Estimating provisional margins of exposure for data-poor chemicals using high-throughput computational methods.

Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.

Considerations for Improving Metabolism Predictions for to Extrapolation.

High-throughput (HT) to extrapolation (IVIVE) is an integral component in new approach method (NAM)-based risk assessment paradigms, for rapidly translating toxicity assay results into the context of exposure. When coupled with rapid exposure predictions, HT-IVIVE supports the use of HT assays for risk-based chemical prioritization. However, the reliability of prioritization based on HT bioactivity data and HT-IVIVE can be limited as the domain of applicability of current HT-IVIVE is generally restricted to intrinsic clearance measured primarily in pharmaceutical compounds.

Application of a combined aggregate exposure pathway and adverse outcome pathway (AEP-AOP) approach to inform a cumulative risk assessment: A case study with phthalates.

Advancements in measurement and modeling capabilities are providing unprecedented access to estimates of chemical exposure and bioactivity. With this influx of new data, there is a need for frameworks that help organize and disseminate information on chemical hazard and exposure in a manner that is accessible and transparent. A case study approach was used to demonstrate integration of the Adverse Outcome Pathway (AOP) and Aggregate Exposure Pathway (AEP) frameworks to support cumulative risk assessment of co-exposure to two phthalate esters that are ubiquitous in the environment and that are associated with disruption of male sexual development in the rat: di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP).

The role of fit-for-purpose assays within tiered testing approaches: A case study evaluating prioritized estrogen-active compounds in an in vitro human uterotrophic assay.

Chemical risk assessment relies on toxicity tests that require significant numbers of animals, time and costs. For the >30,000 chemicals in commerce, the current scale of animal testing is insufficient to address chemical safety concerns as regulatory and product stewardship considerations evolve to require more comprehensive understanding of potential biological effects, conditions of use, and associated exposures. We demonstrate the use of a multi-level new approach methodology (NAMs) strategy for hazard- and risk-based prioritization to reduce animal testing.

Assessing Toxicokinetic Uncertainty and Variability in Risk Prioritization.

High(er) throughput toxicokinetics (HTTK) encompasses in vitro measures of key determinants of chemical toxicokinetics and reverse dosimetry approaches for in vitro-in vivo extrapolation (IVIVE). With HTTK, the bioactivity identified by any in vitro assay can be converted to human equivalent doses and compared with chemical intake estimates. Biological variability in HTTK has been previously considered, but the relative impact of measurement uncertainty has not.

Rapid experimental measurements of physicochemical properties to inform models and testing.

The structures and physicochemical properties of chemicals are important for determining their potential toxicological effects, toxicokinetics, and route(s) of exposure. These data are needed to prioritize the risk for thousands of environmental chemicals, but experimental values are often lacking. In an attempt to efficiently fill data gaps in physicochemical property information, we generated new data for 200 structurally diverse compounds, which were rigorously selected from the USEPA ToxCast chemical library, and whose structures are available within the Distributed Structure-Searchable Toxicity Database (DSSTox).

Evaluating opportunities for advancing the use of alternative methods in risk assessment through the development of fit-for-purpose in vitro assays.

An evolving regulatory, scientific, and legislative landscape is driving a fundamental change in how chemical safety decisions are made. As we move to implement changes, regulatory agencies and industry are beginning to adopt tiered approaches, which leverage high-throughput screening technologies for prioritization and read across, followed by interrogation of "hit chemicals" with more rigorous dose-response assessment either in fit-for-purpose human cell-based assays or with traditional in vivo tests. However, to date, suitable in vitro alternatives do not exist for the vast majority of the organ toxicities that form the basis of current regulatory decisions.

High-throughput dietary exposure predictions for chemical migrants from food contact substances for use in chemical prioritization.

Under the ExpoCast program, United States Environmental Protection Agency (EPA) researchers have developed a high-throughput (HT) framework for estimating aggregate exposures to chemicals from multiple pathways to support rapid prioritization of chemicals. Here, we present methods to estimate HT exposures to chemicals migrating into food from food contact substances (FCS). These methods consisted of combining an empirical model of chemical migration with estimates of daily population food intakes derived from food diaries from the National Health and Nutrition Examination Survey (NHANES).

Tunable Doping in Graphene by Light-Switchable Molecules.

Noncovalent functionalization provides an effective way to modulate the electronic properties of graphene. Recent experimental work has demonstrated that hybrids of dipolar phototransductive molecules tethered to graphene are reversibly tunable in doping. We have studied the electronic structure characteristics of chromophore/graphene hybrids using dispersion-corrected density functional theory.

Band Gap Opening in the Cycloaddition Functionalization of Carbon Nanotubes.

Covalent functionalization represents a promising avenue to tailor the electronic properties of carbon nanotubes. Recent experimental work has shown that cycloaddition of fluorinated olefins represents an effective approach to reduce the off-currents of mixed nanotube mats for transistor applications. We have studied the electronic structure characteristics of the corresponding [2 + 2] cycloaddition using dispersion-corrected density functional calculations.