Maricel V. Maffini

In the United States, regulatory agencies have approved tens of thousands of chemicals for uses ranging from agricultural and industrial purposes, in food and personal care products, and in other consumer goods (Wang et al., 2020). For many of these chemicals, exposures to human populations are ubiquitous. Many of them have been allowed to be used with little or no scrutiny from regulatory agencies. Using food as an example, less than 40% of the chemicals the US Food and Drug Administration has allowed to be included in Americans' diets have enough data to estimate the amount that would be safe for the public to ingest (Neltner et al., 2013); the vast majority of chemicals allowed in food lack reproductive or developmental toxicity data.The presence of these chemicals in the bodies of people, combined with the adverse effects they cause in controlled animal studies, as well as their association with adverse health outcomes in human populations, suggest that the approaches used to protect public health from hazardous chemicals are insufficient for these purposes (Maffini and Vandenberg, 2017). There are failures in the testing strategies used to evaluate chemicals, the analysis of hazard data by regulatory agencies (Sass et al., 2024), as well as the approaches used to manage risks (Maffini and Vandenberg, 2024) .Numerous emerging topics on chemical safety assessment need attention from the scientific community, regulators, and the regulated industries. These include:Better use of available hazard assessment data: The mammary gland is sensitive to chemical exposures; however, the organ is rarely analyzed properly in regulatory toxicology testing (Kay et al., 2022). A recent study found 76 potential breast carcinogens migrating from food contact materials sold globally (Parkinson et al., 2024) . Science-based policy amendments addressing weaknesses in hazard assessment could be an opportunity for breast cancer prevention.The endpoints commonly measured in conventional toxicology have not kept up with scientific advances. These can include the tools used to measure epigenetic modifications induced by chemical exposures, effects of pollutants on the microbiome, outcomes relevant to endocrine disruption, and complex neurobehavioral outcomes associated with human conditions such as autism spectrum disorder. It should not be assumed that mechanistic data are not also evidence for adversity. For example, developmental exposure to glyphosate and glyphosate-based herbicides contributed to failed embryonic implantation through a mechanism likely to involve genetic and epigenetic modifications in the uterus (Lorenz et al., 2024) .Improving exposure assessments and environmental monitoring: Improving risk assessments and risk management requires more than improved hazard assessment; many updates to exposure assessments are also needed (Vandenberg et al., 2023). In settings where complex chemical mixtures (e.g., pesticides, detergents, disinfection byproducts) are expected, rapid screening techniques could be used to measure discharge pf endocrine active compounds and prevent inadvertent contamination of environmental matrixes (Aneck-Hahn et al., 2024) .The concept of 'essential use' is a decades-old approach to minimize and phase-out toxic chemicals (Protocol, 1987). More recently, the European Commission announced it would apply the same concept that eliminated the use of ozone-depleting chemicals to prioritize for phase-out "the most harmful" chemicals (European Commission: Directorate-General for et al., 2023). An analysis of 100 of ECHA's REACH authorization applications for information needed to qualify substances' uses as "essential" identified major challenges in this categorization including a lack of clear detailed use information and guidance for the applicants (Borchert et al., 2024).One of the critiques of regulatory agencies is that a chemical can be considered too hazardous for use in one sector but allowed for use in other products (e.g., toys vs food). The Globally Harmonized System (GHS) of Classification and Labelling of Chemicals is a useful tool to enhance protections to human health and the environment if they can achieve the aim of "one substance, one assessment". In the European Union, for example, the classification, labeling and packaging of chemicals can be used to improve risk management and chemical regulations (Kättström et al., 2024) . However, even these straightforward approaches need to be continuously improved to avoid ambiguity in how hazard labels are interpreted, and whether self-classification by chemical manufacturers uses appropriate evidence and is consistent between companies. Scientific contributions from many different disciplines and fields have improved our knowledge of the effects chemical exposures have on chronic diseases of increasing concern to human populations. Stalled agencies, under pressure from industry, have halted regulatory progress and allowed exposures to harmful chemicals and pollutants to continue. Conflicts of interest, changes in governmental administrations, and a regulatory ecosystem that is resistant to change are also contributing to the inertia that plagues regulatory toxicology. When regulations fail to protect the public, other remedies can be available, including educational and advocacy campaigns designed to shift consumer behaviors away from the use of hazardous chemicals, citizen petitions to push regulatory agencies to take action, and use of the judicial system to hold both regulatory agencies and polluting industries accountable for their failure to act and the harm they inflict (Maffini and Vandenberg, 2024).Ultimately, the best available scientific evidence must be used to support decision-making by regulatory authorities, and their decisions should be reviewed with the latest and best scientific evidence in mind. Approaches to toxicity testing, exposure assessment, risk assessment, and risk management...

Background: Over 1800 food contact chemicals (FCCs) are known to migrate from food contact articles used to store, process, package, and serve foodstuffs. Many of these FCCs have hazard properties of concern, and still others have never been tested for toxicity. Humans are known to be exposed to FCCs via foods, but the full extent of human exposure to all FCCs is unknown. Objective: To close this important knowledge gap, we conducted a systematic overview of FCCs that have been monitored and detected in human biomonitoring studies according to a previously published protocol. Methods: We first compared the more than 14,000 known FCCs to five biomonitoring programs and three metabolome/exposome databases. In a second step, we prioritized FCCs that have been frequently detected in food contact materials and systematically mapped the available evidence for their presence in humans. Results: For 25% of the known FCCs (3601), we found evidence for their presence in humans. This includes 194 FCCs from human biomonitoring programs, with 80 of these having hazard properties of high concern. Of the 3528 FCCs included in metabolome/exposome databases, most are from the Blood Exposome Database. We found evidence for the presence in humans for 63 of the 175 prioritized FCCs included in the systematic evidence map, and 59 of the prioritized FCCs lack hazard data. Significance: Notwithstanding that there are also other sources of exposure for many FCCs, these data will help to prioritize FCCs of concern by linking information on migration and biomonitoring. Our results on FCCs monitored in humans are available as an interactive dashboard (FCChumon) to enable policymakers, public health researchers, and food industry decision-makers to make food contact materials and articles safer, reduce human exposure to hazardous FCCs and improve public health. Impact statement: We present systematically compiled evidence on human exposure to 3601 food contact chemicals (FCCs) and highlight FCCs that are of concern because of their known hazard properties. Further, we identify relevant data gaps for FCCs found in food contact materials and foods. This article improves the understanding of food contact materials’ contribution to chemical exposure for the human population and highlights opportunities for improving public health.

Manufacturers of chemicals added to food are responsible for determining that the use of their products is safe. There are two major legal definitions of chemicals in food: (1) food additives which includes ingredients and chemicals indirectly entering food from packaging and processing equipment, and (2) generally recognized as safe (GRAS) substances mostly used as ingredients. The law requires food additives to undergo approval by the U.S. Food and Drug Administration (FDA) before they are sold, but it GRAS substances are exempted from pre-market approval. In 1997, FDA created a voluntary program for manufacturers to submit their chemical’s safety determination in the form of a GRAS notice to the agency. Manufacturers make GRAS determinations regardless of whether they voluntarily submit a notice to FDA for review. They rely on their own employees, the employee of a hired consulting firm or a panel of experts, known as GRAS panel, to review the safety information. Because this process determines whether a chemical is safe for use in food, conflicts of interest and biases need to be avoided or minimized to credibly ensure food is safe. Recently, FDA has published guidance for industry on best practices to convene GRAS panels to manage conflicts of interest and reduce biases that have plagued the process. Here, we perform a qualitative assessment of the compliance of GRAS panels with basic elements of FDA’s guidance. We assessed 403 GRAS notices filed by FDA between 2015 and 2020 and identified whether a GRAS panel was convened and by whom, its members, affiliations, and relationships between panelists and panel conveners. Then, we compared FDA’s recommendations against the information included in the notices voluntarily submitted by manufacturers. We found no evidence that GRAS panels have adhered to FDA’s guidance. Panels are populated from a very small pool of professionals; we found that seven panel members alone occupied almost half of all available panel positions and that they often serve together. Against guidance recommendations, ad-hoc panels have been substituted by panels with recurring members in hired consulting firms’ payroll. The widespread persistence of conflicts of interest, appearance of conflict and bias in GRAS determinations continue to put the health of Americans at risk and undermine confidence in the safety of food ingredients in the US market. FDA should require notice for all GRAS determinations including how the financial conflicts of interest of those who make these determinations are minimized.

Endocrine-disrupting chemicals (EDCs) are substances generated by human industrial activities that are detrimental to human health through their effects on the endocrine system. The global societal and economic burden posed by EDCs is substantial. Poorly defined or unenforced policies can increase human exposure to EDCs, thereby contributing to human disease, disability and economic damage. Researchers have shown that policies and interventions implemented at both individual and government levels have the potential to reduce exposure to EDCs. This Review describes a set of evidence-based policy actions to manage, minimize or even eliminate the widespread use of these chemicals and better protect human health and society. A number of specific challenges exist: defining, identifying and prioritizing EDCs; considering the non-linear or non-monotonic properties of EDCs; accounting for EDC exposure effects that are latent and do not appear until later in life; and updating testing paradigms to reflect ‘real-world’ mixtures of chemicals and cumulative exposure. A sound strategy also requires partnering with health-care providers to integrate strategies to prevent EDC exposure in clinical care. Critical next steps include addressing EDCs within global policy frameworks by integrating EDC exposure prevention into emerging climate policy.

Background: Hazard identification, risk assessment, regulatory, and policy activity are usually conducted on a chemical-by-chemical basis. Grouping chemicals into categories or classes is an underutilized approach that could make risk assessment and management of chemicals more efficient for regulators.Objective and methods: While there are some available methods and regulatory frameworks that include the grouping of chemicals (e.g.,same molecular mechanism or similar chemical structure) there has not been a comprehensive evaluation of these different approaches nor a recommended course of action to better consider chemical classes in decision-making. This manuscript: 1) reviews current national and international approaches to grouping; 2) describes how groups could be defined based on the decision context (e.g., hazard/risk assessment, restrictions, prioritization, product development) and scientific considerations (e.g., intrinsic physical-chemical properties); 3) discusses advantages of developing a decision tree approach for grouping; 4) uses ortho-phthalates as a case study to identify and organize frameworks that could be used across agencies; and 5) discusses opportunities to advance the class concept within various regulatory decision-making scenarios.Results: Structural similarity was the most common grouping approach for risk assessment among regulatory agencies (national and state level) and non-regulatory organizations, albeit with some variations in its definition. Toxicity to the same target organ or to the same biological function was also used in a few cases. The phthalates case study showed that a decision tree approach for grouping should include questions about uses regulated by other agencies to encourage more efficient, coherent, and protective chemical risk management.Discussion and conclusion: Our evaluation of how classes of chemicals are defined and used identified commonalities and differences based on regulatory frameworks, risk assessments, and business strategies. We also identified that using a class-based approach could result in a more efficient process to reduce exposures to multiple hazardous chemicals and, ultimately, reduce health risks. We concluded that, in the absence of a prescribed method, a decision tree approach could facilitate the selection of chemicals belonging to a pre-defined class (e.g., chemicals with endocrine-disrupting activity; organohalogen flame retardants [OFR]) based on the decision-making context (e.g., regulatory risk management).

It has been 25 years since the U.S. Congress passed the Food Quality Protection Act of 1996, an amendment to the Food Drug and Cosmetic Act, which mandated that the US Environmental Protection Agency (EPA) test all pesticide chemicals used in food for endocrine disruption. Soon after the law passed, EPA established the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) to provide recommendations to the agency on how its Endocrine Disruptor Screening Program (EDSP) should work. Among them, the committee recommended that EDSP screening should 1) evaluate both human and ecological effects; 2) test for disruption of the estrogen, androgen, and thyroid systems; 3) evaluate pesticide and non-pesticide chemicals; and 4) implement a tiered approach. EPA adopted the recommendations and the EDSP was created in 1998. To date, the EPA has yet to fully implement the law; in other words, it has failed to test all pesticide chemicals for endocrine disruption. Of the small number that have been tested, not a single pesticide chemical has been determined to be an endocrine disruptor, and no regulatory actions have been taken. Here, we review the missed opportunities EPA had to make the EDSP a functional and effective program aimed at protecting human health and the environment. Two reports by the EPA’s Office of Inspector General from 2011 to 2021 provide the framework for our discussion.