Risk Characterization and Probabilistic Concentration–Response Modeling of Complex Environmental Mixtures Using New Approach Methodologies (NAMs) Data from Organotypic in Vitro Human Stem Cell Assays

Abstract

BACKGROUND: Risk assessment of chemical mixtures or complex substances remains a major methodological challenge due to lack of available hazard or exposure data. Therefore, risk assessors usually infer hazard or risk from data on the subset of constituents with available toxicity values. OBJECTIVES: We evaluated the validity of the widely used traditional mixtures risk assessment paradigms, Independent Action (IA) and Concentration Addition (CA), with new approach methodologies (NAMs) data from human cell-based in vitro assays. METHODS: A diverse set of 42 chemicals was tested both individually and as mixtures for functional and cytotoxic effects in vitro. A panel of induced pluripotent stem cell (iPSCs)-derived models (hepatocytes, cardiomyocytes, endothelial, and neurons) and one primary cell type (HUVEC) were used. Bayesian concentration-response modeling of individual chemicals or their mixtures was performed for a total of 47 phenotypes to derive point-ofdeparture (POD) values. Probabilistic IA or CA was conducted to estimate the mixture effects based on the bioactivity profiles from the individual chemicals and compared with mixture bioactivity. RESULTS: All mixtures showed significant bioactivity, even though some were constructed using individual chemical concentrations considered "low" or "safe." Even though CA is much more accurate as a predictor of mixture effects in comparison with IA, with CA-based POD typically within an order of magnitude of the actual mixture, in some cases, the bioactivity of the mixtures appeared to be much greater than that of their components under either additivity assumption. DISCUSSION: These results suggest that CA is a preferred first approximation for predicting mixture toxicity when data for all constituents are available. However, because the accuracy of additivity assumptions varies greatly across phenotypes, we posit that mixtures and complex substances need to be directly tested for their hazard potential. NAMs provide a practical solution that rapidly yields highly informative data for mixtures risk assessment.

Enhanced ASGR2 by microplastic exposure leads to resistance to therapy in gastric cancer

“…The dose determination for in vitro and in vivo experiments should be considered in future studies. Mathematical modeling has been attempted to bridge the gap between in vivo and in vitro doses 63 - 65 .…”

Human Chemical Exposure from Background Emissions in the United States and the Implication for Quantifying Risks from Marginal Emission Increase

“…Based on this study, exposures resulting from background emissions are likely in the low-dose range and will stay in this range unless incremental emission causes an increase of orders of magnitude higher. Therefore, it is vital to better understand how to characterize human risks for low-dose exposure, which the development of New Approach Methodologies could offer assistance in [1,[41][42][43][44].…”

Potential Human Health Hazard of Post-Hurricane Harvey Sediments in Galveston Bay and Houston Ship Channel: A Case Study of Using In Vitro Bioactivity Data to Inform Risk Management Decisions

“…We selected these cell types because many of the environmental chemicals expected to be present in tested sediments are known to be associated with hepatotoxicity, neurotoxicity, cardiotoxicity, and vascular toxicity (see literature review of the effects of Superfund priority list chemicals on different organs in [ 20 ]). We have published methods for using iPSC-derived cells [ 21 , 22 , 23 , 24 , 25 , 26 , 27 ] to assess the toxicity of the individual chemicals [ 20 , 28 , 29 , 30 , 31 , 32 ], whole mixtures [ 11 , 16 ], and complex substances [ 33 , 34 ]. The reasons we chose iPSC-derived cells are because: (i) these cells are more physiological than immortalized cell lines and can be derived for different tissues/organs [ 35 ]; (ii) they can be obtained from the same individual(s) to enable highly reproducible experiments [ 36 ]; (iii) despite some limitations with the degree of maturation, these cells compare well to primary cells in terms of their function and expected organ-specific toxicity [ 35 , 37 , 38 ]; and (iv) a small number of iPSC-derived cell types can be as informative about hazard and safety margins as the larger set of in vitro models [ 33 ], or many ToxCast bioassays [ 20 ].…”

“…Similarly, biological assays show the potential to facilitate identification of mixtures that may pose human and/or environmental health risks [ 11 , 12 , 13 ]. Finally, computational approaches have also been developed, many of them based on utilizing the information from both exposure characterization and bioactivity measurements, to identify the chemicals of concern in mixtures that may be the drivers to the overall bioactivity [ 14 , 15 , 16 ].…”