Editorial overview: Risk assessment in toxicology

TY - JOUR

T1 - Editorial overview

T2 - Risk assessment in toxicology

AU - Boobis, Alan

AU - Safe, Stephen H.

AU - Farland, William

N1 - Funding Information: Alan Boobis ∗ a.boobis@imperial.ac.uk Imperial College London, United Kingdom Kensington, London, SW7 2AZ, UK Imperial College London United Kingdom Kensington London SW7 2AZ UK ∗ Corresponding author: Boobis, Alan Stephen H. Safe ∗ ssafe@cvm.tamu.edu Texas A&M University, Translational Environmental Health Research, Department of Molecular & Cellular Medicine, 400 Bizzell St, College Station, TX, 77843, USA Texas A&M University Translational Environmental Health Research Department of Molecular & Cellular Medicine 400 Bizzell St College Station TX 77843 USA ∗ Corresponding author: Safe, Stephen H. William Farland ∗ william.farland@colostate.edu Colorado State University CSU, Department of Environmental & Radiological Health Sciences, USA Colorado State University CSU Department of Environmental & Radiological Health Sciences USA ∗ Corresponding author: Farland, William This review comes from a themed issue on Risk assessment in toxicology Edited by Alan Boobis , Stephen H. Safe and William Farland Risk assessment involves the translation of scientific knowledge and experimental data into advice on the level of concern resulting from exposure to chemicals. Hence, information is required on the potential hazards posed by the chemical and on exposures to the chemical that occur or that are likely to occur. As science and technology advance, there is a need to consider how best to incorporate these developments into risk assessment. This requires a balance between embracing advances that improve our ability to anticipate risks whilst not prematurely jettisoning what is already serving us well. This issue of CoT comprises a series of articles by distinguished experts in their fields, which address a number of aspects of risk assessment, where scientific advances are likely to have a significant impact in the near to mid-term. Topics addressed cover experimental and computational approaches to hazard characterisation, emerging endpoints of concern, leveraging new methods using increased biological insight and exposure assessment. Not all of the approaches outlined will change risk assessment overnight, but in every case, they provide insights that merit careful consideration of how implementation could impact on the protection of human health. How could risk assessment change to capitalise on these advances, and what would be necessary for this to occur? High content methods, such as toxicogenomics, provide unparalleled opportunities for global assessment of the biological and toxicological responses of a cell or a tissue to chemical exposure. Analysis of changes in gene expression by individual chemicals and chemical mixtures can be instrumental in identifying modes of action (MOA) and various tools have been developed for analyzing transcriptomic data. Anderson et al review the use of this type of approach and the tools of analysis by heatmaps, pathway enrichment analysis, benchmark dose estimations to inform results of dose–response modeling and MOA. Risk assessment of environmental chemicals has always been an important but difficult component of risk assessment and environmental epidemiology. As reviewed by Aylward in her paper, an important contributor to the difficulties in this field is associated with the complex mixture of chemicals in environmental matrices and this translates in exposure to complex mixtures which may have multiple MOAs. Biomonitoring, which is a major focus of this paper, is one approach which can assist in risk assessment of complex mixtures and integrate potential exposure and risks from these mixtures. Concern that chemicals in the environment can disrupt the endocrine systems of humans and ecological species (fish, frogs, birds) has driven the development of bioassays to test for endocrine activity. In the last decade, there has been increased focus on in vitro and high-throughput screening (HTS) assays and in silico models that allow the rapid evaluation of hundreds to thousands of compounds. Judson et al review efforts at the US EPA and the National Toxicology Program to develop assays and models to predict estrogen, androgen and steroidogenesis activity. These approaches combine in vitro HTS assays, computational models that link the results of multiple assays and reduce the impact of assay artifacts and noise, and structure-based QSAR models. These approaches have been shown to be robust enough to move from research to application in regulatory risk assessment. Is risk assessment out of control, addressing every conceivable hazard, rather than focusing on the effects of most concern? Goldstein explores this issue in his paper examining Finkel's concept of solution-focused risk assessment (SFRA). In this, rather than a comprehensive examination of the toxicological effects of a chemical, the emphasis is on solving the problem. A key concept in SFRA is that initiation is detection of a “signal of harm”. This should be followed by a dialogue between risk assessors and risk managers of possible solutions. Finkel envisages that this would require broadening risk assessment from how it is currently practiced, to include consideration of issues such as options appraisal and cost-benefit. Goldstein sees advantages to SRFA, at least conceptually, but he does have some concerns. Amongst these is how much of a departure is SRFA from current practice. Is the distinction more semantic that implementation? In recent years there has been increasing focus on formalising problem formulation, which is an aspect of risk management, involving dialogue with risk assessors. Hence, problem formulation reflects a key element of SRFA. A second significant issue is what is a “signal of harm”? As Goldstein points out, this is not well defined by Finkel. This a critical issue, as a “signal of harm” can be used to justify application of the precautionary principle. Goldstein also expresses a word of caution about the sources of such “signals of harm” and is of the view that much descriptive epidemiology is not in itself suitable for this purpose, despite those who would argue otherwise. In this respect, toxicology has an important role to play in establishing causation. Goldstein is cautiously optimistic about the value of SRFA, but is concerned that in supporting the approach, it would be unfortunate to conclude that current risk assessment is not playing an important role in public health protection. Overall, Goldstein is appealing for a more transparent approach to risk analysis, with a broader consideration of potential options, in addition to traditional risk reduction by managing exposure. Over time, risk assessment has shifted from establishing relationships between exposure to a single chemical and a resulting adverse health outcome, to evaluation of multiple chemicals and disease outcomes simultaneously. As a result, there is an increasing need to better understand the complex mechanisms that influence risk of chemical and non-chemical stressors, beginning at their source and ending at a biological endpoint relevant to human or ecosystem health risk assessment. As reviewed by Tan et al , just as the Adverse Outcome Pathway (AOP) framework has emerged as a means of providing insight into mechanism-based toxicity, the exposure science community has seen the recent introduction of the Aggregate Exposure Pathway (AEP) framework. AEPs aid in making exposure data applicable to the FAIR (i.e., findable, accessible, interoperable, and reusable) principle, especially by (1) organizing continuous flow of disjointed exposure information; (2) identifying data gaps, to focus resources on acquiring the most relevant data; (3) optimizing use and repurposing of existing exposure data; and (4) facilitating interoperability among predictive models. Herein, Tan et al discuss integration of the AOP and AEP frameworks and how such integration can improve confidence in both traditional and cumulative risk assessment approaches. Human health is threatened by exposure to reactive toxins that can damage fundamental biomolecules such as DNA and proteins. One of these molecules is formaldehyde, the simplest and one of the most reactive aldehydes. Despite the fact that it is 150 years since formaldehyde was discovered, there is still much to learn about its biology and toxicology. This is highlighted by Pontel in his review of recent advances in our understanding of the sources, biology and adverse effects of formaldehyde. Formaldehyde is ubiquitous in the environment and can be derived from some food components. However, as Pontel points out, a great burden of formaldehyde is also generated endogenously. Numerous pathways can lead to the formation of formaldehyde, as a product of intermediary metabolism. To counteract this reactive molecule, organisms have evolved a detoxification system centered on the enzyme alcohol dehydrogenase 5 (ADH5). This system converts formaldehyde to formate, a less reactive molecule that plays a role in the 1C cycle, such as in nucleotide biosynthesis. Whilst formaldehyde is an obligate and necessary intermediate in intermediary metabolism, recent work has shown that it is produced at sufficient levels to pose a significant threat to genome stability. Hence, as Pontel explains in his paper, genetic abnormalities in detoxification pathways can lead to a number of adverse effects on human health, depending on the pathway affected. The Fanconi Anemia (FA) DNA repair pathway guarantees additional protection against formaldehyde by alleviating DNA damage. Indeed, the simultaneous inactivation of both ADH5 and the FA-DNA repair pathway in mice leads to dysfunction of vital organs and cancer. These findings suggest that formaldehyde might be a driver of the human disease FA. Additional work also links this genotoxin to the etiology of other human illnesses, such as the Ruijs-Aalfs syndrome and the cancer predisposition of BRCA2 mutation carriers. Pontel discusses how greater insight into the role of formaldehyde in these conditions can provide strategies for therapeutic intervention. These might involve reducing formaldehyde levels, for example in Fanconi Anemia, but could also involve capitalising on the cytotoxicity of formaldehyde, in some types of cancer, such as BRCA-deficient tumors. Pontel's review of the role of endogenous formaldehyde in human disease, provides an example of how increased understanding of fundamental biology and the genetic bases of human disease can provide powerful insights into the effects of exogenous chemicals. Such studies can inform risk assessment by characterising the range of human tolerance to reactive chemicals, help put into perspective the potential effects of exogenous exposures and enable susceptible sub-populations to be identified. The adverse outcome pathway (AOP) framework serves as a knowledge assembly, interpretation, and communication tool designed to support the translation of pathway-specific mechanistic data into responses relevant to assessing and managing risks of chemicals to human health and the environment. As such, AOPs facilitate the use of data streams often not employed by risk assessors, including information from in silico models, in vitro assays and short-term in vivo tests with molecular/biochemical endpoints. This translational capability can increase the capacity and efficiency of safety assessments both for single chemicals and chemical mixtures. The mini-review by Ankley & Edwards describes the conceptual basis of the AOP framework and aspects of its current status relative to use by toxicologists and risk assessors, including four illustrative applications of the framework to diverse assessment scenarios. This issue of CoT illustrates some of the exciting advances, both scientific and conceptual, that are, or have the potential, to impact on chemical risk assessment. However, as a number of the experts contributing to this volume point out, just because something is new does not necessarily mean that it is better. At the very least, its fitness-for-purpose needs to be assessed. Will it replace existing practice or supplement it? What else needs to change to accommodate its adoption into the conduct of risk assessment. We hope that these papers will stimulate discussion and provide at least some examples of where there are real opportunities to improve risk assessment. Alan Boobis is Professor of Toxicology (part-time), Imperial College London. He retired from his substantive position at the College in June 2017, after over 40 years. His main research interests lie in mechanistic toxicology, drug metabolism and chemical risk assessment. He has published 250 research papers (H-factor 80). He is a member of several advisory committees, including the UK Committee on Toxicity (chair), the WHO Study Group on Tobacco Product Regulation (TobReg), FAO/WHO JECFA (veterinary residues – previous chair) and FAO/WHO JMPR (pesticide residues – previous chair). He has received a number of fellowships and awards, including the civilian award of Officer of the British Empire (OBE). Dr. Stephen H. Safe is a Distinguished Professor of Veterinary Physiology and Pharmacology and of Biochemistry and Biophysics. He holds the Sid Kyle Chair in Toxicology. He received his BSc and MSc from Queen's University in 1962 and 1963, respectively. He obtained his DPhil from Oxford University in 1965. His postdoctoral research was at Oxford University and Harvard University from 1966 to 1968. Safe joined the faculty at Texas A&M University in 1981. He has been with the Institute of Biosciences & Technology at Texas A&M Health Science Center since 2002 where he is the Director of the Center for Translational Environmental Health Research. He became a joint faculty member in the Department of Molecular & Cellular Medicine in 2009. William Farland is an independent consultant in environmental and public health, and a Professor Emeritus in Environmental and Radiological Health Sciences, School of Veterinary Medicine and Biomedical Sciences, Colorado State University. Formerly, Dr. Farland served as Vice President for Research from 2006 to 2013. Dr. Farland served as Deputy Assistant Administrator for Science in the U.S. Environmental Protection Agency's Office of Research and Development (ORD) from 2001 to 2006. Dr. Farland's 27-year federal career was characterized by a commitment to the development of national and international approaches to research, testing and assessment of the fate and effects of environmental agents. Dr. Farland holds a Ph.D. (1976) from UCLA in cell biology and biochemistry. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2018/6

Y1 - 2018/6

UR - http://www.scopus.com/inward/record.url?scp=85057161263&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057161263&partnerID=8YFLogxK

U2 - 10.1016/j.cotox.2018.11.001

DO - 10.1016/j.cotox.2018.11.001

M3 - Editorial

AN - SCOPUS:85057161263

VL - 9

SP - iii-v

JO - Current Opinion in Toxicology

JF - Current Opinion in Toxicology

SN - 2468-2020

ER -