Grouping of UVCB substances with new approach methodologies (NAMs) data

Abstract

One of the most challenging areas in regulatory science is assessment of the substances known as UVCB (unknown or variable composition, complex reaction products and biological materials). Because the inherent complexity and variability of UVCBs present considerable challenges for establishing sufficient substance similarity based on chemical characteristics or other data, we hypothesized that new approach methodologies (NAMs), including in vitro test-derived biological activity signatures to characterize substance similarity, could be used to support grouping of UVCBs. We tested 141 petroleum substances as representative UVCBs in a compendium of 15 human cell types representing a variety of tissues. Petroleum substances were assayed in dilution series to derive point of departure estimates for each cell type and phenotype. Extensive quality control measures were taken to ensure that only high-confidence in vitro data were used to determine whether current groupings of these petroleum substances, based largely on the manufacturing process and physico-chemical properties, are justifiable. We found that bioactivity data-based groupings of petroleum substances were generally consistent with the manufacturing class-based categories. We also showed that these data, especially bioactivity from human induced pluripotent stem cell (iPSC)-derived and primary cells, can be used to rank substances in a manner highly concordant with their expected in vivo hazard potential based on their chemical compositional profile. Overall, this study demonstrates that NAMs can be used to inform groupings of UVCBs, to assist in identification of representative substances in each group for testing when needed, and to fill data gaps by read-across.

Cardiotoxicity Hazard and Risk Characterization of ToxCast Chemicals Using Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Multiple Donors

“…The lack of cardiotoxicity testing requirements is concerning, because epidemiological data suggest that about one-third of ischemic heart disease burden can be attributed to environmental exposures . In addition, there is emerging evidence from in vitro studies that environmental chemicals have the potential to affect human cardiomyocytes − or pathways that are known to be important for cardiovascular health . Collectively, recent studies that examined dozens of environmental chemicals representative of a number of chemical classes serve as a proof of concept to elevate the concern to various regulatory agencies in the United States, European Union, and other countries .…”

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 ].…”

“…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 ]. Specifically, in a study of petroleum substances [ 33 ] we found that bioactivity data from four human iPSC-derived and HUVEC cells are superior to other immortalized cell lines to rank substances in a manner highly concordant with their expected in vivo hazard potential.…”

“…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 ]. Specifically, in a study of petroleum substances [ 33 ] we found that bioactivity data from four human iPSC-derived and HUVEC cells are superior to other immortalized cell lines to rank substances in a manner highly concordant with their expected in vivo hazard potential. In addition, when we tested 42 Superfund priority list chemicals (selected to represent a diverse set of chemical classes) using these five cell types [ 20 ], we found that each chemical had an effect in at least one cell type and no correlation in quantitative effects on each phenotype was evident among cell types, indicating cell type-specific effects.…”

ToxPi*GIS Toolkit: creating, viewing, and sharing integrative visualizations for geospatial data using ArcGIS

“…The framework can flexibly incorporate whatever combination(s) of data the user chooses, and the typical model is built so that a higher score translates to higher risk/concern/vulnerability/etc. The ToxPi framework has been used with a wide range of data types with many different outcomes of interest, including decision support and hazard assessment by bodies such as the International Agency for Research on Cancer and the National Academy of Sciences [ 5 – 7 ], environmental impact due to natural disasters [ 8 , 9 ], data-driven clustering for substances of unknown/variable composition [ 10 ], and clinical phenotype evaluation [ 11 ]. Models can be built with a user-friendly ToxPi GUI (Graphical User Interface) application [ 12 ] or the toxpiR package ( https://CRAN.R-project.org/package=toxpiR ).…”