Addressing the safety of new food sources and production systems.

New food sources and production systems (NFPS) are garnering much attention, driven by international trade, changing consumer preferences, potential sustainability benefits, and innovations in climate-resilient food production systems. However, NFPS can introduce new challenges for food safety agencies and food manufacturers. Most food safety hazards linked to new foods have been identified in traditional foods. However, there can be some food safety challenges that are unique to new foods. New food ingredients, inputs, and processes can introduce unexpected contaminants. To realize the full potential of NFPS, there is a need for stakeholders from governments, the food industry, and the research community to collectively work to address and communicate the safety of NFPS products. This review outlines known food safety hazards associated with select NFPS products on the market, namely, plant-derived proteins, seaweeds, jellyfish, insects, microbial proteins, as well as foods derived from cell-based food production, precision fermentation, vertical farming, and 3D food printing. We identify common elements in emerging NFPS regulatory frameworks in various countries/regions. Furthermore, we highlight current efforts in harmonization of terminologies, use of recent scientific tools to fill in food safety knowledge gaps, and international multi-stakeholder collaborations to tackle safety challenges. Although there cannot be a one-size-fits-all approach when it comes to the regulatory oversight for ensuring the safety of NFPS, there is a need to develop consensus-based structured protocols or workflows among stakeholders to facilitate comprehensive, robust, and internationally harmonized approaches. These efforts increase consumers' confidence in the safety of new foods and contribute toward fair practices in the international trade of such foods.

Assessment of veterinary drug residues in food: Considerations when dealing with sub-optimal data.

The use of veterinary drugs in food-producing animals may lead to residues in animal-derived foodstuffs, potentially posing a risk to human safety. While the process of veterinary drug residue risk assessment continues to evolve as new data emerges, a recurring challenge is when sub-optimal or incomplete data are provided with the expectation of supporting a robust risk assessment. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) is comprised of international experts who routinely deal with such data challenges when performing veterinary drug residue evaluations. Recent developments in veterinary drug residue risk assessment are described, including specific consequences of sub-optimal data during the risk assessment process. When feasible, practical solutions to such challenges are also highlighted. Case examples from recent JECFA veterinary drug evaluations are provided to clearly quantify and illustrate the concepts described. The information provided is intended to facilitate the generation of improved quality data, enabling more timely and robust veterinary drug residue risk assessments.

Harmonized methodology to assess chronic dietary exposure to residues from compounds used as pesticide and veterinary drug.

Risk assessments for pesticide and veterinary drug residues in food are performed respectively by the Joint FAO/WHO Expert Meeting on Pesticide Residues (JMPR) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA). The models used by the two Committees to assess chronic dietary exposure are based on different data and assumptions which may be confusing, particularly for risk managers, when the same compound is used to treat plants and animals. This publication details the results of combined chronic dietary exposure assessments for eight compounds used both as pesticide and veterinary drugs. It compares the results from models in use by JMPR and JECFA with those from national estimates performed by 17 countries. Results show that the JECFA model is better reflecting less than lifetime dietary exposure by considering consumption of children and high consumers. The JMPR model is a suitable model for estimating average chronic (lifetime) exposure to residues present in widely and regularly consumed staple commodities. However, it is suitable neither for estimating children's exposure nor more generally for assessing less than lifetime dietary exposure. In order to select the appropriate exposure model related to the occurrence of adverse effects i.e. effects occurring over less-than-lifetime or effects occurring only over lifetime, this paper proposes criteria to match the toxicological profile of the compound and the appropriate exposure scenarios. These approaches will continue to be harmonized to ensure the most scientifically sound basis for the risk assessment for pesticides and veterinary drug residues and consequently for other chemicals in food.

Characterizing chronic and acute health risks of residues of veterinary drugs in food: latest methodological developments by the joint FAO/WHO expert committee on food additives.

The risk assessment of residues of veterinary drugs in food is a field that continues to evolve. The toxicological end-points to be considered are becoming more nuanced and in light of growing concern about the development of antimicrobial resistance, detailed analysis of the antimicrobial activity of the residues of veterinary drugs in food is increasingly incorporated in the assessment. In recent years, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) has refined its approaches to provide a more comprehensive and fit-for-purpose risk assessment. This publication describes in detail the consideration of acute and chronic effects, the estimation of acute and chronic dietary exposure, current approaches for including microbiological endpoints in the risk assessment, and JECFA's considerations for the potential effects of food processing on residues from veterinary drugs. JECFA now applies these approaches in the development of health-based guidance values (i.e. safe exposure levels) for residues of veterinary drugs. JECFA, thus, comprehensively addresses acute and chronic risks by using corresponding estimates for acute and chronic exposure and suitable correction for the limited bioavailability of bound residues by the Gallo-Torres model. On a case-by-case basis, JECFA also considers degradation products that occur from normal food processing of food containing veterinary drug residues. These approaches will continue to be refined to ensure the most scientifically sound basis for the establishment of health-based guidance values for veterinary drug residues.

Effects of postnatal ethanol exposure at different developmental phases on neurotrophic factors and phosphorylated proteins on signal transductions in rat brain.

Exposure to ethanol during development induces severe brain damage resulting in a number of CNS dysfunctions including microencephaly and mental retardation in humans and in laboratory animals. The most vulnerable period to ethanol neurotoxicity coincides with the peak of brain growth spurt. Recently, neurotrophic factors and/or their signal transduction pathways have been reported as a potential relevant target for the developmental neurotoxicity of ethanol. The present studies were designed to investigate the effects of ethanol given in various developmental phases during the brain growth spurt in rats. Rat pups were assigned to the three treatment groups and treated with 5 g/kg of ethanol for three days, on postnatal days (PND) 2-4, 6-8 or 13-15. Whole brain weights were reduced only in the PND 6-8 group concurrently with the reduction of GDNF mRNA in cortex in this group. BDNF mRNA expression was reduced in both the PND 6-8 and 13-15 groups, while mRNA expressions of NT-3 and NGF were unchanged in all three groups. Phospho-Akt level was mostly reduced in the PND 6-8 group. Both phospho-MAPK and p-70S6 kinase levels were decreased in all groups whereas no changes were observed in either phospho-PKCzeta or CREB level. The phosphorylation of Akt was immediately inhibited after single administration of ethanol, and its inhibition was correlated with variations in blood ethanol concentration. These findings suggest that GDNF and the phosphorylation of Akt play a possible key role in the ethanol-induced developmental neurotoxicity.

Neurobehavioral assessment of rats exposed to low doses of PCB126 and methyl mercury during development.

Epidemiological and laboratory studies have suggested that polychlorinated biphenyls (PCBs) and methyl mercury (MeHg) may have additive or synergistic effects on CNS function. Aim of this study was to characterize the effects of exposure to low levels of MeHg (0.5mg/kgday in drinking water) and PCB126 (100ng/kgday in food), alone and in combination, on neurobehavioral development in Wistar rats. Dams were treated from gestational day 7 to post-natal day (PND) 21. Animals were tested for developmental landmarks and reflexes (PND1-21), attention deficits (PND40), locomotor activity (PND30, 110), spatial learning (PND75), coordination and balance (PND90), object discrimination (PND80), anxiety (PND100), and conditioned learning (PND110). Parameters related to pregnancy, sex ratio at birth, and physical development (at weaning) did not differ among groups, though PCB126 decreased number of pups at birth. A slight delay in negative geotaxis was found in female rats in all treatment groups. No significant effects were seen in attention, coordination and balance, object discrimination, and spatial and conditioned learning. Increased motor activity was present in PCB126-treated male and in MeHg+PCB-treated female rats in the elevated plus maze test, and in PCB126-treated male rats in the open field test (PND110). The results do not support the hypothesis that co-exposure to MeHg and PCB126 results in additive or synergistic effects. This finding is in agreement with more recent in vitro and in vivo studies.

An in vitro approach to assess the toxicity of certain food contaminants: methylmercury and polychlorinated biphenyls.

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are widespread environmental pollutants and food contaminants, and known developmental neurotoxicants. Aim of this study was to evaluate the effects of MeHg, PCB 126 and PCB 153 in a battery of in vitro cell systems. A total of 17 cell types were utilized, including nervous system (neuronal and astroglial) and non-nervous system cells. End-points measured included MTT reduction, Trypan blue exclusion and (3)H-thymidine incorporation into DNA. Results indicate that this approach would identify these three compounds as neurotoxicants, and would also point out to the thyroid (for PCB 126 and MeHg) and the prostate (for both PCBs) as important additional targets. Tests of binary combinations of MeHg and PCBs indicated no interaction and an additive response, in agreement with other recent reports. Cerebellar granule neurons from mice with genetically determined low glutathione levels were more sensitive than wild-type neurons to the toxicity of all three compounds, supporting a role for oxidative stress in their neurotoxicity. These findings provide initial evidence that a relatively rapid in vitro screening approach can be developed, that would provide initial information useful for assessing neurotoxicity, as well as indication on potential other targets of biological action or toxicity.

Differential in vitro neurotoxicity of the flame retardant PBDE-99 and of the PCB Aroclor 1254 in human astrocytoma cells.

Polybrominated diphenyl ethers (PBDEs) are an important class of flame retardants. Because of their presence in maternal milk and their structural similarity to polychlorinated biphenyls (PCBs), concern has been raised on their possible developmental neurotoxicity. Aim of the present study was to investigate the in vitro effects of PBDE-99 (2,2', 4,4', 5-pentabromodiphenyl ether) on astroglial cells (human 132-1N1 astrocytoma cells) and comparing it with those of the PCB mixture Aroclor 1254. Both PBDE-99 and Aroclor 1254 caused a concentration-dependent inhibition of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction, however, only the latter increased lactate dehydrogenase (LDH) release or cell death, assessed by the trypan blue assay. PBDE-99 caused translocation of the three protein kinase C (PKC) isozymes (alpha, epsilon, zeta) present in 132-1N1 astrocytoma cells, while Aroclor 1254 affected only PKCalpha and epsilon translocation. However, pre-incubation with the PKC inhibitor GF109203X or PKC down-regulation by the phorbol ester PMA, had minimal or no effect on PBDE-99 or Aroclor 1254-induced cytotoxicity. Similarly, the calcium chelator BAPTA-AM, the tyrosine kinase inhibitor genistein, and the MEK (mitogen activated protein kinase kinase) inhibitor PD98059 had no effect on PBDE-99 and Aroclor 1254 cytoxicity. On the other hand, the phosphatidylinositol 3 kinase (PI-3K) inhibitor LY290042 enhanced PBDE-99 toxicity, but did not affect Aroclor 1254. Because of the involvement of PI-3K in apoptotic cell death, the ability of PBDE-99 and Aroclor 1254 to induce apoptosis in astrocytoma cells was investigated. PBDE-99, but not Aroclor 1254, caused apoptotic cell death in astrocytoma cells, assessed by the TUNEL method and by Hoechst 33258 staining, via a p53 dependent mechanism. These results suggest that PBDE-99 and Aroclor 1254 exert differential cytotoxic effects on human astroglial cells.

Long-term effects of developmental exposure to low doses of PCB 126 and methylmercury.

Methylmercury (MeHg) and polychlorinated biphenyls (PCBs) are food contaminants often found in fish. Experimental and epidemiological studies indicate that both PCBs and MeHg are developmental neurotoxicants, and some reports suggest that they may cause additive and/or synergistic neurotoxicity. We had previously investigated the effects of exposure to low doses of MeHg (0.5 mg/kg/day in drinking water) and PCB 126 (100 ng/kg/day in food) alone or in combination, from gestational day 7 to post-partum day 21, on neurobehavioral development in Wistar rats. The main finding was hyperactivity in male rats exposed to PCB 126, and in female animals exposed to PCB 126+MeHg at 4 months of age (Vitalone et al., 2008). Since effects caused by developmental exposure may be exacerbated as the animal ages, aim of the present study was to investigate behavioral effects of the same developmental exposure to PCB 126 and/or MeHg up to the age of 20 months. Results indicate that aging did not enhance the behavioral effects of early exposures; however, behavioral alterations found in the first months of life in male rats exposed to PCB 126, or in female rats exposed to PCB 126+MeHg, were persistent. Furthermore, an additional effect (increased body weight) was unmasked in adulthood in male rats exposed to PCB 126. These results indicate that developmental exposure to a low, environmentally relevant dose of PCB 126 causes long-lasting hyperactivity in male rats, and a significant increase in body weight.

Effects of postnatal ethanol exposure on neurotrophic factors and signal transduction pathways in rat brain.

Exposure to ethanol during development induces severe brain damage, resulting in a number of CNS dysfunctions including microencephaly and mental retardation. Potential targets of ethanol-induced neurotoxicity include neurotrophic factors and their signal transduction pathways. In the present study, rat pups were given ethanol at the dose of 5 g kg(-1) via gavage from postnatal day (PND) 5 to 8, and mRNA expression of nerve growth-factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophic factor-3 (NT-3) in the cerebral cortex was examined, with attention to signal transduction, on PND 8. The mRNA level of BDNF was decreased by ethanol while those of NGF or NT-3 were not changed. Brain weights were decreased and the levels of phospho-MAPK, phospho-p70S6K and phospho Akt were decreased while phosphor-PKCzeta and phospho-CREB remained unchanged. These results suggest that BDNF and its related signal pathways involving Akt, MAPK and p70S6K are potential targets of ethanol-induced developmental neurotoxicity.