Regulatory Forum Opinion Piece

Long, Gerald G.; Hardisty, Jerry F.

doi:10.1177/0192623312443322

Cited by 18 publications

(5 citation statements)

References 9 publications

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“…8 Considering a broad definition of background lesions, variations on normal may be included, especially if the changes represent unique histological features of certain species. 20,24 Mineralization likely falls into this category for freshwater mussels. Given that there was a range of mineralization observed in this study, with some individuals displaying little or no mineralization, pathologists may want to be aware of mineralization levels histologically, as shifts within populations could indicate underlying issues.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, background lesions are important in the context of differentiating spontaneous lesions from those induced by test articles. 20 Thus, entire textbooks have been written, detailing the background findings in those species used in the pharmaceutical industry. Varied definitions of what constitutes a background lesion have been formulated and include incidental or individual variations of normal, a spontaneous change in tissue morphology outside normal variation, physiological or hormonal changes, expected aging changes, and even normal histological findings unique to a particular species.…”

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confidence: 99%

“…Varied definitions of what constitutes a background lesion have been formulated and include incidental or individual variations of normal, a spontaneous change in tissue morphology outside normal variation, physiological or hormonal changes, expected aging changes, and even normal histological findings unique to a particular species. 20,24 Recent research trends have seen the incorporation of less-traditional laboratory animals as models, including swine, sheep, and goats, sourced from less biosecure sources. 14 Thus, some investigators have broadened the scope of background lesions to include those spontaneous infectious conditions that commonly affect livestock species.…”

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confidence: 99%

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Histopathologic survey of free-living populations of 2 species of freshwater mussels in Indiana

2023

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Freshwater mussels are one of the most endangered groups of animals in Indiana, with nearly half of the native species either extirpated or listed as “state endangered” or of “special concern.” Nationally, numerous freshwater mussel species are considered threatened. Freshwater mussel diseases are not well understood and few published accounts of freshwater mussel diseases with detailed histological descriptions exist. Mass mortality events within mussel populations are increasingly recognized, often with undetermined etiology. Our objective was to determine baseline histopathology in free-living populations of freshwater mussels. One-hundred twenty individual mussels representing 2 species—plain pocketbook ( Lampsilis cardium) and fatmucket ( Lampsilis siliquoidea)—were collected from 3 different locations within the Wildcat Creek watershed in central Indiana during June and July 2019. A cross-section through the visceral mass was obtained and immersed in 10% neutral-buffered formalin, with routine processing and hematoxylin and eosin staining. Branchial acariasis occurred in 43/60 fatmuckets and 22/60 plain pocketbooks. Infection with a bucephalid trematode was recognized in 18/60 fatmuckets, while infection of the gonadal duct with an unidentified trematode species was identified in 4/60 fatmuckets and 18/59 plain pocketbooks. Additional changes associated with unidentified trematodes, bacteria, fungi or oomycetes, and ciliates were observed. Other miscellaneous changes included mineralization, neuronal lipofuscinosis, and gonadal atrophy/atresia. A range of histological changes were observed. These changes likely represented background lesions: incidental findings, spontaneous infectious or endosymbiotic conditions, or normal physiological changes that routinely occur in free-living wild populations. Awareness of baseline lesions should inform future diagnostic investigations of mussel mortality events.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Histopathologic survey of free-living populations of 2 species of freshwater mussels in Indiana

2023

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“…For this reason, severity grades are essential tools for discriminating treatment-related effects from incidental background findings and establishing thresholds (e.g., highest non-severely toxic dose [HNSTD], lowest observed adverse effect level [LOAEL], or NOAEL) for risk assessment. 149 An STP “Points to Consider” paper on severity grading provides general guidance for defining relevant grading criteria. 147 Typically, severity grades are devised as non-linear, semi-quantitative, ascending levels identified using integers and terms.…”

Section: Collection Processing and Evaluation Of Ganglia For Nonclini...mentioning

confidence: 99%

Scientific and Regulatory Policy Committee Points to Consider: Sampling, Processing, Evaluation, Interpretation, and Reporting of Test Article-Related Ganglion Pathology for Nonclinical Toxicity Studies

Bennet,

Pardo,

Assaf

et al. 2023

Toxicol Pathol

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Certain biopharmaceutical products consistently affect dorsal root ganglia, trigeminal ganglia, and/or autonomic ganglia. Product classes targeting ganglia include antineoplastic chemotherapeutics, adeno-associated virus-based gene therapies, antisense oligonucleotides, and anti-nerve growth factor agents. This article outlines “points to consider” for sample collection, processing, evaluation, interpretation, and reporting of ganglion findings; these points are consistent with published best practices for peripheral nervous system evaluation in nonclinical toxicity studies. Ganglion findings often occur as a combination of neuronal injury (e.g., degeneration, necrosis, and/or loss) and/or glial effects (e.g., increased satellite glial cell cellularity) with leukocyte accumulation (e.g., mononuclear cell infiltration or inflammation). Nerve fiber degeneration and/or glial reactions may be seen in nerves, dorsal spinal nerve roots, spinal cord, and occasionally brainstem. Interpretation of test article (TA)-associated effects may be confounded by incidental background changes or experimental procedure-related changes and limited historical control data. Reports should describe findings at these sites, any TA relationship, and the criteria used for assigning severity grades. Contextualizing adversity of ganglia findings can require a weight-of-evidence approach because morphologic changes of variable severity occur in ganglia but often are not accompanied by observable overt in-life functional alterations detectable by conventional behavioral and neurological testing techniques.

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“…13 However, reasonable variations in terminology, recording threshold, and scoring exist between individuals and between institutions in reporting spontaneous findings (including which background lesions are routinely recorded) and classification of lesions ("lumping" different features into a single diagnosis or "splitting" features out into different diagnoses). 6,7 Due to these variations, the best comparator for histopathology is usually from CC animals.…”

Section: Anatomic Toxicologic Pathology In the Context Of Vcgmentioning

confidence: 99%

Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective

Grevot,

Boisclair,

Guffroy

et al. 2023

Toxicol Pathol

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In the last decade, numerous initiatives have emerged worldwide to reduce the use of animals in drug development, including more recently the introduction of Virtual Control Groups (VCGs) concept for nonclinical toxicity studies. Although replacement of concurrent controls (CCs) by virtual controls (VCs) represents an exciting opportunity, there are associated challenges that will be discussed in this paper with a more specific focus on anatomic pathology. Coordinated efforts will be needed from toxicologists, clinical and anatomic pathologists, and regulators to support approaches that will facilitate a staggered implementation of VCGs in nonclinical toxicity studies. Notably, the authors believe that a validated database for VC animals will need to include histopathology (digital) slides for microscopic assessment. Ultimately, the most important step lies in the validation of the concept by performing VCG and the full control group in parallel for studies of varying duration over a reasonable timespan to confirm there are no differences in outcomes (dual study design). The authors also discuss a hybrid approach, whereby control groups comprised both concurrent and VCs to demonstrate proof-of-concept. Once confidence is established by sponsors and regulators, VCs have the potential to replace some or all CC animals.

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Regulatory Forum Opinion Piece

Cited by 18 publications

References 9 publications

Histopathologic survey of free-living populations of 2 species of freshwater mussels in Indiana

Histopathologic survey of free-living populations of 2 species of freshwater mussels in Indiana

Scientific and Regulatory Policy Committee Points to Consider: Sampling, Processing, Evaluation, Interpretation, and Reporting of Test Article-Related Ganglion Pathology for Nonclinical Toxicity Studies

Toxicologic Pathology Forum Opinion Piece: Use of Virtual Control Groups in Nonclinical Toxicity Studies: The Anatomic Pathology Perspective

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