This manuscript addresses guidance in the use of kinetic and dynamic data to inform quantitatively extrapolations for interspecies differences and human variability in dose-response assessment developed in a project of the International Programme on Chemical Safety (IPCS) initiative on Harmonisation of Approaches to the Assessment of Risk from Exposure to Chemicals. The guidance has been developed and refined through a series of planning and technical meetings and larger workshops of a broad range of participants from academia, government agencies and the private sector. The guidance for adequacy of data for replacement of common defaults for interspecies differences and human variability is presented in the context of several generic categories including: determination of the active chemical species, choice of the appropriate metric (kinetic components) or endpoint (dynamic components) and nature of experimental data, the latter which includes reference to the relevance of population, route and dose and the adequacy of the number of subjects/samples. The principal objective of this guidance developed primarily as a resource for risk assessors, is to foster better understanding of the components of and criteria for adequacy of chemical-specific data to quantitate interspecies differences and human variability in kinetics and dynamics. It is anticipated that this guidance will also encourage the development of appropriate data and facilitate their incorporation in a consistent fashion in dose-response assessment for regulatory purposes (IPCS, 2001).

A workshop was held on 7-8 March 2001 in Orlando, Florida, to review the state-of-thescience in the application of genomic technologies in toxicology, ecotoxicology, and molecular epidemiology and the importance of these new developments in understanding the potential impacts of chemicals on humans and the environment. Ethical, legal, and regulatory issues and their influence on the direction and application of genomic research were also discussed. The workshop was sponsored by the International Council of Chemical Associations, which is a council of leading trade associations representing chemical manufacturers worldwide. The workshop was attended by more than 80 representatives from industry, academia, and various government agencies from the United States, Canada, Europe, and Japan.This report highlights the issues and recommendations discussed in each of the three areas: toxicology (including ecotoxicology), epidemiology, and ethical, social, and legal issues. Although the workshop presentations described genomics, proteomics, metabonomics, transcriptomics, and associated bioinformatics technologies (collectively referred to in this report as "omics") and the applications of the technologies for risk assessment and epidemiology, the reader is referred to Corton et al. (1999), Afshari et al. (1999), European Centre for Ecotoxicology and Toxicology of Chemicals (2001), and the National Institute of Environmental Health Sciences (NIEHS), National Center for Toxicogenomics (2001) for background information.Four overarching themes emerged from the workshop:• "Omics" technology should be used within a framework of toxicology and epidemiology principles so that it can be applied in a context that is understood for risk assessment.• Effective application of "omics" to epidemiology studies will require suitable biologic samples from large and diverse population groups at relevant time periods of exposure.• Discussion from ethical, social, and legal perspectives highlighted the fact that the use of "omics" technology will require the involvement of all stakeholder communities (i.e., research, academic, regulatory, public, and industry).• Recommendations for research and future use are broadly applicable across government, industry, and academia. A unified research agenda as applied to toxicology and epidemiology is urgently needed for the regulatory and scientific communities to realize the potential power and benefits of these new technologies. It was recognized that "omics" have the potential to reduce uncertainties in risk assessment and facilitate rapid assessments of a chemical's toxic potential. However, there is a critical need to establish relationships between gene expression data and toxicologic changes, enabling an integration of "omics" information with known toxicologic measures and other approaches to a better understanding of mechanism of chemical effects on biologic systems. In the interim, "omics" findings will likely be misinterpreted, because no guidelines currently exist for correlating quantitativ...

Significant advancements have been made toward the use of all relevant scientific information in health risk assessments. This principle has been set forth in risk-assessment guidance documents of international agencies including those of the World Health Organization's International Programme on Chemical Safety, the U.S. Environmental Protection Agency, and Health Canada. Improving the scientific basis of risk assessment is a leading strategic goal of the Society of Toxicology. In recent years, there has been a plethora of mechanistic research on modes of chemical toxicity that establishes mechanistic links between noncancer responses to toxic agents and subsequent overt manifestations of toxicity such as cancer. The research suggests that differences in approaches to assessing risk of cancer and noncancer toxicity need to be resolved and a common broad paradigm for dose-response assessments developed for all toxicity endpoints. In November 1999, a workshop entitled "Harmonization of Cancer and Noncancer Risk Assessment" was held to discuss the most critical issues involved in developing a more consistent and unified approach to risk assessment for all endpoints. Invited participants from government, industry, and academia discussed focus questions in the areas of mode of action as the basis for harmonization, common levels of adverse effect across toxicities for use in dose-response assessments, and scaling and uncertainty factors. This report summarizes the results of those discussions. There was broad agreement, albeit not unanimous, that current science supports the development of a harmonized set of principles that guide risk assessments for all toxic endpoints. There was an acceptance among the participants that understanding the mode of action of a chemical is ultimately critical for nondefault risk assessments, that common modes of action for different toxicities can be defined, and that our approach to assessing toxicity should be biologically consistent.

We considered whether there are discrete windows of vulnerability in the development of cancer and which time periods may be of the greatest importance. Cancer was considered broadly, including cancers in childhood as well as adult cancers that may have an in utero or childhood origin. We concluded that there was evidence from animal and epidemiologic studies for causal relationships for preconceptional, in utero, and childhood exposures and cancer occurrence in children and adults. However, the evidence is incomplete and all relevant critical windows may not have been identified. The comprehensive evaluation of the relative importance of specific time windows of exposure is limited. Improvements in the design of epidemiologic studies and additional animal studies of mechanisms are warranted.