This blog entry describes the possible ways in which uses of algae or cyanobacteria for fuel or chemical production might be regulated in the United States. This entry is one of several posts that provide additional information in support of a poster I’m presenting at the 2013 Algae Biomass Summit on the regulations in various countries around the world that may be applicable to the use of naturally-occurring or genetically modified algae or cyanobacteria in fuel production. These include three general categories of regulation: biotechnology or biosafety regulations, aquaculture regulations, and renewable fuel standards or volume mandates. You can access the poster on my SlideShare site, and please refer back to my September 16 introductory post for links to posts on the regulatory situation in other countries. Although this discussion centers on algae and cyanobacteria, much of the discussion (other than the section on aquaculture) would be applicable to the use of other genetically modified microorganisms for production of fuel or chemicals.
The discussion of the situation in the U.S. is in two parts. This blog entry discusses biotechnology regulations, and the entry that follows will discuss aquaculture and renewable fuels regulations.
The use of genetically modified algae or cyanobacteria for production of renewable fuels in the U.S. will likely be subject to regulations promulgated by the U.S. Environmental Protection Agency (EPA) under the Toxic Substances Control Act (TSCA). These regulations would likely cover both “contained” uses as well as open-pond applications. It is possible that certain open-pond uses of modified algae might also involve oversight by the U.S. Department of Agriculture (USDA), either alongside or in place of EPA regulation. I’ve written extensively about many aspects of both these biotechnology regulatory programs in earlier blog entries (e.g., describing the TSCA biotechnology program here, the USDA regulations here, and possible avenues for regulation of algae here), but the following is a brief summary.
Under the federal biotechnology framework adopted in 1986, EPA uses TSCA to regulate the applications of genetically modified microorganisms that are not regulated by other federal agencies. Among the several areas of commercial application potentially subject to these rules, production of biofuels and bio-based chemicals have in recent years become the most prominent.
After many years of discussion and debate among several federal agencies over three presidential administrations, EPA finally, on April 11, 1997, issued the final rule for regulation of biotechnology under TSCA (62 Federal Register 17910-17958). These rules created a new section of the Code of Federal Regulations (40 CFR Part 725), which specifies the procedures for EPA oversight over commercial use and research activities involving microorganisms subject to TSCA. The biotechnology rule requires premanufacture reporting for new organisms intended for commercial use, with “new organism” defined as an “intergeneric organism”, which in turn is defined to mean “a microorganism that is formed by the deliberate combination of genetic material originally isolated from organisms of different taxonomic genera”(please see my earlier blog posts for the rationale for this definition). Under this formulation, microorganisms that are not intergeneric are considered not to be new, and such organisms, including naturally occurring and classically mutated or selected microbes, are exempt from reporting requirements under TSCA.
The TSCA regulations state that the term “microorganism” encompasses “organisms classified in the kingdoms Monera (or Procaryotae), Protista, and Fungi, the Chlorophyta and the Rhodophyta of the Plantae, and viruses and virus-like particles”. Because cyanobacteria are prokaryotes, intergeneric strains of cyanobacteria would clearly fall under the scope of this regulation. Although the status of eukaryotic algae is less clear, the preamble to the 1997 Federal Register notice implementing the regulations specifically stated: “Therefore, this definition includes, but is not limited to, bacteria, protozoa, fungi, mycoplasmas, mycoplasma-like organisms, spiroplasmas, microphytoplanktons, green and red algae, viruses, and viruslike particles (e.g., viroids, satellites, and virusoids)”, making it likely that modified algae would be considered to be within the scope of the regulations.
The U.S. Department of Agriculture maintains biotechnology regulations at in 7 CFR Part 340 of the Code of Federal Regulations. Although largely used to regulate transgenic plants of agricultural importance, the regulations potentially also cover outdoor uses of certain modified microorganisms. Although algae and cyanobacteria are clearly within EPA’s jurisdiction, as discussed above, there has been some discussion as to whether open-pond uses of modified algae for biofuel production might fall under USDA’s jurisdiction rather than EPA’s. I’ll briefly discuss this issue later in this blog post.
It is worth noting that certain uses of genetically modified organisms, particularly those in the open environment (e.g. open-pond algae reactors) might fall subject to state regulation if the activity is to take place in one of the few U.S. states having biotechnology-specific laws. Among the states having such laws are Hawaii, Florida, Illinois and Wisconsin. Describing all applicable state laws is beyond the scope of this post, and perhaps I’ll address these in a future blog entry. In addition, several states have “invasive species” regulations that, while largely focused on invasive plant species, might be broad enough to affect algae. I’ve written about these laws in a previous blog entry. And some of the state aquaculture regulations described below might also come into play. I’d be happy to entertain any questions about biotechnology regulations in any specific U.S. state.
Microorganisms meeting the “new microorganism” definition that are to be used or imported for commercial purposes subject to TSCA’s jurisdiction require premanufacture reporting 90 days in advance of the commercial activity, through the filing with EPA of a Microbial Commercial Activity Notification (MCAN). I’ve described MCAN information and data requirements in earlier blog entries, and there is ample guidance in the regulation itself, and in a detailed “Points to Consider” document which EPA has created. As of September 2013, there have been over 50 MCANs submitted, one of which was withdrawn by the submitter: most of the others were able to proceed to commercial use. EPA does not formally “approve” MCANs, and if EPA does not conclude that the proposed use poses an unreasonable risk to health or the environment, or a substantial or significant exposure, the MCAN is “dropped from review,” and the submitter can begin commercialization after the review period has expired. Of the MCANs filed to date, Notices of Commencement have been filed by the applicants for only 23 of these, meaning the microorganisms covered by the other MCANs have not yet entered commercial use. Most of the filed MCANs have been submitted by manufacturers of microbial enzymes. There have been 16 MCANs filed for microorganisms modified for biofuel production (all for ethanol), including 9 for S. cerevisiae strains, 3 for Zymomonas mobilis, and 4 for other host organisms.
The Biotech Rule provides certain exemptions from MCAN reporting that are available for specific organisms that qualify. The primary qualification is that the host, or recipient, organism must be one that is included on the list found in Section 725.420 of the regulations. This list includes many well-studied species including E. coli K12, Saccharomyces cerevisiae, Bacillus subtilis, and others. For intergeneric organisms based on one of these host strains, there are additional requirements regarding the nature of the genetic modifications and the facilities and procedures that will be used to minimize the potential for release of the microorganism from the facility. I’ve described these in detail in earlier blog entries. Although EPA has not published any information regarding how often these exemptions have been used, it is believed that a number of companies developing modified E. coli or S. cerevisiae strains for biofuel application have taken advantage of the exemptions.
Generally speaking, research activities involving new microbes are exempt from reporting if used only in “contained structures”. The basis for this provision is the exemption under the TSCA statute for R&D activities using only “small quantities” of chemicals. The rule specifically contemplates that this exemption would apply broadly to many types of structures, including greenhouses, fermenters and process stream bioreactors. The rule gives applicants fairly broad leeway in designing and operating facilities to meet the “contained structure” definition. When conducted in suitably contained structures, most R&D activities would be exempt from MCAN reporting under the “small quantities” exemption in the statute. Under this definition, it is likely that most laboratory research in biofuels would be exempt from commercial reporting. In addition, many uses of engineered microorganisms in biofuel pilot plants could also qualify for this exemption, as long as the microbe were used “solely” for research and development.
Applicability of EPA Regulations
The use of genetically modified algae in an open-pond or other minimally contained reactor would also be covered under the EPA TSCA biotechnology regulations, but would face a different, and likely more stringent, path for review. Use of an intergeneric microorganism in any reactor that was judged by EPA not to be sufficiently “contained” would be subject to regulatory oversight at the research level and likely also a greater level of scrutiny at commercial scale.
Research activities with intergeneric microbes that are conducted outside a contained facility, i.e. outdoor experimentation like agricultural field tests, are potentially subject to some sort of reporting, with only limited exemptions. Such activities not qualifying for one of a limited number of exemptions can be conducted under a reduced reporting requirement known as TSCA Environmental Release Application (TERA). The TERA process is meant to be an expedited review procedure for small-scale field tests and other R&D uses of new organisms. The data requirements (§§725.255 and 725.260) are similar to those that EPA had been using under its interim procedures, and EPA is obligated to make its decision on whether or not to approve the proposed outdoor R&D activity within 60 days, although the rule indicates that early TERA reviews could require an extension to 120 days, particularly if coordination with another agency or an advisory committee meeting of outside scientific experts were needed.
When a TERA is approved, EPA can limit the testing to the terms and conditions originally specified in the application, or can ask the submitter to enter into a “TERA approval” document, specifying more restrictive conditions (§725.270).
There has only been limited experience with TERAs since the biotechnology rule was put into place in 1997. There have been 23 TERAs submitted for field use of engineered organisms, almost exclusively for agricultural microorganisms or for microbes for bioremediation. 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. 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, the 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.
Applicability of USDA Regulations
USDA’s biotechnology regulations, found in 7 CFR Part 340 of the Code of Federal Regulations, have been the major U.S. government rules that have covered uses of transgenic plants and other agricultural organisms. These regulations were first issued in June 1987 (52 Federal Register 22892- 22915), and they cover environmental releases and interstate transport of certain genetically modified plants and other organisms that have been engineered to contain nucleic acid sequences from certain genera that contain species that were considered to be potential plant pests. Most transgenic plants have been captured under these regulations because USDA included the common vector organism Agrobacterium on the list of potential pathogens. The regulations possibly cover modified microorganisms that may be plant pests, and a number of such microbes have been reviewed by USDA under these regulations.
Under the original regulations, permits were required from USDA for any field use of a plant or microorganism falling under the rule’s jurisdiction. The rule was later substantially relaxed, first in 1993 (58 Federal Register 17044-17059), and then again in 1997 (62 Federal Register 23945-23958), with the creation of a much simpler notification process for those plant species deemed to have low potential risks. Under the current version of the regulations, research field tests of most plant species can be carried out simply upon 30 days advance notice to USDA. This notification process would not be available for field tests of microorganisms that might be subject to the USDA regulation, so that permits would likely still be required for such uses.
The regulations also provide a path for commercialization of organisms that have successfully completed field testing. This process involves petitioning to have the organism in question “delisted” or removed from the list of regulated articles – a number of plant varieties have gone through this process, which in recent years has been encumbered by the need for USDA to carry out complete environmental assessments for each approval.
Some observers feel that open-pond uses of modified algae for biofuel production might fall under USDA’s jurisdiction rather than EPA’s, particularly since photosynthetic algae have historically been classified as plants, and in fact the definition of “plant” in the USDA rule includes “eukaryotic algae”. However, as I’ve pointed out in an earlier post, under the biotechnology rule, USDA does not regulate “plants”, but instead “plant pests”, and so the fact that “eukaryotic algae” are included in the definition of “plant” may have little bearing on the question. As stated above, the only microorganisms that would fall under these regulations would be ones that contained sequences from any of the specific microbial, plant and animal genera listed in 7 CFR Part 340.2 of the rule. This list does not appear to include the names of any of the genera of algae that have been suggested for biofuel use. Also, the USDA rule only applies for deliberate uses of regulated organisms in the open environment, and so the rule could arguably only apply to open-pond uses of modified algae.
The regulations give USDA the leeway to determine that other organisms are “potentially” plant pests and therefore subject to the rule. Moreover, there would be nothing stopping an applicant from requesting that USDA become voluntarily involved in review of a proposed activity that was otherwise subject to EPA jurisdiction. So, it remains to be seen if a role for USDA will emerge in the regulation of modified algae used in fuel or chemical production.
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.