Juvenile Bone Toxicity: Study Considerations, Regulations, and Techniques for Assessment.

Recommendations on study designs that adequately evaluate the in-life effects leading to juvenile bone toxicity, the various imaging modalities that can aid interpretation of the bone effects, biomarkers that may be useful, and regulatory issues were presented in this 2020 ACT symposium. The pathologies encountered in past studies were briefly mentioned. The first speaker covered study design and the numbers of juveniles that may be necessary to power the evaluation.

Scientific and Regulatory Policy Committee Points to Consider for Medical Device Implant Site Evaluation in Nonclinical Studies.

Nonclinical implantation studies are a common and often critical step for medical device safety assessment in the bench-to-market pathway. Nonclinical implanted medical devices or drug-device combination products require complex macroscopic and microscopic pathology evaluations due to the physical presence of the device itself and unique tissue responses to device materials. The Medical Device Implant Site Evaluation working group of the Society of Toxicologic Pathology's (STP) Scientific and Regulatory Policy Committee (SRPC) was tasked with reviewing scientific, technical, and regulatory considerations for these studies.

Confounding Factors in the Interpretation of Preclinical Studies.

A number of issues may arise during the conduct of a study which can complicate interpretation of in vitro and in vivo datasets. Speakers discussed the implications of differing interpretations and how to avoid complicating factors during study planning and execution. Consideration needs to be given to study design factors including defining objectives, consideration of expected pharmacological effects, dose selection and drug kinetics, species used, and vehicle selection.

Compilation of International Standards and Regulatory Guidance Documents for Evaluation of Biomaterials, Medical Devices, and 3-D Printed and Regenerative Medicine Products.

The development of biomaterials, medical device components, finished medical products, and 3-D printed and regenerative medicine products is governed by a variety of international and country-specific standards and guidelines. Of greatest importance to planning, executing, and reporting biocompatibility, safety and efficacy studies for most biomaterials and medical components or products are the International Organization for Standardization guidelines, U.S.

The Standard for the Exchange of Nonclinical Data (SEND): Challenges and Promises.

The Standard for the Exchange of Nonclinical Data (SEND) is an implementation of the Study Data Tabulation Model for nonclinical studies that enables the U.S. Food and Drug Administration (FDA) to modernize and streamline the review process.

The First Cut Is the Deepest: The History and Development of Safe Treatments for Wound Healing and Tissue Repair.

As the skin is the primary barrier to infection, the importance of wound healing has been understood since ancient times. This article provides a synopsis on the symposium presentations focusing on how wounds were traditionally treated, what models and pathology endpoints exist to study wound healing, special considerations for wound healing studies, an overview of regulatory aspects of new pharmaceutical and medical device development, and the clinical relevance of such models. The clinical treatment of small and large wounds is also considered.

Regulatory Forum Opinion Piece*: An Experienced Pathologist Should Be Present at Necropsy for Novel Medical Device Studies.

Necropsies conducted to support medical device development may be conducted in facilities that do not have the infrastructure in place to support Good Laboratory Practice for Nonclinical Laboratory Studies (GLP) studies and for a variety of reasons they may be conducted without a pathologist present at necropsy. However, when a novel medical device or one that is expected to significantly alter tissues is deployed, or when the surgical model confounds interpretation of device effects, it is the opinion of the authors that an experienced pathologist should be present at necropsy.

Evaluation of a collagen-coated, resorbable fiber scaffold loaded with a peptide basic fibroblast growth factor mimetic in a sheep model of rotator cuff repair.

Background: A new scaffold design combined with a peptide growth factor was tested prospectively for safety and for improved tendon healing in sheep.

Methods: The infraspinatus tendon was detached and then surgically repaired to the humerus using sutures and anchors in 50 adult sheep. The repairs in 40 of these sheep were reinforced with a scaffold containing F2A, a peptide mimetic of basic fibroblast growth factor.

Stem Cell Research.

Stem cells have great potential in basic research and are being slowly integrated into toxicological research. This symposium provided an overview of the state of the field, stem cell models, described allogenic stem cell treatments and issues of immunogenicity associated with protein therapeutics, and tehn concentrated on stem cell uses in regenerative medicine focusing on lung and testing strategies on engineered tissues from a pathologist's perspective.

The role of the pathologist in GLP studies.

This continuing education course presented at the Society of Toxicologic Pathology's 31st Annual Symposium explored and defined the many roles that toxicologic pathologists serve Good Laboratory Practice (GLP)-conducted toxicology and carcinogenicity studies.

Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts.

Three anatase titanium dioxide (TiO(2)) nanoparticles (NPs) were prepared; nanospheres (NSs), short nanobelts (NB1), and long nanobelts (NB2). These NPs were used to investigate the effect of NP shape and length on lung toxicity. Mice were exposed (0-30 µg per mouse) by pharyngeal aspiration and pulmonary toxicity was assessed over a 112-day time course.

Subchronic urinary bladder toxicity evaluation of N-Nitrosodiphenylamine in Fischer 344 rats.

Female Fischer 344 (F344) rats were exposed to N-nitrosodiphenylamine (NDPA) by dietary feed at concentrations of 0, 250, 1000, 2000, 3000 or 4000 ppm for 5 days, 2, 4 and 13 weeks duration. Endpoints evaluated included clinical observations, body weights, urinary bladder weights, blood NDPA, gross pathology and urinary bladder histopathology. There were no NDPA exposure-related clinical signs of toxicity.

Subchronic thyroid toxicity evaluation of 4,4'-methylenebis(N,N'-dimethyl)aniline in Fischer 344 rats.

Female F344 rats were exposed to 4,4'-methylenebis(N,N'-dimethyl)aniline (MDA) by dietary feed at concentrations of 0, 50, 200, 375, 500, or 750 ppm for 5 d, 2 wk, 4 wk, and 13 wk duration. Endpoints evaluated included clinical observations, body weights, thyroid weights, serum thyroid hormones, blood MDA, gross pathology, and thyroid histopathology. There were no MDA exposure-related clinical signs of toxicity.

Subchronic hepatotoxicity evaluation of 1,2,4-tribromobenzene in Sprague-Dawley rats.

Male Sprague-Dawley rats were exposed to 1,2,4-tribromobenzene (TBB) by gavage for 5 days, 2, 4, and 13 weeks at 0, 2.5, 5, 10, 25, or 75 mg/kg per d. There were no TBB exposure-related clinical signs of toxicity or changes in body weight.

Nasal turbinate enlargement due to cartilage and bone proliferation: a normal developmental finding in young ferrets.

Toxicity studies of intranasally administered, live attenuated influenza virus vaccine candidates conducted in male and female ferrets led to the microscopic observation of individual differences in the size of nasal turbinates, especially in the dorsal aspect of the nasal cavity. The association of these enlarged turbinates with acute to subacute inflammation, which is sometimes common in ferrets given live attenuated influenza virus vaccine candidates, led to this detailed microscopic evaluation of turbinate enlargement (cartilaginous and osseous thickening, or COT) in control animals dosed intranasally with saline. Results of this evaluation led to the conclusion that COT is a normal developmental feature of growing ferrets, irrespective of inflammation in nasal tissues or inflammatory exudate in the nasal cavity.

Transplacental carcinogenicity of 3'-azido-3'-deoxythymidine in B6C3F1 mice and F344 rats.

The prophylactic use of zidovudine (3'-azido-3'-deoxythymidine, AZT) during pregnancy greatly reduces transmission of HIV-1 from infected mothers to their infants; however, the affinity of host cell DNA polymerases for AZT also allows for its incorporation into host cell DNA, predisposing to cancer development. To expand upon previous transplacental carcinogenesis assays performed in CD-1 mice, the transplacental carcinogenicity of AZT was evaluated in a second mouse strain and a second rodent species. Date-mated female mice and rats were gavaged daily with 0, 80, 240, or 480 mg AZT/kg bw during the last 7 days of gestation.

Refining the effects observed in a developmental neurobehavioral study of ammonium perchlorate administered orally in drinking water to rats. I. Thyroid and reproductive effects.

A recent study further investigated the potential effects of maternal thyroid function and morphology on fetal development upon maternal exposure to ammonium perchlorate during gestation and lactation. Female Sprague-Dawley rats (25/group) were given continual access to 0 (carrier), 0.01, 0.

Does 5-hydroxytryptophan cause acute and chronic toxic perturbations in rats?

In 1989, an epidemic of eosinophilia-myalgia syndrome (EMS) occurred in the United States that was attributed to contaminated l-tryptophan (LT). Features of tryptophan-induced EMS included debilitating myalgia and marked peripheral eosinophilia. Although the contaminant(s) was found only in the product produced by a single manufacturer (Showa Denko), all LT was withdrawn from the market and replaced by 5 hydroxytryptophan (5HTP).

Oral (drinking water) developmental toxicity study of ammonium perchlorate in Sprague-Dawley rats.

A developmental toxicity study was conducted with ammonium perchlorate (AP) in the drinking water at doses of 0.0, 0.01, 0.