Abstract
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.
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Introduction
Humans are exposed to synthetic chemicals from food, drugs, household and personal care products, and environmental pollutants. Some of these chemicals have been associated with the increasing prevalence of non-communicable diseases [1,2,3]. Food packaging and other food contact articles (FCAs), such as tableware and food processing equipment, contribute to the human chemical burden via oral exposure, because food contact chemicals (FCCs) migrate from different food contact materials (FCMs) into foodstuffs and are then ingested [4,5,6,7,8].
For individual FCCs, such as bisphenol A (BPA) and several phthalates, the contribution of chemical migration from FCMs to human exposure has been studied in detail, taking into account that other exposure sources exist [9,10,11,12]. BPA is banned in some food contact applications, such as baby bottles, in many parts of the world, but is still regularly measured in FCMs (e.g [13,14,15].). Currently, a complete ban on BPA in FCMs is proposed by the European Commission [16]. However, hundreds of FCCs have been shown to migrate from FCMs into foods, and thousands of FCCs have been extracted from FCMs [5]. In total, over 12,000 FCCs could be intentionally used during the manufacturing of different types of FCMs [17] and even more chemicals could be present in FCMs as non-intentionally added substances (NIAS) that are introduced or formed during manufacture or use [5, 18, 19].
Many FCCs are of concern for human health because they have hazard properties such as carcinogenicity, mutagenicity, and reprotoxicity (CMR), endocrine disrupting properties, bioaccumulation potential, and/or persistence [17, 20, 21]. In addition, toxicity data are often incomplete or missing, which means that safe use cannot be assessed [17, 22, 23]. Therefore, reducing exposure to known hazardous FCCs and assessing untested FCCs can contribute to the prevention of non-communicable diseases that are associated with chemical exposures [24, 25].
The challenges in regulating FCMs and managing the health risks associated with FCCs are diverse and legislation often does not keep up with the latest scientific understanding [26, 27]. Publicly available evidence on intentionally used FCCs and their known hazards is available in our earlier work where we compiled the Food Contact Chemicals Database (FCCdb) [17]. The FCCdb gives an overview of all chemicals that are known to be used in the manufacture of FCMs. Further, we systematically mapped data on migrating and extractable FCCs, and our Database on Migrating and Extractable Food Contact Chemicals (FCCmigex) provides evidence for FCCs that have been detected in extracts of FCMs and/or their migrates into food and food simulants, indicating the potential for human exposure [5]. Only 30% of the chemicals present in FCMs are listed in the FCCdb, based on information from the most recent update of the FCCmigex database [28]. This indicates that the non-listed FCCs are either NIAS or have been intentionally used although they are not recorded in any of the FCCdb’s sources. Even though it is well-established that chemicals migrating from FCMs contribute to human exposure, the presence of FCCs in human samples has not yet been systematically assessed.
Here, we provide a systematic overview of FCCs that have been monitored and detected in humans by including information from biomonitoring programs, metabolome and exposome databases, and the primary scientific literature. We detailed our approach in a previously published protocol [29]. The resulting Database on Food Contact Chemicals Monitored in Humans (FCChumon) is a publicly available tool integrating empirical data on FCCs in human samples, and it complements the FCCdb and FCCmigex databases. Our goal is to provide scientific evidence that supports advancing global FCM regulations and the safety assessments of FCCs.
Methods
Overview of the two-step approach
The evidence for FCCs that have been monitored and detected in human samples was compiled according to a protocol initially registered on Zenodo in September 2022 and updated in April 2023 [29]. We followed the structure of a Population-Outcome (PO) question:
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Question: Which known FCCs have been monitored in the human body?
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Population (P): Human samples, such as blood, urine, hair, and breast milk, from people of any age, gender, or ethnicity
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Outcome (O): Any result describing the monitoring/detection of a known FCC or its metabolite
As detailed in the protocol and further specified below, we applied a stepwise approach and referred to biomonitoring programs, databases on the human exposome and metabolome, and the primary scientific literature to map the evidence for FCCs’ presence in humans. Briefly, in step 1, FCCs included in the FCCdb and the FCCmigex databases were matched to the chemicals listed in biomonitoring programs and metabolome and exposome databases (Fig. 1). During protocol development, we found that thousands of FCCs were neither included in the selected metabolome/exposome databases nor in biomonitoring programs, while the primary scientific literature reported the monitoring of some of these FCCs in human samples. In step 2, we therefore applied the methodology of a systematic evidence map to obtain relevant information from the scientific literature. FCCs not found in any of the sources consulted in step 1 were prioritized based on their presence in FCMs, according to evidence from FCCmigex. These prioritized FCCs were included in the systematic evidence mapping performed in step 2 to understand their presence in human samples.
Information sources for chemical comparisons
Together, the FCCdb and the FCCmigex databases presently consist of 14,402 known FCCs with assigned CAS Registry Numbers (Fig. 1). The FCCdb is an inventory for FCCs that are potentially used in the manufacture of FCMs and FCAs [17]. It currently contains 12,285 distinct FCCs of which 11,593 have a CAS Registry Number. The FCCmigex database systematically maps scientific evidence of FCCs that have been measured in FCMs and FCAs [5, 28]. The most recent version of the FCCmigex database contains 4262 chemicals with a CAS Registry Number, of which 3995 FCCs have been detected at least once in an FCM migrate or extract. Each FCCmigex database entry is linked to the reference from which it was generated and provides information about the FCC, what type of FCA and which FCM(s) were tested, details about the experimental set-up, and whether the FCC was detected or not. Chemicals that have been targeted but never detected in FCMs, and that are not in the FCCdb, are not included in this study.
In the first step, we consulted five biomonitoring programs that encompass different ranges of chemicals and provide wide geographic coverage, namely the National Health and Nutrition Examination Survey (NHANES) of the US [30], the Canadian Health Measures Survey (CHMS) [31], the Human Biomonitoring for Europe project (HBM4EU) [32, 33], the Korean National Environmental Health Survey (KoNEHS) [34], and Biomonitoring California [35]. Further, three metabolome/exposome databases were used to identify FCCs that have been monitored in humans: the Human Metabolome Database (HMDB) [36, 37]; the Blood Exposome Database [38, 39], and the Exposome Explorer [40, 41]. In addition to these sources, in the second step we systematically searched the primary scientific literature for human biomonitoring data on specific FCCs, using bibliographic databases (PubMed, Web of Science Core Collection (WoS), ScienceDirect, and CAS SciFindern).
Data processing and comparisons (step 1)
All known FCCs with CAS Registry Numbers were included in the comparisons of step 1, regardless of whether the CAS Registry Number indicates a specific structure or a chemical mixture. If available, additional chemical identifiers, such as INChI Keys and SMILES, were retrieved from the collections of FCCs associated with lists S77 and S112 from the NORMAN Suspect List Exchange [42,43,44].
In step 1A, information on chemicals that are part of any of the biomonitoring programs was downloaded from the respective sources. We also collected information on whether a chemical has been ‘monitored but never detected’ or ‘monitored and detected’. If it was stated in the biomonitoring programs that the analyte was a metabolite of a specific parent compound, we paired the metabolite and the parent compound for comparison with the known FCCs. For example, the analyte mono-ethyl phthalate (CAS 863029-89-4) is listed as a metabolite of di-ethyl phthalate (CAS 84-66-2) in NHANES, and we used both CAS Registry Numbers in the comparisons to the known FCCs. In this way, we ensured that FCCs were identified in the biomonitoring programs regardless of whether detection in human samples was reported for parent compounds or their metabolites. We manually added CAS Registry Numbers to chemicals missing these identifiers in the biomonitoring lists to enable their comparisons to the FCCs.
In step 1B, the data set ‘biomarkers’ was downloaded from the Exposome Explorer, and the full content of the Blood Exposome Database was retrieved. From the HMDB, all chemicals were included that were labeled by metabolite status as ‘detected and quantified’, ‘detected but not quantified’, and ‘expected but not quantified’. The metabolome/exposome databases do not systematically report links between parent compounds and metabolites. We used these chemical lists from the metabolome/exposome databases without any further editing.
Based on their CAS Registry Numbers, InChI Keys, or SMILES identifiers, FCCs were then compared to the chemical lists retrieved from the biomonitoring programs and metabolome/exposome databases. These comparisons were performed by means of Python (v3.10.8) pandas package (v1.5.3).
Systematic evidence mapping (step 2)
Prioritization and grouping of FCCs
In step 2, we focused on the FCCs that were not found in any of the sources of step 1, i.e., all FCCs, or their metabolites, that have never been included in a biomonitoring program (regardless of whether they have been detected or not) and all FCCs that did not generate any match in the metabolome/exposome databases. These FCCs not monitored in any of the sources of step 1 were candidates for the systematic evidence mapping in step 2. For this step, we prioritized FCCs that have at least five database entries in the FCCmigex, reporting their detection in migrates and/or extracts of FCMs. To verify the absence of any prioritized chemicals in step 1, we also searched the HMDB for the chemical names that are used in the FCCmigex database and in Norman SLE.
For further data analysis and interpretation, prioritized FCCs were assigned to chemical groups based on functional categories and/or chemical structures. During grouping, we referred to the primary literature included in this systematic evidence map and in the FCCmigex database to understand the function and/or chemical features of an FCC. Additionally, we used the tool Classyfire [45], the Plastics Additives Handbook [46], and expert knowledge to group FCCs based on their applications in FCMs and/or chemical features, such as functional groups and structural properties.
Literature searches and screening
For each of the prioritized FCCs, individual literature searches were performed. For PubMed, WoS, and ScienceDirect, search strategies included the chemical name as used in the FCCdb or the FCCmigex, and generic search terms related to human biomonitoring (e.g., human, blood, urine, biomonitoring) that were connected by the Boolean operator OR. Searches in CAS SciFindern used CAS Registry Numbers instead of chemical names. Search strings and settings were slightly adapted depending on the requirements of each database. The searches were not restricted by publication date or language and included all literature published by February 2023. Full details on search strings, applied filters, and settings have been published previously [29].
Individual literature searches were stored in separate Endnote files, from which duplicates were removed. All individual libraries were uploaded into the online evidence synthesis tool Cadima [47], where further duplicates were deleted. The references were then screened in a two-level process, beginning with title-and-abstract screening and followed by full-text screening. During the screening, the eligibility criteria specified in the protocol were applied to all prioritized FCCs that were analyzed in the respective reference [29]. In brief, studies were considered eligible and included in the systematic evidence map if the analyzed sample originated from a human specimen (e.g., urine, blood, and breast milk) and at least one prioritized FCC was analyzed. Ten percent of the references were independently screened by two reviewers in parallel at title-and-abstract and full-text levels, and disagreements were resolved bilaterally. Reasons for exclusion were recorded during full-text screening.
Data extraction
Eligible studies were used to collect information on whether FCCs have been monitored in human samples and if they have been detected. Details on the sample type and analytical approaches were part of the data extraction process (see Supplementary Information). The process was based on the data extraction software tool SciExtract [5] which allowed us to use precoded options to systematically compile the data. SciExtract was also used to organize and manage the workflow and to store the extracted data.
Hazard mapping
For FCCs included in the biomonitoring programs (step 1A) and those prioritized in step 2, we compiled the hazard properties according to human-health-related criteria described in the EU’s Chemicals Strategy for Sustainability (CSS) [48]. The CSS seeks to ban the most harmful chemicals from consumer products, including FCMs, and defines chemicals as ‘most harmful’ to human health if they are carcinogenic, mutagenic or toxic to reproduction (CMR) or exhibit specific target organ toxicity (STOT). Hazards associated with endocrine-disrupting properties, persistence, bioaccumulation, and mobility of a chemical are also mentioned in the CSS but were not included in this analysis. We consulted the European Chemicals Agency’s (ECHA) Classification and Labelling Inventory aligned with the Globally Harmonized System (GHS) for chemical classification and labeling [49] and referred to GHS-aligned classifications by the Japanese Government [50] for identifying human health-related hazards. Following the GHS criteria for classification and labeling, we identified chemicals as ‘high concern’ if they exhibit CMR properties belonging to categories 1A and 1B (known and presumed CMR, respectively) and/or have been classified as STOT category 1 after repeated exposure (RE) (Fig. S1). Chemicals of ‘medium concern’ were those suspected to have CMR and/or STOT RE properties, as indicated by their classifications in category 2. Chemicals that have been classified based on other concerns, such as aquatic toxicity or skin sensitization, were marked as ‘other concern’. FCCs with data in at least one hazard category and without any classification were labeled as ‘not classified’. FCCs that were not included in the hazard inventories, or for which no data were available in any hazard category, were labelled with ‘no hazard data’.
Results
Overall evidence for the presence of FCCs in humans
For a total of 3601 (or 25%) of the 14,402 known FCCs, we found evidence for their presence in human samples (Fig. 2). Of these, 194 FCCs have been detected in biomonitoring programs, and 3528 FCCs are listed in metabolome/exposome databases, with an overlap of 184 FCCs found in both types of sources. The total of 3601 FCCs also includes 63 out of 175 prioritized FCCs that have been detected in humans according to the results of the systematic evidence map (step 2).
Based on the results of this stepwise approach, we set up the FCChumon database, which is provided as an interactive tool that is freely available, searchable, and linking to the relevant sources (https://www.foodpackagingforum.org/fcchumon).
Analysis of biomonitoring programs and metabolome/exposome databases
In step 1, we identified 3538 FCCs that have been detected in humans, which can be divided into 1883, 863, and 792 FCCs that are included only in the FCCdb, only in the FCCmigex, and in both databases, respectively (Fig. 3, lower panel). These numbers indicate that 23% of the FCCs in the FCCdb and 41% of the FCCs in the FCCmigex are listed in at least one of the sources in Step 1. Sixty-seven percent of FCCs that are listed in both FCC databases have evidence of presence in humans.
Of the 265 FCCs monitored in at least one of the five biomonitoring programs, 194 FCCs (or their metabolites) have been detected in human samples, and 71 FCCs (or their metabolites) have been monitored but not detected in any of the biomonitoring programs (Fig. 3, middle panel; Table S1). The most extensive national program, NHANES, has monitored over 400 different chemicals in human samples since 1999, and 154 of these are FCCs (Figure S2). We also found 84, 66, 66, and 25 FCCs with evidence for the presence in humans in the biomonitoring programs CHMS, HBM4EU, Biomonitoring California, and KoNEHS, respectively. One hundred and twenty-four FCCs have only been monitored in a single biomonitoring program, and 55 of these have not been detected, whereas 13 FCCs have been included across all five programs, of which 8 have been detected in all programs (Figure S3; Table S1).
The overlap of known FCCs with metabolome/exposome databases is much larger than the overlap with biomonitoring programs: of the three metabolome/exposome databases, the Blood Exposome Database includes the highest number of FCCs (2918 FCCs), followed by the HMDB (2211 FCCs) and the Exposome Explorer (253 FCCs) (Fig. 3, middle panel; Figure S4). The HMDB lists 367, 1072, and 772 FCCs that are labelled as “detected and quantified”, “detected but not quantified”, and “expected but not quantified”, respectively, according to the classification system of the database (Figure S5) [36].
Sixty-one out of the 71 FCCs that have been monitored but not detected in biomonitoring programs are listed in at least one of the metabolome/exposome databases. This means that only 10 FCCs fall under the category “monitored but not detected” in step 1 (Fig. 2).
Systematic evidence mapping of prioritized FCCs
In step 1 we show that 75% of the known FCCs are not listed in any of the biomonitoring programs or metabolome/exposome databases. However, for some of these FCCs, scoping searches resulted in additional evidence from the primary literature. Therefore, we decided to systematically map the evidence for 175 FCCs which we prioritized based on the number of FCCmigex database entries that report their detection in FCMs.
In this systematic approach, we found 3152 scientific studies for 147 out of the 175 prioritized FCCs (Figure S6) and considered 251 and 159 studies eligible after title-and abstract and full-text screening, respectively. These studies refer to 68 FCCs – for the other 107 FCCs, no studies fulfilled the eligibility criteria.
Of the 68 FCCs for which scientific studies were found, 63 have been detected in human samples and five have been monitored, but not detected, i.e., Irganox 1330 (CAS 1709-70-2), 2,6-(1,1-dimethylethyl)phenol (CAS 128-39-2), phenyl-bis-(2,4,6-trimethylbenzoyl) phosphinoxid (CAS 162881-26-7), 2,5-bis(5-tert-butyl-2-benzoxazolyl) thiophene (CAS 7128-64-5), and Tinuvin 622 (CAS 65447-77-0) (Fig. 4A). The detected chemicals have been detected in urine (28 FCCs), serum (20), blood (13), and plasma (12) (Fig. 4B). FCCs have also been found in breast milk (13) and samples taken from umbilical cords (18) and placentas (6). One hundred and thirteen studies have used targeted analyses, whereas 47 studies have used non-targeted approaches (Fig. 4C), and only one study has applied both methods [51]. The vast majority of FCCs have been detected directly, i.e. as parent compounds, in human samples (Fig. 4D), while antioxidant 1098 (CAS 23128-74-7) and Irganox 1035 (CAS 4148-35-9) have been putatively identified based on an unspecific common metabolite in one study [52].
FCCs monitored in humans
FCCs detected in biomonitoring programs
Among the 235 FCCs present in FCMs that have been included in human biomonitoring programs, there are 51 volatile organic compounds (VOCs), 29 per- and polyfluoroalkyl substances (PFAS), 25 pesticides, 23 metals, 23 dioxin-like compounds, 20 flame retardants, and 19 phthalates and their alternatives (Fig. 5A, right panel; Table S1). Phthalates and alternative plasticizers, and metals are frequently detected FCCs in FCMs and have also been often found in humans (Fig. 5A, bar charts). Furthermore, PFAS, VOCs, and phenolic compounds, including bisphenols, parabens, and benzophenones, have been frequently monitored and detected in FCMs and in humans. In contrast, for dioxin-like compounds, pesticides, flame retardants, polyaromatic hydrocarbons (PAHs), amines, and perchlorate there is less evidence for their presence in FCMs. Interestingly, 71 of the 95 FCCs belonging to these six groups would not be expected to be present in FCMs, since they are not included in the FCCdb (Table S1). The evidence for presence of FCCs in FCMs varies widely between but also within chemical groups. For example, the VOC styrene (CAS 100-42-5) has been listed 99 times as “detected in FCMs” in the FCCmigex database, while 16 other VOCs found in humans have been listed less than ten times each (Table S1). The presence of styrene, or its metabolites, in humans has been shown by NHANES, CHMS, and KoNEHS, but there is no evidence for 18 of the 51 VOCs from any of the five biomonitoring programs.
FCCs included in the systematic evidence map
Among the 175 FCCs included in the systematic evidence map, there are 38 oligomers (mainly siloxane, polyamide, and polyethylene terephthalate (PET) derivatives), 15 antioxidants and degradation products, 14 photoinitiators, and 14 plasticizers (Fig. 5B, right panel; Table S2).
For oligomers and antioxidants and their degradation products, 424 and 499 FCCmigex database entries, respectively, imply that FCMs play a role in human exposure to these chemical groups (Fig. 5B). However, there is limited evidence for the presence of antioxidants and oligomers in humans, as indicated by 6 and 12 studies, respectively, reporting the detection of the chemicals of these groups. For only five out of 38 prioritized oligomers, we found evidence for their detection in humans: a PET cyclic trimer (CAS 7441-32-9), three cyclic siloxanes (D7, CAS 107-50-6; D8, CAS 556-68-3 and D9, CAS 556-71-8), and 1,6-dioxacyclododecane-7,12-dione (CAS 777-95-7) (Table S2). With 209 FCCmigex database entries and 9 studies reporting detection in humans, photoinitiators are regularly found in FCMs, but less frequently monitored in humans. For the five BADGE derivatives BADGE·H2O, BADGE·2H2O, BADGE·HCl, BADGE·2HCl, and BADGE·H2O·HCl, 23 studies confirm the detection of at least one of these FCCs in humans. In addition, they have 65 database entries in the FCCmigex, confirming their regular detection in migrates and/or extracts from coated metal FCMs.
FCCs of concern
Of the 235 FCCs included in biomonitoring studies and with evidence for their presence in FCMs, 100 FCCs have hazard properties of high concern for human health, and 44 FCCs have hazard properties of medium concern, i.e., they are assigned to categories 1 and 2, respectively (Fig. 6A, Table S1). Among the FCCs detected in humans are several category 1 A and 1B carcinogens, of which, e.g., styrene, benzophenone (CAS 119-61-9), formaldehyde (CAS 50-00-0), and cadmium (CAS 7440-43-9) have also been frequently found in FCMs. Dozens of FCCs are classified as toxic to reproduction, for example, nine phthalates, which are all classified as 1B reprotoxicants. Over 30 FCCs are mutagens (e.g., benzene (CAS 71-43-2), lead, cadmium, and cobalt), and many more exhibit specific target organ toxicity after repeated exposure (e.g., 4,4’-methylenedianiline (CAS 101-77-9) and perfluorooctanoic acid (CAS 335-67-1)). Seventy-seven FCCs have other concerns or have not been classified as hazardous based on the available data, and 14 do not have hazard data or are not listed.
Among the 175 FCCs included in the systematic evidence map, 5 and 13 FCCs are classified in categories 1 and 2, respectively, resulting in high and medium concern for CMR and/or STOT RE properties (Fig. 6B, Table S2). Di-n-octylisophthalate (CAS 137-89-3), 2-benzyl-2-(dimethylamino)-4-morpholino-butyrophenone (CAS 119313-12-1), ethyl-4-dimethylaminobenzoate (CAS 10287-53-3), and medium-chain chlorinated paraffins (CAS 85535-85-9) are reproductive toxicants of high concern (category 1B) and have been detected in FCMs and in humans. For the category 1B carcinogen 2,4’-methylenedianiline (CAS 1208-52-2), however, we found no evidence concerning its presence in humans. Ninety-eight FCCs are allocated to other hazard categories or have not been classified, and 59 FCCs are not listed in the hazard inventories, indicating a lack of data for these chemicals. Based on this evidence map, 49 FCCs without hazard data have also never been targeted in human samples, but they are known to migrate so the implications of the probable human exposure from these FCCs are unknown. Among these are 29 oligomers that have been mainly detected in PA, PET, and siloxane FCMs.
Discussion
Relevance of this study
There is evidence of human exposure for at least 3601 (or 25%) of the known FCCs (Fig. 1). While other exposure sources (than FCMs) exist for FCCs, it is likely that humans are exposed to more FCCs than reported here, as we only searched the scientific literature for a small subset of chemicals. The novel database on FCCs monitored in humans (FCChumon) lends itself to integration with our previously published database of chemicals present in/migrating from specific FCMs (FCCmigex) [5], thereby enabling hypothesis-driven research for closing pertinent knowledge gaps on human exposure to chemicals originating from FCMs. Together, these databases can also be used as information sources for elucidating FCCs’ health impacts and highlighting other priority research needs.
Parent compounds vs. metabolites
For the exposure assessment of chemicals with well-known metabolic fate in humans, such as phthalates and certain VOCs, metabolites instead of their parent compounds are monitored [53, 54]. We considered this aspect when comparing FCCs to chemicals from the biomonitoring programs and when analyzing the primary literature. Various tools could support identifying FCC metabolites by predicting chemical biotransformation [55, 56], but they are associated with large scientific uncertainty, as shown, e.g., for the metabolism of agrochemicals in rats [57] or for 15 structurally different groups of flame retardants [58]. Given the high number of FCCs included in this study, we did not attempt to systematically predict potential metabolites and only considered information on specific metabolites if it was readily available in the biomonitoring programs. Only one unspecific metabolite was identified in the systematic evidence map, indicating potential exposure to two antioxidants [52].
Focus on chemical groups
FCMs are a well-known and relevant exposure source for phthalates and their alternatives, metals, VOCs, and phenolic compounds. These chemicals are regularly monitored and detected in human biomonitoring programs and frequently found in FCMs (Fig. 5A), and there is ample evidence for their migration, e.g. [17, 59,60,61]. There is also evidence for the presence of PFAS in humans and in FCMs. Although most PFAS have never been authorized for food contact use [62], the contribution of food packaging to human exposure has been mapped [63]. Dioxin-like compounds, many pesticides, and flame retardants are not intentionally added FCCs, but they may be present in FCMs because they are introduced or formed during FCM use, manufacture, and recycling, as their detection in FCMs shows [64,65,66]. FCMs may therefore contribute to human exposure to FCCs intentionally used in the manufacture of FCMs, various types of NIAS, and illicitly added chemicals. Yet, for most FCCs, comprehensive assessments of the relative contribution of FCMs to human body burden are missing.
Antioxidants are of special interest because many are high-production volume chemicals that are widely used in plastic food packaging [67] and robust evidence for their presence in FCMs exists (Fig. 5B, Table S2). Important groups of antioxidants are sterically hindered phenols and phosphite antioxidants that are very common in FCMs, e.g., Irgafos 168 (CAS 31570-04-4), Irganox 1076 (CAS 2082-79-3), and Irganox 1010 (CAS 6683-19-8). However, neither of these substances is included in the biomonitoring programs and exposome/metabolome databases (step 1), and we found only limited evidence for their presence in humans in step 2 [52, 68, 69]. Major degradation products of these antioxidants, such as 2,4-di-tert-butylphenol (CAS 96-76-4), 2,6-di-tert-butylbenzoquinone (CAS 719-22-2), and tris(2,4-di-tert-butylphenyl)phosphate (CAS 95906-11-9), have been detected in humans in a few studies, but at high levels and with frequent detection in sampled populations [70,71,72]. These results show that the contribution of FCMs to human exposure to antioxidants and their degradation products has not yet received much attention. Such gaps need to be filled by better understanding the overall exposure to antioxidants and their metabolism in humans.
Oligomers are another group of FCCs requiring more attention. PET, PA, and siloxane oligomers are known side-products of polymerization, and they have been detected in extracts and migrates of FCMs. There is however only very limited evidence for their presence in humans, e.g. for PET oligomers [73]. This is likely due to the challenging chemical analysis of oligomers, especially in complex media, such as human samples, and the fact that chemical standards required for the identification and quantification of oligomers are rarely available [74, 75]. BADGE and its derivatives are commonly observed side-products formed during the polymerization of epoxy resins [76]. Toxic effects, such as endocrine disruption, genotoxicity, and allergic reactions, have been linked to BADGE derivatives and epoxy resins, but information on their toxicity is still limited [77]. Seventeen BADGE derivatives have been detected in extracts or migrates of FCMs, and five of them have been found in humans. This illustrates that targeted analysis of structurally related chemicals is possible and should be prioritized, to close this important knowledge gap on human exposure to expected side-products of polymerization reactions [76].
Photoinitiators form a group of structurally diverse FCCs that are used in various FCMs, such as coatings, printing inks, and adhesives [78]. While there is substantial evidence for their presence in FCMs, their presence in human samples has not been extensively investigated. Liu and Mabury showed that 18 photoinitiators and their sulfoxidation products are present in human sera [79], and human exposure, environmental occurrence, and toxicity of 25 photoinitiators have recently been reviewed [78]. According to the FCCmigex and FCChumon databases, several of these photoinitiators have been detected in FCMs and there is evidence for human exposure. Among these, benzophenone (CAS 119-61-9) is the most frequently detected photoinitiator in FCMs. Since benzophenone is a presumed carcinogen (class 1B, Table S1) as well as a suspected endocrine disruptor [80], exposure via FCMs should be prevented.
Limitations affecting data interpretation
The sources used for the compilation of the FCChumon data vary with respect to the chemical space, curation level, and details provided. In general, we consider data collected in biomonitoring programs (Step 1A) as having a high level of confidence because they are usually derived from a representative population by following strict analytical standards and guidelines [81]. However, only a limited number of several hundred chemicals is monitored in these programs. We also rate the results of step 2 with a high level of confidence because they were generated by the robust approach of a systematic evidence map (including data extraction by a trained team of scientists but excluding the quality rating of each included study [29]). Conversely, the metabolome/exposome databases contain many thousands of different chemicals that have been assembled by different means, also including automated approaches [36, 38]. The matches between the known FCCs and these databases may therefore require further review before being used in future assessments (e.g., by checking the “metabolite status” integrated in the HMDB).
Some of the FCCs listed in the FCCdb and FCCmigex consist of chemical mixtures of, e.g., polymeric molecules, stereoisomers, or structural isomers. Converting the CAS Registry Number of such mixtures into other identifiers was not always possible and could therefore result in some FCCs not being found in some sources of step 1. For example, short-chain chlorinated paraffins (SCCPs, CAS 85535-84-8) and medium-chain chlorinated paraffins (MCCPs, CAS 85535-85-9) do not have any identifiers other than CAS and were not matched in step 1, but we found ample evidence for the presence of these mixtures in humans in step 2, because they have been monitored regularly and the chemical names are reported in a standardized manner in the primary literature e.g. [82,83,84]. Nonylphenol (CAS 25154-52-3) is another example of a mixture of undefined stereoisomers and structural isomers that was not found in step 1 but prioritized in step 2. However, due to the listing of more defined nonylphenol isomers in the FCC databases as well as the metabolome/exposome databases, we decided to exclude this technical mixture from the systematic evidence map. These examples show that searches for (alternative) names and/or identifiers were helpful during the systematic evidence map and may be recommended for users of the FCChumon database.
Implications for assessing and managing FCCs
The data presented here lend support to the possible contribution of FCMs towards human exposure to FCCs. Since there are various FCCs with hazard properties of concern among the chemicals detected in humans and FCMs, their use in FCMs should be restricted to minimize human exposure. This is now recognized and currently under discussion for a few of these chemicals, including PFAS [85, 86], BPA [10, 16] and phthalates [87]. However, it does not mean that the remaining FCCs can be considered safe, as shown, e.g., by the absence of biomonitoring and hazard data for 107 (61%) and 59 (34%), respectively, of the 175 FCCs included in step 2. Importantly, even for chemicals where hazard data have been submitted to authorities there are significant data gaps for one or more hazard categories, as has been demonstrated for certain PFAS [62, 88]. For FCCs migrating into foods, such related hazard data gaps need to be filled with high priority to characterize risk on human health [89]. This is especially urgent for intentionally added FCCs found at high levels in humans, such as antioxidants and photoinitiators, and expected NIAS, such as oligomers and BADGE derivatives.
In summary, this study systematically maps 3601 chemicals from different FCAs (food packaging, tableware, etc.) for which there is evidence for human exposure, and for 10,786 FCCs, no evidence could be provided at all. Only 15 FCCs have been monitored but have never been detected in humans. Based on two subsets totalling 410 FCCs, this study further identifies 105 FCCs of high concern due to their hazard properties and highlights the many data gaps related to hazards and human health risks. We make these data accessible in the user-friendly, freely accessible FCChumon dashboard, which complements our previously published FCCmigex dashboard on extractable and migrating FCCs. In combination, FCChumon and FCCmigex enable the prioritization of FCCs requiring more detailed investigations, either because they are frequently found in FCMs, despite having only little or no information on their presence in humans, or because they are measured in humans but lack hazard information. Furthermore, this evidence base supports policy and decision-making and highlights the urgent need to ban the most hazardous chemicals shown to migrate from food packaging and other types of FCAs into foods, to protect human health.
Data availability
The data are publicly and freely available as interactive dashboard that is based on Microsoft PowerBI under the following link (https://www.foodpackagingforum.org/fcchumon). The references that were included in the systematic evidence map (step 2) are also provided under this link.
References
WHO. Human biomonitoring: Facts and figures. Copenhagen: WHO Regional Office for Europe. 2015.
Choi J, Mørck TA, Joas A, Knudsen LE. Major national human biomonitoring programs in chemical exposure assessment. AIMS Environ Sci. 2015;2:782–802.
Landrigan PJ, Fuller R, Acosta NJR, Adeyi O, Arnold R, Basu N, et al. The Lancet Commission on pollution and health. Lancet. 2018;391:462–512.
Grob K, Biedermann M, Scherbaum E, Roth M, Rieger K. Food contamination with organic materials in perspective: packaging materials as the largest and least controlled source? A view focusing on the European situation. Crit Rev Food Sci Nutr. 2006;46:529–35.
Geueke B, Groh KJ, Maffini MV, Martin OV, Boucher JM, Chiang Y-T, et al. Systematic evidence on migrating and extractable food contact chemicals: Most chemicals detected in food contact materials are not listed for use. Crit Rev Food Sci Nutr. 2022;63:9425–35.
Jeddi MZ, Boon PE, Cubadda F, Hoogenboom R, Mol H, Verhagen H, et al. A vision on the ‘foodture’ role of dietary exposure sciences in the interplay between food safety and nutrition. Trends Food Sci Tech. 2022;120:288–300.
Barnes KA, Sinclair CR, Watson DH, (eds.). Chemical migration and food contact materials. Woodhead Publishing, 2007.
Hahladakis JN, Velis CA, Weber R, Iacovidou E, Purnell P. An overview of chemical additives present in plastics: Migration, release, fate and environmental impact during their use, disposal and recycling. J Hazard Mater. 2018;344:179–99.
Wang Y, Zhu H, Kannan K. A review of biomonitoring of phthalate exposures. Toxics. 2019;7:21.
EFSA CEP Panel. Re-evaluation of the risks to public health related to the presence of bisphenol A (BPA) in foodstuffs. EFSA J. 2023;21:e06857.
EFSA CEP Panel. Update of the risk assessment of di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and di-isodecylphthalate (DIDP) for use in food contact materials. EFSA J. 2019;17:e05838.
HBM4EU. Substance report - Bisphenols. 2022. https://www.hbm4eu.eu/wp-content/uploads/2022/07/Bisphenols_Substance-report.pdf. Accessed 7 February 2024.
Banaderakhshan R, Kemp P, Breul L, Steinbichl P, Hartmann C, Fürhacker M. Bisphenol A and its alternatives in Austrian thermal paper receipts, and the migration from reusable plastic drinking bottles into water and artificial saliva using UHPLC-MS/MS. Chemosphere. 2022;286:131842.
Siddique S, Zhang G, Coleman K, Kubwabo C. Investigation of the migration of bisphenols from baby bottles and sippy cups. Curr Res Food Sci. 2021;4:619–26.
Marchiandi J, Alghamdi W, Dagnino S, Green MP, Clarke BO. Exposure to endocrine disrupting chemicals from beverage packaging materials and risk assessment for consumers. J Hazard Mater. 2024;465:133314.
EC. Draft regulation on the use of BPA and other bisphenols in FCMs. 2024. https://ec.europa.eu/transparency/comitology-register/core/api/integration/ers/400274/097818/1/attachment. Accessed 16 July 2024.
Groh KJ, Geueke B, Martin O, Maffini M, Muncke J. Overview of intentionally used food contact chemicals and their hazards. Environ Int. 2021;150:106225.
Nerín C, Bourdoux S, Faust B, Gude T, Lesueur C, Simat T, et al. Guidance in selecting analytical techniques for identification and quantification of non-intentionally added substances (NIAS) in food contact materials (FCMS). Food Addit Contam A. 2022;39:620–43.
Geueke B. Dossier - Non-intentionally added substances. 2018. https://www.foodpackagingforum.org/fpf-2016/wp-content/uploads/2018/06/FPF_Dossier03_NIAS_2nd-edition.pdf. Accessed 7 February 2024.
Zimmermann L, Scheringer M, Geueke B, Boucher JM, Parkinson LV, Groh KJ, et al. Implementing the EU Chemicals Strategy for Sustainability: The case of food contact chemicals of concern. J Hazard Mater. 2022;437:129167.
vom Saal FS, Vandenberg LN. Update on the health effects of bisphenol A: Overwhelming evidence of harm. Endocrinology. 2020;162.
Neltner TG, Alger HM, Leonard JE, Maffini MV. Data gaps in toxicity testing of chemicals allowed in food in the United States. Reprod Toxicol. 2013;42:85–94.
Muncke J, Andersson A-M, Backhaus T, Belcher SM, Boucher JM, Carney Almroth B, et al. A vision for safer food contact materials: Public health concerns as drivers for improved testing. Environ Int. 2023;180:108161.
Balbus JM, Barouki R, Birnbaum LS, Etzel RA, Gluckman PD, Grandjean P, et al. Early-life prevention of non-communicable diseases. Lancet. 2013;381:3–4.
Muncke J, Myers JP, Scheringer M, Porta M. Food packaging and migration of food contact materials: will epidemiologists rise to the neotoxic challenge? J Epidemiol Commun H. 2014;68:592.
Simoneau C, Raffael B, Garbin S, Hoekstra E, Mieth A, Lopes J, et al. Non-harmonised food contact materials in the EU: Regulatory and market situation. Baseline study, final report. Publications Office of the European Union. 2016; JRC104198.
Muncke J, Backhaus T, Geueke B, Maffini MV, Martin OV, Myers JP, et al. Scientific challenges in the risk assessment of food contact materials. Environ Health Perspect. 2017;125:095001.
Food Packaging Forum. FCCmigex Database. 2023. https://www.foodpackagingforum.org/resources/fccmigex. Accessed 16 July 2024.
Geueke B, Parkinson LV, Dolenc J, Groh KJ, Kassotis CD, Maffini MV et al. Protocol for assessing the evidence of food contact chemicals monitored in humans. 2023; https://doi.org/10.5281/zenodo.7857837.
National Center for Environmental Health, National Center for Health Statistics, National Health and Nutrition Examination Survey. Fourth national report on human exposure to environmental chemicals. Updated tables, March 2021, volume three: Analysis of pooled serum samples for select chemicals, NHANES 2005-16. 2021.
Health Canada. Sixth report on human biomonitoring of environmental chemicals in Canada. Minister of Health, Ottawa, ON. 2021. https://www.canada.ca/en/health-canada/services/environmental-workplace-health/reports-publications/environmental-contaminants/sixth-report-human-biomonitoring.html. Accessed 7 February 2023.
HBM4EU. EU HBM Dashboard. 2022. https://www.hbm4eu.eu/what-we-do/european-hbm-platform/eu-hbm-dashboard/. Accessed 7 February 2023.
IPCHEM. Human Biomonitorin Data Module: HBM4EU-aggregated - HBM4EU aggregated workbook by VITO. 2022. https://ipchem.jrc.ec.europa.eu/#showmetadata/HBM4EUAGGREGATED. Accessed 7 February 2023.
Jung SK, Choi W, Kim SY, Hong S, Jeon HL, Joo Y, et al. Profile of environmental chemicals in the Korean population - Results of the Korean National Environmental Health Survey (KoNEHS) cycle 3, 2015-2017. Int J Environ Res Pub He. 2022;19:626.
Biomonitoring California. Chemicals biomonitored in California. 2022. https://biomonitoring.ca.gov/chemicals/chemicals-biomonitored-california. Accessed 7 February 2023.
Wishart DS, Guo A, Oler E, Wang F, Anjum A, Peters H, et al. HMDB 5.0: the Human Metabolome Database for 2022. Nucleic Acids Res. 2022;50:D622–31.
Wishart Research Group. The Human Metabolome Database. https://hmdb.ca/. Accessed 7 February 2023.
Barupal DK, Fiehn O. Generating the Blood Exposome Database using a comprehensive text mining and database fusion approach. Environ Health Perspect. 2019;127:97008.
Barupal D, Fiehn O. Blood Exposome Database. https://bloodexposome.org/. Accessed 9 February 2023.
Neveu V, Nicolas G, Salek RM, Wishart DS, Scalbert A. Exposome-Explorer 2.0: an update incorporating candidate dietary biomarkers and dietary associations with cancer risk. Nucleic Acids Res. 2019;48:D908–12.
IARC. Exposome Explorer 3.0. 2021. http://exposome-explorer.iarc.fr/. Accessed 9 February 2023.
Geueke B, Parkinson LV. S112 | FCCMIGEX | List of Migrating & Extractable Food Contact Chemicals (FCCmigex) by FPF. Zenodo. 2024. https://doi.org/10.5281/zenodo.10551195.
Groh KJ, Geueke B, Chirsir P, Schymanski EL, Muncke J. S77 | FCCDB | Food Contact Chemicals Database v5.0. Zenodo. 2022. https://doi.org/10.5281/zenodo.7304977.
Mohammed Taha H, Aalizadeh R, Alygizakis N, Antignac J-P, Arp HPH, Bade R, et al. The NORMAN Suspect List Exchange (NORMAN-SLE): facilitating European and worldwide collaboration on suspect screening in high resolution mass spectrometry. Environ Sci Eur. 2022;34:104.
Djoumbou Feunang Y, Eisner R, Knox C, Chepelev L, Hastings J, Owen G, et al. ClassyFire: automated chemical classification with a comprehensive, computable taxonomy. J Cheminform. 2016;8:61.
Zweifel H, Maier RD, Schiller M Plastics Additives Handbook. Carl Hanser Verlag: Munich, Germany, 2009.
Kohl C, McIntosh EJ, Unger S, Haddaway NR, Kecke S, Schiemann J, et al. Online tools supporting the conduct and reporting of systematic reviews and systematic maps: a case study on CADIMA and review of existing tools. Environ Evid. 2018;7:8.
EC. Chemicals Strategy for Sustainability, towards a toxic-free environment. COM(2020) 667 final. 2020.
ECHA. C&L Inventory. 2023. https://echa.europa.eu/information-on-chemicals/cl-inventory-database. Accessed 16 November 2023.
NITE. Chemical Management - GHS General Information. 2023. https://www.nite.go.jp/chem/english/ghs/ghs_index.html. Accessed 16 November 2023.
Tkalec Ž, Codling G, Tratnik JS, Mazej D, Klánová J, Horvat M, et al. Suspect and non-targeted screening-based human biomonitoring identified 74 biomarkers of exposure in urine of Slovenian children. Environ Pollut. 2022;313:120091.
Liu R, Mabury SA. Rat metabolism study suggests 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid as a potential urinary biomarker of human exposure to representative 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate antioxidants. Environ Sci Technol. 2021;55:14051–8.
Frederiksen H, Upners EN, Ljubicic ML, Fischer MB, Busch AS, Hagen CP, et al. Exposure to 15 phthalates and two substitutes (DEHTP and DINCH) assessed in trios of infants and their parents as well as longitudinally in infants exclusively breastfed and after the introduction of a mixed diet. Environ Int. 2022;161:107107.
Haines DA, Saravanabhavan G, Werry K, Khoury C. An overview of human biomonitoring of environmental chemicals in the Canadian Health Measures Survey: 2007-2019. Int J Hyg Environ Health. 2017;220:13–28.
de Bruyn Kops C, Šícho M, Mazzolari A, Kirchmair J. GLORYx: Prediction of the metabolites resulting from phase 1 and phase 2 biotransformations of xenobiotics. Chem Res Toxicol. 2021;34:286–99.
Mazzolari A, Scaccabarozzi A, Vistoli G, Pedretti A. MetaClass, a comprehensive classification system for predicting the occurrence of metabolic reactions based on the MetaQSAR database. Molecules. 2021;26:17.
Scholz VA, Stork C, Frericks M, Kirchmair J. Computational prediction of the metabolites of agrochemicals formed in rats. Sci Total Environ. 2023;895:11.
Kincaid B, Piechota P, Golden E, Maertens M, Hartung T, Maertens A. Using in silico tools to predict flame retardant metabolites for more informative exposomics-based approaches. Front Toxicol. 2023;5:16.
Rudel RA, Gray JM, Engel CL, Rawsthorne TW, Dodson RE, Ackerman JM, et al. Food packaging and bisphenol A and bis(2-ethyhexyl) phthalate exposure: findings from a dietary intervention. Environ Health Perspect. 2011;119:914–20.
Tang W, Hemm I, Eisenbrand G. Estimation of human exposure to styrene and ethylbenzene. Toxicology. 2000;144:39–50.
Stahl T, Falk S, Rohrbeck A, Georgii S, Herzog C, Wiegand A, et al. Migration of aluminum from food contact materials to food-a health risk for consumers? Part I of III: exposure to aluminum, release of aluminum, tolerable weekly intake (TWI), toxicological effects of aluminum, study design, and methods. Environ Sci Eur. 2017;29:19.
Phelps DW, Parkinson LV, Boucher JM, Muncke J, Geueke B. Per- and polyfluoroalkyl substances in food packaging: migration, toxicity, and management strategies. Environ Sci Technol. 2024;58:5670–84.
Holder C, DeLuca N, Luh J, Alexander P, Minucci JM, Vallero DA, et al. Systematic evidence mapping of potential exposure pathways for per- and polyfluoroalkyl substances based on measured occurrence in multiple media. Environ Sci Technol. 2023;57:5107–16.
Paseiro-Cerrato R, Ackerman L, de Jager L, Begley T. Brominated flame retardants (BFRs) in contaminated food contact articles: identification using DART-HRMS and GC-MS. Food Addit Contam A. 2021;38:350–9.
BEUC. Towards safe and sustainable food packaging - European consumer organisations call for action on single-use tableware made of alterantives to plastic. BEUC-X-2021-050. 2021.
Cramer G, Bolger M, Henry S, Lorentzen R. Usfda assessment of exposure to 2,3,7,8-TCDD and 2,3,7,8-TCDF from foods contacting bleached paper products. Chemosphere. 1991;23:1537–50.
Huang Y-Q, Zeng Y, Mai J-L, Huang Z-S, Guan Y-F, Chen S-J. Disposable plastic waste and associated antioxidants and plasticizers generated by online food delivery services in china: national mass inventories and environmental release. Environ Sci Technol. 2024; https://doi.org/10.1021/acs.est.3c06345.
Cortéjade A, Buleté A, Prouteau L, Chatti S, Cren C, Vulliet E. Development and optimisation of home-made stir bar sorptive extraction for analysis of plastic additives: application in human urine. Anal Methods. 2017;9:3549–60.
Pouech C, Kiss A, Lafay F, Léonard D, Wiest L, Cren-Olivé C, et al. Human exposure assessment to a large set of polymer additives through the analysis of urine by solid phase extraction followed by ultra high performance liquid chromatography coupled to tandem mass spectrometry. J Chromatogr A. 2015;1423:111–23.
Liu R, Mabury SA. Unexpectedly high concentrations of 2,4-di-tert-butylphenol in human urine. Environ Pollut. 2019;252:1423–8.
Raman M, Ahmed I, Gillevet PM, Probert CS, Ratcliffe NM, Smith S, et al. Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease. Clin Gastroenterol H. 2013;11:868–75.
Ibrahim B, Basanta M, Cadden P, Singh D, Douce D, Woodcock A, et al. Non-invasive phenotyping using exhaled volatile organic compounds in asthma. Thorax. 2011;66:804–9.
Diamantidou D, Mastrogianni O, Tsochatzis E, Theodoridis G, Raikos N, Gika H, et al. Liquid chromatography-mass spectrometry method for the determination of polyethylene terephthalate and polybutylene terephthalate cyclic oligomers in blood samples. Anal Bioanal Chem. 2022;414:1503–12.
Alberto Lopes J, Tsochatzis ED. Poly(ethylene terephthalate), poly(butylene terephthalate), and polystyrene oligomers: occurrence and analysis in food contact materials and food. J Agr Food Chem. 2023;71:2244–58.
Schreier VN, Appenzeller-Herzog C, Bruschweiler BJ, Geueke B, Wilks MF, Simat TJ, et al. Evaluating the food safety and risk assessment evidence-base of polyethylene terephthalate oligomers: Protocol for a systematic evidence map. Environ Int. 2022;167:107387.
Wang D, Zhao H, Fei X, Synder SA, Fang M, Liu M. A comprehensive review on the analytical method, occurrence, transformation and toxicity of a reactive pollutant: BADGE. Environ Int. 2021;155:106701.
Xue J, Liu Y, Yang D, Zhao Y, Cai Y, Zhang T, et al. A review of properties, production, human exposure, biomonitoring, toxicity, and regulation of bisphenol A diglycidyl ethers and novolac glycidyl ethers. J. Environ Chem Ecotoxicol. 2022;4:216–30.
Ji X, Liang J, Liu J, Shen J, Li Y, Wang Y, et al. Occurrence, fate, human exposure, and toxicity of commercial photoinitiators. Environ Sci Technol. 2023;57:11704–17.
Liu R, Mabury SA. First detection of photoinitiators and metabolites in human sera from United States donors. Environ Sci Technol. 2018;52:10089–96.
Lee J, Kim S, Park YJ, Moon H-B, Choi K. Thyroid hormone-disrupting potentials of major benzophenones in two cell lines (GH3 and FRTL-5) and embryo-larval zebrafish. Environ Sci Technol. 2018;52:8858–65.
Govarts E, Gilles L, Rodriguez Martin L, Santonen T, Apel P, Alvito P, et al. Harmonized human biomonitoring in European children, teenagers and adults: EU-wide exposure data of 11 chemical substance groups from the HBM4EU Aligned Studies (2014-2021). Int J Hyg Environ Health. 2023;249:114119.
Liu Y, Aamir M, Li M, Liu K, Hu Y, Liu N, et al. Prenatal and postnatal exposure risk assessment of chlorinated paraffins in mothers and neonates: Occurrence, congener profile, and transfer behavior. J Hazard Mater. 2020;395:122660.
Martínez C, Martínez Arroyo A, Barrientos Alemán D, Gavilán García A, Caba M, Calderón Garcidueñas AL, et al. Persistent organic compounds in human milk and evaluation of the effectiveness of the Stockholm convention in Mexico. Environ Adv. 2022;8:100190.
Xia D, Gao L-R, Zheng M-H, Li J-G, Zhang L, Wu Y-N, et al. Health risks posed to infants in rural China by exposure to short- and medium-chain chlorinated paraffins in breast milk. Environ Int. 2017;103:1–7.
ECHA. Annex XV. Restriction Report, Proposal for a restriction, Per and polyfluoroalkyl substances (PFASs). 2023. https://echa.europa.eu/documents/10162/1c480180-ece9-1bdd-1eb8-0f3f8e7c0c49. Accessed 6 February 2024.
US FDA. FDA Announces PFAS Used in Grease-Proofing Agents for Food Packaging No Longer Being Sold in the U.S. 2024. https://www.fda.gov/food/cfsan-constituent-updates/fda-announces-pfas-used-grease-proofing-agents-food-packaging-no-longer-being-sold-us. Accessed 28 February 2024.
EFSA CEP Panel. Identification and prioritisation for risk assessment of phthalates, structurally similar substances and replacement substances potentially used as plasticisers in materials and articles intended to come into contact with food. EFSA Journal. 2022;20:e07231.
Rudin E, Glüge J, Scheringer M. Per- and polyfluoroalkyl substances (PFASs) registered under REACH-What can we learn from the submitted data and how important will mobility be in PFASs hazard assessment? Sci Total Environ. 2023;877:162618.
Pellizzari ED, Woodruff TJ, Boyles RR, Kannan K, Beamer PI, Buckley JP, et al. Identifying and prioritizing chemicals with uncertain burden of exposure: Opportunities for biomonitoring and health-related research. Environ Health Persp. 2019;127:126001.
Acknowledgements
We thank all members of the FCCH project’s scientific advisory group for their contributions, especially John Peterson Myers, Katie Pelch, Rob Sargis, Emma Schymanski, and Martin Wagner. We thank Jozica Dolenc for help with the development of the literature search strategy and Frank Gwodsz and Christian Kohl for technical support during the compilation of the systematic evidence map.
Funding
This work was carried out as part of the FCCH project, which is funded by project-related funds from Adessium Foundation, MAVA Foundation, Stiftung Minerva, Sympany Stiftung, and the Food Packaging Forum’s own resources from unrestricted donations. All FPF funding sources are listed here: https://www.foodpackagingforum.org/about-us/funding.
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BG: Conceptualization, Literature screening, Data extraction, Visualization, Writing (original draft), Project administration; LVP: Data processing, Dashboard development, Writing (review & editing); LZ: Literature screening, Data extraction, Writing (review & editing); KJG: Conceptualization, Writing (review & editing); CK: Conceptualization, Writing (review & editing); MVM: Conceptualization, Writing (review & editing); OVM: Conceptualization, Writing (review & editing); MS: Data interpretation, Writing (review & editing); JM : Conceptualization, Data interpretation, Writing (review & editing), Funding acquisition. All authors reviewed the results and approved the final version of the manuscript.
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Geueke, B., Parkinson, L.V., Groh, K.J. et al. Evidence for widespread human exposure to food contact chemicals. J Expo Sci Environ Epidemiol (2024). https://doi.org/10.1038/s41370-024-00718-2
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DOI: https://doi.org/10.1038/s41370-024-00718-2