HESI Project Committee on the Biological Significance of DNA Adducts

The mission of this Project Committee is to bring basic science and scientific consensus to issues around the biological significance of low levels of DNA adducts by providing a unique public forum for sharing these initiatives and their implications for risk assessment.  The objective is to produce a consensus-based, science-driven framework for the application of DNA adduct data to the cancer risk assessment process.

Analytical techniques for the detection of DNA adducts (electrophilic molecules or free radicals bound to DNA) have increased greatly in both their sensitivity and specificity in recent years.  It is routine to quantify 1 DNA adduct per 10 billion nucleotides, which translates to <1 adduct/cell.  With these advances in detection, comes the need to address recurring questions about the mechanistic and toxicological relevance of low-concentration measured adducts. 

Despite the abundance of research in this field, the diversity of opinions as to the role of DNA adducts in cellular processing, repair mechanisms, and mutagenesis (and vice versa) suggests the need for a mechanism to reach scientific consensus.  Concurrent with the increasingly widespread collection of DNA adduct measurements as human biomarker data, the scientific community is also currently debating the relevance of these data for risk assessment.

The HESI membership identified DNA adducts as a mutually important issue at the January 2003 Annual Meeting as part of the Emerging Issues Process.  Since that time, the Subcommittee has undertaken important collaborative initiatives in this scientific area.

n        On April 13-14, 2004, the Subcommittee, in conjunction with the National Institute for Environmental Health Sciences, held a public workshop in Washington, D.C. titled DNA Adducts: Biological Significance and Application to Risk Assessment.  This successful, 150 person workshop featured international experts in DNA adduct formation, detection, and interpretation.  A report from this workshop was published in Toxicology and Applied Pharmacology [TAAP, 208 (2005):1-20].

n        In fall 2004, the Subcommittee elected to pursue the recommendations that emerged from the April 2004 workshop.  Specifically, an international steering team agreed to initiate the development of a consensus-based framework for the use and interpretation of DNA adduct data in a risk assessment context.

n        During 2005, the Subcommittee met routinely either in person or via teleconference.  Four subteams were formulated focused on: Risk Assessment of Adducts, Measurement of Adducts, Thresholds for Adducts, and Mode of Action for Adducts.  The groups made significant progress in the development of a series of manuscripts outlining key issues in adduct interpretation and measurement and defining the Subcommittee’s path forward.

n        In January 2006, the Subcommittee became a HESI Project Committee and continued to operate with funding from its participants.

n        Throughout 2006, the group continued to work in specialized multi-sector and multi-expertise working groups to address the following subjects:  use of DNA adduct data in risk assessment, low-dose interpretation, mechanism of action, and adduct measurement.

n        The committee prepared two manuscripts that reflect upon key issues and questions surrounding DNA adduct data use and interpretation:  "Low-Dose Interpretation and Application of DNA Adduct Data to Risk Assessment" and "DNA Adduct Measurement," both of which will be submitted to peer-reviewed journals in early 2007.

n        The committee began work on three “data-rich” candidate case-study chemicals:  vinyl chloride, tamoxifen, and alfatoxin, to facilitate the development of decision criteria on the interpretation of DNA adduct data.