Use of acceptable daily intake (ADI) as a health-based benchmark in nutrition research studies that consider the safety of low-calorie sweeteners (LCS): a systematic map

Background It is well-recognized that consumers face many challenges in understanding and applying nutritional guidance for low-calorie sweeteners (LCS). Thus, this research aims to (1) assess how benchmarks for safe levels of consumption of LCS are utilized by researchers, and (2) understand how varying use of such benchmarks may contribute to challenges in understanding and applying nutritional guidance for LCS consumption. Methods A systematic mapping exercise was employed to characterize when and how acceptable daily intake (ADI) values are used as health-based benchmarks in nutrition research studies that consider the safety of LCS. Results Based on results from charting 121 studies, our findings demonstrate that comparisons of LCS intake to an ADI derived by an authoritative body have been made in a diverse set of published literature, varying widely in their objectives, approaches, and populations of interest. The majority of studies compared the ADI to intake in a population under study; these represent the type of comparison that is most consistent with the intent of the ADI. Other applications of the ADI included use as a benchmark in experimental studies, risk-benefit analyses, and metabolism studies. Conclusion Although most instances of ADI use were reasonable within the context of the individual studies’ objectives, the diversity in use by original-study authors amplifies the continued need for development of “best practices” regarding the use and interpretation of the ADIs in current research. Using comparisons to the ADI can be a helpful way to provide context to research findings. However, in doing so, it is important that researchers utilize the value in a manner specific with its intent, as the ADI is a metric that represents an estimate of the amount of a substance that can be consumed daily over a lifetime without presenting an appreciable risk to health. Supplementary Information The online version contains supplementary material available at 10.1186/s12889-021-10934-2.


Development of the Title, Objective, and Question
The overall objective of the research project is to systematically map when and how acceptable daily intake (ADI) values are used as health-based benchmarks in nutrition research studies that consider the safety of low-calorie sweeteners (LCS) as it relates to measured or estimated consumption. Results will be synthesized and integrated relative to the definition, development, and use of ADI values for LCS by authoritative bodies, such as the Joint FAO/WHO Expert Committee on Food Additives (JECFA), the U.S. Food and Drug Administration (FDA) or the European Food Safety Authority (EFSA).
Regarding the terminology of the type of review, it is recognized that scoping reviews (the term used in the JBI manual) are often also referred to as mapping reviews or systematic maps 3,4 . Herein, we have elected the term "systematic map" to describe the type of review as it best aligns with the overall objective.
The research question (boxed) was developed to reflect the population, concept, and contextor PCC, as described by JBI.
• Population: normal and sensitive human populations (including unhealthy populations; populations with chronic disease, etc.); any age, any sex • Concept: comparison of ADI values established by authoritative bodies to the measured or estimated daily intake of LCS

Background
It is well-recognized that consumers face many challenges in understanding and applying nutritional guidance. This is especially true as consumers and health professionals alike seek to understand how to safely consume LCS due to conflicting information about safe use levels. This scenario is highlighted by a Science Advisory issued by the American Heart Association (AHA) in 2018, which reviews evidence on cardiometabolic outcomes of LCS beverages and provides recommendations related to consumption for selected populations. This includes advising against prolonged consumption of LCS by children due to a dearth of evidence on the potential adverse effects of LCS beverages relative to potential benefits (AHA, 2018) 5 . Another example is that from the American Acacemy of Pediatrics Policy Statement which also discusses the scarcity of data on long-term benefits for weight management in children and adolescents or the concsequences of long-term consumption (AAP, 2015) 6 . Such advisories may be viewed as confusing in context of the positions of authoritative bodies, such as the U.S. FDA, EFSA, or the JECFAall of whom have established positions regarding the safety of individual LCS.
Using the U.S. FDA as an example, their website 7 clearly describes which high-intensity sweeteners are permitted for use which, "like all other ingredients added to food in the United States, must be safe for consumption." By law, the FDA undergoes a rigorous process to determine the safety of food ingredients, including the determination of the daily amount that is safe (i.e. the ADI) 8 . This involves review of scientific data by chemists, toxicologists, and other scientists to determine if there is "reasonable certainty of no harm" as defined by the laws that govern the Agency and ingredient safety requirements. As part 5 American Heart Association (AHA Review Question: In nutrition research studies, how are daily intake levels of low-calorie sweeteners in human populations assessed in the context of ADIs derived by authoritative bodies? of such, many factors are considered: intake of the additive relative to the petitioned use, cumulative use/intake of the additive, and toxicological data to support the safety. Inherent to this process is the recognition that, if approved, the food additives must be safe for all populations of all ages, as well as sensitive populations (e.g., elderly, pregnant) 9 .
Critical to the approval process for any authoritative body is consideration of the margin of safety. This involves a comparison of the estimated daily intake (EDI) to the acceptable daily intake (ADI). The ADI values traditionally used are those established by JECFA and other authoritative bodies, such as the U.S. FDA, Health Canada, or EFSA. ADIs are also developed using rigorous processes. As described by the World Health Organization (WHO) Environmental Health Criteria 70, "Assessing human health risks of chemicals: Derivation of guidance values for health-based exposure limits" 10 , such guidance values represent estimates of intake of a substance daily over a lifetime that is considered to be without appreciable health risk. The guidance also describes how such values should be used e.g., not intended as a threshold for safety at one moment in time.
Thus, science underlying the derivation of the ADI, as well as the definition and appropriate interpretation of the ADI, are critical to enabling appropriate application when considering the safety of LCS. Recognizing the widespread consumption and global interest in LCSparticularly as they relate to public health goals of lowering added sugars as part of improving health outcomes -it is important that LCS intake be assessed appropriately relative to ADIs developed by authoritative bodies. Thus, the overarching goal of the research project is to provide a resource to assist healthcare practitioners, public health professionals, and consumers' trusted advisors in providing clarity and support for safe and appropriate use of LCS to achieve nutritional goals. By approaching the issue in a systematic manner, which involves a multidisciplinary team and reporting the resulting information as a published manuscript, the output will provide transparent, evidence-based, and peer-reviewed evidence that can be used to appropriately inform strategies for improving health outcomes.
Preliminary searches for existing scoping reviews or other evidence-based summaries did not result in any with the objectives presented herein 11 . Several recent publications that provide important context, however, were identified. For example, a review of global intakes of low/no-calorie sweeteners was published early in 2018 12 . This review examined published data on the intake of all major low-/no-calorie sweeteners and included a characterization of exposure assessment approaches. While the findings also include a comparison of findings to ADI values, this comparison was not based exclusively on that reported by the authors (which is a key differentiation with that described herein). When presenting intake estimates, Martyn et al. (2018) used "%ADI" as a metric, which could have been reported in publications or calculated by the review authors. Thus, this review provides a comprehensive summary of intake studies that will be subject to handsearching; this study also serves as a publication used in validation for developing syntax for this systematic map. Additionally, a publication presenting an evidence map of LCS and health studies was identified 13 . Though this map was generated with the objective of demonstrating how an evidence-map database can be generated (using LCS and selected health outcomes as an example), it was informative to topic formulation and protocol development given the similarities approach and subject (though the concept and context were different).

Inclusion Criteria
Types • Papers without title and abstract available in English • Commentaries or editorial pieces that do not make original comparisons of intake to ADIs; such pieces may be retained for context • Literature that is unpublished, or not peer-reviewed (i.e., grey literature with the exception of authoritative reports)

Search Strategy
The search strategy was developed by an Information Specialist (SF), informed by input from stakeholders and reviewed by the Advisory Panel. The strategy generally conforms to the three-step search strategy recommended by JBI with modifications 14 unique to the research question and underlying evidence base. The search strategy involves the following steps, both further described below: 1. Searches in two online databases (PubMed and Embase) relevant to the topic (initial and refined syntax based on a comprehensive series of validation exercises) 2. Hand-searching and reference harvesting from relevant studies and reports. The reviewers do not intend to contact authors of primary studies or reviews for further information.
The online database search will be facilitated by DistillerSR. Following removal of duplicates from PubMed and Embase, studies will be screened by title and abstract (TiAb) using DistillerSR. Subsequently, all studies included following the TiAb will be screened using full text to confirm inclusion.

Search syntax development and validation
Using LCS identifiers provided to the team, search syntax was developed for queries in two citation databases, PubMed and Embase. The fully developed syntax is provided below. Syntax specific to the individual sweeteners included terms to target publications using other chemical identifiers (e.g., CASRN, synonyms), trade names, and spelling variations. The second portion of the syntax consists of key words linked to food frequency intake and exposure assessments. Indexing vocabulary were included for appropriate terms in both PubMed and Embase (i.e., MeSH and Emtree, respectively).
Following initial development of syntax, search validation was performed to ensure that the syntax selection would be broad enough to capture all relevant studies (less restrictive) but narrow enough to reduce unnecessary screening (more restrictive). Based on results of the validation using previously identified publications (n=19 15 ) as a proxy for efficacy, revisions to syntax were made based on terms and key words identified in studies that were not initially retrieved by the queries. Revisions to syntax increased retrieval from 58% (11/19) to 89% (17/19) and it was determined that a more restrictive search (i.e., filtered for human studies), with the addition of a very specific supplementary search captured is most appropriate for this exercise. The two remaining records (2/19) that were not retrieved evaluated plasma concentrations rather than intake, or general risk assessment methods for food additives, and thus would not be an expected result of the query.

Hand-searching, etc.
In addition to the traditional citation database search efforts, hand-searching and reference harvesting techniques will be applied. For hand-searching, high-impact journals in the field of nutrition will be identified with guidance of the Advisory Panel. The most recent edition(s) will be reviewed to identify any relevant articles which may not yet be indexed in citation databases. In regard to reference harvesting, titles in the citation list of the most relevant publications will be reviewed and any relevant titles will be added to the screening process.
Due to the complexity of the search, a key word feedback loop will be utilized following title and abstract screening. Studies determined to be highly relevant will be analyzed for key words and index terms, which will be compared to the original search string. If necessary, syntax will be revised, and an expanded search will be performed.

Extraction of the Results
The review team will chart results via a project-specific form developed in DistillerSR, following the framework for scoping reviews as described by JBI. Briefly, key information such as citation details (e.g., author, year), study details (e.g., objective, population, methods), quantitative or qualitative results as related to the application of an ADI to LCS exposures, and strengths and limitations of the studies will be documented. If possible, details regarding geographical region and ADI authority (e.g., EFSA, JECFA, US-FDA) will also be collected. Following the development of a draft form, the review team will pilot extraction to ensure reviewer consistency and to identify any additional data determined to be useful to informing the research question. The pilot exercises may result in iterative refinement of the DistillerSR form. All information from DistillerSR will be exported into Microsoft Excel to develop tabular summaries for distribution, synthesis, and reporting.

Presentation of Results
Tabular summaries and data visualizations of the extracted information will be constructed as warranted to characterize the landscape map of how ADI information is used in context of studies which consider the safety of LCS. It is anticipated that maps will be developed for individual sweeteners; as part of such the ADI value utilized will be mapped as well as to how it was used relative to the populations of interest. Maps will help facilitate synthesis and determination of how ADI values are being applied, and if they are being utilized in a manner consistent with the prescribed definition, development, and use of ADI values for LCS by authoritative bodies, such as JECFA, the US-FDA or EFSA. It is anticipated that findings will also be discussed in context of selected public-facing sources, such as websites from WebMD, the Mayo Clinic, AHA, American Diabetes Association (ADA), etc. Key findings, data gaps, and future research recommendations will be developed narratively and supported by the tabular summaries and data visualizations.
The systematic map will be reported in a manuscript that will be submitted to a peer-review journal. The goal of the manuscript will be to both report the systematic map with discussion aimed at increasing clarity surrounding the derivation and intended use of ADIs. It is anticipated that the manuscript will contain background on the history of deriving an ADI (including lifetime daily average intakes, life stages, risk assessment context of intakes) in addition to the systematic map findings. The target audience includes researchers, clinicians and dietitians, and other practitioners who may consult ADIs when providing nutritional advice to individuals.