Scientific Tools and Methods

Dr. Richard Becker

The research supported and catalyzed by ACC LRI has led to the development of a number of methods and tools to investigate and characterize toxicity, exposures, dosimetry, and risks. Information on the ACC LRI tools and methods can be accessed via the hyperlinks below.

LRI Tools and Methods: Exposure Science

Exposure science focuses on understanding the fate and transport of chemicals from sources of manufacturing, use and disposal and includes studies of exposure scenarios, behaviors and use patterns related to contact and interactions with, and uptake by, environmental receptors and humans. Research support from ACC’s LRI has contributed to the exposure science methods and tools listed below. Click on the hyperlinks to learn more about each method.

Tool/Method	Organization and Description
In Vitro to In Vivo Extrapolation (IVIVE)	SciotoVation IVIVE model for extrapolating in vitro measured metabolism values to predicted in vivo values is fully integrated into PLETHEM. New step-by-step User Guide now available here.
Population Lifecourse Exposure-to-Health-Effects Model (PLETHEM)	ScitoVation PLETHEM is a modular open source modeling platform that provides users the ability to create, share, and audit PBPK models and connect them to existing exposure tools. Developed by ScitoVation with funding from ACC and under a Memorandum of Understanding with EPA-NCCT. New step-by-step User Guides now available for: Forward dosimetry Deriving biomonitoring equivalents Conducting route to route extrapolation Reverse Dosimetry Developing kinetically derived MTDs
Risk Assessment, Identification, and Ranking (RAIDAR)	ARC Arnot Research & Consulting RAIDAR is an evaluative, regional-scale, mass balance model for screening level exposure and risk assessment. The model simulates chemical fate and transport in the environment, bioaccumulation in a range of species, food web bioaccumulation, far-field exposures to humans and representative ecological species, and effects (risk). Developed by Jon Arnot.
Risk Assessment, Identification, and Ranking-Indoor and Consumer Exposure (RAIDAR-ICE)	ARC Arnot Research & Consulting RAIDAR-ICE adapts the RAIDAR technique particularly for human exposure via indoor use or direct application of chemicals.
Exposure And Safety Estimation (EAS-E) Suite	ARC Arnot Research & Consulting The EAS-E Suite platform was developed to address some challenges for ecological and human health assessment. EAS-E Suite (pronounced “EASY Suite”) includes chemical information databases, quantitative structure activity relationships (QSARs) for predicting chemical information, and some relevant tools and models to support chemical hazard, exposure, and risk estimation. A primary objective of the EAS-E Suite platform is to help with knowledge transfer of new and existing methods to aid chemical safety assessments and sustainability. Databases for approximately 70,000 discrete organic chemicals are used to automatically parameterize the various mass balance models and tools based on a user-input of chemical name, SMILES notation, or Chemical Abstract Service (CAS) number. Users can provide preferred values for chemical information to supplant the provided defaults, if desirable. EAS-E Suite is envisaged to evolve with scientific developments and chemical safety assessment needs. EAS-E Suite is freely accessible on-line using an internet browser and currently includes these models (hyperlinks embedded to key scientific publications): PROduction-To-EXposure High Throughput (PROTEX-HT) for simulating aggregate exposure and potential risks to the general population and representative ecological receptors (plants, invertebrates, fish, mammals, birds) requiring only chemical structure and production volume information as input parameters. Chemicals in Products - Comprehensive Anthropospheric Fate Estimation (CiP-CAFE Ver.2.0) for simulating steady-state chemical emission factors, emission rates, and mode-of-entry to the environment throughout the life-cycle requiring only chemical structure, production volume and functional use category information. Risk Assessment IDentification And Ranking (RAIDAR) for simulating far-field human exposure and potential risks to the general population and representative ecological receptors (plants, invertebrates, fish, mammals, birds). Risk Assessment IDentification And Ranking – Point Source (RAIDAR-PS) for simulating multimedia environmental fate and distribution in air, watr and sediment, and exposures and potential risks to humans and representative ecological receptors (algae, invertebrates, fish, mammals, birds) following point source chemical emissions to water. Point Source Dilution model for simulating chemical dilution in receiving water environments, like the fate calculations in US EPA’s E-FAST model. Risk Assessment IDentification And Ranking – Indoor and Consumer Exposure (RAIDAR-ICE) for simulating near-field human exposure and potential risks to the general population. RAIDAR-ICE includes key indoor fate and exposure pathways (inhalation, non-dietary ingestion/dust/hand-to-mouth, and dermal direct and dermal indirect) as well as a physiologically based biokinetic model to estimate biological concentrations in blood and urine. High Throughput Toxicokinetic (HTTK) one-compartment physiologically based biokinetic models for simulating steady-state toxicokinetics and rate constants in fish, rats and humans. EPA Office of Research and Development (ORD-httk) for simulating toxicokinetics in rats and humans. EPA Consumer Exposure Model (CEM) Dermal for simulating dermal exposures and potential risks under various exposure scenarios. ECETOC TRA Dermal for consumer and workers for simulating dermal exposures and potential risks under various exposure scenarios. EAS-E Dermal for simulating dermal exposures and subsequent toxicokinetics and disposition in humans of different age classes. In Vitro Mass Balance Model (IV-MBM EQP Ver.2.0) for simulating chemical fate and disposition in in vitro bioassays. In Vitro-In Vivo Extrapolation (IVIVE) for scaling in vitro biotransformation rates from hepatocytes, microsomes and S9 bioassays to hepatic clearance and whole-body values for fish, rats, and humans. In Vitro-In Vivo Extrapolation (IVIVE) for converting in vitro bioactivity assay data to Administered Equivalent Doses (AEDs) for fish, rats, and humans Environmental Fate and Persistence (F-PEST) for simulating environmental fate, distribution, overall persistence and characteristic travel distances in air and water. Bioaccumulation Estimation Tool (BET) for calculating bioaccumulation assessment metrics in aquatic invertebrates, fish, birds and mammals in laboratory and field environments. Toxicity Estimation & Simulation Tool (TEST) for simulating internal exposures from external doses for representative aquatic receptors (algae, invertebrates, fish).

LRI Tools and Methods: Exposure Science

Epidemiology is the study and analysis of the patterns, causes, and effects of diseases. Research support from ACC’s LRI has contributed to the epidemiology methods and tools listed below. Click on the hyperlinks to learn more about each method.

Tool/Methods	Organization and Description
Evaluation of reverse causality in epidemiological associations	ScitoVation Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause.
Exploring Microplastics Environmental Monitoring Data: Development of a Dashboard to Track, Analyze, and Display Data	ACC LRI To assist with the broader efforts of the Microplastics Advanced Research and Innovation Initiative (MARII), as a pilot project, LRI created a data visualization tool, the Microplastics Data Crosswalk Dashboard to allow a user to review data from published studies reporting microplastics in environmental media (biological, sediment, soil, and surface water). A video, “Visualizing Microplastics Environmental Monitoring Data” (linked in the dashboard) has been created to provide an in-depth dashboard overview.

Tool/Methods

Organization and Description

Evaluation of reverse causality in epidemiological associations

ScitoVation
Quantitative bias analysis for epidemiological associations of perfluoroalkyl substance serum concentrations and early onset of menopause.

Exploring Microplastics Environmental Monitoring Data: Development of a Dashboard to Track, Analyze, and Display Data

ACC LRI
To assist with the broader efforts of the Microplastics Advanced Research and Innovation Initiative (MARII), as a pilot project, LRI created a data visualization tool, the Microplastics Data Crosswalk Dashboard to allow a user to review data from published studies reporting microplastics in environmental media (biological, sediment, soil, and surface water). A video, “Visualizing Microplastics Environmental Monitoring Data” (linked in the dashboard) has been created to provide an in-depth dashboard overview.

LRI Tools and Methods: Ecological & Environmental

Ecological and environmental science focuses on understanding the potential impacts of chemicals released to environmental media, such as air, water and soil, and how such exposures may influence environmental receptors. Research support from ACC’s LRI has contributed to the ecological and environmental exposure science methods and tools listed below. Click on the hyperlinks to learn more about each method.

Tool/Methods	Organization and Description
Bioaccumulation Assessment Tool (BAT Ver.2.02)	ARC Arnot Research & Consulting The Bioaccumulation Assessment Tool (BAT Ver.2.02) was developed to guide the collection, generation, evaluation, and integration of various lines of evidence to aid bioaccumulation assessment decision-making for aquatic and terrestrial organisms. The BAT facilitates the systematic and transparent integration of information in a consistent framework to inform bioaccumulation assessment decision-making by providing a Weight of Evidence (WOE) approach that includes critical evaluations of data confidence (quality). The BAT WOE approach is aligned with the Guiding Principles and Key Elements for Establishing a Weight of Evidence for Chemical Assessment provided by the Organization for Economic Coordination and Development (OECD). The BAT was developed with stakeholder involvement including representatives from academia, government, and industry. The BAT is implemented (coded) in Visual Basic for Applications (VBA) and the Graphical User Interface is designed in Excel™. The BAT is free to download and introductory video vignettes for getting started with the BAT are available on-line.

Tool/Methods

Organization and Description

Bioaccumulation Assessment Tool (BAT Ver.2.02)

ARC Arnot Research & Consulting
The Bioaccumulation Assessment Tool (BAT Ver.2.02) was developed to guide the collection, generation, evaluation, and integration of various lines of evidence to aid bioaccumulation assessment decision-making for aquatic and terrestrial organisms. The BAT facilitates the systematic and transparent integration of information in a consistent framework to inform bioaccumulation assessment decision-making by providing a Weight of Evidence (WOE) approach that includes critical evaluations of data confidence (quality). The BAT WOE approach is aligned with the Guiding Principles and Key Elements for Establishing a Weight of Evidence for Chemical Assessment provided by the Organization for Economic Coordination and Development (OECD). The BAT was developed with stakeholder involvement including representatives from academia, government, and industry. The BAT is implemented (coded) in Visual Basic for Applications (VBA) and the Graphical User Interface is designed in Excel™.

The BAT is free to download and introductory video vignettes for getting started with the BAT are available on-line.

LRI Tools and Methods: Pathways and Mechanisms of Action

Research of toxicity pathways and mechanisms of action of chemicals focuses on understanding the moleciular and biological interactions of chemicals with living organisms and the dose-related relationships of such interactions with cellular and organ-level events in pathways of causally related events that may lead to adverse health effects. Listed below are methods and tools that research support from ACC’s LRI has contributed to. Click on the hyperlinks to learn more about each method.

Tool/Methods	Organization and Description
Mode of Action Visualization (MoAviz)	ScitoVation MoAviz is a browser-based applet for summarizing, exploring and interpreting gene expression and other high-throughput data
In Vitro Mass Balance Model (IV-MBM EQP v2.0)	ARC Arnot Research & Consulting The In Vitro Mass Balance Model (IV-MBM EQP v2.0) developed by Dr. James Armitage simulates the partitioning and distribution of organic chemicals in in vitro test systems. Using nominal medium concentrations (e.g., AC50s) as input, the model can be used to predict the corresponding freely-dissolved and cellular concentrations along with other information on how the chemical behaves in the test system (e.g., mass fractions present in head space, dissolved in the medium and sorbed to cells). The user can readily parameterize the model for a variety of assay conditions and generate output with only a few key partitioning properties (e.g., octanol-water partition coefficient, air-water partition coefficient, water solubility). The model can be used retrospectively to facilitate the interpretation of existing in vitro toxicity data and prospectively to assist in the design of testing strategies (e.g., more rational selection of exposure concentrations). IV-MBM EQP v2.0 can be downloaded as an Excel™ spreadsheet tool or used in EAS-E Suite.

Tool/Methods

Organization and Description

Mode of Action Visualization (MoAviz)

ScitoVation
MoAviz is a browser-based applet for summarizing, exploring and interpreting gene expression and other high-throughput data

In Vitro Mass Balance Model (IV-MBM EQP v2.0)

ARC Arnot Research & Consulting
The In Vitro Mass Balance Model (IV-MBM EQP v2.0) developed by Dr. James Armitage simulates the partitioning and distribution of organic chemicals in in vitro test systems. Using nominal medium concentrations (e.g., AC50s) as input, the model can be used to predict the corresponding freely-dissolved and cellular concentrations along with other information on how the chemical behaves in the test system (e.g., mass fractions present in head space, dissolved in the medium and sorbed to cells). The user can readily parameterize the model for a variety of assay conditions and generate output with only a few key partitioning properties (e.g., octanol-water partition coefficient, air-water partition coefficient, water solubility). The model can be used retrospectively to facilitate the interpretation of existing in vitro toxicity data and prospectively to assist in the design of testing strategies (e.g., more rational selection of exposure concentrations).
IV-MBM EQP v2.0 can be downloaded as an Excel™ spreadsheet tool or used in EAS-E Suite.

LRI Tools and Methods: Technology and Assessments

Understanding the potential risk of exposures to chemicals requires integration of scientific evidence from epidemiological studies, laboratory animal investigations, and mechanistic research with knowledge of exposure and dosimetery. ACC’s LRI has contributed to the development and improvement of a wide variety of technologies and assessment methods focused in improving risk-based approaches for evaluating chemicals. Click on the hyperlinks to learn more about each method.

Tool/Method	Organization and Description
Predictive Analytics Toolkit (PAT)	ACC This toolkit facilitates automated development and testing of predictive models utilizing machine learning. Outputs include a table of outcomes from each predictive model, confusion matrices, an outcome classification dendrogram, and calibration curves.
Quantitative weight of evidence to assess confidence in potential modes of action	ACC A proof of concept extension of the MoA framework is proposed for scoring confidence in the supporting data to improve scientific justification for MoA use in characterizing hazards and selecting dose-response extrapolation methods for specific chemicals.
Threshold of Toxicological Concern (TTC) applet	ScitoVation This searchable applet provides TTC values, classes, and Kroes decisions for six classes of chemicals.