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Although numerous germ-cell mutagens have been identified in animal model systems, to date, no human germ-cell mutagens have been confirmed. Because the genomic integrity of our germ cells is essential for the continuation of the human species, a resolution of this enduring conundrum is needed. To facilitate such a resolution, we organized a workshop at The Jackson Laboratory in Bar Harbor, Maine on September 28-30, 2004. This interactive workshop brought together scientists from a wide range of disciplines to assess the applicability of emerging molecular methods for genomic analysis to the field of human germ-cell mutagenesis. Participants recommended that focused, coordinated human germ-cell mutation studies be conducted in relation to important societal exposures. Because cancer survivors represent a unique cohort with well-defined exposures, there was a consensus that studies should be designed to assess the mutational impact on children born to parents who had received certain types of mutagenic cancer chemotherapy prior to conceiving their children. Within this high-risk cohort, parents and children could be evaluated for inherited changes in (a) gene sequences and chromosomal structure, (b) repeat sequences and minisatellite regions, and (c) global gene expression and chromatin. Participants also recommended studies to examine trans-generational effects in humans involving mechanisms such as changes in imprinting and methylation patterns, expansion of nucleotide repeats, or induction of mitochondrial DNA mutations. Workshop participants advocated establishment of a bio-bank of human tissue samples that could be used to conduct a multiple-endpoint, comprehensive, and collaborative effort to detect exposure-induced heritable alterations in the human genome. Appropriate animal models of human germ-cell mutagenes is should be used in parallel with human studies to provide insights into the mechanisms of mammalian germ-cell mutagenesis. Finally, participants recommended that scientific specialty groups be convened to address specific questions regarding the potential germ-cell mutagenicity of environmental, occupational, and lifestyle exposures. Strong support from relevant funding agencies and engagement of scientists outside the fields of genomics and germ-cell mutagenesis will be required to launch a full-scale assault on some of the most pressing and enduring questions in environmental mutagenesis: Do human germ-cell mutagens exist, what risk do they pose to future generations, and are some parents at higher risk than others for acquiring and transmitting germ-cell mutations?

The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health. The concept of mode of action has allowed for an opportunity to move off this default position; mutagenicity is now not considered as the driver but rather the mode of action is. In a more precise way, it is the set of key events that define a mode of action that is fundamental in defining the shape of a cancer dose response. A key event is an informative bioindicator of the cancer response and as such should be predictive of the tumor response, at least in a qualitative way. A clear example of the use of key events in cancer risk assessment is for DNA reactive chemicals. A series of such key events is initiated by the production of DNA damage in target cells from direct interaction of the chemical with DNA leading to the production of mutations by misreplication that results in  enhanced cell replication. This enhanced cell replication eventually leads to the development of preneoplastic cells and ultimately overt neoplasms. The response of each of these key events to dose of the chemical can inform the cancer dose–response curve shape. Thus, the dose–response curve for any DNA-reactive chemical can be predicted from knowledge of its mode of action and the behavior of the induced key events. [ABSTRACT FROM PUBLISHER]

Cancer risk assessment involves the steps of hazard identification, dose-response assessment, exposure assessment, and risk characterization. The rapid advances in the use of molecular biology approaches has had an impact on all 4 components, but the greatest overall current and future impact will be on the dose-response assessment because this requires an understanding of the mechanisms of carcinogenesis, both background and induced by environmental agents. In this regard, hazard identification is a qualitative assessment and dose-response is a quantitative estimate. Thus, the latter will ultimately require a quantitative assessment of molecular endpoints that are used to describe the dose-response for cancer. It has been possible for many years to quantitate alterations at the level of the single gene. For example, analysis of mutation frequency by phenotypic selection, analysis of transcription (mRNA) by Northern blot, analysis of translation (proteins) by Western blot, and analysis of kinetics of metabolism from metabolite levels. However, it is becoming clear that it is necessary when considering risk for adverse health outcomes to develop quantitative approaches for whole cell phenotypes or organ effects. For example, cancer is a whole tissue phenotype, not a feature of single gene mutations, in spite of the multistep (multimutation) mode of formation of a tumor. Thus, there is the need to quantitate the circuitry of a cell: the metabolic/biochemical pathways, genetic regulation pathways, and signaling pathways in normal and stressed conditions. The hypothesis presented by Hanahan and Weinberg of the requirement for 6 acquired characteristics for tumor development, independent of tissue type and species or inducer, seems to provide a viable approach. This hypothesis can be addressed through whole cell molecular assessment using microarrays and quantitative PCR together with the emerging proteomic approaches. This is the world of the new computational cell biology. [ABSTRACT FROM AUTHOR]