Apis mellifera L. (HB) is the most influential pollinator in the world. HB colony decline worldwide has been associated to multiple stressors. The EFSA recently devised an integrated framework focused on developing a holistic approach to the risk assessments (RA) of multiple stressors on HB. It requests research data on the influence of genetic diversity on toxicological sensitivity at subspecies (SBP) level. HB is the model organism for RA studies, and there are at least 24 SBP described. Surprisingly, RA require no distinction among them. TOPRA-B will push the known boundaries of RA, by examining for the first time the genetic background of HB. Using 3 SBP and SNP markers, TOPRA-B will perform an innovative study connecting the genetic diversity in the cytochrome P450 to the pesticides and pathogens exposure in HBs. WP1 entails the application of bioinformatic tools on over 176 whole genome sequences owned by the host institution. WP2 will consists of designing the reduced assay from the list of SNPs generated in WP1. WP3 will consist of laboratory-based bioassays of exposure of bees to pesticides and pathogens, and by employing the link between genotypes to the phenotypic responses. The WPs will help solve four of the nine data gaps raised by the current RA, addressing the results for the EFSA’s policymakers. TOPRA-B brings a strong interdisciplinary, intersectoral and international framework. Since it will deal with the principal model organism of RA, the magnitude of this innovative technology and approach will be available worldwide with a high potential of being adopted for universal RA schemes. The importance of the results consists of the optimization of the current and future RA, and the efficiency in genotyping large sample sizes. TOPRA-B will be committed to the United Nations’ 2030 Agenda, lined with Sustainable Development Goals and European Green Deal.