Out of balance: conflicts of interest persist in food chemicals determined to be generally recognized as safe.

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.

A vision for safer food contact materials: Public health concerns as drivers for improved testing.

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.

The regulation of endocrine-disrupting chemicals to minimize their impact on health.

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.

Characterization of a new polymeric food contact coating with emphasis on the chemical analysis and safety assessment of non-intentionally added substances (NIAS).

Regulators have established safety requirements for food packaging raw materials and finished products, including by-products of polymer synthesis known as non-intentionally added substances (NIAS). However, there are no official guidance or regulations for best practices to evaluate the safety of NIAS. Here we described the process we followed to identify, characterize, and prioritize for safety assessment low molecular weight NIAS from an epoxy coating (V70) made with tetramethyl bisphenol F-based diglycidyl ether resin (TMBPF-DGE). We assembled a database of 15000 potential oligomers with masses up to 1000 Da and conducted extraction and migration testing of V70 coating. Acetonitrile extract contained higher number and concentration of substances compared to ethanolic-based food simulants. The extract contained 16 substances with matches in the database with estimated concentration of 18.27 µg/6 dm2; seven of these substances have potentially genotoxic oxirane functionality. TMBPF-DGE + hydroquinone (TMBPF-DGE + HQ) was most abundant (55% of total concentration) and was synthesized and prioritized for safety assessment. TMBPF-DGE + HQ exposure from can beverage was estimated at 5.2 µg/person/day, and it was not mutagenic or genotoxic in in vitro assays. The overall mixture of substances that migrated into ethanolic simulant was also negative in the mutagenicity bioassay. Our findings suggest that exposure to TMBPF-DGE + HQ from the V70 coating is exceedingly small and that the coating migrates are not genotoxic.

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.

Advancing the science on chemical classes.

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).

Systematic evidence on migrating and extractable food contact chemicals: Most chemicals detected in food contact materials are not listed for use.

Food packaging is important for today's globalized food system, but food contact materials (FCMs) can also be a source of hazardous chemicals migrating into foodstuffs. Assessing the impacts of FCMs on human health requires a comprehensive identification of the chemicals they contain, the food contact chemicals (FCCs). We systematically compiled the "database on migrating and extractable food contact chemicals" (FCCmigex) using information from 1210 studies. We found that to date 2881 FCCs have been detected, in a total of six FCM groups (Plastics, Paper & Board, Metal, Multi-materials, Glass & Ceramic, and Other FCMs). 65% of these detected FCCs were previously not known to be used in FCMs. Conversely, of the more than 12'000 FCCs known to be used, only 1013 are included in the FCCmigex database. Plastic is the most studied FCM with 1975 FCCs detected. Our findings expand the universe of known FCCs to 14,153 chemicals. This knowledge contributes to developing non-hazardous FCMs that lead to safer food and support a circular economy.

Failure to Launch: The Endocrine Disruptor Screening Program at the U.S. Environmental Protection Agency.

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.

Diet quality and exposure to endocrine-disrupting chemicals among US adults.

Human exposure to endocrine-disrupting chemicals (EDCs) may increase risk for chronic disease. Diet is a significant source of EDC exposure, yet healthy diets recommended for chronic disease prevention have not been thoroughly examined for associations with EDC exposure. Using data from the National Health and Nutrition Examination Survey 2013-2016, we examined associations of dietary patterns with exposure to non-persistent EDCs potentially consumed through diet. EDCs were measured in spot urine samples. Diet was assessed using 24-h recalls. Multivariable linear regression was used to examine associations of three healthy diet scores [Healthy Eating Index (HEI), relative Mediterranean Diet (rMED), and Dietary Approaches to Stop Hypertension] and fast-food consumption with EDCs. In fully adjusted models, no diet was associated with exposure to the bisphenols, phthalates, or polycyclic aromatic hydrocarbons examined. A 1-point increase in rMED (of 18 possible points) was associated with 2.7% (95% CI: 1.7%, 3.8%) greater urinary nitrate. A 10-point increase in HEI (of 100 possible points) was associated with 5.3% (95% CI: 2.8%, 7.9%) greater nitrate and 6.8% (95% CI: 4.5%, 9.2%) greater perchlorate. Because perchlorate and nitrate can disrupt thyroid hormone production, we conducted an exploratory analysis to examine whether these chemicals mediate an association between diet and thyroid hormones. A 10-point increase in HEI was associated with 0.6% reduced serum total thyroxine (95% CI: 1.7%, 0.5%) among all adults, with 57.5% of the effect explained by perchlorate. Nitrate mediated an association of rMED with modestly reduced total triiodothyronine among females. Most EDCs examined had no association with the diets evaluated, indicating that recommended healthy diets were not protective against EDC exposures. As observed with two thyroid antagonists, some recommended diets may increase EDC exposures and related adverse health outcomes. Additional work should identify effective food production and processing practices to reduce dietary exposures to potentially harmful EDCs.

Role of epidemiology in risk assessment: a case study of five ortho-phthalates.

BACKGROUND: The association between environmental chemical exposures and chronic diseases is of increasing concern. Chemical risk assessment relies heavily on pre-market toxicity testing to identify safe levels of exposure, often known as reference doses (RfD), expected to be protective of human health. Although some RfDs have been reassessed in light of new hazard information, it is not a common practice. Continuous surveillance of animal and human data, both in terms of exposures and associated health outcomes, could provide valuable information to risk assessors and regulators. Using ortho-phthalates as case study, we asked whether RfDs deduced from male reproductive toxicity studies and set by traditional regulatory toxicology approaches sufficiently protect the population for other health outcomes. METHODS: We searched for epidemiological studies on benzyl butyl phthalate (BBP), diisobutyl phthalate (DIBP), dibutyl phthalate (DBP), dicyclohexyl phthalate (DCHP), and bis(2-ethylhexyl) phthalate (DEHP). Data were extracted from studies where any of the five chemicals or their metabolites were measured and showed a statistically significant association with a health outcome; 38 studies met the criteria. We estimated intake for each phthalate from urinary metabolite concentration and compared estimated intake ranges associated with health endpoints to each phthalate's RfD. RESULT: For DBP, DIBP, and BBP, the estimated intake ranges significantly associated with health endpoints were all below their individual RfDs. For DEHP, the intake range included associations at levels both below and above its RfD. For DCHP, no relevant studies could be identified. The significantly affected endpoints revealed by our analysis include metabolic, neurodevelopmental and behavioral disorders, obesity, and changes in hormone levels. Most of these conditions are not routinely evaluated in animal testing employed in regulatory toxicology. CONCLUSION: We conclude that for DBP, DIBP, BBP, and DEHP current RfDs estimated based on male reproductive toxicity may not be sufficiently protective of other health effects. Thus, a new approach is needed where post-market exposures, epidemiological and clinical data are systematically reviewed to ensure adequate health protection.

Impacts of food contact chemicals on human health: a consensus statement.

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.

Scientific Basis for Managing PFAS as a Chemical Class.

This commentary presents a scientific basis for managing as one chemical class the thousands of chemicals known as PFAS (per- and polyfluoroalkyl substances). The class includes perfluoroalkyl acids, perfluoroalkylether acids, and their precursors; fluoropolymers and perfluoropolyethers; and other PFAS. The basis for the class approach is presented in relation to their physicochemical, environmental, and toxicological properties. Specifically, the high persistence, accumulation potential, and/or hazards (known and potential) of PFAS studied to date warrant treating all PFAS as a single class. Examples are provided of how some PFAS are being regulated and how some businesses are avoiding all PFAS in their products and purchasing decisions. We conclude with options for how governments and industry can apply the class-based approach, emphasizing the importance of eliminating non-essential uses of PFAS, and further developing safer alternatives and methods to remove existing PFAS from the environment.

An expanded toxicological profile of tetramethyl bisphenol F (TMBPF), a precursor for a new food-contact metal packaging coating.

Tetramethyl bisphenol F (TMBPF) has been shown to impart unique physical properties critical for high performance of epoxy can coatings without the estrogenic activity concerns associated with other bisphenols. To further characterize the toxicological profile of TMBPF, additional endocrine-related endpoints including in vitro aromatase inhibition and steroidogenesis assays, and in vivo androgen agonism/antagonism were performed. Systemic toxicity was also assessed by a repeat dose 90-day dietary toxicity study followed by 28-day recovery period. TMBPF did not inhibit aromatase activity, and induced estradiol and testosterone at highest non-cytotoxic concentrations (10 µM) in the steroidogenesis assay. In the Hershberger assay, TMBPF showed no androgenic activity at any dose and equivocal anti-androgenic activity at the highest dose (1000 mg/kg-bw/d). In a 90-day dietary toxicity study with 28-day recovery period, observations including changes in clinical pathology, absolute and relative organ weights, and microscopic findings are discussed. In this current study, the no observed adverse effect level was considered to be 750 mg/kg-bw/d for female rats and 1000 mg/kg-bw/d for male rats with no biologically significant changes to endocrine endpoints at any dose level. Our findings provide further evidence that TMBPF is a low-toxicity substance with a toxicology profile distinct from some other bisphenols.

We are what we eat: Regulatory gaps in the United States that put our health at risk.

The American diet has changed dramatically since 1958, when Congress gave the United States Food and Drug Administration (FDA) the authority to ensure the safety of chemicals in food. Since then, thousands of chemicals have entered the food system. Yet their long-term, chronic effects have been woefully understudied, their health risks inadequately assessed. The FDA has been sluggish in considering scientific knowledge about the impact of exposures-particularly at low levels and during susceptible developmental stages. The agency's failure to adequately account for the risks of perchlorate-a well-characterized endocrine-disrupting chemical-to vulnerable populations is representative of systemic problems plaguing the regulation of chemicals in food. Today, we are faced with a regulatory system that, weakened by decades of limited resources, has fallen short of fully enforcing its mandates. The FDA's inability to effectively manage the safety of hundreds of chemicals is putting our children's health at risk.

Scientific Challenges in the Risk Assessment of Food Contact Materials.

BACKGROUND: Food contact articles (FCAs) are manufactured from food contact materials (FCMs) that include plastics, paper, metal, glass, and printing inks. Chemicals can migrate from FCAs into food during storage, processing, and transportation. Food contact materials' safety is evaluated using chemical risk assessment (RA). Several challenges to the RA of FCAs exist. OBJECTIVES: We review regulatory requirements for RA of FCMs in the United States and Europe, identify gaps in RA, and highlight opportunities for improving the protection of public health. We intend to initiate a discussion in the wider scientific community to enhance the safety of food contact articles. DISCUSSION: Based on our evaluation of the evidence, we conclude that current regulations are insufficient for addressing chemical exposures from FCAs. RA currently focuses on monomers and additives used in the manufacture of products, but it does not cover all substances formed in the production processes. Several factors hamper effective RA for many FCMs, including a lack of information on chemical identity, inadequate assessment of hazardous properties, and missing exposure data. Companies make decisions about the safety of some food contact chemicals (FCCs) without review by public authorities. Some chemical migration limits cannot be enforced because analytical standards are unavailable. CONCLUSION: We think that exposures to hazardous substances migrating from FCAs require more attention. We recommend a) limiting the number and types of chemicals authorized for manufacture and b) developing novel approaches for assessing the safety of chemicals in FCAs, including unidentified chemicals that form during or after production. https://doi.org/10.1289/EHP644.

Evidence of Absence: Estrogenicity Assessment of a New Food-Contact Coating and the Bisphenol Used in Its Synthesis.

Consumer concerns about exposure to substances found in food contact materials with estrogenic activity (EA) have created substantial demand for alternatives. We assessed the potential EA of both a new bisphenol monomer used to synthesize polymeric coatings for metal food-contact applications and the nonintentionally added substances (NIAS) that may migrate into food. We evaluated tetramethyl bisphenol F (TMBPF) using in vitro and in vivo assays. We extracted the polymeric coating using food simulants ethanol (50% v/v) and acetic acid (3% w/v) and measured migration using tandem liquid chromatography (LC)/mass spectrometry (MS) and LC time-of-flight MS for TMBPF and NIAS, respectively. We also tested migrants for EA using the E-SCREEN assay. TMBPF did not show estrogenic activity in the uterotrophic assay and did not alter puberty in male and female rats or mammary gland development in female rats. Neither TMBPF nor the migrants from the final polymeric coating increased proliferation of estrogen-sensitive MCF7 cells. TMBPF did not show estrogen-agonist or antagonist activity in the estrogen receptor-transactivation assay. TMBPF migration was below the 0.2 parts per billion detection limit. Our findings provide compelling evidence for the absence of EA by TMBPF and the polymeric coating derived from it and that human exposure to TMBPF would be negligible.

Perchlorate and Diet: Human Exposures, Risks, and Mitigation Strategies.

Perchlorate is an endocrine-disrupting chemical that interferes with the normal functioning of the thyroid gland. Maternal thyroid dysfunction during gestation may alter fetal brain development. Perchlorate contamination is widespread: it is present in the body of all Americans tested and the majority of foods tested. The main sources of food contamination appear to be hypochlorite bleach, a disinfectant and sanitizer, that when poorly managed quickly degrades to perchlorate and perchlorate-laden plastic food packaging for dry food or localized contamination from manufacturing or processing of the chemical. Eliminating perchlorate from food packaging and improving bleach management, such as reducing concentration and storage time and temperature, would result in reduced perchlorate contamination of food and water.

Brain drain: the cost of neglected responsibilities in evaluating cumulative effects of environmental chemicals.

Developmental disabilities affect millions of people and have a great impact on their lives, their families and the societies where they live. The prevalence of disorders such as autism, attention deficit hyperactivity disorder as well as subclinical decrements in brain function cannot be explained solely as genetic diseases. Exposures to environmental chemicals, especially during prenatal and early postnatal life, are one likely explanation for some of the decrements. The current chemical risk assessment approach is typically based on the toxicity caused by a single chemical on a variety of organs without acknowledging additional exposures to other chemicals also affecting the same organ or system. We identified more than 300 chemicals allowed in food that may have potential harmful effects on the developing brain. Each individual chemical may or may not have a harmful effect if it were the only one present, but we know next to nothing about their cumulative biological effects on the brain. An expanded cumulative risk assessment approach is needed, and it should focus on health outcomes, like developmental disabilities, arising from the accumulation of effects of multiple chemicals on the brain. The laws regulating the safety of additives already require that regulators in Europe and the USA consider cumulative effects; so far, they seem to have neglected the mandate. We must move beyond treating chemical exposures as isolated incidents and look at their cumulative biological effects on organs and their role in the onset of chronic diseases. The time has come to overhaul chemical risk assessment.