## 4 Field Efficacy of RNAi for Insect Control, Insect Resistance Management, and RNAi Resistance
### Insect Resistance Management  
The U.S. EPA requires that registrants of PIPs, such as _Bt_ proteins and RNAi traits, complete and submit an IRM plan for the target pest before registration [149]. IRM is the scientific approach to delay the development of resistance in pest populations. SmartStax(r) PRO follows the IRM pyramiding strategy and expresses three different MOAs targeting WCR (_Dv5 nf7_ dsRNA, Cry3 Bb1 and Cry34 Ab1/Cry35 Ab1), and stacks traits against Lepidopteran pests (Cry1F, Cry2 Ab2, and Cry1A.105) and weeds (cp4/epsps (glyphosate resistance)). The IRM value of the pyramid is significantly reduced if individual components are deployed simultaneously, field-evolved resistance to one or more components is present, and/or cross-resistance between components is observed [150]. Confirmed WCR field-evolved resistance to Cry3 Bb1 and/or Cry34 Ab1/Cry35 Ab1 has been reported in some populations [21; 23; 24; 25; 26; 27; 28; 29; 30], which could potentially impact the IRM value of this new pyramid. After this product is commercially available, it will be essential to monitor changes in susceptibility to the three traits, particularly Cry3 Bb1 and Cry34 Ab1/Cry35 Ab1, to ensure durability of all traits in SmartStax(r) PRO.  
An important consideration for IRM with RNA-based traits is that, in contrast to _Bt_ proteins, larvicidal dsRNAs can cause mortality in adult WCR [75; 151; 152; 126]. The adult WCR RNAi response is rapid and can persist throughout most of the life stage. For example, knockdown of _Lac2_ generated 76% knockdown 10 hours after ingestion and 86% knockdown 20 days after ingestion [153]. Expression of _Dv5 nf7_ dsRNA occurs throughout the plant (event MON87411), including two tissues commonly consumed by adults in the field (e.g., pollen, leaves). However, the concentrations expressed _in planta_ are not sufficient to generate mortality in adults and will provide sublethal exposure (mean of 0.103 ng/g and 33.8 ng/g in fresh weight pollen and leaf tissue, respectively [154]; the LC\({}_{50}\) of _Dv5 nf7_ previously observed in WCR adults was 60.2 ng/cm\({}^{2}\)[151]). Therefore, adult sublethal exposure to _Dv5 nf7_ may have implications for resistance management by adding selection pressure benefiting resistant individuals or individuals with resistance alleles [155; 156]. Movement of adult WCR is common as maize phenology changes, with beetles searching for underdeveloped silks and pollinating maize as a primary food source [148]. Intrafield adult WCR movement could increase the likelihood of many individuals emerging from a single commercial maize field feeding on SmartStax(r) PRO tissue at some point during the life cycle, while interfield movement of adult WCR and subsequent feeding on these plants would increase the risk of exposure to sublethal concentrations of dsRNA [157]. No fitness costs were observed in WCR adults exposed to _Dv5c23_ dsRNA LC\({}_{25}\), suggesting that exposure to a sublethal concentration may not affect the fitness of exposed adults and their offspring [126]. However, due to the unique physiological effects of each dsRNA trait, future studies are important to determine the role sublethal exposure to _Dv5 nf7_ field-relevant concentrations will have on adult WCR.  
Reports of _Bt_ trait field-evolved resistance suggested that the high dose refuge (HDR) approach as a standalone IRM strategy was ineffective at delaying _Bt_ resistance in WCR. The most recent draft of the U.S. EPA's \"Framework to Delay Corn Rootworm Resistance\" requires incorporating integrated pest management (IPM) strategies into IRM plans to mitigate the spread of field-evolved resistance and minimize the risk of resistance evolution [158]. Suggested IPM strategies include crop rotation, rotation of PIP MOAs, adulticide application, and area-wide management [158]. Deploying this new dsRNA product within an IPM framework is necessary to increase trait durability and decrease the rate of resistance evolution [159].