EPA Issues Updated Guidance for TSCA Submissions for Genetically Modified Algae

In October of this year, EPA posted on its website, apparently with little fanfare or public notice, an updated and presumably final document entitled the “Algae Supplement to the Guidance Document Points to Consider in the Preparation of TSCA Biotechnology Submissions for Microorganisms.” The website indicates that this document supplements the original 1997 TSCA “Points to Consider” document for biotechnology notices under TSCA by addressing submissions involving R&D or commercial use of genetically engineered algae.

This guidance document is the culmination of a process that EPA first began in 2015. When the Agency issued its biotechnology regulations in 1997, it finalized an earlier-prepared document called “Points to Consider in the Preparation of TSCA Biotechnology Submissions for Microorganisms“, and this document has remained unchanged since that year, and has been used by submitters of Microbial Commercial Activities Notices (MCANs), TSCA Environmental Release Applications (TERAs) and other biotechnology filings under TSCA. Its guidance largely remains relevant, although it was written well before the advent of advanced genetic technologies now in widespread use such as synthetic biology and gene-editing tools, as well as before advances in nucleic acid sequencing technology made it routine to be able to provide detailed sequence information for all the introduced genetic modifications. I believe EPA has for some time been planning a general update of this document, but to my knowledge the “Algae” supplement is the only effort where proposed new guidance has been made available to the public.

The Points to Consider document, while applicable to all biotech submissions under TSCA, was heavily biased towards information needs for applications involving the most common industrially-used heterotrophic microorganisms, primarily including bacteria, yeast and other fungal species. In 2015, EPA first announced its intention to provide a companion document that would provide additional guidance for submissions involving genetically modified algae and cyanobacteria, which, as photosynthetic organisms, were anticipated to be used in ways different from traditional microbial fermentation. Earlier blog posts described the initial public meeting on this topic that EPA held in September 2015 and the follow-up meeting in October 2016. EPA issued a draft algae guidance document in conjunction with the 2016 public meeting, and the present document is an update to the 2016 version, and incorporates the information and feedback EPA received at that open meeting and from the public records docket that was open for comment at that time.

After some introductory sections, the main body of the guidance document is a detailed, comprehensive list of the types of data that EPA would potentially like to see in submissions for uses of algae or cyanobacteria under TSCA. It follows the framework of the 1997 Points to Consider document, in providing lists of the types of data that might be required in EPA submissions, within a series of broad categories. The algae document first asks for information about the recipient microorganism (i.e. the strain that is the starting point for the genetic manipulations) and the genetic changes introduced, information about the potential health and environmental effects (including the environmental fate) of the alga, and information about the proposed use of the modified alga, whether a small-scale field test proposed in a TERA or a manufacturing use proposed in an MCAN. The document provides additional details about information specific for algae or cyanobacteria that would be important for EPA’s risk assessment of proposed use of modified algae in manufacturing, whether in open ponds, enclosed photobioreactors, or heterotrophic fermentation, as well as proposed open pond R&D activities. As with the original Points to Consider document, the algae guidance document provides a comprehensive list of issues to be considered, with the expectation that not every topic identified would be applicable to every submission. In addition, it should be noted that TSCA itself does not impose specific testing requirements on applicants, but only that notices under the Act include all data relevant to health and safety that is known to the applicants.

After brief review of the final document, it appears that EPA made only some minor revisions to the detailed information section as it appeared in the 2016 draft. I found only about 3 or 4 places where the 2020 version included a bullet point for a new topic of information or data not found in the 2016 draft, which were presumably added in response to specific comments from interested parties. This speaks to the thorough job EPA did in creating the original draft, which was so comprehensive in listing potential data needs that there really wasn’t much that needed to be added.

To date, EPA has received very few TSCA submissions for uses of algae or cyanobacteria, some of which I have described in previous blog posts. For example, discussion of MCANs from Joule and Solazyme (now known as TerraVia) posted in 2014, a brief mention of Algenol’s Consolidated MCAN for cyanobacteria posted in 2015, and discussion of the TERA submitted by Sapphire posted in 2013. Presumably this new guidance document will be of value to companies and academic groups planning MCAN or TERA submissions for modified algae or cyanobacteria species in the months and years to come.

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-five 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. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and links to some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available 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 any other organization with which Dr. Glass is affiliated.

EPA TERAs for Agricultural and Environmental R&D with Modified Microorganisms

In past years on the blog, I’ve written about various aspects of the U.S. EPA regulations under the Toxic Substances Control Act (TSCA) that cover industrial and other uses of genetically modified microorganisms, which in recent years have applied to many commercial biofuel and bio-based chemical projects. Today I’m writing about one aspect of these regulations that cover proposed outdoor research activities of certain modified microorganisms, which might affect not only the open-pond use of modified algae to produce fuels or chemicals, but also proposed field testing of certain agricultural microorganisms intended for non-pesticidal use in the open environment. This is the requirement to obtain prior EPA review and approval of field test plans through submission of a TSCA Environmental Release Application (TERA).  

As previously described, the commercial use of modified microorganisms for purposes subject to TSCA jurisdiction might be subject to EPA’s biotechnology regulations under TSCA. 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  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.

By statute, TSCA applies only to new chemicals that are not subject to regulation by other federal agencies, and this same statutory limitation applies to EPA’s biotechnology regulations under this law. For the most part, TSCA jurisdiction includes uses of microorganisms in industrial manufacturing, such as the production of fuels, chemicals, enzymes or any other product that is not regulated as by FDA as a food or food additive, a dietary supplement of any kind, a drug, biologic, or cosmetic, or not regulated by EPA as a pesticide. The TSCA biotech regulations would also cover uses of microorganisms for environmental uses such as bioremediation as well as agricultural uses not regulated as pesticides, including plant inoculants such as those promoting nitrogen fixation, soil amendments and other biofertilizer applications. It is also likely that these regulations would also cover the testing and commercialization of plant biostimulants, a category of products which EPA considers falls outside its pesticide regulations. (EPA has just recently issued an updated draft guidance document for determining which products would be considered as biostimulants and thus not be regulated as pesticides).

Earlier blog posts have described the requirements for determining if an activity qualifies for the broad R&D exemption by virtue of taking place in a “contained structure”. Today’s post deals with EPA regulation of proposed R&D uses of new microorganisms in the open environment, such as agricultural field tests or open-pond uses of modified algae, or other activities that would be deemed not to qualify for the “contained structure” exemption. Such proposed uses would likely require EPA review before the research can be conducted, through the filing of a TERA.  

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 an earlier post on the blog. 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 websites, there have been about 40 TERAs submitted for open environmental use of engineered microorganisms, and all but four of these proposals were approved (those four were either withdrawn or rejected by the agency: further details are not available on the website). The following is a summary of the purposes of the approved TERAS.

From 1998-2015: 30 approved, 3 withdrawn

  • Rhizobia for nitrogen fixation: 5
  • Pesticide research: 3
  • Hazardous waste detection (bioindicators): 13
  • Bioremediation: 2
  • Biofuel research (algae): 5
  • Enzyme production: 2

2016 to date: 6 approved, 1 withdrawn (details not available on the website, due to changes in EPA’s website reporting after the adoption of the 2016 TSCA amendment)

The 5 TERAs for nitrogen fixation all arose in the early 1990s, for a research program that ultimately led to EPA’s approval in September 1997 of limited commercialization of a modified strain of Sinorhizobium meliloti with improved capacity to provide fixed nitrogen to alfalfa. There have apparently been no TERAs since then for microorganisms for improved nitrogen fixation or other biofertilizer applications. It is worth noting that the regulations provided very limited exemptions from TERA reporting for small-scale field testing of modified strains of R. meliloti (now S. meliloti) and Bradyrhizobium japonicum, under 40 CFR Part 725.239, but that these exemptions are extremely narrow and would cover only those proposed tests meeting the stated requirements.

The 3 TERAs which I’ve identified as pesticide research were academic projects from the University of California Riverside in the early 2000s for research on the biology of Alcaligenes xylosoxidans, which was being investigated as a potential biopesticide to control a disease of grapes. I don’t know if this research continued, but these tests were subject to TSCA because they were basic research: if an actual candidate pesticide product had been developed, its field testing would have been subject to EPA regulations under the pesticide law FIFRA and would likely have required obtaining an Experimental Use Permit under those regulations.  

By far the largest category were the 13 TERAs for testing of bioindicators: these were generally microorganisms that had been engineered to contain reporter genes that would be expressed in the presence of hazardous compounds in the environment (e.g. in potentially contaminated soil), triggering a biochemical response that could be detected and quantified. These projects were carried out from 1998 through 2007 by academic and government scientists and one private company, Micro Systems Technologies. It does not appear that this technology has ever been commercialized.

The TERAs in the bioremediation category were submitted in 2013 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. As I previously discussed in the blog, these TERAs appear to be the first in which approval was granted for release of modified microorganisms into the groundwater (all previous TERAs were for introductions into soil). EPA’s approval included significant monitoring and reporting requirements.

The 5 TERAs for biofuel research constituted a single submission from Sapphire Energy for a field test of modified algae in a biofuel research program. These TERAs were the first to cover the use of modified algae in open-pond reactors, and they proposed the testing of five different intergeneric strains of Scenedesmus dimorphus that had been modified to express metabolism-related genes and a marker gene. The stated purpose of this testing, as summarized on the EPA website, was to (1) evaluate the translatability of the genetically modified strains from the laboratory to an outdoor setting, and (2) to characterize the potential ecological impact (dispersion and invasion) of the genetically-modified microalgae. I described this experiment in more detail in a December 2013 blog post, and Sapphire and their collaborators from the University of California San Diego have published the results of these field tests.

Less is publicly known about the remaining two pre-2016 TERAs, which were two applications submitted and approved in 2015 for the use of Bacillus thuringiensis subspecies Israelensis for what was characterized as “enzyme production”. Since this species is known to have pesticidal properties, this designation is curious, but the EPA website does not include a link to a decision document that might provide more information. It’s likely that this too is a basic research proposal related to the development of a biological or biochemical pesticide.

Similarly, the EPA website gives virtually no information at all about the 7 TERAs submitted after the 2016 TSCA Amendments took effect.  I am in the process of filing a FOIA request to obtain more information on these TERAs and the two 2015 TERAs for enzyme production, and I will report on my findings about these TERAs in a future blog post once I have received that information.

 As a final word, I would note that the TERA process is well-suited to allow the assessment of the potential risks of proposed environmental uses of modified organisms. There are legitimate scientific issues that most observers feel should be addressed in the assessment of such uses, and the TERA process allows outdoor uses of modified microorganisms to take place in a stepwise fashion under appropriate monitoring and agency oversight, to enable environmental risk assessment questions to be addressed with data from actual controlled small-scale environmental use, thus facilitating subsequent risk assessments for larger-scale uses.

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-five 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. More information on D. Glass Associates’ regulatory affairs consulting capabilities, and links to some of Dr. Glass’s prior presentations on biofuels and biotechnology regulation, are available 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 any other organization with which Dr. Glass is affiliated.