Integration of data across toxicity endpoints for improved safety assessment of chemicals: the example of carcinogenicity assessment.

In view of the need to enhance the assessment of consumer products called for in the EU Chemicals Strategy for Sustainability, we developed a methodology for evaluating hazard by combining information across different systemic toxicity endpoints and integrating the information with new approach methodologies. This integrates mechanistic information with a view to avoiding redundant in vivo studies, minimising reliance on apical endpoint tests and ultimately devising efficient testing strategies. Here, we present the application of our methodology to carcinogenicity assessment, mapping the available information from toxicity test methods across endpoints to the key characteristics of carcinogens. Test methods are deconstructed to allow the information they provide to be organised in a systematic way, enabling the description of the toxicity mechanisms leading to the adverse outcome. This integrated approach provides a flexible and resource-efficient means of fully exploiting test methods for which test guidelines are available to fulfil regulatory requirements for systemic toxicity assessment as well as identifying where new methods can be integrated.

Systematic Review Methodologies and Endocrine Disrupting Chemicals: Improving Evaluations of the Plastic Monomer Bisphenol A.

BACKGROUND: Endocrine disrupting chemicals (EDCs) are found in plastics, personal care products, household items, and other consumer goods. Risk assessments are intended to characterize a chemical's hazards, identify the doses at which adverse outcomes are observed, quantify exposure levels, and then compare these doses to determine the likelihood of risk in a given population. There are many problems with risk assessments for EDCs, allowing people to be exposed to levels that are later associated with serious health outcomes in epidemiology studies. OBJECTIVE: In this review, we examine issues that affect the evaluation of EDCs in risk assessments (e.g., use of insensitive rodent strains and absence of disease-oriented outcomes in hazard assessments; inadequate exposure assessments). We then review one well-studied chemical, Bisphenol A (BPA; CAS #80-05-7) an EDC found in plastics, food packaging, and other consumer products. More than one hundred epidemiology studies suggest associations between BPA exposures and adverse health outcomes in environmentally exposed human populations. RESULTS: We present support for the use of systematic review methodologies in the evaluation of BPA and other EDCs. Systematic reviews would allow studies to be evaluated for their reliability and risk of bias. They would also allow all data to be used in risk assessments, which is a requirement for some regulatory agencies. CONCLUSION: Systematic review methodologies can be used to improve evaluations of BPA and other EDCs. Their use could help to restore faith in risk assessments and ensure that all data are utilized in decision-making. Regulatory agencies are urged to conduct transparent, well-documented and proper systematic reviews for BPA and other EDCs.

Lack of potential carcinogenicity for aspartame - Systematic evaluation and integration of mechanistic data into the totality of the evidence.

Despite repeated confirmation of aspartame safety in a variety of foods and beverages, there continues to be interest in researching the potential carcinogenic risk associated with its consumption. The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework for quantitatively integrating the key characteristics of carcinogens (KCCs). For aspartame, 1332 endpoints were appraised for quality and relevance and quantitatively integrated using an algorithm to determine the potential for individual KCC activity based on all available evidence, and subsequently assessed in the context of human and animal evidence streams. An overall lack of activity (integrated scores <0 and no "strong" categorizations) was observed for all KCCs except oxidative stressor (#5), for which activity was determined to be unlikely to be related to a carcinogenic response. Overall, the KCC-based analysis, together with the lack of consistent evidence of carcinogenicity in experimental animals, continue to support lack of carcinogenicity from aspartame consumption. This comprehensive evaluation of available mechanistic data demonstrates the need for a systematic approach to identify and appraise all avaialble data as part of weight-of-evidence determinations related use of KCC in evaluations of potential human carcinogenicity.

Lack of potential carcinogenicity for acesulfame potassium - Systematic evaluation and integration of mechanistic data into the totality of the evidence.

The safety of low- and no-calorie sweeteners remains a topic of general interest. Substantial evidence exists demonstrating a lack of carcinogenicity of the no-calorie sweetener acesulfame potassium (Ace K). The objective of this evaluation was to conduct a systematic assessment of available mechanistic data using a framework that quantitatively integrates proposed key characteristics of carcinogens (KCCs) into the totality of the evidence. Over 800 KCC-relevant endpoints from a variety of in vitro and in vivo assays were assessed for quality, relevance, and activity, and integrated to determine the overall strength of the evidence for plausibility that Ace K acts through the KCC. Overall, there was a lack of activity across the KCCs (overall integrated score <0 and no "strong" categorization for evidence of activity) in which data were identified. Together with the absence of treatment-related tumor effects in rodent bioassays, these results support the conclusion that Ace K is unlikely to induce a carcinogenic response. This assessment employed a weight of the evidence analysis that includes the consideration of factors such as reliability, strength of the model system, activity, and dose in a complex and heterogeneous dataset, and the ultimate integration of multiple data streams in the cancer hazard evaluation.