Regulatory Science (RS) is an interdisciplinary science that supports the development and implementation of regulations by providing scientifically grounded evaluations and decisions to ensure public health, safety, and societal benefit, and it plays an equally important role in the food industry as it does in the pharmaceutical field. Reducing uncertainty, communicating with society, and ensuring international consistency are key to the practice of RS. Food additives play a role in improving the quality of life (QOL) and supporting modern society in terms of convenience. Japan's standards and regulations for food additives have evolved independently, but this is not necessarily a negative development, as it contributes to providing high-quality foods and preserving the country's food culture. However, international consistency has also become required recently, so striking a balance between uniqueness and international compatibility is essential. Collaboration among stakeholders and continuous communication will be increasingly essential for responding flexibly to social changes.

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The food additive designation system in Japan began with the promulgation of the Food Sanitation Act in 1947. In response to the subsequent increase in requests for new designations from both within and outside Japan, the Food Additive Designation Consultation Center (FADCC), established at the National Institute of Health Sciences in 2014, has been providing expert advice on how to prepare application documents(e.g., application form and overview document)before designation. While the consultation by FADCC has functioned smoothly, in response to the increasing transparency of systems overseas and the revision of the Food Safety Commission of Japan's "Guidelines for the Risk Assessment of Food Additives", FADCC introduced a stage-gate system with checklists that designation requestors can use to confirm their application documents preparation status, providing scientific clarity regarding visibility and foreseeability for the application process. FADCC also developed and published on its website a "Handbook for the Procedure" that designation requestors can use to prepare an appropriate overview document. These information disclosures, along with the updated "The Procedure for Preparing Application Documents for Designation of Food Additives and Revision of Use Standards for Food Additives", further deepens the fairness and transparency of the food additive regulations in Japan.

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Quantifying the daily intake of food additives is essential for advancing administrative measures to ensure food safety; this data can be used to estimate and better understand the amount of food additives consumed in our daily diets. However, this requires continuous monitoring of food intake because the amount and type of food additives vary with changes in dietary habits. The primary surveys currently used in Japan to estimate food additive intake are categorized into surveys that are used for screening estimation methods, such as production volume surveys of food additives, and surveys that are applied for deterministic exposure estimation methods. This review focuses on the latter, specifically food additive intake surveys using the market basket (MB) method and estimation of food additive intake based on their results, focusing on the implementation and results of the surveys conducted from 2000 to 2023. The surveys were conducted multiple times in approximately four-year cycles, including three-year surveys targeting adults (≧20 years) that change the target food additives each year and one-year surveys targeting children (age 1–6 years). Food additive intake was analyzed and estimated from the survey results, namely the survey targeting children for the estimation in the age group of 1–6 years and the survey targeting adults (≧20 years) for the estimation in all other age groups (7–14 years, 15–19 years, ≧20 years, and ≧1 year). In addition, the role of the MB method in food additive regulation is also discussed. Taken together, this review shows that the MB method survey of food additive intake is a beneficial tool for ensuring food safety in Japan.

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Following the 1995 revision of the Food Sanitation Act, Japan introduced the Designated Food Additives system and the Existing Food Additives system for natural food additives. At that time, 489 natural food additives traditionally used were listed in the List of Existing Food Additives, allowing continued use under the new regulatory framework. Over the past thirty years, the system has been refined to ensure safety and quality based on scientific evidence.

Risk management for Existing Food Additives has progressed through two main approaches: deletion of substances posing health risks or no longer distributed, and establishment of compositional specifications to secure quality. Since 2004, five rounds of deletions have removed 162 additives from the list, leaving 327 as of 2025. Among those deleted was "Madder color", which was found to be carcinogenic. Specifications have been established for 260 additives, while 67 remain without standards.

To address additives difficult to obtain, new management policies are being developed. These include adopting industry-developed voluntary standards as reference specifications and introducing simplified standards focusing on raw materials, manufacturing processes, and purity. For enzyme food additives, a strain notification system is also being considered to prevent confusion from changes in microbial scientific names.

Scientific support has advanced through innovations such as the Relative Molar Sensitivity (RMS) method, which enables quantitative analysis without reference standards and has been adopted in the 10th Edition of the Japan's Specifications and Standards for Food Additives. Simplified heavy metal testing using X-ray fluorescence (XRF) and LC-MS-based confirmation of coloring components are currently under consideration and are expected to further improve analytical efficiency and reliability in the future.

After three decades, the Existing Food Additives framework stands at a new turning point. Continued scientific integration, flexible administration, and evidence-based risk management remain vital for maintaining safety, quality, and consumer confidence.

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Following the revision of the Food Sanitation Act in 1995, the scope of designated food additives was expanded from solely chemically synthesized substances to encompass all additives, including those of natural origin. Consequently, food enzymes that had been distributed as natural additives at the time were permitted to continue distribution as existing additives. However, as no official specifications had been established for existing additives at the inception of the system, there was a prompt need to develop compositional standards and incorporate them into the Japan's Standards and Specifications for Food Additives(JSFA). Since then, under the guidance of the Japan Food Additives Association, the enzyme industry has undertaken extensive deliberations, culminating in the inclusion of all existing enzyme additives (68 items) and two designated enzyme additives in the 9th edition of the JSFA, including Supplement I. This paper provides an overview of the compositional standards for enzymes as stipulated in the JSFA, along with relevant regulatory information. In addition, this paper provides an overview of the application procedures for newly designated food additives, as well as the safety evaluation submissions for food additive enzymes produced using microorganisms developed through recombinant DNA technology.

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The presence of food additives is imperative for the preservation of optimal quality and stability in food products. Nevertheless, concerns regarding their safety persist as a perennial subject of public discourse. In Japan, the 2003 Basic Act on Food Safety established a system whereby the Food Safety Commission (FSCJ) conducts scientific evaluations, and administrative agencies undertake risk management. In 2024, the administration of food hygiene standards was transferred to the Consumer Affairs Agency (CAA), thereby facilitating the integrated management of food labeling and safety control. Designated additives are evaluated based on comprehensive toxicity testing, while existing additives are assessed in line with international standards. For flavorings, the Joint FAO/WHO Meeting on Food Additives (JECFA) and the European Food Safety Authority (EFSA) employ a tiered evaluation approach (TTC concept) using chemical structure and intake information. Japan is conducting reevaluations based on a similar framework. In recent years, new approach methods (NAMs) that do not rely on animal testing have garnered international attention in the safety evaluation of chemicals, including food additives. The NAMs encompass a range of methodologies, including in vitro testing employing microphysiological systems (MPS) and in silico analysis, such as QSAR models and read-across approaches. While regulatory agencies such as the FDA and FSCJ are promoting the introduction and adoption of NAMs, scientific data at the biological level substantiating their health effects remains insufficient. Consequently, animal testing remains an indispensable element in research in this field at present. Nevertheless, progress is being made in the standardization of terminology and the establishment of databases. Concurrent with these efforts, it is anticipated that progress will be made in the establishment of an efficient, internationally harmonized evaluation system that does not rely on animal testing. The safety assessment of food additives, which serves as the foundation linking scientific knowledge, administrative judgment, and societal trust, is expected to continue developing further under international coordination.

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Food additives are used to maintain quality and enhance flavor of food, and their safety has been scientifically verified. However, many consumers remain concerned about their potential health effects. A significant gap in risk perception remains between experts and consumers, who often differ even in their basic understanding of the definition of "food safety". Experts view food safety as a condition in which the risk is within an acceptable range for humans. In contrast, consumers tend to recognize safety as "free from harmful substances (zero risk)". This difference is one of the reasons why scientific explanations of safety are not always convincing to the public.

Furthermore, technical terminology can become a major communication barrier. In particular, "hazard" and "risk" are often confused, leading to the misconception that the mere presence of a hazard implies a serious threat to human health, without considering the magnitude of the actual risk. Emotional and trust-related factors also play a significant role in risk perception. People tend to feel stronger anxiety about unknown or uncontrollable risks, especially when children are involved. Moreover, when trust in the communicator is low, even scientifically accurate explanations are less likely to be accepted. Fragmented and sensational information spread through social media and mass media can further amplify such fears. In these cases, experts should strive to understand the specific reasons and emotions behind consumers' anxieties and consider the factors influencing their perceptions.

Risk communication is one of the three components of risk analysis. It aims to build mutual understanding and trust through the interactive exchange of information and opinions among stakeholders. Risk communication regarding food additives often tends to focus on "persuasive explanation" to gain consumer acceptance. However, risk communication is not meant to be a matter of "persuasion," but rather of "dialogue". To bridge the gap in risk perception, it is essential for consumers, experts, government bodies, and the media to understand each other's perspectives and steadily create opportunities for constructive, ongoing dialogue.

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Imidazole dipeptides (IDPs), such as carnosine, are abundant in meat and have exhibited antioxidant and anti-fatigue properties, contributing to the health benefits associated with meat consumption. However, the detailed mechanisms underlying their physiological activities remain unclear. Recently, we identified the endogenous production of 2-oxo-IDPs, novel oxidized derivatives of IDPs, using mass spectrometry, and demonstrated that their production is associated with oxidative stress. Moreover, we investigated the chemical properties of 2-oxo-IDPs and revealed that they exhibit potent antioxidant capacity, radical-scavenging activity, and cytoprotective effects. Notably, 2-oxo-IDPs resist degradation by carnosinase 1, the carnosine-specific degrading enzyme, and are more stable than carnosine in human serum and Syrian hamsters. Furthermore, we established a highly sensitive method for the absolute quantification of IDPs and 2-oxo-IDPs using mass spectrometry and revealed that 2-oxo-IDPs are contained in various meat samples as well as IDPs. These findings indicate that 2-oxo-IDPs are bioactive molecules present in meat and strongly suggest that they are the primary contributors to the antioxidant effects of IDPs. The finding that IDPs are converted into 2-oxo-IDPs, thereby acquiring antioxidant activity and resistance to degradative enzymes, provides new insights into the roles and potential applications of IDPs and 2-oxo-IDPs in food science and redox biology. In addition, these findings highlight the significant potential of 2-oxo-IDPs as a foundation for the future development of preventive and therapeutic strategies, as well as for advancing drug discovery research.

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l-theanine, a unique amino acid found primarily in green tea, has traditionally been recognized for its relaxation-inducing properties. However, emerging evidence suggests that its benefits extend beyond stress reduction to influence higher-order cognitive functions, particularly memory. In this review, we synthesize current findings on the neurophysiological mechanisms by which l-theanine enhances memory processes, focusing on both direct neural modulation and indirect support via sleep improvement.

Structurally similar to glutamate, l-theanine acts as a "fine-tuning" factor for neurotransmission. It modulates the balance of excitatory and inhibitory activities by regulating glutamate receptors and optimizing concentrations of gamma-aminobutyric acid, dopamine, and serotonin. Crucially, recent animal studies and human trials indicate that l-theanine enhances the functional connectivity of the hippocampal-frontal cortex network. This network is essential for encoding episodic memories and managing working memory. Specifically, l-theanine has been shown to potentiate theta oscillations in the frontal cortex and beta and low gamma oscillations in the hippocampus, possibly facilitating efficient information processing and object recognition.

Furthermore, l-theanine supports memory consolidation indirectly by improving sleep quality. It effectively shortens sleep latency and enhances subjective sleep satisfaction without the adverse effects often associated with pharmaceutical sedatives. By fostering a state of relaxed concentration during wakefulness and promoting restorative sleep at night, l-theanine may provide a dual mechanism for cognitive support.

While short-term benefits of l-theanine on attention and working memory are well-documented, research into its long-term effects on episodic memory and prevention of cognitive decline is still evolving. Future studies should focus on chronic intervention outcomes in humans, considering variables such as age and baseline stress levels. In conclusion, l-theanine holds promise as a safe, multifaceted nutraceutical that optimizes neural activity for learning and memory through synaptic plasticity, network synchronization, and sleep regulation.

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In recent years, a growing number of health problems have been reported in which brain dysfunction is implicated, including eating behavior disorders such as overeating and appetite loss, metabolic abnormalities such as obesity and metabolic syndrome, and mental disorders such as anxiety and depression. However, many drugs that directly act on the brain must cross the blood-brain barrier, which often leads to off-target effects and undesirable side effects. In contrast, vagal sensory nerves transmit information from peripheral organs to the brain can modulate brain function by selectively targeting specific brain regions, thereby offering the potential for regulation with minimal side effects. Food intake is one of the key factors that activate vagal sensory nerves and induces postprandial physiological responses, including the generation of satiation and the suppression of excessive rises in blood glucose levels. In this review, we focus on functional food components that activate vagal sensory nerves, specifically the rare sugar d-allulose and the amino acid γ-aminobutyric acid (GABA), and summarize their physiological functions mediated through the vagal sensory nerve-to-brain axis.

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