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

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.

A tissue dose-based comparative exposure assessment of manganese using physiologically based pharmacokinetic modeling-The importance of homeostatic control for an essential metal.

A physiologically-based pharmacokinetic (PBPK) model (Schroeter et al., 2011) was applied to simulate target tissue manganese (Mn) concentrations following occupational and environmental exposures. These estimates of target tissue Mn concentrations were compared to determine margins of safety (MOS) and to evaluate the biological relevance of applying safety factors to derive acceptable Mn air concentrations. Mn blood concentrations measured in occupational studies permitted verification of the human PBPK models, increasing confidence in the resulting estimates. Mn exposure was determined based on measured ambient air Mn concentrations and dietary data in Canada and the United States (US). Incorporating dietary and inhalation exposures into the models indicated that increases in target tissue concentrations above endogenous levels only begin to occur when humans are exposed to levels of Mn in ambient air (i.e. >10µg/m3) that are far higher than those currently measured in Canada or the US. A MOS greater than three orders of magnitude was observed, indicating that current Mn air concentrations are far below concentrations that would be required to produce the target tissue Mn concentrations associated with subclinical neurological effects. This application of PBPK modeling for an essential element clearly demonstrates that the conventional application of default factors to "convert" an occupational exposure to an equivalent continuous environmental exposure, followed by the application of safety factors, is not appropriate in the case of Mn. PBPK modeling demonstrates that the relationship between ambient Mn exposures and dose-to-target tissue is not linear due to normal tissue background levels and homeostatic controls.

The impact of recent advances in research on arsenic cancer risk assessment.

Scientific debate surrounds the regulatory approach for evaluating carcinogenic risk of arsenic compounds. The arsenic ambient water quality criteria (AWQC), based on the assumption of a linear mode of action for skin cancer risk, results in an allowable limit of 0.018ppb in ambient waters; the drinking water Maximum Contaminant Level (MCL) was determined using a similar linear approach. Integration of results from recent studies investigating arsenic's mode of action provide the basis for a change in the approach for conducting an arsenic cancer risk assessment. Results provide support for a concentration demonstrating a dose-dependent transition in response from those representing adaptive changes to those that may be key events in the development of cancer endpoints. While additional information is needed, integration of current research results provides insight for a new quantitative cancer risk assessment methodology as an alternative toxicologically-based dose response (BBDR) cancer modeling. Integration of the new experimental results, combined with epidemiological evidence, support a dose-dependent transition concentration of approximately 0.1µM arsenic. Some uncertainties remain; additional information from chronic in vitro studies underway is needed. Results to date also provide initial insight into variability in population response at low arsenic exposures.