An orthogonal methods assessment of topical drug concentrations in skin and the impact for risk assessment in the viable epidermis.

Systemic toxicity assessments for oral or parenteral drugs often utilize the concentration of drug in plasma to enable safety margin calculations for human risk assessment. For topical drugs, there is no standard method for measuring drug concentrations in the stratum basale of the viable epidermis. This is particularly important since the superficial part of the epidermis, the stratum corneum (SC), is nonviable and where most of a topically applied drug remains, never penetrating deeper into the skin.

Expression of Hematopoietic Stem and Endothelial Cell Markers in Canine Hemangiosarcoma.

Several chemicals and pharmaceuticals increase the incidence of hemangiosarcomas (HSAs) in mice, but the relevance to humans is uncertain. Recently, canine HSAs were identified as a powerful tool for investigating the pathogenesis of human HSAs. To characterize the cellular phenotype of canine HSAs, we evaluated immunoreactivity and/or messenger RNA (mRNA) expression of markers for hematopoietic stem cells (HSCs), endothelial cells (ECs), a tumor suppressor protein, and a myeloid marker in canine HSAs.

Circulating microRNA and automated motion analysis as novel methods of assessing chemotherapy-induced peripheral neuropathy in mice.

Chemotherapy-induced peripheral neuropathy (CiPN) is a serious adverse effect in the clinic, but nonclinical assessment methods in animal studies are limited to labor intensive behavioral tests or semi-quantitative microscopic evaluation. Hence, microRNA (miRNA) biomarkers and automated in-life behavioral tracking were assessed for their utility as non-invasive methods. To address the lack of diagnostic biomarkers, we explored miR-124, miR-183 and miR-338 in a CiPN model induced by paclitaxel, a well-known neurotoxic agent.

Principles of precision medicine and its application in toxicology.

Precision medicine is an approach to developing drugs that focuses on employing biomarkers to stratify patients in clinical trials with the goal of improving efficacy and/or safety outcomes, ultimately increasing the odds of clinical success and drug approval. Precision medicine is an important tool for toxicologists to utilize, because its principles can be used to decide whether to pursue a drug target, to understand interindividual differences in response to drugs in both nonclinical and clinical settings, to aid in selecting doses that optimize efficacy or reduce adverse events, and to facilitate understanding of a drug's mode-of-action. Nonclinical models such as the mouse and non-human primate can be used to understand genetic variation and its potential translation to humans, and are available for toxicologists to employ in advance of drugs moving into clinical development.

From the Cover: Fenretinide, Troglitazone, and Elmiron Add to Weight of Evidence Support for Hemangiosarcoma Mode-of-Action From Studies in Mice.

Pharmaceuticals and chemicals produce hemangiosarcomas (HS) in mice, often by nongenotoxic, proliferative mechanisms. A mode-of-action (MOA) for hemangiosarcoma was proposed based on information presented at an international workshop (Cohen et al., Hemangiosarcoma in rodents: Mode-of-action evaluation and human relevance.

A novel endpoint for the assessment of chemotherapy-induced peripheral neuropathy in rodents: biomechanical properties of peripheral nerve.

Chemotherapy-induced peripheral neuropathy (CiPN) is a frequent adverse effect in patients and a leading safety consideration in oncology drug development. Although behavioral assessment and microscopic examination of the nerves and dorsal root ganglia can be incorporated into toxicity studies to assess CiPN risk, more sensitive and less labor-intensive endpoints are often lacking. In this study, rats and mice administered vincristine (75 μg kg  day , i.

Why Do Promising Therapies Stall in Development and How Can We Move Them Forward?

There are many reasons that molecules fail to progress to market and various principles of risk-benefit decisions that can help drive the molecule through development. This symposium included discussions on global strategies involved in pushing promising molecules to market, what to do when a molecule stalls in its progress to market, and options for rescuing the molecule and pushing it forward again. Innovative partnerships that bring stalled drugs back into clinical development were also addressed.

Evaluation of expression profiles of hematopoietic stem cell, endothelial cell, and myeloid cell antigens in spontaneous and chemically induced hemangiosarcomas and hemangiomas in mice.

It is unclear whether the process of spontaneous and chemically induced hemangiosarcoma and hemangioma formation in mice involves the transformation of differentiated endothelial cells (ECs) or recruitment of multipotential bone marrow-derived hematopoietic stem cells or endothelial progenitor cells (EPCs), which show some degree of endothelial differentiation. In the present study, immunohistochemical staining for hematopoietic stem cell markers (CD45 and CD34), EC markers (vascular endothelial growth factor receptor 2 [VEGFR2], CD31, and factor VIII-related antigen), and a myeloid lineage marker (CD14) was employed to better define the origin of hemangiosarcomas and hemangiomas in mice. Staining was negative for CD45, factor VIII-related antigen, and CD14 and positive for CD34, VEGFR2, and CD31, indicating that mouse hemangiosarcomas and hemangiomas are composed of cells derived from EPCs expressing CD34, VEGFR2, and CD31 but not factor VIII-related antigen.

Mode of action associated with development of hemangiosarcoma in mice given pregabalin and assessment of human relevance.

Pregabalin increased the incidence of hemangiosarcomas in carcinogenicity studies of 2-year mice but was not tumorigenic in rats. Serum bicarbonate increased within 24 h of pregabalin administration in mice and rats. Rats compensated appropriately, but mice developed metabolic alkalosis and increased blood pH.

Hemangiosarcoma in rodents: mode-of-action evaluation and human relevance.

Although rarely occurring in humans, hemangiosarcomas (HS) have become important in evaluating the potential human risk of several chemicals, including industrial, agricultural, and pharmaceutical agents. Spontaneous HS arise frequently in mice, less commonly in rats, and frequently in numerous breeds of dogs. This review explores knowledge gaps and uncertainties related to the mode of action (MOA) for the induction of HS in rodents, and evaluates the potential relevance for human risk.

Embryo/fetal development studies with hydroxypropyl methylcellulose acetate succinate (HPMCAS) in rats and rabbits.

Background: Hoshi et al. [Hoshi et al. J Toxicol Sci 10(Suppl):187-255, 1985a,b,c,d] evaluated the potential for hydroxypropyl methylcellulose acetate succinate (HPMCAS) to produce developmental and reproductive toxicity in a series of studies that included rat and rabbit teratology studies, a rat fertility study, and a rat peri- and postnatal study.

PPARalpha agonist-induced rodent tumors: modes of action and human relevance.

Widely varied chemicals--including certain herbicides, plasticizers, drugs, and natural products--induce peroxisome proliferation in rodent liver and other tissues. This phenomenon is characterized by increases in the volume density and fatty acid oxidation of these organelles, which contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism. Research showing that some peroxisome proliferating chemicals are nongenotoxic animal carcinogens stimulated interest in developing mode of action (MOA) information to understand and explain the human relevance of animal tumors associated with these chemicals.

Comparison of developmental toxicology of aspirin (acetylsalicylic acid) in rats using selected dosing paradigms.

Background: Analysis of the literature for nonsteroidal anti-inflammatory drugs (NSAIDs) suggests that a low incidence of developmental anomalies occurs in rats given NSAIDs on specific days during organogenesis. Aspirin (acetylsalicylic acid [ASA]), an irreversible cyclooxygenase 1 and 2 inhibitor, induces developmental anomalies when administered to Wistar rats on gestational day (GD) 9, 10, or 11 (Kimmel CA, Wilson JG, Schumacher HJ. Teratology 4:15-24, 1971).

Analysis of the nonsteroidal anti-inflammatory drug literature for potential developmental toxicity in rats and rabbits.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed to pregnant women. Some case-control studies have linked the NSAIDs aspirin and indomethacin with a risk of congenital abnormalities and low birthweight. High doses of aspirin produce developmental toxicity in rats (e.

Uncertainties for endocrine disrupters: our view on progress.

The hypothesis that hormonally active compounds in the environment--endocrine disrupters--are having a significant impact on human and ecological health has captured the public's attention like no other toxicity concern since the publication of Rachel Carson's Silent Spring 1962. In the early 1990s, Theo Colborn and others began to synthesize information about the potential impacts of endocrine-mediated toxicity in the scientific literature (Colborn and Clement, 1992) and the popular press (Colborn et al., 1997).

Evaluation of Tier I screening approaches for detecting endocrine-active compounds (EACs).

In 1996, Congress passed legislation requiring the U.S. Environmental Protection Agency (EPA) to implement screening/testing strategies for endocrine-active compounds (EACs).