Background:The National Academies recommended risk assessments redefine the traditional noncancer Reference Dose (RfD) as a probabilistically derived risk-specific dose, a framework for which was recently developed by the World Health Organization (WHO).Objectives:Our aim was to assess the feasibility and implications of replacing traditional RfDs with probabilistic estimates of the human dose associated with an effect magnitude M and population incidence I (HDMnormalI).Methods:We created a comprehensive, curated database of RfDs derived from animal data and developed a standardized, automated, web-accessible probabilistic dose–response workflow implementing the WHO framework.Results:We identified 1,464 RfDs and associated endpoints, representing 608 chemicals across many types of effects. Applying our standardized workflow resulted in 1,522 HDMnormalI values. Traditional RfDs are generally within an order of magnitude of the HDMnormalI lower confidence bound for I=1% and M values commonly used for benchmark doses. The greatest contributor to uncertainty was lack of benchmark dose estimates, followed by uncertainty in the extent of human variability. Exposure at the traditional RfD frequently implies an upper 95% confidence bound of several percent of the population affected. Whether such incidences are considered acceptable is likely to vary by chemical and risk context, especially given the wide range of severity of the associated effects, from clinical chemistry to mortality.Conclusions:Overall, replacing RfDs with HDMnormalI estimates can provide a more consistent, scientifically rigorous, and transparent basis for risk management decisions, as well as support additional decision contexts such as economic benefit–cost analysis, risk–risk tradeoffs, life-cycle impact analysis, and emergency response. https://doi.org/10.1289/EHP3368
Assessing inter-individual variability in responses to xenobiotics remains a substantial challenge, both in drug development with respect to pharmaceuticals and in public health with respect to environmental chemicals. Although approaches exist to characterize pharmacokinetic variability, there are no methods to routinely address pharmacodynamic variability. In this study, we aimed to demonstrate the feasibility of characterizing inter-individual variability in a human in vitro model. Specifically, we hypothesized that genetic variability across a population of iPSC-derived cardiomyocytes translates into reproducible variability in both baseline phenotypes and drug responses. We measured baseline and drug-related effects in iPSC-derived cardiomyocytes from 27 healthy donors on kinetic Ca2+ flux and high-content live cell imaging. Cells were treated in concentration-response with cardiotoxic drugs: isoproterenol (β-adrenergic receptor agonist/positive inotrope), propranolol (β-adrenergic receptor antagonist/negative inotrope), and cisapride (hERG channel inhibitor/QT prolongation). Cells from four of the 27 donors were further evaluated in terms of baseline and treatment-related gene expression. Reproducibility of phenotypic responses was evaluated across batches and time. iPSC-derived cardiomyocytes exhibited reproducible donor-specific differences in baseline function and drug-induced effects. We demonstrate the feasibility of using a panel of population-based organotypic cells from healthy donors as an animal replacement experimental model. This model can be used to rapidly screen drugs and chemicals for inter-individual variability in cardiotoxicity. This approach demonstrates the feasibility of quantifying inter-individual variability in xenobiotic responses and can be expanded to other cell types for which in vitro populations can be derived from iPSCs.
Among the numerous contaminants of soil, glyphosate and paraquat are two of the most widely used herbicides that are commonly detected in the environment. Soil and sediment contaminated with glyphosate, paraquat, and other environmental toxins can be mobilized and redistributed to lawns, vegetable gardens, parks, and water supplies in vulnerable communities at the site of disasters such as hurricanes and flooding. Glyphosate and paraquat bind strongly to soils containing clays, making their bioavailability (bioaccessibility) from these types of soil very low. Because of their affinity for clay-based soils, it is possible that montmorillonite clays could be administered as a therapeutic agent in the diet of animals and humans to decrease short-term exposure and toxicity. In this study, we investigated the sorption mechanisms of glyphosate and paraquat onto active surfaces of calcium montmorillonite (CM) and sodium montmorillonite (SM) clays and derived binding parameters, including capacity, affinity, and enthalpy. Additionally, we used these parameters to predict the reduction in bioavailability under different pH and temperature conditions and to estimate the theoretical dose of clay that could protect against severe paraquat toxicity and lethality. Computational modeling and simulation studies depicted toxin sorption mechanisms at different pH values. Additionally, a toxin-sensitive living organism (Hydra vulgaris) was used to confirm the safety of the clay and its ability to protect against toxicity from glyphosate and paraquat. The high efficacy of CM and SM shown in this study supports the natural binding activity of glyphosate and paraquat to clay-based soils. Following disasters and medical emergencies, montmorillonite clays could be administered by capsules and tablets, or added to food and flavored water, to reduce toxin bioavailability and human and animal exposures.
“Thorough QT/corrected QT (QTc)” (TQT) studies are cornerstones of clinical cardiovascular safety assessment. However, TQT studies are resource intensive, and preclinical models predictive of the threshold of regulatory concern are lacking. We hypothesized that an in vitro model using induced pluripotent stem cell (iPSC)‐derived cardiomyocytes from a diverse sample of human subjects can serve as a “TQT study in a dish.” For 10 positive and 3 negative control drugs, in vitro concentration‐QTc, computed using a population Bayesian model, accurately predicted known in vivo concentration‐QTc. Moreover, predictions of the percent confidence that the regulatory threshold of 10 ms QTc prolongation would be breached were also consistent with in vivo evidence. This “TQT study in a dish,” consisting of a population‐based iPSC‐derived cardiomyocyte model and Bayesian concentration‐QTc modeling, has several advantages over existing in vitro platforms, including higher throughput, lower cost, and the ability to accurately predict the in vivo concentration range below the threshold of regulatory concern.
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