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.
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
t1/2 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