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Abstract The Threshold of Toxicological Concern (TTC) is an approach for assessing the safety of chemicals with low levels of exposure for which limited toxicology data are available. The original TTC criteria were derived for oral exposures from a distributional analysis of a dataset of 613 chemicals that identified 5th percentile no observed effect level (NOEL) values grouped within three tiers of compounds having specific structural functional groups and/or toxic potencies known as Cramer I, II and III classifications. Subsequent assessments of the TTC approach have established current thresholds to be scientifically robust. While the TTC has gained acknowledgment and acceptance by many regulatory agencies and organizations, use of the TTC approach in evaluating drinking water chemicals has been limited. To apply the TTC concept to drinking water chemicals, an exposure-based approach that incorporates the current weight of evidence for the target chemical is presented. Such an approach provides a comparative point of departure to the 5th percentile TTC NOEL using existing data, while conserving the allocation of toxicological resources for quantitative risk assessment to chemicals with greater exposure or toxicity. This approach will be considered for incorporation into NSF/ANSI/CAN 600, a health effects standard used in the safety evaluation of chemicals present in drinking water from drinking water contact additives and materials certified to NSF/ANSI/CAN 60 and 61, respectively. [ABSTRACT FROM AUTHOR]

Globally, industries and regulatory authorities are faced with an urgent need to assess the potential adverse effects of chemicals more efficiently by embracing new approach methodologies (NAMs). NAMs include cell and tissue methods (in vitro), structure-based/toxicokinetic models (in silico), methods that assess toxicant interactions with biological macromolecules (in chemico), and alternative models. Increasing knowledge on chemical toxicokinetics (what the body does with chemicals) and toxicodynamics (what the chemicals do with the body) obtained from in silico and in vitro systems continues to provide opportunities for modernizing chemical risk assessments. However, directly leveraging in vitro and in silico data for derivation of human health-based reference values has not received regulatory acceptance due to uncertainties in extrapolating NAM results to human populations, including metabolism, complex biological pathways, multiple exposures, interindividual susceptibility and vulnerable populations. The objective of this article is to provide a standardized pragmatic framework that applies integrated approaches with a focus on quantitative in vitro to in vivo extrapolation (QIVIVE) to extrapolate in vitro cellular exposures to human equivalent doses from which human reference values can be derived. The proposed framework intends to systematically account for the complexities in extrapolation and data interpretation to support sound human health safety decisions in diverse industrial sectors (food systems, cosmetics, industrial chemicals, pharmaceuticals etc.). Case studies of chemical entities, using new and existing data, are presented to demonstrate the utility of the proposed framework while highlighting potential sources of human population bias and uncertainty, and the importance of Good Method and Reporting Practices. [ABSTRACT FROM AUTHOR]

The Toxicology Forum convened an international state-of-the-science workshop Assessing Chemical Carcinogenicity: Hazard Identification, Classification, and Risk Assessment in December 2020. Challenges related to assessing chemical carcinogenicity were organized under the topics of (1) problem formulation; (2) modes-of-action; (3) dose-response assessment; and (4) the use of new approach methodologies (NAMs). Key topics included the mechanisms of genotoxic and non-genotoxic carcinogenicity and how these in conjunction with consideration of exposure conditions might inform dose-response assessments and an overall risk assessment; approaches to evaluate the human relevance of modes-of-action observed in rodent studies; and the characterization of uncertainties. While the scientific limitations of the traditional rodent chronic bioassay were widely acknowledged, knowledge gaps that need to be overcome to facilitate the further development and uptake of NAMs were also identified. Since one single NAM is unlikely to replace the bioassay, activities to combine NAMs into integrated approaches for testing and assessment, or preferably into defined approaches for testing and assessment that include data interpretation procedures, were identified as urgent research needs. In addition, adverse outcome pathway networks can provide a framework for organizing the available evidence/data for assessing chemical carcinogenicity. Since a formally accepted decision tree to guide use of the best and most current science to advance carcinogenicity risk assessment is currently unavailable, a Decision Matrix for carcinogenicity assessment could be useful. The workshop organizers developed and presented a decision matrix to be considered within a carcinogenicity hazard and risk assessment that is offered in tabular form. [ABSTRACT FROM AUTHOR]