CAB Reviews 2013 8, No. 013
Harnessing the value of beneficial micro-organisms: role of regulatory
landscapes – Mini Review
Ingvar Sundh, Andrea Wilcks and Mark S. Goettel
Abstract
Beneficial micro-organisms, isolated from various environments, can be ‘domesticated’ and used in
agriculture, food and biotechnology. An analysis is required for new microbial strains and applications to ensure safety. Various regulatory frameworks apply and in some instances registration is
required before marketing. Regulatory demands must be tuned to actual risk. ‘Overregulation’
could hamper the implementation of useful products, whereas the lack of appropriate oversight
could negatively affect public health or the environment. There is a need for further development
and consolidation of safety assessment of beneficial micro-organisms as a unique research
discipline and of risk-benefit analysis where risks are weighed against benefits.
Keywords: Biocontrol, Domestication, Environment, Microbial strains, Micro-organisms, Microbial food
cultures, Biotechnology
Instrumental Value of Micro-organisms
Assessing the Safety of Beneficial Micro-organisms
Single-celled micro-organisms were the earliest life forms
on Earth and collectively have been vital in the evolution
of life on this planet. They constitute the major part of
the described biodiversity and make up roughly as
much of the total of biomass carbon as do plants. They
play indispensable roles in biogeochemical processes and
transformations, e.g. in degradation of organic matter in
soils contributing to nutrient recycling and in the primary
production of biomass in the upper strata of oceans and
lakes [1]. The gastrointestinal systems of invertebrates
and vertebrates (including humans) harbour huge numbers of micro-organisms that maintain functioning of the
system. The essential role of micro-organisms in the evolution of life, for supplying what has been coined ‘ecosystem services’ [2] and generally for health promotion in
higher organisms cannot be questioned, and has been
termed the ‘instrumental value’ of micro-organisms [3].
For millennia, the instrumental value of microorganisms has been widely exploited by humankind in
various beneficial applications such as food preservation
and alcohol production. However, the relatively recent
ability to isolate, culture and mass produce microorganisms in pure culture has resulted in their ‘domestication’ (Figure 1), taking advantage of special properties of
different microbial strains. In this way, humankind is capable of tapping into the huge value of micro-organisms to
its own benefit. For instance, use of microbes has recently
expanded tremendously from food and feed fermentation
and preservation, to production of specific metabolites
and enzymes, for biological control of pests and diseases and for obtaining bulk biomass for animal feed [4].
Evaluation of the safety of a new microbial strain and
application may appear to have similarities to microbiological risk assesment (MRA) for assessing the risk
for food poisoning by unintentional contamination with
pathogenic microbes. However, assessing safety of a new
beneficial microbe/application has fundamental differences
to MRA. To begin with, potential hazards are not as easily
identified. Moreover, the issue is not to quantify the risk
represented by a known hazard, but to demonstrate the
absence of hazards that may lead to harm. However,
a true negative, e.g. the absence of human pathogenicity,
can never be proven without a doubt. Therefore, there is
a need to define a sufficient level of certainty for each
micro-organism and application.
With respect to human health, some micro-organisms
can cause infectious disease, toxicity and/or allergenicity.
Indirect human harm may result from growth of spoilage
microbes in food and feed commodities or in building
materials. In the environment (including agricultural
systems), microbes may cause disease in non-target
organisms that can lead to changed community species
composition and ecosystem functioning.
Safety assessment should start with a careful identification and correct taxonomic affiliation of the strain
according to current phylogenies, followed by an investigation of the organism’s basic biological properties.
Taxonomy is a useful tool in safety assessments as a basis
for comparisons with what is known about potential
hazards in closely related strains and species. Thereafter,
various tests for toxic or pathogenic potential using
biosensors may be relevant, but can be complicated
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CAB Reviews
Safety assessment
Elucidate taxonomy
and identify strain.
Main steps Production& Formulation
Screening for
microorganisms
Develop methods
for testing activity.
Successful candidates
Identify modes of
action.
Evaluation of
candidates
Formulate for
acceptable efficacy
and shelf-life.
The most promising one
Ensure safety to
production staff.
Pilot scale
Conduct larger scale
production and
formulation trials.
If there is a market
Conduct additional
testing, e.g. non-target
effects.
Registration
Identify suitable
production facilities.
If approved
Full-scale
manufacturing
Implement fullscale production.
Figure 1 Main steps in the domestication process of a beneficial micro-organism. Safety assessment should be
considered at every step of the development of a new microbial agent. Adapted from Melin et al. [9].
because of methodological difficulties and ambiguities
when translating the results into actual risk. In many
cases, procedures and guidelines for safety assessment
are outlined in the pertaining regulatory frameworks.
With ever-increasing knowledge and experience, generic
systems and carefully compiled lists of species with a safe
history, e.g. the qualified presumption of safety (QPS)
system in Europe and generally recognized as safe (GRAS)
in the USA are likely to contribute to simplified procedures [5]. These systems rely on a proper taxonomic
identification of the isolate. Nevertheless, the safety of
newly discovered isolates must always to some extent be
evaluated on a case-by-case basis.
How are Development and Utilization of Microbial
Agents Regulated?
Several types of regulatory systems can apply to the
development and use of beneficial micro-organisms: (a)
general legislation concerning occupational, consumer
or environmental protection; (b) specific regulation
requiring pre-market registration of new microbial products; (c) quarantine provisions aiming at protection
from accidental export/import of pathogens; and
(d) international conventions covering proprietary issues
regarding biological and genetical resources (e.g.
CBD, the United Nations Convention on Biological
Diversity).
Regulatory frameworks must be in line with the actual
hazards of microbes and risks connected with their
use. Procedures that are too ambitious, complicated
and costly (‘overregulation’) can unnecessarily hold back
the development of useful microbiological products.
Conversely, a lack of appropriate regulation could result
in serious consequences for public health or for the
environment.
The regulatory landscapes differ profoundly among
different areas of utilization. Microbial food cultures – e.g.
lactobacilli and yeasts in the production of dairy products,
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Ingvar Sundh, Andrea Wilcks and Mark S. Goettel
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bread and alcoholic beverages – have been used for
thousands of years, where safety is presumed from
experience and history of safe use, i.e. ‘familiarity’. These
micro-organisms are essentially unregulated, in the
sense that authorization is not required and their safety
should be ensured by the food manufacturers [5].
In contrast, microbial biocontrol agents (MBCAs) are
strictly regulated and pre-market registration is required
[6]. Data requirements are extensive and after submission
of the dossier, authorization takes several years. The
regulations of MBCAs present an example that conditions
for one specific type of use can differ among countries.
The time from submission of the dossier to registration
of a new MBCA has been substantially longer in the
European Union than in the USA – despite the fact
that data requirements are similar – probably mainly
because the procedures for assessments and registration
differ [6].
It is likely that attitudes and policies have significant
impacts on development and implementation of regulatory frameworks for beneficial micro-organisms. For
example, Bailey et al. [7] argued that what has contributed
to a lack of engagement in the promotion of MBCAs
is that invertebrate animals used in biocontrol are
commonly referred to as ‘natural enemies’ or ‘beneficial
organisms’, whereas MBCAs are often referred to with
the more negatively charged ‘biopesticides’ (i.e. they are
‘still pesticides’).
As a consequence of largely separate research disciplines and regulatory frameworks for different application areas, safety assessment of beneficial microbes has
not yet been established as a unique research discipline in
its own right. Research on overarching issues regarding
development of more relevant and efficient methodology
for determining human and environmental safety of
beneficial microbes should be encouraged and promoted.
to assess potential pathogenicity and toxin production.
Increased attention to development and implementation of risk-benefit analysis, where potential risks are
evaluated in relation to obtained benefits [8].
Future Perspectives: How can the
Implementation of Novel Microbial
Innovations and Applications be Stimulated?
5. Bourdichon F, Casaregola S, Farrokh C, Frisvad JC, Gerds ML,
Hammes WP, et al. Food fermentations: microorganisms with
technological beneficial use. International Journal of Food
Microbiology 2012;154:87–97.
In order to stimulate future development and use of
beneficial micro-organisms, we consider the greatest
needs with respect to research to be:
6. Ehlers R-U, editor. Regulation of Biological Control Agents.
Springer, Dordrecht, The Netherlands; 2011.
Establishment and consolidation of safety assessment
of beneficial micro-organisms as a unique research
discipline, to a substantial extent across different
application areas.
Support of fundamental and applied microbiological
research regarding, e.g. new and innovative ways
that microbes could be used in beneficial applications
and development of more efficient test methodology
On the regulation and policy level, we consider that the
greatest needs are:
Harmonization of the specific regulatory systems
overseeing introduction and utilization of new microbial products. One important aspect is to ensure that
all regulatory interventions are firmly based on up-todate knowledge regarding the fundamental properties
and hazards of micro-organisms.
Increased awareness and understanding in society
about the indispensable role that microbes play for the
evolution and maintenance of life, environmental resilience and the health properties they confer to higher
organisms, including humans.
References
1. Falkowski PG, Fenchel T, Delong EF. The microbial engines
that drive Earth’s biogeochemical cycles. Science
2008;320:1034–38.
2. Ducklow H. Microbial services: challenges for microbial
ecologists in a changing world. Aquatic Microbial Ecology
2008;53:13–9.
3. Cockell CS. The value of microorganisms. Environmental Ethics
2005;27:375–90.
4. Sundh I, Wilcks A, Goettel MS. Microbes and the law – Safety
assessment and regulation of beneficial microorganisms.
In: Sundh I, Wilcks A, Goettel MS, editors. Beneficial
Microorganisms in Agriculture, Food and the Environment –
Safety Assessment and Regulation. CABI, Wallingford, UK;
2012.
7. Bailey A, Chandler D, Grant WP, Greaves J, Prince G, Tatchell
M. Biopesticides – Pest Management and Regulation. CABI,
Wallingford, UK; 2010.
8. Magnússon SH, Gunnlaugsdóttir H, van Loveren H, Holm F,
Kalogeras N, Leino O, et al. State of the art in benefit-risk
analysis: Food microbiology. Food and Chemical Toxicology
2012;50:33–9.
9. Melin P, Sundh I, Håkansson S, Schnürer J. Biological
preservation of plant derived animal feed with antifungal
microorganisms: safety and formulation aspects. Biotechnology
Letters 2007;29:1147–54.
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About the Authors
Ingvar Sundh is a Professor of Ecological Microbiology at the Department of Microbiology
at Swedish University of Agricultural Sciences (SLU). His research focuses on human and
environmental safety assessment of micro-organisms used in beneficial applications. He also
has a strong interest in regulatory issues concerning utilization of micro-organisms and support
national and international organizations and authorities with expert evaluations and advice.
He can be reached at [email protected].
Andrea Wilcks is a former Senior Scientist at the Danish Technical University, National Food
Institute, Division of Food Microbiology, engaged in studies on intestinal microbiology. She has
undertaken studies on genetically modified organisms, antibiotic resistance and horizontal gene transfer. She was an
advisor for the Danish National Environment Agency and has been active in the assessment of microbiological plant
protection agents at EU-level, especially regarding human toxicological risk assessment. She can be reached at
[email protected].
Mark S. Goettel is a former Senior Research Scientist, Insect Pathology, at Agriculture & Agri-Food Canada,
specializing in the development of entomopathogenic fungi as microbial control agents of insects. He has been
extensively involved in the review and revision of regulations for registration of microbial control agents and has
addressed regulatory and safety issues at the international level. He can be reached at [email protected].
doi: 10.1079/PAVSNNR20138013
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CAB International 2013 (Online ISSN 1749-8848)
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