Creating context for the use of DNA adduct data in cancer risk assessment: I. Data organization

Abstract

The assessment of human cancer risk from chemical exposure requires the integration of diverse types of data. Such data involve effects at the cell and tissue levels. This report focuses on the specific utility of one type of data, namely DNA adducts. Emphasis is placed on the appreciation that such DNA adduct data cannot be used in isolation in the risk assessment process but must be used in an integrated fashion with other information. As emerging technologies provide even more sensitive quantitative measurements of DNA adducts, integration that establishes links between DNA adducts and accepted outcome measures becomes critical for risk assessment. The present report proposes an organizational approach for the assessment of DNA adduct data (e.g., type of adduct, frequency, persistence, type of repair process) in concert with other relevant data, such as dosimetry, toxicity, mutagenicity, genotoxicity, and tumor incidence, to inform characterization of the mode of action. DNA adducts are considered biomarkers of exposure, whereas gene mutations and chromosomal alterations are often biomarkers of early biological effects and also can be bioindicators of the carcinogenic process.

Keywords::

• Biomarkers
• cancer
• DNA adducts
• mode of action
• risk assessment

Acknowledgments

The authors thank Dr. Bennett van Houten of the University of Pittsburgh (formerly of the NIEHS) for his contributions to the workshop discussions. The authors are also grateful to Drs. Jeffrey Ross, Stephen Nesnow, and Hisham El-Masri, at EPA, for constructive comments on internal review.

Disclaimer: This document has been subjected to review by the National Health and Environmental Effects Research Laboratory (NHEERL) of the U.S. Environmental Protection Agency and approved for publication. Approval does not signify that the contents reflect the views of that Agency or of the other institutes with which the authors are affiliated, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The U.S. Government has the right to retain a nonexclusive, royalty-free copyright covering this report.

This document represents the consensus of the participants’ views expressed as individual scientists and does not necessarily represent the policies and procedures of their respective institutions.

Declaration of Interest: This publication stems from a subgroup of the HESI Biological Significance of DNA Adducts Project Committee, whose work is funded through ILSI/HESI.

Abbreviations

8-oxo-dG    8-oxo-deoxyguanosine

2-AAF    2-acetylaminofluorene

ACB-PCR    allele-specific competitive blocker polymerase chain reaction

ADME    absorption, distribution, metabolism and elimination

AFB1    aflatoxin B1

ALT    alanine aminotransferase; serum glutamate pyruvate transaminase

AST    aspartate aminotransferase; serum glutamic-oxaloacetic transaminase

B[a]P    benzo[a]pyrene

BER    base excision repair

BrdU    5-bromodeoxyuridine

CPP    cyclophosphamide

CYP    cytochrome P450

DEN    diethylnitrosoamine

DMBA    7,12-dimethylbenz[a]anthracene

E-D-R    exposure-dose-response continuum

EO    ethylene oxide

EPA    United States Environmental Protection Agency

FISH    fluorescence in situ hybridization

GGT    γ-glutamyltransferase

GLP    Good Laboratory Practices

GSH    reduced glutathione

HESI    ILSI Health and Environmental Sciences Institute

HPRT    hypoxanthine-guanine phosphoribosyltransferase

ILSI    International Life Sciences Institute

MDA    malondialdehyde

MDR    multiple drug resistant

MeG    methyl guanine

MGMT    O⁶-methylguanine methyltransferase

MMS    methyl methanesulfonate

MNU    N-nitroso-N-methylurea

MOA    mode of action

N⁷G    N⁷-guanine

N⁷-HEG    N⁷-hydroxyethylguanine

N⁷-MeG    N⁷-methylguanine

NER    nucleotide excision repair

NO(A)EL    no observed (adverse) effect level

NRC    National Research Council

nt    nucleotides

O⁶G    O⁶-guanine

O⁶-MeG    O⁶-methylguanine

O⁶-HEG    O⁶-hydroxyethylguanine

PAH    polycyclic aromatic hydrocarbon

PCNA    proliferating cell nuclear antigen

PO    propylene oxide

ROS    reactive oxygen species

t_1/2    half-life

TD₅₀    chronic dose in mg/kg body wt/day predicted to induce tumors in half the test animals at the end of a standard lifespan for the species

VEGF    vascular endothelial growth factor

WOE    weight of evidence