Section 1.0 1  1 1.0 Insect Resistance Management ( IRM)

More than 150 comments were received by the Agency regarding IRM of event MON 863 corn expressing the Bt Cry3Bb1 protein. Since many of these comments addressed similar areas, comments were grouped and summarized rather than responding to them individually.

General Public Comments One commenter states that the use of this technology will continue to provide an improvement in agricultural environments by reducing the use of pesticides. Another commenter notes that transgenic corn is making it easier and more economical to provide supplemental food that increases the winter survival of some wildlife and that biotechnologies in general have benefitted wildlife by reducing insecticides and improving the habitat for many aquatic and terrestrial species. One commenter believes that reduced insecticide use would have benefits along the whole insecticide supply chain and would reduce exposure of beneficial insects to insecticide, thereby improving ecological balance. Another commenter believes corn rootworm protected corn fits in well with current integrated pest management recommendations and is an important step towards sustainable agriculture.

One commenter quotes Illinois entomologist, Michael Gray, and suggests that IPM alternatives exist and the extra expense of Cry 3Bb corn would not be justified. The commenter states that less than 10 percent of the acres planted to corn following soybeans require insecticide treatment. The commenter also notes that area wide corn rootworm population suppression systems are under development and that new approaches target insects at multiple stages in their life cycle when control interventions can be carried out economically and safely. The commenter believes that these strategies may prove to be cost effective and adequate to restore the former efficacy of the corn soybean rotation in management of corn rootworms.

One commenter identifies several disadvantages to the technology including: ( 1) early availability in desired hybrid backgrounds; ( 2) specificity to one insect; ( 3) IRM requirements may be too restrictive to bring value to farmer; and ( 4) the need to market the product.

EPA's Response The Agency recognizes the potential benefits, including pesticide use reduction, that may result from the adoption of MON 863 corn ( see the Event MON863 Bt Cry3Bb1 Corn Biopesticides Registration Action Document ( BRAD) Section E titled Benefits).

Resistance Public Comments One commenter states that biotechnology should be evaluated with emphasis on insect resistance management and impacts to nontarget organisms. The same commenter believes corn rootworm protected corn can be a useful tool to counteract resistance that has developed. One commenter states that MON 863 Section 1.0 1  2 may benefit farmers and the environment, but will not provide an effective control strategy unless a rigorous and cautious IRM program is adopted. One commenter states that resistance management strategies need to be explored in carefully designed, small scale field trials and laboratory trials before large scale commercialization.

One commenter states that the challenges to managing resistance to Cry 3Bb will be significant and cites a report suggesting the potential for resistance development by corn rootworm is acute and unavoidable. Another commenter states that the history of corn rootworm adaptation emphasizes the need for an IRM plan for MON 863. The commenter notes that rootworms developed resistance to chlorinated hydrocarbon soil insecticides and this resistance affected most of the Corn Belt. The commenter adds that farmers switched to synthetic pyrethroid and organophosphate insecticides and that resistance has been found in organophosphate methyl parathion and carbaryl. One commenter supporting registration of MON 863 cites concerns with the increased use of adult control programs with soil insecticides, leading to insecticide resistance.

One commenter addresses concerns that Bt corn will make insects resistant to Bt and states that non Bt refuges could delay resistance if growers use the refuges properly. The commenter adds that resistance threatens all pesticides, but that we know how to avoid it. The commenter further states that if rootworms did become resistant to Bt corn it would not threaten the use of Bt against other pests and so the possibility of resistance is not a valid argument against registering Bt products.

Another commenter states that the criteria Monsanto provides for defining resistance are not sensitive enough, and could miss cases of corn rootworm resistance. In particular, the commenter believes the EPA should require a definition of resistance that includes slope as well as LC50 and that resistance should depend on increased corn rootworm survival as opposed to corn root damage. The commenter is also concerned that farmers use the same methods to grow MON 863 as refuge corn, including crop rotation history, to ensure that pest management practices on the refuge are compatible with the IRM plan.

EPA's Response The Agency agrees that a rigorous IRM plan is necessary to prolong the efficacy of field corn expressing the Cry3Bb1 protein. Therefore, an acceptable IRM plan was necessary prior to registering Cry3Bb1 corn. In determining an appropriate IRM strategy, the Agency reviews data collected from small scale field and laboratory trials as well as results of simulation models before large scale commercialization. A summary of the information considered in developing an IRM strategy for MON 863 corn can be found in the Event MON863 Bt Cry3Bb1 Corn Biopesticides Registration Action Document ( BRAD) Section D, titled Insect Resistance Management ( pp. IID 1 to IID 19).

An acceptable IRM strategy is intended to delay the onset of resistance rather than guarantee that resistance will never occur. The Agency is aware that populations of the western corn rootworm have developed resistance to certain cultural methods ( e. g., crop rotation) and insecticides including soil applied cyclodienes and organochlorines as well as organophosphate and carbamate sprays. However, resistance was not observed for 12 to 20 years. Published research has shown that an insect must ingest a Bt Cry protein which leads to the toxin binding to receptors in the insects midgut epithelial cells. Ultimately, pores are formed in the cellular membranes and homeostasis of cells occurs. The binding of the toxin to the Section 1.0 1  3 midgut receptor is critical in Bt mode of action and only occurs in susceptible insects. Due to host specificity and specific mode of action of Cry proteins, cross resistance or resistance to other insecticides triggered by Bt resistance is not a concern. The potential for cross resistance is not an issue for MON 863 since no microbial pesticides or plant incorporated protectants ( PIPs) are currently registered for corn with the same mode of action as Cry3Bb1, and corn rootworm ( CRW) is not a listed pest on any current Bt microbial products.

The Agency agrees that the implementation of appropriate resistance management strategies will delay the potential onset of resistance. To ensure a case of resistance is identified a resistance monitoring plan is required by the Agency ( see BRAD Resistance Monitoring Section pp. IID 9 to IID 10). If resistance is observed, the Registrant is required to implement an Agency approved mitigation/ remedial action plan to eradicate the resistant population and prevent the spread of resistance ( see BRAD Remedial Action Section pp. 11 and IID 12).

On August 28 and 29, 2002 the Agency convened a FIFRA Scientific Advisory Panel ( SAP) to provide expert input regarding IRM of MON 863 corn. The SAP did not recommend including slope as a definition of resistance. Important factors should be considered such as behavioral resistance and physical size that may not relate to the slope of an LD50. For instance, corn rootworm that are physically larger than others may take longer to be affected ( behavior and/ or sublethal and non lethal changes) but have the same slope for the survival in a dietary toxicity study. The Agency does not want to restrict the definition of resistance to exclude these factors, especially for a pest which has already shown behavioral adaptation to cultural control techniques.

IRM Practicality Public Comments One commenter supports registration, but urges sustainable implementation taking into consideration the ability of growers to adopt recommendations. Several commenters note that proper stewardship, including managing resistance, is crucial. One of these commenters emphasizes the importance of compliance with IRM requirements. Several commenters addressed the need for flexibility in a workable and consistent IRM plan, noting that world markets may be driven by IRM performance and if the IRM plan does not work the burden will be on the farmers.

EPA's Response The Agency agrees that proper product stewardship and grower compliance are imperative to an IRM plan. Therefore, the Agency requires an appropriate grower education and compliance program ( see BRAD Grower Education and Compliance Section pp. IID 12 and IID 13). Growers are required to sign a technology use agreement that outlines IRM requirements and acknowledges the growers responsibility to comply with them on an annual basis. An annual industry supported survey conducted by a third party will be submitted to the Agency as a tool to monitor grower compliance. Additional education efforts are also recommended to target non compliant growers and access to the technology will be limited for growers found to be non compliant. Section 1.0 1  4 The Agency as well as the August 2002 SAP agree that there is a need for flexibility in an IRM plan. Therefore, two refuge options are considered acceptable; refuges may be planted as in field strips or adjacent blocks. In addition, the Agency has considered the growers need to treat refuges with soil applied insecticides for immature corn rootworm and the potential need to use insecticides to control corn pests other than the corn rootworm ( see BRAD Refuge Section pg. IID 9).

Market Public Comments One commenter supports registration, but expressed concerns with the introduction of the product into the market. The commenter noted the importance of using proper protocols and differentiating this product from other products on the market.

Several commenters challenge the claim that there is no cause for alarm if resistance to Cry 3Bb endotoxins emerge in corn rootworm populations. The commenters state that other companies will commercialize biopesticides containing an endotoxin much like Cry 3Bb and that a soil applied Bt product is likely to result from the phase out of OP and carbamate insecticides. The commenters state that the spread of resistance to synthetic pyrethroid insecticides could also change the market. The commenters add that a resistance to one Bt endotoxin will reduce the selection pressure and time required for others to emerge and notes that EPA and USDA must assure effective resistance management plans are developed and adopted with the introduction of any Bt corn events.

Two commenters suggest local sales limits to assure market penetration is low, noting that the applicant relies on assumptions about national adoption rates. One commenter does not believe the current lack of licensing agreements with seed companies for additional varieties should be used to predict future licensing. The commenter believes local adoption may occur more quickly than national adoption and states that the applicant has not considered that at least one other Bt corn variety is being considered and may impact resistance. The same commenter states that the existence of effective chemical alternatives for corn rootworm control will not necessarily slow the adoption of MON 863, because adoption may be motivated by grower convenience, time saving, or fewer restrictions on crop rotation. Another commenter notes that new and existing management options are available for corn rootworms and that constraints on the potential market share of transgenics may limit adoption. The commenter states that the key to IRM is preventing excessive repetitive use of technology on a local scale.

EPA's Response The Agency agrees that it is important to implement appropriate protocols and differentiate MON 863 corn from other products on the market. Therefore, Monsanto is required to provide growers with a Product Use Guide that outlines IRM requirements. In addition, growers are required to sign a technology use agreement that acknowledges the growers responsibility to comply with requirements outlined in the Product Use Guide on an annual basis. The agreement will also state that growers received the Product Use Guide. This agreement may be a section of the growers order sheet or some other document or format ( see BRAD Grower Education and Compliance Section pp. IID 12 and IID 13). Section 1.0 1  5 Since the Agency recognizes the benefits of Cry3Bb1 corn ( See BRAD Section E. Benefits), an IRM plan that would delay the potential for corn rootworm resistance was required prior to registration. Limiting sales on a local or regional level was considered by the August 2002 SAP. The SAP suggested limiting sales of MON 863 for IRM purposes to an on farm level rather than by region, state or county. The Agency concluded that additional acreage limitations of MON 863 beyond the 20% refuge requirement are not necessary during the interim registration period. Although the Agency recognizes alternatives to MON 863 exist now or will become available in the future, each registration is considered individually. Therefore, the use of MON 863 and the implementation of an appropriate IRM strategy is based on current uses and is not based on the potential of new pesticides in the future such as biopesticides containing an endotoxin much like Cry 3Bb or new synthetic pyrethroids.

Refuges Public Comments One commenter refers to a 2001 study of western corn rootworm and notes that if the allele is recessive, resistance never develops, but if the expression of the allele is dominant, then resistance will occur rapidly after adoption of the technology by farmers. The same commenter notes that for block refuges planted within a field and at different locations each year, the development of resistance should be closer to that simulated with refuges as row strips.

One commenter states that scouting techniques, extended diapause, and oviposition in soybean may enable the use of transgenic varieties in a prescriptive pest management approach. The commenter notes that farmers will expect the option of protecting corn from corn rootworms if refuge areas are required and encourages the use of adult management strategies since larvae targeted insecticides are restricted to the seed furrow and allow roots outside the furrow to produce adult corn rootworms. One commenter believes rotation of control options and prescriptive use of transgenics based on scouting should be considered as alternatives to planned refuges for resistance management.

EPA's Response Since it is unknown whether the resistance allele for MON 863 corn in the corn rootworm is recessive or dominant, simulation models were considered based on a " worst case scenario" ( see BRAD Simulation Models of Resistance Section pp. IID 5 to IID 8). Due to the need for flexibility in refuge options to ensure grower compliance, the Agency has not stipulated the exact placement of in field refuges. Until further research has been conducted, the Agency has not required planting refuges within the field as blocks in different locations each year. However, the Agency may modify requirements for refuge placement based on research conducted during the initial interim registration period ( see BRAD Conclusions and Recommendations Sections pp. IID 14 to IID 17 for research requirements).

The Agency encourages scouting fields, use of economic thresholds and the implementation of integrated pest management ( IPM) approaches for all pesticide products including MON 863 corn. However, CRW resistance to MON 863 is not expected to occur during the interim registration. Therefore, mandatory scouting or prescriptive use of MON 863 is not necessary at this time. According to Monsanto, the risk of resistance will be reduced by encouraging stakeholders such as growers, Extension Agents and crop Section 1.0 1  6 consultants to promote and practice IPM. For instance, scouting fields in the Fall will be encouraged and planting MON 863 on acres with the highest risk of damage will be promoted ( MRID 455770 01).

The Agency realizes that high numbers of corn rootworm larvae in refuges may lead to unacceptable levels of damage. High numbers of corn rootworm may result in dramatically reduced yields that will be cost prohibitive to farmers. It is also possible that refuge corn that is destroyed by corn rootworm damage may result in a decreased number of susceptible insects needed to mate with potentially resistant insects. Therefore, the Agency included the option to treat refuges with seed and granular insecticide treatments to control CRW larvae. However, it is not acceptable to treat refuges for adult CRW control since these treatments may diminish the effectiveness of the refuge. If growers spray their corn fields with insecticides to control pests other than CRW, then all acres ( Bt and non Bt) should be treated identically ( see BRAD Refuge Section pg. IID 9). Since refuges are intended to produce adults susceptible to Cry3Bb1, furrows that produce adult corn rootworms are acceptable.

Dose Public Comments One commenter believes resistance management strategies should explore low dose expression, noting that no effective low dose expression resistance management plans have been developed or tested with transgenic Bt plants yet. The commenter also raises the question of to what degree the low dose for corn rootworm also is a low dose for other nontarget organisms. Another commenter recommends studies to determine the effective dose for resistance management. The same commenter proposes additional studies focus on the change in dose in the roots over the larval period.

Another commenter believes that the probability of rootworms developing resistance to Cry3Bb during an interim registration period appears to be low. The commenter notes that MON 863 is not a high dose event and that survivorship may be linked to changes in larval feeding behavior and the expression of Cry 3Bb endotoxin below the LC50. The commenter adds that resistance models simulating a low dose product and low market penetration predict a low probability of resistance evolution.

EPA's Response Identifying the level of dose, as related to selection intensity, is crucial when determining size and structure of a refuge needed to delay CRW resistance to MON 863 corn. CRW feeding behavior and survival and root expression data can be used to identify the dose of MON 863. From data currently available it can be concluded that MON 863 corn does not provide a high dose for CRW control. The August 2002 SAP suggested that it is not necessary to determine the difference between a low and moderate dose. It is adequate to differentiate between high dose and non high dose products when determining effective refuge size. Therefore, MON 863 should be characterized as a non high dose product ( see BRAD Dose Section pp. IID 4 and IID 5).

The Agency and the August 2002 SAP agree that there is a low probability that corn rootworm will develop resistance to Cry3Bb1 during an interim registration period. Section 1.0 1  7 Crop Rotation Public Comments Several commenters quote the motion approved by the NCR 46 committee which states that NCR 46 does not have concerns about insecticide resistance management by allowing a Section 3 seed increase of MON 863, provided that corn will not be planted the following year in a field used for seed increase.

One commenter believes that rotating the seed to a field crop other than corn would greatly reduce any chance of producing rootworm adults from the seed increase field. The same commenter is concerned that problems are emerging with current management strategies, particularly adaptation to crop rotation and increased use of insecticides to deal with this resistance. The commenter cites several variables that reduce the efficacy of insecticides and states that insecticides present safety issues. The commenter believes that registrations and use patterns of corn rootworm insecticides may change as a result of reviews by EPA under the Food Quality Protection Act.

EPA's Response Although Monsanto does not plan to plant a refuge for inbred seed increase fields, they will treat with insecticides that will probably control any resistant CRW adults that may emerge. It is, therefore, acceptable to plant inbred seed increase acres without a refuge.

It should be noted that the request for public comments was not for a seed increase registration; rather, comments were being requested by the Agency for a Section 3( c) full commercial registration. It should also be noted that recommendations made by the NCR 46 technical committee were considered for the MON 863 registration ( see BRAD Conclusions and Recommendations Sections pp. IID 14 to IID 17). The Agency appreciates the concerns regarding the corn rootworms ability to adapt to current pest control methods. The corn rootworms adaptive ability was considered by Monsanto ( MRID 455770 01) and reviewed by the Agency.

IRM Data Needs Public Comments One commenter believes EPA should request that the SAP, Monsanto, and academic IRM experts develop a new IRM theory applicable to MON 863 before approving MON 863 for registration. The commenter also states that EPA should work with the SAP to evaluate approving MON 863 under a prescription use approach designed to enhance compliance with IRM provisions and other product use requirements and limitations. The commenter believes this approach will support systematic collection of high quality data.

One commenter does not believe that the applicant provides sufficient data to support the proposed IRM Section 1.0 1  8 plan for MON 863. The commenter states that the applicant should be required to develop a more protective IRM plan consulting with independent experts, identifying and addressing data gaps, and considering current means of resistance management.

One commenter notes that the applicant does not offer many specific commitments regarding data collection and states that biological data is needed to assess the effectiveness of the proposed refuge strategy and to determine whether other approaches to IRM would be more effective. The commenter believes additional data is needed on the northern corn rootworm, and on the movement and mating behavior of adult corn rootworm, mechanisms of resistance, initial frequency of resistance alleles, levels of resistance of hetero and homozygous resistant adults and larvae, and fitness costs associated with resistance. The commenter suggests EPA work with the NRC 46 committee to evaluate the impacts of Bt corn on current corn rootworm management strategies, particularly soybean/ corn rotations.

The same commenter states that the applicant's IRM plan should incorporate previously submitted recommendations for improving compliance. The commenter believes the applicants mitigation strategies to delay the spread of resistance are inadequate and suggests a more comprehensive national IRM plan is needed. The same commenter states that the applicant has not given consideration to the impacts of stacked transgenes on resistance management. The commenter is concerned with increased corn earthworm resistance due to stacking of MON 810 with MON 863 and suggests that EPA restrict gene stacking.

One commenter remarks that the single corn rootworm generation per year slows the potential for resistance development, but notes that deviations from the life cycle, such as extended diapause and oviposition outside of corn, have implications that should be considered in IRM approaches. The commenter notes that adult corn rootworm emergence patterns are variable and can be influenced by management strategies. The commenter states that the effects of transgenic events on the synchrony of emergence of males and females are unknown, but could result in selective mating and increase the speed of resistance. The commenter also adds that a realistic product duration should be considered in IRM options and suggests that preferred longevity of corn rootworm susceptibility be clearly defined.

The commenter provides the following questions for EPA to consider: 1. Since dose levels have not been defined for transgenic events against corn rootworms, what constitutes high, moderate, and low dose events? 2. How can the effective dosage of a transgenic event be measured for corn rootworms? 3. How do the diversity of situations that have triggered resistance development previously in corn rootworms ( chlorinated hydrocarbons, crop rotation, adult control with organophosphates) relate to assumptions about resistance to transgene events and IRM? 4. What can be done to develop a robust plan for multiple species, for multiple events? 5. What are baseline toxicity levels for all corn rootworm species, not just western corn rootworms? 6. How does the difficulty of rearing corn rootworms and conducting bioassays complicate the registration of events? 7. What are the appropriate methodologies to use to monitor for corn rootworm resistance to rootworm protected transgenic plants ( laboratory/ field)? 8. What is a realistic time period to try to preserve the life of a transgenic event by preventing resistance through IRM? Section 1.0 1  9 EPA's Response The Agency agrees that SAP, Monsanto, and academic IRM experts should be consulted to develop a new IRM theory applicable to MON 863 before approving MON 863 for registration. Therefore, an SAP was convened on August 28 and 29, 2002 to comment on Monsanto's IRM plan outlined in MRID 455770 01. An SAP report was published on November 6, 2002 and can be viewed at http:// www. epa. gov/ scipoly/ sap/ 2002/ august/ august2002final. pdf. From data currently available it can be concluded that MON 863 corn does not provide a high dose for CRW control. The August 2002 SAP suggested that it is not necessary to determine the difference between a low and moderate dose. It is adequate to differentiate between high dose and non high dose products when determining effective refuge size. Therefore, MON 863 should be characterized as a non high dose product ( see BRAD Dose Section pp. IID 4 and IID 5).

Although the Agency recognizes the importance of grower compliance ( see BRAD Grower Education and Compliance Section pp. IID 12 and IID 13), a prescriptive use approach was not required. According to Monsanto, the risk of resistance will be reduced by encouraging stakeholders such as growers, Extension Agents and crop consultants to promote and practice IPM. For instance, scouting fields in the Fall will be encouraged and planting MON 863 on acres with the highest risk of damage will be promoted ( MRID 455770 01).

The Agency believes there is sufficient information currently available to ensure corn rootworm resistance to Cry3Bb1 will not occur during an interim registration ( see BRAD Chapter D. Insect Resistance Management). To further ensure the delay of resistance, the Agency is requiring the use of non Bt corn refuges ( see BRAD Refuge Section pg. IID 9). The Agency agrees that a comprehensive compliance and remedial action plan are needed for an IRM strategy ( see BRAD Remedial Action and Grower Education and Compliance Sections pp. IID 11 to IID 13). The Agency also recognizes the importance of pest biology when developing an IRM strategy ( see BRAD Pest Biology Section pp. IID 2 to IID 4). However, more data is needed regarding pest biology and its impact on an IRM strategy. Therefore, the Agency has requested additional research be conducted during the interim registration to provide the needed data on corn rootworm biology. In particular, data has been requested on movement, mating and ovipositional patterns of the corn rootworm as well as the information on the potential for rearing. Data has also been requested to establish baseline toxicity levels for all corn rootworm species ( see BRAD Conclusions and Recommendations Sections pp. IID 14 to IID 17).

This registration only addressed Cry3Bb1 expressed in field corn. Therefore, stacked products were not considered.

Applicant Responses Public Comments The applicant responds to public comments on the IRM plan with the following statements:  The proposed interim IRM plan for MON 863 has been designed with input from key stakeholders, including academic, government and industry scientists, crop consultants and growers.  The 1998 EPA SAP recommended a refuge and high dose strategy for the first Bt plant incorporated Section 1.0 1  10 protectants, but the Panel emphasized the need for flexibility in resistance management plans based upon pest biology, the nature of the response to the Bt crop, and economic or logistical feasibility.  To support commercial launch of this product a research strategy is in place with stakeholders to balance the best technical information and grower feasibility to increase the durability of CRW protected hybrids. The IRM plan for MON 863 hybrids will evolve over time as new information is developed, just as the IRM plan for YieldGard Corn Borer evolved over time.  MON 863 presents a negligible cross resistance risk to other Bt events that work via a different mode of action.  MON 863 does not pose an unreasonable cross resistance risk to a future, hypothetical Bt microbial based products for the control of CRW because surface applied Bt microbial formulations cannot be adequately applied to growing root tissues to assure constant coverage of root tissue for a prolonged period of time to control feeding CRW larvae.

In response to comments that adaptation of CRW populations to the Cry3Bb1 protein expressed in MON 863 could limit the longevity of future biopesticide formulations of Cry3Bb, other Cry3Bb events or Bt events with a different mode of action, the applicant provided further scientific background:

The Cry3Bb protein has never been used in any formulated Bt microbial based product to control CRW larvae for two important reasons: delivery and timing. CRW larvae feed on corn roots over a largely unpredictable period of three to eight weeks, and the Bt insecticidal protein must be ingested to elicit a pesticidal physiological response. Thus, in order for CRW larvae to come into contact with a microbial Bt formulation, it would need to be applied so as to constantly cover the root tissue and remain active for a prolonged period of time. Neither of these issues can be addressed with current Bt microbial formulation technology. Thus, it is reasonable to assume that use of MON 863 will not pose an unreasonable risk to a future, hypothetical Bt microbial based product for the control of CRW. Studies also indicate that there is little cross resistance between Bt plant and foliar sprays with similar proteins because of the presence of other critical ingredients, such as spores, in the spray formulations.

Corn event MON 863 produces the Cry3Bbl protein at levels sufficient to minimize CRW larval root damage. Regulatory approval and commercial use of this technology will require the deployment of a scientifically sound and feasible IRM plan that suppresses the emergence of insect resistance in targeted pest populations. In the event that future Cry3Bbl events are introduced, EPA will require and determine the acceptability of appropriate IRM plans for all products.

Event MON 863 represents a negligible risk to other Bt events that work via a different mode of action. It is well understood that Bt proteins having similar modes of action are at a greater risk of exhibiting cross resistance. Conversely, Bt proteins that differ in their mode of action represent a minimal risk of cross resistance. It is for this reason that EPA and the scientific community recommend that developers of Bt crops develop and express Bt proteins with differing modes of action as a means to further reduce the likelihood of resistance development in pest populations. Section 1.0 1  11 The generally recognized mode of action of Bt proteins has several distinct steps after ingestion by the insect. These steps include: solubilization, proteolytic stability, binding to the insect midgut epithelium, formation of ion channels in the insect midgut cells, and finally lysis of these cells. Each of these steps is governed by the sequence dependent structure of the protein and the insect specific midgut environment. Thus, the more two proteins differ structurally, the more likely they are to differ in their mode of action and would exhibit differing mechanisms of resistance. The sequence dissimilarity between two Bt proteins is an empirical measure of their likelihood to act by different modes of action. Recently Cry34Abl and Cry35Ab1 have been listed as new classes of novel Cry proteins, which require them to share less than 45% amino acid identity with any other known Cry protein ( e. g., Cry3Bbl). The Cry34 and Cry35 proteins expressed in CRW protected events under development by Dow AgroSciences and Pioneer Hy Bred International function as a binary protein active against CRW larvae. These proteins not only are very different from Cry3Bbl in amino acid sequence, but both proteins are absolutely required for CRW activity. Due to these differences in protein sequence and mode of action, it is unlikely that Cry3Bb1 and the new Cry34/ Cry35 binary protein have similar modes of action.

The applicant provides the following benefits relative to insect resistance management for MON 863:  Superior pest protection will greatly reduce the use of insecticides to control losses from corn rootworm and reduce human and animal insecticide exposure on the farm and in the agro ecosystem.  The proposed interim IRM plan incorporates all that is known about the biology of the target pest spectrum, grower feasibility of alternative strategies, product dose, as well as other available pest management options that will limit overall selection pressure from MON 863 on CRW populations during the interim period.  The proposed interim IRM plan identifies important areas for on going research and is intended to evolve as needed over time based on the latest scientific information. On going research will be used to design a long term MM plan that will ensure durability of MON 863 corn hybrids.  The proposed interim IRM plan for MON 863 has been designed with input from key stakeholders, including academic, government and industry scientists, crop consultants and growers.  The interim plan does not rely on reduced adoption rates as an MM strategy, as this approach would limit grower access to a safe, simple and effective alternative to current pest management practices that rely heavily on insecticide use.  An appropriate resistance management plan can be developed for products of any dose level.  When a mathematical model was applied to MON 863 and CRW Using conservative low to moderate dose parameters and assuming incomplete adoption of MON 863 during the interim period, the durability of MON 863 was predicted to extend beyond 15 years.

The applicant responds to the question of whether an IRM strategy designed for western and northern corn rootworm is applicable to other corn rootworm species stating that there are subtle differences in the biology of the corn rootworm species targeted by this product, but they should not be at any greater risk for resistance development during the period that this interim plan is in effect. The applicant adds that the western corn rootworm is the most abundant species where this technology will be used and has shown the greatest propensity for developing resistance to other insect control practices. Section 1.1 1  12 EPA's Response The Agency agrees with the comments provided by Monsanto and summarized above with one exception ( see BRAD Insect Resistance Management Chapter). It is unknown whether the current IRM plan will extend the durability of MON 863 for 15 years. Based on the current simulation models that utilize conservative input parameters, a 20% refuge will extend the durability of MON 863 corn for 7 to 16 years ( see BRAD Simulation Models of Resistance Section pp. IID 5 to IID 8). In addition, the Agency recommends gathering more information on biology of all corn rootworm species and subspecies to verify that the IRM strategy is appropriate for western, Mexican and northern corn rootworm.

1.1 Refuges General Public Comments Several commenters addressed the issue of overall adequacy of the IRM plan. One commenter states that the applicant may underestimate the rate of MON 863 adoption by farmers, has not considered the possible impact of gene stacking on the efficacy of its IRM plan, and does not assure that farmers will adequately comply with IRM plan requirements. The commenter further states that the IRM plan should consider all possible means to prevent resistance and not be limited to the refuge strategy, in particular soybean/ corn rotations should be considered.

Another commenter states that the interim IRM plan is flawed and describes shortcomings, including dependence on the marketplace to dictate refuges, an inadequate 20 percent grower established refuge, an incorrect definition of resistance, inadequate requirements for treating refuges, and doubtful assumptions about impacts of MON 863 on continuous corn acreage. The commenter adds that, despite slow penetration of the market overall, some areas may have adoptions as high as 80 percent of corn acres so that the defacto unstructured refuges the applicant is counting on would be lost. The commenter believes it is inappropriate to implement a resistance management plan that relies on the marketplace to ensure low adoption and states that a 20 percent refuge may allow faster than predicted resistance evolution.

Another commenter states that IRM must be closely monitored and supports the proposal for 20 percent refuge within the same field or adjacent field with similar cropping patterns. The commenter also notes that farmers will likely apply insecticide in the refuges and states that refuge requirements that minimize the handling of insecticides would be beneficial. The same commenter states that crop rotation is determined by many factors and suggests that planting adjacent fields with similar cropping patterns could present problems.

The applicant describes alternative strategies and available control tactics considered in the proposed IRM plan, noting that growers will have a variety of pest management options limiting selection pressure on corn rootworm populations. The applicant also states that other management options will prevail initially due to limited availability of seed and grower trials.

In response to requests for discussion on whether the refuge strategy is adequate to delay resistance, the Section 1.1 1  13 applicant states that the IRM plan has been rigorously examined by experts and that the conservative nature of the plan is further reinforced by limited initial adoption and conservative estimations of durability. The applicant quotes the SAP report and a letter submitted by NCR 46 both endorsing the plan.

EPA's Response The Agency realizes that grower adoption rates may be underestimated. Therefore, the simulation models and overall IRM strategy were considered on the basis of 100% grower adoptions which is clearly an overestimation. In addition, corn/ soybean rotations versus continuous corn is considered by the simulation models ( see BRAD Simulation Models of Resistance Section pp IID 5 to IID 8). Since continuous corn would be a worst case scenario, the models indicate that a 20% refuge is adequate to delay resistance so a corn/ soybean rotation requirement is not needed. The Agency agrees with the comment that a 20% refuge planted adjacent to or within fields is adequate to delay resistance and that it is acceptable to apply soil applied insecticides to refuge acres to control immature corn rootworm ( See BRAD Refuge Section pg. IID 9). The Agency based this recommendation, in part, on simulation models utilizing conservative parameters ( see BRAD Simulation Models of Resistance Section pp IID 5 to IID 8). The Agency also recognizes the need to monitor for resistance; therefore, a resistance monitoring program is required as part of the MON 863 IRM strategy ( see BRAD Monitoring for Resistance Section pp. IID 9 to IID 10). Since this registration is for Cry3Bb1 expressed in MON 863 corn, stacked genes were not considered.

Dose Public Comments One commenter believes the high dose refugia model proposed by the applicant may not be appropriate because MON 863 does not deliver a high dose.

The applicant responds to questions about the rationale supporting the commercialization of a low tomoderate dose product by describing dose considerations. The applicant states that other factors, including pest biology, refuge size, refuge proximity, agronomic practices and grower behavior were also considered. The applicant adds that considering these factors, the proposed IRM plan is conservative and acceptable for reducing pest adaptation during the interim period and beyond.

EPA's Response The Agency agrees that a high dose/ refuge model is not appropriate for MON 863 corn since there is not a " high dose" of Cry3Bb1 expressed ( see BRAD Dose Section pp. IID 4 to IID 5). The Agency also agrees that pest biology, refuge size, refuge proximity, agronomic practices and grower behavior are important factors to be considered in an IRM plan ( see BRAD Refuge Section pg. IID 9). The IRM strategy currently recommended is based on conservative parameters and current knowledge of corn rootworm biology ( see BRAD Pest Biology Section pp. IID 2 to IID 4 and Simulation Models of Resistance Section pp IID 5 to IID 8).

Control for Refuges Section 1.1 1  14 Public Comments A few commenters addressed the control strategies for refuge corn. One commenter states that the IRM lacks detailed requirements ensuring the appropriate makeup and treatment of refuges. The commenter offers several suggestions for the IRM plan, including restricting plantings to no more than 25 percent of the corn acreage in a county, requiring at least 30 percent non Bt refuges to accompany MON 863 plantings, and requiring that refuges be planted with nonCry 3Bb corn. Another commenter is concerned that farmers use the same methods to grow MON 863 as refuge corn, including crop rotation history, to ensure that pest management practices on the refuge are compatible with the IRM plan. One commenter states that the IRM plan would include 20 percent refuges, and that growers would have the option to both plant insecticide treated seed and spray insecticides.

In response to a question about how insecticide use in the refuge and/ or Bt fields affects the predictions of time to resistance, the applicant states that empirical evidence suggests that insecticides do not consistently increase or decrease the number of surviving insects and so would not alter the model predictions. Responding to a request to comment on what conditions would allow insecticide use in refuges, the applicant states that use of insecticides is essential to avoid excessive plant lodging and yield loss in the refuge.

One commenter disputes the assumption that a majority of refuge acres will not be treated and states that corn rootworm control is not compatible with refuge management unless it is applied to both refuge and transgenic areas. The commenter also states that refuge design should include consideration of the amount and spatial distribution of refuge plus the potential effect management practices may have on the abundance and relative phenology of susceptible beetles.

EPA's Response Although the Agency agrees that a refuge should be planted with non Cry3Bb corn, the Agency has determined that a 20% refuge is adequate to delay resistance. The Agency also agrees that the same methods to grow MON 863 as refuge corn, including crop rotation history, should be implemented. In addition, the Agency recognizes the growers need to treat refuges to control corn rootworm larvae and to treat MON 863 corn and refuges to control pests other than the corn rootworm. Therefore, seed and granular insecticide treatments to control corn rootworm larvae are acceptable on refuge acres. However, it is not acceptable to treat refuges for adult CRW control since these treatments may diminish the effectiveness of the refuge. If growers spray their corn fields with insecticides to control pests other than corn rootworm, then all acres ( Bt and non Bt) should be treated identically ( see BRAD Refuge Section pg. 9).

Row Strips Public Comments One commenter states that for block refuges planted within a field and at different locations each year, the development of resistance should be closer to that simulated with refuges as row strips and describes supporting data from a 2001 study by Onstad et al. Section 1.1 1  15 Responding to questions about the adequacy of in field row strips and/ or immediately adjacent blocks to delay resistance during a three year period, the applicant states that both options can be used and should be available to growers. For the width of in field strips, the applicant recommends at least four to six rows wide. The applicant adds that this width is appropriate for corn rootworm and provides flexibility for growers, but is the least favored option.

EPA's Response The 2001 Onstad et al. publication was considered in the development of an IRM strategy for MON 863 corn ( see BRAD Simulation Models of Resistance Section pp IID 5 to IID 8). The Agency agrees that adjacent block or in field strips are acceptable options that should be available to growers. In addition, the Agency is recommending that refuges be planted as at least six consecutive rows ( see BRAD Refuge Section pg. IID 9).

Hosts Public Comments Regarding EPA's conclusion that alternate hosts should not be considered and refuges should only consist of non Bt corn, the applicant states that further information is needed to assess the relative value of noncorn host plants, thus they have not been included as refuge in the IRM plan.

EPA's Response The Agency agrees that, based on current information, non corn hosts are not acceptable refuges and that further information is needed to assess the relative value of alternate host plants ( see BRAD Refuge Section pg. IID 9).

Refuge Research Needs Public Comments In response to questions about research needed to determine placement of non Bt corn refuges, the applicant states that the most important research need is to understand insect plant interactions and dispersal under large scale field conditions. The applicant adds that data has only recently been generated on adult and larval dispersal with MON 863 in the laboratory, but researchers are developing techniques to study dispersal of corn rootworm populations under commercial conditions.

In response to questions about additional data needs on mating habitats, ovipositional patterns, number of times a female can mate and fecundity, the applicant states that research to date with MON 863 has shown that changes in the sex ratio among survivors will eliminate a large number of potential matings of resistant individuals, and that emergence delays of approximately ten days will increase the likelihood that resistant females would mate with susceptible males dispersing from nearby refuges. The applicant further states Section 1.2 1  16 that research suggests that males dispersing from nearby refuges will already be present in large numbers and compete favorably with any resistant males emerging from the MON 863 field, thereby reducing the likelihood of resistance development.

EPA's Response The Agency agrees that more information is needed on corn rootworm adult and larval movement to verify the appropriate placement of refuges. In addition, more information is needed on dispersal, mating and ovipositional patterns, fecundity and sex ratio ( see BRAD Conclusions and Recommendations Sections IID 14 to IID 17).

1.2 Resistance Defined General Public Comments One commenter states that the plan's definition of resistance is incorrect. The commenter states that the definition is similar to that used for high dose Bt crops and is not appropriate for MON 863, and that the definition is more applicable to field failure. The commenter also states that resistance is determined by both the LC50 of the line and the slope of the concentration survival curve, not just by the LC50.

In response to a request for discussion of an appropriate method of determining suspected and confirmed resistance for CRW, the applicant states that Monsanto will investigate reported instances of product failure and that cases of suspected resistance will undergo laboratory dose response and whole plant assays. The applicant indicates that a mitigation plan will be implemented if resistance is confirmed.

The applicant responds to requests for comment on the product duration or longevity of CRW susceptibility considered in IRM models by identifying principle factors influencing the rate of resistance development, but noting that current models do not incorporate all the factors. The applicant also notes that the longevity of any management tool is dependent upon the extent of grower adoption, the effectiveness of the IRM plan, the use of alternative management strategies, the relative fitness of resistant genotypes, and the extent of grower compliance with IRM requirements, all of which are also missing from current models. The applicant adds that current models do not incorporate current or future management options, and therefore overestimate the risk of resistance.

The applicant also addresses the question of how insecticide use in the refuge and/ or Bt fields affects the predictions of time to resistance, stating that empirical evidence suggests that insecticides do not consistently increase or decrease the number of surviving insects and so would not alter the model predictions.

The applicant addresses requests for a discussion on whether root ratings are an appropriate indicator of suspected resistance, noting that unexpected high levels are one indicator, but that growers will more likely report unacceptable levels of plant lodging as product failure. Section 1.2 Section 1  17 In response to a request for discussion on the applicability of the three models for assessing the likelihood of CRW developing resistance, the applicant states that the models developed by Drs. Andow and Onstad have been useful for prioritizing research but they have not been useful for predicting CRW resistance to MON 863. The applicant adds that the models were developed to help guide the research program and to develop the IRM strategy, but their predictions must be viewed cautiously. The applicant states that the model developed by Dr. Caprio was used to evaluate the durability of MON 863 in a qualitative sense by examining the relative impact of parameters tested in the other models, parameter values based on the properties of MON863, and conservative estimates of adoption, dose and refuge size. The applicant also provides further information on the goals and outcomes of this model. The applicant listed conservative assumptions used in all three models.

EPA's Response On August 28 and 29, 2002 the Agency convened a FIFRA Scientific Advisory Panel ( SAP) to provide expert input regarding IRM of MON 863 corn. The SAP did not recommend including slope as a definition of resistance. The nature of resistance takes many forms, with important factors considered such as behavioral resistance and physical size that may not relate to the slope of an LC50. For instance, corn rootworm that are physically larger than others may take longer to be affected ( behavior and/ or sublethal and non lethal changes) but have the same slope or the survival in a dietary toxicity study. The Agency does not want to restrict the definition of resistance to exclude these factors, especially for a pest which has already shown behavioral adaptation to cultural control techniques.

The initial observation of unexpected CRW damage or suspected resistance will likely occur by the grower. Unexpected damage will probably be observed as lodged corn plants. Resistance should be confirmed by a standard diet bioassay or evaluation of root node injury. An insect diet bioassay with the Cry3Bb1 protein that results in a LC50 that exceeds the upper limit of the 95% confidence interval of the LC50 established from baseline measurements of susceptible populations could be used to confirm resistance. Alternatively, resistance may be confirmed when one or more root nodes of at least 50% of Cry3Bb1 plants grown in the laboratory are destroyed. Once resistance has been confirmed, mitigation measures must be immediately implemented ( see BRAD Remedial Action Section pp. IID 11 and IID 12).

A model was run by Monsanto that utilized conservative parameters including an initial resistance allele frequencies of .01 and .001, RS dominance values of 0.7 and 0.8 and SS survival ranging from 0.1 to 0.8. Results of the model incorporating these conservative input parameters ( e. g., initial allele frequency = .01; RS dominance value = 0.8; SS survival = 0.1) suggested that CRW resistance to Cry3Bb1 will not occur for at least seven years assuming 100% MON 863 market penetration and 100% IRM compliance ( see BRAD Simulation Models of Resistance Section pp. IID 5 to IID 8). Section 1.3 Section 1  18 1.3 IRM Plan General Public Comments One commenter believes corn rootworm protected corn provides an ideal fit with current integrated pest management ( IPM) recommendations for corn rootworm control. Another commenter encourages producers to implement IRM plans when planting corn rootworm protected corn. Another commenter states that Monsanto recognizes the need for IRM plans and intends to deploy IRM plans involving structured refuges at the time of commercialization.

One commenter points out that there will always be non target effects, but states that most of the significant questions have been addressed. The commenter also states that positive and negative impacts must be compared with those of existing technologies.

One commenter states that any resistance management plan must be effective against all corn rootworm species, applicable to a wide variety of corn production systems, and readily implementable by the farmers. The commenter believes the IRM plan meets these requirements, but should address the unique challenges posed by Cry3Bb, corn rootworm biology and ecology, and corn rootworm management. The commenter notes that future events may be high dose and require different IRM plans.

The applicant quoted the SAP report and noted that, in addition to the recommendation of refuge plus high dose strategy, the Subpanel emphasized the need for flexibility in resistance management plans based upon pest biology, the nature of the response to the Bt crop and economic and logistical feasibility. The applicant also noted that the IRM plan has been designed with input from academic stakeholders, government and industry scientists, crop consultants, and growers and will evolve over time as new information is developed.

The same commenter recommends that EPA proceed in its review of MON 863 with the assistance of the SAP in establishing performance standards. The commenter believes acceptable performance standards might include: 1) expression levels in root that are ten times or more higher than in other tissues; 2) full sequencing of transgenes as expressed in the plant to serve as a baseline in assessing gene silencing and instability of transgene expression over multiple generations; 3) Understanding the genetics of resistance in pests and submission of an IRM plan with a solid prospect of preventing resistance; 4) at least a 10 fold " Margin of Exposure" for all nontarget organisms based on plausible worst case assumptions regarding exposures; and 5) clear delineation of responsibilities for assuring compliance with IRM plans.

EPA's Response Monsanto intends to encourage stakeholders such as growers, Extension Agents and crop consultants to promote and practice IPM. For instance, scouting fields in the Fall will be encouraged and planting MON 863 on acres with the highest risk of damage will be promoted ( MRID 455770 01).

The Agency realizes more research is needed to determine if IRM strategies designed for western corn Section 1.3 Section 1  19 rootworm and northern corn rootworm are appropriate for Mexican corn rootworm. Therefore, research on various aspects of corn rootworm pest biology as it relates to a long term IRM strategy will be conducted during the interim MON 863 registration ( see BRAD Recommendations Section pp. IID 16 and IID 17).

The Agency agrees with the August 2002 SAP that there is a need for flexibility in an IRM plan. Therefore, two refuge options are considered acceptable; refuges may be planted as in field strips or adjacent blocks ( see BRAD Refuge Section pg. IID 9).

The Insect Resistance Management chapter of the MON 863 BRAD summarizes the Agency's reviews of Monsanto's interim IRM plan. The IRM chapter also includes recommendations for research needed during the interim registration that will help verify whether a 20% refuge is adequate to delay resistance ( see BRAD Recommendations Section pp. IID 6 and IID 17).

IRM Inadequacies Public Comments Several commenters identified specific inadequacies with the IRM plan. One commenter states that the applicant may underestimate the rate of MON 863 adoption by farmers, has not considered the possible impact of gene stacking on the efficacy of its IRM plan, and does not assure that farmers will adequately comply with IRM plan requirements. The commenter further states that the IRM plan should consider all possible means to prevent resistance and not be limited to the refuge strategy, in particular soybean/ corn rotations should be considered.

Another commenter states that the interim IRM plan is flawed and describes shortcomings, including dependence on the marketplace to dictate refuges, an inadequate 20% grower established refuge, an incorrect definition of resistance, inadequate requirements for treating refuges, and doubtful assumptions about impacts of MON 863 on continuous corn acreage. The commenter further believes EPA should require Monsanto to expand and revise the interim IRM plan and correct deficiencies, such as incomplete monitoring and mitigation plans, incorrect definition of resistance, failure to address northern corn rootworm resistance issues, and lack of modeling to address the use of insecticides on a non high dose refuge. The commenter further suggests that EPA require Monsanto to conduct statistically valid research and modeling to fill gaps.

The commenter also identifies the following flaws with the IRM plan: 1) lack of modeling results that address the use of insecticide on the non high dose refuge; 2) lack of clear connections between grower education efforts and the implementation of the IRM plan; 3) failure to address resistance issues associated with the northern corn rootworm; and 4) inadequately developed monitoring and mitigation plans.

The same commenter believes the applicant's claim that the IRM plan is conservative may be misleading in some instances. In particular, the commenter states that Monsanto claims that the lack of beetle exposure to Cry3Bb1 in sprays means no prior selection for resistance. The commenter adds that this observation does affect an underlying assumption concerning frequency of resistance in a non conservative direction, leading to the potentially misleading assumption that resistance is rarer than it might actually be. Also, the commenter states that Monsanto implies that CRW resistance to MON 863 will take at least as long, if not Section 1.3 Section 1  20 longer, to develop, particularly in light of adoption of IRM plans, however, similar CRW survival levels in the presence of chemical insecticides will likely be higher for Bt than for insecticides given the same level of survival, and therefore evolution of resistance to Bt will be faster. The commenter also states that the claim that mortality caused by other environmental factors will exert stronger selective pressure on corn rootworm than MON 863 is faulty because a strong mortality force is not necessarily a strong selective force.

Another commenter refers to recently published research on design features of Bt transgenic crop resistance management plans and states that it raises unique challenges in the case of corn rootworm. According to the commenter, the research shows that refuges need to be separate from crop fields and that spraying of refuges undermines their effectiveness. The commenter notes that mating occurs during the adult stage of the rootworm life cycle in the summer months, but that few farmers spray cornfields in the summer for adult corn rootworms.

Two commenters contrasted ECB and corn rootworm resistance management. One commenter states that EPA should consider the impact of spraying refuge acres for ECB to the corn rootworm resistance management plan. Another commenter states that in contrast to ECB larval movement, corn rootworm larval movement is limited in the soil and may permit closer integration of transgenic and non transgenic corn in IRM plans. The same commenter notes that migratory behaviors for ECB and corn rootworms have implications on the selection for resistance, its spread and the design of IRM plans. The commenter encourages the development of corn rootworm specific IRM plans including refuge options, without defacto acceptance of the ECB plan. The same commenter recommends that the IRM plan require that the refuge occur in the same field as the transgenic crop.

The applicant responds to comments suggesting there is insufficient data to support the proposed IRM plan by stating that the plan includes extensive input and research by CRW experts from academic laboratories across the U. S. The applicant states that this input, consideration of currently available data, and the conservative nature of the plan provide a reasonable and appropriate strategy for limiting pest adaptation during the interim period. The applicant adds that the proposed IRM plan is intended to evolve over time based on the latest scientific information.

EPA's Response The Agency realizes that grower adoption rates may be underestimated. Therefore, the simulation models and overall IRM strategy were considered on the basis of 100% grower adoptions which is clearly an overestimation. In addition, corn/ soybean rotations versus continuous corn is considered by the simulation models. In general, the current simulation model summarized in the Insect Resistance Management Chapter of the MON 863 BRAD is based on conservative parameters and verifies that a 20% refuge is adequate to delay resistance during the interim registration ( see BRAD Simulation Models of Resistance Section pp IID 5 to IID 8). In addition, details of the monitoring for resistance, remedial action and grower education and compliance plans can be found in the IRM chapter. During the interim registration, the Agency has requested Monsanto develop methods to improve these areas of their IRM plan.

Corn rootworm biology was considered in developing the IRM plan for MON 863 corn ( see BRAD Pest Biology Section pp. IID 2 to IID 4). In addition, the Agency recommends gathering more information on Section 1.3 Section 1  21 biology of all corn rootworm species and subspecies to verify that the IRM strategy is appropriate for western, Mexican and northern corn rootworm.

The Agency requires that same methods to grow MON 863 as refuge corn, including crop rotation history, should be implemented. In addition, the Agency recognizes the growers need to treat refuges to control corn rootworm larvae and to treat MON 863 corn and refuges to control pests other than the corn rootworm. Therefore, seed and granular insecticide treatments to control corn rootworm larvae are acceptable on refuge acres. However, it is not acceptable to treat refuges for adult CRW control since these treatments may diminish the effectiveness of the refuge. If growers spray their corn fields with insecticides to control pests other than corn rootworm, then all acres ( Bt and non Bt) should be treated identically ( see BRAD Refuge Section pg. IID 9).

Resistance should be confirmed by a standard diet bioassay or evaluation of root node injury. An insect diet bioassay with the Cry3Bb1 protein that results in a LC50 that exceeds the upper limit of the 95% confidence interval of the LC50 established from baseline measurements of susceptible populations could be used to confirm resistance. Alternatively, resistance may be confirmed when one or more root nodes of at least 50% of Cry3Bb1 plants grown in the laboratory are destroyed. Once resistance has been confirmed, mitigation measures must be immediately implemented ( see BRAD Remedial Action Section pp. IID 11 and IID 12). The Agency also recognizes the need to monitor for resistance; therefore, a resistance monitoring program is required as part of the MON 863 IRM strategy ( see BRAD Monitoring for Resistance Section pp. IID 9 to IID 10). Since this registration is for Cry3Bb1 expressed in MON 863 corn, stacked genes were not considered.

Growers should be required to sign a technology use agreement that outlines IRM requirements and acknowledges the growers responsibility to comply with them on an annual basis. The agreement will also state that growers received the Product Use Guide. This agreement may be a section of the growers order sheet or some other document or format ( see BRAD Grower Education and Compliance Section pp. IID 12 and IID13).

Dose Public Comments One commenter states EPA should reject Monsanto's IRM plan because it relies on an unacceptable lowto moderate toxin dose. The commenter further states that the IRM would include 20 percent refuges and growers would have the option to both plant insecticide treated seed and spray insecticides for corn rootworms or cutworms. The commenter believes that the applicant ignores recommendations from the SAP for high dose refuge strategies.

One commenter believes the high dose refugia model proposed by the applicant may not be appropriate because MON 863 does not deliver a high dose.

EPA's Response The high dose/ refuge strategy recommended by the February 1998 SAP was developed for lepidopteran Section 1.3 Section 1  22 active Bt corn. The August 2002 was convened to address MON 863 corn and identified MON 863 corn as a non high dose product. The SAP acknowledged that "[ d] ose, as related to selection intensity, is important in determining appropriate refuge size." The Panel did not state that a high dose was necessary for corn rootworm active Bt corn. Since there in not a high dose of Cry3Bb1 to control corn rootworm in MON 863 corn, the high dose/ refuge strategy does not apply.

Durability Public Comments One commenter objects to the 15 year goal for product durability and states that the only prudent goal for an IRM plan is to prevent resistance.

The applicant responds to requests for comment on the product duration or longevity of CRW susceptibility considered in IRM models by identifying principle factors influencing the rate of resistance development, but noting that current models do not incorporate all the factors. The applicant also notes that the longevity of any management tool is dependent upon the extent of grower adoption, the effectiveness of the IRM plan, the use of alternative management strategies, the relative fitness of resistant genotypes, and the extent of grower compliance with IRM requirements, all of which are also missing from current models. The applicant adds that current models do not incorporate current or future management options, and therefore overestimate the risk of resistance ( See BRAD Simulation Models of Resistance Section pp. IID 5 to IID 8).

EPA's Response An IRM strategy is not intended to prevent resistance for an indefinite period of time. An IRM strategy is intended to delay resistance. Based on the conservative parameters used in simulation models, a 20% refuge will delay corn rootworm resistance to MON 863 corn for at least seven to sixteen years. Since the models assume 100% market penetration and are based on conservative parameters, it is likely that resistance will be delayed longer than seven to sixteen years. Based on these models, the Agency has determined the a 20% refuge is adequate to delay resistance during the interim registration period.

Compliance Public Comments One commenter states that the IRM provisions to ensure compliance are inadequate. The commenter does not believe grower education is adequate to ensure compliance and that additional actions including penalties are needed. The same commenter states that the applicant's IRM plan should incorporate previously submitted recommendations for improving compliance. The commenter believes the applicants mitigation strategies to delay the spread of resistance are inadequate and suggests a more comprehensive national IRM plan is needed.

EPA's Response Section 1.3 Section 1  23 Growers are perhaps the most essential element for the implementation and success of any IRM plan as they will ultimately be responsible for ensuring that refuges are planted according to guidelines and that Bt fields are monitored for unexpected pest damage. Therefore, a program that educates growers as to the necessity of IRM and provides guidance as to how to deploy IRM should be an integral part of any resistance management strategy. The October 2000 SAP also suggested that a comprehensive education program may help increase IRM compliance. Ideally, the educational messages presented to growers should be consistent ( among different registrants if applicable for CRW) and reflect the most current resistance management guidelines. Specific examples of education tools for growers can include grower guides, technical bulletins, sales materials, training sessions, Internet sites, toll free numbers for questions or further information, and educational publications.

To avoid confusing or discouraging growers, new IRM programs should be kept simple and consistent with existing programs so that growers will not be discourage from properly implementing IRM or from growing transgenic crops. Growers should be required to sign a technology use agreement that outlines IRM requirements and acknowledges the growers responsibility to comply with them on an annual basis. The agreement will also state that growers received the Product Use Guide. This agreement may be a section of the growers order sheet or some other document or format. An annual industry supported survey conducted by a third party should be submitted to the Agency as a tool to monitor grower compliance. Additional education efforts should target non compliant growers and access to the technology will be limited for growers found to be non compliant ( see BRAD Grower Education and Compliance Section pp. IID 12 and IID 13).

Adoption Rates Public Comments One commenter states that, despite slow penetration of the market overall, some areas may have adoptions as high as 80 percent of corn acres so that the de facto unstructured refuges the applicant is counting on would be lost. The commenter believes it is inappropriate to implement a resistance management plan that relies on the marketplace to ensure low adoption and states that a 20 percent refuge may allow faster than predicted resistance evolution. The same commenter disputes the assumption in the IRM plan about MON 863' s effect on acreage of continuous corn. The commenter believes incentive payments for corn production will prove attractive to many farmers and that more continuous corn will increase populations of some rootworm species.

In response to suggestions that EPA should mandate local sales limits or caps to assure sufficiently low market penetration, the applicant states that the interim plan does not rely on reduced adoption rates as an IRM strategy, but instead considers that incremental adoption during the interim period reduces selection pressure and limits pest adaptation while additional research focused on CRW biology and insect plant interactions is underway. The applicant adds that it typically requires several years before grower demand and seed availability allow for peak adoption.

In response to the question of whether there should be limitations on acres planted while the interim IRM plan is in place, the applicant states that acreage limitations are not appropriate and notes that conservatism is already built into the plan. Section 1.3 Section 1  24 EPA's Response The Agency agrees that a resistance management plan should not be based on potential market penetration. Therefore, the simulation models of resistance that demonstrate the adequacy of a 20% refuge are based on 100% adoption of MON 863 by corn growers ( see BRAD Simulation Models of Resistance Section pp. IID 5 to IID 8).

The 2002 SAP suggested limiting sales of MON 863 for IRM purposes to an on farm level rather than by region, state or county. The Agency has concluded that additional acreage limitations of MON 863 beyond the 20% refuge requirement are not necessary during the three interim period.

Conditional Registration Public Comments One commenter notes that the IRM may not be complete with respect to factors that could influence resistance evolution, but states that the conditional registration will allow the scientific community to begin addressing critical issues. The commenter states that revisions can be made to the plan should future information reveal inadequacies.

Another commenter supports a conditional registration and believes that enough biological information is available to support the revised IRM plan on an interim basis. The commenter also believes the IRM plan should be biologically responsible and have the end user in mind. The commenter states that conditional registration would allow farmers to gain experience with technology on a limited basis and permit IRM adjustments to be made to address the needs of end users.

EPA's Response The Agency agrees with these comments. Section 1.4 Section 1  25 1.4 Data Needs and Methods General Public Comments One commenter is concerned that EPA is relying too heavily on data provided by proponents of biotechnology. Another commenter states that the applicant has not developed the data necessary for a long term, effective IRM plan. The commenter believes data is lacking in a number of areas, including the dispersal of adult CRW, the feeding behavior of larvae, the effective dose of MON 863, and rootworm genetics. The same commenter recommends that EPA require the applicant to expand and revise the interim IRM plan to correct deficiencies, such as incomplete monitoring and mitigation plans, incorrect definition of resistance, failure to address northern corn rootworm resistance issues, lack of modeling to address the use of insecticides on a non high dose refuge. The commenter also recommends EPA require the applicant to conduct statistically valid research and modeling to fill gaps that prevent the development of effective, long term IRM plans.

One commenter working in an academic environment concedes that there are environmental, ecological, and resistance concerns associated with the introduction of Cry 3Bb transgenic corn. The commenter notes, however, that the same is true for any pest control technology and that researchers are generating data addressing these concerns. The same commenter states that the next step for gathering data on product performance, nontarget impacts, and resistance potential is on farm trials, which are only possible with product registration.

EPA's Response The Agency has determined that a 20% non Bt corn refuge planted adjacent to or within fields will ensure resistance does not develop during the interim registration. The Agency's conclusion is based on information provided by the registrant, public comments, published research, communication with expert researchers from universities and the August 2002 SAP. During the interim registration period, Monsanto will develop the necessary data to verify that the current IRM plan will ensure that resistance is delayed ( see BRAD Conclusions and Recommendations Sections pp. IID 14 to IID17). The Agency expects that this data will be developed by Monsanto's research scientists as well as university collaborators. For all pesticide registrations, it is the registrants responsibility to provide appropriate data to the Agency to support the registration.

Protein Expression Public Comments One commenter states that Monsanto's intentions are unclear regarding future combinations of the Cry 3Bb gene with the Cry 1Ab, Cry 1Ac, or other Cry proteins for European corn borer ( ECB) control. The commenter provides suggestions for combinations and engineered expressions and states that the alternative strategies would have profoundly different regulatory consequences. The commenter notes that one alternative crossing parental lines each with a single Cry gene would not be subject to regulatory review Section 1.4 Section 1  26 since no new genetic transformation event would be used, but that another alternative of a single event expressing two Cry proteins would require the development and review of new data. The commenter believes these different regulatory consequences provide evidence that the regulations are out of step with the practical applications of biotechnology and states that EPA should clarify additional data and regulatory review that may be needed.

EPA's Response This registration only addressed Cry3Bb1 expressed in field corn. Therefore, stacked products were not considered.

Original Data Public Comments Another commenter notes that the plan assumes universal applicability to all species and strains of corn rootworms despite biological and ecological differences. The commenter adds that the majority of research has been conducted on western corn rootworms in classical continuous corn situations and that less information is available on northern corn rootworms in classic or extended diapause situations. The same commenter suggests that differences between ECB and corn rootworms support the development of corn rootworm specific resistance management plans. The commenter states that further research is required to develop a robust IRM plan and provides a list of specific topics that should be explored.. The same commenter adds that interim registration is needed to generate necessary data to develop a more robust IRM plan. The commenter notes that IRM models are untested and have not been validated, but states that the revised IRM plan provides the flexibility needed to evaluate IRM deployment strategies and to address rootworm biology questions on a commercial scale. The commenter also identifies additional data needs.

EPA's Response The Agency recommends gathering more information on biology of all corn rootworm species and subspecies to verify that the IRM strategy is appropriate for western, Mexican and northern corn rootworm. Since MON 863 corn will not be labeled for southern corn rootworm, it is not considered in the IRM strategy. Additional research needs are outlined in the Conclusions and Recommendations Sections of the IRM chapter in the MON 863 BRAD ( pp. IID 14 to IID 17).

Resistance Public Comments Another commenter states that the applicant's definitions of resistance are inappropriate and should be defined using slope and LC50, as well as increased CRW survival on MON 863 corn compared to nonresistant CRW. Another commenter cites a 2002 report recommending continued research on management strategies to slow the development of resistance to new and existing pest control tools.

The applicant addresses the request for comment on the appropriateness of the following input parameters Section 1.4 Section 1  27 of these simulation models for CRW protected field corn: resistance allele frequency, dominance of the heterozygote, movement of the males and females, mating and ovipositional behavior and other genetic and behavioral parameters. The applicant states that these parameters have been incorporated into models, but urges caution in using models for predicting product longevity. The applicant adds that some of the parameters can be estimated based upon available MON 863 data but other parameters can only be input based upon conservative assumptions.

In response to a request for comment on the Agency's conclusions regarding refinements to Monsanto's resistance monitoring program, the applicant described the components of the monitoring plan for MON 863. The applicant also stated that populations have already been assayed and monitoring following commercialization will include dose response assays in high adoption areas. The applicant also states that the monitoring plan addresses collection, assay techniques, and expenses. The applicant notes that interpreting results from laboratory colonies has limitations.

EPA's Response The August 2002 SAP did not recommend including slope as a definition of resistance. The nature of resistance takes many forms, with important factors considered such as behavioral resistance and physical size that may not relate to the slope of an LC50. For instance, corn rootworm that are physically larger than others may take longer to be affected ( behavior and/ or sublethal and non lethal changes) but have the same slope or the survival in a dietary toxicity study. The Agency does not want to restrict the definition of resistance to exclude these factors, especially for a pest which has already shown behavioral adaptation to cultural control techniques.

The Simulation Models of Resistance Section of the IRM chapter in the MON 863 BRAD summarizes the parameters included Monsanto's modified Caprio model ( pp. IID 5 to IID 8). These parameters are considered conservative and verify that a 20% refuge will delay corn rootworm resistance to MON 863 corn for at least seven to sixteen years.

To ensure a case of resistance is identified a resistance monitoring plan is required by the Agency ( see BRAD pp. IID 9 to IID 10 for details on resistance monitoring). Detecting shifts in the frequency of resistance genes ( i. e., susceptibility changes) through resistance monitoring can be an aggressive method to detect the onset of resistance before widespread crop failure occurs. As such, the utilization of sensitive and effective resistance monitoring techniques is critical to the success of an IRM plan. Monitoring techniques such as discriminating dose concentration assays need to be thoroughly investigated for corn rootworm species for their feasibility as resistance monitoring tools. Section 1.5 Section 1  28 1.5 Expression Levels General Public Comments Commenters state that characterizing the expression levels as " moderate to low" is misleading. These commenters said that, from the perspective of likely environmental impacts and potential food safety risks, the expression levels are actually very high. One commenter states that, because the expression levels are " moderate to low" and because the corn rootworm has already demonstrated its ability to quickly develop resistance to multiple pesticides, the proposed use of MON 863 guarantees the quick development of resistance to the Cry 3Bb proteins in corn rootworms.

The applicant responds to concerns that the characterization of Cy3Bb1 expression level in MON 863 as low to moderate dose is misleading with the following background information: It is inappropriate to make hazard and risk assertions based upon a comparison of the levels of Cry3Bb1 in MON 863 corn with Cry protein levels in other biotech crops because human and environmental safety must be examined on a case by case basis for each new plant incorporated protectant. Cry3Bb1 failed to produce any adverse effects in mammalian toxicity studies conducted at maximum attainable concentrations. It was on this basis that EPA established the tolerance exemption for Cry3Bbl in corn. All references by Monsanto to low or moderate dose have been made in the context of defining a strategy for insect resistance management. In the context of IRM, the level of Cry3Bbl protein expressed in MON 863 is not consistent with EPA's definition of " high dose"; therefore, MON 863 has been appropriately described as " low or moderate dose."

The applicant also states that MON 863 expresses Cry3Bb1 at much less than a high dose level and allows a large number of individuals to survive. The applicant also states that the large and highly variable impact of environmental conditions on CRW mortality means that the selection for physiological resistance to the Cry3Bb protein in MON 863 will likely be much less than would otherwise be expected. The applicant adds that IRM plans can be developed for products of any dose level.

The applicant also addresses questions about what techniques should be used to determine dose for Cry3Bb1, providing results of field studies showing a low to moderate dose and suggesting that dose can be assessed by examining adult emergence compared to conventional corn under field conditions, by comparing the level of Cry3Bb1 plant expression to the LC50 of purified protein determined from laboratory artificial diet bioassays, or by observing larval feeding behavior on MON 863 roots compared to conventional corn roots.

EPA's Response The August 2002 SAP has identified MON 863 corn as a non high dose product meaning there is not a high dose of Cry3Bb1 protein to control the corn rootworm. The SAP also stated that it does not matter if a product is a moderate or low dose; rather, a distinction should be made between high dose and non high dose products. Simulation models were created based on a non high dose product and verified that a 20% refuge will delay resistance ( see BRAD Simulation Models of Resistance Section pp. IID 5 to IID 8). The Section 1.5 Section 1  29 Agency agrees that it is inappropriate to make hazard and risk assertions based upon a comparison of the levels of Cry3Bb1 in MON 863 corn with Cry protein levels in other biotech crops; therefore, a risk assessment was conducted specifically for MON 863 corn.

Identifying the level of dose, as related to selection intensity, is crucial when determining size and structure of a refuge needed to delay CRW resistance to MON 863 corn. CRW feeding behavior and survival and root expression data can be used to identify the dose of MON 863.

According to the August 2002 SAP, comparing measures of fitness levels of susceptible homozygotes on MON 863 and non Bt corn would provide a good approximation of selection intensity. The SAP suggested that the first step in approximating selection intensity would be to measure efficacy of MON 863 corn against CRW larvae. However, the Panel pointed out that selection intensity based on larval efficacy may be underestimated if sublethal effects or fitness costs occur. Selection intensity based on larval survival may also be underestimated if density dependent mortality is occurring. Resistant colonies of CRW should be developed to aid in determining selection intensity ( see BRAD Dose Section pp. IID 4 and IID 5).


MEMORANDUM

DATE:	November 21, 2014

TO:	Carbon Power Plan for Existing Power Plants; Docket ID: OAR-2013-0602

FROM:	Rob Lawrence EPA/Region 6/PD

SUBJECT:	October 28, 2014 Call with the Public Service Company of New Mexico (PNM) regarding the Proposed Carbon Power Plan for Existing Power Plants

SUMMARY

A conference call was made by EPA to the Public Service Company of New Mexico on October 28, 2014, to discuss the proposed Carbon Power Plan for Existing Power Plants, which was proposed on June 2, 2014.

ATTENDEES

Participant:		Jeanette Pablo

EPA Participant:	Terry Johnson