Showing papers by "Christer Hogstrand published in 2016"

Risks for human health related to the presence of 3- and 2-monochloropropanediol (MCPD), and their fatty acid esters, and glycidyl fatty acid esters in food

Abstract: The Panel wishes to thank the members of the Working Group on MCPD and glycidyl esters: Mona-Lise Binderup, Colin Crews, Daniel Doerge, Peter Furst, Christer Hogstrand, Alfonso Lampen, Ian Morris and Dieter Schrenk, for the preparatory work on this scientific opinion; and EFSA staff members: Davide Arcella, Marco Binaglia, Barbara Dorr, Natalie Thatcher, Ruth Roldan Torres, Eniko Varga and Francesco Vernazza, for the support provided to this scientific opinion.

Erucic acid in feed and food

Abstract: Erucic acid is the trivial name of the fatty acid cis-13-docosenoic acid and occurs at high concentrations mainly in the seeds of species of the Brassicaceae (e.g. rape seed or mustard seed). The European Commission requested EFSA to deliver a scientific opinion on the risks for animal and human health related to the presence of erucic acid in feed and food. For most humans, the main contributor to dietary exposure to erucic acid was the food group ‘Fine bakery wares’. In ‘Infants’, ‘Food for infants and small children’ was the main contributor to exposure. The heart is the principal target organ for toxic effects after exposure. Myocardial lipidosis was identified as the critical effect for chronic exposure to erucic acid. This effect is reversible and transient during prolonged exposure. A tolerable daily intake (TDI) of 7 mg/kg body weight (bw) per day for erucic acid was established, based on a no observed adverse effect level of 0.7 g/kg bw per day for lipidosis in young rats and newborn piglets. Mean chronic exposure of the different groups of the population did not exceed the TDI. The 95th percentile dietary exposure level was highest in infants and other children, ranging from 1.3 to 7.4 mg/kg bw per day; the higher level being at the level of the TDI. This may indicate a risk for young individuals with high erucic acid exposure. In pigs, levels of erucic acid are unlikely to represent a health concern. However, for poultry, the small margin between the lowest observed adverse effect level (LOAEL) and the estimated exposure may indicate a health risk where maximum inclusion rates are applied. Due to the absence of adequate data, the risk for ruminants, horses, fish and rabbits could not be assessed.

Zinc transporter ZIP10 forms a heteromer with ZIP6 which regulates embryonic development and cell migration.

Abstract: There is growing evidence that zinc and its transporters are involved in cell migration during development and in cancer. In the present study, we show that zinc transporter ZIP10 (SLC39A10) stimulates cell motility and proliferation, both in mammalian cells and in the zebrafish embryo. This is associated with inactivation of GSK (glycogen synthase kinase)-3α and -3β and down-regulation of E-cadherin (CDH1). Morpholino-mediated knockdown of zip10 causes delayed epiboly and deformities of the head, eye, heart and tail. Furthermore, zip10 deficiency results in overexpression of cdh1 , zip6 and stat3 , the latter gene product driving transcription of both zip6 and zip10 . The non-redundant requirement of Zip6 and Zip10 for epithelial to mesenchymal transition (EMT) is consistent with our finding that they exist as a heteromer. We postulate that a subset of ZIPs carrying prion protein (PrP)-like ectodomains, including ZIP6 and ZIP10, are integral to cellular pathways and plasticity programmes, such as EMT. * CDH1/E-cadherin, : epithelial cadherin; CHO, : Chinese-hamster ovary; EMT, : epithelial–mesenchymal transition; ER, : endoplasmic reticulum; GSK, : glycogen synthase kinase; hpf, : hours post fertilization; IRT1, : iron(II) transport protein 1; ISH, : in situ hybridization; Morpholino, : morpholino-modified antisense oligonucleotide; PLA, : proximity ligation assay; PM, : plasma membrane; PrP, : prion protein; qPCR, : quantitative real-time polymerase chain reaction; STAT, : signal transducer and activator of transcription; TMT, : tandem mass tag; β-TRCP, : β-transducin repeat containing E3 ubiquitin protein ligase; ZIP, : Zrt- and Irt-like proteins

Acute health risks related to the presence of cyanogenic glycosides in raw apricot kernels and products derived from raw apricot kernels

Abstract: Amygdalin is the major cyanogenic glycoside present in apricot kernels and is degraded to cyanide by chewing or grinding. Cyanide is of high acute toxicity in humans. The lethal dose is reported to be 0.5–3.5 mg/kg body weight (bw). An acute reference dose (ARfD) of 20 μg/kg bw was derived from an exposure of 0.105 mg/kg bw associated with a non-toxic blood cyanide level of 20 micro mol (μM), and applying an uncertainty factor of 1.5 to account for toxicokinetic and of 3.16 to account for toxicodynamic inter-individual differences. In the absence of consumption data and thus using highest intakes of kernels promoted (10 and 60 kernels/day for the general population and cancer patients, respectively), exposures exceeded the ARfD 17–413 and 3–71 times in toddlers and adults, respectively. The estimated maximum quantity of apricot kernels (or raw apricot material) that can be consumed without exceeding the ARfD is 0.06 and 0.37 g in toddlers and adults, respectively. Thus the ARfD would be exceeded already by consumption of one small kernel in toddlers, while adults could consume three small kernels. However, consumption of less than half of a large kernel could already exceed the ARfD in adults.

Procedures for the reconstruction, primary culture and experimental use of rainbow trout gill epithelia.

Abstract: This protocol describes how to reconstruct and culture the freshwater rainbow trout gill epithelium on flat permeable membrane supports within cell culture inserts. The protocol describes gill cell isolation, cultured gill epithelium formation, maintenance, monitoring and preparation for use in experimental procedures. To produce a heterogeneous gill epithelium, as seen in vivo, seeding of isolated gill cells twice over a 2-d period is required. As a consequence, this is termed the double-seeded insert technique. Approximately 5-12 d after cell isolation and seeding, preparations develop electrically tight gill epithelia that can withstand freshwater on the apical cell surface. The system can be used to study freshwater gill physiology, and it is a humane alternative for toxicity testing, bioaccumulation studies and environmental water quality monitoring.

Malachite green in food

Abstract: Malachite green (MG) has been used globally in aquaculture but is not registered for use in food-producing animals in the European Union. The European Commission requested EFSA to evaluate whether a reference point for action (RPA) of 2 μg/kg for the sum of MG and its major metabolite leucomalachite green (LMG) is adequate to protect public health. Available occurrence data were not suitable for a reliable exposure assessment. The hypothetical dietary exposure was calculated, considering the RPA as occurrence value for all types of fish, fish products and crustaceans. Mean dietary exposure across different European dietary surveys and age classes would range from 0.1 to 5.0 ng/kg body weight (bw) per day. For high and frequent fish consumers, the exposure would range from 1.3 to 11.8 ng/kg bw per day. Both MG and LMG induced formation of DNA adducts in livers of rats and/or mice, and of micronuclei in mice. LMG also induced cII transgene mutations in mouse liver. MG caused a small, not dose-related, increase in thyroid gland follicular adenomas and carcinomas, and of mammary gland carcinomas in female rats. LMG caused an increase in hepatocellular adenomas and carcinomas in female mice. Both MG and LMG may be considered as carcinogenic and as genotoxic in vivo. A lower 95% confidence limit for a benchmark response of 10% extra risk (BMDL10) of 13 mg/kg bw per day for hepatocellular adenomas and carcinomas was selected as reference point for neoplastic effects. For non-neoplastic effects, a lower 95% confidence limit for a benchmark response of 5% extra risk (BMDL05) of 6 mg/kg bw per day was selected for the effect of MG on liver weight and of LMG on body weight. The margins of exposure were 1.1 × 106 or greater for neoplastic effects and 4.9 × 105 or greater for non-neoplastic effects. The CONTAM Panel concluded that it is unlikely that exposure to food contaminated with MG/LMG at or below the RPA of 2 μg/kg represents a health concern.

Genetics of Human Zinc Deficiencies

Abstract: The numerous mutations in two families of human zinc transporters (SLC30, 10 ZNT proteins and SLC39, 14 ZIP proteins) indicate that the inherited diseases established for ZIP4 (acrodermatitis enteropathica), ZIP13 (spondylocheirodysplastic Ehlers–Danlos syndrome), ZNT2 (transient neonatal zinc deficiency) and ZNT10 (manganism) signify an emerging field that is important for a wide variety of diseases. Discoveries also impact nutrition and toxicology as differences in requirements for zinc and sensitivities towards an excess of zinc are genetically determined. The spectrum of mutations leads to phenotypes of different severity and risk factors for diseases. Some mutations are rare but others such as the ones in ZNT2 and ZNT8 (the latter associated with diabetes risk) are important for the health of majorities in populations. Inherited diseases of zinc metabolism are also due to mutations in other genes. As metal ions interact and their concentrations are balanced, mutations affect the metabolism of metals ions other than zinc as already shown for manganese, iron and toxic metal ions such as cadmium. Key Concepts Zinc is involved in virtually all biological processes. Zinc transporters, metallothioneins and other proteins are involved in inherited diseases of zinc metabolism with a large spectrum of phenotypes. Two members of the human zinc transporter family ZNT (SLC30) have mutations that lead to inherited diseases: ZNT2 (transient neonatal zinc deficiency) and ZNT10 (manganism) – the list is likely to grow. Two members of the human zinc transporter family ZIP (SLC39) have mutations that lead to inherited diseases: ZIP4 (acrodermatitis enteropathica) and ZIP13 (spondylocheirodysplastic Ehlers–Danlos syndrome) – the list is likely to grow. Genome-wide association studies (GWASs) reveal relationships between zinc transporters and a wide range of diseases. Some associations between zinc transporters and diseases affect large fractions of populations. Mutations in bona fide zinc transporters affect the metabolism of other metal ions and possibly other trace elements, for example, selenium. Keywords: zinc; zinc transporters; ZNT (SLC30) family; ZIP (SLC39) family; diabetes; cancer; cardiovascular disease; autism; Parkinsonism; psychiatric disease

Effect and mechanism of waterborne prolonged Zn exposure influencing hepatic lipid metabolism in javelin goby Synechogobius hasta

Abstract: The present study was conducted to determine the effect and mechanism of waterborne Zn exposure influencing hepatic lipid deposition and metabolism in javelin goby Synechogobius hasta. S. hasta were exposed to four waterborne Zn concentrations (Zn 0.005 [control], 0.18, 0.36 and 0.55 mg l(-1) , respectively) for 60 days. Sampling occurred at days 20, 40 and 60, respectively. Zn exposure increased Zn content, declined hepatic lipid content and reduced viscerosomatic and hepatosomatic indices and lipogenic enzyme activities, including 6-phosphogluconate dehydrogenase (6PGD), glucose-6-phosphate dehydrogenase (G6PD), malic enzyme (ME) and fatty acid synthase (FAS). At days 20 and 60, Zn exposure decreased hepatic mRNA levels of 6PGD, G6PD, ME, FAS, acetyl-CoA carboxylase (ACC)α, ACCβ, hormone-sensitive lipase (HSL)a, HSLb, sterol-regulator element-binding protein (SREBP)-1, peroxisome proliferators-activated receptor (PPAR)α and PPARγ. However, the mRNA levels of CPT 1 and adipose triglyceride lipase increased following Zn exposure. On day 40, Zn exposure reduced hepatic mRNA expression of 6PGD, G6PD, ME, FAS, ACCα, ACCβ, HSLa, HSLb, SREBP-1 and PPARγ but increased mRNA expression of CPT 1, adipose triglyceride lipase and PPARα. General speaking, Zn exposure reduced hepatic lipid content by inhibiting lipogenesis and stimulating lipolysis. For the first time, the present study provided evidence that chronic Zn exposure differentially influenced mRNA expression and activities of genes and enzymes involved in lipogenic and lipolytic metabolism in a duration-dependent manner, and provided new insight into the relationship between metal elements and lipid metabolism. Copyright © 2015 John Wiley & Sons, Ltd.

Expression of the zinc importer protein ZIP9/SLC39A9 in glioblastoma cells affects phosphorylation states of p53 and GSK-3β and causes increased cell migration.

Abstract: Zinc importer proteins (ZIPs) have been proven as important molecular regulators in different cancers. As a member of the solute carrier family, ZIP9/SLC39A9 is overexpressed in prostate and breast cancer and affects B-cell receptor signaling. Here, we present data indicating that changes in intracellular zinc levels in glioblastoma cells can cause enhanced cell survival and cell migration, both hallmarks of the disease process. In particular, treatment of human glioblastoma cells with sublethal doses of cell-permeable heavy metal (Zn2+ > Fe2+ > Mn2+) chelator (N,N,N′,N′-tetrakis (2-pyridylmethyl)ethylenediamine (TPEN)) induced ZIP9 expression. Either TPEN treatment or expression of ZIP9 cDNA causes enhanced migration behavior of glioblastoma cells. Compared to untreated glioblastoma cells TPEN treatment or expression of ZIP9 results in activation of the tumor suppressor p53 by phosphorylation at serine residue 46 (Ser46) and in inactivation of the migration relevant glycogen synthase kinase 3 beta (GSK-3β) by phosphorylation at serine residue 9 (Ser9). Whilst p53 activation affects cell survival in response to TPEN, GSK-3β inactivation directly affects glioblastoma cell migration. Therefore, ZIP9 expression could regulate the migratory behavior of glioblastoma cells, so that ZIP9 may be of biological, but not of clinical relevance for glioblastomas, since in GBM tumor tissues, ZIP9 expression is not significantly increased compared to normal brain.

Safety and efficacy of furfuryl and furan derivatives belonging to chemical group 14 when used as flavourings for all animal species and categories

Abstract: Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of 18 compounds belonging to chemical group 14 (furfuryl and furan derivatives with and without additional side-chain substituents and heteroatoms). They are currently authorised as flavours in food. This opinion concerns 13 compounds from this group. The FEEDAP Panel concludes that all compounds except 5-methylfurfural are safe at the proposed maximum use level for all animal species: furfural and furfuryl alcohol at 5 mg/kg complete feed; methyl 2-furoate and furfuryl acetate at 0.5 mg/kg complete feed; bis-(2-methyl-3-furyl) disulfide, furanmethanethiol, S-furfuryl acetothioate, difurfuryl disulfide, methyl furfuryl sulfide, 2-methylfuran-3-thiol, methyl furfuryl disulfide and methyl 2-methyl-3-furyl disulfide at 0.05 mg/kg complete feed. 5-Methylfurfural is safe at the proposed use level of 0.5 mg/kg complete feed for cattle, salmonids and non-food producing animals and at the use level of 0.3 mg/kg complete feed for pigs and poultry. No safety concern would arise for the consumer from the use of these compounds up to the highest safe level in feeds. Hazards for skin and eye contact and respiratory exposure are recognised for the majority of the compounds under application. Most are classified as irritating to the respiratory system. The concentrations considered safe for the target species are unlikely to have detrimental effects on the terrestrial and freshwater environments. Since all the compounds under assessment are used in food as flavourings, and their function in feed is essentially the same as that in food, no further demonstration of efficacy is necessary. In the absence of data on the stability in water for drinking, the FEEDAP Panel is unable to conclude on the safety or efficacy of the substances under this mode of delivery. © European Food Safety Authority, 2016

Guidance to develop specific protection goal options for environmental risk assessment at EFSA, in relation to biodiversity and ecosystem services

Abstract: Maintaining a healthy environment and conserving biodiversity are major goals of environmental protection. A challenge is that protection goals outlined in legislation are often too general and broad to be directly applicable for environmental risk assessment (ERA) performed by EFSA. Therefore, they need to be translated into specific protection goals (SPGs). This Guidance presents a framework, which accounts for biodiversity and ecosystem services, to make general protection goals operational for use in all areas of EFSA's ERAs. The approach to follow has three sequential steps: (1) the identification of relevant ecosystem services; (2) the identification of service providing units (SPUs) for these ecosystem services; and (3) the specification of options for the level/parameters of protection of the SPUs using five interrelated dimensions. This last step involves the specification of options for the ecological entity and attribute to protect and the magnitude, temporal scale and spatial scale of the biologically relevant and, in the case of regulated products, tolerable effects, the latter defined in dialogue with risk managers. In order to promote transparency and consistency when developing options for the level/parameters of protection, this guidance provides considerations to justify the selected options.

Safety and efficacy of secondary aliphatic saturated or unsaturated alcohols, ketones, ketals and esters with a second secondary or tertiary oxygenated functional group belonging to chemical group 10 when used as flavourings for all animal species

Abstract: Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of 11 compounds belonging to chemical group 10. They are currently authorised as flavours in food. The FEEDAP Panel concludes that: diacetyl [07.052] is safe at the proposed maximum use level of 25 mg/kg complete feed for all target species, except piglets, chickens for fattening, laying hens and cats, for which the proposed normal use level of 5 mg/kg is safe; 3-hydroxybutan-2-one [07.051], 3-methylcyclo-pentan-1,2-dione [07.056], 3ethylcyclopentan-1,2-dione [07.057], pentan-2,3-dione [07.060], 3,4-dimethylcyclopentan-1,2-dione [07.075], 3,5-dimethyl cyclopentan-1,2-dione [07.076], hexan-3,4-dione [07.077] and sec-butan-3-onyl acetate [09.186] are safe at the proposed maximum dose level of 5 mg/kg for all target species; 2,6,6-trimethylcyclohex-2-en1,4-dione [07.109] and 3-methylnona-2,4-dione [07.184] are safe only at concentrations below the proposed use levels (0.5 mg/kg for cattle, salmonids and non-food producing animals, and 0.3 mg/kg for pigs and poultry). No safety concern would arise for the consumer from the use of these compounds up to the highest proposed level in feeds. Hazards for skin and eye contact and respiratory exposure are recognised for the majority of the compounds under application. Most are classified as irritating to the respiratory system. For 3hydroxybutan-2-one [07.051], diacetyl [07.052], pentan-2,3-dione [07.060], hexan-3,4-dione [07.077], 2,6,6trimethylcyclohex-2-en-1,4-dione [07.109], 3-methylnona-2,4-dione [07.184] and sec-butan-3-onyl acetate [09.186], the maximum proposed use levels are considered safe for the environment. For cyclopentanediones (3-methylcyclopentan-1,2-dione [07.056], 3-ethylcyclopentan-1.2-dione [07.057], 3,4 dimethylcyclopentan1,2-dione [07.075] and 3,5-dimethylcyclopentan-1,2-dione [07.076]) usage at levels up to 0.5 mg/kg feed is unlikely to have an adverse effect on the terrestrial or freshwater environments. Because all the compounds under assessment are used in food as flavourings and their function in feed is essentially the same as that in food, no further demonstration of efficacy is necessary. © 2016 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority.

Safety and efficacy of pyridine and pyrrole derivatives belonging to chemical group 28 when used as flavourings for all animal species

Abstract: Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of nine compounds belonging to chemical group 28 (pyridine, pyrrole and quinoline derivatives). They are currently authorised as flavours in food. The FEEDAP Panel concludes that piperine, 3-methylindole, indole, 2-acetylpyridine and 2-acetylpyrrole are safe at the proposed maximum use level of 0.5 mg/kg complete feed for all animal species; trimethyloxazole, 3-ethylpyridine, pyrrolidine and 2,6-dimethylpyridine are safe at the proposed use level of 0.5 mg/kg complete feed for cattle, salmonids and non-food-producing animals, and at the use level of 0.3 mg/kg complete feed for pigs and poultry. No safety concern would arise for the consumer from the use of these compounds up to the highest safe level in feeds. Hazards for skin and eye contact, and respiratory exposure are recognised for the majority of the compounds under application. Most are classified as irritating to the respiratory system. The concentrations considered safe for the target species are unlikely to have detrimental effects on the terrestrial and fresh water environments. As all the compounds under assessment are used in food as flavourings, and their function in feed is essentially the same as that in food, no further demonstration of efficacy is necessary. In the absence of data on the stability in water for drinking, the FEEDAP Panel is unable to conclude on the safety or efficacy of the substances under this mode of delivery. © European Food Safety Authority, 2016