Risk assessment of azo dyes as food additives: Revision and discussion of data gaps toward their improvement.

The food industry uses dyes mainly to overcome color loss during the processing and storage of products, with the azo dyes currently being the most employed. Studies on the safety of using these dyes in foods started in the 1950s and have indicated the potential for concern. This review discusses the risk assessment of food intake containing artificial azo dyes. There are case reports and, subsequently, double-blind placebo-controlled trials in some individuals who may experience adverse effects from the intake of azo dyes, but it is unclear whether these adverse effects are restricted to specific populations or more generalized. In view of this, different toxicological endpoints are evaluated to verify toxic effects in in vitro and in vivo models and to establish the no observed adverse effect level. Exposure estimation studies have shown that human exposure to azo dyes via oral intake is mainly below the acceptable daily intake established by advisory bodies. However, most countries do not have studies that estimate the oral intake of azo dyes. In this case, local food diversity and racial-ethnic specificities are not considered when stating the exposure estimate is below the acceptable daily intake for the human population and thus may not represent actual intake. Concerning the scenario established above, this review discusses the most critical gaps to be overcome to contribute to the direction of future studies and the development of more effective public policies concerning the safety of the intake of artificial azo dyes.

Food additive emulsifiers: a review of their role in foods, legislation and classifications, presence in food supply, dietary exposure, and safety assessment.

Food additive intakes have increased with the increase in "ultra-processed" food consumption. Food additive emulsifiers have received particular research attention in recent years due to preliminary evidence of adverse gastrointestinal and metabolic health effects. In this review, the use of emulsifiers as food additives is discussed, and the current estimations of exposure to, and safety of, emulsifiers are critically assessed. Food additive emulsifier research is complicated by heterogeneity in additives considered to be emulsifiers and labelling of them on foods globally. Major limitations exist in estimating food additive emulsifier exposure, relating predominantly to a lack of available food occurrence and concentration data. Development of brand-specific food additive emulsifier databases are crucial to accurately estimating emulsifier exposure. Current research on the health effects of food additive emulsifiers are limited to in vitro and murine studies and small, acute studies in humans, and future research should focus on controlled human trials of longer duration.

Edible additive effects on zebrafish cardiovascular functionality with hydrodynamic assessment.

Food coloring is often used as a coloring agent in foods, medicines and cosmetics, and it was reported to have certain carcinogenic and mutagenic effects in living organisms. Investigation of physiological parameters using zebrafish is a promising methodology to understand disease biology and drug toxicity for various drug discovery on humans. Zebrafish (Danio rerio) is a well-acknowledged model organism with combining assets such as body transparency, small size, low cost of cultivation, and high genetic homology with humans and is used as a specimen tool for the in-vivo throughput screening approach. In addition, recent advances in microfluidics show a promising alternative for zebrafish manipulation in terms of drug administration and extensive imaging capability. This pilot work highlighted the design and development of a microfluidic detection platform for zebrafish larvae through investigating the effects of food coloring on cardiovascular functionality and pectoral fin swing ability. The zebrafish embryos were exposed to the Cochineal Red and Brilliant Blue FCF pigment solution in a concentration of (0.02‰, 0.2‰) cultured in the laboratory from the embryo stage to hatching and development until 9 days post fertilization (d.p.f.). In addition, zebrafish swimming behaviors in terms of pectoral fin beating towards the toxicity screening were further studied by visualizing the induced flow field. It was evidenced that Cochineal Red pigment at a concentration of 0.2‰ not only significantly affected the zebrafish pectoral fin swing behavior, but also significantly increased the heart rate of juvenile fish. The higher concentration of Brilliant Blue FCF pigment (0.2%) increased heart rate during early embryonic stages of zebrafish. However, zebrafish exposed to food coloring did not show any significant changes in cardiac output. The applications of this proposed platform can be further extended towards observing the neurobiological/hydrodynamic behaviors of zebrafish larvae for practical applications in drug tests.

Aggregated aluminium exposure: risk assessment for the general population.

Aluminium is one of the most abundant elements in earth's crust and its manifold uses result in an exposure of the population from many sources. Developmental toxicity, effects on the urinary tract and neurotoxicity are known effects of aluminium and its compounds. Here, we assessed the health risks resulting from total consumer exposure towards aluminium and various aluminium compounds, including contributions from foodstuffs, food additives, food contact materials (FCM), and cosmetic products. For the estimation of aluminium contents in foodstuff, data from the German "Pilot-Total-Diet-Study" were used, which was conducted as part of the European TDS-Exposure project. These were combined with consumption data from the German National Consumption Survey II to yield aluminium exposure via food for adults. It was found that the average weekly aluminium exposure resulting from food intake amounts to approx. 50% of the tolerable weekly intake (TWI) of 1 mg/kg body weight (bw)/week, derived by the European Food Safety Authority (EFSA). For children, data from the French "Infant Total Diet Study" and the "Second French Total Diet Study" were used to estimate aluminium exposure via food. As a result, the TWI can be exhausted or slightly exceeded-particularly for infants who are not exclusively breastfed and young children relying on specially adapted diets (e.g. soy-based, lactose free, hypoallergenic). When taking into account the overall aluminium exposure from foods, cosmetic products (cosmetics), pharmaceuticals and FCM from uncoated aluminium, a significant exceedance of the EFSA-derived TWI and even the PTWI of 2 mg/kg bw/week, derived by the Joint FAO/WHO Expert Committee on Food Additives, may occur. Specifically, high exposure levels were found for adolescents aged 11-14 years. Although exposure data were collected with special regard to the German population, it is also representative for European and comparable to international consumers. From a toxicological point of view, regular exceedance of the lifetime tolerable aluminium intake (TWI/PTWI) is undesirable, since this results in an increased risk for health impairments. Consequently, recommendations on how to reduce overall aluminium exposure are given.

Food Additives and Child Health.

Increasing scientific evidence suggests potential adverse effects on children's health from synthetic chemicals used as food additives, both those deliberately added to food during processing (direct) and those used in materials that may contaminate food as part of packaging or manufacturing (indirect). Concern regarding food additives has increased in the past 2 decades in part because of studies that increasingly document endocrine disruption and other adverse health effects. In some cases, exposure to these chemicals is disproportionate among minority and low-income populations. This report focuses on those food additives with the strongest scientific evidence for concern. Further research is needed to study effects of exposure over various points in the life course, and toxicity testing must be advanced to be able to better identify health concerns prior to widespread population exposure. The accompanying policy statement describes approaches policy makers and pediatricians can take to prevent the disease and disability that are increasingly being identified in relation to chemicals used as food additives, among other uses.

Food Additives and Child Health.

Our purposes with this policy statement and its accompanying technical report are to review and highlight emerging child health concerns related to the use of colorings, flavorings, and chemicals deliberately added to food during processing (direct food additives) as well as substances in food contact materials, including adhesives, dyes, coatings, paper, paperboard, plastic, and other polymers, which may contaminate food as part of packaging or manufacturing equipment (indirect food additives); to make reasonable recommendations that the pediatrician might be able to adopt into the guidance provided during pediatric visits; and to propose urgently needed reforms to the current regulatory process at the US Food and Drug Administration (FDA) for food additives. Concern regarding food additives has increased in the past 2 decades, in part because of studies in which authors document endocrine disruption and other adverse health effects. In some cases, exposure to these chemicals is disproportionate among minority and low-income populations. Regulation and oversight of many food additives is inadequate because of several key problems in the Federal Food, Drug, and Cosmetic Act. Current requirements for a "generally recognized as safe" (GRAS) designation are insufficient to ensure the safety of food additives and do not contain sufficient protections against conflict of interest. Additionally, the FDA does not have adequate authority to acquire data on chemicals on the market or reassess their safety for human health. These are critical weaknesses in the current regulatory system for food additives. Data about health effects of food additives on infants and children are limited or missing; however, in general, infants and children are more vulnerable to chemical exposures. Substantial improvements to the food additives regulatory system are urgently needed, including greatly strengthening or replacing the "generally recognized as safe" (GRAS) determination process, updating the scientific foundation of the FDA's safety assessment program, retesting all previously approved chemicals, and labeling direct additives with limited or no toxicity data.

Nanomaterials in food and agriculture: An overview on their safety concerns and regulatory issues.

Nanotechnology has seen exponential growth in last decade due to its unique physicochemical properties; however, the risk associated with this emerging technology has withdrawn ample attention in the past decade. Nanotoxicity is majorly contributed to the small size and large surface area of nanomaterials, which allow easy dispersion and invasion of anatomical barriers in human body. Unique physio-chemical properties of nanoparticles make the investigation of their toxic consequences intricate and challenging. This makes it important to have an in-depth knowledge of different mechanisms involved in nanomaterials's action and toxicity. Nano-toxicity has various effects on human health and diseases as they can easily enter into the humans via different routes, mainly respiratory, dermal, and gastrointestinal routes. This also limits the use of nanomaterials as therapeutic and diagnostic tools. This review focuses on the nanomaterial-cell interactions leading to toxicological responses. Different mechanisms involved in nanoparticle-mediated toxicity with the main focus on oxidative stress, genotoxic, and carcinogenic potential has also been discussed. Different methods and techniques used for the characterization of nanomaterials in food and other biological matrices have also been discussed in detail. Nano-toxicity on different organs-with the major focus on the cardiac and respiratory system-have been discussed. Conclusively, the risk management of nanotoxicity is also summarized. This review provides a better understanding of the current scenario of the nanotoxicology, disease progression due to nanomaterials, and their use in the food industry and medical therapeutics. Briefly, the required rules, regulations, and the need of policy makers has been discussed critically.

Application of hydrolases and probiotic Pediococcus acidilactici BaltBio01 strain for cereal by-products conversion to bioproduct for food/feed.

The aim of this study was to apply the enzymatic treatment and fermentation by Pediococcus acidilactici BaltBio01 strain for industrial cereal by-products conversion to food/feed bioproducts with high amount of probiotic lactic acid bacteria (LAB). LAB propagated in potato media and spray-dried remained viable during 12 months (7.0 log10 cfu/g) of storage and was used as a starter for cereal by-products fermentation. The changes of microbial profile, biogenic amines (BAs), mycotoxins, lactic acid (L+/D-), lignans and alkylresorcinols (ARs) contents in fermented cereal by-product were analysed. Cereal by-products enzymatic hydrolysis before fermentation allows to obtain a higher count of LAB during fermentation. Fermentation with P. acidilactici reduce mycotoxins content in fermented cereal by-products. According to our results, P. acidilactici multiplied in potato juice could be used for cereal by-products fermentation, as a potential source to produce safer food/feed bioproduct with high amount of probiotic LAB for industrial production.

Japan Flavour and Fragrance Materials Association's (JFFMA) safety assessment of food-flavouring substances uniquely used in Japan that belong to the class of aliphatic primary alcohols, aldehydes, carboxylic acids, acetals and esters containing additional oxygenated functional groups.

We performed a safety evaluation using the procedure devised by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) of the following four flavouring substances that belong to the class of 'aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups' and are uniquely used in Japan: butyl butyrylacetate, ethyl 2-hydroxy-4-methylpentanoate, 3-hydroxyhexanoic acid and methyl hydroxyacetate. Although no genotoxicity study data were found in the published literature, none of the four substances had chemical structural alerts predicting genotoxicity. All four substances were categorised as class I by using Cramer's classification. The estimated daily intake of each of the four substances was determined to be 0.007-2.9 µg/person/day by using the maximised survey-derived intake method and based on the annual production data in Japan in 2001, 2005 and 2010, and was determined to be 0.250-600.0 µg/person/day by using the single-portion exposure technique and based on average-use levels in standard portion sizes of flavoured foods. Both of these estimated daily intake ranges were below the threshold of toxicological concern for class I substances, which is 1800 µg/person/day. Although no information from in vitro and in vivo toxicity studies for the four substances was available, these substances were judged to raise no safety concerns at the current levels of intake.

Shrinking the food-print: A qualitative study into consumer perceptions, experiences and attitudes towards healthy and environmentally friendly food behaviours.

Internationally, there is increasing recognition of the importance of multilevel policies and actions that address healthy and environmentally friendly food behaviours. However it is not yet clear which actions are most suitable to support consumers to adopt both behaviours concurrently. To this end, we undertook a qualitative study to assess consumer perceptions, experiences and attitudes towards healthy and environmentally friendly foods and four target behaviours: reducing overconsumption of food beyond energy needs, reducing consumption of low-nutrient energy dense foods, eating less animal- and more plant-derived foods, and reducing food waste. Online in-depth interviews were held with 29 Australian food shoppers representing different levels of involvement with health and environment in daily food choices. The results indicate that compared to health, the relationship between food and the environment is rarely considered by consumers. The four target food behaviours were primarily associated and motivated by an impact on health, except for not wasting foods. Participants had the most positive attitude and highest motivation for eating less processed and packaged foods, mostly to avoid excessive packaging and 'chemicals' in foods. This was followed by the behaviours reducing food waste and overconsumption. Conversely, there was a predominantly negative attitude towards, and low motivation for, eating less animal-derived products and more plant based foods. Overall, consumers found a joined concept of healthy and environmentally friendly foods an acceptable idea. We recommend that health should remain the overarching principle for policies and actions concerned with shifting consumer behaviours, as this personal benefit appears to have a greater potential to support behaviour change. Future consumer focused work could pay attention to framing behavioural messages, providing intermediate behavioural goals, and a multiple target approach to change habitual behaviours.

Safety assessment of a natural tomato oleoresin containing high amounts of Z-isomers of lycopene prepared with supercritical carbon dioxide.

BACKGROUND: Z-isomers of lycopene, which are abundantly present in processed tomato products, are more bioavailable than (all-E)-lycopene found predominantly in raw tomatoes. Despite extensive studies on the bioavailability and biological activities of Z-isomers of lycopene, detailed studies on their safety and toxicology are limited. RESULTS: The geno-, acute and subacute toxicities of tomato oleoresin that contained high amounts of lycopene Z-isomers (10.9% lycopene with 66.3% Z-isomer content) and had been prepared with supercritical carbon dioxide were investigated. The oleoresin was non-mutagenic in the Ames test with and without metabolic activation (S9 mix). The medial lethal dose (LD50 ) of the oleoresin in rats, as determined by a single-dose oral test, was more than 5000 mg kg body weight-1 (bw) [361 mg (Z)-lycopene kg bw-1 ]. In the 4-week repeated-dose oral toxicity test, rats were administered oleoresin at 4500 mg kg-1 day-1 [325 mg (Z)-lycopene kg bw-1 day-1 ]. There were no clinically significant changes with respect to vital signs, physical examination outcomes and laboratory test values during the test period. CONCLUSION: Based on our findings and as supported by its long history of consumption, tomato oleoresin that contains high amounts of Z-isomers of lycopene prepared with supercritical carbon dioxide can be considered as safe for human consumption. © 2016 Society of Chemical Industry.

Reviewing the Nutrition and Health Claims Regulation (EC) No. 1924/2006: What do we know about its challenges and potential impact on innovation?

Health claims potentially represent an opportunity for firms to engage in product differentiation and thereby induce investment into R&D and innovation in the food sector. The Nutrition and Health Claims Regulation (EC) No. 1924/2006 (NHCR) aims at protecting and promoting innovation as one of its objectives. However, existing studies indicate that this regulation may create several challenges for innovation in the food sector. To this end, we review the challenges related to the NHCR (Article 13.1) and its impact on innovation. Extant literature suggests that companies face challenges related to changing list of ingredients, missing transparency, wording of claims, limited financial resources, limited R&D resources, switching product categories and abandoning the functional foods sector. Moreover, current studies imply that so far the NHCR (in specific Article 13.1) does not seem to encourage innovation in the EU food sector.

Exploring the Nutrition and Health Claims Regulation (EC) No. 1924/2006: What is the impact on innovation in the EU food sector?

Literature suggests that despite its positive aim of promoting innovation, the Nutrition and Health Claims Regulation (EC) No. 1924/2006 (NHCR) may bring along several compliance challenges, which might affect innovation in the EU food sector. This study investigates the challenges faced by companies to comply with the NHCR (specifically Article 13.1) and their impact on innovation. To this end, we conducted an online survey with 105 companies involved in the EU food sector. Results indicate that companies perceive wording of claims, missing transparency and limited financial resources as major challenges to comply with the NHCR (Article 13.1). Companies reported not to have increased their R&D expenditure or innovation activities after the NHCR (Article 13.1) was implemented. Thus, this study highlights specific compliance challenges related to the NHCR (Article 13.1) and indicates that currently, the regulation does not seem to have fostered innovation in the EU food sector.

Advances in assessing ingredient safety.

The safety of food ingredients will be assessed in the 21st century by mixture of traditional methods, such as the "safe" dose concept, which is thought to be an accurate but imprecise estimation of dose below the population threshold for adverse effect, and contemporary methods, such as the Benchmark Dose (BMD), Chemical Specific Adjustment Factors (CSAF), physiologically-based pharmacokinetic models, and biologically-informed dose response modeling. New research on the horizon related to toxicology 21 may also improve these risk assessment methods, or suggest new ones. These traditional, contemporary and new methods and research will be briefly described.

Overview of the ISRTP October 2014 workshop on GRAS determinations.

On October 12-13, 2014 the ISRTP held a very successful Workshop on GRAS Determinations in Washington DC that was not only well-attended by seasoned public and private professionals from a wide swath of food safety disciplines but featured a series of very insightful and informative presentations from current and past officials from the US Food & Drug Administration (FDA). To stay true to our international nature as a Society, we had regulatory and industry representatives from Canada and Europe.

Chemistry, manufacturing and exposure assessments to support generally recognized as safe (GRAS) determinations.

Identity, stability, purity, intended use levels in what foods and technical effects, and probable intake are among the key components in an assessment to support GRAS determinations. The specifications of identity of a food substance are an important component of the safety assessment as changes in the physical and chemical properties of a food substance can influence its technical effect in food and can influence its nutritional or toxicological properties of the food substance. Estimating exposure is a key determining step in the safety evaluation of a food substance. Intake assessment in GRAS determination is necessarily comprehensive based on cumulative exposure, i.e. proposed new uses plus background dietary exposure. Intake estimates for safety assurance in a GRAS determination also represent conservative overestimate of chronic exposure as they are based on 2-day average daily intake and the upper percentile (90th) intake among consumers. In contrast, in a nutrient assessment where realistic intake estimates are of interest, usual intake estimates are relied upon. It should also be noted that intake estimates for GRAS determinations are also more conservative than estimate of dietary exposure by EPA (FIFRA), where mean per capita are used to assess chronic exposure. Overall, for safety assurance, intake assessments in GRAS determinations are comprehensively cumulative and typically conservative overestimate of exposures.

The relevance of international assessments to GRAS determinations.

A discussion of the risk assessment process as applied to the Generally Recognized As Safe (GRAS) determination of safety for new ingredients can benefit from an international perspective. When we think about how risk assessments are performed around the world it is critical to assess what can be learned. What are the similarities? What are the differences? What are the takeaways? It is important to talk about the similarities in processes, because it validates the approach taken by risk assessors who are charged with protecting the food supply. It is also instructive to evaluate the differences in order to determine where improvements can be made to our process.

A hard look at FDA's review of GRAS notices.

Generally Recognized as Safe (GRAS) substances are exempt from premarket approval; however, the standard of "reasonable certainty of no harm" is the same. In 1997, the voluntary GRAS affirmation process was replaced with the voluntary U.S. Food and Drug Administration (FDA) GRAS notice process. Under the GRAS notice process, pivotal safety data are required to be in the public domain, and consensus of safety among experts is required. FDA issues responses of "FDA has no questions", "Notice does not provide a basis for a GRAS determination", or, "At Notifier's request, FDA ceased to evaluate the notice." Of 528 notices reviewed, there were 393 "no questions letters", 17 "insufficient basis letters", and 84 "cease to evaluate letters". Of those deemed to be insufficient, most failed to meet the general recognition criteria. Only four raised questions about potential safety, of which three received a no questions letter upon providing more data. Of the 84 withdrawn notices, 22 received a no questions letter upon resubmission. In spite of criticisms, the FDA GRAS notice process is clearly defined, efficient, and cost-effective, and there have been no known public health issues following its implementation.

Critical review of the safety assessment of nano-structured silica additives in food.

The development of nano-materials is viewed as one of the most important technological advances of the 21st century and new applications of nano-sized particles in the production, processing, packaging or storage of food are expected to emerge soon. This trend of growing commercialization of engineered nano-particles as part of modern diet will substantially increase oral exposure. Contrary to the proven benefits of nano-materials, however, possible adverse health effects have generally received less attention. This problem is very well illustrated by nano-structured synthetic amorphous silica (SAS), which is a common food additive since several decades although the relevant risk assessment has never been satisfactorily completed. A no observed adverse effect level of 2500 mg SAS particles/kg body weight per day was derived from the only available long-term administration study in rodents. However, extrapolation to a safe daily intake for humans is problematic due to limitations of this chronic animal study and knowledge gaps as to possible local intestinal effects of SAS particles, primarily on the gut-associated lymphoid system. This uncertainty is aggravated by digestion experiments indicating that dietary SAS particles preserve their nano-sized structure when reaching the intestinal lumen. An important aspect is whether food-borne particles like SAS alter the function of dendritic cells that, embedded in the intestinal mucosa, act as first-line sentinels of foreign materials. We conclude that nano-particles do not represent a completely new threat and that most potential risks can be assessed following procedures established for conventional chemical hazards. However, specific properties of food-borne nano-particles should be further examined and, for that purpose, in vitro tests with decision-making cells of the immune system are needed to complement existing in vivo studies.