Beyond the Lab: The Regulation of Micro-organisms
used in Large-Scale Industrial and Environmental
Applications under the Canadian Environmental
Protection Act (CEPA)
Kassim Ali
New Substances Assessment and Control Bureau,
Safe Environments Directorate,
Healthy Environments and Consumer Safety Branch, Health Canada.
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Overview
 CEPA, new substances and the regulation of new micro-organisms
 Large scale work under the New Substances Notification Regulations
(Organisms)
 Risk assessment of new micro-organisms under CEPA
 Some Issues or Concerns Identified During the Course of an Assessment
 Hazard, exposure and risk assessment considerations
 Conclusion and further information
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The New Substances Program
 A joint program with Environment & Climate Change Canada (ECCC)
and Health Canada (HC);
 Administers Parts 5 and 6 of the Canadian Environmental Protection
Act (CEPA);
 Part 6 deals with animate products of biotechnology; and ensures
that 'new' products of biotechnology are assessed for potential risks
to the environment and human health before manufacture or import
into Canada;
 As part of this regulatory approach under CEPA, the New Substances
Program conducts risk assessments of new micro-organisms
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The Canadian Environmental Protection Act
(CEPA), Objective and Declaration
Objective:
An Act respecting pollution prevention and
protection of the environment and human
health in order to contribute to sustainable
development
Declaration:
… the protection of the environment is essential to
the well-being of Canadians and the primary
purpose of this Act is to contribute to sustainable
development through pollution prevention.
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New Substances under CEPA
Substance
Any distinguishable kind of
organic or inorganic matter,
whether inanimate or animate
Animate
Living organisms:
animate products of
biotechnology
Inanimate
Chemicals & Polymers
Micro-organisms: e.g.
bacteria, archaea, protozoa,
algae, fungi, etc.; viruses and
virus-like particles; cultured
cells; & any other culture
*Domestic Substances List
(DSL): A list of substances that
are in commerce in Canada
Existing
(On DSL*)
Organisms
other than
microorganisms
(higher
organisms)
New (Not
on DSL*)
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Animate Products of Biotechnology
 Biotechnology means the application of science and engineering in the
direct or indirect use of living organisms or parts or products of living
organisms in their natural or modified forms
 A living organism is an animate product of biotechnology, if, for
example:
– There is an application of science and engineering to the organism (ex.
Genetic engineering, cloning); or
– Naturally occurring but used for a purpose that involves science and
engineering (ex. Bioremediation);
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Industrial and other CEPA-regulated uses of
micro-organisms
New Microorganisms in
Other Uses*
* Uses regulated by Acts and Regulations
not listed under Schedule 4 of CEPA
New Microorganisms in
Industrial
products
Subject to
CEPA and
the NSNR(O)
Notify Environment
and Climate Change
Canada before
import or
manufacture
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Notification Requirements for New MicroOrganisms under the NSNR (O)
“A person who manufactures or imports a micro-organism must
provide the information specified in Schedules 1, 2, 3 or 4” … (ss. 3(1),
3(2), 3(3) & 3(4))
Unless:
 the
use is regulated by
another Act or Regulation
listed under Schedule 4 of
CEPA (ss. 2(1));
 in
transit (ss. 2(2)); or
Seeds Act &
Regulations
Health of
Animals Act &
Regulations
Feeds Act &
Regulations
Fertilizers Act
& Regulations
Pest Control
Products Act &
Regulations
 used
for research and
development (ss. 2(3)).
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Notification Schedules for New Micro-Organisms
under the NSNR (O)
Notification Schedules*:
For introduction
Anywhere in Canada
Sch. 1 (120)
Sch. 4 (30)
)
In an ecozone where not
indigenous
Ecozone: Terrestrial
Ecozones of Canada 1995
In accordance with
confinement procedures
Confinement procedures:
... restrict the exit or
dispersal of a microorganisms
In an ecozone where
indigenous
New MicroOrganisms
(
* days before
import or
manufacture
Sch. 2
(30)
Not outside a contained
facility or for export only
Sch. 3
(90)
In an experimental field
study
Contained facility: ... in
accordance with Laboratory
Biosafety Guidelines or
Appendix K of the NIH
Guidelines
At the same site where isolated
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Large Scale Work (Canadian Biosafety Standard)
 According to the Canadian Biosafety Standard, large scale work
includes:
– Activities generally involving volumes of toxins or the in vitro culture of
infectious material on a scale of 10 litres or greater.
– This could be a single vessel with a volume of 10 litres or greater, or based
on the processes and pathogen used, could be multiple vessels with a total
volume of 10 litres or greater.
– It is determined in consultation with the Public Health Agency of Canada
and/or the Canadian Food Inspection Agency on a case-by-case basis,
whether or not particular activities conducted in a containment zone are
required to follow the increased or unique requirements for large scale
production areas.
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Large-Scale Work under the NSNR (O)
 Large-scale work not
defined under the
NSNR(O)
 Up to 1000 L can be
exempted if intended
for Research and
Development not
for introduction
outside a
contained* facility;
 If the micro-organism is:
 imported to a contained facility in a quantity of less
than 50 mL / 50 g at the time of import;
 manufactured and present at any one time in a
contained facility in a quantity of less than 1000 L,
unless if CL 2, 3, or 4 is required;
 manufactured and present at any one time in a
contained facility in a quantity of less than 250 L,
if CL 2 is required;
 human pathogen manufactured and present at any
one time in a contained facility in a quantity of less
than 250 L and CL 3 or 4 is required and import
permit or approval has been granted under the
Human Pathogens Importation Regulations.
*Containment in accordance with: Laboratory Biosafety Guidelines or
Appendix K of the NIH Guidelines
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Quantities under the NSNR (O)
 Under the NSNR (O), quantities
can be much higher than the 10 L
cut-off;
Quantities Notified for
Import/Manufacture (146 NSNs)
 Up to 24 000 tonnes have been
notified (average: 300.9 tonnes)
 Notifications for multiple sites and
environmental releases
43
32
20
 Includes consumer applications
(degreasers, cleaning products,
industrial applications, etc.)
21
13
9
8
Tonnes
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Risk Assessment and the Determination of
“Toxic” according to CEPA
Risk assessment
decisions are based on
the determination of
whether substances are
toxic or not based on s.
64 of CEPA:
- have or may have an
immediate or long-term
harmful effect on the
environment or its biological
diversity;
ECCC
A substance is “toxic”, if
entering or may enter the
environment in a quantity
or concentration or under
conditions that:
- constitute or may constitute a
danger to the environment on
which life depends; or
- constitute or may constitute a
danger in Canada to human
life or health.
HC
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Risk Assessment of New Micro-Organisms
Risk Assessment
Hazard Assessment
X
Exposure Assessment
Risk
characterization
Low
Medium
High
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Risk Assessment Conclusion and
Recommendations
 If not of concern for intended or other uses - no further action is
recommended;
 If not of concern for intended uses but suspected of posing risk for other
uses – a Significant New Activity Notice is recommended;
 If considered to pose risk for intended or other uses:
– Prohibit if the risk cannot be mitigated with conditions;
– Permit subject to conditions if the risk can be mitigated with conditions; or
– Request additional information if the risk relates only to the notified use.
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Commonly Notified Species
 A variety of micro-organisms are notified under the New Substances Notification
Regulations (Organisms); about 47 genera.
90
80
70
60
50
Strains
Genera
40
30
20
10
0
Bacteria
Fungi
Micro-algae
Viruses
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General Concerns with some notified organisms
 Risk Group 2 in many jurisdictions (Species or Genus
level)
 Plant pathogens and opportunistic pathogens of
humans and animals
 Risk Group 1, not human pathogens or less known but
produce lethal toxins
 Naturally occurring and ubiquitous in the environment
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Some Issues or Concerns Identified During the
Course of an Assessment (1)
 Poorly identified and uncharacterized micro-organisms: impair
hazard assessment;
 Aerosols: either as microbial particles (e.g. spores) or live or dead
micro-organisms can be associated with allergenicity, hypersensitivity,
toxicity or infections;
 Opportunistic pathogens, toxicity and allergenicity: Repeated and
prolonged large-scale manufacture and use of products containing live
micro-organisms, toxins or metabolites may lead to chronic exposures
and predispose the general public to the risk of opportunistic infections,
toxicity or allergenic reactions;
 Resistance to anti microbials: may arise from the use of antibiotics
and other anti microbial drugs used during strain development;
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Some Issues or Concerns Identified During the
Course of an Assessment (2)
 Other potential uses: Notified micro-organisms may have other
potential uses for which information has not been provided to warrant
full assessment;
 Survival, persistence and proliferation: Introduced micro-organisms
may survive, persist and proliferate in the environment particularly
leading to chronic exposures to humans and other components of the
environment;
 Processing conditions: Some processing conditions (e.g. solid-state
fermentations) have been associated with the production of toxic
metabolites;
 Contaminants: Where proper QA & QC procedures are lacking, there
may be a build-up of contaminants (e.g. Lactic acid bacteria in Biofuel
facilities)
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Some Issues or Concerns Identified During the
Course of an Assessment (3)
 Decontamination and waste disposal: is generally challenging for
large-scale production of micro-organisms particularly when the
volumes are in the area of several thousand tonnes;
 Metabolites, toxins and other chemicals: Even when the waste
(liquids, gaseous effluents, and residual biomass) has been adequately
decontaminated, it may be challenging to deal with metabolites, toxins,
and other chemicals;
 Disposed waste: may end up in water bodies and protected lands and
endangering plants, animals and biodiversity.
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Hazard Assessment Considerations
ID, Strain history &
Modifications
- Adequacy of taxonomic
identification;
- Distinguish and detect from
closely related pathogens
- Any concerns with strain history;
and
- Any concerns with modifications
Biological characteristics
- Relationship to closely related
pathogens;
- Virulence characteristics;
- Persistence and proliferation in
hosts;
- Toxins or metabolites ; and
- Traits of concern and dispersal
by horizontal gene transfer
History of use
- Nature and
frequency of
adverse effects
associated with
the history of use
Human health effects
- Adverse effects in humans;
- Evidence from pathogenicity
or toxicity testing;
- Data from tests of
antimicrobial susceptibility;
Environmental effects
Hazard
Assessment
- Adverse effects in
terrestrial or aquatic plants,
vertebrates or invertebrates;
- Evidence from
pathogenicity or toxicity
testing;
- Deleterious effects on
ecological processes or the
ecosystem, displacement of
species & effects on
biodiversity;
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Exposure Assessment Considerations
Sources of exposure
- Quantity to be imported or
manufactured (including
concentration);
- Routes of exposure;
- Physical state of formulation and
packaging;
Other
potential uses
- Potential or
foreseeable
uses
Exposure
Assessment
Introduction
- Intended use and nature of
release;
- Sites of introduction;
- Quantity to be released
(concentration, frequency
and duration);
- Dispersal considerations
Import or manufacture
Environmental fate
- Location and distance to
populated areas
- Containment requirements of the
manufacturing facilities;
- Manufacturing process, storage
and transportation, QC & QA, and
procedures for treatment of waste
- Releases from manufacturing
facilities and contingency
measures
- Mechanisms of dispersal
beyond introduction;
- Environmental conditions
(favour/limit survival, growth
& replication);
- Estimated concentration at
the site(s) of introduction;
- Plant & animal species
likely to be exposed
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Industrial Biotechnology, Virulence Factors and
Risk Assessment Considerations
Microbial diversity
- bacteria, fungi, algae,
viruses, etc.;
- structural differences;
- growth conditions;
- tolerance or resistance to
environmental stresses;
- energy sources; etc
Industrial biotechnology
- Microbial diversity make it
easier to replicate conditions
industrially and tailor
products for specific uses
- Technologies from selective
breeding to recombinant
DNA techniques
Virulence factors (examples)
-growth at elevated
temperatures (≥37 oC);
-production of toxins and
other metabolites;
-production of hydrolytic
enzymes (proteinases
and lipases);
-physiological and
morphological switching;
-biofilm formation;
-iron binding
siderophores;
-tolerance to higher
concentrations of
chemicals (e.g. alcohol
biofuel);
-resistance to antimicrobials; etc.
Risk Assessment
Considerations
Are there any concerns with
its biological characteristics?
Is there a potential for
increased virulence with
industrial use?
How serious are the
concerns?
Is treatment available?
Is there a potential for
environmental and/or human
exposure?
Overall, what is the likelihood
of adverse effects happening
during its use?
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Conclusion
 The objective of CEPA is pollution prevention and protection of the
environment and human health;
 Under CEPA, micro-organisms new to Canada must be notified under the
New Substances Notification Regulations (Organisms) prior to import or
manufacture;
 Risk assessment under CEPA is conducted by assessing the hazard and
exposure potential of new micro-organisms;
 Large scale use of micro-organisms in industrial and environmental
applications pose additional challenges compared to laboratory work ;
 Environmental releases from large scale use may be harmful to the
environment and predispose the general public to the risk of infections,
anti-microbial resistance, toxicity and allergenicity.
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Further Information
 You are always welcome to contact the New Substances Program by email or
phone using the following contact information
E-mail: [email protected]
Telephone:
In Canada (toll free): 1-800-567-1999
Outside Canada: (819) 938-3232
Facsimile: (819) 953-7155
Website:
https://www.ec.gc.ca/subsnouvelles-newsubs/default.asp?lang=En&n=AB189605-1
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