This workshop seeks to provide training in mentoring to EMS participants and to establish a robust Mentoring Program by providing development of mentoring skills. The objectives are:

• To provide training on the bases of Mentoring, as well as information about the operation of a Mentoring Program.
• To provide the basic principles for the establishment of an effective Mentoring Program in EMS
• To motivate members to cultivate a strong network of mentors in EMS

This interactive Workshop will be open to 20 registrants from EMS. Preference would be given to those individuals in mid-career and with access to mentees. The general topics are:

• What is a Mentoring Program?
• What is a Mentor? (Profile and competences)
• What is a Mentee? (Profile and competences)
• How to establish a good Mentor-Mentee Interaction

Symposium 4
Genotoxic Impurities: The Current Environment and Future Possibilities

The DNA repair enzyme poly(ADP-ribose) polymerase 1 (PARP1) polymerizes NAD+ into polymers of ADP-ribose attached to target proteins in response to DNA breaks, providing an initial signal to initiate DNA repair, chromatin relaxation and changes in gene transcription in response to environmental and chemotherapeutic genotoxin exposure. The emergence of PARP inhibitors in cancer therapy and the realization that PARP inhibitors can provide tumor selective response in homologous recombination deficient tumors (e.g., BRCA1-mutant) has provided a novel and new approach of synthetic lethality in cancer therapy. To advance our understanding of the role of PARP enzymes in response to genotoxins, this symposium will include basic and translational presentations on PARP1 and PARP1 inhibitors, the PAR degrading enzyme PARG, the substrate NAD+ and the action of PARP1, PAR and ADP-ribose in chromatin relaxation and gene expression and the role of this PARP-pathway in the treatment of DNA repair deficient tumors.

This session will address recent developments in epigenetics and epigenomics as they relate to disease susceptibility and risk, disease etiology and the development of potential therapeutic approaches. Epigenetic mechanisms including DNA methylation, histone remodeling and nucleosomal are thought to play a key role in the etiology of cancer and CNS disease states. Epigenomic analysis has allowed for genome-scale identification of epigenetic changes in diseased tissue states, across both coding and “gene-desert” regions formerly assumed to be of limited functional importance, and is the focus of the NIH Epigenomics Roadmap initiative. The session will highlight the history and current perspectives of key opinion leaders and investigators in basic and applied epigenetics research in human diseases, and examine new techniques for epigenomic analysis.

Formaldehyde is a ubiquitous chemical that can be found in work places, office buildings, new homes, some food and drugs, and almost everywhere in our environment, along with its natural production in the body. Recently, the International Agency for Research on Cancer (IARC) and the US National Toxicology Program (NTP) has reevaluated the weights of evidence on the adverse health effects of formaldehyde. Both IARC and NTP concluded that formaldehyde causes nasopharyngeal cancer and myeloid leukemia in humans. Formaldehyde may also exert non-cancer effects on a wide range of bodily systems including irritation, allergies, and toxicity to immune, neural, respiratory, reproductive, and hematological systems. While the mechanisms underlying formaldehyde-induced cancer and other health effects currently are poorly understood, findings from recent studies have provided new insight. Thus, this symposium will: 1) provide an overview of systemic effects of formaldehyde, 2) present results from current studies of bone marrow toxicity, and reproductive and developmental toxicity; 3) describe potential genetic and epigenetic mechanisms involved; and 4) discuss future research directions.

Next generation DNA sequencing of tumors is revealing the catalog of somatic mutations which provides insights into the initiation and evolution of environmentally induced cancers. This symposium will highlight recent work that reveals the DNA damage, repair, mutation, and selection processes that occur.

Transcription is an essential process that requires chromatin modifications, histone eviction, DNA helicase-mediated unwinding and DNA topoisomerases-induced single and double-strand breaks. Transcription is potentially a dangerous process that can promote genomic instability by transcription-associated mutagenesis and recombination. In addition, the transcription machinery may act as a sensor for DNA damage and will activate stress response signalling and potentially apoptosis after encountering transcription-blocking lesions. A repair pathway that specifically deals with transcription-blocking lesions is transcription-coupled repair (TCR) and the list of potential DNA damage substrates for TCR is growing. In this symposium we will discuss recent findings in this field.

The strategies and approaches will be discussed to ensure that pharmaceuticals in their discovery, manufacture, use and disposal processes remain properly controlled. Challenges faced by the pharma industry over the full range of drug development to manage the risk of cross contamination and maintain a balance between product quality and environmental and operator safety will be presented, as well as occupational hazards.

The biological significance and role of DNA adduct data in risk assessment are debatable. An ILSI/HESI committee published a systematic approach for the evaluation of DNA adduct data in a key event dose-response framework for a mutagenic mode of action (MOA) analysis for cancer risk (Jarabek et al., 2009). The approach stresses the need to create a context for adduct data in conjunction with other key types of data such as dosimetry, mechanistic response data, and tumor incidence. The proposed 2011 symposium will provide background on the approach and describe the case studies developed by application of this systematic approach to data on aflatoxin B1, tamoxifen, and vinyl chloride (L. H. Pottenger). Specific challenges to adduct data interpretation for these chemicals included: background or endogenous adduct levels, different key events in the carcinogenesis pathway in rodents vs. humans, and data quality and reliability. Analysis of the case studies led to a set of general principles for evaluating the role of DNA adduct data in the Mode of Action (MOA), such as the following: Target tissue and adduct type depend on exposure concentration, duration, and internal dose determinants such as physico-chemical properties, anatomical and physiological factors, and ADME processes. Adduct profiles can change with duration or dose, due to differences in repair/persistence of specific adducts. Characterization, along with structural identification, is necessary for DNA adduct use in MOA assessment. Key conclusions include the following: DNA adduct data cannot be used in isolation to determine a mutagenic MOA; DNA adducts represent biomarkers of exposure and not of effect; and DNA adduct data alone are informative but not sufficient to assign a mutagenic MOA. Taking this approach to the next step with application of decision analysis allows for a more quantitative aspect to the evaluation (A. Jarabek). A rigorous examination of the categories of evidence and coherence of extrapolation premises form key steps in the decision analytic approach described. Evidence of mutagenic efficiency of the specifically identified DNA adducts can be critical to understanding of any potential for biological impact. Recent data on site-specific mutagenicity of low molecular weight O6- and N7-alkylguanine adducts will be presented, demonstrating clear differences in mutagenic outcome for these different adducts (R. Fuchs). Finally integration of all these types of information into a risk assessment is typically conducted by regulatory scientists and risk assessors. Regulatory perspective on how such information can inform risk assessment and possible forward paths will be addressed from the point-of-view of a practitioner (R. Schoeny). (The authors’ views do not represent U.S. EPA policy).

The issue of oil contamination has been in the news in recent months because of the explosion and sinking of the Deep Water Horizon in the spring of 2010, which lead to hundreds of thousands of gallons of oil leaking into the Gulf of Mexico during a 4 month period. This was the first spill in which large quantities of the dispersant Corexit was used to contain the oil in small bubbles that presumably allowed for faster natural elimination. Among the first U.S. Government responders to this event were a team from the National Institute for Occupational Safety and Health (NIOSH), who rostered 44,000 workers and conducted Health Hazard Evaluations related to various aspects of the contamination. Indeed, this may be one of the most thoroughly-documented oil spills with regards to post-exposure surveillance in the sea and on land. In order to highlight the widespread effects of past and future large-scale oil contamination, the proposed symposium will consider effects of the oil on marine life, and include what has been learned regarding the human health consequences of this and other oil spills.

Mutagenesis is an active cellular process, and numerous types of mutations and chromosomal rearrangements are the direct result of DNA polymerase errors. The maintenance of genome integrity depends upon accurate DNA synthesis during DNA replication, DNA repair, and recombination. Human cells contain at least 15 distinct DNA polymerases, yet the precise roles of the various enzymes have not been fully elucidated. This session will bring together emerging evidence from several areas of genome research, all of which suggest that multiple polymerases cooperate in a particular genome maintenance pathway. The session will highlight the importance of DNA polymerases for maintaining genetic stability, as well as the disease consequences of aberrant DNA polymerase function and/or regulation.