title: An Integrated Experimental Design for the Assessment of Multiple Toxicological End Points in Rat Bioassays.
abstract: For nearly five decades long-term studies in rodents have been the accepted benchmark for assessing chronic long-term toxic effects, particularly carcinogenicity, of chemicals. The European Food Safety Authority (EFSA) and the World Health Organization (WHO) have pointed out that the current set of internationally utilized test methods capture only some of the potential adverse effects associated with exposures to these agents over the lifetime.
  
  
  
  In this paper, we propose the adaption of the carcinogenicity bioassay to integrate additional protocols for comprehensive long-term toxicity assessment that includes developmental exposures and long-term outcomes, capable of generating information on a broad spectrum of different end points.
  
  
  
  An integrated study design based on a stepwise process is described that includes the priority end points of the Economic Co-operation and Development and the National Toxicology Program guidelines on carcinogenicity and chronic toxicity and developmental and reproductive toxicity. Integrating a comprehensive set of relevant toxicological end points in a single protocol represents an opportunity to optimize animal use in accordance with the 3Rs (replacement, reduction and refinement). This strategy has the potential to provide sufficient data on multiple windows of susceptibility of specific interest for risk assessments and public health decision-making by including prenatal, lactational, neonatal exposures and evaluating outcomes over the lifespan.
  
  
  
  This integrated study design is efficient in that the same generational cohort of rats used for evaluating long-term outcomes can be monitored in satellite parallel experiments to measure biomarkers and other parameters related to system-specific responses including metabolic alterations and endocrine disturbances. Citation: Manservisi F, Babot Marquillas C, Buscaroli A, Huff J, Lauriola M, Mandrioli D, Manservigi M, Panzacchi S, Silbergeld EK, Belpoggi F. 2017. An integrated experimental design for the assessment of multiple toxicological end points in rat bioassays. Environ Health Perspect 125:289-295; http://dx.doi.org/10.1289/EHP419.
authors.affiliation: Cesare Maltoni Cancer Research Center, Ramazzini Institute, Bentivoglio, Bologna, Italy.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Manservisi
authors.forename: Clara Babot
authors.initials: CB
authors.lastname: Marquillas
authors.forename: Annalisa
authors.initials: A
authors.lastname: Buscaroli
authors.forename: James
authors.initials: J
authors.lastname: Huff
authors.forename: Michelina
authors.initials: M
authors.lastname: Lauriola
authors.forename: Daniele
authors.initials: D
authors.lastname: Mandrioli
authors.forename: Marco
authors.initials: M
authors.lastname: Manservigi
authors.forename: Simona
authors.initials: S
authors.lastname: Panzacchi
authors.forename: Ellen K
authors.initials: EK
authors.lastname: Silbergeld
authors.forename: Fiorella
authors.initials: F
authors.lastname: Belpoggi
mesh_terms: D000818:Animals; D019985:Benchmarking; D001681:Biological Assay / Q000379:methods* / Q000592:standards; D002273:Carcinogens / Q000592:standards / Q000633:toxicity*; D003657:Decision Making; D051381:Rats; D012107:Research Design; D018570:Risk Assessment / Q000379:methods / Q000592:standards; D018675:Toxicity Tests / Q000379:methods* / Q000592:standards
chemical_list: D002273:Carcinogens