State-of-the-Art in Biosafety and Biosecurity in European Countries

The terms biosafety and biosecurity are widely used in different concepts and refer not only to protection of human beings and their surrounding environment against hazardous biological agent, but also to global disarmament of weapons of mass destruction. As a result, the biosafety and biosecurity issues should be considered interdisciplinary based on multilateral agreements against proliferation of biological weapons, public health and environmental protection. This publication presents information on both, international and national biosafety and biosecurity legislation. Status of national implementation of the Biological and Toxin Weapons Convention, penalization issues and measures to account for and secure production, use, storage of particularly dangerous pathogens or activities involving humans, plants and animals where infection may pose a risk have been analyzed. Safety and security measures in laboratories have been studied. Moreover, dual-use technology and measures of secure transport of biohazard materials have been also taken into account. In addition, genetic engineering regulations, biosecurity activities in laboratories and code of conducts have been investigated, as well.


Introduction
The terms biosafety and biosecurity are widely used in different concepts and frameworks which basically include best practices in working safely and securely with biological agents and toxins in different workplaces and environments.
However, biosafety and biosecurity initiatives refer not only to protection of human beings and their surrounding environment against hazardous biological agent, but also to global disarmament of weapons of mass destruction. As a result, the biosafety and biosecurity issues need to be considered interdisciplinary based on multilateral agreements against proliferation of biological weapons, public health and environmental protection.
The Biological and Toxin Weapons Convention (BTWC) is a key element in the international community's efforts to address the proliferation of weapons of mass destruction. The main provisions of the BTWC cover prohibitions, implementation, protection and peaceful usage of biological and toxin weapons (Millett 2010). The Convention was opened for signature on 10 April 1972 and entered into force on 26 March 1975. Currently, there are 170 States Parties, which signed and ratified the BTWC, another 10 states have signed, but not ratified the treaty and 16 states are not members (UNOG The United Nations Office at Geneva, Membership of Biological Weapons Convention 2013).
In accordance with article IV of the BTWC, each State Party shall, in agreement with its constitutional ordinance, take activities to prohibit and prevent the development, production, stockpiling, acquisition of biological agents, toxins, weapons, equipment and means of delivery. In addition, article III requires all States Parties to refrain from transferring biological weapons to anyone and from assisting, encouraging or including anyone to produce or acquire them. Based on this, some issues should be considered in a particular way, namely, penal measures, biosafety and biosecurity measures, import and export controls, enforcement measures and both, domestic and international cooperation and assistance.
It is still difficult to balance efforts to improve public health with efforts to counter bioterrorism despite slight/ subtle differences between natural and deliberate outbreaks of diseases (Dembek et al. 2007;Hunger et al. 2013). Moreover, clinical symptoms caused by biological agents of public health concern may mimic some agents of bioterrorism concern and vice versa. To assist State Parties in the implementation of the article X of BTWC, an International Health Regulation (IHR) has been issued by the World Health Organization (WHO). The IHR supports the State Parties in capability building to prepare and respond to natural, accidental and intentional spread of diseases as well as to improve the Confidence Building Measures information exchange process. By adoption of IHR, States Parties become more aware of the connection between public health and biological weapons reflecting in closer integration of WHO and BTWC activities on biosafety, biosecurity, disease surveillance and reporting.
Finally, environmental protection needs to be in biological safety and security concern, as well. Modern biotechnology, including synthetic biology, -nomics sciences, is an emerging instrument with potentials in improving human and animal health, agriculture, industrial and agricultural production as well as environmental protection. Nevertheless, the development and applications of it may have potential side effects to human and animal health as well as environment, counting biodiversity risks. Regulation of modern biotechnology products ought to safeguard the right of consumers to have access to safe products, information about the products and live in a safe and sustainable environment. The Cartagena Protocol on Biosafety has established a legal framework for international trade in genetically modified organism (GMOs) and provides Signatory State Parties with orientation and the framework for development of complementary national biosafety regulations. It however, does not address the risks and safe practices of handling of such organisms in different workplaces.
As a result, State Parties were obligated to review their domestic legislation and/or implement an additional law(s). National implementation of BTWC includes not only legislative and administrative measures, but also actions to enhance native compliance with the BTWC, export control system, biological safety and security, disease surveillance, biological agents detection, education and awareness raising.
This publication presents information on both, international and national biosafety and biosecurity legislation. Status of national implementation of BTWC, penalization issues and measures to account for and secure production, use, storage of particularly dangerous pathogens or activities involving humans, plants and animals where infection may pose a risk have been analyzed. Safety and security measures in laboratories including laboratory safety equipment, personnel protective equipment, waste handling and accident reporting have been studied. Moreover, dualuse technology and measures of secure transport of biohazard materials have been also taken into account. In addition, genetic engineering regulations, biosecurity activities in laboratories and code of conducts have been investigated, as well.

European Union Regulations in Biosafety and Biosecurity
The second, third and fourth Review Conferences noted ''the importance of … legislation regarding the physical protection of laboratories and facilities to prevent unauthorized access to and removal of microbial or other biological agents, or toxins'' (Final Declaration of the Fourth Review Conference 1996a; Final Declaration of the Third Review Conference 1991a; Final Declaration of the Second Review Conference 1986a). Following, the Sixth Review Conference recognized ''that states must take all necessary safety and security provisions to protect populations and the environment when carrying out such destruction and/or diversion'' (Final Declaration of the Sixth Review Conference 2006a). Moreover, the Sixth Review Conference called ''upon States Parties to adopt, in accordance with their constitutional processes, legislative, administrative, judicial and other measures, including penal legislation, designed to … ensure the safety and security of microbial or other biological agents or toxins in laboratories, facilities, and during transportation, to prevent unauthorized access to and removal of such agents and toxins'' (Final Declaration of the Sixth Review Conference 2006b).
Final Declaration of the Seventh Review Conference calls for ''need to implement safety and security measures to protect human populations and the environment, including animals and plants'' in accordance to article II (Final Declaration of the Seventh Review Conference 2012a), ''need to ensure safety and security of microbial or other biological agents or toxins in laboratories, facilities, and during transportation, to prevent unauthorized access to and removal of such agents and toxins'' in accordance to article IV (Final Declaration of the Seventh Review Conference 2012b). as well as ''need to national implementation measures'' regarding standards on biosafety and biosecurity, awareness among relevant professionals in public sector and sciences, promulgation of codes of conduct, training and education programs, capability building for surveillance and detection of outbreaks (IHR), equipment and means of delivery control of transport in accordance to paragraph 13 of article IV (Final Declaration of the Seventh Review Conference 2012b). In reference to disease surveillance and detection, the Sixth Review Conference has previously reaffirmed that ''the commitment of State Parties to take the necessary national measures to strengthen methods and capabilities for surveillance and detection of outbreaks of disease at the national, regional and international levels'' (Final Declaration of the Sixth Review Conference 2006c).
Referring to public, human and animal health the second, third and fourth Review Conferences called ''for greater cooperation in international public health and disease control'' (Final Declaration of the Second Review Conference 1986b; Final Declaration of the Third Review Conference 1991b; Final Declaration of the Fourth Review Conference 1996b). The third and fourth Review Conferences additionally urged ''in providing information on national epidemiological surveillance and data reporting systems, and (…) assistance, on a bilateral level and/or in conjunction with WHO, the Food and Agriculture Organization (FAO) of the United Nations and the World Organization for Animal Health (OIE), regarding epidemiological and epizootical surveillance, with a review to improvements in the identification and timely reporting of significant outbreaks of human and animal diseases'' (Final Declaration of the Third Review Conference 1991b; Final Declaration of the Fourth Review Conference 1996b). The Sixth Review Conference broadens above area calling for disease surveillance specific for humans, animals and plants (Final Declaration of the Sixth Review Conference 2006e), improvement of ''communication on disease surveillance at all levels'' (Final Declaration of the Sixth Review Conference 2006f) and ''improving national and regional capabilities to survey, detect, diagnose and combat infectious diseases as well as other possible biological threats and integrate these efforts into national and/or regional emergency and disease management plans'' (Final Declaration of the Sixth Review Conference 2006f). Moreover, it also calls for promotion of development and production of vaccines and drugs used in infectious diseases treatment (Final Declaration of the Sixth Review Conference 2006d, f).
The European Union Member States in parallel with the BTWC process have also collectively and individually established effective regulations towards implementation of biosafety and biosecurity.
The list of currently applicable laws and regulations related to biosafety and biosecurity in European Union (EU) is shown in Table 1.
Apart from legally binding agreements and legislative measures, biorisk management standards play supportive  List of the most important standards in biosafety and biosecurity fields is presented in Table 2.

National Implementation
In accordance to BTWC, biosafety and biosecurity need to cover measures to account for and secure production, use, storage and transport of highly dangerous pathogens and GMOs Genetically modified organisms, GMMs genetically modified microorganisms, WMD weapon of mass destruction, CBRN chemical biological radiological nuclear threats The national implementation of each State Party is essential to enforce the provisions of the BTWC, namely, prohibition and prevention of development, production, stockpiling, acquisition, retention, transfer or use of biological weapons by any person under their domestic jurisdiction. Furthermore, each country is obligated to implement additional measures into the current valid legislation to more preferably protect and prevent encouraging, inciting or assisting others.
National implementation of BTWC has been approved in most European countries so far, and determines the measures to account for and secure production, use and storage particularly dangerous pathogens or activities involving humans, plants or animals where infection may pose a risk (BTWC Legislation Database, VERTIC 2013).

Penalization
The penalization measures related to biological safety and security are implemented in the national BTWC regulations. Countries without national implementation of BTWC regulate penalization issues fragmentarily by national Penal Codes, e.g., in section on penalization of crimes against international law (BTWC Legislation Database, VERTIC 2013).

Protection of Employees Working with Biological Agents
Directive 2000/54/EC is the most important in protection of workers from risks related to exposure to biological agents at work.
National regulations on protection of employees working with biological agents have been implemented in most of the European countries (BTWC Legislation Database, VERTIC 2013). Austria regulate this issue by the Ordinance on protection of employees against hazards caused by biological agents, the Ordinance on work with GMOs in contained use (analogical ordinance applies in Switzerland), Law on the protection of employees, Regulation on biological work material and Regulation on safety of workplace (the last is similar to Ireland regulation). In Germany, apart from the Ordinance on safety and health protection at work involving biological agents, Technical Regulations for Biological Agents and Labour Protection Act are valid. The Royal Decree on protection of employees working with biological agents has been issued in Belgium. Comparable Decree on protection of employees' health at work is valid in Czech Republic and France. In France, the Work Code that affects the use of biohazards as well as Order on health and safety signs at work has been additionally implemented. The objectives of Directive 2000/54/EC have been implemented also in Swedish, British and Norwegian national regulations. Provisions of Directive 2000/54/EC introduces into Polish law the Minister of Health of 22 April 2005 the harmful biological agents for health in the workplace and protection of the health of workers occupationally exposed to these factors. Simultaneously, the Labour Code requires the employer to evaluate and document the occupational risks associated with performed work, the use of the necessary preventive measures to reduce risk and to inform employees about the occupational risk that is associated with their daily work, and the principles of risk protection. Labour Codes in Belarus and Kazakhstan as well as the Labour Regulation Act in Macedonia regulate some aspects of above Directive. In Moldova, some obligations of Directive 2000/54/ EC are implemented in Law on Biosecurity; nevertheless, it is mainly related to GMOs and GMO products.
Austria, Ireland, Moldova, Germany, Norway, Poland, Portugal, Sweden and UK have implemented obligations of Directive 2009/41/EC in national regulations (BTWC Legislation Database, VERTIC 2013). In general, contained use of non-GM pathogenic microorganisms has not been taken into account. In Switzerland, the handling of GMOs is governed by the Gene Technology Law, while the handling of non-GM pathogenic organisms is governed by the Federal Laws on Epidemics and Environmental Protection. The Ordinance on the contained use of organisms of 25 August 1999 (as of 23 November 1999) regulates the contained use of organisms, in particular genetically modified or pathogenic organisms.

Waste Management
Waste management is regulated in almost all European countries as separate legal act (France, Belgium, the Netherlands, Switzerland, Germany, Poland, Turkey, Spain, Macedonia, Belarus, Bosnia and Herzegovina, Moldova). In Belgium and France, the Directive 98/81/EC is implemented into national legislation. In France, requirements of above Directive are completed by specific regulations on waste originating from medical care and dangerous waste in general, imposing rules for storage, for incineration and for collection by an approved company. The Netherlands implements Directive 2008/98/EC. Some countries implement both, GMOs and GMO products waste as well as contained material management as an annex to currently applicable law or code (Czech Republic, Sweden). The Albanian Law of Environmental Protection regulates the management of hazardous waste and dangerous matters. In Croatia are applicable both, the Regulation on Categories, Types and Classification of Waste with a Waste Catalogue and List of Hazardous Waste and Regulation on supervision of transboundary movement of waste (BTWC Legislation Database, VER-TIC 2013).

Handling of Laboratory Animals
National legislation concerning laboratory animal handling is neglected in almost all European countries. In France applies the Order of 19 April 1988 setting out conditions for the provision to accredited laboratories of animals used for purposes of experimental and scientific research, setting out conditions for issuing authorizations to conduct animal experiments, and setting out conditions for accreditation, fitting out and operation of animal experimentation establishments. Some elements including isolation or removal of sick animals, disinfection, safety lodge of the animal carcasses, rendering and other wastes, in an approved place, safety lodge or sanitary treatment of the excrement as well as elimination of transmission vectors of the contagious diseases and safety handling of animal cadavers are regulated by national legislations concerning veterinary service and inspectorate (e.g., Albania). Other elements are regulated in Law on health and well-being of animals (e.g., the Netherlands) (BTWC Legislation Database, VERTIC 2013).

Reporting of Accidents
In general, reporting of incidents and accidents in laboratories is included in national ordinances, acts and regulations (Denmark, Switzerland, Belgium, Portugal, United Kingdom, Spain, Poland, Serbia, Turkey, Ukraine, Macedonia, Kazakhstan). In some countries, this aspect is specifically related to GMO and GMO products, e.g., Austrian Ordinance on Work with GMOs in Contained Use regulates safety aspects and the measures to be taken in case of accidents. A Czech Republic Law Act on GMO Products covers accident reporting in Article 20 and 21, concerning, respectively, emergency response plan and measures taken in case of an accident. Nevertheless, no uniform mechanism to report on incidents/accidents in European countries has been established. Some legal acts mention about necessity of it, but do not provide detailed information how to do it or provide only overall information (BTWC Legislation Database, VERTIC 2013).

Laboratory Measures Related to Biosafety and Biosecurity
Legal obligation on Standard Operational Procedures is applicable in many countries in relation to biological safety and security. In general, procedures and Good Laboratory Practice issues are within responsibility of directors and supervisors of the laboratories as occupational safety and health rules.

Transportation of Biological Agents
National measures to account for and secure transport of particularly dangerous pathogens or activities involving humans, plants or animals where infection may pose a risk have been analyzed. Most of the European countries have applicable regulation concerning transport of dangerous goods (Austria, the Netherlands, Germany, Bulgaria, Denmark, Estonia, Finland, France, Spain, Latvia, Macedonia, Moldova, Liechtenstein, Norway, Poland, Portugal, Russian Federation, Romania, Serbia, Slovak Republic, Turkey, Ukraine, Kazakhstan, Iceland, Lithuania, Montenegro, Andorra). Some countries have also implemented Law on transportation of hazardous goods (e.g., Switzerland) or both (e.g., UK, Czech Republic) (BTWC Legislation Database, VERTIC 2013).

Biosecurity Measures
Only three European countries have a Law on Biosecurity (Sweden, Moldova, Turkey), but in general it is focused on GMOs and GMO products. The physical containment of laboratories is dedicated particularly to GMOs. Law on national security of Romania covers overall issues. Executive Order on securing specific biological substances, delivery systems and related material is applicable in Denmark. Legal requirements to impose secure storage and use of dangerous pathogens and toxins are listed in Schedule 5 of Part 7 of the Antiterrorism, Crime and Security Act 2001 and the Security of Pathogens and Toxins (Exceptions to Dangerous Substances Regulations 2002) in UK (BTWC Legislation Database, VERTIC 2013).
No EU level legislation exists that has been specifically developed to address the protection of biological agents in the laboratory from loss or misuse, thus, biosecurity aspect is in principle neglected. Nevertheless, due to many synergies between biosafety and biosecurity, the EU Directives developed to protect workers from exposure to biological agents or GMMs address most of the issues related to laboratory biosecurity. Overall, competences and responsibilities of persons responsible for biosafety and biosecurity are fragmentarily defined. Licensing staffs to authorized access to the laboratory is neglected in most countries. Many institutions implement some biosecurity controls, but these are often focused on physical security. Less attention is focused on information security or organizational security issues, despite the fact that internal threats from individuals with authorized access to the laboratory must be recognized.

Bioethics
In most of the European countries, national code of ethics for scientific research or codes of bioethics is applied, e.g., Belgium, Czech Republic, the Netherlands, Ireland, Latvia, Germany, UK, Switzerland, Italy. In Italy, additionally the Conduct for Biosecurity has been implemented in 2010. Other countries use manuals or guides, e.g., Good Practice for Scientific Research and Good Manners in Science issued by the Polish Academy of Science.

Conclusion
In general, most of the biosafety and biosecurity aspects are covered independently in national laws, procedures and on technical and physical measures related to human, plant and animal pathogens. Based on the national legislation review, risk management is better documented for GMOs than for native pathogens. There is lack of legislative unification in GMOs and pathogenic agents. Usually, the GMOs regulation covers biosafety and biosecurity issues only in relation to GMOs and GMO products.
Still applicable becomes a need for global unification of national regulations in biosafety and biosecurity fields (Stavskiy et al. 2003).
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