Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks

Abstract

Although emissions of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have been dramatically reduced, the persistence and bioaccumulation of these chemicals result in detectable levels in the U.S. population. Despite declining emissions, there is continued widespread exposure to both chemicals and a number of studies have reported potential PFOA-and PFOS-associated immunotoxicity in both humans and non-human animals. The NTP conducted a systematic review to evaluate the evidence on exposure to PFOS or PFOA and immune-related health effects to determine whether exposure to either chemical is associated with immunotoxicity for humans. The literature search and screening process identified 33 human studies, 93 animal studies, and 27 in vitro/mechanistic studies relevant for addressing the objective. The health effects data for PFOA and PFOS were considered separately in developing hazard identification conclusions. Conclusions for each chemical were reached by integrating evidence from human and animal studies with consideration of any mechanistic data. PEER REVIEW OF THE DRAFT NTP MONOGRAPHPeer review of the draft NTP Monograph was conducted by an ad hoc expert panel in a public meeting held July 19, 2016, at the National Institute of Environmental Health Sciences, Research triangle park and via WebEx (see http://ntp.niehs.nih.gov/go/37090 for meeting materials and peer review report). The selection of panel members and conduct of the peer review were performed in accordance with the Federal Advisory Committee Act and Federal policies and regulations. The panel members served as independent scientists, not as representatives of any institution, company, or governmental agency. In this capacity, panel members had two major responsibilities in reviewing the draft NTP Monograph:(1) to determine whether the scientific information cited in the draft monograph was technically correct and clearly stated, and whether NTP has objectively presented and assessed the scientific evidence;(2) to determine whether the scientific evidence presented in the draft monograph supported the NTP's conclusions regarding whether immunotoxicity is associated with exposure to PFOA or PFOS.The panel agreed with the draft conclusions that PFOA and PFOS are both presumed to be immune hazards to humans; however, they recommended changing the level of evidence conclusion for hypersensitivity-related outcomes for the animal body of evidence from "high" to "moderate". NTP concurred with this recommendation. Comments from the peer reviewers and written public comments were considered during finalization of the document.

Application of AOPs to assist regulatory assessment of chemical risks – Case studies, needs and recommendations

“…The OECD AOP-Wiki ( https://aopwiki.org/ ) was launched in 2013 and serves as an AOPs open-access repository allowing the contribution to AOP content by international crowdsourcing. However, although the number of AOPs, general awareness of the AOP framework, and training of different stakeholders have substantially increased, the actual application of AOPs in RA processes remains limited, and discussions on how to best use AOPs for regulatory purposes are still ongoing ( Carusi et al, 2018 ; Zuang and Dura, 2022 ; Hoffmann, 2022 ; Sauer et al, 2020 ).…”

“…In that context, various activities have been organized within the European Partnership Human Biomonitoring for Europe, HBM4EU ( https://www.hbm4eu.eu/ ), the Eurion Cluster ( https://eurion-cluster.eu/ ), the United States Environmental Protection Agency (US EPA) ( https://www.epa.gov/ ), the OECD Working Party on Hazard Assessment (WPHA), Working Party on Exposure Assessment (WPEA) project, EU Horizon 2020 projects EuroMix ( https://www.euromixproject.eu/ ) and EU-ToxRisk ( https://www.eu-toxrisk.eu/ ), ASPIS cluster ( https://aspis-cluster.eu/ ) or the Mystery of ROS consortium ( Tanabe et al, 2022a , 2022b ). These initiatives also organized workshops ( Hoffmann, 2022 ; Paini et al, 2022 ) or OECD webinars on AOPs ( https://www.oecd.org/chemicalsafety/testing/webinars-on-testing-and-assessment-methodologies.htm ) . To bridge from HBM4EU to a follow-up pan-European Partnership on Risk Assessment of Chemicals (PARC), a workshop was organized in April 2022, which discussed issues related to using AOPs in a regulatory context from various perspectives.…”

Development of adverse outcome pathways relevant for the identification of substances having endocrine disruption properties Uterine adenocarcinoma as adverse outcome

“…The gradient of comprehensiveness and systematicity varied across subgroups though reflecting the level of certainty and consolidated knowledge available for the various components of the AOP. This was considered appropriate also in light of the discussions taking place in EFSA and more generally in the scientific community on the best way to adapt the use of systematic approaches in the AOP framework (Hoffmann et al., 2022 ; Svingen et al., 2021 ).…”

A call for a Human Exposome Project

“…The board of trustees includes members of leading regulatory agencies from the US and Europe. The collaboration has produced guidance on systematic reviews (Stephens et al, 2016;Hoffmann et al, 2017Hoffmann et al, , 2022a, including case studies (Stephens et al, 2019;Hoffmann et al, 2021), quality scoring (Samuel et al, 2016), evidence integration, mechanistic frameworks (de Vries et al, 2021;Hoffmann et al, 2022b), etc. About 1,000 researchers have interacted with EBTC, and the number of systematic reviews in environmental health has increased greatly in the last decade.…”