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Winston, GA, United States

Simon T.W.,Ted Simon LLC | Simons Jr. S.S.,U.S. National Institutes of Health | Preston R.J.,Us Epa National Health And Environmental Effects Research Laboratory | Boobis A.R.,Imperial College London | And 6 more authors.
Critical Reviews in Toxicology | Year: 2014

The HESI RISK21 project formed the Dose-Response/Mode-of-Action Subteam to develop strategies for using all available data (in vitro, in vivo, and in silico) to advance the next-generation of chemical risk assessments. A goal of the Subteam is to enhance the existing Mode of Action/Human Relevance Framework and Key Events/Dose Response Framework (KEDRF) to make the best use of quantitative dose-response and timing information for Key Events (KEs). The resulting Quantitative Key Events/Dose-Response Framework (Q-KEDRF) provides a structured quantitative approach for systematic examination of the dose-response and timing of KEs resulting from a dose of a bioactive agent that causes a potential adverse outcome. Two concepts are described as aids to increasing the understanding of mode of action-Associative Events and Modulating Factors. These concepts are illustrated in two case studies; 1) cholinesterase inhibition by the pesticide chlorpyrifos, which illustrates the necessity of considering quantitative dose-response information when assessing the effect of a Modulating Factor, that is, enzyme polymorphisms in humans, and 2) estrogen-induced uterotrophic responses in rodents, which demonstrate how quantitative dose-response modeling for KE, the understanding of temporal relationships between KEs and a counterfactual examination of hypothesized KEs can determine whether they are Associative Events or true KEs. © 2014 Informa Healthcare USA, Inc. Source

Beck N.B.,American Chemistry Council | Becker R.A.,American Chemistry Council | Erraguntla N.,Texas Commission on Environmental Quality | Farland W.H.,Colorado State University | And 14 more authors.
Environment International | Year: 2016

Single point estimates of human health hazard/toxicity values such as a reference dose (RfD) are generally used in chemical hazard and risk assessment programs for assessing potential risks associated with site- or use-specific exposures. The resulting point estimates are often used by risk managers for regulatory decision-making, including standard setting, determination of emission controls, and mitigation of exposures to chemical substances. Risk managers, as well as stakeholders (interested and affected parties), often have limited information regarding assumptions and uncertainty factors in numerical estimates of both hazards and risks. Further, the use of different approaches for addressing uncertainty, which vary in transparency, can lead to a lack of confidence in the scientific underpinning of regulatory decision-making. The overarching goal of this paper, which was developed from an invited participant workshop, is to offer five approaches for presenting toxicity values in a transparent manner in order to improve the understanding, consideration, and informed use of uncertainty by risk assessors, risk managers, and stakeholders. The five approaches for improving the presentation and communication of uncertainty are described using U.S. Environmental Protection Agency's (EPA's) Integrated Risk Information System (IRIS) as a case study. These approaches will ensure transparency in the documentation, development, and use of toxicity values at EPA, the Agency for Toxic Substances and Disease Registry (ATSDR), and other similar assessment programs in the public and private sector. Further empirical testing will help to inform the approaches that will work best for specific audiences and situations. © 2016 The Authors. Source

Stephens M.L.,Center for Alternatives to Animal Testing | Andersen M.,Hamner Institutes for Health Sciences | Becker R.A.,American Chemistry Council | Boekelheide K.,Brown University | And 20 more authors.
Altex | Year: 2013

The Evidence-based Toxicology Collaboration (EBTC) was established recently to translate evidence-based approaches from medicine and health care to toxicology in an organized and sustained effort. The EBTC held a workshop on "Evidence-based Toxicology for the 21st Century: Opportunities and Challenges" in Research Triangle Park, North Carolina, USA on January 24-25, 2012. The presentations largely reflected two EBTC priorities: to apply evidence-based methods to assessing the performance of emerging pathwaybased testing methods consistent with the 2007 National Research Council report on "Toxicity Testing in the 21st Century" as well as to adopt a governance structure and work processes to move that effort forward. The workshop served to clarify evidence-based approaches and to provide food for thought on substantive and administrative activities for the EBTC. Priority activities include conducting pilot studies to demonstrate the value of evidence-based approaches to toxicology, as well as conducting educational outreach on these approaches. Source

Kirman C.,Summit Toxicology | Budinsky R.A.,Dow Chemical Company | Yost L.,Exponent, Inc. | Baker B.F.,Sugar River Consulting | And 4 more authors.
Human and Ecological Risk Assessment | Year: 2011

While risk assessments are extensively used for guiding critical and resource intensive decisions, assessments that rigorously integrate key exposure and toxicity terms are less often published. This article derives residential soil clean-up levels accounting for ingestion and dermal contact (direct contact criteria [DCC]) for a chlorinated dibenzo-p-dioxin and furan (PCDD/F as toxicity equivalence TEQD/F) impacted site using site-specific information and deterministic and probabilistic methods. In addition, TEQD/F risk assessment has been the subject of extensive scientific and regulatory debate including in-depth comments from two USEPA Science Advisory Boards and the National Academy of Sciences (NAS) on the proposed USEPA Draft Dioxin Risk Assessment. This article presents and applies toxicity values seeking to address the NAS recommendations regarding cancer risk assessment. Deterministic DCC estimates ranged from 19 to 250 ppb through application of linear and nonlinear cancer toxicity values, and a DCC of 5.3 ppb was estimated based on the World Health Organization's Joint Exposure Committee on Food Additive's assessment value for noncancer and cancer endpoints. A wide range of DCC estimates were calculated using probabilistic methods, with the prior USEPA 1 ppb clean-up value falling below the first percentile of estimates, suggesting that the 1 ppb value is health protective. © Taylor & Francis Group, LLC. Source

Patlewicz G.,DuPont Company | Simon T.W.,Ted Simon LLC | Rowlands J.C.,Dow Chemical Company | Budinsky R.A.,Dow Chemical Company | Becker R.A.,American Chemistry Council ACC
Regulatory Toxicology and Pharmacology | Year: 2015

An adverse outcome pathway (AOP) describes the causal linkage between initial molecular events and an adverse outcome at individual or population levels. Whilst there has been considerable momentum in AOP development, far less attention has been paid to how AOPs might be practically applied for different regulatory purposes. This paper proposes a scientific confidence framework (SCF) for evaluating and applying a given AOP for different regulatory purposes ranging from prioritizing chemicals for further evaluation, to hazard prediction, and ultimately, risk assessment. The framework is illustrated using three different AOPs for several typical regulatory applications. The AOPs chosen are ones that have been recently developed and/or published, namely those for estrogenic effects, skin sensitisation, and rodent liver tumor promotion. The examples confirm how critical the data-richness of an AOP is for driving its practical application. In terms of performing risk assessment, human dosimetry methods are necessary to inform meaningful comparisons with human exposures; dosimetry is applied to effect levels based on non-testing approaches and in vitro data. Such a comparison is presented in the form of an exposure:activity ratio (EAR) to interpret biological activity in the context of exposure and to provide a basis for product stewardship and regulatory decision making. © 2015 The Authors. Source

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