The purpose of the project RITA (Registry of Industrial Toxicology Animal-data) is to centralize the collection of historical data of control animals used on rodent carcinogenicity studies from different laboratories in a consistent manner. The availability of harmonised data from these studies in a comprehensive database can make the decisive difference in interpretation of these data.

The tumor data base RITA is a unique international cooperation between chemical and pharmaceutical companies and a non-profit organisation. It is maintained by the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) Hannover. The cross organisational review of studies means that the histopathological assessment of tumors meets optimized standards for reliability, robustness and quality.

RITA is much more than a data archive. The joint effort of the participants has created a communication platform for the conduct, evaluation and assessment of rodent carcinogenicity studies, including study design, technical procedures, diagnostic approaches, development of the database hardware platform, recognition by regulatory agencies and more.

With these features RITA is facilitating the standardization for the conduct and histopathological evaluation of carcinogenicity studies. Such studies are requested by regulatory authorities in the course of the human risk assessment of chemicals or pharmaceuticals.

RITA current status (March 2024)

The objective of RITA is to optimize the comparability and interpretation of tumor data within and across rodent carcinogenicity studies by exploiting shared expertise and resources.

Extensive knowledge of the spontaneous frequency of certain pathological changes is essential for the evaluation of carcinogenicity studies, because there may be substantial differences between species and strains. Also other parameters such as environmental and husbandry conditions may influence the spontaneous tumor profile. Due to the potential dependency of spontaneous tumor incidences on such factors like animal source, food consumption, body weight, housing conditions or survival time this information is collected in addition to the tumor incidences. This allows the definition of reliable historical control data on a scientific basis.

This objective turned out to be a complex and challenging task involving much more than merely storage of study data from different sources or laboratories in one physical database. The project focuses primarily on the collection of historical control data (HCD) not only from neoplastic but also from pre-neoplastic alterations (including foci of hepatocellular alteration) in control rats and mice from life-time carcinogenicity bioassays. However, it also includes related study types, e.g. carcinogenicity tests in genetically modified mice.

In 2006 the Societies of Toxicologic Pathology from North America (STP), Europe (ESTP/BSTP) and Japan (JSTP) joined in a common effort to review the diagnostic terms and criteria for a standard nomenclature of lesions in rodents, the INHAND initative. RITA is contributing scientifically and is also providing the tools for the online review collection of manuscripts and images.

The feasibility of employing TelePathology equipment is under evaluation.

Tumor data acquisition and interpretation require skills and hardware platforms. Of vital importance are the standards and rules that define the properties of the data to be stored. They link the hardware platform to the communication platform. The skills for the communication platform include mutual agreement on those linking rules and standards and their consistent application. Other important aspects are sharing of professional expertise and specific continuous professional development of the participants, first of all the pathologists. The hardware platforms include microscopes and data storing equipment.

To ensure consistency across and between studies, a unique review process has been established, relying on pathologists from all participating companies. This review process facilitates further development of the skills of pathologists by sharing and multiplying professional expertise. The result is a continuous refinement of established procedures which has a substantial impact on the community of toxicological pathology, study conduct in companies and CROs, and recognition by regulatory authorities, besides a continuously growing number of collected tumor data.

Certification detailing time spent and the major topics covered during the meetings at Fraunhofer ITEM is provided to every participant. The attendance of RITA meetings is acknowledged for ATF accreditation.

All required information for individual studies is submitted by the participating companies and stored in the RITA database. Before finalization, all data are checked and validated. The process of validation is absolutely mandatory to ensure that the stored information is complete and only terminology defined in the glossary is used and diagnostic criteria are applied in a consistent manner across all studies. All submitted data are checked by computer programs for completeness, plausibility and compliance to the defined "rules". Of major importance is the quality check on the histopathological findings. A unique review process has been established for this purpose.

To ensure data consistency, a unique validation procedure is applied to the histopathological diagnoses. Before they are accepted for the data base all histological slides containing tumors or pre-neoplastic lesions are reviewed by a pathologist from Fraunhofer ITEM, checking the diagnoses for consistency with the WHO classification/nomenclature. Questionable findings are submitted to a panel of pathologists for final review. Such a panel consists of the pathologists from the participating companies and from Fraunhofer ITEM. The panel review is performed at a multi-headed microscope equipped for a maximum of 21 participants. A digital camera with beamer projection is in place to allow additional pathologists to participate in the panel discussions.

Pathologists reviewing case in the Panel by using the 21-headed discussion microscope.

Future Meetings: November 25 – 27, 2024 March 18 – 20, 2025 Registration: rita.panel@item.fraunhofer.de

Computer systems are used to document the conclusions of the panel on-line in the database, to retrieve additional information on particular animals or on the standardized nomenclature.

The feasibility of employing TelePathology equipment is under evaluation.

The RITA group is organizing an education program focusing on the evaluation of carcinogenicity studies. Participants of the seminar should be those veterinarians, who are working in the field of toxicologic pathology and will be involved in the histopathologic evaluation of carcinogenicity studies with rodents but have not yet that much experience. The speakers are veterinary pathologists who have a long time of experience in that field and thus, can give you a broad overview on all the issues, problems, pitfalls one has to deal with when reading or peer reviewing carcinogenicity studies.

It will be expected that the participants are familiar with the INHAND nomenclature and the diagnostic criteria of the pre-/neoplastic lesions of the respective module. Active participation of delegates is required. At the end of the half-day each participant would be requested to examine one case, present the diagnosis, and defend it in a discussion.

RITA Education Program – 3rd round 2023-2025 Online Teams 2:00 – 6:00 pm CET

2:00 – 3:45	Seminar
3:45 – 4:15	Coffee break
4:15 – 6:00	Seminar
Participants Activity:	Discussion of cases by participants included during the seminar

Seminar for 2023 open for registration (see below)

Day	Organ system/Topic	Speaker
01	Introduction to histopathology of carcinogenicity studies
16-May-2023		D. Schaudien R. Kellner M. Rinke (U. Bach)
02	Respiratory System
25-Jul-2023		S. Rittinghausen
03	Hematopoietic System
12-Sep-2023		C. Rühl-Fehlert J. Funk
04	Female Reproductive System
10-Oct-2023		U. Bach H. Marxfeld
05	Male Reproductive System
14-Nov-2023		T. Nolte
06	Cardiovascular and Mesothelium
30-Jan-2024		S. Rittinghausen M. Rinke
07	Hepatobiliary System
26-Mar-2024		T. Nolte M. Rinke
08	Urinary System
14-May-2024		M. Rinke
09	Endocrine System (Thyroid, Parathyroid gland)
11-Jun-2024		A. Brändli
10	Endocrine System (Adrenal Glands)
10-Sep-2024		M. Rinke K. Siudak
11	Endocrine System (Pituitary gland, Pineal gland, endocrine pancreas)
12-Nov-2024		B. Lenz S. Rittinghausen
12	Skeleton and Teeth
11-Feb-2025		D. Schaudien S. Rittinghausen
13	Soft tissue and Muscle
11-Mar-2025		M. Rinke S. Rittinghausen
14	Integument and Mammary gland
08-Apr-2025		S. Treumann M. Huisinga
15	Digestive System
13-May-2025		T. Nolte
16	Nervous System and Special senses
10-Jun-2025		S. Gröters H. Marxfeld S. Rittinghausen U. Bach

Registration is required via email: rita.panel@item.fraunhofer.de

Beyond essential technical checks to achieve comparability of data coming from different laboratories, additional quality control procedures are necessary. Quality control is applied to all steps from study design to the final data storage, including mutually accepted technical procedures, e.g. trimming procedures, glossaries and diagnostic criteria, and the consistent application of these procedures and criteria, facilitated by initial training and continuous professional development of the involved pathologists and technicians.

This process results in substantial improvement of data quality, namely comparability of the historical control data across studies in the RITA database and even more important of the original carcinogenicity studies across laboratories and companies with a significant impact on CROs and non participating companies.

A variety of reports is available. Standard reports may be requested from Fraunhofer ITEM or be generated locally at the companies with a dedicated RENI software. More detailed reports or ad hoc specific reports may be requested from Fraunhofer ITEM. Depending on the complexity of the request these reports are available within a few days, standard reports and non demanding specific reports are usually available within a few hours on the day of request.

Access to the database or to RITA tools is also granted under certain conditions to those who are not member or cannot participate in the project.

• Observers: Non-RITA members may join the regular meetings of RITA.
  The major purpose of these meetings hosted by the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) in Hannover is to perform the final step of the slide review process at a 21 head discussion microscope.
• Free access to goRENI: Representatives from regulatory agencies may get free access to goRENI on request. Meanwhile all members of ESTP, STP, JSTP, BSTP and other societies of Toxicological Pathology have free access to this system. goRENI is the diagnostic tool of the RITA group featuring easy access to diagnostic terms, diagnostic criteria, images of lesions and a collection of references.
• Report verification: Extend verification of RITA data is available for regulatory agencies. They have the option to request additional data and reports or are welcome to on site visits of RITA in Hannover.
• Publications: see References

The definition and consistent application of a systematized and standardized nomenclature of histopathological findings is the first prerequisite in order to operate a centralized pathology data base.

Terms: Only the use of the same terminology for organs and lesions by all participants allows a reliable comparison of incidences across different experiments and therefore of study results. In the RITA database, the use of standardized terminology is controlled by the integrated lexicon.

Criteria: Standardization of names is just the basic prerequisite for a systematized nomenclature. An even more important requirement is the use of the same diagnostic criteria to characterize a specific lesion. A team of pathologists has established detailed descriptions and definitions for all tumors and pre-neoplastic lesions in all organ systems. The results have been reviewed, prior to publication, by internationally recognized experts in the area of toxicological pathology or veterinary pathology. The manuscripts present in a compact and ready-to-use format clear definitions on the light microscopic features and criteria for the differentiation of hyperplastic lesions, benign and malignant tumors.

The diagnostic criteria of proliferative lesions in the rat have been published by WHO/IARC in a series of 10 fascicles, entitled "International Classification of Rodent Tumours, Part I: The Rat" (IARC Scientific Publications, No. 122; click here for a list of all titles and ISBN numbers).

The corresponding publication on lesions in the mouse has been prepared in a joint initiative between the RITA group and members of many societies of toxicologic pathology (like GTP, STP, BSTP, JSTP). Springer Press has published the comprehensive results under the title "International Classification of Rodent Tumors, The Mouse" in April 2001.

In 1998 an international committee was formed to harmonize the terminology of rat proliferative lesions among pathologists and organizations worldwide. For more details see the Web site International Harmonization of Rat Nomenclature.

An extended electronic version of the "International Classification of Rodent Tumours" is also available, known as the global open RENI System - goRENI. It has been developed initially for local support of the RITA project panel meetings at Hannover, however, since 1998 it is accessible via the Internet and in February 2007 it has been made available to all registered toxicologic pathologists. Besides the nomenclature and diagnostic criteria goRENI contains a growing number of histopathological images (current status: 7600). For most of the references links to the corresponding abstracts in MEDLINE are provided. goRENI is a dynamic tool which is continuously adapted to changing needs.

Agreement on and consistent application of standards has proven to be essential for maintaining a pathology data base. Consequently, the tissue collection and processing procedures were reviewed and a guidance for trimming of tissue was established. The guidance has been revisited and updated. It is integrated into goRENI and available as publication.

A number of tools were developed to facilitate fast, reliable, and secure data transfer from different pathology data acquisition systems to the RITA database. Additional tools are available for review of diagnostic terms and criteria and last but not least for the transfer of RITA database data back to the companies for the creation of off-site local ad hoc user customized reports. These tools are:

goRENI	Web based review tool for nomenclature, diagnostic terms and criteria, trimming guides, and access to online images
WebRegina	Data transfer to RITA

Histopathological findings of tumors and other proliferative pre-neoplastic lesions are the major part of the information stored in the RITA pathology database. However, detailed study-related and animal-related data on animal status, husbandry conditions, diet, source of the animals, age, body weights, etc. are also collected, because these parameters may have an influence on the spontaneous tumor profile. The structure of RITA provides the facilities to store not only the histopathological diagnoses but all associated relevant study- and animal-related information.

Schematical structure of the RITA Data Base

Some procedures serve a dual purpose. Initially designed as quality control procedure or standardization efforts the following activities proved to be highly envisaged opportunities of continuous professional development.

During the regular meetings at Fraunhofer ITEM in Hannover any equivocal cases are reviewed at the discussion microscope and finally decided upon by majority vote from members of participating companies. Voting rights depend on having attended a minimum number of such meetings. Currently, 5 panel meetings per year are hosted at Fraunhofer ITEM providing a unique opportunity for training and continuous professional development of pathologists.

Certification detailing time spent and the major topics covered during the meetings at Fraunhofer ITEM is provided to every participant.

Additional companies are welcome to join RITA to support the mutual efforts to broaden the data base, increase the quality of the data, and share in the continuous professional development benefits of the panel discussions. See the contact address below.

For more information, please contact

RITA-Team Fraunhofer Institute for Toxicology and Experimental Medicine Department of Pathology Nikolai-Fuchs-Str. 1 30625 Hannover, Germany e-mail: rita.info@item.fraunhofer.de

There are several articles published on the RITA data base:

• Mohr U, Bader R, Ernst H, Ettlin R, Gembardt C, Harleman JH, Hartig F, Jahn W, Kaliner G, Karbe E, Kaufmann W, Krieg K, Krinke G, Küttler K, Landes C, Mettler F, Morawietz G, Notman J, Püschner H, Qureshi S, Reznik G, Rittinghausen S, Tuch K, Urwyler H, Weisse G, Weisse I, Zehnder J (1990) Tumor Registry Data Base: Suggestions for a systematized nomenclature for pre-neoplastic and neoplastic lesions in rats. Exp Pathol 38: 1–18
  
  
• Morawietz G, Rittinghausen S (1992) Variations in prevalence of endocrine tumors among different colonies of rats? A retrospective study in the Hannover Tumor REGISTRY Data Base. Arch Toxicol, Suppl 15: 205–214
  
  
• Morawietz G, Rittinghausen S, Mohr U (1992) Visual documentation of neoplasms as part of the REGISTRYnomenclature information system. Zentralbl Pathol 138: 431–434
  
  
• Morawietz G, Rittinghausen S, Mohr U (1992) RITA - Registry of Industrial Toxicology Animal-data – Progress of the working group. Exp Toxic Pathol 44: 301–309
  
  
• Mohr U (Editor, 1992 - 1997) International classification of rodent tumours, Part 1: The rat. IARC Scientific Publications No. 122, Lyon (10 fascicles)
  
  
• Bode G (1993) Computerized control-animal pathology databases: Will they be used? – A pathologist's viewpoint. In: McAuslane JAN, Parkinson C, Lumley CE (eds) Computerized Control Animal Pathology Databases: Will they be used. Centre for Medicines Research, Carshalton, pp 49–51
  
  
• Karbe E (1993) The use of historical control animal pathology data: An industry viewpoint of the RITA database. In: McAuslane JAN, Parkinson C, Lumley CE (eds) Computerized Control Animal Pathology Databases: Will they be used. Centre for Medicines Research, Carshalton, pp 43–46
  
  
• Morawietz, G (1993) RENI - The Registry Nomenclature Information System. In: McAuslane JAN, Parkinson C, Lumley CE (eds) Computerized Control Animal Pathology Databases: Will they be used. Centre for Medicines Research, Carshalton, pp 35–42
  
  
• Mohr U, Morawietz, G (1993) RITA - Registry of Industrial Toxicology Animal-data. In: McAuslane JAN, Parkinson C, Lumley CE (eds) Computerized Control Animal Pathology Databases: Will they be used. Centre for Medicines Research, Carshalton, pp 27–34
  
  
• Bahnemann R, Jacobs M, Karbe E, Kaufmann W, Morawietz G, Nolte T, Rittinghausen S (1995) RITA – Registry of Industrial Toxicology Animal-data – Guides for organ sampling and trimming procedures in rats. Exp Toxic Pathol 47: 247–266
  
  
• Mohr U, Morawietz G (1995) Recent progress in the field of toxicologic pathology in Europe and the need for standardization. J Toxicol Pathol 8: 219–226
  
  
• Mohr U (Editorial, 1999) RITA – Registry of Industrial Toxicology Animal-data: Optimization of carcinogenicity bioassays. Exp Toxic Pathol 51: 461–475
  
  
• Mohr U (Editor, 2001) International classification of rodent tumors, The Mouse. Springer, Berlin Heidelberg New York
  
  
• Keenan C, Hughes-Earle A, Case M, Stuart B, Lake S, Mahrt C, Halliwell W, Westhouse R, Elwell M, Morton D, Morawietz G, Rittinghausen S, Deschl U, Mohr U (2002) The North American Control Animal Database: a resource based on standardized nomenclature and diagnostic criteria. Toxicol Pathol 30: 75–79
  
  
• Deschl U, Kittel B, Rittinghausen S, Morawietz G, Kohler M, Mohr U, Keenan C (2002) The value of historical control data-scientific advantages for pathologists, industry and agencies. Toxicol Pathol 30: 80–87
  
  
• Ruehl-Fehlert C, Kittel B, Morawietz G, Deslex P, Keenan C, Mahrt CR, Nolte T, Robinson M, Stuart BP, Deschl U (2003) Revised guides for organ sampling and trimming in rats and mice - Part 1. Exp Toxicol Pathol 55: 91–106
  
  
• Kittel B, Ruehl-Fehlert C, Morawietz G, Klapwijk J, Elwell MR, Lenz B, O'Sullivan MG, Roth DR, Wadsworth PF (2004) Revised guides for organ sampling and trimming in rats and mice - Part 2. Exp Toxicol Pathol 55: 413–431
  
  
• Morawietz G, Ruehl-Fehlert C, Kittel B, Bube A, Keane K, Halm S, Heuser A, Hellmann J (2004) Revised guides for organ sampling and trimming in rats and mice - Part 3. Exp Toxicol Pathol 55: 433–449
  
  
• Nolte T, Kellner R, Rittinghausen S (2009) Slide seminar case 7. Leydig cell tumors in rats: the application of RITA historical control data. In: 6th European Congress of Toxicologic Pathology. Speaker Abstracts of the Joint ETS/ESTP Congress, September24-26, 2008, Edinburgh, Scotland. Exp Toxicol Pathol 61: 402 [doi:10.1016/j.etp.2009.02.086]
  
  
• Nolte T, Rittinghausen S, Kellner R, Karbe E, Kittel B, Rinke M, Deschl U (2011) RITA–Registry of Industrial Toxicology Animal data: The application of historical control data for Leydig cell tumors in rats. Exp Toxicol Pathol 63: 645–656 [doi:10.1016/j.etp.2010.05.006]
  
  
• Harleman JH, Hargreaves A, Andersson H, Kirk S (2012) A review of the incidence and coincidence of uterine and mammary tumors in Wistar and Sprague-Dawley rats based on the RITA database and the role of prolactin. Toxicol Pathol 40: 926–930 [doi:10.1177/0192623312444621]
  
  
• Lapp S, Bube A, Colbatzky FA, Ernst H, Kellner R, Nolte T, Rinke M (2018) Best Practice Approach for Assessment of Microchip-associated Tumors in Preclinical Safety Studies: Position of the Registry of Industrial Toxicology Animal-data (RITA). Toxicol Pathol 46: 728–734 [doi:10.1177/0192623318792541]
  
  
• Funk J, Ruehl-Fehlert C, Leonard C, Kellner R, Rittinghausen S (2022) Immunohistochemical characterization of proliferative lesions in the thymus of aging CD-1 mice from two studies on the RITA database, with special reference to the perivascular space. Toxicol Pathol 50: 308–328 [doi:10.1177/01926233221082972]

The following list shows some links to Web sites which are related to the current topic.

goRENI: The global open Registry Nomenclature Information System
Software documentation for WebREGINA
International harmonization of Rat Nomenclature
Standardized Organ Sampling and Trimming Guides
Web site of the European Society of Toxicologic Pathology, ESTP: www.eurotoxpath.org
DevTox: The Developmental Toxicology Web site (www.devtox.org)