Mechanistic data and cancer risk assessment: The need for quantitative molecular endpoints

Abstract

The cancer risk assessment process as currently proposed by the U.S. Environmental Protection Agency allows for the use of mechanistic data to inform the low-dose tumor response in humans and in laboratory animals. The aim is to reduce the reliance on defaults that introduce a relatively high level of uncertainty to the risk estimates. The types of data required for this purpose are those that help identify key events in tumor formation following exposure to environmental chemicals. Informative biomarkers of tumor responses could then be developed for describing the shape of a dose-response curve at low doses (i.e., a qualitative assessment) and for predicting tumor frequency at these low doses (i.e., a quantitative assessment). A number of recently developed molecular approaches could aid in the development of qualitatively and quantitatively informative biomarkers. An overview of these with examples of their use is presented. These methods include quantitative gene expression array techniques, quantitative proteomic assays, and the assessment of DNA alterations at the single gene level and at the genome level of detection. It is most likely that a combination of approaches at different levels of cellular organization (i.e., DNA, RNA, and protein) will be the most productive for biomarker development. The rapid progress that is being made will make this tool kit even more applicable for the cancer risk assessment process.

Combined Toxic Exposures and Human Health: Biomarkers of Exposure and Effect

“…Large number of genes can be monitored and alterations in gene expression after combined exposure can be analysed [17]. The best biomarker in this sense would be a combination of approaches at different levels of cellular organization, such as DNA, RNA and proteins [79]. There is also a need for development of methods that measure effects at low dose levels [17].…”

Human cancers express mutator phenotypes: origin, consequences and targeting

“…The human genome is dynamic; it is estimated that each cell undergoes >20,000 DNA damaging events 3–5 and >10,000 replication errors per cell per day 6 . As a result, mutations occur throughout the genome, including in genes that maintain genetic stability.…”

Comparative genomic hybridization (CGH) in molecular diagnostics

“…Karyotyping is a time-consuming procedure that has yet to be automated, which is the fundamental reason for CGH's lengthy duration. CGH has influenced tumor microarray analysis, which uses competitive hybridization of differently labeled RNA/cDNA and the computation of ratio values to quantify gene expression [28]. The CGH patterns of similar cancers showed a high degree of concordance in studies on primary and metastatic tumors, which might be beneficial in establishing a clonal link.…”