Toxicological evaluation of the ketogenic ester bis hexanoyl (R)-1,3-butanediol: Subchronic toxicity in Sprague Dawley rats.

Bis-hexanoyl (R)-1,3-butanediol (BH-BD) is novel ketone ester undergoing development as a food ingredient to achieve nutritional ketosis in humans. Male and female Crl:CD(SD) rats were administered BH-BD twice daily at 9000, 12,000 or 15,000 mg/kg/day, by oral gavage in a 90-day toxicity study with 28-day recovery period; and an interim 28-day phase. Test substance-related early deaths occurred in four females at 15,000 mg/kg/day.

Correction to: Letter to the editor regarding "safety of safety evaluation of pesticides: developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl" by Mie et al. (environmental health. 2018. 17:77).

Following publication of the original article.

Submarine exposure guideline recommendations for carbon dioxide based on the prenatal developmental effects of exposure in rats.

Background: To protect crewmember health, the U.S. Navy sets exposure limits for more than 200 components of submarine atmospheres.

When is a terrace not a terrace? The importance of understanding landscape evolution in studies of terraced agriculture.

Before the invention of modern, large-scale engineering projects, terrace systems were rarely built in single phases of construction, but instead developed gradually, and could even be said to have evolved. Understanding this process of landscape change is therefore important in order to fully appreciate how terrace systems were built and functioned, and is also pivotal to understanding how the communities that farmed these systems responded to changes; whether these are changes to the landscape brought about by the farming practices themselves, or changes to social, economic or climatic conditions. Combining archaeological stratigraphy, soil micromorphology and geochemistry, this paper presents a case-study from the historic and extensive terraced landscape at Konso, southwest Ethiopia, and demonstrates - in one important river valley at least - that the original topsoil and much of the subsoil was lost prior to the construction of hillside terraces.

Use of the Reamer/Irrigator/Aspirator Decreases Carotid and Cranial Embolic Events in a Canine Model.

Background: Approximately 2 million patients in the United States annually undergo total joint arthroplasty with reaming and placement of intramedullary nails, resulting in extravasation of bone marrow and fat into the circulatory system and potentially causing fat embolism syndrome. Acute and chronic changes in mental status documented after these procedures may be related to embolic events. The Reamer/Irrigator/Aspirator (RIA) device has been shown to decrease intramedullary pressure during reaming.

Absence of developmental toxicity in a canine model after infusion of a hemoglobin-based oxygen carrier: Implications for risk assessment.

Bovine-derived hemoglobin-based oxygen carriers (HBOCs) have been investigated for use in humans (HBOC-201) and approved for veterinary medicine (HBOC-301). We infused pregnant beagles with HBOC-201 to test whether HBOC-induced developmental toxicity previously observed in rats would occur in a species devoid of an inverted visceral yolk sac (invVYS). Phase 1 assessed developmental toxicity of 6g/kg HBOC-201 on gestational day (GD) 21.

Developmental toxicity in rats of a hemoglobin-based oxygen carrier results from impeded function of the inverted visceral yolk sac.

HBOC-201 is a bovine-derived, cross-linked, and stabilized hemoglobin (250kDa) in physiological saline. Daily intravenous infusions of HBOC (1.95, 3.

Postnatal development of the testis in the rat: morphologic study and correlation of morphology to neuroendocrine parameters.

Histopathologic examination of the testis from juvenile rats is often necessary to characterize the safety of new drugs for pediatric use and is a required end point in male pubertal development and thyroid function assays. To aid in evaluation and interpretation of the immature testis, the characteristic histologic features of the developing rat testis throughout postnatal development are described and correlated with published neuroendocrine parameter changes. During the neonatal period (postnatal day [PND] 3-7), seminiferous tubules contained gonocytes and mitotically active immature Sertoli cells.

Postnatal ovary development in the rat: morphologic study and correlation of morphology to neuroendocrine parameters.

Histopathologic examination of the immature ovary is a required end point on juvenile toxicity studies and female pubertal and thyroid function assays. To aid in this evaluation and interpretation of the immature ovary, the characteristic histologic features of rat ovary through the developmental periods are described. These histologic features are correlated with published changes in neuroendocrine profiles as the hypothalamic-pituitary-gonadal axis matures.

Key lessons from performance of the U.S. EPA Endocrine Disruptor Screening Program (EDSP) Tier 1 male and female pubertal assays.

The male and female pubertal assays, which are included in the U.S. Environmental Protection Agency's (EPA) Endocrine Disruptor Screening Program (EDSP) Tier 1 battery, can detect endocrine-active compounds operating by various modes of action.

Characterization of the T-dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) in the Göttingen minipig.

Recently, there has been a renewed interest in the use of the minipig as an alternative to dogs and non-human primates for conducting toxicological assessments in non-rodent species. Since the T-dependent antibody response (TDAR) is one of the most widely-accepted assays used in the assessment of immunocompetence, the present study was undertaken to characterize the primary and secondary TDAR to keyhole limpet hemocyanin (KLH) in the Göttingen Minipig(®). Following primary immunization with either 2 or 10 mg KLH, anti-swine IgM and IgG ELISAs were optimized and individual animal responses were evaluated over time.

Longitudinal evaluation of neurobehavioral outcomes after carotid revascularization.

Background: Carotid revascularization, including carotid endarterectomy (CEA) and carotid angioplasty and stenting (CAS), is performed for stroke risk reduction but may also impact cognitive function. Cognitive outcomes observed after carotid revascularization have been inconsistent, and mechanistic relationships with procedural factors are poorly understood. To further explore associations between carotid revascularization and cognitive outcomes, a prospective longitudinal evaluation was conducted of patients undergoing elective CEA or CAS for hemodynamically significant carotid stenosis.

Molecular modeling and functional confirmation of a predicted fatty acid binding site of mitochondrial aspartate aminotransferase.

Molecular interactions are necessary for proteins to perform their functions. The identification of a putative plasma membrane fatty acid transporter as mitochondrial aspartate aminotransferase (mAsp-AT) indicated that the protein must have a fatty acid binding site. Molecular modeling suggests that such a site exists in the form of a 500-Å(3) hydrophobic cleft on the surface of the molecule and identifies specific amino acid residues that are likely to be important for binding.

An oral developmental neurotoxicity study of decabromodiphenyl ether (DecaBDE) in rats.

Background: Decabromodiphenyl ether (DecaBDE; CASRN 1163-19-5) is a flame retardant used in a variety of manufactured products. A single oral dose of 20.1 mg/kg administered to mice on postnatal day 3 has been reported to alter motor activity at 2, 4, and 6 months of age.

Cannula design reduces particulate and gaseous emboli during cardiopulmonary bypass for coronary revascularization.

Purpose: The incidence of neurocognitive deficits after coronary bypass surgery remains problematic, with atheroembolism being one of the major causes. External manipulation of aorta and the "sandblasting" effect of the high-velocity perfusion jet can cause dislodgement of atheromatous debris.

Description: A new arterial cannula features a tip configuration that diffuses the flow through multiple outlets, providing reduced velocity and shear with one central and three diverted flow streams.

Effects of dose, administration route, and/or vehicle on decabromodiphenyl ether concentrations in plasma of maternal, fetal, and neonatal rats and in milk of maternal rats.

The effects of route and vehicle on blood and milk levels of decabromodiphenyl ether (DecaBDE; CASRN 1163-19-5) were investigated in the rat to assist in the design and conduct of a developmental neurotoxicity study. Blood plasma and/or milk concentrations were determined in dams, fetuses, and/or nursing pups after repeated DecaBDE administration by gavage throughout gestation or gestation and lactation using corn oil (CO) or soyaphospholipon/Lutrol F 127-water (SPL) as the vehicle. The impact of vehicle on plasma levels was also investigated in pups derived from naive dams after a single postnatal dose.

Consensus statement: minimal criteria for reporting the systemic inflammatory response to cardiopulmonary bypass.

The lack of established cause and effect between putative mediators of inflammation and adverse clinical outcomes has been responsible for many failed anti-inflammatory interventions in cardiopulmonary bypass (CPB). Candidate interventions that impress in preclinical trials by suppressing a given inflammation marker might fail at the clinical trial stage because the marker of interest is not linked causally to an adverse outcome. Alternatively, there exist examples in which pharmaceutical agents or other interventions improve clinical outcomes but for which we are uncertain of any antiinflammatory mechanism.

Assessing the toxicological significance of ejaculatory plugs as a clinical observation in rat toxicology studies: CNS-mediated increases in plug production vs. gustatory-mediated decreases in plug consumption.

Spontaneous ejaculation has been reported in a variety of mammalian species and may occur either as a result of pharmacological treatment or as a component of the daily behavior of normal, untreated animals. Infrequently, increased numbers of spontaneous ejaculatory plugs have been reported among the clinical signs in rat toxicology studies. This mini-review presents an overview on the presence of ejaculatory plugs in rodents and provides recommendations to consider when attempting to understand the toxicological significance of increased numbers of ejaculatory plugs in rat toxicology studies.

Oral gavage subchronic neurotoxicity and inhalation subchronic immunotoxicity studies of ethylbenzene in the rat.

The potential for neurotoxicological and immunotoxicological effects of ethylbenzene was studied in young adult Crl:CD(SD) rats following 90-day oral (neurotoxicity) or 28-day inhalation (immunotoxicity) exposures. In the neurotoxicity study, ethylbenzene was administered orally via gavage twice daily at 0, 25, 125, or 250 mg/kg per dose (total daily dosages of 0, 50, 250, or 500 mg/kg bwt/day [mg/kg bwt/day]) for 13 weeks and the functional observational battery (FOB), automated tests for motor activity and neuropathological examination were conducted. In the immunotoxicity study, animals were exposed by inhalation to 0, 25, 100, or 500 ppm ethylbenzene (approximately 26, 90, or 342 mg/kg bwt/day as calculated from physiologically based pharmacokinetic modeling).

Developmental neurotoxicity study of dietary bisphenol A in Sprague-Dawley rats.

This study was conducted to determine the potential of bisphenol A (BPA) to induce functional and/or morphological effects to the nervous system of F(1) offspring from dietary exposure during gestation and lactation according to the Organization for Economic Cooperation and Development and U.S. Environmental Protection Agency guidelines for the study of developmental neurotoxicity.

Juvenile animal toxicity study designs to support pediatric drug development.

The objective of juvenile animal toxicity studies of pharmaceuticals is to obtain safety data, including information on the potential for adverse effects on postnatal growth and development. Studies in juvenile animals may assist in identifying postnatal developmental toxicities or other adverse effects that are not adequately assessed in the routine toxicity evaluations and that cannot be safely or adequately measured in pediatric clinical trials. Unlike the traditional reproductive and developmental toxicology studies that have been discussed in the accompanying reports, the design requirements for toxicity studies in juvenile animals are not explicitly defined in regulatory guidance.

The nonclinical fertility study design for pharmaceuticals.

Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the ICH S5(R2) document, "Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male Fertility." Studies that assess a candidate drug's effect on fertility are generally conducted in rats. The evolution of, and ultimate harmonization of, fertility study designs are reviewed, and specific elements of an acceptable design, as well as the recommendations for presentation of data, are described in detail.

Embryo-fetal developmental toxicity study design for pharmaceuticals.

Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the International Conference on Harmonization (ICH) S5(R2) document (available at http://www.ich.org).