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.

IWGT report on quantitative approaches to genotoxicity risk assessment II. Use of point-of-departure (PoD) metrics in defining acceptable exposure limits and assessing human risk

“…The stability of a DNA adduct and its consequent conversion into a stable mutation is determined by the cell's DNA repair capacity and the turnover rate of the damaged target cells. The risk of conversion into permanent genetic damage before repair is completed is dependent on many factors, including the nature of the adduct and its position in the DNA as well as the number of induced adducts in a specific tissue and specific factors such as cellular replication rate [48]. Thus, the likelihood that an adduct will be converted to a mutation depends on the type of DNA adduct, its effect on base pairing, and the efficiency and fidelity of DNA repair in a particular tissue or cell type.…”

“…Due to the active removal of DNA adducts by repair mechanisms, a quantitative evaluation needs to take into account the kinetics of these processes. When using DNA adducts to support quantitative risk assessment, it is of course necessary to take into account the level of DNA adducts formed endogenously by normal cellular metabolism, oxidative stress, and daily background exposures [56], as well as the chemical's toxicokinetic properties, including absorption, distribution, metabolism, and excretion (ADME) [48][49][50]56].…”

“…Exposure information can be obtained by direct analytical methods that determine levels of the agent under study and its important metabolites in blood and tissues, or by measurement of cellular reaction products such as DNA or protein adducts [48][49][50]. DNA adducts are formed by reaction of a chemical with DNA [51,52] and can thus be used as a surrogate marker of a biologically effective dose.…”

Oncomutations as biomarkers of cancer risk

“…However, cancer is described as a genetic disease because the acquisition of oncogene and tumor suppressor gene mutations are early obligatory steps in carcinogenesis, with many additional genetic lesions being acquired as tumors develop. Mutations on the causal pathway to cancer have been described as bioindicators, meaning they are directly relevant to cancer risk [Jarabek et al, 2009]. The theoretical advantage of measuring oncomutations as an endpoint for assessing cancer risk encouraged the development of sensitive methodologies to quantify levels of specific base substitution mutations within DNA samples, an approach that became known as genotypic selection.…”

New approaches for biomonitoring exposure to the human carcinogen aristolochic acid

“…2 DNA adducts are regarded as one important factor in the carcinogenic potential of genotoxicants and have been used for cross-species extrapolation of toxicity data for human risk assessment. 3,4 The quantitative measurement of DNA adducts of carcinogens has been a long sought goal for risk assessment and molecular epidemiological studies. However, the lack of specific and sensitive methods to quantitate DNA adducts have hampered the use of DNA adducts as biomarkers in human studies.…”