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* t\ v UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
* WASHINGTON, D.C. 20460
AugUSt 11, 1993 OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD
EPA-SAB-EPEC-LTR-93-012
Honorable Carol M, Browner
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, DC 20460
Subject: Review of the Research Program for Environmental Release of
Biotechnology Products
Dear Ms, Browner:
The Biotechnology Research Review Subcommittee of the Science Advisory ,
Board's (SAB) Ecological Processes and Effects Committee met on February 18-19,
1993, at the Gulf Breeze Environmental Research Laboratory to review the
Agency's biotechnology research program. The Subcommittee reviewed the draft
"Environmental Release of Biotechnology Products Research Plan" (dated May 29,
1992} and other supporting documentation.
We were asked by the Agency to evaluate both the ongoing research and the
proposed future direction for the biotechnology research program. Specifically, we
were asked to assess the program's scientific productivity, use of extramural
research, level of interaction with other biotechnology research programs, proposed
research on transgenic'plants with pesticidal activity, and whether the research
questions and approaches were appropriate and reflected the state of the science.
At the time of the review the Agency's biotechnology research effort was in a
period of transition to the draft "Environmental Release of Biotechnology Products
Research Plan." This 5-year research plan was the primary focus of our review,
although we also addressed the productivity and results of previous research
efforts. We were pleased to note that the revised plan incorporates several new
elements and directions recommended by a previous SAB review panel in 1988.
Previous work by the Biotechnology Risk Assessment Research Program has
made significant contributions to the scientific basis for assessing the potential
risks associated with the development and release of biotechnology products. The
early focus of the Agency's research program was on the development of methods
and protocols for determining the environmental fate of released geneticaily-
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engineered microorganisms (OEMs). The revised research plan proposes to apply
those protocols to assess potential risks associated with the deliberate or accidental
release of genetically modified organisms and pest control agents. We are
impressed by both the amount and quality of the Agency's research in this area,
and generally agree that the knowledge base is sufficient to allow this change in
program emphasis.
The new research plan is the result of considerable work by individuals
from several Agency laboratories. This planning group has done an excellent job
of defining the major issues surrounding the release of genetically modified
organisms into the environment, and has formulated a comprehensive research
plan to address these issues, We encourage the Agency to implement the plan,
with the modifications suggested below. However, the plan is very ambitious, and
we question whether all aspects defined as important can realistically be addressed
given the personnel and funding likely to be available. While the plan does
contain a list of seven priority research issues, there is little indication of priorities
among the specific projects within each research, area. For example, there is no
indication of how implementation of the plan would be affected by changing
budgets (either increases or decreases), The definition of critical information
needs should be done by the Office of Research and Development (QRD), in
cooperation with the Office of Prevention, Pesticides and Toxic Substances
(OPPTS).
Our specific comments on each of the seven issue areas identified in the
plan will be addressed below. However, we would first like to make some general
observations on the program as a whole:
a) Much of the work to date has focused on developing bioassays to
measure the impact of GEMs on selected ecological endpoints. While
this research has produced useful techniques and protocols, the
results have shown that impacts are difficult to detect. We suggest
that future research place greater emphasis on: 1) identifying new,
more sensitive, ecological endpoints for effects, and 2) understanding
the fate of specific introduced organisms or genes,
b) The research program on release of biotechnology products should
take full advantage of relevant non-GEM models for assessing health
effects, as well as environmental fate and effects where appropriate.
The focus of the current biotechnology research program has been
almost exclusively on the fate and effects of GEMs. At the beginning
of this effort that focus may have been appropriate. However, past
work has shown little reason to believe that the fate and effects of
GEMs are significantly different from that of other introduced
microorganisms, such as those used for bioremediation.
c) Biotechnology products are a rapidly expanding field of endeavor with
significant research being conducted by industry, academia, and other
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government laboratories. In light of the limited budget for research
on fate and effects of these products, it is critical that the Agency
take advantage of the information and resources that are available
from other sources, While the biotechnology research group is in
contact with several other government agencies, this interaction has
been mostly in the form of sharing information about program goals
and objectives. We commend the ORD headquarters and laboratory
personnel for the outreach efforts to date, but we encourage greater
attention to substantive interaction and coordination with relevant
groups. For example, there are significant opportunities for sharing
data, joint planning of research projects, and even collaborative
studies, with agencies like the U.S. Department of Agriculture
(USDA), Department of Energy (DOE), National Institutes of
Environmental Health Sciences (N1EHS) and the Food and Drug
Administration (FDA). In addition, the Agency should seek
opportunities to expand collaboration with industry researchers,
COMMENTS ON SPECIFIC ISSUE AREAS
1. BIOASSAY TECHNIQUES
We support the objectives of the bioassay technique research area, as
described in the issue plan; namely the development of test systems to detect
ecological effects. However, the research approach does not reflect this focus,
Greater emphasis should be placed on determining sensitive environmental
processes or endpoints where effects would be expected ("vulnerability
assessment"), and then developing bioassays for these sensitive points.
Researchers should not be constrained to using OEMs, since the best system to
measure perturbations may be non-GEMs. In addition, this research need not be
directed totally to providing protocols for the Agency's regulatory programs. The
microcosm research should support bioassay and gene survival research elements
as outlined in the research plan.
We feel that further refinement of existing bioassays, which have not shown
significant effects, will not appreciably improve the Agency's ability to do risk
assessment of releases of OEMs or other biotechnology products. Greater
emphasis on identifying new ecologically relevant endpoints would be a more
productive research area. The Agency has had the tendency to deal with
microorganisms as if they were chemicals, with specific, constant properties and
environmental effects. Microorganisms may be both more specific, in that their
effects may be much narrower than a single chemical, and more diverse, in that
they can catalyze many reactions. Therefore, the research group should consider
broadening the emphasis from single species to consortia or communities, which
are more realistic models of nature. Of course, exposure should be related to
expected application methods, dosage, and bioassay organism life stages at the
time of release.
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2, GENE SURVIVAL
The study of transfer of natural genetic elements under environmental
conditions is an important research area which should improve otir understanding
of the ecological significance of naturally-occurring gene transfer. However,
further development of sensitive (and sophisticated) tools to study the transfer of
DNA from GEMs could have limited utility from a risk assessment perspective.
Past and ongoing research by this team and others has demonstrated extremely
limited transfer of DNA between microorganisms under realistic, natural
conditions. Further and more complex analysis of this low probability transfer is
unlikely to alter the risk evaluation based on DNA exchange. In other words, if
we already have the ability to detect gene transfer at. ecologically relevant levels,
does development of the ability to detect even lower levels add anything to our
ability to assess risk?
In contrast, the transfer of modified DNA from transgenic plants by pollen
or other mechanisms is not well characterized, and therefore research in these
areas could improve the Agency's risk evaluations. We also encourage the Agency
to continue work on the mathematical modeling of gene transfer. Although
detectable transfer has been found in aqueous systems, microbial gene transfer
appears to be rare in soil environments, and modeling may be the most reasonable
way to assess the probability of gene transfer and the potential effects. Such
modeling will provide focus and direction for micro-/mesocosm research.
3. MICRO-/MESOCOSMS
The Agency has a long and distinguished history of microcosm research and
has appropriately adapted that technology to biotechnology product fate studies,
The goals of this research area have been largely completed since adequate micro-
/mesoeosm protocols now exist for most current test systems. Remaining needs
may be the development of systems (including micro-/mesocosms with multiple
trophic levels) to complement newly developed bioassays, gene survival studies, or
ecological endpoints.
The micrO'/misocosm research would benefit from a broader view toward
biological risk assessment (microbes are not chemicals) and not being constrained
by working only with GEMs. As noted previously, risk assessment is complicated
by the difficulty in defining measurable endpoints for studying effects. Therefore,
we recommend that test systems be sought where ecological effects can be
measured,
4. TRANSGENIC PLANTS
The proposed research on transgenic plants, a new research area for the
Agency, is comprehensive in its scope and goals. The subject of transgenic plants,
particularly pesticidal plants, is important because of the potential economic
significance of this new technology (several transgenic crop plants are close to
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commercialization), and the potential effects of food crops containing foreign genes
which produce insect toxins. The proposed research goals include a comprehensive
assessment of potential impacts on soil organisms (bacteria and invertebrates)
from release of genetically engineered plants. The research plan does aoj address
the possible human health risks from consumption of transgenic food crops or
toxic effects of pestieidal plants on indigenous plants and animals. These topics
should be addressed. It is unlikely that the proposed research can be
accomplished with the levels of funding, resources, and staffing that are proposed
and likely to be realized in the near future. This suggests the need for greater
focus, and especially cooperation with other agencies.
In order to validate the protocols being developed and ensure credibility for
this new research area, rigorous external peer review and use of extramural
funding is critical until the Agency is able to strengthen its in-house expertise in
plant ecology and plant molecular biology, Because other agencies currently have
significant expertise in plant science, food science, etc., we recommend close liaison
with agencies such as the 0SDA and FDA. These interagency interactions should
be directed toward true exchange of expertise, joint research planning, and joint
research projects in appropriate cases.
5, RISK CONTROL FOR LARGE SCALE RELEASES
We recommend that current large scale release of non-indigenous organisms'
(non-GEMs) be used as a model system to evaluate potential effects of large scale
releases of GEMs, Land application of sludge, bioaugmentation projects and some
bioretnediation projects all offer potential research sites. Research on the effects
of releasing non-GEMs should also be an important reference point for assessing
potential non-target impacts from a large scale GEM release. As already noted,
we encourage the Agency to develop and test fate methods and models because of
the difficulty in choosing appropriate and sensitive endpoints for ecological effects.
While much good science has been achieved under the biological
containment project area, we question the use of this approach for large scale
commercial applications for two reasons. First, introduction of lethal genes is
unlikely to be effective as a containment strategy. When induced, the gene would
have to be lethal 100 percent of the time, and when not induced," produce zero
gene product. Since this scenario of perfect regulation is unlikely, natural
selection will almost certainly overcome any introduced lethal trait with the
development of resistance, Second, the risk associated with introducing lethal
genes into the environment may exceed risks from the organisms to be controlled.
Clearly, other mechanisms of control need to be examined.
6, HUMAN HEALTH EFFECTS
The Agency's research on human health effects has been particularly
productive and responsive to previous recommendations of the SAB and the needs
of the Agency. The goals outlined in the research plan are reasonable, and the
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research questions are particularly relevant to a government agency. However, we
believe that little is unique about the biological properties of GEMs which would
require their exclusive use in this research effort. Much is known about the
mfectivity of non-GEMs which is directly applicable to the health risk assessment
for GEMs, The focus of research under this project area should be on
biotechnology products in general.
We question the value of a new evaluation of toxic intermediates from
bioremediatlon, as proposed in this section of the plan, NIEHS already has such
an evaluation as a major research goal, and duplication of this effort is
unnecessary. Also, the SAB's Environmental Engineering Committee, in its 1992
review of the Agency's bioremediation program, concluded that this research was
not high priority (SAB Report No. EPA-SAB-B1C-92-026), If this work is pursued
by the Agency, it should only be in cooperation and coordination with NIEHS.
7. LARGE-SCALE MANUFACTURING FACILITIES
Most fermentation processes using GEMs presently follow cautionary
guidelines, such as Good Manufacturing Practices or the NIH/FDA guidelines for
large scale containment of microorganisms. The research plan does not adequately
justify the need for more defined or stricter controls. The proposed research
would benefit from greater input and interaction with potential users (the
fermentation industry), other relevant agencies (National Institute for Occupational
Safety and Health, and FDA), and industrial associations (e.g., Chemical
Manufacturers Association, and Pharmaceutical Manufacturers Association).
Information on engineering risk control technologies may be more readily available
by transfer of existing data or technology from other organizations or equipment
manufacturers.
In summary, we find that the Agency's research program on Environmental
Release of Biotechnology Products has been extremely productive and is admirably
addressing both the science associated with environmental release of GEMs and
the Agency's need to assess risk. For continued improvement, we urge the Agency
to consider the following recommendations:
a) establish priorities for research within the seven issue areas;
b) identify more sensitive ecological endpoints for effects;*
c) assess the fate of specific introduced organisms or genes;
d) utilize appropriate non-GEM models for assessing health and
ecological effects;
e) increase coordination of research with other agencies and industry
researchers; and,
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f) address possible human health and ecological effects of pestieidal
plants.
We are pleased to have had the opportunity to review the biotechnology
research program. We hope our recommendations will assist the Agency to
strengthen and refine this important program, and we look forward to your
response.
Sincerely,
Dr, Raymond C, Loelir, Chair
Science Advisory Board
Dr. Kenneth L. Dickson, Chair
Ecological Processes and
1 Effects Committee
jO*"****1*"*
Dr, Frederic K. PfaeiMJjIr, Chair
Biotechnology Research Review
Subcommittee
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U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
BIOTECHNOLOGY RESEARCH REVIEW SUBCOMMITTEE
February 18-19, 1993
CHAIR
Dr. Frederic KL Pfamder, Institute for Environmental Studies, Department
of Environmental Sciences and Engineering, University of North Carolina,
Chapel Hill, North Carolina
MEMBERS/CONSULTANTS
Dr. Burt D. Ensley, Emdrogen, Inc., Lawreneevile, New Jersey
Dr. Daniel D. Jones, Federal Liaison, U.S. Dept. of Agriculture, Office of
Agricultural Biotechnology, Washington, DC
Dr. Philip J. Regal, Dept. of Ecology, Evolution & Behavior, University of
Minnesota, St. Paul, Minnesota
Dr. Donald W. Roberts, Insect Pathology Resource Center, Boyce Thompson
Institute, Cornell University, Ithaca, New York
Dr. James M. Tiedje, Center for Microbial Ecology, Michigan State
University, East Lansing, Michigan
SCIENCE ADVISORY BOARD STAFF
Stephanie Sanzone, Designated Federal Official, Science Advisory Board,
U.S. EPA, 401 M Street, S,W, (A-101F), Washington, DC
Marcia IL Jolly (Marcy), Staff Secretary, Ecological Processes and Effects
Committee, Science Advisory Board, U.S. EPA, 401 M Street, S.W. (A-101F),
Washington, DC
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NOTICE
This report has been written as a part of the activities of the Science
Advisory Board, a public advisory group providing extramural scientific
information and advice to the Administrator and other officials of the
Environmental Protection Agency. The Board is structured to provide balanced,
expert assessment of scientific matters related to problems facing the Agency.
This report has not been reviewed for approval by the Agency and, hence, the
contents of this report do not necessarily represent the views and policies of the
Environmental Protection Agency, nor of other agencies in the Executive Branch
of the Federal government, nor does mention of trade names or commercial
products constitute a recommendation for use.
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