Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 Contents lists available at ScienceDirect Journal of Trace Elements in Medicine and Biology journal homepage: www.elsevier.com/locate/jtemb Review Consensus document on the prevention of methylmercury exposure in Spain Study group for the prevention of Me-Hg exposure in Spain (GEPREM-Hg)夽 Montserrat González-Estecha m,∗ , Andrés Bodas-Pinedo a , José Jesús Guillén-Pérez a , Miguel Ángel Rubio-Herrera h , Jesús Román Martínez-Álvarez g , Miguel Ángel Herráiz-Martínez i , Nieves Martell-Claros j , José Ma Ordóñez-Iriarte k , María Sáinz-Martín a , Rosaura Farré-Rovira d , Txantón Martínez-Astorquiza i , José Antonio García-Donaire j , Elpidio Calvo-Manuel e , Irene Bretón-Lesmes h , Santiago Prieto-Menchero b , Ma Teresa Llorente-Ballesteros f , Ma José Martínez-García l , Rafael Moreno-Rojas g , Jordi Salas-Salvadó d , Pilar Bermejo-Barrera f , Ma Ángeles Cuadrado-Cenzual b , Carmen Gallardo-Pino a , María Blanco Fuentes a , Miriam Torres-Moreno d , Elena M. Trasobares-Iglesias f , Bernardino Barceló Martín c , Manuel Arroyo-Fernández m , Alfonso Calle-Pascual m a Spanish Association of Health Education (ADEPS), Spain Spanish Association of Medical Biopathology (AEBM), Spain c Spanish Association of Pharmaceutical Analysts (AEFA), Spain d Spanish Federation of Nutrition, Food and Dietetics Societies (FESNAD), Spain e Madrid-Castilla La Mancha Society of Internal Medicine (SOMIMACA), Spain f Spanish Society of Clinical Biochemistry and Molecular Pathology (SEQC), Spain g Spanish Society of Dietetics and Food Science (SEDCA), Spain h Spanish Society of Endocrinology and Nutrition (SEEN), Spain i Spanish Society of Gynaecology and Obstetrics, Perinatal Medicine Section (SEMEPE-SEGO), Spain j Spanish Hypertension Society – Spanish Hypertension League (SEH-LELHA), Spain k Spanish Society of Public Health and Health Administration (SESPAS), Spain l Spanish Society of Environmental Health (SESA), Spain m Hospital Clínico San Carlos, Instituto de Investigación Sanitaria (IdISSC) b a r t i c l e i n f o Article history: Received 21 May 2015 Accepted 26 May 2015 Keywords: Methylmercury Fish Health Advisory Biomarkers Cost-benefit a b s t r a c t The beneficial effects of fish consumption in both children and adults are well known. However, the intake of methylmercury, mainly from contaminated fish and shellfish, can have adverse health effects. The study group on the prevention of exposure to methylmercury (GEPREM-Hg), made up of representatives from different Spanish scientific societies, has prepared a consensus document in a question and answer format, containing the group’s main conclusions, recommendations and proposals. The objective of the document is to provide broader knowledge of factors associated with methylmercury exposure, its possible effects on health amongst the Spanish population, methods of analysis, interpretation of the results and economic costs, and to then set recommendations for fish and shellfish consumption. The group sees the merit of all initiatives aimed at reducing or prohibiting the use of mercury as well as the need to be aware of the results of contaminant analyses performed on fish and shellfish marketed in Spain. In addition, the group 夽 This article is a translation of an article originally published in Spanish in the journal “Nutrición Hospitalaria” (Hospital Nutrition) (Nutr. Hosp. 2015;31(1):16-31). ∗ Corresponding author at: Servicio de Análisis Clínicos (Unidad de Elementos Traza). Hospital Clínico San Carlos. C/Prof. Martín Lagos s/n. 28040 Madrid, Spain. E-mail address: [email protected] (M. González-Estecha). http://dx.doi.org/10.1016/j.jtemb.2015.05.007 0946-672X/© 2015 Elsevier GmbH. All rights reserved. M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 123 believes that biomonitoring systems should be set up in order to follow the evolution of methylmercury exposure in children and adults and perform studies designed to learn more about the possible health effects of concentrations found in the Spanish population, taking into account the lifestyle, eating patterns and the Mediterranean diet. © 2015 Elsevier GmbH. All rights reserved. Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. Background, justification and objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Where do mercury (Hg) and methylmercury come from? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Is eating fish good for health? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 What is the main source of MeHg exposure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Which fish have the highest levels of mercury? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Can MeHg be eliminated by cleaning or cooking the fish? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Which Spanish regulation governs the maximum permitted level of mercury in fish and shellfish? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 What is the provisional tolerable weekly intake of MeHg? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Do mercury levels differ depending on whether the fish is fresh, frozen or canned? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 What species of tuna is in canned white tuna, tuna and light tuna? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Does the packing media of canned tuna affect mercury levels? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Where can I find information on fish mercury levels? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Is it necessary to limit consumption only of fish with high mercury levels? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 How is MeHg distributed and metabolised in the human body? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Does MeHg toxicity differ by gender? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Do polyunsaturated fatty acids mitigate MeHg toxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Does selenium offset the toxicity of MeHg? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Do other dietary components modulate MeHg toxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Is there a genetic predisposition to MeHg toxicity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Can MeHg from the consumption of contaminated fish affect the health of children and adults? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 What are the neurological effects in children? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Can it have other effects on children? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 What is the mercury level in children in Spain? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Does MeHg exposure from the consumption of contaminated fish cause adverse health effects in adults?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .126 What are the cardiovascular effects of MeHg in adults? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 What are the other adverse health effects of MeHg in adults? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 What is the mercury level in adults in Spain? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 Is it enough to reduce mercury emissions? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Are there any recommendations for reducing MeHg exposure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 What biological specimens are most used for analysing Hg? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 30.1. Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 30.2. Urine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 30.3. Hair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 30.4. Nails . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 30.5. Breast milk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 Which is the best specimen for evaluating MeHg exposure? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 What methods are used to analyse Hg and MeHg? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 What laboratories can analyse mercury in human samples? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 How should laboratory results be interpreted? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Should chelators be used? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 What is the economic cost of implementing public health measures? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 What does the GEPREM-Hg group recommend to individuals who have blood mercury? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 GEPREM-Hg dietary recommendations in connection with MeHg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 Final comments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132 1. Background, justification and objectives Mercury is an environmental toxin that causes a wide range of harmful health effects in humans and impacts natural ecosystems. The general population is exposed to low levels of mercury. Various factors determine the appearance and severity of harmful effects, amongst them: the chemical form of mercury (elemental, inorganic, organic), the dose, age, the duration and route of the exposure, as well as environmental, nutritional and genetic factors [1–3]. The benefits of fish consumption for both children and adults are well-known. However, the intake of methylmercury (MeHg), mainly from contaminated fish and shellfish, can have adverse health effects on foetal and new-born nervous system development. Some studies have also suggested that exposure to MeHg in adults who consume large quantities of fish can cause adverse health effects, particularly cardiovascular effects [4–6]. Fish consumption in Spain is one of the highest in the world, as are its blood mercury levels, according to various recent population-based studies [6]. 124 M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 The Study Group for the Prevention of Me-Hg Exposure (Grupo de Estudio para la Prevención de la Exposición al Me-Hg or GEPREM-Hg, its Spanish acronym) was set up at the Hospital Clínico San Carlos of Madrid with the objective of providing recommendations for the prevention and evaluation of MeHg exposure in Spain in both children and adults. This document only discusses exposure to methylmercury (MeHg), mainly through the consumption of contaminated fish and shellfish, and it should be borne in mind that the recommendations may be very different for intoxication from other forms of mercury, which also have different routes of exposure. Nor does this document deal with other fish contaminants such as certain heavy metals (Pb, Cd), polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), dioxins and furans (PCDD/F); the dietary recommendations refer only to MeHg. The GEPREM-Hg group is made up of representatives from different Spanish scientific societies in the fields of environmental health, laboratory medicine, endocrinology, nutrition, food and diet, health education, hypertension, public health, health management, epidemiology and gynaecology, amongst others. The group has prepared three technical documents [3,6,7] as well as this position paper, which is the result of the evaluation and synthesis of existing scientific evidence on methylmercury exposure amongst the general Spanish population, which is higher than in neighbouring countries due to our higher fish consumption. The first technical document summarises routes of exposure, toxicokinetics, differences according to gender and the nutritional and genetic factors associated with MeHg exposure [3]. The second document details health effects in children and adults, studies performed in different countries and mercury levels in Spain and other countries [6]. The third technical document sets out existing recommendations for the general population, particularly vulnerable groups such as women and children, the advantages and limitations of the biological matrices used to evaluate MeHg exposure, methods of analysis, the interpretation of laboratory results, possible treatments and an economic evaluation of MeHg exposure [7]. Lastly, this consensus document, drawn up by the participating societies, contains the group’s main recommendations, identifies shortcomings and suggests that further studies be performed to increase knowledge of current exposure levels and the possible health effects of MeHg, especially neurological and cardiovascular effects in the Spanish population. The main conclusions, recommendations and proposals regarding the questions raised by the group are set out below: 4. What is the main source of MeHg exposure? The main source of exposure to methylmercury (MeHg) is the consumption of contaminated wild fish and shellfish [1]. Although it is not the main source of exposure, consumption of farmed fish can be a source of exposure due to the possible presence of MeHg in the grains it is fed [5]. Contaminated rice has also recently been described as a source of exposure to MeHg in some regions of the south of China such as Guizhou [13,14]. 5. Which fish have the highest levels of mercury? Large predatory fish, such as swordfish, shark, tuna or marlin, as well as other marine animals such as whales, have the highest mercury levels [1,3]. 6. Can MeHg be eliminated by cleaning or cooking the fish? No. Between 90 and 100% of the mercury content of fish is in the form of MeHg, which binds to proteins (not fat) and therefore cannot be eliminated by cleaning or cooking the fish [11]. 7. Which Spanish regulation governs the maximum permitted level of mercury in fish and shellfish? European Union Regulation 629/2008 provides that the maximum permitted level of mercury in fish and shellfish is 0.5 mg/kg wet weight in fish and shellfish, except for the products listed in subsection 3.3.2 of such regulation, which have a maximum level of 1 mg/kg [15] and include the following fish with high mercury levels: angler, Atlantic catfish, white tuna, eel, orange roughy, grenadier, halibut, kingklip, marlin, megrim, mullet, pink cusk eel, pike, poor cod, Portuguese dogfish, rays, redfish, sail fish, scabbard fish, seabream, pandora, shark, snake mackerel or butterfish, sturgeon, swordfish and tuna. The scientific name for each fish on the list should be borne in mind because, for example, Greenland halibut, black-bellied angler and megrim are types of fish consumed in Spain which have lower mercury levels than other fish with similar commercial names [3,16,17]. 8. What is the provisional tolerable weekly intake of MeHg? 2. Where do mercury (Hg) and methylmercury come from? Mercury pollution comes from natural sources such as volcanic eruptions or anthropogenic emissions like the combustion of fossil fuels, emissions from incineration, cement production, the chloralkali industry, polyurethane elastomer production, mining and artisanal and small-scale gold mining, as well as deposits formed by these emissions, which are released into the atmosphere by evaporation and enter the food chain [8,9]. Once this toxic element has been deposited in the aquatic mercury cycle, it is transformed into methylmercury (MeHg) by certain sulphate-reducing bacteria, bioaccumulates in aquatic organisms and moves up the food chain, biomagnifying as it does so (i.e. it increases in concentration as it moves through the food chain) [10–12]. 3. Is eating fish good for health? Yes. Fish is an important source of nutrients such as omega3 long chain fatty acids, high-quality proteins, selenium (Se) and vitamin D, amongst others [1,10]. The US National Research Council established a weekly intake level of 0.7 g/kg body weight in 2000, and based on this recommendation the EPA set limits of <1 g/g for hair mercury and 5.8 g/L for blood mercury [18] (MeHg is estimated to make up about 90% of total mercury, so the corresponding level of total mercury in blood is 6,4 g/L) [11]. At the international level, the JECFA (Joint FAO/WHO Expert Committee on Food Additives) set a provisional tolerable weekly intake of 1.6 g of MeHg per kilo of body weight in 2003 [19]. In 2012, the EFSA (European Food Safety Authority) reduced the provisional tolerable weekly intake to 1.3 g MeHg per kilo of body weight, which corresponds to a blood MeHg level of approximately 10.8 g/L and a total blood mercury level of 12 g/L [20]. 9. Do mercury levels differ depending on whether the fish is fresh, frozen or canned? The form that fish comes in (fresh, frozen or canned) does not affect its mercury content [21]. M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 125 10. What species of tuna is in canned white tuna, tuna and light tuna? mercury content (0.05 mg/kg), that child could eat fish every day, even in higher quantities (115 g per day). Based on the Munsell grey scale, the FDA denominates “white tuna” as Thunnus alalunga not darker than Munsell value 6.3 and “light tuna” as tuna between Munsell values 6.3 and 5.3. White tuna or albacore (Thunnus alalunga) is named “bonito del Norte” in Spanish [21,22]. In the USA, light tuna is made up mainly of skipjack (Katsuwonus pelamis) and small amounts of yellowfin (Thunnus albacares), although in can include other species [21,23]. However, in Spain, the Royal Decree approved in 2009 classifies light tuna as yellowfin and bigeye (Thunnus obesus) [24]. In Spain, canned skipjack may also simply be called tuna. 14. How is MeHg distributed and metabolised in the human body? 11. Does the packing media of canned tuna affect mercury levels? Mercury levels in canned tuna do not depend on the packing media (oil, water or vinegar) but instead depend on several factors such as the species of tuna, size and origin, which is why in some countries the mercury level of canned light tuna can be low but not necessarily in others. For example, in a study performed in Spain on different brands of canned tuna, the authors found mercury levels in cans of light tuna higher than those in other countries such as the USA [21,25]. Nevertheless, the authors did not find any differences between the mercury levels of white tuna (bonito del Norte) and the levels published by the FDA in 2010, nor those of canned mackerel, which had much lower levels than canned tuna [23,25]. Around 95% of MeHg is absorbed in the gastrointestinal tract. Once absorbed, MeHg enters the bloodstream in a proportion of about 20 (erythrocytes)/1 (plasma), where it has a relatively long half-life of about 44–80 days. It is distributed amongst all the tissues, readily crossing the blood-brain barrier and the placenta. The main route of excretion of MeHg is through the faeces (up to 90%) and hair, with a very small amount being excreted through urine via the demethylation of inorganic mercury. Little MeHg is excreted via milk, as the main component is inorganic mercury. Antibiotic treatments have been shown to reduce excretion via faeces, while a fibre-rich diet increases excretion [2,11]. 15. Does MeHg toxicity differ by gender? Gender-related susceptibility to MeHg neurotoxicity has not been widely studied and the available results are inconclusive. In the Iraqi mercury poisoning incident, women were affected more than men (in exposure amongst adults) [1,11]. However, epidemiological studies in children have shown that boys are more susceptible than girls to the neurotoxic effects of MeHg when the exposure occurs at a young age [30]. 16. Do polyunsaturated fatty acids mitigate MeHg toxicity? 12. Where can I find information on fish mercury levels? The results of mercury analyses of fresh, frozen and canned fish are not available to the public in Spain. In other countries, such as the USA, the FDA publishes the results of its monitoring programmes and it is possible to know which are the most contaminated fish by state [23]. Mercury levels differ according to species and geographical area, so it is not a good idea to depend on data from other countries. For example, hake is considered to have low mercury according to many published studies such as the FDA 1994–2009 study, which found a median of 0.067 mg/kg [23]. However, in the Catalan Food Safety Agency-led study conducted from 2005 to 2007 on “Chemical contaminants in fish and shellfish consumed in Catalonia”, the largest increase in mercury amongst hake, sardines and mussel was hake, which increased from 0.09 mg/kg in 2000 to 0.9 in 2005 [26]. This mercury level in hake is similar to the data published in 1995 by the Basque Country food monitoring programme [27] and higher than that found in whiting, cod, pilchards, anchovies, megrim and squid [27–29]. 13. Is it necessary to limit consumption only of fish with high mercury levels? It is essential to know the real levels of mercury in the fish and shellfish (including cans) consumed habitually in Spain as well as serving sizes in order to be able to issue recommendations to the public, as the amount consumed of any given fish can influence an individual’s body burden more than whether or not a fish exceeds a legal limit. Similarly, a high one-time dose of MeHg can be more harmful to the developing nervous system than a chronic low dose [11]. For example, according to the 2012 EFSA recommendations [20], a 25 kilo child who eats a 75 g serving of fish with 0.5 mg/kg of mercury should not eat any more fish for 8 days. According to the more restrictive EPA recommendations [18], that child should not eat any more fish for 15 days. However, if the fish had a lower Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are polyunsaturated fatty acids found in fish and other dietary components. Their intake is important during the foetal and neurological development of children exposed to MeHg. It has been suggested that the dietary intake of long chain polyunsaturated fatty acids prevents or mitigates the toxicity of MeHg in general and its neurological and cardiovascular effects in particular [31]. 17. Does selenium offset the toxicity of MeHg? Selenium has received a great deal of attention as a potential protector from methylmercury toxicity in populations with high fish consumption [31]. Selenium status is measured in serum or plasma. Despite being an essential element, it can also be toxic and has a very narrow safe range without adverse effects. Selenium intake in Europe is low and its evaluation must take into account that low plasma selenium could partly indicate a low production of plasma GPx3 by an inefficient kidney or low selenoprotein synthesis resulting from the action of inflammatory cytokines (in the acute-phase response) [32]. In the case of fish, it was recently discovered that selenoneine has strong anti-free radical properties and is the predominant component in tuna and mackerel, while lower levels are found in squid and tilapia [32]. Some researchers [33] state that the toxicity of MeHg cannot be predicted by tissue mercury but rather by the presence of both selenium and MeHg since the formation of MeHg-selenocisteine compounds (pseudomethionine) probably reduces the bioavailability of selenium and thus interferes with the synthesis of the selenium-dependent antioxidant enzymes (selenoenymes) that provide antioxidant protection to the brain. They conclude that the molar ratio Hg:Se appears to provide more interpretable and physiologically meaningful information concerning the risk from MeHg exposure than does mere blood mercury, as MeHg toxicity directly targets the selenoenzymes [31,33,34]. 126 M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 18. Do other dietary components modulate MeHg toxicity? Some dietary components such as alcohol increase MeHg toxicity, especially in the kidneys [11]. Other elements, however, such as fruits, vegetables and fibre, seem to decrease MeHg levels in the organism [35–37]. In vitro digestion of fish has shown that phytochemical-rich foods such as green tea, black tea and soy protein reduce mercury bioaccessibility when consumed simultaneously with fish. Thiol compounds found in garlic also act as mercury chelators [36,37]. 19. Is there a genetic predisposition to MeHg toxicity? Studies performed in recent years have begun to document genetic and epigenetic factors that can influence the toxicokinetics of mercury and modify individual health risks associated with exposure, which would explain part of the variability in susceptibility to mercury toxicity [38,39]. 20. Can MeHg from the consumption of contaminated fish affect the health of children and adults? Yes, although the developing foetus and small children are most vulnerable to the neurotoxic effects of MeHg. Some studies of adults who consume large amounts of fish have also described that MeHg exposure can cause adverse health effects, and it has been suggested that it could increase the risk of cardiovascular events in the exposed population [1,2,6]. 21. What are the neurological effects in children? Very high exposure to MeHg, such as occurred in Minamata, caused children affected by in-utero mercury exposure to develop symptoms similar to serious cerebral palsy, with severe developmental delays, blindness, deafness and alterations in muscle tone and deep tendon reflexes [4,40,41]. In children, MeHg neurotoxicity at lower doses than those in Minamata particularly affects memory [42–44], language, attention, verbal abilities [42,45,46] and, to a lesser degree, visuospatial ability and motor function [46,47]. 22. Can it have other effects on children? Some studies have found a relationship between cord blood mercury levels and low birth weight and prematurity [48–50]. Cardiovascular effects have also been described, such as heart rate variability or increased blood pressure [51,52] as well as an association with systemic inflammation [53]. 23. What is the mercury level in children in Spain? Mercury levels found by different researchers in Spanish children are similar to each other and lower than those found in adults. They are higher, however, than those described in children in other European countries such as the Czech Republic, Germany and Belgium, as well as in the US, Korea and Canada. Other countries such as Japan, in turn, have much higher mercury levels than Spain; this is also the case in the Brazilian Amazon and French Guiana, where children consume fish that is highly contaminated due to gold mining [6,54–62]. The Infancia y Medio Ambiente Project (Childhood and the Environment or INMA, its Spanish acronym) found arithmetic mean hair mercury of between 0.94 g/g and 1.68 g/g depending on the cohorts studied, which is equivalent to blood levels of 3.76 g/L and 6.72 g/L, respectively, as well as an association with fish consumption [63]. Another study conducted by the Autonomous Region of Madrid also found significant differences between hair mercury in a group that did not consume fish (median of 0.68 g/g) and another group that consumed fish more than 4 times a week (median of 2.34 g/g), which is equivalent to blood levels of 2.72 g/L and 9.36 g/L, respectively [64]. A further study of children’s blood mercury levels in the Autonomous Region of Madrid showed a median blood Hg level of 3.67 (RIC: 1.09–4.55) g/L. 18,9% of the children had blood mercury levels higher than the EPA MeHg limit of 5.8 g/L. This study observed, in addition to the association with fish consumption, a correlation between mercury and selenium. Children in the third mercury tertile (>3.5 g/L) had higher selenium levels (mean of 74.49 vs 64.98 g/L) than children in the first tertile (≤1.35 g/L) [65]. 24. Does MeHg exposure from the consumption of contaminated fish cause adverse health effects in adults? Yes. Although the best-documented harmful effects of MeHg are those that impact foetal and new-born nervous system development, an increasing number of studies indicate that MeHg in the general population can also affect cognitive function, reproduction and cardiovascular risk in adults [6]. 25. What are the cardiovascular effects of MeHg in adults? Exposure to MeHg can cause oxidative stress which can in turn lead to cardiovascular disease, as it contributes to arrhythmias, high blood pressure, the build-up of atherosclerotic plaque and heart rate variability. The development of a dose–response function relating MeHg exposures with myocardial infarction for use in regulatory benefits analyses of future rules targeting Hg air emissions has been recommended [66–68]. 26. What are the other adverse health effects of MeHg in adults? In the Minamata poisoning, which led to hair mercury levels of between 50 and 700 g/g (corresponding to between approximately 200 and 2800 g/L in blood), the effects observed in adults were perioral and distal paraesthesia, ataxia, narrowing of the visual field, hearing problems, speech impairment and hand and foot tremors. The most serious cases involved severe encephalopathy, leading to coma and death [40,41]. Amongst the general population, which has levels much lower than in the Minamata poisoning, MeHg-associated deficits have been observed in motor, psychomotor, visual and cognitive functions in Brazilian Amazonian populations as well as Italians who consume large amounts of tuna [69,70]. Possible adverse reproduction and immunity-related effects have also been described [6]. 27. What is the mercury level in adults in Spain? Few studies of MeHg exposure have been conducted on the Spanish general adult population. All the studies described below found an association between blood or hair mercury levels and fish consumption [6]. Researchers in a study that took place from 1992 to 1995 in Guipúzcoa found a mean blood mercury level of 17.9 g/L [28]. A study in 2007 in Madrid described a geometric mean hair mercury of 2.23 g/g (corresponding to approximately 8.92 g/L of M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 mercury in blood) [71]. Also in Madrid, another study found similar results, with a median blood mercury level of 6.1 g/L [72]. The EMA (Exposure to Mercury amongst Adults) study conducted in 2008 in three Spanish cities, which also measured essential elements such as selenium, found the highest median blood mercury level in Santiago de Compostela (15.1 g/L; RIC: 10.2–19.9), followed by Cartagena (8.95 g/L: RIC: 6.7–13.8) and lastly, Madrid (7.9 g/L; RIC: 5.2–11.5) [73]. It is notable that the published mercury data for the Spanish population is comparable to that of Japan, which has much higher fish consumption than Spain [74]. On the other hand, Spanish mercury levels are much higher than those described in the US, Canada, and other European countries [6]. There is a great deal of variability between countries, which may be explained not only by the amount of fish consumed, but also by the type or species of fish consumed as well as other kinds of factors. 28. Is it enough to reduce mercury emissions? An international treaty called the Minamata Convention on Mercury was signed in October 2013. This document includes both compulsory and voluntary measures to control mercury emissions from various sources, to phase the element out of certain products and industrial processes, to restrict its trade, and to eliminate mining of it. It allows continued mercury trade for use in artisanal and small scale gold mining and for thimerosal in some vaccines, due to their role in protecting the world’s poorest children. However, even if the Minamata Convention manages to successfully reduce new mercury emissions, already existing atmospheric deposition levels may remain for hundreds more years, making it essential to issue dietary recommendations for vulnerable groups [75,76]. 29. Are there any recommendations for reducing MeHg exposure? Yes. Some countries such as the USA, Canada, Australia, New Zealand and Europe have had fish consumption recommendations in place for years. It should be borne in mind that the same type of fish may have differing mercury levels depending on such diverse factors as the origin or size, and that there are also local recommendations in place for certain fish that is sold only in some areas. In Spain, the Spanish Food Safety and Nutrition Agency (AESAN, its Spanish acronym) issued recommendations for vulnerable groups (pregnant or nursing women and children) in 2011 [77]: It is recommended that pregnant and nursing women, women who may get pregnant and young children (from 1 to 30 months) consume a broad variety of fish due to its nutritional benefits, avoiding the species with highest mercury contamination, which should be limited at certain times. The recommended consumption of swordfish, shark, Atlantic bluefin tuna (Thunnus thynnus: a large species, normally consumed fresh or frozen in filets) and pike is as follows: • Pregnant and nursing women and women who may get pregnant: avoid consumption. • Children <3 years old. Avoid consumption. • Children 3–12 years old. Limit consumption to 50 g/week or 100 g/2 weeks (do not consume any other fish in this category during the same week) [77]. 127 30. What biological specimens are most used for analysing Hg? 30.1. Blood Whole blood is the best specimen for evaluating MeHg as it concentrates in erythrocytes. Approximately 90% of mercury in blood is MeHg. The use of blood mixed with the anticoagulant K2 EDTA in tubes that have been previously tested to ensure they are mercuryfree is recommended, as blood mixed with heparin tends to form small clots over time [7,11]. 30.2. Urine The measurement of mercury in urine is not helpful in evaluating MeHg, although a small fraction of the inorganic mercury in urine comes from the demethylation of MeHg (approximately 10%). In order to correctly interpret mercury concentrations in urine, urine values should be corrected for creatinine or analysed in urine excreted over 24 h although, as already pointed out, it is not the most appropriate specimen for evaluating MeHg [78,79]. 30.3. Hair MeHg accumulates in hair, where it can reach levels of between 250 and 300 times that found in erythrocytes (blood mercury concentrations in g/L can be estimated by multiplying hair mercury concentrations in g/L by 4). Hair analysis has been widely used in epidemiological studies and to document a history of exposure, although there was and continues to be a great deal of controversy in respect of this type of analysis. The main limitations of hair are the difficulty in distinguishing endogenous from exogenous exposure, the need to standardise methods and preanalytical protocols, the lack of reference ranges due to individual and biological variability and the lesser availability of reference and quality control materials [11,80]. 30.4. Nails As occurs with blood and hair, mercury in nails is mainly MeHg, and its analysis has similar limitations to hair analysis: exogenous contamination, heterogeneous distribution, the lack of standardisation of methods and absence of external quality control programmes and certified reference materials all lead to a great deal of uncertainty in the measurement of mercury and other elements in nails [81]. 30.5. Breast milk Approximately 50–80% of the mercury in breast milk is estimated to be inorganic, thus breast milk does not properly reflect MeHg exposure from fish [82–84]. 31. Which is the best specimen for evaluating MeHg exposure? Whole blood is the best biological matrix for the evaluation of MeHg, given the absence of contamination, the standardisation of collection and handling procedures and the existence of exact and precise methods as well as reference materials and external quality control programmes involving a large number of laboratories [7,85]. The main indication for the use of hair to measure MeHg exposure is for epidemiological studies, especially in children due to the ease in obtaining this kind of simple. However, due to its limitations, the routine use of hair is not recommended for diagnostic 128 M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 purposes and even less so for therapeutic purposes. In respect of foetal exposure, although there is a correlation between maternal hair mercury and cord blood mercury, cord blood mercury is considered to be a better marker [80,81,86]. 32. What methods are used to analyse Hg and MeHg? The most widely used method for determining mercury in any specimen used to be cold vapour (CV) atomic absorption spectrometry (AAS). Mercury can also be measured directly in solid or liquid samples with “mercury analysers” – the mercury is released by way of thermal decomposition and then then measured by AAS. In addition, mercury can be analysed by way of inductively coupled plasma mass spectrometry (ICP-MS) [7,85,87]. Conventional methods of CV-AAS with two different reduction agents can be used to differentiate between inorganic and organic mercury. Different species of mercury can be measured by using gas chromatography with ICP-MS detection and isotopic dilution and, more recently, by high performance liquid chromatography (HPLC) to separate the species and cold vapour (CV) to introduce the sample into the ICP-MS detection. Thus, the HPLC-CV-ICP-MS system can be used to analyse inorganic mercury, ethylmercury and methylmercury [7,88,89]. 33. What laboratories can analyse mercury in human samples? Hair and blood mercury analyses are not performed on a routine basis at all clinical analysis laboratories. Regardless of the analytical method selected for the task, careful consideration must be given both to specimen collection procedures and to the control of preanalytical variables as the result may otherwise not be valid. In addition, it is essential for the laboratory to use internal quality controls with matrices similar to the specimens (blood, hair) on a daily basis and to participate in External Quality Assessment Schemes (EQAS) in order to ensure the accuracy, precision and reproducibility of its results [7,79,85]. The Spanish Society of Clinical Biochemistry and Molecular Pathology (SEQC, its Spanish acronym) collaborates in the organisation of the Occupational and Environmental Laboratory Medicine (OELM) External Quality Assessment Scheme, along with members from Australia, France, Italy, Belgium and Netherlands (http:// www.trace-elements.eu). 34. How should laboratory results be interpreted? There is no known safe level of mercury. The preferred specimen for evaluation of MeHg is blood, which reflects not only recent exposure but also chronic accumulation, although it is also possible to detect acute exposure to mercury vapour and inorganic mercury (iHg). Blood mercury levels tend to increase with age and peak in the 5th or 6th decade [90–92]. Hair analysis, albeit adequate for measuring MeHg, has limitations and thus should not be relied on to diagnose and even less so to begin unnecessary and potentially dangerous treatments [93–95]. The most appropriate manner of proceeding with a patient with suspected mercury poisoning is to collect blood and urine. Although MeHg is not found in urine, the latter can provide information on additional exposure to other types of mercury. The EPA recommends blood MeHg levels of less than 5.8 g/L, which corresponds to 6.4 g/L of total mercury, for pregnant women and women planning to get pregnant. MeHg crosses the placenta and levels in cord blood are 1.7 times greater than in maternal blood. Hence, some authors consider that maternal blood MeHg levels should be no greater than 3.5 g/L in order to keep foetal blood MeHg below the EPA reference level of 5.8 g/L [91]. Based on the EFSA recommendations (provisional tolerable weekly intake of 1.3 g MeHg/kg weight rather than the EPA recommended intake of 0.7) [20], the recommended blood level would be 10.8 g/L of MeHg or 12 g/L of total mercury, assuming that MeHg comprises 90% of total blood mercury, except in cases of acute poisoning from another type of mercury [11]. In addition, the Centers for Disease Control and Prevention (CDC) defines high level exposure to Hg as a blood level greater than 10 g/L [96]. When interpreting MeHg exposure, some authors consider that a mere measurement of mercury levels does not provide sufficiently true and precise information regarding the potential risks of MeHg, unless selenium (Se) is also included in the evaluation. [33]. In this regard, a high mercury level may be more toxic if the subject has a serum Se level lower than 60 g/L, while selenium greater than 99 g/L, taking into account that excess Se also causes adverse effects, may decrease mercury toxicity [97]. 35. Should chelators be used? The first measure should always be to remove the source of mercury exposure as this will improve or even reverse the patient’s symptoms. The use of chelators for diagnostic purposes (mobilisation test) or in asymptomatic patients is unnecessary and risky for the patient [98–100]. Chelators have adverse effects, for example, they increase the elimination of essential elements such as Cu and Zn, and their effectiveness is uncertain [101,102]. Furthermore, they do not effectively eliminate organic mercury such as MeHg or ethylmercury. The use of chelators such as dimercaprol may even be contra-indicated as it redistributes mercury from other tissues to the brain [103]. 36. What is the economic cost of implementing public health measures? MeHg exposure in children is linked to a loss in Intelligence Quotient (IQ), with long-term economic impacts in terms of future productivity, and a monetary estimate of such impact could be very important for the establishment of public health priorities. The DEMOCOPHES Project estimates that the total EU benefit for each cohort of new-born children would be 39,061 million, of which 15,564 would correspond to Spain [104]. It seems clear that despite the uncertainties regarding the MeHg dose–response relationship, public health measures aimed at reducing mercury exposure are necessary, as is the need to evaluate the benefits of such measures from an economic and social point of view [105–107]. 37. What does the GEPREM-Hg group recommend to individuals who have blood mercury? Mercury analysis for evaluation of individual cases of MeHg exposure should only be ordered by a doctor. Although international recommendations refer to MeHg, which comprises approximately 90% of total blood Hg, our recommendations refer to total blood mercury levels (Table 1). 38. GEPREM-Hg dietary recommendations in connection with MeHg Most fish and shellfish contains some mercury and some has a great deal of mercury. The general rule is that as the age of a fish increases, so do its MeHg levels. Given that size increases with M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 Table 1 GEPREM-Hg recommendations for individuals with blood mercury. Population group Total blood Hg Recommendation Children up to 14 years of age Pregnant and nursing women and those planning to get pregnant Children up to 18 years of age >6.4 g/La Dietary recommendations >20 g/L Adults 20–40 g/L >40 g/L Adults with cardiovascular or renal riskb >12 g/L Medical evaluation and dietary recommendations Dietary recommendations Medical evaluation and dietary recommendations Dietary recommendations a The EPA reference blood level of MeHg is 5.8 g/L, which corresponds to 6.4 g/L of total Hg. b Patients with high and very high totalcardiovascular risk per European arterial hypertension guidelines [108]. age, bigger fish within the same species are more likely to have higher MeHg levels. Some marine waters are more contaminated than others, although in the case of highly migratory species such as sharks, swordfish and tuna, the MeHg content cannot be attributed to a specific marine region. In addition, special attention should be paid to the scientific name, as sometimes the commercial name (hake, halibut, megrim. . .) encompasses a great number of different species which, due to their different biological characteristics, feeding habits and the area where they are harvested, have completely different Hg levels. The list of commercial names used in the different autonomous regions for the fishing and aquaculture species admitted in Spain, as well as their scientific names, can be found in the Official Journal of Spain (BOE, its Spanish acronym) of 10 April 2014 [109]. The following recommendations for fish and shellfish consumption (fish, cephalopods, crustaceans and bivalve molluscs) are made only in connection with MeHg. This document does not take into account other fish contaminants or the differences amongst different fish and shellfish in terms of beneficial nutrients such as polyunsaturated fatty acids, selenium or vitamin D. • The variables described above, as well as the limited and insufficient information available in Spain, make it very difficult to classify fish by mercury content. • A variable percentage of fish can exceed the maximum mercury content permitted by Spanish legislation. Some of the highest percentages were found by the Spanish Oceanographic Institute study performed in the Levantine–Balearic marine area. These high MeHg levels were related to size or age, and some fish exceeded the maximum permitted mercury content by as much as 22.7% (hake), 14.3% (swordfish), 14.3% (blue whiting), 10% (angler), 13% (red shrimp), 8.7% (pandora), 8% (forkbeard), 5.3% (megrim), 4.8% (blackspot seabream) and 0.4% (red mullet). The study performed in the Canary marine area found considerably lower MeHg content in pandora, striped red mullet and pilchards [16,17]. • Hake is one of the most consumed fish in Spain and can reach a very large size, so the most vulnerable groups should consume only those that weigh less than 2 kg. • A great deal of canned light tuna is also consumed in Spain and contains a wide range of Hg levels due to the different species, size and origin. We recommend that more information be provided on packaging labels and that the vulnerable population preferably consume canned mackerel, which is much lower in Hg. • Atlantic halibut (Hippoglossus hippoglossus), which is exempted (maximum permitted content of 1mg/kg wet weight), is a very 129 Table 2 Estimated maximum recommended intake of Hg in mg/kg wet weight of fish based on number of 125 g servings per week and the weight of the individual, pursuant to the EFSA recommendation. Number of servings perweek Weight of the individual 40 kg 50 kg 60 kg 70 kg 80 kg 90 kg 100 kg 2 4 6 7 0.208 0.26 0.312 0.364 0.416 0.468 0.52 0.104 0.13 0.156 0.182 0.208 0.234 0.26 0.069 0.087 0.104 0.121 0.139 0.156 0.173 0.059 0.074 0.089 0.104 0.119 0.134 0.149 long lived species and can reach lengths of up to 1 m and weights of up to 200kg, and thus should not be consumed by vulnerable populations. Greenland halibut (Reinhardtius hippoglossoides), however, is smaller and has much lower Hg levels [15–17]. • Some species are particularly difficult to classify by mercury content (low, moderate or high) because the published analyses show wide variability, even within the same marine area. Others species, however, such as pilchards or mackerel, have less variability. Sometimes these differences are due to the fact that different species are included under the same commercial name (megrim, angler). The Spanish Oceanographic Institute study, for example, found [16,17]: Four spot megrim (Lepidorhombus boscii): from 0.018 to 0.788 mg/kg wet weight Megrim (Lepidorhombus whiffiagonis): has lower levels: 0.033–0.468 mg/kg wet weight. Angler (Lophius piscatorius): from 0.026 to 0.616 mg/kg wet weight Black bellied angler (Lophius budegassa): has lower levels: from 0.103 to 0.331 mg/kg wet weight. Blackspot seabream (Pagellus bogaraveo): from 0.050 to 0.438 mg/kg wet weight. Striped red mullet (Mullus surmuletus): from 0.183 to 1.34 mg/kg wet weight. In this case, 7% was found to exceed the legal limit. Canned light tuna: from 0.139-0.601 mg/kg wet weight. European pilchard (Sardina pilchardus): from 0.017 to 0.048 mg/kg wet weight. Atlantic mackerel (Scomber scombrus): from 0.012 to 0.098 mg/kg wet weight. • The amount of mercury ingested due to fish consumption depends on three main factors: 1. The species of fish, size and geographical area where it was caught. 2. Frequency of fish consumption. 3. The serving size. A serving should be 125 g for adults and 70 g for children. • In 2012, the EFSA (European Food Safety Authority) lowered the provisional tolerable weekly intake to 1.3 g of MeHg per kilo of body weight [20]. • Based on this recommendation, the table below shows the maximum amount of mercury (mg/kg) individuals can consume in each serving of fish, according to their weight and number of servings per week. The amounts for children take into account their lower weight and smaller serving sizes (Table 2). 130 M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 Table 3 Estimated maximum recommended intake of Hg in mg/kg wet weight of fish based on number of 125 g servings per week and the weight of the individual, pursuant to the EPA recommendation. Number of servings per week Weight of the individual 40 kg 50 kg 60 kg 70 kg 80 kg 90 kg 100 kg 2 4 6 7 0.112 0.140 0.168 0.196 0.224 0.252 0.280 0.056 0.070 0.084 0.098 0.112 0.126 0.140 0.037 0.047 0.056 0.065 0.075 0.084 0.093 0.032 0.040 0.048 0.056 0.064 0.072 0.080 • The European Union has established the maximum permitted level of mercury at 0.5 mg/kg wet weight of fish and shellfish, except for those exempted species listed in subsection 3.3.2 of Regulation 629/2008, which have a limit of 1 mg/kg; however, based on the above estimates the maximum Hg limit should be lower. • If we take into account the EPA recommendation of 0.7 g MeHg/kg weight/week) the maximum permitted level of mercury goes down by almost half [18] (Table 3). The GEPREM-Hg group’s recommendations are based on the EFSA guidelines. However, we believe it is better to be cautious in the case of vulnerable groups such as children and pregnant or nursing women and follow the more restrictive EPA guidelines. In line with these guidelines, for a 25 kg child who consumes 2 servings (70 g/serving) of fish per week, each serving should contain an average of no more than 0.125 mg/kg, and 0.063 mg/kg of mercury in the case of 4 servings. Taking into account these estimates and the different studies published in Spain [25–29,77,110], most particularly the Spanish Oceanographic Institute study [16,17], the GEPREM-Hg group recommends the following maximum number of weekly fish and shellfish servings (125 g for adults and 70 g for children):Frequent consumption (several servings per week) Approximate mercury levels of <0.10–0.15 mg/kg wet weight. • • • • • • • • • • • • • • • • • • • • • • • • European anchovy (Engraulis encrasicholus). Skipjack tuna (Katsuwonus pelamis). Blue whiting (Micromesistius potassou). Greenland cod (Gadus ogac). Atlantic mackerel (Scomber scombrus). Gilt-head bream (Sparus aurata) (from fish farms). Greenland halibut (Reinhardtius hippoglossoides). Megrim (Lepidorhombus species). Atlantic horse mackerel (Trachurus trachurus). Dover sole (Solea solea). European seabass (Dicentrarchus labrax) (from fish farms). European hake (Merluccius merluccius). Argentine hake (Merluccius hubbsi). Southern hake (Merluccius australis). Shallow-water Cape hake (Merluccius capensis). Patagonian grenadier (Macruronus magellanicus). Common moro (Mora moro). Atlantic pomfret (Brama brama). Black bellied angler (Lophius budegassa). Kingklip (Genypterus capensis). Salmon (Salmo salar). European pilchar (Sardina pilchardus). Brown trout (Salmo trutta). European squid (Loligo vulgaris). • • • • • • • • • • • • • • • Cuttlefish (Sepia orbyniana). Southern shortfin squid (Illex coindetii). Lesser flying squid (Todaropsis eblenae). Common octopus (Octopus vulgaris). Common cuttlefish (Sepia officinalis). Pullet carpet shell (Venerupis pullastra). Grooved carpet shell (Ruditapes decussatus). Common cockle (Cerastoderma edule). Northern prawn (Pandalus borealis). Crab (Maja species). Rose shrimp (Parapenaeus longirostris). Prawns (Penaeus species). Mediterranean mussel (Mytilus galloprovincialis). Razor clam (Ensis arcuatus). European flat oyster (Ostrea edulis). Moderate consumption (no more than twice/week) Approximate mercury levels of 0.20–0.30 mg/kg. • • • • Albacore tuna (Thunnus alalunga). Canned light tuna. Yellowfin tuna (Thunnus albacares). Blue ling (Molva dypterygia). Limited consumption (no more than once/week) Approximate mercury levels of 0.35–0.50 mg/kg. • • • • • • • Bigeye tuna (Thunnus obesus) (from the Indian Ocean). Blackspot seabream (Pagellus bogaraveo). European hake (Merluccius merluccius) (from the Mediterranean). Angler (Lophius species) (from the Mediterranean). Striped red mullet (Mullus surmuletus). Norway lobster/langoustine (Nephrops norvegicus). Red shrimp (Aristeus antenatus). Occasional consumption by adults (no more than once or twice/month). To be avoided by pregnant or nursing women and children up to 14 years of age Approximate average mercury levels of 0.60–1 mg/kg. • • • • • • • • • • • • Bigeye tuna (Thunnus obesus) (from the Atlantic Ocean). Atlantic bluefin tuna (Thunnus thynnus). School shark (Galeorhinus galeus). Atlantic halibut (Hippoglossus hippoglossus). Northern pike (Esox lucius). Marlin (Makaira species). Shortfin mako shark (Isurus oxyrinchus). Swordfish (Xiphias gladius). Small-spotted catshark (Scyliorhinus canicula). Orange roughy (Hoplostethus mediterraneus). Shark (Carcharhinus species). Blue shark (Prionace glauca). M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 131 GEPREM-Hg recommendaons for fish consumpon based on the EFSA tolerable weekly MeHg intake* occasional consumpon ‡ (no more than. 1-2/month 1,200 Body weight bigeye tuna (Atlanc), bluefin tuna, school shark, Atlanc halibut, northern pike,marlin, shorin mako shark, swordfish, small-spoed, catshark, orange roughy, shark, blue shark 1,000 40 Kg. 50 Kg. 60 Kg. 70 Kg. [Hg] mg/kg wet weight fish 80 Kg. limited consumpon (no more than 1/week) 0,800 bigeye tuna (Indian Ocean), blackspot seabream, European hake (Mediterranean), angler (Mediterranean), striped red mullet, Norway lobster, red shrimp 90 Kg. 100 Kg. 0,600 moderate consumpon (no more than 2/week) albacore, [canned] light,and yellowfin tuna, blue ling frequent consumpon (>2/week) European anchovy, skipjack tuna, blue whing, Greenland cod, Atlanc mackerel, gilt-head bream, Greenland halibut, megrim, Atlanc pomfret, Atlanc horse mackerel, Dover sole, European seabass, European, southern, and shallow-water Cape hake), Patagonian grenadier, common moro, blackbellied angler, kingklip, salmon, pilchard trout, squid, etc. 0,400 0,200 0,000 1 2 3 4 5 6 7 Servings (125g) of fish per week * 1,3 μg MeHg/kg weight ‡ not to be consumed by pregnant or nursing women or children under 14 years of age 39. Final comments It is important to point out that there can be substantial differences in mercury levels within the same species, depending on the size of the fish and the geographical area where it was harvested. It is essential to know the result of analyses of fish and shellfish in Spain, thus these recommendations will be updated with all available information. In summary, in connection with MeHg exposure due to fish consumption, the GEPREM-Hg group recommends: • • • • Consuming at least two servings of fish per week. Choosing fish with low mercury levels. Eating a variety of species. Eating smaller fish within the same species and within legal limits. • Small serving sizes. • Limiting the consumption of fish high in mercury. • Pregnant and nursing women and children up to 14 years of age should preferably consume fish with mercury levels below 0.15 mg/kg. As a final point, we believe it is fundamental to know the results of contaminant analyses of seafood sold in Spain. Food chain operators must perform their own checks to verify that the products they sell satisfy the requirements of health legislation. The competent authority, also under the provisions of current legislation, is responsible for overseeing that food chain operators comply with laws. In addition to inspections and audits, one strategy is sampling and analysis for the official control of the levels of contaminants in foodstuffs, including MeHg, pursuant to the requirements set out in the Annex to Regulation 333/2007 [111]. The competent authorities make the results of official controls available to the general public in the annual reports prepared pursuant to the requirements of Regulation 882/2004 [112]. This information, however, is aggregated and does not specify the MeHg levels found in fresh fish sold at Spanish ports or those found in frozen and canned fish sold in Spain. Other countries, including the USA, do make information available to the public regarding MeHg levels in fresh fish, noting the species, area where it was harvested, etc.; this allows consumers to make informed choices. From a public health point of view, all initiatives aimed at reducing or prohibiting the use of mercury have merit. In addition, and for the particular benefit of vulnerable groups, both the general population and healthcare workers should be able to find information on the mercury levels of fish sold in Spain, broken down by type of fish, by FAO fishing area where it was harvested, form in which it is sold (fresh or frozen) as well as of canned fish. Knowledge of such levels would help to establish appropriate dietary guidelines and regulate blood mercury levels. Biomonitoring systems should be established in order to follow the evolution of MeHg exposure in children and adults and perform studies designed to learn more about the possible health effects of concentrations found in the Spanish population, taking into account the lifestyle, eating patterns and the Mediterranean diet. Acknowledgments The authors express their thanks to Dr Victoria Besada Montenegro, a researcher at the Spanish Oceanographic Institute in Vigo, for the information she provided, her observations and her kind cooperation. We also thank the International Commission for the Conservation of Atlantic Tuna (ICCAT), particularly the Executive Secretary, Mr Driss Meski, Dr Avellaneda Díaz Díaz for her assistance in reviewing the bibliography and Dr Nicolás Olea Serrano of the Universidad de Granada for his observations. In addition, we thank Prof Patrick Parsons (Chief, Laboratory of Inorganic and Nuclear Chemistry, Deputy Director Division of Environmental Health Sciences. Wadsworth Center, New York State Department of Health, Albany, NY, USA) for his comments on hair and urine mercury analysis as well as Dr Jennifer A. Lowry (Chief, Section of Clinical Toxicology. Children’s Mercy Hospitals and Clinics. Kansas City, Missouri, USA) for her contribution regarding the use of chelators. 132 M. González-Estecha et al. / Journal of Trace Elements in Medicine and Biology 32 (2015) 122–134 We are grateful for the comments received from: Sociedad Española de Sanidad Ambiental (SESA): Ángel Gómez Amorín, Isabel Marín Rodríguez, Emiliano Aránguez Ruiz and Ma Luisa Pita Toledo. 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