Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

Palazzi, Xavier; Burkhardt, John E.; Caplain, H; Dellarco, Vicki L.; Fant, Pierluigi; Foster, John R.; Francke, Sabine; Germann, Paul G.; Gröters, Sibylle; Harada, Takanori; Harleman, Johannes H.; Inui, Kosei; Kaufmann, Wolfgang; Lenz, Barbara; Nagai, Hirofumi; Pohlmeyer-Esch, Gabriele; Schulte, Agnes; Skydsgaard, Mikala; Tomlinson, Lindsay; Wood, Charles E.; Yoshida, Midori

doi:10.1177/0192623316642527

Cited by 82 publications

(93 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A more challenging question is whether non-a2u accumulations (e.g., hyaline droplets) in the tubular epithelium of female rats should be considered adverse. This latter scenario would be interpreted on a case-by-case basis integrating other renal effects, distribution and severity of accumulation, reversibility, and other knowledge about the compound being studied (Palazzi et al 2016).…”

Section: Alpha-2u Globulin Accumulationmentioning

confidence: 99%

Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop

et al. 2018

View full text Add to dashboard Cite

Lysosomes have a central role in cellular catabolism, trafficking, and processing of foreign particles. Accumulation of endogenous and exogenous materials in lysosomes represents a common finding in nonclinical toxicity studies. Histologically, these accumulations often lack distinctive features indicative of lysosomal or cellular dysfunction, making it difficult to consistently interpret and assign adverse dose levels. To help address this issue, the European Society of Toxicologic Pathology organized a workshop where representative types of lysosomal accumulation induced by pharmaceuticals and environmental chemicals were presented and discussed. The expert working group agreed that the diversity of lysosomal accumulations requires a case-by-case weight-of-evidence approach and outlined several factors to consider in the adversity assessment, including location and type of cell affected, lysosomal contents, severity of the accumulation, and related pathological effects as evidence of cellular or organ dysfunction. Lysosomal accumulations associated with cytotoxicity, inflammation, or fibrosis were generally considered to be adverse, while those found in isolation (without morphologic or functional consequences) were not. Workshop examples highlighted the importance of thoroughly characterizing the biological context of lysosomal effects, including mechanistic data and functional in vitro readouts if available. The information provided here should facilitate greater consistency and transparency in the interpretation of lysosomal effects.

show abstract

Section: Alpha-2u Globulin Accumulationmentioning

confidence: 99%

Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Several recent publications aimed to provide guidance in determining adversity in preclinical toxicology studies (ECETOC, 2002, Lewis et al ., 2002, Dorato and Engelhardt, 2005, Keller et al ., 2012, Kerlin et al ., 2016, Palazzi et al ., 2016). The readers are encouraged to refer to these publications for more in depth information on adversity in toxicology studies.…”

Section: Introductionmentioning

confidence: 99%

“…The readers are encouraged to refer to these publications for more in depth information on adversity in toxicology studies. Due to the increased interest in the topic of adverse versus adaptive responses in toxicology studies, several recent workshops, and symposia were organized by the American College of Toxicology (Cavagnaro and Beilke, 2014, Kiorpes and Pandiri, 2014), the Society of Toxicologic Pathology (Kerlin et al ., 2016), and the European Society of Toxicologic Pathology (Palazzi et al ., 2016). This continuing education course at the 2016 STP annual meeting in San Diego, CA, aims to provide a forum to disseminate information and to enable discussion within the STP membership.…”

Section: Introductionmentioning

confidence: 99%

Is It Adverse, Nonadverse, Adaptive, or Artifact?

et al. 2016

View full text Add to dashboard Cite

One of the principal challenges facing a toxicologic pathologist is to determine and differentiate a true adverse effect from a non-adverse or an adaptive response. Recent publications from the Society of Toxicologic Pathology (STP) and the European STP provide guidance for determining and communicating adversity in nonclinical toxicology studies. In order to provide a forum to inform and engage in a discussion on this important topic, a continuing education (CE) course was held during the 2016 STP Annual meeting in San Diego, CA. The lectures at this course provided guidance on determining and communicating adversity using case studies involving both clinical pathology and anatomic pathology. In addition, one talk also focused on data quality, study design and interpretation of artifacts that could hinder the determination of adversity. The CE course ended with a talk on understanding adversity in preclinical studies and engaging the regulatory agencies in the decision making process. This manuscript is designed to provide brief summaries of all the talks in this well received CE course.

show abstract

“…These recommendations are based on general principles that are well considered and broadly applicable, but are largely focused on anatomic pathology and provide limited guidance for CP. In a recent complementary effort, the European Society of Toxicological Pathology (ESTP) coordinated an international workshop to further characterize the concept of adversity and to frame discussions specific to particular organs or types of lesions (Palazzi et al 2016). One workshop session of the ESTP working group concluded that CP changes should not be considered adverse in isolation without consideration for associated anatomic pathology findings and adverse in-life outcomes.…”

mentioning

confidence: 99%

“…One workshop session of the ESTP working group concluded that CP changes should not be considered adverse in isolation without consideration for associated anatomic pathology findings and adverse in-life outcomes. The current article applies the fundamental principles identified in Kerlin et al (2016) and Palazzi et al (2016) to the specific challenges of adversity determination in CP. Here, toxicologic clinical pathologists representing the Regulatory Affairs Committee (RAC) of the American Society of Veterinary Clinical Pathology (ASVCP) and the Clinical Pathology Interest Group (CPIG) of the STP delineate overarching principles and unique considerations for assessing adversity in CP data interpretation.…”

mentioning

confidence: 99%

Principles for Assessing Adversity in Toxicologic Clinical Pathology

et al. 2017

Self Cite

View full text Add to dashboard Cite

There is limited direction in the literature or regulatory guidance on determination of adversity for clinical pathology (CP) biomarkers in preclinical safety studies. Toxicologic clinical pathologists representing the American Society for Veterinary Clinical Pathology-Regulatory Affairs Committee and Society of Toxicologic Pathology-Clinical Pathology Interest Group identified principles, overall approach, and unique considerations for assessing adversity in CP data interpretation to provide a consensus opinion. Emphasized is the need for pathophysiologic context and a weight-of-evidence approach. Most CP biomarkers do not have the potential to be adverse in isolation, regardless of magnitude of change. Rather, they quantify or describe the impact of effects, provide adjunct or supportive information regarding a process or pathogenesis, and provide translational biomarkers of effect. Most often, CP changes are part of a constellation of findings that collectively are adverse. Thus, most CP changes must be interpreted in conjunction with other study findings and require contextual and integrative interpretation. Exceptions include critical CP changes without correlates that indicate a health risk in the tested species. Overall, CP changes should not be interpreted in isolation and their adversity is best addressed with an integrated approach.

show abstract

Characterizing “Adversity” of Pathology Findings in Nonclinical Toxicity Studies

Cited by 82 publications

References 33 publications

Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop

Characterizing Adversity of Lysosomal Accumulation in Nonclinical Toxicity Studies: Results from the 5th ESTP International Expert Workshop

Is It Adverse, Nonadverse, Adaptive, or Artifact?

Principles for Assessing Adversity in Toxicologic Clinical Pathology

Contact Info

Product

Resources

About