OFFICE OF POLLUTION PREVENTION AND TOXICS (OPPT)
In December 1984, EPA published its proposed policy specifically discussing the applicability of TSCA to products of modern biotechnology. The emphasis of the discussion was on section 5, since this provision allows for prior review of planned environmental releases, although EPA also has tried to address, at least in the past, the applicability of other sections of TSCA to products of modern biotechnology. The notice was aimed at a “process-based” theory of regulation for implementation of section 5, and focused on the methods used to produce an organism, to decide whether such organisms were "new" chemical substances and, hence, subject to PMN. See generally Office of Science and Technology Policy, Proposal for a Coordinated Framework for Regulation of Biotechnology, Notice for Public Comment, 49 Fed. Reg. 50856, 50886-95 (1984).
In 1986, 1988, and 1994 EPA tried to refine its approach. It took roughly 15 years to finalize the regulation under TSCA of certain microbial products of modern biotechnology. The final rule became effective on June 10, 1997. See EPA, Microbial Products of Biotechnology; Final Regulation Under the Toxic Substances Control Act, Final Rule, 62 Fed. Reg. 17910 (1997). It establishes a new part 725 of title 40 of the Code of Federal Regulations pertaining to reporting requirements and review processes for certain microorganisms. Part 725 contains nine subparts containing provisions adapted from current EPA regulations governing conventional chemicals. Subparts A, B, and C contain provisions primarily adopted from parts 720 and 721 for conventional chemicals. Subpart A contains definitions and other provisions related to part 725. Subpart B describes administrative procedures and subpart C describes confidentiality provisions. Subpart D, which combines the general PMN and Significant New Use Rules (SNUR) requirements adapted from parts 720 and 721, describes the reporting requirements and review practices pertaining to microbial commercial activity notices (MCANs). A MCAN is the equivalent of a PMN for conventional chemicals and a Significant New Use Notice (SNUN) is the equivalent of a SNUR. A guidance exists on TSCA submissions for microbes. See EPA, Office of Pollution Prevention and Toxics, Points to Consider in the Preparation of TSCA Biotechnology Submissions for Microorganisms, at www.epa.gov/biotech_rule/pubs/pdf/ptcbio.pdf.
Subparts E, F, and G describe the reporting requirements and review processes for applications for exemptions from full MCAN reporting requirements. Subpart E, which is almost entirely new, describes a new reporting process for commercial R&D activities as well as the submission of TSCA Environmental Release Applications (TERAs), which are intended to relieve some of the reporting requirements applicable to non-R&D commercial activities. Subpart E also describes other criteria for exemption from EPA review for certain types of commercial R&D activities. Subpart F, which is an adaptation of section 720.38, describes requirements for obtaining a test marketing exemption (TME) for microorganisms. Subpart G, also new, describes criteria that must be met in order to qualify for a Tier I or Tier II exemption for certain microorganisms for general commercial use not constituting commercial R&D activities. Subpart L, adapted from part 721, describes additional procedures for reporting significant new uses of microorganisms, although no significant new use rules proposed. Thus, new subpart M, which would list microorganisms subject to SNUNs, contains no substantive provisions as of yet.
The focus of the 1994 proposed rules and the 1997 final rules is on section 5 and its coverage of new microorganisms. Under the final rules, an organism is “new” based on the taxonomic standard of whether it contains sequences of genetic material originally isolated from organisms classified in different genera, which is similar to the definition in the 1986 OSTP Notice. Section 5 coverage continues to pertain to such intergeneric organisms because genetic material not commonly shared between donor and recipient organisms has a significantly higher probability of exhibiting new traits or new combinations of traits compared to that from naturally occurring microorganisms.
Such new traits may affect the survivability, host range, substrate utilization, and competitiveness of altered microorganisms, including their protein and polysaccharide production. The behavior of such altered organisms is much less predictable. EPA further noted that while taxonomy may not be a perfect standard, in that microorganisms will be reclassified into different genera, its use is likely to capture the appropriate microorganisms for review that display new traits or new combinations of traits. Excluded from the definition of a “new microorganism” are those microbes that contain introduced genetic material consisting only of well-characterized, noncoding regulatory regions from a microbe in another genus.
With respect to the exemption for well-characterized, noncoding regulatory regions, EPA noted that microorganisms that contain such regions would not contain distinctly new combinations of traits, and that only the level of expression of the existing traits would be altered. A noncoding regulatory region is defined as a segment of introduced genetic material for which the regulatory region and inserted flanking sequence does not code for protein peptide or functional ribonucleic molecules, and the regulatory region solely controls the activity of other regions that code for protein or peptide molecules or act as recognition sites for the initiation of nucleic acid or protein synthesis.
“Well-characterized” genetic material is defined to mean that the function of all the products expressed from the structural genes has been determined; the function of the sequences that participate in the regulation of expression of a structural genes has been determined; and the presence or absence of associate nucleotide sequences and/or their associated functions are determined, where associated nucleotide sequences are those sequences needed to move genetic material including linkers, adapters, etc.
The new rules also cover mobile genetic elements (MGEs). EPA defines the term “intergeneric microorganism” to include a microorganism that contains a mobile genetic element which is first identified as a microorganism and a genus different from a recipient microorganism. Thus, genetic information (other than well-characterized, noncoding regulatory regions) first obtained from organism A of a different genera than the recipient organism B is still subject to notification under section 5 if transferred from B to C, if the genera of microorganisms A and C are different. Microorganisms that are not intergeneric are automatically included on the TSCA Inventory. In other words, intrageneric organisms are not subject to section 5 TSCA jurisdiction although, in theory at least, they are subject to other TSCA sections.
Commercial R&D activities are subject to special reporting requirements and to certain exemptions to reduce the burdens on researchers and to foster technological innovation. Pure R&D activities with no commercial purpose are not subject to section 5. Commercial purposes for R&D means that activities are conducted with the purpose of obtaining an immediate or eventual commercial advantage. R&D activities that are at least partially funded by a commercial entity or by a commercial contract, or are the subject of patent protection are indicia of commercial purposes.
Certain microbial pesticide uses of intergeneric microbes are excluded from TSCA commercial R&D reporting requirements. Also excluded are R&D activities that must be conducted in accordance with the NIH Guidelines and where there is no intentional testing of a microorganism outside of a contained structure. Otherwise, R&D activities conducted in a contained structure could be exempt, regardless of NIH Guideline compliance considerations, if other requirements pertaining to use by a technically qualified individual and certain containment and inactivation conditions are met.
To the extent that R&D activities are conducted outside of a contained structure, a number of other exemptions exist. If recipient organisms involve Bradyrhizobium japonicum or Rhizobium maliloti and the test site is no more than ten terrestrial acres, then another exemption may apply. Otherwise, environmental releases may be subject to TERA requirements. A TERA is required to be submitted sixty days before a person intends to initiate the proposed R&D activity in the environment, and the period of review by EPA is sixty days from the date the agency receives a complete TERA. Research is not allowed to proceed unless and until EPA provides written approval of the TERA.
If commercial R&D does not qualify for the exemptions or that the activity does not involve R&D at work at all, then intergeneric microorganisms are potentially subject to MCANs and the 90 day premanufacture requirement. Alternatively, for commercial work beyond the R&D stage, limited exemptions pertaining to test marketing may apply. Certain other exemptions, called tiered exemptions (Tier I and Tier II), can apply if particular recipient microorganisms are used. The recipient microorganism subject to Tier I or Tier II exemptions are Acetobacter aceti, Aspergillus niger, Aspergillus oryzae, Bacillus licheniformis, Bacillus subtilis, Clostridium acetobutylicum, Escherichia coli K-12, Penicillium roqueforti, Saccharomyces cerevisiae, and Saccharomyces uvarum. Other restrictions are placed on introduced genetic material and physical containment, among other requirements.
A Tier II exemption request may be submitted in lieu of a Tier I request and an MCAN. A Tier I exemption is not subject to EPA prior review, whereas a Tier II exemption is; in the case of a Tier I exemption only certification is required at least ten days before commencing initial manufacture or import of a new microorganism. The other primary difference between Tier I and Tier II exemptions is that for Tier II exemptions only the requirements pertaining to the recipient microorganism and introduced genetic material of the Tier I exemption must be met. Manufacturers in the Tier II exemption request must select containment appropriate to minimize release of microorganisms, whereas Tier I specifies physical containment conditions to minimize organisms emitted from the manufacturing facility.
Chemicals used directly for FDA-regulated purposes are exempt from TSCA. The regulatory status under TSCA of materials used to produce such FDA-regulated articles is somewhat unclear, but as a matter of policy has EPA noted that microorganisms (and presumably any other material) used to produce foods, food additives, drugs, cosmetics, and medical devices are not reviewed under TSCA. This position was adopted in EPA's 1994 draft and 1997 final TSCA rules. Plants and animals were not and currently are not subject to TSCA review as a matter of policy, either as whole organisms or as in vitro cultures, because such genetically-engineered organisms likely will be used for food-related purposes that are exempt from TSCA or are under USDA jurisdiction.
Except for these exclusions, microorganisms and other materials produced for environmental, industrial, or consumer uses are subject to TSCA, including those used to make pesticides. The distinction between TSCA not being applicable to materials used to prepare FDA-regulated articles, yet being applicable to those used to make pesticides, is largely historical and arguably inconsistent.
Also covered by TSCA are chemicals produced by microorganisms if they are used for TSCA purposes, as has always been the case with respect to chemicals made by conventional methods. In other words, chemicals produced by microorganisms are subject to the same requirements and procedures as chemicals produced by other means. The use of chemical synthesis or microorganisms to manufacture a substance not listed on the TSCA Inventory potentially creates a new chemical subject to PMN, regardless of whether or not an identical substance is naturally occurring. For example, the manufacture of modern biotechnology laboratory reagents, such as vectors, linkage sequences (including isolated nucleic acid fragments), chemicals for nucleic acid synthesis, soil inoculants, biofertilizers, pollutant degradants, and industrial enzymes could be subject to PMN or MCAN if produced for commercial purposes. As long as these substances are sold solely for use in R&D activities, however, they are exempt from PMN, consistent with the treatment afforded other research chemicals under TSCA. Chemicals such as DNA fragments and plasmids used as devices for medical testing or as drugs are not subject to PMN requirements or TSCA.
On the other hand, many chemical substances that are likely to be made in the future by “genetically engineered” microorganisms already are listed on the TSCA Inventory because currently they are produced by conventional methods. These chemicals are not treated differently from existing products made by conventional means, although this possibility was under consideration at one time.
The first PMN notifications of proposed field testing involved three genetically engineered strains of Rhizobium meliloti to enhance nitrogen fixation of alfalfa. These strains were altered to contain genetic material from more than one taxonomic genus using R-DNA techniques. The PMN submission resulted in a section 5(e) consent order allowing testing under certain conditions. The first biotechnology PMN to make it through the ninety-day review process without EPA challenge was for E. coli K-12, which was genetically engineered to produce a growth factor to culture cells used in the production of monoclonal antibodies and other such products. For a list of notifications under TSCA since 1998, see EPA, Notifications, FY98 to Present at http://www.epa.gov/biotech_rule/pubs/submiss.htm.
Agency permits/notifications, registrations, or approvals under FIFRA or TSCA are not subject to NEPA because of the functional equivalence doctrine; their environmental analyses are deemed the equivalent of a NEPA assessment.
