Identifying important life stages for monitoring and assessing risks from exposures to environmental contaminants: results of a World Health Organization review.

In this paper, we summarize exposure-related issues to consider in determining the most appropriate age ranges and life stages for risk assessment. We then propose a harmonized set of age bins for monitoring and assessing risks from exposures to chemicals for global use. The focus is on preconception through adolescence, though the approach should be applicable to additional life stages. A two-tiered set of early life age groups is recommended. The first tier involves the adoption of guidance similar to the childhood age groups recommended by the U.S. Environmental Protection Agency, whereas the second tier consolidates some of those age groups to reduce the burden of developing age-specific exposure factors for different regions. While there is no single "correct" means of choosing a common set of age groups to use internationally in assessing early life exposure and risk, use of a set of defined age groups is recommended to facilitate comparisons of potential exposures and risks around the globe, the collection of data and analyses of aggregate exposure and cumulative risk. Application of these age groups for robust assessment of exposure and risk for specific populations will require region-specific exposure factors as well as local environmental monitoring data.

Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework.

This paper describes a framework for the risk assessment of combined exposure to multiple chemicals based on and developed subsequent to the World Health Organization/International Programme on Chemical Safety Workshop on Aggregate/Cumulative Risk Assessment (Combined Exposures to Multiple Chemicals) held in 2007. The framework is designed to aid risk assessors in identifying priorities for risk management for a wide range of applications where co-exposures to multiple chemicals are expected. It is based on a hierarchical (phased) approach that involves integrated and iterative consideration of exposure and hazard at all phases, with each tier being more refined (i.e., less cautious and more certain) than the previous one, but more labor and data intensive. It includes reference to predictive and probabilistic methodology in various tiers in addition to tiered consideration of uncertainty. The paper also annexes two case studies that have been developed to test and refine the framework.

Using mode of action information to improve regulatory decision-making: an ECETOC/ILSI RF/HESI workshop overview.

The European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), the International Life Sciences Institute (ILSI) Research Foundation (RF), and the ILSI Health and Environmental Sciences Institute (HESI) hosted a workshop in November 2009 to review current practice in the application of mode of action (MOA) considerations in chemical risk assessment. The aim was to provide a rationale for a more general, but flexible approach and to propose steps to facilitate broader uptake and use of the MOA concept. There was consensus amongst the workshop participants that it will require substantial effort and cooperation from the multiple disciplines involved to embrace a common, consistent, and transparent approach. Setting up a repository of accepted MOAs and associated guidance concerning appropriate data to support specific MOAs for critical effects would facilitate categorization of chemicals and allow predictions of toxicity outcomes by read-across. This should in future contribute to the reduction of toxicity testing in animals. The workshop participants also acknowledged the value and importance of human data and the importance of integrating information from biological pathway analyses into current MOA/human relevance frameworks.

Mutagenicity testing for chemical risk assessment: update of the WHO/IPCS Harmonized Scheme.

Since the publication of the International Programme on Chemical Safety (IPCS) Harmonized Scheme for Mutagenicity Testing, there have been a number of publications addressing test strategies for mutagenicity. Safety assessments of substances with regard to genotoxicity are generally based on a combination of tests to assess effects on three major end points of genetic damage associated with human disease: gene mutation, clastogenicity and aneuploidy. It is now clear from the results of international collaborative studies and the large databases that are currently available for the assays evaluated that no single assay can detect all genotoxic substances. The World Health Organization therefore decided to update the IPCS Harmonized Scheme for Mutagenicity Testing as part of the IPCS project on the Harmonization of Approaches to the Assessment of Risk from Exposure to Chemicals. The approach presented in this paper focuses on the identification of mutagens and genotoxic carcinogens. Selection of appropriate in vitro and in vivo tests as well as a strategy for germ cell testing are described.

Skin sensitization in chemical risk assessment: report of a WHO/IPCS international workshop focusing on dose-response assessment.

An international workshop was held in 2006 to evaluate experimental techniques for hazard identification and hazard characterization of sensitizing agents in terms of their ability to produce data, including dose-response information, to inform risk assessment. Human testing to identify skin sensitizers is discouraged for ethical reasons. Animal-free alternatives, such as quantitative structure-activity relationships and in vitro testing approaches, have not been sufficiently developed for such application. Guinea pig tests do not generally include dose-response assessment and are therefore not designed for the assessment of potency, defined as the relative ability of a chemical to induce sensitization in a previously naive individual. In contrast, the mouse local lymph node assay does include dose-response assessment and is appropriate for this purpose. Epidemiological evidence can be used only under certain circumstances for the evaluation of the sensitizing potency of chemicals, as it reflects degree of exposure as well as intrinsic potency. Nevertheless, human diagnostic patch test data and quantitative elicitation data have provided very important information in reducing allergic contact dermatitis risk and sensitization in the general population. It is therefore recommended that clinical data, particularly dose-response data derived from sensitized patients, be included in risk assessment.