The EFSA’s use of a default methodology for establishment of a health-based guidance value (HBGV) from a neurobehavioral study resulted in an acceptable daily intake (ADI) for glutamates (E620-625) of 30 mg/kg bw/day which is below the normal dietary glutamate intake, and lower than the intake of free glutamate by breast fed babies. To resolve this dilemma, the present study investigated the interspecies variability in plasma glutamate levels to define a chemical-specific adjustment factor (CSAF) for the interspecies variation in kinetics (AKAF). Human, mouse and rat plasma glutamate levels available following the administration of MSG in a standard liquid diet (Sustagen) and water were analysed. The normalized Cmax values resulted in a AKAF value of 1 following administration in food and 1.4 in water in a fasted state. The administration in a food vehicle being the more applicable mode of dietary consumption for MSG. Combining these numbers with the (HKAF) for interindividual human differences in glutamate kinetics value of 2 and the default factors for interspecies and interindividual differences in dynamics of 2.5 and 3.16, results in an overall CSAF of 16. This CSAF results in a HBGV for glutamate that is no longer below the acceptable range of oral intake.

The pharmacokinetics and metabolism of [14C]-siamenoside I were studied following single oral doses of 5 mg/kg bodyweight with intact and bile duct-cannulated rats. Elimination of radioactivity was rapid and essentially complete by the end of the sample collection period (0-168 h), with the primary excretion route being the feces (101 % males and 92 % females). The estimate of absorption determined from the level of radiolabel in the bile of bile duct-cannulated rats was approximately 43 % in males and 42 % in females. The resultant systemic exposure as determined via urinary as well as blood and plasma radioactivity levels was low relative to the administered dose with only 1-1.5 % eliminated in intact and bile duct-cannulated male and female urine. Blood, plasma and tissue radioactivity levels were rapidly and widely distributed with the overall distribution low relative to administered dose. Metabolism of siamenoside I, to mogrol following cleavage of the sugar groups was the major component of feces (53-59 %), which appears to occur in the gastrointestinal tract prior to absorption. This was supported by mogrol being a significant component of radioactivity in plasma and tissues. The biotransformation of absorbed radioactivity also involved formation of several oxidized metabolites of mogrol, generally addition of oxygen and/or dehydrogenation. Overall absorption and subsequent excretion of [14C]-siamenoside I was similar in male and female rats as determined by the levels of radioactivity present in the urine and bile with no evidence of accumulation or retention observed in any tissue.

Miraculin is a glycoprotein present in miracle fruit berries (Richadella dulcifica or Synsepalum dulcificum) known to have taste modifying properties: conversion of sour into sweet taste. So far, research has shown that the effects occur when consuming miracle fruit powder or miracle fruit berries prior to consumption of a sour drink or food product. However, limited research has examined the effects of miraculin consumed within a food or drink product and if there might be any taste-modifying effects on other food and drinks consumed subsequently. This research looks at miraculin, from freeze-dried miracle fruit powder, served within model soft drink formulations at concentrations ethically approved for consumption in soft drink beverages (50 and 80 ppm miracle fruit powder). Three experiments were carried out. The first investigated how long any taste-modifying effects would last following consumption and whether the effects were dose-dependent. Experiment 2 looked at the effect of repeated exposure on perception of sweet, sour, and bitter tastes, whilst experiment 3 explored whether the receptor binding of miraculin in miracle fruit powder would affect sweetness perception of other sweeteners. All results showed minimal effects of using freeze-dried miracle fruit powder within a model beverage at the 50 and 80 ppm levels suggesting that future water-based beverages produced containing low levels of miraculin protein will have little or no taste-modifying effects on foods and beverages subsequently consumed.Practical ApplicationsMiraculin, derived from miracle fruit berries, acts as a taste modifier and can change food or drink from tasting sour to tasting sweet. This property is known to occur if either a fresh or freeze-dried powder of miraculin is ingested before food or drink. Miraculin has potential as an ingredient in water-based beverages to enhance sweetness, reduce the undesirable aftertaste associated with some high-potency sweeteners, and to add mouthfeel. However, until now, it was unknown whether, by adding miraculin to a beverage at levels considered safe for human consumption, the taste of other foods consumed with or after the beverage would be affected. Here, we show that a low level of miraculin protein within a water-based beverage has little to no taste-modifying effects on products that are subsequently consumed. Our study therefore opens new avenues for using miraculin as a taste modifier.

Caffeine is the one of the most widely consumed food ingredients in the world. Every day, millions of people around the world enjoy beverages and other foods containing caffeine including coffee, tea, soft drinks, and chocolate. It has been estimated that in the order of 2.25 billion cups of coffee, the major source of dietary caffeine, are served every day, and that more than 80% of the world’s population consume at least one caffeine-containing beverage on a daily basis. Global consumption of coffee for the year 2018–19 was estimated in the order of 165.35 million bags (each bag weights approximately 60 kg) or approximately 10 million tons, making coffee the world's most consumed substance (ICA 2018–2019). As a food ingredient, caffeine also has one of the longest histories of human consumption due to its natural occurrence in the beans, leaves, or fruit of more than 60 different plants including coffee, tea, guarana, cola nuts, and cocoa pods.

The developmental neurotoxicity of calcium cyclamate was evaluated in Sprague Dawley [Crl:CD(SD)] rats, administered in drinking water, in comparison to a concurrent control group (water) and a positive control group given propylthiouracil (PTU). Calcium cyclamate was administered to F0 females for 4 weeks prior to pairing, throughout mating, gestation and lactation and to F1 offspring from weaning to 12 weeks of age, PTU was administered by gavage to F0 females from Day 6 of gestation up to Day 20 of lactation. Target calcium cyclamate doses were 0, 250, 500 and 1,000 mg/kg bw/day, while the PTU dose was 0.5 mg/kg bw/day. No treatment-related effects of cyclamate were observed in either the F0 or F1 generations on reproductive performance or neurobehavioral development. In comparison, PTU exposure resulted in developmental delays, memory impairment and a number of neuropathological and morphometric outcomes. The results from the unique developmental neurotoxicity study design, corroborate the absence of hyperactivity and any other neurotoxic effects following cyclamate administration at levels up to 878 mg/kg bw/day in F0 females and 784 mg/kg bw/day in F1 animals. This demonstrates the suitability of PTU as a positive control and confirms the safe use of cyclamate as a no-calorie sweetener.

The increase of the prevalence of type-2 diabetes as a consequence of overweight and obesity has stimulated public health authorities worldwide to develop strategies for its risk management and prevention. Among them, a reduction on the content of sugar in sugar-sweetened foods and beverages has been suggested, which led the food industry to replace partially sucrose with food additives, such as low- and no-calorie sweeteners (LNCS). As a consequence, there has been an increase of their consumption, which has made regulatory agencies to evaluate their exposure and possible consequences. At the same time, speculations about adverse effects, such as carcinogenicity, preterm delivery and metabolic changes involving appetite, weight increase and glucose intolerance, have been published. This scenario led ILSI Brasil to organize a meeting to update scientific knowledge on the safety of LNCS and to promote discussions among academia, regulatory bodies and food industries to clarify currently controversial information. The results of this initiative are presented in this review. It is suggested that LNCS, when used according to recommendations provided by scientific committees and regulatory authorities are considered safe. Further studies are required to evaluate the current level of exposure in general population and specific ones as children.

Abstract Glutaminase (glutamine aminohydrolase EC 3.5.1.2) is used in the production of food ingredients rich in l‐glutamic acid that are added to finished foods for the purpose of enhancing or improving the savory flavor profile of food. The glutaminase enzyme preparation evaluated in these studies, designated as Sumizyme GT hereafter, is obtained by fermentation of Aspergillus niger strain GT147. The safety of Sumizyme GT was evaluated in a series of standard toxicological studies, including a 90‐day oral toxicity study in rats, an in vitro bacterial reverse mutation assay, an in vitro mammalian chromosome aberration test, and an in vivo alkaline Comet assay. Sumizyme GT was not mutagenic or genotoxic, and administration of the enzyme by gavage at doses up to 2,570 mg total organic solids (TOS)/kg body weight (bw) per day for 90 days was without any systemic toxicity. The no‐observed‐adverse‐effect level was concluded to be 2,570 mg TOS/kg bw per day, the highest dose tested. Considering that A. niger has an established history of safe use in the food industry and its safety in the production of food ingredients and food enzymes is well documented, the results of these studies provide further support of the safety of glutaminase from A. niger when used in food production.

Low/no-calorie sweeteners (LNCS) are continually under the spotlight in terms of their safety and benefits; in 2014 a study was published linking LNCS to an enhanced risk of glucose intolerance through modulation of the gut microbiota. In response, an in-depth review of the literature was undertaken to evaluate the major contributors to potential changes in the gut microbiota and their corresponding sequelae, and to determine if consuming LNCS (e.g., acesulfame K, aspartame, cyclamate, neotame, saccharin, sucralose, steviol glycosides) contributes to changes in the microbiome based on the data reported in human and animal studies. A few rodent studies with saccharin have reported changes in the gut microbiome, but primarily at high doses that bear no relevance to human consumption. This and other studies suggesting an effect of LNCS on the gut microbiota were found to show no evidence of an actual adverse effect on human health. The sum of the data provides clear evidence that changes in the diet unrelated to LNCS consumption are likely the major determinants of change in gut microbiota numbers and phyla, confirming the viewpoint supported by all the major international food safety and health regulatory authorities that LNCS are safe at currently approved levels.

Given the widespread use of the low-calorie sweetener aspartame over the last 30 years, the current work was undertaken to evaluate aspartame epidemiology studies looking at cancer endpoints against quality appraisal criteria. The quality appraisal tool used was from the National Heart, Lung and Blood Institute (NHLBI) of the National Institute of Health. Studies identified included nine case-control studies and five prospective cohort studies. Most studies assessed low-calorie or diet beverages rather than aspartame intake specifically; however, common use of aspartame in diet sodas does allow for some general extrapolation of results. Following consideration of study quality, two case-control and five prospective studies were considered to meet the majority of the NHLBI criteria. The primary limitation of the other case-control studies was an inadequate sample size. Overall, the results of the studies do not support that exposures to low and no-calorie sweeteners and beverages, and by extension aspartame, are associated with an increased risk of cancer in humans.

AbstractArabinase is an enzyme recognized for its ability to degrade arabinan, a plant cell wall constituent. It has been applied in the food industry most commonly for juice processing. One commercial source of arabinase is Aspergillus tubingensis (A. tubingensis), a black Aspergillus species. Given the intended use in food for human consumption, and noting its potential presence at trace levels in finished products, a series of safety studies including in vitro Ames and chromosome aberration assays, in vivo mammalian erythrocyte micronucleus and alkaline comet assays, and a 90‐day rat oral toxicity study were conducted. No test article‐related mutagenic activity was observed in the Ames assay. Although positive activity was observed in the chromosome aberration assay, this was not replicated in the in vivo genotoxicity assays including in preabsorptive cells. In the subchronic toxicity study, no test article‐related adverse effects were observed following oral administration of arabinase at doses of 15.3, 153, or 1,530 mg total organic solids (TOS)/kg body weight/day to Sprague Dawley rats. The no‐observed‐adverse‐effect level was considered to be the highest dose tested (1,530 mg TOS/kg body weight/day). The results of the genotoxicity studies and the subchronic toxicity study support the safe use of arabinase from A. tubingensis in food production.

Miraculin is a glycoprotein with the ability to make sour substances taste sweet. The safety of miraculin has been evaluated using an approach proposed by the Food and Agriculture Organization of the United Nations and the World Health Organization for assessing the safety of novel proteins. Miraculin was shown to be fully and rapidly digested by pepsin in an in vitro digestibility assay. The proteomic analysis of miraculin's pepsin digests further corroborated that it is highly unlikely that any of the protein will remain intact within the gastrointestinal tract for potential absorption. The potential allergenicity and toxigenicity of miraculin, investigated using in silico bioinformatic analyses, demonstrated that miraculin does not represent a risk of allergy or toxicity to humans with low potential for cross-reactivity with other allergens. The results of a sensory study, characterizing the taste receptor activity of miraculin, showed that the taste-modifying effect of miraculin at the concentration intended for product development has a rapid onset and disappearance with no desensitizing impact on the receptor. Overall, the results of this study demonstrate that the use of miraculin to impact the sensory qualities of orally administered products with a bitter/sour taste profile is not associated with any safety concerns.

The current review assessed cancer studies of aspartame based on a quality appraisal using the Klimisch grading system. Nine studies having complete histopathology were included: three 2-year studies by Searle; three transgenic mice studies by the NTP; three lifetime studies by the Ramazzini Institute. A tenth study limited to brain tumors was not rated. None were determined as Klimisch Code 1 (reliable without restrictions). The Searle studies predated GLP standards but their methodology was comparable; transgenic mouse models are not validated, but are accepted as supporting data. These studies were rated Klimisch Code 2 (reliable with restrictions). The Ramazzini Institute used a lifetime model of their own design that has been questioned due to high rates of spontaneous tumors, issues with tumor type diagnosis and concerns about the impact of chronic infections. As many of these problems could be attributed to using animals that died or were terminated near end of life, along with the other problems noted, these studies were rated Klimisch Code 3 (not reliable). As the Klimisch Code 2 studies demonstrated a lack of carcinogenic potential, and as aspartame is hydrolyzed to common components and lacks genotoxic activity, a conclusion that aspartame is not carcinogenic is supported.

Researchers from the Ramazzini Institute have reported that lifespan dosing of rats with aspartame treatment is associated with an increased overall incidence of malignant tumors, including leukemias/lymphomas, transitional cell carcinomas of the renal pelvis/ureter, and malignant schwannomas of the peripheral nerves. Other carcinogenicity studies conducted on aspartame have shown no such carcinogenic potential in any organ system. Additional data to assess the carcinogenic potential of aspartame, especially in relation to the publications of the Ramazzini Institute, were obtained from a third-party histological evaluation of tissues from a carcinogenicity study previously conducted to assess the potential for aspartame to induce tumors of the brain. The results of this histological evaluation provide no evidence of a tumorigenic effect of aspartame in any organ group, including those organs/tissues reportedly affected in the Ramazzini Institute's studies. The only effects identified were an increased incidence of renal pelvic mineralization and renal pelvic hyperplasia secondary to the irritant properties of the mineralization process. The toxicological significance of these particular findings is widely considered minimal. There is no evidence that aspartame is carcinogenic in rats, at least to doses of 4 g/kg body weight/day administered over a 2-year period.

The 2018 Dietary Glutamate Workshop was organized and sponsored by the International Glutamate Technical Committee to provide a platform for a broad expert discussion on all relevant aspects of glutamate metabolism and safety in human nutrition. The participants reached a consensus with previous safety evaluations conducted by the global expert bodies, but contradicted the 2017 re-evaluation of dietary glutamates by the European Food Safety Authority, which proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight per day. The participants of the Workshop concluded that the present knowledge on metabolism, kinetics, developmental and general toxicity of dietary glutamates did not warrant a change in the previous ADI of “not specified.”

Background: Re-evaluation of the use of glutamic acid and glutamate salts (referred to as glutamate hereafter) by the European Food Safety Authority (EFSA) proposed a group acceptable daily intake (ADI) of 30 mg/kg body weight (bw)/day. Summary: This ADI is below the normal dietary intake, while even intake of free glutamate by breast-fed babies can be above this ADI. In addition, the pre-natal developmental toxicity study selected by EFSA, has never been used by regulatory authorities worldwide for the safety assessment of glutamate despite it being available for nearly 40 years. Also, the EFSA ignored that toxicokinetic data provide support for eliminating the use of an uncertainty factor for interspecies differences in kinetics. Key Messages: A 3-generation reproductive toxicity study in mice that includes extensive brain histopathology, provides a better point of departure showing no effects up to the highest dose tested of 6,000 mg/kg bw/day. Furthermore, kinetic data support use of a compound-specific uncertainty factor of 25 instead of 100. Thus, an ADI of at least 240 mg/kg bw/day would be indicated. In fact, there is no compelling evidence to indicate that the previous ADI of “not specified” warrants any change.

Emulsifiers are commonly used in food processing for the technological purpose of altering the flavor or to improve the texture of foods. Due to their ubiquity, these substances are consumed daily at low levels in the human diet. Recently published in vitro and in vivo studies suggest dietary exposure to emulsifiers modulate the gut microbiota and contribute to the increasing prevalence of metabolic disease. A literature search was conducted which identified eight studies investigating the interaction of sodium carboxymethyl cellulose, polysorbate 80, gum arabic, carrageenan, and arabinogalactan with the gut microbiota in murine and in vitro models. Numerous inconsistent changes in various phyla and genera were identified. These studies were conducted at high doses that have no relevance to the current dietary levels consumed in the United States. Subtle changes in gut microbiota composition as a toxicological endpoint is not supported by established internationally recognized toxicology testing guidelines. Therefore, the results of these studies are difficult to interpret and extrapolate to humans and are not supported by previous safety conclusions of international food safety authorities. The current understanding of the gut microbiota is that the structure is highly dynamic and is heavily influenced by the diet. Thus, the results of these studies may not necessarily suggest a safety concern, but rather reflect an adaptive response of the gut microbiota to an external stressor. Future research will need to further elucidate the mechanisms of metabolic disease in rodents and humans and establish clinically relevant and reliable endpoints to assess changes in gut microflora.