Application of the adverse outcome pathway (AOP) approach to inform mode of action (MOA): A case study with inorganic arsenic

ABSTRACT

The aim of this study was to establish a process for deriving a chemical-specific mode of action (MOA) from chemical-agnostic adverse outcome pathway (AOPs), using inorganic arsenic (iAs) as a case study. The AOP developed for this case study are related to disruption of cellular signaling by chemicals that strongly bind to vicinal dithiols in cellular proteins, leading to disruption of inflammatory and oxidative stress signaling along with inhibition of the DNA damage responses. The proposed MOA for iAs incorporates this AOP, overlaid on a background of increasing oxidative stress and/or co-exposure to mutagenic chemicals or radiation. The most challenging aspect of developing a MOA from AOP is the incorporation of metabolism and dose-response, neither of which may be considered in the development of an AOP. The cellular responses to relatively low concentrations (below 100 parts per billion) of iAs in drinking water appear to be secondary to binding of trivalent arsenite and its trivalent metabolite, monomethyl arsenous acid to key cellular vicinal dithiols in target tissues, resulting in a co-carcinogenic MOA. The proposed AOP may also be applied to non-cancer endpoints, enabling an integrated approach to conducting a risk assessment for iAs.

Disclosure statement

As stated in the Funding section, the Electric Power Research Institute (EPRI) funded this study as stated in the manuscript. EPRI is a non-profit private research institute located in Palo Alto, CA, USA. EPRI supports the development of research for public benefit. It is not an industrial trade association. EPRI does not oversee research results or review manuscripts before submission to journals. Therefore, funding by this research institute does not constitute a conflict of interest for the authors of the manuscript.

Additional information

Funding

The research underlying the development of the AOPs and MOA presented in this paper was supported by Electric Power Research Institute (EPRI), Palo Alto CA. A preliminary version of the contents of this paper were presented at the Alliance for Risk Assessment Workshop IX (http://allianceforrisk.org/wp-content/uploads/2015/07/DR9-Meeting-Report1.pdf), and the authors wish to thank the Science Panel for their extremely valuable inputs and advice: Barbara Beck, Gradient, Michael L Dourson, U. Cincinnati, Stephen W Edwards, USEPA, Annie M Jarabek, USEPA, Mike Jayjock, Jayjock Associates, R Jeffrey Lewis, ExxonMobil Biomedical Sciences Inc., Bette Meek, U. Ottawa, Gregory Paoli, Risk Science International, Joel Tickner, U. Mass. Lowell, and Daniel Villeneuve, USEPA.