Nutrient Intake from Voluntary Fortified Foods and Dietary Supplements in Japanese Consumers: A Cross-Sectional Online Survey.

Consuming voluntary fortified foods (vFFs) and dietary supplements (DSs) is one method for addressing micronutrient inadequacy, but their efficacy is unclear. This study explored the use of vFFs and DSs, and the role of package labels. We conducted a nationwide online survey of 4933 Japanese adults in 2020. The use of vFFs and DSs was 23.3%. The reported vFFs were cereal products (n = 370), milk products/milk substitutes (n = 229), and one-shot drinks (n = 144). Vitamins, calcium, and iron were the main micronutrients added to the vFFs. Most users consumed vitamins C and B from vFFs and/or DSs, and females also consumed iron. The median intake of vitamins B6 and C, selenium, and zinc (plus vitamin B2 and copper in females) exceeded 50% of the respective estimated average requirement values. Approximately 60-70% of the users referred to nutrition labels. However, only a small percent of the respondents clearly understood the nutrient content. To address insufficient nutrient intake, the use of vFFs and DSs may be a good alternative; however, consumer education on the use of vFFs/DSs and package labels needs to be implemented before encouraging their use.

[Frequency of Worsening Clinical Test Values Related to Supplement Use: Estimation by Using Nationwide Online Survey].

This study examined the frequency of worsening clinical test values related to supplement use using a nationwide online survey, with a focus on liver function markers, and clarified the differences between outcome indices of diarrhea or skin manifestations. A nationwide online survey was conducted with 73,010 supplement users from the previous year. Of these, 221 individuals with worsening clinical test values responded to the full-scale survey. To compare surveys with different outcome indices, we used previously reported data from similar surveys.Only 0.5% of individuals who self-reported worsening of clinical test values caused by supplement use recognized an almost certain causal relationship. Among the test items, blood lipids were the most frequently reported. The frequency of worsening liver function markers was 0.2% in supplement users. Among those who experienced worsening clinical test values, 56.1% received no treatment and 82.4% did not report the incidence of worsening clinical test values anywhere. The ingredient-based classification of products revealed more "Peptides or animal by-products" and "Combination products/not classifiable products" than those associated with other categories. Compared to the results of the survey about the experience of diarrhea or skin manifestations, those who experienced worsening clinical test values were predominantly men, frequent and long-term users, and individuals whose products could not be identified.Few supplement users experience worsening of liver function markers, which does not seem serious. However, it is difficult for supplement users to recognize abnormal changes by themselves. Thus, it is important to record product information, usage, and changes in physical condition.

The Prevalence of Dietary Supplements That Claim Estrogen-like Effects in Japanese Women.

Recently, adverse events, such as irregular vaginal bleeding and menstrual disorders, associated with the use of dietary supplements containing Pueraria mirifica, have been reported in Japan. P. mirifica contains phytoestrogens, such as deoxymiroestrol and miroestrol. Therefore, we investigated the use of supplements that claim to have estrogen-like effects (i.e., estrogen-like supplements) in Japanese women aged from 15 to 69 years old in an online survey. The prevalence of estrogen-like supplement use was 5%, accounting for approximately 15% of the sample, including ex-users. The majority of the users were in their 40s and 50s, mainly using these supplements for the treatment of menopausal symptoms. In contrast, the younger generation mainly used them for beauty purposes, such as weight loss, mastogenic effects, and skin care. Many of them visited a clinic or took medicines for menstrual-related troubles. In all age groups, soybeans/isoflavones were the most commonly used, followed by equol and placenta. Participants in their teens and 20s also used P. mirifica. Among them, 16.2% had experienced adverse events, including irregular vaginal bleeding, breast swelling and pain, and heavy menstruation. In conclusion, estrogen-like supplement use is associated with adverse events; thus, it is necessary to pay attention to the use of these supplement. Furthermore, because the purpose of use differs depending on generation, caution according to each generation is necessary.

The Perception of Minerals and Their Prevalence in Fortified Foods and Supplements in Japan.

People's intake of some minerals does not meet the nutrient reference values even in high-income countries. Recently, the deficiency of zinc and/or selenium has been considered to cause greater risk of COVID-19 infection and severity. To investigate consumer awareness, we conducted a cross-sectional questionnaire online survey among Japanese people (7500 males and 7500 females) concerning their perceptions of each mineral and the prevalence of mineral-fortified foods and/or mineral supplements. People's perception of each mineral varied: the highest was for calcium (91.8%) and the lowest was for selenium (44.7%). In addition, only a portion of participants believed that they consumed a sufficient amount of each mineral; the highest was sodium (23.7%), and the lowest was manganese (5.2%). In addition, 18.2% of them felt that they could not consume enough sodium, even though most of the Japanese's intake is excessive. Among mineral-fortified-food and/or mineral-supplement users, the purposes for these products were to maintain health (80.6%), supplement nutrients (48.0%), and prevent infectious diseases (23.2%). Only 18.4% of participants knew what amount they took. In conclusion, education is needed to prevent not only the insufficiency/deficiency of each mineral but also an excess intake of sodium.

The Perception of Vitamins and Their Prevalence in Fortified Food and Supplements in Japan.

Most vitamins are primarily ingested from foods. However, it has been reported that intakes of some vitamins do not meet the nutrition reference values even in high-income countries. In this case, vitamin-fortified foods and/or vitamin supplements are helpful to fix insufficient/deficient status. However, it is not clear whether consumers are aware of their nutritional status or whether they use these products efficiently. To address this issue, we conducted an online cross-sectional questionnaire survey among 14,741 Japanese adults (over 20 years old, 7489 males and 7252 females) concerning the perceptions and prevalence of vitamin-fortified food and/or vitamin supplements. Differences in distribution among groups were compared using the chi-squared test. According to dietary habits, 33.2% of the participants consumed a well-balanced diet every day, but 25.5% could not because of time (41.6%) or money (36.9%) constraints. The perception of each vitamin varied: the highest was for vitamin C (93.2%) and the lowest was for biotin (41.9%). In addition, only a portion of the participants believed that they took sufficient amounts of each vitamin; the highest was vitamin C (22.3%) and the lowest was biotin (5.2%). Despite this situation, most did not use vitamin-fortified food and/or vitamin supplements due to economic reasons. Among vitamin-fortified food and/or vitamin supplement users, the purposes for the usage of these products were varied, such as maintaining health (80.5%), supplementation of nutrients (47.8%), beauty-related purposes (27.5%), and to prevent infectious disease (23.2%). To remedy nutritional status in individuals, it is important to improve not only consumer awareness but also the environment, which can lead consumers to use acceptable vitamin products without any burden.

Coleus forskohlii Extract Attenuated the Beneficial Effect of Diet-Treatment on NASH in Mouse Model.

Obesity is one of the main causes of non-alcoholic steatohepatitis (NASH), which is associated with impaired liver functions including drug metabolism. Coleus forskohlii extract (CFE) is a popular ingredient of weight loss dietary supplements in Japan. In this study, we examined the effect of CFE on the treatment of NASH. C57BL/6 mice (male, 10-wk-old) were fed a NASH diet (high-fat, low-methionine, and choline-deficient diet) for 12 wk to establish NASH. Then, we examined the effect of 0.5% (w/w) CFE in diet during diet-treatment (change to control diet) and/or treadmill-exercise (45 min at 20 m/min, 5 d/wk) to improve NASH for 3 wk. After experimental period, lipids profiles and liver functional markers in the blood, and hepatic lipid content and major CYP subtype mRNA expression and activity in liver were measured. Diet-treatment, but not exercise decreased liver weight and hepatic lipid contents in NASH induced mice. CFE attenuated the effects of diet-treatment which reduced liver weight, even though body weight and adipose tissue weight were reduced. Further, CFE significantly increased liver microsomal CYP1A1, CYP1A2, CYP2C, and CYP3A activities in each condition, and CYP inductions were greater in diet-treatment group compared to those in exercise group. These results suggest that taking CFE should be avoided during diet-treatment of NASH, especially in patients under medication.

[Consulting Pharmacists Who Have Advisory Staff License Regarding the Use of Medicines and Health Foods].

The widespread use of health foods, including supplements, is now common among patients. This is because many health foods are being claimed to be beneficial. If patients use medicines and health foods concurrently, the interaction between the two might lead to adverse events. Additionally, it is reported that pharmacists do not generally care about health food use in their patients, because they also lack sufficient knowledge about health foods. On the contrary, there are some licenses to be a health food advisor in Japan, and the generic name of these licenses is "advisory staff". Pharmacists who have this license are specialists in both medicines and health foods, and thus, they might pay more attention to the concurrent use of medicines and health foods compared to those who do not have the advisory staff license. To address this issue, we conducted a study with an online questionnaire about health food consultation, and 87 pharmacists with advisory staff license participated. Only 36.8% of participants were found to always ask their patients about health food use. However, 92.0% of them had experience of consultation about the simultaneous use of medicines and health foods, and 17.2% of them recognized adverse events by knowing about the concurrent use. Patients who experienced adverse events have used either eicosapentaenoic acid/docosahexaenoic acid supplement with epadel or Ginkgo biloba extract with warfarin. Therefore, an active interview with pharmacists is important to avoid such adverse events in patients.

Concomitant Use of Dietary Supplements and Medicines among Preschool and School-Aged Children in Japan.

Dietary supplement use is widespread amongst the general population including in children and adolescents. The ingredients in dietary supplements can interact with medicines when patients take them concomitantly. However, the prevalence of the concomitant use of dietary supplements and medicines in Japan among children remains unclear. To clarify this issue, a nationwide internet survey was administered to 55,038 mothers (25 to 60 years old) of preschool- or school-aged children in Japan. Among them, 7.6% currently provide dietary supplements and 3.2% concomitantly provide dietary supplements and prescription or over-the-counter medicines to their children. The prevalence of concomitant use increased with the children's grade. Among 1057 mothers with 1154 children who were concomitantly using dietary supplements and medicines, 69.1% provided dietary supplements without physician consultation because they considered dietary supplements as only foods and therefore safe. Although the purpose of the use and types of dietary supplement differed between boys and girls, the most popular product was probiotics in both boys and girls. Among concomitant users, 8.3% of mothers gave dietary supplements for treatment of diseases and 4.9% mothers recognized the adverse events of dietary supplements in their child. The findings of this study suggest that mothers' knowledge about the risk of using dietary supplement with medicines is insufficient. Parental education about the safety of dietary supplements and potential risk of drug-supplement interaction is needed.

Are There Adverse Events after the Use of Sexual Enhancement Nutrition Supplements? A Nationwide Online Survey from Japan.

Dozens of safety alerts for sexual enhancement and weight loss dietary supplements have been launched from the government not only in Japan but also overseas. However, adverse events have been reported only for the use of weight loss supplements, and the prevalence of use and adverse events in sexual enhancement supplements is not known in Japan. To address this issue, we assessed the situation of sexual enhancement supplement use through a nationwide online survey. The prevalence of sexual enhancement supplement use among males was 23.0%. Use of these supplements was higher among younger people than among older people (p < 0.001). In total, 17.6% of users had experienced adverse events, but 58.3% of them did not consult about the events with anybody because of the temporality of their symptoms and their sense of shame. In addition, eight supplement products were found to be possible adulterated supplements in this survey. It is necessary to inform the public about the risk of sexual enhancement supplement use and also prepare a place for consultation on media channels that younger people are more familiar with, in order to monitor adverse events while also preserving their privacy.

[Systematic Review of Case Reports on the Adverse Events Due to Health Food Intake by Cancer Patients].

Cancer patients use health foods (HFs) as complementary and alternative medicine, although the details of their adverse events (AEs) are unclear. We searched three databases [PubMed, "Igaku Chuo Zasshi", and Information System on Safety and Effectiveness for Health Foods website (https://hfnet.nibiohn.go.jp/)] for case reports on AEs related to HF intake in cancer patients published before October 2018. Of the matched reports, 76 studies and 92 patients (31 in Japan, 61 overseas) that met the selection criteria were included in this review. Thus, the severity of AEs and outcomes were not related to either the concomitant use of HF with cancer chemotherapy or cancer stages of patients. AEs caused by HF intake itself accounted for 87%, while drug-HF interaction accounted for 11%. According to the Common Terminology Criteria for Adverse Events (CTCAE) classification, 70% of patients whose grades were identified had severe cases (grades 3 to 5). In Japanese patients, hepatic and respiratory disorders accounted for 52% of the severe cases. Cases were predominantly developed as a result of an allergic mechanism, and mushroom products were mostly used. Overseas, serious cases were induced by products that were already indicated for safety problems. Moreover, notable AEs were recognized, such as hypercalcemia, which were caused by intake of HF containing calcium, vitamin D, and shark cartilage, and bacterial infection caused by probiotic products. Analyzing the details of AEs related to HF intake can help health professionals and cancer patients prevent health hazards.

[Evaluation of Safety Information of the Foods with Function Claims Based on Adverse Event Reports in Information System on Safety and Effectiveness for Health Foods Database].

Foods with Function Claims are allowed to label health claims based on scientific evidence evaluated by the manufacturers. To prevent health problems caused by inadequate use, the manufacturers should label proper safety information. To evaluate whether safety information is sufficiently provided, we conducted the adverse event review focused on popular functional ingredients using the database; Information system on safety and effectiveness for health food. The data suggested that causal factor of adverse events related to products containing soy isoflavone, ginkgo biloba extract and docosahexaenoic acid/eicosapentaenoic acid were overdose intake, concomitant use with certain medicines, and use by whom with an allergic predisposition. However, the safety information on the label was insufficient to prevent adverse events on each products' label. It is important not only to encourage food manufacturers to provide sufficient information based on safety review, but also to inform consumers about adverse events.

A Nationwide Survey of the Attitudes toward the Use of Dietary Supplements among Japanese High-School Students.

We previously studied the prevalence of dietary supplement use in Japanese high-school students by conducting a study on mothers. However, there is often a discrepancy between mothers' understanding and children's attitudes. Thus, we conducted an internet survey of high-school students to clarify their attitudes toward the use of dietary supplements. An invitation to the internet survey was e-mailed to registrants of a research company aged 15 to 18 years. A total of 1031 students (276 male, 755 female) answered the questionnaire on a first come, first served basis. The participants were classified according to the purchasers of their supplements: students who purchased supplements themselves were defined as active users, and others were defined as passive users. The prevalence of dietary supplement use was 30.8% in males and 26.7% in females. Among the users, 42.4% of males and 43.8% of females were active users. Males used supplements for health regardless of active or passive use. However, in females, more active users (40.9%) used supplements for weight loss than passive users (20.4%); the corresponding prevalence was 2.3% in our previous report on mothers' understanding of their daughters. The most frequently used source of information for active users was the internet, whereas for passive users it was family. The frequency of adverse events was 9.4% in males and 14.4% in females, with gastrointestinal symptoms being the most commonly experienced events. Our results suggest that dietary education, including healthy eating and the appropriate use of dietary supplements, should be provided to high-school students.

Nationwide Online Survey Enables the Reevaluation of the Safety of Coleus forskohlii Extract Intake Based on the Adverse Event Frequencies.

The formulations of the functional ingredients of dietary supplements was studied with a small number of subjects, with a particular focus on their effectiveness, but not enough to evaluate their safety. In this regard, the reevaluation and estimation of the safe use of marketed products, with regards to their adverse event (AE) frequencies, are important. To address this issue, a post-marketing nationwide online survey was conducted for the herbal ingredient Coleus forskohlii extract (CFE), a popular weight-loss ingredient. The questionnaire included product names, adherence to the claimed amount, and AE experiences. The safe intake amount was estimated by the relationship between the claimed amount of CFE and the frequencies of AEs of each product. The number of users who experienced AEs was 75 (10.5% of all users). Gastrointestinal symptoms accounted for 92.0% (n = 69) of all AEs, and diarrhea alone accounted for 81.3% (n = 61). The amount of CFE was significantly associated with the occurrence of diarrhea (p = 0.005). The fitted curve showed that the safe intake amount of CFE was less than 250 mg/day; however, considering its effectiveness, 500 mg/day of CFE might be acceptable. In conclusion, nationwide online surveys of users enable us to confirm and reevaluate the safety of herbal supplements.

Nationwide Online Survey to Complement the Current Voluntary Reporting System for Adverse Events Associated with Dietary Supplements: Application to the Case of Skin Manifestations.

The current adverse event reporting system for dietary supplements lacks the ability to collect and analyze ongoing case reports in sufficient numbers to detect health issues. We conducted an online survey to collect data on skin manifestations due to supplement use in consumers and to identify the suspected products and ingredients. An online survey was conducted among 63,737 dietary supplement users in 2016. Those who self-reported experiences of skin anthema or itching caused by supplement use and recognized a causal relationship as almost certain (0.8%) were invited to provide further details of symptoms and products. Most of the users experienced mild symptoms with "itching and/or rash of body part." After the onset of skin manifestations, 69.3% ceased supplement use, while 26.6% continued supplement use, including those who reduced the amount or frequency of use. Respondents who visited the hospital in response to symptoms accounted for 26.0%, while 53.3% did not seek treatment. The products used were identified in 155 of 300 eligible respondents. Although those products were composed of multiple ingredients, the accumulated data suggested that cutaneous symptoms were related to the following constituents: "Peptides or animal by-products" (31.0%), "Herbal/Botanical" (23.2%) and "Fats and lipid" (13.5%). Conducting an online survey to elicit information directly from consumers identified components of supplements that are involved in skin manifestations that could lead to serious damage, and may fill a void in the current adverse event reporting system.

The Prevalence of Dietary Supplement Use Among Elementary, Junior High, and High School Students: A Nationwide Survey in Japan.

The prevalence of dietary supplement use, such as vitamins, minerals, or fish oil, has increased among children in Japan; however, whether children are using dietary supplements appropriately remains unclear. This study aimed to determine dietary supplement use among children. In August 2017, a nationwide internet preliminary survey of 265,629 mothers aged from 25 to 59 years old was undertaken. Of these, 19,041 mothers of children attending either elementary school, junior high school, or high school were selected. Among them, 16.4% were currently providing their children with dietary supplements and 5.2% had previously given dietary supplements to their children. The prevalence of dietary supplement use was higher in boys than in girls, and the prevalence increased according to their grade. A total of 2439 participants were eligible to undertake a targeted survey on dietary supplement use. Dietary supplements were being taken to maintain health, supplement nutrients, and enhance growth in both boys and girls, and many children (37.5%) were provided with vitamin and mineral supplements. Mothers mainly obtained information concerning dietary supplements via the internet, and supplements were purchased in drug stores or via the internet. The prevalence of dietary supplement use in mothers was 65.4% and may be associated with the prevalence rates in children. Some mothers reported adverse events (3.6%) in their children, such as stomachache, diarrhea, nausea and vomiting, and constipation. The cause-and-effect relationships for adverse events were not clear, but some children were given products for adults. Children are more influenced by dietary supplements compared to adults. To prevent adverse events due to inappropriate use, parental education concerning dietary supplements is essential.

[Nationwide Online Survey Method to Estimate Ongoing Adverse Events Caused by Supplement Use: Application to Diarrhea].

The current adverse event reporting systems are inadequate to prevent potential health damage caused by dietary supplement use, and a better case-collecting system is needed. The aim of this study was to examine whether online surveys would be a useful methodology for estimating ongoing adverse events, focusing on diarrhea as a model symptom. We used four online survey companies and requested that they administer the same questionnaire to their registrants regarding experiences of adverse events associated with supplement use and details of diarrhea symptoms, as well as the product and ingredient names of suspected supplements. Of 78,220 dietary supplement users, 9% to 25% reported experiencing adverse events in the previous year. A total of 723 participants who answered affirmatively about a putative causal relationship between supplement use and the onset of diarrhea and who clearly identified the product and/or ingredient were eligible for final analysis. Comparisons among the survey companies showed differences in the proportions of reported symptoms; however, the rank orders were consistent in the preliminary survey. Also, when analysis was limited to specific participants from a full-scale survey, even the numerical values of the proportions were consistent among the four companies. Herbal/botanical ingredients, specifically Coleus forskohlii, were the ingredients most frequently reported to be associated with diarrhea. These results indicate that online survey can be a useful method to complement the current system for estimating ongoing adverse events and identifying the responsible supplements.

Medical cost savings in Sakado City and worldwide achieved by preventing disease by folic acid fortification.

The introduction of mandatory fortification of grains with folate in 1998 in the United States resulted in 767 fewer spina bifida cases annually and a cost saving of $603 million per year. However, far more significant medical cost savings result from preventing common diseases, including myocardial infarction, stroke, dementia and osteoporosis. A cost-effectiveness analysis showed a gain of 266 649 quality-adjusted life-years and $3.6 billion saved annually, mainly due to the reduction of cardiac infarction. The recommended folate intake in Japan is 240 µg/day whereas it is 400 µg/day internationally. Our Sakado Folate Project targeted individuals with genetic polymorphism of methylenetetrahydrofolate reductase or with hyperhomocysteinemia. Using, for example, folate-fortified rice, resulted in an increase in serum folate and a decrease in serum homocysteine in the participants, and reduced medical costs were achieved by decreasing myocardial infarction, stroke, dementia and fracture. Due to the small population of Sakado City (approximately 101 000) and small number of births (693) in 2015, a decrease in spina bifida could not be confirmed but there was a significant decrease in the number of very low birthweight infants. The genome notification of subjects was effective in motivating intake of folate, but the increase in serum folate (from 17.4 to 22.5 nmol/L, 129%) was less than that observed following compulsory folic acid fortification of cereals in the USA (from 12.1 to 30.2 nmol/L, 149.6%). Mandatory folic acid fortification is cheap in decreasing medical costs and is thus recommended in Japan.