Need for Integrative Assessment of Toxicology Data

We live in a world of specialization, and the rate of specialization is increasing daily. Such specialization is particularly prominent in the areas of scientific investigation, whether in basic or applied science. Specialization has provided the opportunity for advancements in toxicological sciences, including toxicologic pathology, which simply could not have been achieved without the efforts of individuals being focused on increasing smaller segments of scientific questions and technologies. Indeed, such specialization is necessary to resolve the increasingly complex scientific questions that must be addressed now and in the future. However, the scientific community is paying an increasing price for such specialization; the cost is hindrance to advancement that could be made if there were increasing communication and collaboration between scientists of specialized disciplines. We too frequently (although certainly not consistently) see limited interaction between specialists and lack of understanding (perhaps lack of interest in) of disciplines outside personal scientific interests, resulting in limitations in advancements in toxicological sciences. Within toxicological science, including toxicological pathology, there are opportunities and needs for increased interaction to achieve an integrative assessment of toxicological data for the purpose of advancing human, animal, and environmental health.

Let’s look at specifics, starting with toxicologic pathology. One area where integration of data interpretation is less than optimal and provides the opportunity for vast improvement is the interpretation of clinical pathology data. There are two components to this issue. First, the reporting and publishing of clinical pathology data too frequently appear to be a “laundry list” of observations, with no integration of interpretation across various clinical pathology parameters. The second level of this issue is the lack of integration of interpretation of clinical pathology with anatomic pathology data and other data from research or toxicity evaluation results. It is stressed that this view is not an indictment of clinical pathologists, but rather a plea for those who are generating clinical pathology data to seek and accept input from colleagues who have specialty training and expertise in interpreting such data.

The generation of anatomic pathology data has progressively been refined over the years through the standardization of nomenclature and very importunately the Pathology Peer Review system. The Society of Toxicologic Pathology should be proud of the contributions made to this advancement through the generation of Standardized System of Nomenclature and Diagnostic Criteria (SSNDC) Guidelines on nomenclature of proliferative lesions and published Best Practices documents. Nevertheless, further standardization of diagnostic terms in anatomic pathology, which will result in improved data quality, requires further improvement, as is underway with the International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice (INHAND) efforts. However, such standardization only provides the basis for integration of interpretation of anatomic pathology data. Quite simply, the pathologist must be more aggressive at thinking about the integration of the anatomic pathology data with the other toxicological data. We are, or should be, long past the time when toxicologic pathologists view their responsibility as generating data that others must integrate to develop a full understanding of the toxicity or toxic mechanism being defined.

The world of toxicology and toxicologic pathology is changing and becoming more complex, as previously noted. The introduction of new technologies provides an opportunity for scientific advancement, but the opportunities are not being fully realized. Whether in the toxicology research community or in the evaluation of toxicity of pharmaceuticals and environmental contaminants, there is an opportunity for greater integration of “omic” data for contribution to addressing specific health issues. Specifically, there is an opportunity to focus “omic” data acquisition, but more importantly, interpretation of “omic” data to address issues and problems in an approach more fully integrated with pathology. Integration of interpretation of pharmacokinetic and metabolic data with other areas of toxicity evaluation is far from optimal in many areas of toxicological research and evaluation. Indeed, how many times have we heard the story of a toxicological investigation “failing” (meaning the expected result was not obtained) when in fact there was a lack of absorption of the agent being evaluated? Such efforts demonstrate waste of resources, including the efforts of the pathologist. At least in this case, the basis for lack of responsiveness was determined (albeit retrospectively), whereas in other cases, the area of research or toxicity evaluation is dropped because an expected result that is easily understandable through the generation of appropriate data was not obtained. Statistics provides yet another example of suboptimal integration of special expertise to study design and result interpretation. The examples here are numerous and will not be further addressed.

Despite the obvious need for further integration of sub-specialties contributing to the advancement and contributions of toxicology, it is clear that integration of approaches and data interpretation occur in many research and product development efforts. These efforts are to be commended and expanded, but they should not be used as examples that we are doing enough in the integration of expertise. One only needs to critically read the literature or safety assessment reports to easily find examples where the interpretation of data has not relied on a complete integration of the available information, whether the information is from a given study or from the available literature.

Assuming acceptance of the basic premise that there is a need for greater integration of specialty expertise in the design, performance, and most importantly, interpretation of toxicological data, what is the solution? Certainly the solution is not to return to the days of the “generalist.” Issues and approaches are far too complex. Rather, it is important for each of us to not only further develop subspecialty expertise, but also to develop greater appreciation of the approaches, expertise, and limitations in other subspecialties in toxicology. It is necessary to develop greater dialogue with other subspecialists and to take time to read the reviews in other subspecialty areas. This responsibility should include two components. The first and obvious component is for self-education, but the second and equally important component is to have the basis to challenge established dogma in other areas. Science frequently advances most rapidly when there is a new or fresh perspective on an area of research or problematic issue of understanding. If each of us were to devote a very small percentage of our professional effort to understanding areas that are not of primary interest to us, including interaction with colleagues and reading reviews that do not seem to be particularly interesting at first, we would provide a basis for enhanced integration of our efforts in the future, resulting in more rapid advancements in toxicology and toxicologic pathology. However, accumulation of increased knowledge does not guarantee an advancement of science. Only application of knowledge will provide increased success. Therefore, it is important to develop true interdisciplinary efforts where there are contributions and challenges by all participating members. To use the overly trite term, we need to have research “teams” in the classic sense of the word team. The designation of a team for the purpose of developing a grant or for the purpose of developing a pharmaceutical is simply inadequate based on personal experience. Success is achieved not only when every member brings something to the forum that cannot be provided by others, but also when each member assumes the responsibility for success by challenging others. The toxicological pathologist should accept this responsibility and provide the expertise not only in pathology in general, but also in a well-developed subspecialty of pathology, while also providing a focus on interpretation of results in the context of the complete biological system, whether that be animal or human. The toxicological pathologist with a diverse background in biomedical sciences in addition to specialty expertise frequently has the greatest responsibility for focusing the questions, approaches, and interpretation on the ultimate issue of whole-animal health.