Resource Summary:IARC has begun using ToxCast/Tox21 data in efforts to represent key characteristics of carcinogens to organize and weigh mechanistic evidence in cancer hazard determinations and this implicit inference approach also is being considered by USEPA. To determine how well ToxCast/Tox21 data can explicitly predict cancer hazard, this approach was evaluated with statistical analyses and machine learning prediction algorithms. Substances USEPA previously classified as having cancer hazard potential were designated as positives and substances not posing a carcinogenic hazard were designated as negatives. Then ToxCast/Tox21 data were analyzed both with and without adjusting for the cytotoxicity burst effect commonly observed in such assays. Using the same assignments as IARC of ToxCast/Tox21 assays to the seven key characteristics of carcinogens, the ability to predict cancer hazard for each key characteristic, alone or in combination, was found to be no better than chance. Hence, we have little scientific confidence in IARC's inference models derived from current ToxCast/Tox21 assays for key characteristics to predict cancer. This finding supports the need for a more rigorous mode-of-action pathway-based framework to organize, evaluate, and integrate mechanistic evidence with animal toxicity, epidemiological investigations, and knowledge of exposure and dosimetry to evaluate potential carcinogenic hazards and risks to humans.

Resource Summary:The International Agency for Research on Cancer's (IARC) key characteristics of carcinogens (KCCs) have sparked debate, offering a framework to organize data for simplifying cancer hazard identification and risk assessment. However, guidance for integrating KCC evidence into decisions is limited and inconsistent; examples of KCC use show failure to predict classifications and can lead to mislabeling compared to IARC and U.S. EPA outcomes. Modern understanding of chemical carcinogenesis—encompassing multifaceted molecular, cellular, and dose-dependent processes—far surpasses knowledge from decades ago, demanding application in risk assessments to safeguard public health while enabling chemical benefits. Scientific progress in cancer and risk evaluation trends toward greater complexity, emphasizing hypothesis testing and causal analysis; simplistic approaches like the Delaney Clause or standalone KCCs hinder this. Becker et al. advocate returning to hypothesis generation and testing via four archetypal chemical carcinogenesis modes of action (MOA), exemplified by an advanced causal evidence scoring system that compares support for each MOA, identifies the probable operative one, and advances it with toxicity values for risk assessment.

Resource Summary:The International Agency for Research on Cancer (IARC) has proposed using “ten key characteristics of human carcinogens” (TKCs) to assess agents' harmful potential. However, TKCs may exacerbate poor correlations in testing regimes by overlooking species-specific differences in cellular changes, stem cell, and somatic cell phylogenies between short- and long-lived species. Their broad nature risks elevating the already high false-positive rate. Testing well-established, safe therapeutics against this TKC framework could prove informative. Cancers arise from heritable and transient gene expression shifts, followed by clonal expansion and progression through mutations and epigenetic changes conferring evolutionary advantages. Regulatory genotoxicity tests prioritize mutational potential, while two-year rodent bioassays aim to capture full carcinogenic processes. Yet, employing cytotoxic doses that induce sustained proliferation and genetic damage yields excessive false positives in tumor induction. Overall, existing hazard assessment protocols and weight-of-evidence analyses misalign with human carcinoma pathogenesis, necessitating modernization as outlined herein.

Resource Summary:The Consensus Key Characteristics Approach (CKCA) applied to carcinogens or endocrine disruptors is either: 1. Unscientific: as it cannot be falsified (all endogenous and biologically relevant chemicals are carcinogens and endocrine disruptors). OR 2. False: CKCA rewards confirmation bias. Evidence of meeting 1 single criterion is sufficient to be labeled a Carcinogen or Endocrine Disruptor. Proponents specifically state the following question should be answered: “Does exposure to the agent induce end points associated with one or more specific key characteristic properties of carcinogens?

Resource Summary:Regulatory WoE assessments are clear that GLY does not show EATS modalities. • The methodological deficiencies of KCs explain the incorrect classification of glyphosate’s potential as an ED using this novel approach compared to the application of wellestablished WoE approaches developed by regulatory agencies over the past decade. • ED KCs like other KCs have not been validated against negative controls and the GLY data is an ideal example of a negative control and demonstrates how the KC approach lacks a means to get to a negative conclusion about a chemical’s ED properties.

Resource Summary: For more than a decade, weight of evidence (WoE) evaluations have been the standard method for determining whether a chemical meets the definition of an endocrine disrupting chemical (EDC). WoE methods consider all data pertinent to satisfying the EDC definition and evaluating those data with respect to relevance, reliability, strength, and coherence with established endocrine physiology and pharmacology. A new approach for identifying EDC hazards has been proposed that organizes and evaluates data according to ten so-called “Key Characteristics (KCs) of EDCs”.

Resource Summary: - The KCs for EDCs were developed based on KCs for carcinogens. - Flaws in the KC approach for carcinogens have not been addressed or corrected and were repeated in the KCs for EDCs. - The KC approach requires less data and fewer resources than the WoE approach but lacks the basic elements of rigor and reproducibility that should be a standard requirement for regulatory science.