Fluorinated substances

Fluorinated substances have been widely used for decades because of their water and oil repellent abilities, but they did not gain much attention until approximately ten years ago. Although substances in this class are associated with plasma proteins and are not fat-

soluble, they are persistent and the highest concentrations are found in organisms high up in the food chain. Perfluorooctanosulphonate (PFOS) and perfluorooctanoacid (PFOA) are found at highest levels in food, and food (particularly seafood) is the most importand source of these contaminants. They are found in muscle from all kinds of fish (lean or fatty), but at higher levels in liver (Haug et al., 2010). Estimated intakes in Europe and Norway are low (PFOS: 0.27 to 5.2 ng/kg bw/day; PFOA 0.08-4.3 ng/kg bw/day). The TDIs set by EFSA in 2008 (for PFOS 150 ng/kg bw/day and for PFOA 1.5 µg/kg bw/day) are orders of magnitude higher than the dietary exposure.

Veterinary medicine residues in farmed fish

2.2.4

Sometimes it is necessary to treat farmed fish with veterinary medicinal products (VMPs). When farmed fish is medicated, several measures are taken to ensure food safety for the consumer.

 Only authorized veterinarians/aquamedicine biologists can prescribe approved veterinary medicinal products.

 Only therapeutic agents that have been evaluated and approved in accordance with the EU regulations can be applied. For each substance and animal group, Maximum Residue Limits (MRLs) have been established.

 Withdrawal times for medicated fish are applied.

Withdrawal time denotes the time from completion of therapy with a veterinary medicinal product (VMP) until slaughtering of the fish can be done, and the purpose is to ensure that residual levels of the VMP in the fish are below the legal limit. The Norwegian Medicinal Agency is responsible for setting withdrawal times for VMPs holding a Norwegian marketing Authorisation. When setting maximum residue levels (MRLs) eventual effects of VMPs on future processing of food, and if the VMP has additional use (e.g. as pesticide) which could lead to additional exposure for the consumer, is taken into account as outlined in the The Norwegian Pharmaceutical Product Compendium (http://www.felleskatalogen.no/medisin- vet/tilbakeholdelsestider). The veterinarian or aquamedicine biologist initiating the theraphy as well as the fish farmer is responsible to ensure that fish is not slaughtered during this period. All use of VMPs must be reported to the Norwegian Food Safety Authority (NFSA) by the veterinarian/aquamedicine biologist in charge of the use. It is mandatory for the fish farmer to submit plans for slaughtering before effectuation. These actions enable the NFSA inspector to control that withdrawal times have been complied with at fish slaughtering. The fish can be banned from slaughter if the withdrawal times are not being withheld.

To avoid the presence of residues of VMPs at levels that might cause harm for the consumers, acceptable legal residue concentrations in food producing animals have been established. According to current EU legislation (EU 37/2010) each substance is assigned a maximum residue level (MRL), which is the highest permitted residual concentration of legally applied pharmacologically active substances in products (food) intended for human consumption. Consumption of food with medicine residues below the MRL should, by a wide

muscle and skin in natural proportions. For more details se the latest report on Monitoring program for pharmaceuticals, illegal substances, and contaminants in farmed fish (Hannisdal et al. 2014).

On behalf of the NFSA, the National Institute of Nutrition and Seafood Research (NIFES) carry out a continuous surveillance programme on veterinary medicinal products in seafood in accordance with EU Directive 96/23/EC. One sample per 100 tons of produced fish has been analysed each year since 1998. Samples have been collected by official inspectors from the NFSA at the farm, without prior notification to the farmer, and sampling has been done after the expiration of the withdrawal period. Additionally, samples representative of the farmed fish ready for the market have been collected at the slaughterhouse/processing plants.

According to Hannisdal et al. (2014), banned substances include growth promoters such as steroids and stilbenes, and substances listed in Commission Regulation (EU) No 37/2010 under prohibited substances for which MRLs cannot be established. Prohibited compounds considered relevant for aquaculture are chloramphenicol, nitrofurans, and metronidazole. To ensure harmonized levels for the control of banned substances, analytical methods used for banned compounds should meet minimum required performance limits (MRPLs) set by the community reference laboratories (CRLs), national reference laboratories (NRLs) and member states of the European Union (Commission Decision 2003/181/EC; Commission Decision 2004/25/EC; CRL Guidance Paper 2007).

During the years 1998-2013, more than 30 000 samples from farmed salmon have been analysed. So far (November 2014), no residues of banned substances or medicine residues above EU MRLs for VMPs including antibiotics have been detected in any of the samples. Antibiotics

The use of antibiotics in farmed fish in Norway has been low since mid and late 1990 (NORM/NORM-VET, 2013). In relation to the biomass of farmed fish, there have been marginal changes in antibiotics sales during the latest years. The amount of antibiotics sold in recent years represents approximately one treatment in 0.5-1% of the fish.

Effective vaccines against bacterial infections in fish farming were developed in 1990s and the implementation of vaccination programmes of fish was established. This resulted in a major decrease in the usage of antibiotics in fish farming despite a rapid growth in the biomass slaughtered fish (Figure 2.2.4-1).

Figure 2.2.4-1 The total sale in tonnes of active ingredients of antibiotics sold in Norway and used in Norwegian farmed fish during the years 1981 to 2012, and the concurrent biomass farmed fish slaughtered during the same time span. Source: NORM/NORM-VET 2013 (with permission) (NORM/NORM-VET, 2013)

Agents against sea lice

Infestation caused by sea lice, an ectoparasite of salmonids in salt water, mainly

Lepeophtheirus salmonis, is at present a challenging health issue in Norwegian aquaculture. Sea lice infestation may cause skin lesions and subsequent osmo-regulatory problems, thereby subjecting the fish to secondary infections. Resistance to some sea lice agents has resulted in increased sales of other agents. Use of veterinary medicinal products for

treatment of sea lice has been high since 2009.

An increasing use of flubenzurons has raised concerns over its possible environmental dissemination and impacts. In short, sea lice belong to the crustacean group, and

flubenzurons from aquaculture may be expected to influence other crustacean species near the treated fish cages (Samuelsen et al., 2014). Crustaceans, shellfish and wild fish near cages receiving treatments may obtain flubenzurons from excess medicated feed pellets or from active substances in fish faeces. However, there is a ban to catch wild fish close to farming sites, and data show that the risk of exceeding acceptable daily intake (ADI) of teflubenzuron (ADI = 0.01 mg/kg bw) from wild fish is neglectable (Samuelsen et al., 2013). However, this issue is beyond the scope of this opinion to comment on.

VMP against sea lice are included in surveillance programme on veterinary medicinal

products in food in accordance with EU- Directive 96/23/EC, and no residues above the given MRL for the various VMPs has been detected (Hannisdal et al., 2014).

Other agents

As in 2006, several disinfectants and cleaning agents are approved for use in the food industry including the seafood industry. The risk from exposure to these substances from farmed fish is probably limited.

In aquaculture, prevention and treatment of fungal infections (Saprolegnia spp) are done by topical application of fungicides (veterinary medicinal product, VMP) to farmed fish and roe (only prevention). The use of the fungicide bronopol (a VMP), for bath treatment of fish has been relatively stable in the period 2010-2012, but increased by 30% in 2013.

Malachite green is no longer allowed for application in aquaculture. The regular surveillance programme has not detected malachite green in farmed fish.

2.3 Summary of reference values for selected nutrients and

undesirable substances

The majority of health authorities worldwide recommend a regular fish intake in order to ensure proper nutrition and health benefits (Chapter 1).

Nutrients in fish

Several updates of recommendations for nutrients present in fish have been published.  In 2010 EFSA established recommendations for intake of EPA and DHA

o Adults: 250 mg/day for primary prevention of coronary heart diseases in healthy subjects

o Pregnant and lactating women: Additional 100 to 200 mg DHA per day was recommended

o Older infants (older than 6 months of age) and young children below the age of 24 months, an Adequate Intake of 100 mg DHA was proposed

o Young children above 2 years: EFSA proposed that dietary advice for should be consistent with advice for the adult population (i.e., 1-2 fatty fish meals per week or ~125 mg of EPA and DHA per day when adjusted for portion size)

 In 2014, based on the Nordic Nutrition Recommendations 5th _{edition (2012), the}

Norwegian Directorate of Health revised the Norwegian recommendations. They: o established a new recommendation for DHA of 200 mg/day for pregnant and

lactating women

o increased the recommended intake of vitamin D from 7.5 μg to 10 μg/day for children above 2 years and adults, and to 20 μg/day for the elderly (75 or more years of age)

o increased the recommended intake of selenium from 50 μg to 60 μg/day for men and from 40 μg to 50 μg/day for women

o kept the recommendations for iodine intake unchanged Contaminants in fish

 The substances mainly addressed in this opinion are methylmercury and dioxins and dl-PCBs because they occur in fish at levels that may result in exposure close to tolerable intakes. Other contaminants are also present in fish. Several of the compounds in the group of chlorine-, fluorine or bromine-substituted organic

compounds, including dioxins and dl-PCBs, are declining in the environment because they are no longer in use.

 Fish is the only important dietary source of methylmercury. Since the VKM benefit risk assessment of fish consumption in 2006, a new tolerable intake for methylmercury has been set by EFSA which implicated a reduction from 1.6 to 1.3 μg/kg bw/week, expressed as mercury.

 For dioxins and dl-PCBs, the TWI established by SCF at 14 pg TE/kg bw/week in 2001 (SCF, 2001) is still valid.

 For ndl-PCBs, EFSA could not establish a tolerable intake because of difficulties in distinguishing effects of ndl-PCBs from those of dl-PCBs (EFSA, 2005). Since exposure to ndl-PCBs is normally highly correlated with exposure to dioxins and dl-PCBs, VKM concluded in 2008 that with the combination of dioxins and PCBs in Norwegian food, exposure to dioxins below the TWI would also protect against toxicological effects from exposure to ndl-PCBs (VKM, 2008).

 For PBDEs and HBCDs, EFSA concluded that the risk of adverse health effects from exposure is low (EFSA, 2011), but no tolerable intakes could be set. The margins between levels in Europeans and levels excerting toxicity in experimental animals was high, indicating low concern.

 For fluorinated substances, the TDIs set by EFSA in 2008 for PFOS and PFOA are orders of magnitude higher than the dietary exposure in Norway.

Medicine residues in farmed fish

 When farmed fish is medicated, several measures are taken to ensure food safety for the consumer. These include retention times after treatment and large programs to control that the maximal residue limits (MRL) for veterinary medicinal products are not exceeded in farmed fish.

 No residues of banned substances or medicine residues above EU maximal residue limitsfor veterinary medicinal products have been detected in any of the analysed 30 000 samples from farmed fish (1998-2013). The residues controlled include e.g. antibiotics and agents agains sea lice.

The reference values used by VKM as basis for benefit and risk characterization of nutrient intake and contaminant exposures from fish in the present opinion are shown in Tables 2.3-1 and 2.3-1.

Table 2.3-1 Recommended daily intakes for nutrients used for benefit and risk characterisation

(Chapter 8)

Population groups Recommended intakes for nutrients EPA+DHA mg/day Vitamin D c µg/day Iodine c µg/day Selenium c µg/day 2-year- olds ~125a _{10 90 25} Adults ~250b _{10 (20)}d _{150 50 (women)} 60 (men)

Pregnant women ~250 (+100-200 DHA)b

200 DHAc

10 175 60

a_{according to EFSA (2010b) and adjusted for portion size for children being 50% of an adult portion of}

150 g

b_{according to EFSA (2010b)}

c_{according to Norwegian dietary recommendations (Norwegian Directorate of Health, 2014), which}

were based on the Nordic Nutrition Recommendations 5th _{edition (NNR5, 2012)} d_{For elderly (>74 years), vitamin D is recommended at 20 µg/day}

Table 2.3-2 Tolerable weekly intakes for contaminants used for benefit and risk characterisation

(Chapter 8)

Population groups Tolerable weekly intake for contaminants Methylmercurya

µg/kg bw/week

Sum dioxins and dl-PCBsb

pg TEQ/kg bw/week

2-year-olds 1.3 14

Adults 1.3 14

Pregnant women 1.3 14

a_{according to EFSA (2012a)} b_{according to SCF (2001)}

3 Fish and fish products in the