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The Norwegian Scientific Committee for Food and Environment (VKM) initiated this work to examine the extent to which organisms developed by genome-editing technologies pose new challenges in terms of risk assessment. This report considers whether the risk assessment guidance on genetically modified organisms, developed by the European Food Safety Authority (EFSA), can be applied to evaluate potential risks of organisms developed by genome editing.

The Norwegian Scientific Committee for Food and Environment (VKM) initiated this work to examine the extent to which organisms developed by genome-editing technologies pose new challenges in terms of risk assessment. This report considers whether the risk assessment guidance on genetically modified organisms, developed by the European Food Safety Authority (EFSA), can be applied to evaluate potential risks of organisms developed by genome editing.

The request from NFSA and NEA: Antimicrobial agents and microorganisms are introduced to sewage systems by different human activities, from private homes, institutions such as schools and hospitals, office buildings, industrial and commercial activities, i.e., from everywhere where people work and live. The Norwegian Food Safety Authority (NFSA) and Norwegian Environment Agency (NEA) asked the Norwegian Scientific Committee for Food and Environment (Vitenskapskomiteen for mat og miljø, VKM) for an extension of the 2009 VKM report “Risk assessment of contaminants in sewage sludge applied on Norwegian soils” regarding the impact of wastewater (WW)- and sewage sludge treatment methods used in Norway, on the fate and survival of antimicrobial resistant bacteria, fate of antimicrobial resistance genes, and main drivers for resistance (e.g. antibiotics, antifungal agents, heavy metals, disinfectants). The request addressed by VKM: VKM appointed a working group, consisting of three members of the Panel on Microbial Ecology, four external members and VKM staff to prepare a draft Opinion document. The Panel on Microbial Ecology has reviewed and revised the draft prepared by the working group and approved the Opinion document “Assessment of the impact of wastewater and sewage sludge treatment methods on antimicrobial resistance”. The antimicrobial resistance cycle: Exposure to antimicrobial agents is regarded as the most important driver for development and dissemination of AMR in microorganisms. Consequently, an important location for the development of AMR is the gut of humans or animals receiving antimicrobial drug therapy. As ARB, ARG, resistance genes and antimicrobial agents will end up in the WW system, this system could be regarded as a potential hot spot for interactions between different microorganisms, between different antimicrobial agents, and between microorganisms and antimicrobial agents. Hospitals and pharmaceutical companies are regarded as being an important source for antimicrobial drug residues released in WW. At the wastewater treatment plant (WWTP), bacteria and genes end up either in the effluent wastewater fraction or in the sludge fraction. When ARB and ARG are distributed with the WW sludge, they may reach arable land when the sludge is used as soil improver and fertilising product, and thus be recycled into the food-production chain. When following the effluent WW fraction, ARB and ARB will be released into WW recipients, such as lakes, rivers or fjords, and may, from these environments, also be recycled into food production. In each step of these cycles, ARB and ARG will be introduced into new environmental compartments to which they must adapt, and to microbial communities with which they must compete for survival and growth. Depending on the bacterial species, these new environmental compartments will be more or less hostile, but they will also provide opportunities for microbial interactions, like dissemination of ARG due to horizontal gene transfer (HGT) within and between bacterial species. Findings: It is challenging to deliver a general assessment of the nature of as well as the probability for direct discharge of ARB and ARG into effluent WW and applied sludge. This is due to the combined complexity of resistance carriers, traits, various sources of variation, and the WW systems. Moreover, there is currently a lack of harmonized methods and protocols to compare studies from different systems. However, there are no strong indications that there is a significant enrichment of ARB in WWTP operated under European conditions, which, on a general level, also applies to the Norwegian situation. Although some studies indicate a slight increase in the fraction of ARB, the absolute reduction in bacterial load during WW treatment (WWT) is significant; removal of between 99 % to 99.9 % of faecal indicator bacteria is generally achieved by secondary treatment, including biological and physico chemical treatment steps. Effluent WW is often released into water recipients, and there are many mechanisms (physical, mechanical, and chemical) that will limit the extent that ARB of faecal origin are transferred to the food-production chain. However, there are different views on the significance of this release for the development of AMR. Results from single studies indicate that WWTP effluents contribute little to the total AMR exposure of micro – and macro organisms in aquatic and marine environments. On the other hand, freshwater environments in general are regarded as an important reservoir of novel antibiotic resistance determinants, and in some areas, relative abundance of resistance determinants in effluents has been observed to be considerably higher than in pristine natural water sources. Some imprint of AMR in recipient waters, compared to pristine waters, is unavoidable. During WWT, bacteria largely adhere to particles that are aggregated and precipitated to form a solid sludge. The mandatory hygienisation of sludge kills a large proportion of these bacteria, notably all thermosensitive faecal bacteria. However, the resulting hygienised sludge is still rich in bacteria, some of which are carriers of ARGs. The current Norwegian regulations on use of sludge on soil contribute to prevent contamination of food with antimicrobial resistant bacteria and antimicrobial resistance genes from sludge. Yet, soils do contain a pool of both natural and sludge-derived antimicrobial resistance. The contribution of sludge to this antimicrobial resistance pool is probably temporally limited to a period after soil amendment with sludge. A recent, comprehensive study from Sweden showed that long-term application of sewage sludge on farmland only resulted in minor changes of soil bacterial community composition. No evidence could be found for enrichment of antimicrobial resistant bacteria or antimicrobial resistance genes in soil amended with digested and stored sewage. Hospital WW contains more ARB, ARG, and antibiotic residues than municipal sewage, but the difference is not large for ARB and the impact may be minimal in large WW systems. In smaller WW infrastructures, a hospital or similar institution may have a higher impact on the effluent water from the WWTP, and this might suggest that local treatment of the WW at the hospital could be advantageous. A recent Norwegian study monitored bacterial diversity in different WW in the Oslo area, and found the highest concentration of AMR (ARB and/or ARG) in hospital WW. But surprisingly, high concentrations were also found in the studied community wastewater. The relative contribution of hospital effluents seemed low in terms of dissemination of antimicrobial resistant bacteria to the wastewater treatment plant. All measures that can be taken at source to avoid dissemination of antimicrobial agents, ARB, and ARG should be evaluated for their contribution towards combatting AMR emergence. Concentrations of antimicrobial agents, ARB, and ARG are highest in the sewage system and at the inlet to WWTPs. Separation of the different fractions of antimicrobials, ARB, and ARG for individual treatment may therefore reduce the total load reaching the WWTPs. Due to the high concentrations of ARB and ARG in the sewage system, risks from sewage pipe leakages are of concern. Intrusion of contaminated water into the drinking water distribution system should also raise concern. Rehabilitation of the sewage and drinking water networks will considerably mitigate risks. The level of sewage treatment in Norway is rather low, and upgrading will decrease the concentration of bacteria discharged. However, WWTPs are generally not designed for removal of AMR. Membrane processes seem to be the most promising option for increasing such removal rates. Future perspectives: The opinion discusses how the “concept of sensitive recipients” for requirements of the level of WWT could be revisited. This concept is currently based on controlling nutrient loads to the environment, rather than on trace contaminants or contaminants such as ARB and ARG that develop in the stressed environment. In the future, it might be of value to define requirements for WWT based on the relative increase caused by the discharge to the pollution level. Using such a paradigm, a small load with contaminants to a rather unpolluted environment would be rated as being highly critical and the discharge would require further treatment. In addition to the amount of ARB, the type of resistance and their level of horizontal mobility are also important in this aspect. This opinion also proposes the establishment of a new monitoring programme, parallel to the existing NORM and NORM-VET monitoring programmes; “NORM-ECO”. There is relatively little knowledge on AMR in non-clinical compartments, compared with hospital and other clinical settings, and parameters that would trigger immediate responses from NFAS or NEA are not yet identified. However, establishment of a “NORM-ECO”-system requires clarification of that needs further definition.

There is growing understanding that the environment plays an important role both in the transmission of antibiotic resistant pathogens and in their evolution. Accordingly, researchers and stakeholders world-wide seek to further explore the mechanisms and drivers involved, quantify risks and identify suitable interventions. There is a clear value in establishing research needs and coordinating efforts within and across nations in order to best tackle this global challenge. At an international workshop in late September 2017, scientists from 14 countries with expertise on the environmental dimensions of antibiotic resistance gathered to define critical knowledge gaps. Four key areas were identified where research is urgently needed: 1) the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment; 2) the role of the environment, and particularly anthropogenic inputs, in the evolution of resistance; 3) the overall human and animal health impacts caused by exposure to environmental resistant bacteria; and 4) the efficacy and feasibility of different technological, social, economic and behavioral interventions to mitigate environmental antibiotic resistance.1. The workshop was organized and supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR), the Swedish Research Council (SRC) and the Centre for Antibiotic Resistance Research at University of Gothenburg, Sweden (CARe). This project received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement JPI-EC-AMR No 681055. Individual member states of the JPIAMR also covered travel costs for participants. Sí

VKM Report 2017:21 The Norwegian Environment Agency (NEA) and the Norwegian Food Safety Authority (NFSA) requested the Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) for an opinion of potential risks to biodiversity and agriculture in Norway associated with import of seeds for sowing, and cultivation of insect-resistant and herbicide-tolerant genetically modified maize 1507 under Directive 2001/18/EC (Notification C/ES/01/01). The notification is still pending for authorisation in the European Union. VKM is also requested to assess the applicant´s post-market environmental monitoring plan, and the management measures suggested in the draft implementing decision of the European Commission.

Maize MON 87427 was developed by Agrobacterium tumefaciens-mediated transformation to express the CP4 5-enolpyruvyl-shikimate-3-phosphate synthase (EPSPS) protein, in all tissues except for the male reproductive tissues, conferring tissue-selective tolerance to glyphosate. The molecular characterisation of maize MON 87427 did not give rise to safety issues. Agronomic and phenotypic characteristics as well as compositional data of maize MON 87427 did not raise food/feed and environmental safety concerns. No differences in the compositional data requiring further safety assessment were identified. There were no concerns regarding the potential toxicity and allergenicity of the newly expressed CP4 EPSPS protein. The nutritional value of maize MON 87427 is not expected to differ from that of non-genetically modified (GM) maize varieties. There are no indications of an increased likelihood of establishment or spread of feral maize plants. Given its intended use in food and feed, interactions with the biotic and abiotic environment were not considered an issue. Risks associated with an unlikely, but theoretically possible, horizontal gene transfer from maize MON 87427 to bacteria have not been identified. The monitoring plan and reporting intervals are in line with the scope of the application for maize MON 87427. In conclusion, the EFSA Panel on Genetically Modified Organisms considers that the information available for maize MON 87427 addresses the scientific comments raised by Member States and that the maize MON 87427, as described in this application, is as safe as its conventional counterpart and non-GM reference varieties with respect to potential effects on human and animal health and the environment in the context of the scope of the application. © European Food Safety Authority, 2015.

Using mathematical model ling , the EFSA GMO Panel ha s previously quantified the risk to non - target (NT) Lepidoptera of conservation concern, potentially occurring within protected habitats, associated with the ingestion of Bt - maize pollen deposited on their host plants. To reduce the estimated larval mortality to a negligible level, an isolation distance of 20 and 30 m was recommended between protected habitats and the nearest fields of maize MON 810/Bt11 and 1507, respectively. Here , the EFSA GMO Panel refines its model predictions , accounting for new ly reported information on maize pollen deposition over long distances . For its calculations , the EFSA GMO Panel considered three exposure scenarios at a range of isolation distances, at two protection levels and for a range of lepidopteran species, including hypothetical ones, with a wide spectrum of sensitivities to Bt toxins . An analysis of various sources of uncertainties affecting the exposure of NT Lepidoptera to Bt - maize pollen was conducted, in order to provide quantitative estimates of realistic exposure levels. The EFSA GMO Panel therefore provides risk managers with a tool to estimate and mitigate the risk for NT Lepidoptera of conservation concern. In contrast to its previous o utcomes obtained for unrealistically large levels of exposure that would not be expected in practice, the EFSA GMO Panel reports here mortality estimates for a more realistic level of exposure. The EFSA GMO Panel concludes that its previous recommendation for a 20 m isolation distance around protected habitats, within which maize MON810/Bt11 should not be cultivated, remains valid. New calculations show that the previously recommended isolation distance of 30 m from the nearest maize 1507 field would still protect NT Lepidoptera with known levels of sensitivity, including the ‘highly - sensitive’ Plutella xylostella . Should hypothetical species with greater sensitivities exist, larger isolation distances would be needed to ensure the desired level of protection.

Following a request from the European Commission, the Panel on Genetically Modified Organisms of the European Food Safety Authority (EFSA GMO Panel) assessed the results of the general surveillance activities contained in the revised annual post-market environmental monitoring (PMEM) report for the 2013 growing season of maize MON 810 provided by Monsanto Europe S.A. The supplied data do not indicate any unanticipated adverse effects on human and animal health or the environment arising from the cultivation of maize MON 810 cultivation in 2013. Similar methodological shortcomings to those observed in previous annual PMEM reports were identified in the analysis of farmer questionnaires and the conduct of the literature review. The EFSA GMO Panel therefore strongly reiterates its previous recommendations to improve the methodology of future annual PMEM reports on maize MON 810. The EFSA GMO Panel urges the applicant to consider how to make best use of the information recorded in national registers in order to optimise sampling for farmer questionnaires, reiterates its previous recommendations on insect resistance monitoring and continued screening, and requests to continue reviewing and discussing relevant scientific publications on possible adverse effects of maize MON 810 on rove beetles. Also, the EFSA GMO Panel encourages relevant parties to continue developing a methodological framework to use existing networks in the broader context of environmental monitoring. EFSA Journal is an open-access, online scientific journal

Maize 5307 was developed by Agrobacterium tumefaciens-mediated transformation to express two proteins: eCry3.1Ab, conferring resistance to certain coleopteran pests, and phosphomannose isomerase (PMI), used as selection marker. The molecular characterisation showed relevant similarities between the amino acid sequence of PMI and a known allergen, and between the amino acid sequence of eCry3.1Ab and a potential toxin. Some agronomic and phenotypic differences between maize 5307 and its conventional counterpart were observed (higher ‘heat units to 50 % pollen shed’, grain moisture, plant height, grain yield); however, the EFSA GMO Panel considered that these do not give rise to food/feed or environmental safety concerns. No differences in the compositional data requiring further safety assessment were identified. There were no concerns regarding the potential toxicity and allergenicity of the PMI protein. The EFSA GMO Panel could not conclude on the safety of the eCry3.1Ab protein due to the inadequate 28-day toxicity study provided. The outcome of a broiler feeding study with maize 5307 was not assessed by the EFSA GMO Panel, due to study weaknesses. There are no indications of an increased likelihood of the establishment and spread of feral maize plants. Interactions with the biotic and abiotic environment were not considered to be a relevant issue. Risks associated with the unlikely but theoretically possible horizontal gene transfer of recombinant genes from maize 5307 to bacteria were not identified. The post-market environmental monitoring plan and reporting intervals are in line with the scope of the application. In conclusion, in the absence of an appropriate assessment of eCry3.1Ab, the EFSA GMO Panel is not in a position to complete its food/feed risk assessment of maize 5307. However, the EFSA GMO Panel concludes that the maize 5307 is unlikely to have any adverse effect on the environment in the context of its scope. © European Food Safety Authority, 2015.