CELEX: 51978PC0664
Language: en
Date: 1978-12-04
Title: PROPOSAL FOR A COUNCIL DIRECTIVE establishing safety measures against the conjectural risks risks associated with recombinant DNA work (submitted to the Council by the Commission)

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COM (78) 664
Vol. 1978/0254
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 ---pagebreak---  COMMISSION OF THE EUROPEAN COMMUNITIES
                                                           COM(78) 664 final
                                                           Brussels . 4 December 1978
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                                   PROPOSAL FOR A COUNCIL DIRECTIVE
              establishing safety measures against the conjectural risks
                             risks associated with recombinant USA work
                          ( submitted to the Council by the Commission )
COM(78 ) 664 final
 ---pagebreak---                        PROPOSAL FOR A COUNCIL DIRECTIVE
             establishing safety measures against the conjectural
                   risks associated with recombinant UNA work
The aims of this preamble are to introduce the essential features of recombi­
nant DMA work in the general background of modern developments in biotechnolo­
gy and to present the considerations which have led the Commission to prepare
the project of a directive compelling the Member States to adopt general pre­
cautions against hazards possibly associated to certain forms of recombinant
DNA work .
Recombinant PITA work and its importance for Research and Development
Modern techniques and most particularly the use of recently discovered enzymes ,
called restriction enzymes , now allow the arrangement of genetic material in
combinations which at the moment do not exist under natural conditions . The
general method involves the isolation of SNA from a donor organism , its frag­
mentation by restriction enzymes into groups of one or more genes , the coupling
of selected fragments to a vector (usually a virus or a constituent of the
cell to be used as host ) and its introduction in a host-cell which may
be propagated to form populations of identical cells called clones .
Provided that the genetic material transferred in this manner replicates and
expresses itself in its new surroundings , there are theoretically no limits
to the range of organisms with new properties which may be produced through
the use of recombinant DNA technology . In practice , however , the cloning and
expression of foreign D1TA into widely unrelated host–organisms are extremely
difficult to achieve and, in some cases , probably impossible. Yet , DJTA sequences
 coding for human placental lactogen and human growth hormone have been cloned
in the bacteria Escherichia coli (a natural resident of the human digestive
tract ) and in at least two instances ( expression in E. coli of a chemically
nynthotized gene for the hormone somatostatin and of the yeast structural
 ---pagebreak--- gene for the enzyme imidazole-glycerophosphate dehydratase ) has it "been shown
that the expression problem could "be overcome .
It is obvious , in view of these prospects and of these results , that recombi­
nant DNA technology opens up new avenues for fundamental and applied work
which will certainly lead to an enormous improvement in our knowledge of
genetic structures and genetic functions and which , in the long run , could
completely revolutionize certain production methods in agriculture and indus­
try . While growth hormone and insulin represent well know examples of products
which could be elaborated at industrial level by manipulated bacteria , several
other substances ( calcitonin, prolactin , neurotransmitters , antibodies •••)
may also be produced in the same manner by the pharmaceutical industries .      In
the medical sciences , one may conceive that the repairing of genetio defects
in man will one day become feasible^ with the help of recombinant DfTA work.
In agriculture , through appropriate genetic transfers in isolated protoplasts
regenerated afterwards into entire plants , modified crop species could be
obtained which would combine the characteristics of unrelated species and
present novel properties with regard to nitrogen uptake , disease resistance
and a wide range of different quality factors . Such progresses are not yet
in sight but are within our reach as long term objectives . Countries with
modern technologies , such as the USA and Japan, have fully realized the impor­
tance of research in this area and in all related fields of applied molecular
biology.
Rinks associated to recombinant DM work
While it is difficult to predict what a competent microbiologist could achieve
if he undertook to improve systematically , through genetic manipulations , the
virulence of important plant pathogens or to incorporate in E. coli the MA
from highly pathogenic organisms like Bacillus anthracis or Clostridium
botulinum , it appears that , except for such deliberate attempts to endanger
man and his environment , the risk associated to recombinant DNA work is at the
moment conjectural and , to a very large extent , controllable .
- Conjectural nature of the associated risks
   There is , in theory, a risk that living organisms , and particularly micro­
   organisms residing in man or in species important to man, acquire upon
                                                                               ./
 ---pagebreak---                                       - 3 -
 receipt of foreign INA properties which render them dangerous and harmfully
 As a matter of fact , any transfer of genetic information which confers simul­
 taneously to the host-organism a selective advantage and a modification of
 characters will to some extent affect our environment .      The effects may be
 almost negligible or beneficial if the new characters are nearly neutral or
 useful to man ; they may be devastating , either at short or long term , if
 they promote new factors ( pathogenicity , induction or propagation of cancers ,
 modification of environmental equilibrium , rupture of food chains ...) which
 man and the surroundings he has domesticated are unable to tolerate .
  In practice , however , this risk has not yet been verified .   On the contrary ,
  most of the experiments and model scenarios ( see for instance CURTISS R.
  Ann . Rev. Microbiol . 30 : 507-533 » 1976 and report of the U.S. - EMBO Work­
  shop held in Ascot , England , January 27-29 , 1978 ) constructed for assessment
  purposes do point out that organisms bearing recombinant ENA are perhaps
  unlikely , for various reasons dealing with the low adaptive fitness of
  manipulated cells and the general requirements for transcription and infec­
  tion , to generate biohazards greater than those associated to conventional
  research with pathogens .   In addition , it may be suggested from the fact
  that the reproductive barriers and isolating mechanisms operating in nature
  are error-prone and overlapping that there is perhaps no such thing , under
  natural conditions , as an absolute barrier to gene exchange between any two
  organisms .   Thence man and his environment , since they survived the conti­
  nuous flow of genetic information between species , may possibly be conside­
   red as relatively tolerant to any new form of recombinant MA .
- P oss ibilities for control
  Particularly because the scientists engaged in recombinant DMA work were
   the first to point out ( Asilomar Conference , 1973 ) the dangers possibly
   associated to their activities , research in this area has continuously been
   connected to the development of containment devices and of monitoring
   systems . As a result of this , methods , crippled host strains and facilities
   have been created which greatly reduce the chance that an organism bearing
   recombinant UNA escapes the laboratory (physical containment ) or survives
   to conditions prevailing outside the laboratory (biological containment ).
                                                                               ./■
 ---pagebreak---  While the forms of containment available , and particularly those pertaining
 to biological containment , certainly need to be improved and sophisticated,
they already provide , when used correctly , a very strong protection against
the risk that man and his environment are contaminated by recombinant DNA .
Guidelines and national safety measures
The development of recombinant DNA techniques has caused intense public and
scientific debate in many countries which involved such issue as the defini­
tion of the field covered by recombinant DNA work , the classification of this
work in categories of risks and in levels of containment , the necessity for
state control , the type of control ( voluntary or statutory ) to be involved
and the protection of intellectual property .
In the USA , the National Institute of Health ( NIH ) released very detailed
guidelines providing an accurate classification of research activities in
categories of risks and of assigned containment levels . At the moment only
the laboratories sponsored by the NIH are compelled to follow these guidelines
which are presently under revision and will probably be made less stringent .
Guidelines somewhat similar to those of the NIH have been prepared or are in
preparation , outside the Community , in all countries with advanced technolo­
gies but , as yet , no compulsory order have been issued on the matter in these
countries .
Within the European Community , the United Kingdom has rendered compulsory
advance notification of genetic manipulation work by all those who intend to
carry out such work on the national territory . A code of practice, which
differs from that of the NIH on essential points dealing with classification
procedures and containment methods , is at the moment operated under a volun­
tary basis but with the understanding that the inspectors of the Health and
Safety executive have extensive powers to enforce duties as well as pre­
cautions recommended by the British Advisory Group . The other Member
States have also prepared or adopted guidelines to research with recombinant
DNA which in some cases adhere to either the British or the American system
and in others represent a compromise between the two sets of guidelines .
 ---pagebreak---                                      - 5 -
 In France , The Netherlands , Denmark and. Belgium , the National Advisory
 Committees have "been assigned the task to register the work at hand and to review
 research proposals . While a declaration of agreement has "been drafted in
 Prance under which governmental , academic and industrial laboratories
 will submit to review and approval any project for recombinant DNA work , only
 two Member States ( The Federal Republic of Germany and The Netherlands )
 have , in addition to the United Kingdom , clearly indicated an intention
 to introduce regulations on recombinant DNA research# In the Federal
 Republic of Germany , the compulsory orders will first be restricted to
 research financed by national funds ; at a later stage , they will be extended
 to activities supported by the "Lender" and by private Bources .
  The elaboration or adoption of guidelines in the Member States and in other
 European countries has been greatly facilitated by the critical reviews and
  recommendations which were issued by the ad-hoo committee on recombinant DNA
  research of the European Science Foundation and by the Standing Committee
  of E.M.B«0 » on recombinant DNA#
  Necessity for national legislations based on Community standards
  It is the view of the Commission that six different sets of considerations
  strongly underline the necessity for national laws on the matter :
- Harmony between Member States
   Although it is not desirable , in view of the differences between the various
   containment facilities available in Europe , that identical guidelines are
   adopted and followed by all Member States , it is nevertheless essential ,
   to avoid large variations in research potentialities , that certain basic
                                                                              /
 ---pagebreak---  principles of safety are accepted and adhered to by the Community of
Member States .   The present situation in which some Member States have
 adopted legislation on recombinant DNA work or are planning to do so while
 others haven't as yet defined any formal policy on the matter is , in this
 respect , unacceptable to the eyes of the Commission because it will lead to
the development of differing conditions of safety , work and success between
Member States and , subsequently , to the concentration of research activities
at the most permissive sites .    Such an expansion of divergences will not
arise if national legislations , harmonized in part around a core of Community
principles , are adopted in each Member State and provide the necessary tools
for the permanent implementation of safety measures comparable in essence
throughout the entire Community .
The exemplary value of legislation on recombinant IfPTA technology
Genetic manipulations only form a small part of the attempts which man is
now making for assuming the responsibility for life on this planet and for
transforming his approach to the domestication of lower forms .     Several new
methods have now been developed which allow the immobilization on carriers ,
for industrial use , of enzymes and of cells , the production of new synthetic
compounds , the mass-production of proteins in fermentation batches and, in
a general manner , a complete modification of the relationship between man
and nature . In the long term , the applications of molecular biology to
agriculture and industry will unavoidably transform life in society and will
induce significant and , possibly , irreversible changes to our environment .
To request that the techniques which are to bring these changes are subjec­
ted , from the start , to statutory control and to legislation does not cons­
titute an aggression to progress but , on the contrary , a recognition of the
need to adapt society to new scientific developments .
Recombinant DNA work, even though the risk it represents is conj ectural ,
well analysed in the Member States and possibly not greater than the dangers
associated to conventional research with pathogens , constitutes , in this
connexion , a choice material for establishing compatibilities between legis­
lation and the development of modern technologies and for preparing a first
basis to the dispositions which will undoubtedly have to be taken in the
future to protect man against his own achievements .   Provided that the
legislation adopted is tolerant , flexible , and associated to a, stimulation
of research through funding, the opportunity should not be missed.
                                                                            •/
 ---pagebreak---                                          _ T -
I
  - Gravity of the hazards
     The classification of a risk as conjectural does not imply that the risk
     under consideration is benign. While scenarios representing the planet
     colonized by a new class of organisms combining the requirements and
     features of bacteria and mammals are of course purely fictitious the expansion
     of myxomatosis in Europe or the destruction of a tobacco field by black
     shank illustrate the gravity of the dangers which may be associated to the
     sudden spread of microorganisms with properties adapted to their environ­
     ment . It is , as a matter of fact , in prevision of such conjectural dangers
     that various forms of physical containment and certified strains of bacteria
     unable to suryive outside laboratory conditions are being produced through­
     out the Western world .   If the gravity of the risk involved is such as to
      require the elaboration of these expensive protection devices it certainly
      justifies the preparation of orders intended to insure that they effecti­
      vely serve their purpose and are used to protect against the risk which
      they are supposed to contain .
   - Exoansion of recombinant MA work
      Scientific progress in the field is occuring so rapidly that a number of
      experiments involving the production and use of recombinant UNA can now be
      executed on a routine basis and constitute classical approaches to certain
      investigations in molecular genetics » What appeared to be , a few years
      ago , a very sophisticated technique accessible to a small number of highly
      specialized institutes is being commonly used , in many laboratories , for
      specifying genes and their products 0 In addition , several centers devoted
      to applied research , and among than many laboratories operated by private
      industriesj have "bocorae aware of the potentialities of recombinant DNA
      techniques for genetic engineering purposes and have launched, or are
      contemplating to launch , important research actions centred upon the produc­
      tion and use of recombinant M® Thus the risk, if there is one , which is
      associated to recoiabinsni MA is increasing with time in proportion with
      the total number of eites where such work is carried out .
 ---pagebreak---                                         - 8 -
- Transnational nature of the risk
    The fact that the biological material subjected to recom"binant DNA work
    usually includes viruses and bacteria which , assuming their escape from
    the laboratory , are not subjected to the barrier of national borders reduces
    to a certain extent the liberty of individual nations to define and to follow
    independent policies in the field of genetic manipulations#    Agreement must
    be reached within communities of neighbouring countries on the general
    objectives and scale of the protection systems which   are to be established
    and guarantees must be given to the respect of these   agreements® Such
  ^ agreements and such guarantees can best be generated   through legal disposi­
    tions , taken in each country , which are based upon a core of principles
    adopted in common *
- Research in laboratories from private enterprises
    While it is possible to conceive , in the absence of national legislations
    regulating work with recombinant DNA , that the governmental funding agencies
    maintain a certain level of control over the research activities of univer­
    sities and national institutes , it is far more difficult to envisage , in the
    absence of legal dispositions , a system compelling the laboratories from
    private industries to adhere to the terms of national guidelines on recombi­
    nant MA » There is , in other words , in a country where such guidelines are
    followed on a voluntary basis , a risk that different laboratories working
    at identical levels of risks do not observe the same rules to safeguards
    and to containment® Whereas it is obvious that a situation of this type is
    unacceptable it is also equally obvious , in view of the importance of
    recombinant MA technology for the promotion of European bio-industries ,
    that a legislation on recombinant UTA work must not endanger intellectual
    property rights and that special attempts will have to be made by the
    legislator to restrict to a minimum the disclosure by industries of confi­
    dential scientific information#
                                                                               ./■
 ---pagebreak--- 9
                                        - 9 ~
  A Community directive on recombinant DNA work
  The problems raised by genetic manipulations and the possible need for a
  Community directive compelling each Member State to adopt certain measures
  of protection and of control against conjectural risks have been discussed
  several times by the Committee on Medical and Public Health Research ( C.R.M. )
   and by ad hoc expert groups in the presence of representatives of E„S.F.
   and EMBO .
   Following this period of consultation, the Commission prepared the attached
   project for a Council directive regulating work on recombinant DNA . This
   project takes simultaneously into account the necessary requirements for
   safety and the need for flexibility and adaptation to local circumstances .
   While stipulating that recombinant DNA considered to be associated to con­
    jectural hazards cannot be performed if it is not first registered and autho­
    rized by the National Authority , the proposed directive leaves entire liber­
    ty to this National Authority in each Member State to establish the catego­
    rization and containment levels which it deems most appropriate . Special
    provision is taken for work tabulated as low risk and attempts are made to
    reduce at a minimum the amount of scientific information which is to be
    disclosed for registration and authorization purposes .     Finally , full refe­
    rence is made in the text of the directive to the fact that the terms of the
    present orders will have to be reviewed regularly at short intervals and
    revised , when necessary , at the light of new developments and scientific
    progresses . In addition, the Commission will study "the special case ,
    covered at the ntoment by the terms of the praeent directive , which oonoems
    the us® of recoHihinajit 32$A matex-ial for large soale industrial production ;
    if neoeseary additional directives adapted to suoh caa© will be proposed
    by tha Commission®
                                         *     #
 ---pagebreak---                                                              Original    Eng Li sh
                 CONJECTURAL HAZARDS OF RECOMBINANT DNA WORK
                                 Council Directive
The Council of the European Communities ,
Having regard to the Treaty establishing the European Economic Community , and
in particular Article 235 thereof ,
Having regard to the proposal from the Commission,                     ,
Having regard to the opinion of the European Parliament ,
Whereas Article 2 of the Treaty assigns to the Commission the task , among
others , to promote throughout the Community a harmonious development of econo­
mic activities , a continuous and balanced expansion and an increase in stabi­
lity ;
Whereas the development of basic and applied biological research is of a kind
to contribute with efficiency towards the achievement of these objectives ;
Whereas this development implies , in several sectors , that recombinant DNA
work be performed on certain organisms ;
Whereas recombinant DNA work performed on certain organims , and particularly
on microorganisms resident in man, or in certain animal and plant species used
 in agriculture , may present conjectural hazards to man , to his food resources
 and to his environment in general ;
 ---pagebreak--- Whereas           measures of protection settled "by "the authorities against
such conjectural hazards must be combined with the development of recombinant
DNA work ;
Whereas this development involves epidemiological and hence international
conjectural hazards ;
Whereas           the disparities "between the provisions in force or in prepa­
ration in the different Member States for establishing measures of protection
against the conjectural hazards of recombinant MA work may give rise to
differing conditions of safety , work and success affecting directly the
scientific and technological competitiveness of the laboratories concerned in
tho Member States ?
Whereas action by the Community in the matter is tnerefore
necessary to the realization of the objectives of the Treaty ;
'whereas it is necessary to take into account the complexity of the problem
 posed by the conjectural hazards of certain types of recombinant DNA work ,
 the rapid evolution in the understanding of this problem , the extent of the
 research sector concerned and the importance that must be attached to the con­
 sideration of local circumstances when assessing the hazards involved in pei–
 forming scientific work ;
 Whereas protocols are prepared for experiments in recombinant DNA work and it
 is necessary to minimize the dissemination of the substance of those protocols
 and research projects based on the production and use of recombinant DNA in
 order to safeguard scientific and industrial secrecy and to protect intellec­
 tual property ;
 Whereas the Treaty has not provided the necessary powers for this purpose ;
 HAS ADOPTED THIS DIRECTIVE :
 Article 1
 1.1 This directive concerns the conjectural hazards associated with recombinant
     DNA work .
                                                                              /•
 ---pagebreak---  For the purpose of this directive, the following terms have the meaning
 hereby assigned to them :
 a ) Recombinant DNA work : the formation of new combinations of heritable
     material by the insertion of nucleic acid molecules produced , by whatever
     means , outside the cell , into any virus , bacterial plasmid or other
     vector system so as to allow their incorporation into a host organism in
     which they do not naturally occur but in which they are capable of con­
     tinued propagation .
 b ) Recombinant DNA materials : the product of recombinant DNA work consis­
     ting of organisms , including viruses and viroids, containing recombinant
     DNA molecules .
 c ) Laboratory : the site where one or more persons are engaged or planning
     to become engaged in recombinant DNA work and / or where one or more per­
     sons have introduced or are planning to introduce recombinant DNA
     materials .
icle 2
 Each Member State shall take appropriate steps to ensure that no activities
  involving recombinant INA work or the acquisition and use of recombinant
 DNA materials may be performed on its territory without prior notification
 to the appropriate national authorities and , except for activities falling
  in categories of low risk , without prior authorization from these authori­
 ties .
 To this effect , each Member State shall subdivide in classes , according to
 their nature and the conjectural hazards that they involve , the various
 types of recombinant MA work.
  This distribution in classes shall be based upon the
  source and degree of purity of the DNA molecule , the vector-host system
 utilized and the manipulative procedures proposed. The classes of recom­
 binant DNA work thus established shall then be grouped into categories
  defined on the basis of the particular safety and supervisory measures
  that must be adopted in order to prevent man or his environment from
  incurring any hazard that the Member State may deea excessive . The safety
  and supervisory measures assigned to the various classes of recombinant
  ERA work shall include the implementation of sound laboratory practice
                                                                            /•
 ---pagebreak---                                       - 4 -
    ( if necessary through proper training of safety officers , researen worKers
    and technicians ) and the use of physical ana. biological means of contain­
    ment .
  3 Notification of the intention to undertake recombinant SITA work or to
    acquire recombinant USA materials shall be lodged by the requesting labo­
    ratory with the national authority# The notification shall be accompanied
    by :
    - the portion of the experimental protocol which is required for the
       evaluation of safety at the site where the proposed activities are to
       be carried out and , in the case of the acquisition of recombinant DUA
       materials , by the description of these materials and of shipping condi­
       tions ;
    - the list of the protective and supervisory measures to be applied
       throughout the duration of the experimental work and during storage ,
       propagation and handling of recombinant UNA materials ;
    - the description of the general education in recombinant RIA research and
       of the training received by the members of the staff who will participate
       to the proposed activities or will be responsible for supervision , moni­
       toring or safety .
  4 The national authority shall assess or have assessed , according to the
    criteria it deems most suitable , the conjectural hazards associated to the
    proposed activities . It may require                from the applicant
    further information for the evaluation of conj ectural risks and safety
    conditions and , wherever such investigation seems necessary, it shall
    make a detailed on-site examination of the conditions of protection and
    safeguards .
Article
  1 On the basis of the information available , the national authority shall
    take one of the following decisions :
    – to authorize the proposed activities under the conditions described by
       the applicant :
 ---pagebreak---      - to authorize the proposed activities on certain conditions ;
     - to prohibit the proposed activities .
  2 The decision of the national authority shall be notified in writing to
     the laboratory concerned within a period not exceeding ninety days from
     the date of receipt of the original application for authorization .
  3 The national authority shall ensure , by the methods , it deems most effec­
     tive and appropriate, that only the activities that it has authorized are
     carried out on the national territory .  The national authority shall ensure
     that the protective and supervisory measures referred to in Article 2(3),
     second indent, and the conditions referred to in Article 3 ( l), second indent ,
     are strictly adhered to. Member States shall provide for appropriate
     sanctions against any breach of these rules .
  4 The national authority has the power to revoke any authorization it has
     given .
  5 If the Member State amends the definition of any of the categories of
     recombinant DNA work requiring special safety measures , or if these
     measures are amended, the national authority shall ensure that any new
     requirement shall be immediately fulfilled by the laboratories in posses­
     sion of recombinant DNA materials or performing recombinant DNA work on
     the national territory . The national authority shall revoke any authori­
     zation which does not comply with the new requirement and , in this case ,
     shall order the suspension of activities in hand ; resumption of these
     activities shall be conditional upon the issue of a new authorization which
     may be established only after examination of the protective and supervi­
     sory measures adopted by the laboratory concerned .
Article 4
   1 Member States shall bring into force the provisions needed in order to
     comply with this directive within one year of its notification. They
      shall forthwith inform the Commission of the European Communities thereof .
 ---pagebreak---  2 Member States shall ensure that the text of the measures which they adopt
    in the field covered by this Directive is communicated to the Commission .
    Each   text   shall be published by the Commission .
 3 Member States shall transmit to the Commission the details of the
    categorization system which they have adopted and shall immediately
    inform the Commission of any modification made to this system .    The
    Commission will publish the details of these categorization systems as
    well as any amendment made to them by Member States .
 4 Member States shall submit to the Commission , at the end of each
    calendar year , the list of authorizations delivered during the year and
    a general report of their experience and problems encountered with the
    regulation of recombinant UNA work .
Article 5
  1 Because of the unceasing progress of knowledge and techniques in the
     field of basic and applied biology , this Directive and its continued
     applicability to production activities of industries shall be throughly
     reviewed , and revised if necessary , at regular intervals not exceeding
     two years .
Article 6
  1 This Directive is addressed to the Member States .
                                       Done at
                                        For the Council
                                        The President