A survey by the United States Food and Drug Administration (USFDA), in 2008, has revealed that more than 80 nanomaterial-containing food and drink items were available for consumption around the world at that time, and estimated that the Japanese market for nanomaterial-containing food could reach 250 billion yen in 2030. Potential uses of nanotechnology have been identified in almost all segments of the industry, including the following four key areas: agriculture, nutritional supplements and nutraceuticals, food processing, and food packaging. Despite a rapid development of its use in the food sector, little is known about the in vivo and in vitro kinetics of nanomaterials. Consequently, the risks of nanomaterials have not been analyzed. Nanoparticles are reported to be absorbed across the intestinal barrier via transcellular, paracellular, and junctional pathways, but the bioavailability of each material may be different due to different effects of various factors. Questions about these compounds already raised safety concerns, although the history of their use in the food sector is yet short. In this review, we overview the currently available information regarding the safety of the three main nanomaterials used in the food industry to provide the scientific basis for the risk assessments that are necessary for the development and safe use of nanomaterials in the food sector.
The present work provides a brief review of basic concepts in developmental neurotoxicology, as well as current representative testing guidelines for evaluating developmental neurotoxicity (DNT) of xenobiotics. Historically, DNT was initially recognized as a “functional” teratogenicity: the main concern was that prenatal and/or early postnatal exposures to chemicals during critical periods of central nervous system (CNS) development would cause later functional abnormalities of the brain. Current internationally harmonized DNT study guidelines are thus intended to predict adverse effects of test compounds on the developing CNS by observing such postnatal parameters as motor activity, startle response, and learning and memory, as well as neuropathological alterations. The reliability of current DNT study guidelines and sensitivity of testing methodologies recommended in these guidelines have been confirmed by retrospective evaluations of the many international and domestic collaborative validation studies in developed nations including Japan.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on ochratoxin A (hereinafter referred to as OTA) as a self-tasking risk assessment. OTA is a mycotoxin produced by fungal species such as Aspergillus ochraceus and Penicilium verrucosum, which occur mainly in stored foods. Food contamination with OTA has been reported in various food commodities including cereal, coffee, cocoa, beer and wine. Nephrotoxicity was observed in all the animal species examined in the subacute toxicity studies. Pathological changes observed in the studies are karyomegaly and cytomegaly as well as tubular atrophy and degeneration in proximal tubules at the outer zone of renal medulla. The dose- and treatment period-dependent changes were observed in kidneys in rats and pigs. In chronic toxicity/carcinogenicity studies with oral administration, tumor induction was observed at the outer zone of renal medulla in rodents, mainly in male rats. Chromosome aberration was observed both in in vitro and in vivo genotoxicity studies, but gene point mutation was not detected. After reviewing the results of various toxicological studies, FSCJ considered that OTA is a non-genotoxic carcinogen acting indirectly on DNA, and that tolerable daily intake (TDI) is able to be specified for OTA. Regarding non-carcinogenic toxicity of OTA, the effects observed at the lowest dose in various studies were decreased ability to concentrate urine and degenerative changes in epithelial cells of the tubules observed in a 120-day subacute toxicity study in pigs. The lowest-observed-adverse-effect level (LOAEL) in these studies was set at 8 µg/kg bw/day. FSCJ specified the TDI of 16 ng/kg bw/day, applying an uncertainty factor of 500 (10 for species difference, 10 for individual difference and 5 for the use of LOAEL based on irreversible renal failure indices) to the LOAEL. Regarding carcinogenicity of OTA, FSCJ specified the TDI of 15 ng/kg bw/day, applying an uncertainty factor of 1000 (10 for species difference, 10 for individual difference and 10 for carcinogenicity) to the no-observed-adverse-effect level (NOAEL) of 15 µg/kg bw/day, which was derived from a two-year carcinogenicity study in rats (administered 5 times a week at 21 µg/kg bw) performed by the National Toxicology Program (NTP). The estimated exposure levels of OTA in Japan for average (the 50th percentile) and high risk consumers (the 95th percentile) are 0.14 ng/kg bw/day and 2.21 ng/kg bw/day, respectively. These estimations suggest the intake of OTA to be below the TDI even in the high risk consumers. Therefore, FSCJ considers that no apparent adverse effect is expected in Japan from the current risk estimate. OTA-producing fungi grow in agricultural products and food under different environmental conditions. OTA contamination in these products varies depending on environmental conditions such as climate. Therefore, the risk management organizations are encouraged to monitor OTA contamination in foods continuously. The monitoring is a key importance to consider the necessity of the regulation for OTA.
The Food Safety Commission of Japan (FSCJ) conducted a risk assessment on foods highly containing diacylglycerol (DAG) (hereinafter referred to as DAG foods), based on results from various studies. The safety of DAG foods, as foods for specified health use, was once evaluated by the Pharmaceutical Affairs and Food Sanitation Council of the Ministry of Health, Labour and Welfare (MHLW). On September 11, 2003, FSCJ approved the evaluation of the MHLW’s council to be appropriate. Subsequent MHLW’s two-stage carcinogenicity studies on edible oils highly containing DAG (hereinafter referred to as DAG oils) conducted from September 2005 to February 2009 supported the MHLW’s judgment “No concern relevant to human health even though all the edible conventional oils were substituted with DAG oils”. FSCJ continued to conduct also a risk assessment of DAG oils focusing on the minor constituent, glycidol fatty acid esters (GE). DAG oils and related products have been, however, retracted from the market in September 2009 in Japan. DAG foods are thus unlikely to expose people, and no further data necessary for the assessment are available on the consumption of DAG foods (period, amount, age, etc.) and varieties of confounding factors in lifestyle. Lack of individual data on the exposure makes it difficult from the reliable estimation of lifetime cancer risk. The food safety assessment thus could not be completed. Current scientific considerations on the possible adverse effects of DAG oils and GE as contaminants in food oils are summarized in the appendices.
As a part of a safety assessment of foods highly containing diacylglycerol (DAG), the Food Safety Commission of Japan (FSCJ) conducted a safety assessment of glycidol and its fatty acid esters (GE) in foods based on results from various studies. The level of GE in the currently available edible oils is maintained as minute, and even if all of the GE were assumed to be converted to the equimoles of glycidol in the body, the extra risks of tumor incidence were estimated to be very low, and a certain level of margin of exposure (MOE), slightly lower than 10,000, was allocated. Additionally, so far no reports on adverse effects of consuming oils containing GE on human health have been reported. While these data suggest no apparent adverse effects due to the consumption of edible oils currently available, the genotoxic carcinogenicity of glycidol was not denied. Therefore, GE exposure levels should be kept as low as possible according to the principle of ALARA (As Low As Reasonably Achievable).