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
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
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.
Tackling the toxics in plastics packaging
The widespread use of plastic packaging for storing, transporting, and conveniently preparing or serving foodstuffs is significantly contributing to the global plastic pollution crisis. This has led to many efforts directed toward amending plastic packaging’s end of life, such as recycling, or alternative material approaches, like increasingly using paper for food packaging. But these approaches often neglect the critical issue of chemical migration: When contacting foodstuffs, chemicals that are present in packaging transfer into food and thus unwittingly become part of the human diet. Hazardous chemicals, such as endocrine disrupters, carcinogens, or substances that bioaccumulate, are collectively referred to as “chemicals of concern.” They can transfer from plastic packaging into food, together with other unknown or toxicologically uncharacterized chemicals. This chemical transfer is scientifically undisputed and makes plastic packaging a known, and avoidable, source of human exposure to synthetic, hazardous, and untested chemicals. Here, I discuss this issue and highlight aspects in need of improvement, namely the way that chemicals present in food packaging are assessed for toxicity. Further, I provide an outlook on how chemical contamination from food packaging could be addressed in the future. Robust innovations must attempt systemic change and tackle the issue of plastic pollution and chemical migration in a way that integrates all existing knowledge.
Overview of intentionally used food contact chemicals and their hazards
Food contact materials (FCMs) are used to make food contact articles (FCAs) that come into contact with food and beverages during, e.g., processing, storing, packaging, or consumption. FCMs/FCAs can cause chemical contamination of food when migration of their chemical constituents (known as food contact chemicals, FCCs) occurs. Some FCCs are known to be hazardous. However, the total extent of exposure to FCCs, as well as their health and environmental effects, remain unknown, because information on chemical structures, use patterns, migration potential, and health effects of FCCs is often absent or scattered across multiple sources. Therefore, we initiated a research project to systematically collect, analyze, and publicly share information on FCCs. As a first step, we compiled a database of intentionally added food contact chemicals (FCCdb), presented here. The FCCdb lists 12′285 substances that could possibly be used worldwide to make FCMs/FCAs, identified based on 67 FCC lists from publicly available sources, such as regulatory lists and industry inventories. We further explored FCCdb chemicals’ hazards using several authoritative sources of hazard information, including (i) classifications for health and environmental hazards under the globally harmonized system for classification and labeling of chemicals (GHS), (ii) the identification of chemicals of concern due to endocrine disruption or persistence related hazards, and (iii) the inclusion on selected EU- or US-relevant regulatory lists of hazardous chemicals. This analysis prioritized 608 hazardous FCCs for further assessment and substitution in FCMs/FCAs. Evaluation based on non-authoritative, predictive hazard data (e.g., by in silico modeling or literature analysis) highlighted an additional 1411 FCCdb substances that could thus present similar levels of concern, but have not been officially classified so far. Lastly, for over a quarter of all FCCdb chemicals no hazard information could be found in the sources consulted, revealing a significant data gap and research need.
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.
Overview of known plastic packaging-associated chemicals and their hazards
Global plastics production has reached 380 million metric tons in 2015, with around 40% used for packaging. Plastic packaging is diverse and made of multiple polymers and numerous additives, along with other components, such as adhesives or coatings. Further, packaging can contain residues from substances used during manufacturing, such as solvents, along with non-intentionally added substances (NIAS), such as impurities, oligomers, or degradation products. To characterize risks from chemicals potentially released during manufacturing, use, disposal, and/or recycling of packaging, comprehensive information on all chemicals involved is needed. Here, we present a database of Chemicals associated with Plastic Packaging (CPPdb), which includes chemicals used during manufacturing and/or present in final packaging articles. The CPPdb lists 906 chemicals likely associated with plastic packaging and 3377 substances that are possibly associated. Of the 906 chemicals likely associated with plastic packaging, 63 rank highest for human health hazards and 68 for environmental hazards according to the harmonized hazard classifications assigned by the European Chemicals Agency within the Classification, Labeling and Packaging (CLP) regulation implementing the United Nations' Globally Harmonized System (GHS). Further, 7 of the 906 substances are classified in the European Union as persistent, bioaccumulative, and toxic (PBT), or very persistent, very bioaccumulative (vPvB), and 15 as endocrine disrupting chemicals (EDC). Thirty-four of the 906 chemicals are also recognized as EDC or potential EDC in the recent EDC report by the United Nations Environment Programme. The identified hazardous chemicals are used in plastics as monomers, intermediates, solvents, surfactants, plasticizers, stabilizers, biocides, flame retardants, accelerators, and colorants, among other functions. Our work was challenged by a lack of transparency and incompleteness of publicly available information on both the use and toxicity of numerous substances. The most hazardous chemicals identified here should be assessed in detail as potential candidates for substitution.
Reference: “Database of chemicals associated with Plastic Packaging (CPPdb).” DOI: 10.5281/zenodo.1287773
Food packaging in the circular economy: Overview of chemical safety aspects for commonly used materials
Food packaging facilitates storage, handling, transport, and preservation of food and is essential for preventing food waste. Besides these beneficial properties, food packaging causes rising concern for the environment
due to its high production volume, often short usage time, and problems related to waste management and littering. Reduction, reuse, and recycling, but also redesign support the aims of the circular economy. These
tools also have the potential to decrease the environmental impact of food packaging. In this article, we focus on chemical safety aspects of recycled food packaging, as recycling is currently seen as an important measure to manage packaging waste. However, recycling may increase the levels of potentially hazardous chemicals in the packaging and -after migration- in the food. Since exposure to certain chemicals migrating from food packaging has been associated with chronic diseases, it is of high importance to assess the safety of recycled packaging. Therefore, we describe recycling processes of commonly used food packaging materials, including plastics, paper and board, aluminum, steel, and multimaterial multilayers (e.g., beverage cartons). Further, we give an overview of typical migrants from all types of recycled food packaging materials, and summarize approaches to reduce chemical contamination. We discuss the role of food packaging in the circular economy, where recycling is only one of many complementary tools for providing environmentally-friendly and safe food packaging.
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.
Food contact materials and gut health: Implications for toxicity assessment and relevance of high molecular weight migrants
Gut health is determined by an intact epithelial barrier and balanced gut microbiota, both involved in the regulation of immune responses in the gut. Disruption of this system contributes to the etiology of various non-communicable diseases, including intestinal, metabolic, and autoimmune disorders. Studies suggest that some direct food additives, but also some food contaminants, such as pesticide residues and substances migrating from food contact materials (FCMs), may adversely affect the gut barrier or gut microbiota. Here, we focus on gut-related effects of FCM-relevant substances (e.g. surfactants, N-ring containing substances, nanoparticles, and antimicrobials) and show that gut health is an underappreciated target in the toxicity assessment of FCMs. Understanding FCMs’ impact on gut health requires more attention to ensure safety and prevent gut-related chronic diseases. Our review further points to the existence of large population subgroups with an increased intestinal permeability; this may lead to higher uptake of compounds of not only low (<1000 Da) but also high (>1000 Da) molecular weight. We discuss the potential toxicological relevance of high molecular weight compounds in the gut and suggest that the scientific justification for the application of a molecular weight-based cut-off in risk assessment of FCMs should be reevaluated.
In vitro toxicity testing of food contact materials: State-of-the-art and future challenges
- Published article DOI: 10.1111/1541-4337.12280
Currently, toxicological testing of food contact materials (FCMs) is focused on single substances and their genotoxicity. However, people are exposed to mixtures of chemicals migrating from food contact articles (FCAs) into food, and toxic effects other than genotoxic damage may also be relevant. Since FCMs can be made of more than 8 thousand substances, assessing them one-by-one is very resource-consuming. Moreover, finished FCAs usually contain non-intentionally added substances (NIAS). NIAS toxicity can only be tested if a substance’s chemical identity is known and if it is available as a pure chemical. Often, this is not the case. Nonetheless, regulations require safety assessments for all substances migrating from FCAs, including NIAS, hence new approaches to meet this legal obligation are needed. Testing the overall migrate or extract from an FCM/FCA is an option. Ideally, such an assessment would be performed by means of in vitro bioassays, as they are rapid and cost-effective. Here, we review the studies using in vitro bioassays to test toxicity of FCMs/FCAs. Three main categories of in vitro assays that have been applied include assays for cytotoxicity, genotoxicity, and endocrine disruption potential. In addition, we reviewed studies with small multicellular animal-based bioassays. Our overview shows that in vitro testing of FCMs is in principle feasible. We discuss future research needs and FCM-specific challenges. Sample preparation procedures need to be optimized and standardized. Further, the array of in vitro tests should be expanded to include those of highest relevance for the most prevalent human diseases of concern.
Substances of very high concern in food contact materials: Migration and regulatory background
Food contact materials (FCMs) are needed to produce, transport, process and store our food. Although essential for handling and protecting food from farm to fork, FCMs are often not inert, and chemical components may partition into food. In Europe, FCMs are regulated under the FCM Framework Regulation 1935/2004 which covers their effects on human health. Environmental effects of FCM substances are included in the scope of the European Chemicals Regulation [Regulation (EC) No 1907/2006 on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)] which aims at substituting Substances of Very High Concern (SVHCs) by safer alternatives. In this study, we focus on 10 FCM substances that are SVHCs and already included in the authorization list of REACH (Annex XIV): We show their possible application in the manufacture of FCMs and give evidence or highlight the absence thereof for migration into food or food simulants. An overview on migration of four phthalates (diisobutyl phthalate, dibutyl phthalate, benzyl butyl phthalate and bis(2-ethylhexyl) phthalate) and 4,4′-methylenedianiline from FCMs is provided, based on peer-reviewed studies and notifications from the Rapid Alert System for Food and Feed. Different approaches in evaluating and handling SVHCs under REACH and the European FCM legislation are discussed, and recommendations on how to increase the safety of FCMs are included. Combining better enforcement, an explicit ban of SVHCs without specific authorization for use in FCMs, and re-evaluations of previously authorized FCM substances could lead to safer FCMs. In conclusion, a harmonization between REACH and European FCM legislation is desirable for improving legal certainty for FCM users as well as in the interest of public health.