EPA/600/R-14/002 SUMMARY REPORT State-of-the-Science Workshop on Chemically-induced Mouse Lung Tumors: Applications to Human Health Assessments Held on January 7-8, 2014 US EPA Auditorium, Research Triangle Park, NC Final – December 2014 National Center for Environmental Assessment US Environmental Protection Agency Research Triangle Park, North Carolina DISCLAIMER This document reflects the proceedings of the workshop, including presentations made by invited speakers, the discussions consequent to those presentations, and summaries of the individual Sessions. Any statements included in this document which were made by the presenters or by participants in the discussions or in the session summary discussions are those of the individuals and should not be interpreted as statement of the US Environmental Protection Agency. Summary Report – Mouse Lung Tumor Workshop (MLTW) EPA/600/R-14/002 Contents Contents ....................................................................................................................................................... iii Acknowledgements ...................................................................................................................................... vi Background ................................................................................................................................................... 1 Welcome and Introductory Remarks ............................................................................................... 1 Context for the Workshop ................................................................................................................. 2 Goals of the Workshop ......................................................................................................................... 2 Scope of the MLTW ............................................................................................................................. 2 Organizational Structure for the MLTW............................................................................................... 2 Key Discussion Topics.......................................................................................................................... 3 Preliminary Materials ............................................................................................................................ 4 Logistical Considerations ...................................................................................................................... 4 Post Workshop Activities...................................................................................................................... 4 Session 1: Human Cancer – Epidemiology and Pathophysiology ......................................................... 6 Background and Introduction .................................................................................................................... 6 1.1 Approaches to Determining Carcinogenic Risks in Humans ........................................................ 6 1.2 Epidemiological Studies of Human Lung Cancer ......................................................................... 9 1.3 Lung Cancer Mortality: Workers Exposed to Styrene, Ethylbenzene, or Naphthalene .............. 10 1.4 Human Lung Cancer Pathology and Cellular Biology ............................................................... 11 References ............................................................................................................................................... 14 Session 2: Comparative Pathological Evidence ................................................................................... 19 Background ............................................................................................................................................. 19 2.1 Introduction ................................................................................................................................. 19 2.2 Comparative pathology of mouse lung tumors ........................................................................... 20 2.3 Mouse Lung Tumor Model Considerations ................................................................................ 21 2.4 Rodent Lung Tumors in National Toxicology Program Studies................................................. 23 2.5 Species differences in compound responses and cell of origin considerations ........................... 25 2.6 Animal and Human Tumour Site Concordance .......................................................................... 27 Session 2 Summary Discussion .............................................................................................................. 29 References ............................................................................................................................................... 31 Session 3: Biological Mechanisms ....................................................................................................... 37 Background and Introduction .................................................................................................................. 37 iii Summary Report – Mouse Lung Tumor Workshop (MLTW) EPA/600/R-14/002 3.1 A Framework for Considering the CYP2F2 MOA Hypothesis & Relevance of Mouse Lung ... 37 3.2 Hypothesis-driven MOA Analysis .............................................................................................. 38 Discussion of Theme 1: Mode of Action ............................................................................................ 39 3.3 Pharmacokinetics and Pharmacodynamics of Ethylbenzene ...................................................... 40 3.4 Pharmacokinetics and Pharmacodynamics of Naphthalene ........................................................ 41 3.5 Pharmacokinetics and Pharmacodynamics of Styrene ................................................................ 44 3.6 Related Chemicals: CYP2F2 Substrates & Other Mouse Lung Tumorigens ............................. 47 Methylene chloride (MC).................................................................................................................... 47 Benzene ............................................................................................................................................... 47 Fluensulfone ........................................................................................................................................ 48 Trichloroethylene (TCE) ..................................................................................................................... 48 3.7 Integration of Cross-Cutting Issues ............................................................................................. 49 Session 3 Summary Discussion .............................................................................................................. 52 Focus on CYP2F2 and 2F1? ............................................................................................................... 52 Types of genotoxic damage ................................................................................................................ 52 Human variability ............................................................................................................................... 52 Combination of effects ........................................................................................................................ 53 Alternate dosimetric tools ................................................................................................................... 53 Neonatal mice ..................................................................................................................................... 53 Focus on mouse lung .......................................................................................................................... 53 Concern for animal welfare ................................................................................................................. 53 References ............................................................................................................................................... 53 Session 4: Evidence for Cellular, Genetic, and Molecular Toxicity .................................................... 57 Background and Introduction .................................................................................................................. 57 4.1 An Overview of the Genotoxicity of Aromatic Hydrocarbons and their Reactive Intermediates .................................................................................................................................................... 57 4.2 Mouse Lung Carcinogens, Reactive Metabolites, and Toxicity ................................................. 60 4.3 Overview of New and Developing Omic Technologies: Assessing Molecular Toxicity and Disease Susceptibility ................................................................................................................. 61 4.4 Metabolomics .............................................................................................................................. 62 References ............................................................................................................................................... 62 Workshop Summary Session ...................................................................................................................... 66 Parking Lot of