EPA Regulation of R&D Use of Genetically Modified Algae: Contained Structures and TERAs

In the preceding post on this blog, I discussed the need for risk assessment for proposed uses of genetically modified (GM) algae in open-pond reactors or other open environment applications. I made the point that government regulations were largely in place to ensure that such risk assessments occurred, and moreover that regulatory schemes assume that that introductions of novel organisms into the environment will only be done in a stepwise manner, where laboratory studies would be followed first by small-scale field tests, and then by increasingly-larger field experiments before commercial approvals would be sought, so that risks could be assessed at smaller scales before moving to larger-scale field use. The U.S. EPA biotechnology regulations under the Toxic Substances Control Act (TSCA) provide a good example of such a stepwise approach, so in today’s post, I’d like to discuss the way R&D, both in contained structures and in the open environment, is regulated under these rules. This post will be limited to discussing the EPA TSCA regulations, but it is worth noting that, for any microorganisms used as pesticides which would instead be subject to EPA oversight under the federal pesticide law FIFRA, there is an equivalent procedure where even small-scale outdoor testing must be conducted under experimental use permits and where stepwise field testing is common before a product can be approved for commercial use in the open environment.

The commercial use of GM algae to produce fuels or chemicals might be subject to EPA’s biotechnology regulations under TSCA. I’ve described these regulations in previous blog posts. Commercial use of certain modified microorganisms (i.e., “new organisms” containing coding nucleic acids from more than one taxonomic genus) for purposes that are within TSCA’s jurisdiction (for production of fuels, chemicals or any other product not regulated as a food, drug, cosmetic or pesticide) require prior submittal to EPA of a Microbial Commercial Activity Notice (MCAN). These rules include an exemption for R&D activities that in practice is fairly broad and which potentially covers most laboratory or pilot plant activities if conducted in a suitably contained facility or reactor. However, research uses of GM algae in an open-pond or other minimally contained reactor would not be eligible for this exemption, and would instead require EPA review before the research can be conducted, through the filing of a TSCA Environmental Release Application (TERA).  (Note that there are a limited number of exemptions from TERA obligations, but that these are unlikely to apply to GM algae).

The key issue in determining if an activity qualifies for the broad R&D exemption is whether or not it will take place in a “contained structure”. The term “structure” is defined in the biotechnology rule at §725.3, and includes any “building or vessel which effectively surrounds and encloses the microorganism and includes features designed to restrict the microorganism from leaving” (emphasis added). The key point of this definition is that the structure minimize (rather than prevent) the potential for microorganisms to escape and become established in the environment. This clarifies a measure of uncertainty under EPA’s pre-1997 interim policies, with some early interpretations implying that strict compliance with the NIH Large-Scale Recombinant DNA Guidelines would be required to meet the criteria for “containment”. The final rule gives EPA staff and the regulated community broad leeway in determining which structures are suitably “contained”.  It has become clear that many laboratories and  greenhouses, as well as most fermentation reactor vessels would meet the definition of a contained structure under the rule.

This is important because, under §§725.234 and 725.235 of the rules, activities in contained structures would qualify for the small quantities exemption under TSCA section 5(h)(3) if conducted “solely for research and development” and meeting other procedural requirements. For example, the R&D must be conducted under the supervision of a technically qualified individual (TQI), who must adopt specific containment procedures. In addition, appropriate records must be kept and workers must be adequately notified of any risks. R&D meeting these requirements can be conducted with no EPA oversight or prior notice (in fact, entities determine for themselves if they are in compliance). However, R&D conducted outside a “contained structure” requires prior EPA review, under the TERA process. While it seems clear that most open-pond algae reactors would not qualify as contained structures under the rule, it is likely that many enclosed photobioreactors would potentially qualify, depending on the specifics of their design and operation, and if the procedural requirements for the exemption are also met. It may therefore be important for manufacturers or users of algae photobioreactors to determine whether their reactors can qualify for the exemption.

Turning back to potential environmental uses of GM algae, the TERA process provides an expedited review procedure for small-scale field tests and other outdoor R&D uses of new organisms. Applicants proposing such uses must file a TERA with the EPA at least 60 days in advance of the proposed activity. The data requirements for TERAs are outlined in §§725.255 and 725.260 of the regulations, and these requirements address the key issues which should be considered in environmental risk assessments, as described in the published papers mentioned in the previous post. This includes all information in the applicant’s possession pertaining to:

• phenotypic and ecological characteristics of the microorganism
• a detailed description of the proposed R&D activity
• number of microorganisms proposed to be released, and the methods proposed for the release
• characteristics of the test site(s), including location, geographical, physical, chemical and biological features
• target organisms (e.g., prey) of the modified microorganism (if any)
• Information on monitoring, confinement, mitigation, and emergency termination procedures for the microorganisms to be released

EPA is required to review the submitted information and decide whether or not to approve the proposed outdoor R&D activity within 60 days, although the agency could extend the review by an additional 60 days. If EPA determines that the proposed activity does not present an unreasonable risk of injury to health or the environment, it will notify the applicant in writing that the TERA has been approved.  When a TERA is approved, the applicant must carry out the testing under the conditions and limitations described in the TERA application document, but also in accordance with any requirements or conditions included in EPA’s written approval. In most cases, it is likely that EPA will require applicants to conduct some form of monitoring, to detect the possible spread or dispersal of the microorganism from the test site, or to detect any other potential adverse environmental effects. EPA may require collection and submission of other data as well. As specified in §725.270 of the regulations, EPA’s approval is legally binding on the applicant, and violations are subject to civil and criminal penalties. EPA further has the authority to modify or revoke the approval upon receipt of evidence that raises significant questions about the potential risk of the activity.

There has only been limited experience with TERAs since the biotechnology rule was put into place in 1997.  According to EPA’s website, here have been 25 TERAs submitted for field use of engineered microorganisms, almost exclusively for agricultural microorganisms, or for microbes to be used for bioremediation or for detection of hazardous contaminants in soil. None of these TERAs describe proposed uses of GM algae. All but three of these were approved (the status of the 3 not approved, which were the most recent TERAs to be filed, is not clear from the website).  All of these have been for small-scale, early-stage R&D projects.

Interestingly, after a 6-year hiatus when no TERAs were submitted, EPA recently updated its website to show that two TERAs submitted in 2013 have been approved. These TERAs were submitted by the US Army Engineer Research and Development Center and the US Army Corps of Engineers to propose the use of modified strains of Gordonia terrae and Rhodococcus jostii in a field demonstration of bioaugmentation (i.e. bioremediation) to enhance the degradation of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in contaminated groundwater. Although numerous previous TERAs have involved microorganisms in bioremediation or related activities, all the previous applications have been for use of the organisms in soils or encapsulated in devices for contaminant detection: these new TERAs appear to be the first in which release of GMOs into the groundwater was approved. EPA’s approval included significant monitoring and reporting requirements.

None of the projects covered by these TERAs have progressed to commercial use, although EPA has approved commercial sale of one product covered by TSCA. In September 1997, EPA approved limited commercialization of the intergeneric microorganism Sinorhizobium meliloti (S. meliloti) strain RMBPC-2, a modified strain with improved capacity to provide fixed nitrogen to alfalfa plants as a nutrient. This product was field tested under approvals granted by EPA under its pre-1997 interim biotechnology policy, and EPA concluded that the commercial use of this inoculant did not pose significant environmental risks, provided it was subject to production limits of 500,000 pounds of the microbial seed inoculant during any consecutive 12-month period. Although this is the only live engineered microorganism approved for commercial use in the open environment under the EPA TSCA regulations, it does establish a precedent that EPA would be prepared to grant such approvals where warranted by the science and the data package accumulated by the applicant.

Although there has been only limited experience with TERAs, none of which has involved proposed uses of GM algae, the process is well-suited to carry out the kinds of risk assessments that are appropriate for proposed industrial uses of GM algae in open-pond reactors. The need for TERA approval under EPA’s biotechnology regulations ensures that the initial outdoor uses of GM algae receive agency review, regardless of the scale; and the issues EPA will consider in its review of a TERA address the key concerns about the possible use of genetically modified microorganisms in the environment (e.g. potential for adverse health effects, survival and persistence in the environment, potential for horizontal gene transfer, etc.). Most importantly, by allowing small-scale outdoor uses to take place under TERAs, the regulations enable the important environmental risk assessment questions to be addressed with data from actual environmental use, thus facilitating subsequent risk assessments for larger-scale uses.

Many ecologists and public sector critics of use of GMOs in the environment have raised legitimate questions about how well we can assess the risks of such uses. The answer to these concerns is not to prevent any outdoor uses until all risks are ruled out (e.g., as proponents of the precautionary principle would demand), but instead to allow risks to be addressed through the stepwise progression from small scale to larger scale, under a regulatory regime that not only provides oversight but also flexibility and accountability.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. Dr. Glass also serves as director of regulatory affairs for Joule Unlimited Technologies, Inc. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of Joule Unlimited Technologies, Inc. or any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.

Advertisement

Risk Assessment and Regulation of Open-Pond Use of Genetically Modified Algae

For several reasons, I’ve recently been thinking about the possible use of genetically modified algae in fuel or chemical production, and how such applications would be regulated if the algae were grown in open ponds. For starters, I spent some time considering how open-environment use of modified algae might be regulated in different countries, as I prepared for my poster presentation at the 2013 Algae Biomass Summit, and the series of blog entries which expanded on the information in the poster.  Then, as I attended the Summit, I saw how many companies and academic groups were continuing to plan for uses of algae in traditional open-pond reactors – to be sure, pretty much everyone was talking about using non-engineered algal strains, but it got me thinking that it was almost inevitable that someone would someday want to use a modified strain in an open pond, even for research purposes. Finally, at around the same time, I became aware of several papers in the scientific literature discussing the need to carry out appropriate risk assessments for any open environment use of modified algae for industrial purposes.

So, I’d like to discuss these issues in today’s blog post and in a post to follow next week, primarily to convey the following points. First, although I believe the risks will in most cases be low, it is appropriate to conduct scientific risk assessments before introducing genetically modified algae (or other organisms) into the environment; and second, the regulatory regimes in place in most countries, particularly in the U.S., are sufficient to provide such risk assessments, and stepwise oversight, as uses of GM algae move from small-scale or pilot-scale testing to full-scale commercial use. A third point, which almost goes without saying, is that health and environmental risk issues should be taken into account when choosing algae strains either for experimentation or for commercial development.

Just about all the current commercial activities involving the use of algae to produce fuels or other industrial products involves naturally occurring strains, or strains that have been modified using traditional (i.e., nonrecombinant) methods. However, it is not too difficult to envision legitimate reasons why one might turn to genetic engineering to improve the capabilities of native strains. I discussed many of these strategies in a very early post in this blog back in 2010, and there are several published reviews summarizing possible genetic engineering approaches, including Rosenberg et al. 2008, Li et al. 2008; Angermayr et al. 2009 and Mayfield (undated) and Radakovits et al 2010. It’s not known to what extent any of these strategies are being seriously pursued with commercial intentions, but it’s almost inevitable that someone will propose such a use someday, possibly quite soon.

Algae can be used industrially either in open ponds (the traditional method of cultivating algae at large scale) or in enclosed photobioreactors. The latter uses present fewer environmental or regulatory issues – although not resembling the fermentation systems in which industrial microorganisms have been safely used for decades, in theory a photobioreactor can be operated in a way that minimizes or prevents release of algae into the environment, so that such uses can be evaluated and regulated in the same manner as industrial uses of other microorganisms. For example, industrial use of genetically modified algae in an enclosed photobioreactor can be regulated under existing regulations for “contained” industrial manufacturing (e.g., the U.S. EPA regulations requiring Microbial Commercial Activity Notices; the European Union Contained Uses Directive, etc.), and the risk assessments inherent in such regulatory processes could proceed on the assumption that environmental release of significant amounts of the engineered algae would be highly unlikely. Moreover, under the EPA regulations, R&D uses of modified algae in many contained photobioreactors would be exempt from regulatory oversight (depending on the nature of the reactor, the containment measures used in the research, and other factors).

The same cannot be said about possible open-pond use of genetically modified algae (which I’ll call “GM algae”). In that case, release and dispersal from the production site are almost inevitable, thus substantially changing the nature of the risk assessment. Furthermore, proposals for such uses of genetically engineered algae would be regulated much differently, and in generally more stringently, than would proposed photobioreactor uses – open-pond uses of engineered strains would be considered to be environmental uses (what used to be called “deliberate releases into the environment”) and in most countries would be subject to different legal or regulatory requirements. Such requirements would likely apply even for small-scale research applications of GM algae in open-pond reactors.

In that regard, there have been several recently-published papers in the scientific literature regarding the potential environmental impacts of the use of GM algae and the types of risk assessments needed to evaluate such potential impacts. These include Snow and Smith 2012, Henley et al. 2013, and Menetrez 2012. A comprehensive review or critique of these papers is beyond the scope of this blog, but I can briefly comment on the issues these papers discuss. Henley et al. presents the most comprehensive review of the potential environmental impacts of the “commodity-scale” use of GM algae, discussing such issues as the potential of a released strain to grow, persist and mutate in the environment, the possibility that GM algae could produce toxins or harmful algal blooms (HABs) or have other negative effects of aquatic ecosystems, and the possibility that introduced genes could spread by horizontal gene transfer and be expressed in indigenous microorganisms. In a shorter paper, Snow and Smith cover many of these same issues, particularly the need to assess environmental survival and persistence of an introduced strain and the potential for horizontal gene transfer. Both papers speculate on possible physical barriers or biological containment (e.g. so-called “suicide genes”) that might be effective in reducing environmental dispersal or survival of a released GM algae strain. Finally, the Menetrez paper, while touching on several aspects of the possible environmental impacts of GM algae strains (e.g. the potential health risks arising from algal toxin production),  more broadly reviews the possible uses of GM algae and the industrial and governmental programs that might affect commercial use.

Collectively, these papers identify and discuss what should be the primary issues in risk assessments of industrial uses of GM algae. In fact, the list of these issues parallels the types of general concerns that have long been voiced about the possible use of genetically modified microorganisms (and to some extent, plants) in the environment. As such, and taken in the abstract, it is hard to argue with these authors’ arguments – they’ve identified the scientific questions that need to be addressed (at some level) before any proposed large-scale outdoor use of GM algae is to proceed. However, these are all generally-stated issues, not all of which may be issues for any specific proposed application. For example, it is hard to see any company choosing for commercial use an algae species or strain known to cause HABs or to express toxins: while such decisions clearly arise from consideration of risk potential, this should reduce concerns that any given outdoor use of GM algae might cause or exacerbate toxic blooms, although the potential for horizontal gene transfer to a bloom-causing native species would need to be ruled out. (I also realize that academic groups may choose to work with bloom-forming species for research purposes, and in those cases the possibility of HAB formation would of course be a key feature of a risk assessment).

While acknowledging the importance of risk assessment, we need to keep in mind that the mere potential for risk should not unduly hinder or even prevent promising research or commercial activity, as long as there are adequate regulations in place to assess risk. And in fact, government regulatory regimes for oversight over environmental uses of modified organisms are based on the very same scientific considerations discussed in the literature. But there’s an important point to make: these regulations generally assume that introductions of novel organisms into the environment will only be done in an ordered manner, where laboratory studies (often including microcosm studies in the lab) would be followed first by small-scale field tests, which, if successful, would be followed by increasingly-larger field experiments culminating in an application for commercial approval. This stepwise process is essential in commercial R&D, to ensure that costly large-scale trials are only begun with suitable proof of concept at smaller scale testing. This approach is also extremely valuable from a regulatory and risk assessment perspective: small-scale tests can more easily be monitored than larger-scale uses, and are also invaluable for collecting information about environmental behavior to inform a proper risk assessment before progressing to larger scale.

Such a stepwise approach is indeed embedded in the U.S. EPA biotechnology regulations. Under the TSCA biotech rule, outdoor uses of new microorganisms are not exempt from the requirement for oversight, even for research use. Research activities involving environmental use of new microorganisms must be reviewed and approved by EPA through the filing of a TSCA Environmental Release Application (TERA). This process, which involves a shorter review period than for commercial notifications under the rules (MCANs), provides a mechanism for EPA to review potential environmental risks before a field experiment begins, but is also a mechanism for small-scale R&D to take place, in part to gather data that will ultimately be important for risk assessments of larger-scale activities. (I’d note that, should any GM algae strain be intended for use as a pesticide, there is an analogous procedure under U.S. EPA pesticide regulation where Experimental Use Permits would be needed to conduct small-scale research on either modified or naturally occurring microorganisms with biopesticidal properties). I have briefly described the TERA process in one of my Algae Biomass Summit posts, but I have posted a more detailed description of the TERA regulations and their impact on GM algae in the next entry in the blog. But for now, let me reiterate my bottom line: although the need for risk assessment of environmental uses of GM algae is legitimate, regulations in place in the U.S. and elsewhere are adequate to ensure that such risk assessments take place.

D. Glass Associates, Inc. is a consulting company specializing in government and regulatory affairs support for renewable fuels and industrial biotechnology. David Glass, Ph.D. is a veteran of over thirty years in the biotechnology industry, with expertise in industrial biotechnology regulatory affairs, U.S. and international renewable fuels regulation, patents, technology licensing, and market and technology assessments. Dr. Glass also serves as director of regulatory affairs for Joule Unlimited Technologies, Inc. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and copies of some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available at www.slideshare.net/djglass99 and at www.dglassassociates.com. The views expressed in this blog are those of Dr. Glass and D. Glass Associates and do not represent the views of Joule Unlimited Technologies, Inc. or any other organization with which Dr. Glass is affiliated. Please visit our other blog, Biofuel Policy Watch.