Toxicologic pathology integrates the disciplines of toxicology and pathology [[1]]. Those who practice in this field identify the effects of test articles (e.g., drugs, chemicals and other therapeutic devices) on research models.

The data generated are a critical component of the safety assessment process and can be used to predict responses in humans and other animals exposed to such compounds.

In the early days of toxicologic pathology, pathologists often worked independently. Their evaluations of chemical-induced changes were limited to morphologic observations made at necropsy and during microscopic examination of tissue sections. In most cases, the toxicologic pathologist was provided minimal information, such as toxicokinetic data, organ weight data, clinical pathology data and clinical observations. There was also very little literature in the field [[2]] to guide toxicologic pathologists in their examinations. This was also true for diagnostic terms to describe morphologic changes.

The lack of a professional society, and an exchange of ideas through the literature, limited toxicological pathologists to the expertise within their institution when it came to consultations. Consultations with offsite pathologists required the shipment of slides, transfer of images or a conversation without the aid of slides or images. This situation was less than ideal and often produced a pathology report listing gross and microscopic findings, with minimum interpretation of the findings.

As toxicologic pathology data became a major component of risk assessment, toxicologic pathologists needed a knowledge base beyond understanding morphologic changes in tissues. For example, knowledge of what the body does to a xenobiotic (pharmacokinetics and toxicokinetics) and what a xenobiotic does to the body (pharmacologic effect and potential adverse effects) are important considerations in a risk assessment [1]. Additionally, toxicologic pathologists needed to understand the use of consistent terminology and how to integrate toxicologic pathology data into assessments of health risks. Finally, effective communication of each of these elements is essential  [1] for explaining findings to other scientists, customers, management and regulatory agencies.

Guidance gradually became more available as more emphasis was put on toxicologic pathology [1,[3]]. The Society of Toxicologic Pathology (STP) has published best practices for histopathologic examination [[4]], reporting of toxicologic pathology data [[5]], examination of various organ systems [[6],[7],[8], [9], [10]], and recommendations for pathology peer review [[11]]. STP best practices are available publicly on their website. Recently, several of our Charles River colleagues contributed to a position paper on the optimal interactions between CROs and industry scientists to produce the best quality pathology report [[12]]. Additionally, toxicologic pathology organizations around the world have developed harmonized nomenclature through the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice (INHAND) initiative, which will promote international agreement and consistency needed to improve the safety assessment of drugs, biologics and chemicals [[13]].

The advent of whole slide digital images (WSI) is also a great advancement in the field of pathology, as it facilitates consultations in toxicologic pathology and enables interaction with experts. With WSI, study pathologists and consultant pathologists can view the same morphologic changes simultaneously. Today, thanks to these technologic advances, a peer toxicologic pathologist can easily review initial findings. This ensures that data is generated using a broader knowledge base and while the final pathology report represents the pathologist’s opinion, it is a more informed opinion.

What does the future hold for toxicologic pathology? Continued publication of new best practices and position papers will keep toxicologic pathologists current. Refinement of previously published practices or positions papers will also help in this regard. The INHAND initiative should continue defining harmonization diagnostic terminology used in toxicologic pathology, which may be used in Standard for Exchange of Nonclinical Data (SEND) submissions [[14]]. Such progress should facilitate submission reviews. Consultations will continue to use WSI in the future. Advances in computer-aided image analysis, which provides quantitative and reproducible data, should lead to the wider use and acceptance of digital pathology.

Toxicologic pathology continues to evolve and the skills of the toxicologic pathologist are keeping pace with this evolution. The result is high-quality and timely data that contributes to more informed decisions for clinical programs and regulations and ultimately leads to improvement of human, animal, and environmental health.

References

  1. Hascheck, W; Rousseaux, C and Walling, M; editors. Handbook of Toxicologic Pathology, Second Edition, Academic Press, Volume 1, Pg 3; 2002.
  2. Hascheck, W; and Rousseaux, C; editors. Handbook of Toxicologic Pathology, First Edition, Academic Press, Pg xxiii; 1991.
  3. Greaves, P; Histopathology of Preclinical Toxicity Studies, Interpretation and Relevance in Drug Safety Evaluation; Third Edition, Elsevier / Academic Press, 2007.
  4. Crissman, J; et. al. Best Practices Guideline:  Toxicologic Histopathology, Toxicologic Pathology, 32, 126-131, 2004.
  5. Morton, D; et. al. Best Practices for Reporting Pathology Interpretations within GLP Toxicology Studies, Toxicologic Pathology, 34, 806-809, 2006.
  6. Haley, P; et. al. STP Position Paper:  Best Practice Guideline for Routine Pathology Evaluation of the Immune System; Toxicologic Pathology, 33:404-407, 2005.
  7. Regan, K; et. al. STP Position Paper:  Ovarian Follicular Counting in the Assessment of Rodent Reproductive Toxicity; Toxicologic Pathology, 33:409-412, 2005.
  8. Lanning, L; et. al. STP Position Paper:  Recommended Approaches for the Evaluation of Testicular and Epididymal Toxicity; Toxicologic Pathology, 30, No 4, pp 507-520, 2002.
  9. Bolon, B; et. al. STP Position Paper:  A ‘Best Practices’ Approach to Neuropathologic Assessment in Developmental Neurotoxicity Testing-For Today; Toxicologic Pathology, 34:296-313, 2006.
  10. Rao, D; et. al. Histopathological Evaluation of the Nervous System in National Toxicology Program Rodent Studies:  A Modified Approach; Toxicologic Pathology, 39:463-470, 2011.
  11. Morton, D; et. al. Recommendations for Pathology Peer Review, Toxicologic Pathology, 38, 1118-1127, 2010.
  12. Gosselin, S, et. al. Industry – Contract Research Organization Pathology Interactions:  A Perspective of CROs in Producing the Best Quality Pathology Report. Toxicologic Pathology, 39:422-428, 2011.
  13. Mann, P; et. al. International Harmonization of Toxicologic Pathology Nomenclature:  An Overview and Review of Basic Principles, Toxicologic Pathology, 40:7S-13S, 2012
  14. INHAND:  International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice, Collaboration with the FDA on SEND-Standard for the Exchange of Nonclinical Data, STP Website:  https://www.toxpath.org/STP_inhand-84x42v2%20pdf.pdf