The Toxicology Forum is an international non-profit organization that is devoted to fostering deliberative dialogue which shapes decision-making and outcomes on critical issues in toxicology and its applications for purposes of promoting and protecting public health.

The Center for Truth in Science is proud to be the sponsor of a scientific session at the 2024 Toxicology Forum Summer Meeting, to be held in Alexandria, VA, July 15-17. The title of the session is: Systematic Review – Is the Method Getting in the Way of the Science? – and will feature experts from private consulting, academia, the NIH, and EPA discussing systematic review methods as applied to questions in risk management, toxicology, and environmental health.

In the session, speakers will survey and discuss the current landscape of applications for systematic review, focusing on fundamental aspects of toxicity and risk assessment for which required adaptations have been identified and proposed, as well as tools and techniques that facilitate the application of systematic review to a broad variety of research questions in chemical risk assessment. Case study examples will be provided of lessons learned in making systematic review more efficient through careful problem formulation and leveraging existing reviews, adapting critical appraisal tools to address both relevance and reliability, and reframing standard systematic review methods for evaluating a body of evidence to improve evidence integration and toxicity value derivation.

As a key component of lessons learned, the session will address the increased reliance on the use of epidemiological data in risk assessment, which has occurred concurrent with the increased use of systematic review, and highlight areas where adaptations of existing methods have been proposed to evaluate causation, dose-response, and mode of action more directly.

Three of the Center’s published systematic reviews on talc, ethylene oxide, and formaldehyde will be used as case examples to help illustrate presenters’ points about robust systematic review techniques. For more information on these, please see the following links:

The line-up of speakers will be as follows:

A Decade of Systematic Review in Toxicology – Impact of the OHAT Approach

Andrew Rooney and Kyla W. Taylor, NIEHS, Division of Translational Toxicology 

The OHAT [Office of Health Assessment and Translation] approach for systematic review and evidence integration was published a decade ago, on the leading edge of efforts that adapted systematic review methods for addressing toxicology and environmental health questions. Although there are differences across major methods (e.g., OHAT, EFSA, EPA-IRIS, Navigation Guide, OHAT, RoC) an engaged community of practitioners and methodologists has contributed to harmonization and consistency on principle issues. Speakers will highlight the uptake of these methods and the importance of the increased transparency and objectivity they provide to decision-making in public health. They will also address the major challenge of systematic review methods – the time and level of effort required – discussing how close we are to reducing these challenges with advances in automation and evidence informatics.       

A Cross-Walk of Risk Assessment and Systematic Review – Strengths, Challenges, and a Path Forward 

Lynne Haber, University of Cincinnati Risk Science Center 

The use of systematic review methods has seen a substantial increase as part of the development of assessments by regulatory agencies and others. This presentation will highlight how systematic review helps to support evidence-based toxicology and will use case studies to illustrate limitations in the procedure. The importance of critical evaluation of causality, consideration of studies in the context of relevant test guidelines, building on prior knowledge, and careful construction of the evaluation criteria will be highlighted. 

Strategies for Improving Consideration of Study Quality in Evidence Integration and Causality Assessment

Heather Lynch, Stantec ChemRisk 

Study quality is critical for many aspects of chemical risk assessment, from drawing causal inferences to selecting the highest-quality studies for the derivation of toxicity values, and for setting regulations. Most risk of bias and study quality tools average or aggregate ratings or scores in each quality domain to arrive at overall ratings of bias, and thus have limited ability to identify and more strongly weight critical domains of quality or determine the direction and magnitude of various biases on study result.

This speaker will evaluate a systematic review of talc and reproductive cancers in which a tiered assessment emphasizing the exposure assessment domain revealed that recall bias from historical talc exposure likely was responsible for the apparent “inconsistency” in associations among epidemiological studies. A second case study presents examples from a systematic review on ethylene oxide demonstrating how analytic choices by authors (in this case, the chosen referent population) can affect interpretation of a body of evidence. A third case study on formaldehyde will provide insight into utilizing epidemiological triangulation methods ─ the topic of a recent National Academies of Science workshop ─ to improve upon meta-analytic and systematic review methods for causal inference.  

Applying Existing Assessments for Problem Formulation in the IRIS Program: Case Example for the Uranium Oral Toxicological Review

X. Arzuaga, and M. B. Powers, US EPA, Office of Research and Development, Washington, DC.

The U.S. EPA IRIS Program is developing a Toxicological Review of the noncancer health effects of depleted and natural uranium after oral exposure. The IRIS assessment examines whether newly available evidence indicate a need to update these conclusions and consider other noncancer effects for hazard evaluation and/or a reference value derivation. A Systematic Evidence Map (SEM) of the uranium toxicological and epidemiological evidence (from 2011 to early 2023) was developed to explore newly available data. This approach is aimed to leverage existing assessments to develop a literature search strategy and analysis that is focused on outcomes for which there is new evidence that can inform hazard evaluation and dose-response. Disclaimer: The views expressed are those of the authors and do not necessarily represent the views or policies of the US EPA.

Pragmatic Solutions for Better Using Evidence-Based Methods to Assess Causality and Facilitate Risk Assessment

Daniele Wikoff, ToxStrategies 

This speaker will explore a series of solutions for better use of evidence-based methods to facilitate risk assessment. Using three case studies, demonstrations in pragmatic and risk-focused applications of various steps of the systematic review process will be highlighted: 1) Utilizing a priori knowledge of a substance to refine critical appraisal criteria in the development of a toxicity value for micro plastics and developmental outcomes, 2) Reframing the body of evidence assessment in an evaluation of causality for formaldehyde and hematopoietic cancer by adding Bradford Hill concepts of biological plausibility (addressed via mode of action), experiment, and others to standard GRADE-based criteria and allowing the data to drive directions of up- or down- grades in a manner which is more consistent with standard weight of evidence practice, and 3) Using underlying data from a systematic review of dioxin-like compounds to quantitatively inform uncertainty in toxicological values.

Moving from evidence to action: a new framework to facilitate integration of systematic reviews with additional considerations for decision-making

Emily Senerth, Evidence-Based Toxicology Collaboration

There is no prevailing approach to integrating evidence, such as the output of a hazard identification or risk characterization process, with additional decision factors that are considered during the formulation of regulations or policies about environmental exposures. Decision frameworks that do exist have been developed to address specific scenarios and have poor generalizability outside of their niche. The GRADE working group recently approved new guidance describing an evidence-to-decision framework for environmental health. This framework represents a new approach to decision-making about environmental exposures that is grounded in an exhaustive review of EOH decision-making. The purpose of this session is to introduce the framework to policymakers using a real-world example, presenting the background and development methods then leading attendees through a decision-making process about an environmental exposure.

The Center for Truth in Science has funded several research projects in the subject matters related to these presentations: