Resource Summary:The kinetically-derived maximal dose (KMD) is the maximum external dose where kinetics remain unchanged relative to lower doses. Toxicity may differ qualitatively above versus below the KMD. This evaluation tests whether high-dose toxic effects of octamethylcyclotetrasiloxane (D4), a lipophilic silicone monomer, stem from kinetic overload. Chronic rat inhalation at doses 10,000-fold above human exposures causes mild respiratory, hepatic, renal, uterine, and fertility effects, mostly lacking human relevance due to rodent-specific mechanisms. Bayesian analysis with differential equations was applied to information from kinetic studies on D4 to build statistical distributions of plausible values of the Km and Vmax for D4 elimination. A set of Michaelis–Menten equations were generated to represent the slope function for the relationship between D4 exposure and blood concentration. The resulting Michaelis–Menten functions were investigated using a change-point methodology known as the “kneedle” algorithm to identify the probable KMD range. Analysis of the Michaelis–Menten elimination curve generated from those Vmax and Km values indicates a KMD with an interquartile range of 230.0–488.0 ppm, which is consistent with prior work indicating saturation of D4 metabolism at approximately 300 ppm. The results support the hypothesis that many adverse effects of D4 arise secondary to high-dose-dependent events, likely due to mechanisms of action that cannot occur at concentrations below the KMD. Regulatory methods to evaluate D4 for human health protection should avoid endpoint data from rodents exposed to D4 above the KMD range and future toxicological testing should focus on doses below the KMD range.

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:In this commentary, we emphasize the central importance of ring trials in the validation of experimental methods. Ring trials are sometimes considered to be a major hold-up with little value added to the validation. Here, we clarify that ring trials are indispensable to demonstrate the robustness and reproducibility of a new method. Further, that methods do fail in method transfer and ring trials due to different stumbling blocks, but these provide learnings to ensure the robustness of new methods. At the same time, we identify what it would take to perform ring trials more efficiently, and how ring trials fit into the much-needed update to the guidance on the validation of NAMs.

Resource Summary: If you are having difficulty separating the latest data from speculation when it comes to endocrine disrupting chemicals, you’re not alone. Clinicians around the world are challenged with providing informed medical opinions for their patients based on a profusion of misinterpreted data and misguided claims. Here are some common questions directly from clinicians, and answers with evidence-based information.

Resource Summary: Patients and healthcare professionals alike are inundated with unproven allegations about the health effects of common chemicals on our endocrine systems. How do you form a clear opinion of your own and weed out the myths on endocrine active chemicals? The best place to start is with the facts…

Resource Summary:Due to the amount of inaccurate and sensationalized information about endocrine disruptors at the public’s fingertips, clinicians are consistently faced with questions from concerned patients. To help navigate that challenging patient dialogue, consider the following tips.