A science-based agenda for health-protective chemical assessments and decisions: overview and consensus statement.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Current practice and recommendations for advancing how human variability and susceptibility are considered in chemical risk assessment.

A key element of risk assessment is accounting for the full range of variability in response to environmental exposures. Default dose-response methods typically assume a 10-fold difference in response to chemical exposures between average (healthy) and susceptible humans, despite evidence of wider variability. Experts and authoritative bodies support using advanced techniques to better account for human variability due to factors such as in utero or early life exposure and exposure to multiple environmental, social, and economic stressors.This review describes: 1) sources of human variability and susceptibility in dose-response assessment, 2) existing US frameworks for addressing response variability in risk assessment; 3) key scientific inadequacies necessitating updated methods; 4) improved approaches and opportunities for better use of science; and 5) specific and quantitative recommendations to address evidence and policy needs.Current default adjustment factors do not sufficiently capture human variability in dose-response and thus are inadequate to protect the entire population. Susceptible groups are not appropriately protected under current regulatory guidelines. Emerging tools and data sources that better account for human variability and susceptibility include probabilistic methods, genetically diverse in vivo and in vitro models, and the use of human data to capture underlying risk and/or assess combined effects from chemical and non-chemical stressors.We recommend using updated methods and data to improve consideration of human variability and susceptibility in risk assessment, including the use of increased default human variability factors and separate adjustment factors for capturing age/life stage of development and exposure to multiple chemical and non-chemical stressors. Updated methods would result in greater transparency and protection for susceptible groups, including children, infants, people who are pregnant or nursing, people with disabilities, and those burdened by additional environmental exposures and/or social factors such as poverty and racism.

Conducting evaluations of evidence that are transparent, timely and can lead to health-protective actions.

BACKGROUND: In February 2021, over one hundred scientists and policy experts participated in a web-based Workshop to discuss the ways that divergent evaluations of evidence and scientific uncertainties are used to delay timely protection of human health and the environment from exposures to hazardous agents. The Workshop arose from a previous workshop organized by the European Environment Agency (EEA) in 2008 and which also drew on case studies from the EEA reports on 'Late Lessons from Early Warnings' (2001, 2013). These reports documented dozens of hazardous agents including many chemicals, for which risk reduction measures were delayed for decades after scientists and others had issued early and later warnings about the harm likely to be caused by those agents. RESULTS: Workshop participants used recent case studies including Perfluorooctanoic acid (PFOA), Extremely Low Frequency - Electrical Magnetic Fields (ELF-EMF fields), glyphosate, and Bisphenol A (BPA) to explore myriad reasons for divergent outcomes of evaluations, which has led to delayed and inadequate protection of the public's health. Strategies to overcome these barriers must, therefore, at a minimum include approaches that 1) Make better use of existing data and information, 2) Ensure timeliness, 3) Increase transparency, consistency and minimize bias in evidence evaluations, and 4) Minimize the influence of financial conflicts of interest. CONCLUSION: The recommendations should enhance the production of "actionable evidence," that is, reliable evaluations of the scientific evidence to support timely actions to protect health and environments from exposures to hazardous agents. The recommendations are applicable to policy and regulatory settings at the local, state, federal and international levels.

Response to Toshihide Tsuda, Yumiko Miyano and Eiji Yamamoto [1].

BACKGROUND: In August 2021, we published in Environmental Health a Toolkit for detecting misused epidemiological methods with the goal of providing an organizational framework for transparently evaluating epidemiological studies, a body of evidence, and resultant conclusions. Tsuda et al., the first group to utilize the Toolkit in a systematic fashion, have offered suggestions for its modification. MAIN BODY: Among the suggested modifications made by Tsuda et al., we agree that rearrangement of Part A of the Toolkit to reflect the sequence of the epidemiological study process would facilitate its usefulness. Expansion or adaptation of the Toolkit to other disciplines would be valuable but would require the input of discipline-specific expertise. We caution against using the sections of the Toolkit to produce a tally or cumulative score, because none of the items are weighted as to importance or impact. Rather, we suggest a visual representation of how a study meets the Toolkit items, such as the heat maps used to present risk of bias criteria for studies included in Cochrane reviews. We suggest that the Toolkit be incorporated in the sub-specialty known as "forensic epidemiology," as well as in graduate training curricula, continuing education programs, and conferences, with the recognition that it is an extension of widely accepted ethics guidelines for epidemiological research. CONCLUSION: We welcome feedback from the research community about ways to strengthen the Toolkit as it is applied to a broader assemblage of research studies and disciplines, contributing to its value as a living tool/instrument. The application of the Toolkit by Tsuda et al. exemplifies the usefulness of this framework for transparently evaluating, in a systematic way, epidemiological research, conclusions relating to causation, and policy decisions. POSTSCRIPT: We note that our Toolkit has, most recently, inspired authors with discipline-specific expertise in the field of Conservation Biology to adapt it for use in the Biological Sciences.

Toolkit for detecting misused epidemiological methods.

BACKGROUND: Critical knowledge of what we know about health and disease, risk factors, causation, prevention, and treatment, derives from epidemiology. Unfortunately, its methods and language can be misused and improperly applied. A repertoire of methods, techniques, arguments, and tactics are used by some people to manipulate science, usually in the service of powerful interests, and particularly those with a financial stake related to toxic agents. Such interests work to foment uncertainty, cast doubt, and mislead decision makers by seeding confusion about cause-and-effect relating to population health. We have compiled a toolkit of the methods used by those whose interests are not aligned with the public health sciences. Professional epidemiologists, as well as those who rely on their work, will thereby be more readily equipped to detect bias and flaws resulting from financial conflict-of-interest, improper study design, data collection, analysis, or interpretation, bringing greater clarity-not only to the advancement of knowledge, but, more immediately, to policy debates. METHODS: The summary of techniques used to manipulate epidemiological findings, compiled as part of the 2020 Position Statement of the International Network for Epidemiology in Policy (INEP) entitled Conflict-of-Interest and Disclosure in Epidemiology, has been expanded and further elucidated in this commentary. RESULTS: Some level of uncertainty is inherent in science. However, corrupted and incomplete literature contributes to confuse, foment further uncertainty, and cast doubt about the evidence under consideration. Confusion delays scientific advancement and leads to the inability of policymakers to make changes that, if enacted, would-supported by the body of valid evidence-protect, maintain, and improve public health. An accessible toolkit is provided that brings attention to the misuse of the methods of epidemiology. Its usefulness is as a compendium of what those trained in epidemiology, as well as those reviewing epidemiological studies, should identify methodologically when assessing the transparency and validity of any epidemiological inquiry, evaluation, or argument. The problems resulting from financial conflicting interests and the misuse of scientific methods, in conjunction with the strategies that can be used to safeguard public health against them, apply not only to epidemiologists, but also to other public health professionals. CONCLUSIONS: This novel toolkit is for use in protecting the public. It is provided to assist public health professionals as gatekeepers of their respective specialty and subspecialty disciplines whose mission includes protecting, maintaining, and improving the public's health. It is intended to serve our roles as educators, reviewers, and researchers.

A Cumulative Framework for Identifying Overburdened Populations under the Toxic Substances Control Act: Formaldehyde Case Study.

Extensive scholarship has demonstrated that communities of color, low-income communities, and Indigenous communities face greater environmental and health hazards compared to communities with more White or affluent people. Low-income, Indigenous, Black, and/or other populations of color are also more likely to lack access to health care facilities, healthy food, and adequate formal education opportunities. Despite the mountains of evidence that demonstrate the existence and significance of the elevated toxic social and environmental exposures experienced by these communities, the inclusion of these factors into chemical evaluations has been scarce. In this paper, we demonstrate a process built with publicly available data and simple geospatial techniques that could be utilized by the U.S. Environmental Protection Agency (USEPA) to incorporate cumulative approaches into risk assessments under the Toxic Substances Control Act. The use of these approaches, particularly as they relate to identifying potentially exposed and susceptible subpopulations, would help USEPA develop appropriate risk estimates and mitigation strategies to protect disproportionately burdened populations from the adverse effects of chemical exposures. By utilizing such approaches to inform risk evaluation and mitigation, USEPA can identify and protect those most burdened and impacted by toxic chemicals, and finally begin to close the gap of environmental health inequities.

Organophosphate exposures during pregnancy and child neurodevelopment: Recommendations for essential policy reforms.

In a Policy Forum, Irva Hertz-Picciotto and colleagues review the scientific evidence linking organophosphate pesticides to cognitive, behavioral, and neurological deficits in children and recommend actions to reduce exposures.

Use of a modified GreenScreen tool to conduct a screening-level comparative hazard assessment of conventional silver and two forms of nanosilver.

BACKGROUND: Increased concern for potential health and environmental impacts of chemicals, including nanomaterials, in consumer products is driving demand for greater transparency regarding potential risks. Chemical hazard assessment is a powerful tool to inform product design, development and procurement and has been integrated into alternative assessment frameworks. The extent to which assessment methods originally designed for conventionally-sized materials can be used for nanomaterials, which have size-dependent physical and chemical properties, have not been well established. We contracted with a certified GreenScreen profiler to conduct three GreenScreen hazard assessments, for conventional silver and two forms of nanosilver. The contractor summarized publicly available literature, and used defined GreenScreen hazard criteria and expert judgment to assign and report hazard classification levels, along with indications of confidence in those assignments. Where data were not available, a data gap (DG) was assigned. Using the individual endpoint scores, an aggregated benchmark score (BM) was applied. RESULTS: Conventional silver and low-soluble nanosilver were assigned the highest possible hazard score and a silica-silver nanocomposite called AGS-20 could not be scored due to data gaps. AGS-20 is approved for use as antimicrobials by the US Environmental Protection Agency. CONCLUSIONS: An existing method for chemical hazard assessment and communication can be used - with minor adaptations- to compare hazards across conventional and nano forms of a substance. The differences in data gaps and in hazard profiles support the argument that each silver form should be considered unique and subjected to hazard assessment to inform regulatory decisions and decisions about product design and development. A critical limitation of hazard assessments for nanomaterials is the lack of nano-specific hazard data - where data are available, we demonstrate that existing hazard assessment systems can work. The work is relevant for risk assessors and regulators. We recommend that regulatory agencies and others require more robust data sets on each novel nanomaterial before granting market approval.

Meeting report: hazard assessment for nanoparticles--report from an interdisciplinary workshop.

In this report we present the findings from a nanotoxicology workshop held 6-7 April 2006 at the Woodrow Wilson International Center for Scholars in Washington, DC. Over 2 days, 26 scientists from government, academia, industry, and nonprofit organizations addressed two specific questions: what information is needed to understand the human health impact of engineered nanoparticles and how is this information best obtained? To assess hazards of nanoparticles in the near-term, most participants noted the need to use existing in vivo toxicologic tests because of their greater familiarity and interpretability. For all types of toxicology tests, the best measures of nanoparticle dose need to be determined. Most participants agreed that a standard set of nanoparticles should be validated by laboratories worldwide and made available for benchmarking tests of other newly created nanoparticles. The group concluded that a battery of tests should be developed to uncover particularly hazardous properties. Given the large number of diverse materials, most participants favored a tiered approach. Over the long term, research aimed at developing a mechanistic understanding of the numerous characteristics that influence nanoparticle toxicity was deemed essential. Predicting the potential toxicity of emerging nanoparticles will require hypothesis-driven research that elucidates how physicochemical parameters influence toxic effects on biological systems. Research needs should be determined in the context of the current availability of testing methods for nanoscale particles. Finally, the group identified general policy and strategic opportunities to accelerate the development and implementation of testing protocols and ensure that the information generated is translated effectively for all stakeholders.

Require comprehensive safety data for all chemicals.

Reform No. 5 of the Louisville Charter addresses the pervasive lack of publicly available information about the effects of many chemicals on human health and the environment. This lack of information persists for the majority of chemicals in commerce because the current laws in the United States do not systematically require it to be produced or motivate its voluntary production. These information gaps undermine the effectiveness of the existing environmental statutes, the liability system, the ability of the market to stimulate development of safer chemicals and, if they persist, complete realization of the other elements of the Louisville Charter. Therefore, this Reform calls for manufacturers of chemicals to be required to provide health and safety information as a condition for placing and keeping a chemical on the market.

European Union bans atrazine, while the United States negotiates continued use.

Atrazine is a common agricultural herbicide with endocrine disruptor activity. There is evidence that it interferes with reproduction and development, and may cause cancer. Although the U.S. Environmental Protection Agency (EPA) approved its continued use in October 2003, that same month the European Union (EU) announced a ban of atrazine because of ubiquitous and unpreventable water contamination. The authors reviewed regulatory procedures and government documents, and report efforts by the manufacturer of atrazine, Syngenta, to influence the U.S. atrazine assessment, by submitting flawed scientific data as evidence of no harm, and by meeting repeatedly and privately with EPA to negotiate the government's regulatory approach. Many of the details of these negotiations continue to be withheld from the public, despite EPA regulations and federal open-government laws that require such decisions to be made in the open.