Exploring current read-across applications and needs among selected U.S. Federal Agencies

Patlewicz, Grace; Lizarraga, Lucina E.; Rua, Diego; Allen, David; Daniel, Amber; Fitzpatrick, Suzanne; García-Reyero, Natàlia; Gordon, J. D. M.; Hakkinen, Pertti J.; Howard, Angela S.; Karmaus, Agnes L.; Matheson, Joanna; Mumtaz, Moiz; Richarz, Andrea-Nicole; Ruíz, Patricia; Scarano, Louis; Yamada, Takashi; Kleinstreuer, Nicole

doi:10.1016/j.yrtph.2019.05.011

Cited by 31 publications

(26 citation statements)

References 43 publications

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“…The resource intensive nature of traditional toxicological testing—including both time and cost—and the lack of data for many chemicals has spawned a number of initiatives to improve toxicity testing by increasing speed, reducing costs, and improving efficiency. Many of these efforts have focused on replacing traditional in vivo test systems with a range of in silico, in vitro , and in chemico methods, along with integrated approaches to testing and assessment (CCA, 2012 ; Cronin et al., 2009 ; Krewski et al., 2010; Patlewicz et al., 2019 ; Thomas et al., 2019 ). Although progress has been slow, the release of strategic planning documents across multiple U.S. federal agencies (ICCVAM, 2018 ; U.S. FDA, 2017 ; U.S. EPA, 2018a , 2018 b , 2020 ) has generated new momentum toward development and application of alternative toxicity‐testing methods in regulatory decisions.…”

Section: Introductionmentioning

confidence: 99%

A Framework that Considers the Impacts of Time, Cost, and Uncertainty in the Determination of the Cost Effectiveness of Toxicity‐Testing Methodologies

et al. 2021

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Regulatory agencies are required to evaluate the impacts of thousands of chemicals. Toxicological tests currently used in such evaluations are time-consuming and resource intensive; however, advances in toxicology and related fields are providing new testing methodologies that reduce the cost and time required for testing. The selection of a preferred methodology is challenging because the new methodologies vary in duration and cost, and the data they generate vary in the level of uncertainty. This article presents a framework for performing cost-effectiveness analyses (CEAs) of toxicity tests that account for cost, duration, and uncertainty. This is achieved by using an output metric-the cost per correct regulatory decisionthat reflects the three elements. The framework is demonstrated in two example CEAs, one for a simple decision of risk acceptability and a second, more complex decision, involving the selection of regulatory actions. Each example CEA evaluates five hypothetical toxicitytesting methodologies which differ with respect to cost, time, and uncertainty. The results of the examples indicate that either a fivefold reduction in cost or duration can be a larger driver of the selection of an optimal toxicity-testing methodology than a fivefold reduction in uncertainty. Uncertainty becomes of similar importance to cost and duration when decisionmakers are required to make more complex decisions that require the determination of small differences in risk predictions. The framework presented in this article may provide a useful basis for the identification of cost-effective methods for toxicity testing of large numbers of chemicals.

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Section: Introductionmentioning

confidence: 99%

A Framework that Considers the Impacts of Time, Cost, and Uncertainty in the Determination of the Cost Effectiveness of Toxicity‐Testing Methodologies

et al. 2021

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“…While there is a growing mass of literature published in peer-reviewed journals and considerable guidance from bodies such as OECD, ECHA, ECETOC, etc., there is no overall knowledge source. Books such as by Cronin et al (2013) provide a sound basis to the theory, and recent papers such as Patlewicz et al (2017 , 2018 , 2019 ) include updates on the tools that may be applied. Aspects of computational toxicology have been included in under- and postgraduate education for many years, from Bachelor level degrees to PhDs, while RAx as a subject has only recently been included in some academic curricula.…”

Section: Methodsmentioning

confidence: 99%

“… Patlewicz et al (2017) performed a review of available in silico tools for grouping and inter alia compared them with a RAx workflow. The recent ICCVAM RAx working group publication also provides a description of freely available tools and insight into those used by regulatory agencies to support decision-making ( Patlewicz et al, 2019 ). A fundamental prerequisite of any tool is the clear definition of the approach, with defined integration of QSAR assessment and the possibility to backtrack data history and version of the tools, as well as a simple format output adhering to the OECD principles for QSAR validation ( OECD, 2007 ).…”

Section: Methodsmentioning

confidence: 99%

“…In 2016, ICCVAM broadcast a dedicated webinar 6 and established a working group focused on RAx, which was assigned the task of summarizing best practices for the application and implementation of RAx in the different regulatory settings of interest. A recent publication by the ICCVAM RAx working group summarized current needs and opportunities across US agencies, including decision contexts, desired activities, and any available guidance, and provided a list of freely available RAx tools ( Patlewicz et al, 2019 ). This paper also detailed two specific case studies to illustrate how RAx is applied in practice: the EPA evaluation of n-heptanal under the Superfund program and a toxicological risk assessment for a medical device at the US FDA.…”

Section: Introductionmentioning

confidence: 99%

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Internationalization of read-across as a validated new approach method (NAM) for regulatory toxicology

Rovida

Barton-Maclaren

Benfenati

et al. 2020

ALTEX

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dossier to the European Chemicals Agency (ECHA) containing an extensive list of data on the intrinsic properties of a substance, ranging from chemical characterization and physicochemical properties to toxicological and ecotoxicological data, with increasing demands depending on the tonnage band of the quantity of the substance placed on the market. In addition, registrants should collect information on use and exposure to perform a chemical safety assessment (CSA) based on the toxicity profile of the substance. The minimum data requirements are described in Annexes VI-X of the regulation. For toxicological testing, the standard require-

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“…Knowledge of modes and mechanisms of action of chemicals allows a more detailed consideration of interspecies differences and the relevance of animal findings for the human situation. Studies in isolated organs, organoids and cell cultures have proven instrumental in revealing mechanistic properties of chemicals, enabling more refined human safety assessment and support read-across or grouping approaches to facilitate the assessment of the enormous number of substances on the market (Ball et al 2016;ECHA 2016;Patlewicz et al 2019). These approaches are based on the concept of Quantitative structure-activity relationships (QSARs) correlating chemical structure with biological activity using statistical approaches and commonly used in drug discovery as well as toxicology (Perkins et al 2003).…”

Section: Current and Developing Approaches In Regulatory Pharmacology And Toxicologymentioning

confidence: 99%

Applicability of organ-on-chip systems in toxicology and pharmacology

Schneider

Oelgeschlaeger

Burgdorf

et al. 2021

Critical Reviews in Toxicology

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Organ-on-chip (OoC) systems are microfabricated cell culture devices designed to model functional units of human organs by harboring an in vitro generated organ surrogate. In the present study, we reviewed issues and opportunities related to the application of OoC in the safety and efficacy assessment of chemicals and pharmaceuticals, as well as the steps needed to achieve this goal. The relative complexity of OoC over simple in vitro assays provides advantages and disadvantages in the context of compound testing. The broader biological domain of OoC potentially enhances their predictive value, whereas their complexity present issues with throughput, standardization and transferability. Using OoCs for regulatory purposes requires detailed and standardized protocols, providing reproducible results in an interlaboratory setting. The extent to which interlaboratory standardization of OoC is feasible and necessary for regulatory application is a matter of debate. The focus of applying OoCs in safety assessment is currently directed to characterization (the biology represented in the test) and qualification (the performance of the test). To this aim, OoCs are evaluated on a limited scale, especially in the pharmaceutical industry, with restricted sets of reference substances. Given the low throughput of OoC, it is questionable whether formal validation, in which many reference substances are extensively tested in different laboratories, is feasible for OoCs. Rather, initiatives such as open technology platforms, and collaboration between OoC developers and risk assessors may prove an expedient strategy to build confidence in OoCs for application in safety and efficacy assessment.

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Exploring current read-across applications and needs among selected U.S. Federal Agencies

Cited by 31 publications

References 43 publications

A Framework that Considers the Impacts of Time, Cost, and Uncertainty in the Determination of the Cost Effectiveness of Toxicity‐Testing Methodologies

A Framework that Considers the Impacts of Time, Cost, and Uncertainty in the Determination of the Cost Effectiveness of Toxicity‐Testing Methodologies

Internationalization of read-across as a validated new approach method (NAM) for regulatory toxicology

Applicability of organ-on-chip systems in toxicology and pharmacology

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