Social housing of non-rodents during cardiovascular recordings in safety pharmacology and toxicology studies.

INTRODUCTION: The Safety Pharmacology Society (SPS) and National Centre for the Replacement, Refinement & Reduction of Animals in Research (NC3Rs) conducted a survey and workshop in 2015 to define current industry practices relating to housing of non-rodents during telemetry recordings in safety pharmacology and toxicology studies. The aim was to share experiences, canvas opinion on the study procedures/designs that could be used and explore the barriers to social housing. METHODS: Thirty-nine sites, either running studies (Sponsors or Contract Research Organisations, CROs) and/or outsourcing work responded to the survey (51% from Europe; 41% from USA). RESULTS: During safety pharmacology studies, 84, 67 and 100% of respondents socially house dogs, minipigs and non-human primates (NHPs) respectively on non-recording days. However, on recording days 20, 20 and 33% of respondents socially house the animals, respectively. The main barriers for social housing were limitations in the recording equipment used, study design and animal temperament/activity. During toxicology studies, 94, 100 and 100% of respondents socially house dogs, minipigs and NHPs respectively on non-recording days. However, on recording days 31, 25 and 50% of respondents socially house the animals, respectively. The main barriers for social housing were risk of damage to and limitations in the recording equipment used, food consumption recording and temperament/activity of the animals. CONCLUSIONS: Although the majority of the industry does not yet socially house animals during telemetry recordings in safety pharmacology and toxicology studies, there is support to implement this refinement. Continued discussions, sharing of best practice and data from companies already socially housing, combined with technology improvements and investments in infrastructure are required to maintain the forward momentum of this refinement across the industry.

Evaluation of Nonacog Beta Pegol Long-term Safety in the Immune-deficient Rowett Nude Rat (Crl:NIH-Foxn1rnu).

Nonacog beta pegol is a 40-kDa polyethylene glycosylated (PEGylated) human recombinant coagulation factor IX, intended for the treatment of hemophilia B. Human coagulation factors are immunogenic in animals; therefore, to evaluate the long-term toxicity of nonacog beta pegol, an immune-deficient, athymic rat (Rowett nude; Crl:NIH-Foxn1(rnu)) was used. Rats (n = 216) were given intravenous nonacog beta pegol 0, 40, 150, 600, or 1,200 IU/kg every 5th day for 26 weeks. To avoid infections, the animals were housed in a full-barrier environment with sterilized food and bedding. Standard toxicity end points were unaffected by treatment. All treated animals were exposed to nonacog beta pegol throughout the study, and no animals developed antidrug antibodies. Immunohistochemical staining revealed PEG in choroid plexus epithelial cells in a dose-dependent manner. Transmission electron microscopy showed that PEG was distributed in cytoplasmic vesicles of these cells, with no apparent effect on cellular organelle structures. Fourteen (6.5%) animals were euthanized or died prematurely due to nontreatment-related infections in the urogenital system and skin. In conclusion, the athymic rat is a suitable model for testing chronic toxicity of human proteins that are immunogenic in animals. Nonacog beta pegol was generally well tolerated, with no adverse effect of PEG on choroid plexus epithelial cells.

Detection of Mild and Reversible Neurohistopathological Changes in the Brain of Juvenile (Preweaned) Beagle Dogs Treated with Vigabatrin for up to 91 Days.

Neurohistopathological changes in the brain were assessed in juvenile beagle dogs given vigabatrin at 30 or 100 mg/kg/day by oral gavage from postnatal day 22 (PND22) until 16 weeks of age (PND112), when brain myelination is considered to reach the adult stage in dogs. Separate subgroups were treated from PND22 to PND35 or PND36 to PND49 to assess early effects. In addition to extensive brain histopathology, there were assessments of toxicokinetics, clinical condition, body weight, organ weights, and macroscopic pathology. In animals treated for 14 days from PND22, minimal or slight vacuolation was seen in the neuropil of the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus at 100 mg/kg/day and minimal vacuolation in the thalamus, globus pallidus, and cerebellum at 30 mg/kg/day. In animals given 100 mg/kg/day for 91 days from PND22, minimal or slight vacuolation was observed only in the hippocampus, hypothalamus, and thalamus. No vigabatrin-related brain vacuolation was observed in animals given 30 or 100 mg/kg/day for 14 days from PND36. Clear evidence of recovery was observed after 14-day and 6-week off-dose periods that followed treatment from PND22 to PND35 or PND22 to PND112, respectively.

Neurobehavioural effects of electromagnetic fields.

Very few laboratory studies in children have explored the effects of exposure to low level electromagnetic fields (EMFs) on neurobehavioural function. Studies investigating effect on neurotransmitters, cognitive function and brain activity in adults and animals indicate that acute exposure to EMFs does not appear to engender any consistent physiological or behavioural impairment although a few subtle effects may occur. This suggests that exposure of children to low level EMFs may not cause significant detrimental effects on brain function. However the available evidence is not sufficient to draw any definite conclusions, and further laboratory studies are required. In particular, experiments investigating the effects of radiofrequency (RF) fields on the performance of well-characterised cognitive and behavioural tasks by immature and developing animals are recommended, if studies with children cannot be performed for ethical and practical reasons.