Hodgson | North Carolina State University
8:30 amSession Overview (PDF) (5 pp, 1.06M)
Paul Schlosser | EPA
  • Introduction of Co-Chairs, Panelists, and Presenters
  • Session Goals
  • Agenda
  • Discussion Topics
8:35 amA Framework for Considering the CYP2F2 MOA Hypothesis & Relevance of Mouse Lung Tumors to Humans (PDF) (7 pp, 677K)
Ron Melnick | Ron Melnick Consulting
8:45 amHypothesis-Driven MOA Analysis: CYP2F2 (PDF) (24 pp, 833K)
George Cruzan | ToxWorks
9:05 amClarifying Q&A
9:15 amPharmacokinetics and Pharmacodynamics of Ethylbenzene (PDF) (16 pp, 1.01M)
Ernest Hodgson | North Carolina State University
9:25 amClarifying Q&A
9:30 amPharmacokinetics and Pharmacodynamics of Naphthalene (PDF) (20 pp, 1.06M)
Laura Van Winkle | University of California, Davis
9:40 amClarifying Q&A
9:45 amPharmacokinetics and Pharmacodynamics of Styrene (PDF) (21 pp, 978K)
Tim Fennell | Research Triangle Institute
10:00 amClarifying Q&A
10:10 amBreak
10:30 amRelated Chemicals: CYP2F2 Substrates & Other Mouse Lung Tumorigens (PDF) (9 pp, 1.79M)
Paul Schlosser | US EPA
  • Methylene chloride
  • Benzene
  • Fluensulfone
  • Trichloroethylene
10:40 amClarifying Q&A
10:45 amIntegration of Cross Cutting Issues (PDF) (4 pp, 75K)
John Lipscomb, PhD | US EPA
10:55 amSession-wide Open Discussion
11:30 amLunch

Session 4: Evidence for Cellular, Genetic, and Molecular Toxicity

Co-Chairs:
Nagu Keshava | US EPA
Gary Stoner, PhD | Medical College of Wisconsin
Panelists:
David Eastmond, PhD | University of California, Riverside
Andrew Kligerman, PhD | US EPA, NHEERL
Andrew Salmon, PhD | CalEPA, OEHHA
12:30 pmSession Overview (PDF) (5 pp, 73K)
Nagu Keshava and Gary Stoner
  • Introduction of Co-Chairs, panelists, and Presenters
  • Session Goals
  • Agenda
  • Discussion Topics
12:40 pmAn Overview of the Genotoxicity of Aromatic Hydrocarbons and their Reactive Intermediates (PDF) (12 pp, 367K)
Stephen Nesnow | Independent Consultant
  • Parent compounds, intermediates (stability, formation) and their effects on genotoxicity
  • Specific genotoxicity induced by chemicals of interest and their intermediates
  • Discuss individual chemicals and commonalities and relationship to MLT genesis
1:00 pmGuided discussion
1:10 pmMouse Lung Carcinogens, Reactive Metabolites and Toxicity (PDF) (26 pp, 708K)
David Eastmond | University of California, Riverside
  • Mouse carcinogen toxicity and metabolism
  • In vitro and in vivo cytotoxicity of chemicals and their intermediates
  • Postulated metabolism and mode of action of interested chemicals
  • Common reactions of quinones, epoxides etc.
  • Interrelationship between cytotoxicity and genotoxicity
1:30 pmGuided discussion
1:40 pmOverview of New and Developing Omic Technologies: Assessing Molecular Toxicity and Disease Susceptibility (PDF) (28 pp, 2.39M)
Brian Chorley| US Environmental Protection Agency, RTP
  • Contribution of data from new technologies in understanding the mode of action
  • Strengths and limitations of these technologies in terms of pathway analysis
  • Discuss commonalities and relationship to MLT genesis
  • Discuss available data and identify data gaps with respect to these new technologies
2:00 pmMetabolomics (PDF) (9 pp, 1.09M)
Timothy Fennel | RTI International
2:10 pmBreak
2:25 pmIntegration of Sessions 3 and 4
Gary Stoner | Medical College of Wisconsin
2:45 pmGuided discussion
3:00 pmSession Summary Discussion

Summary Session

Workshop Chair:
George Woodall | US EPA
3:30 pmSummaries of Key Points from each Workshop Session
Session Co-chairs and Workshop Chair
  • Recap of Key Points from each Session
  • Identify Topics Needing Additional Consideration/Discussion
4:30 pmNext Steps
Workshop Chair to lead the discussion
  • Planning for Follow-on Virtual Workshops
  • Developing a Workshop Summary Report and Peer-review publications
5:00 pmAdjourn Workshop

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