Sequani Ltd.

Ledbury, United Kingdom

Sequani Ltd.

Ledbury, United Kingdom
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Downes N.,Sequani Ltd | Foster J.,Cheshire Impact
Toxicologic Pathology | Year: 2015

Throughout the last 50 years, the paradigm for carcinogenicity assessment has depended on lifetime bioassays in rodents. Since 1997, the International Conference on Harmonisation (ICH) S1B has permitted the use of a 2-year rodent bioassay (usually in the rat) and an alternative, genetically modified mouse model to support cancer risk assessment of pharmaceuticals. Since its introduction, it has become apparent that many of the stated advantages of the 6-month Tg mouse bioassay have, in actual fact, not been realized, and the concern exists that an albeit imperfect, 2-year mouse bioassay has been replaced by a similarly imperfect 6-month equivalent. This essay argues strongly that model systems, using cancer as the end point, should be discontinued, and that the recent initiatives, from the Organization for Economic Cooperation and Development and Institute of Peace and Conflict Studies, on 'mode of action,' 'adverse outcome pathways,' and 'human relevance framework' should be embraced as being risk assessments based upon the available science. The recent suggested revisions to the ICH S1 guidelines, utilizing carcinogenicity assessment documents, go some way to developing a science-based risk assessment that does not depend almost entirely on a single, imperfect, cancer-based end point in nonrelevant animal species. © 2015 by The Author(s).


PubMed | Cheshire and Sequani Ltd
Type: Historical Article | Journal: Toxicologic pathology | Year: 2015

Throughout the last 50 years, the paradigm for carcinogenicity assessment has depended on lifetime bioassays in rodents. Since 1997, the International Conference on Harmonisation (ICH) S1B has permitted the use of a 2-year rodent bioassay (usually in the rat) and an alternative, genetically modified mouse model to support cancer risk assessment of pharmaceuticals. Since its introduction, it has become apparent that many of the stated advantages of the 6-month Tg mouse bioassay have, in actual fact, not been realized, and the concern exists that an albeit imperfect, 2-year mouse bioassay has been replaced by a similarly imperfect 6-month equivalent. This essay argues strongly that model systems, using cancer as the end point, should be discontinued, and that the recent initiatives, from the Organization for Economic Cooperation and Development and Institute of Peace and Conflict Studies, on mode of action, adverse outcome pathways, and human relevance framework should be embraced as being risk assessments based upon the available science. The recent suggested revisions to the ICH S1 guidelines, utilizing carcinogenicity assessment documents, go some way to developing a science-based risk assessment that does not depend almost entirely on a single, imperfect, cancer-based end point in nonrelevant animal species.


Downes N.,Sequani Ltd | Mullins P.,Sequani Ltd
Toxicologic Pathology | Year: 2014

The development process of myelination varies between region and species. Fully myelinated fibers are required if mammalian neural circuits are to function normally. Histology samples at staggered time points throughout the study were examined at days 4, 5, 7, 8, 10, 14, 17, 24, 37, and 44. We suggest that the development of myelin in the juvenile rodent brain can be conveniently separated into 3 phases. Evaluation of myelin basic protein-stained sections of the areas of brain that contain the elements of the developing limbic system over the sensitive period from postnatal day (PND) 14 to 34 may provide an insight into possible toxicity that may lead to cognition and learning issues in adults. We will hope to develop this notion further in the future. The precise chronology of the development of the blood-brain barrier in rats has yet to be established; thus, there is potential for significant exposure of the juvenile brain to chemicals that do not cross the blood-brain barrier in the adult. Thus, it is suggested that evaluation of myelin development should probably be extended to all new chemical entities intended for pediatric use, and not just those that are intended for central nervous system use. © 2014 by The Author(s).


Downes N.,Sequani Ltd
Toxicologic Pathology | Year: 2012

The recent increase in numbers of juvenile toxicity studies over the past few years has doubtless added to our knowledge of the development of organ systems in the young rodent, but it is perhaps rather more difficult to answer the questions as to whether this body of work has served us well in terms of assessing risk in the pediatric population. If there are shortcomings, are they the result of poor study design or poor sensitivity of the model, or are the wrong questions being posed? This article provides a superficial overview of the progress made thus far and considers which aspects of study design and model choice currently fail to adequately address the major issues surrounding pediatric toxicology. © 2012 by The Author(s).


Rickard M.,Sequani Ltd. | Rickard M.,Animal Health and Veterinary Laboratories Agency AHVLA
Animal Technology and Welfare | Year: 2011

When it is not feasible to accommodate and maintain a parent flock and hatchery for varying reasons that might include avoiding production of surplus stock, it is necessary to purchase day old turkeys from selected commercial suppliers and rear them to age. The successful rearing of the required number of turkeys which are 'fit for purpose' to enter a study is challenging. Batches of turkeys may suffer from 'failure to survive syndrome' or 'starve out' 1 during which they fail to eat and subsequently die, excessive feather and vent pecking will lead to further mortalities. The aim of this investigation was to study whether the provision of enrichment items reduced the occurrence of feather pecking therefore reducing mortality within batches of turkeys aged between one day old to 4 weeks of age. This knowledge would be used to implement a reduction in the number of day old turkeys being purchased in order to supplement expected heavy losses and ensure the active program of animal welfare continues to remain at a high standard.


Rasmussen A.D.,Lundbeck | Richmond E.,Sequani Ltd | Wegener K.M.,Lundbeck | Downes N.,Sequani Ltd | Mullins P.,Sequani Ltd
NeuroToxicology | Year: 2015

The purpose of this study was to expand on the knowledge previously published on the central nervous system effects of Vigabatrin in juvenile animals. By employing extended sectioning of the brain and by using four different tissue staining techniques it is demonstrated that oral administration of Vigabatrin to juvenile rats (treatment periods of post-natal day (PND) 4-7, 7-14 or 14-30) will cause histological CNS changes at dose levels of 15 and 50 mg/kg/day, but not at a dose level of 5 mg/kg/day. No evidence of neuronal degeneration or gliosis was seen at any stage of treatment. Consistent with previous reports microvacuolation, as well as effects on myelination and on oligodendrocytes were recorded. The present study expands on these findings and demonstrates that the variation in the location of the vigabatrin-induced lesions in the juvenile rat brain (both neuropil vacuolation and reduction of myelin) appears to be consistent with the process of myelination: In the youngest animals (PND 4-7) myelination occurs mainly in the hind brain (medulla oblongata and pons) where neuropil vacuolations is recorded. In animals dosed during PNDs 7-14 or during PNDs 14-30, the first changes were found in the thalamus. It seems likely that the earlier stages of myelination are more vulnerable to treatment related effects and the swollen oligodendrocytes seen as the initial change in the thalamus in animals treated during PNDs 4-7 and 7-14 represents an early stage in the development of the myelin lesion which is seen later as neuropil vacuolation. © 2014 Elsevier Inc.


Downes N.,Sequani Ltd
Toxicologic Pathology | Year: 2010

The rodent bioassay has been a mainstay of carcinogenic risk assessment for close to half a century; not that it has been without criticism in that time. As early as the 1990s, there were clearly established shortcomings with regard to relevance and extrapolation, but despite these concerns, this test continues relatively unchanged. As our understanding of the mechanisms of carcinogenesis and the availability of investigative techniques improve, there seems less reason than ever to persist with this exercise that provides little meaningful scientific data at great cost in terms of animal usage and pathologist time. This article highlights possible ways to gather and present data pertinent to carcinogenesis in man and suggests that it is the toxicological pathology community that should take the lead here in persuading regulators that there is great room for improvement in this particular aspect of regulatory pathology. Copyright © 2010 by The Author(s).


PubMed | Envigo, CiToxLAB Scantox A S, A Charles River Company Lyon, Ellegaard Gottingen Minipigs A S and 2 more.
Type: | Journal: Reproductive toxicology (Elmsford, N.Y.) | Year: 2016

Knowledge of the incidence of spontaneous congenital abnormalities is critical for the accurate interpretation of findings in teratogenicity studies in any species. In this paper, results of the examination of 1739 neonatal Gttingen Minipigs are presented. Over the 2-year period under consideration, the incidence of external and visceral malformations was less than 0.2 and 0.1%, respectively. The most common external malformations were syndactyly, limb hyperflexion, domed head and scoliosis. The most common internal malformations were undescended testes, ventricular septal defect, diaphragmatic hernia and atrial septal defects. Pentadactyly and variation in the aortic archs bifurcation (absent truncus bicaroticus) were the most common variations. These data will help support the use of the Gttingen Minipig as a non-rodent species in embryofetal development studies where concerns persist about the availability of background data.


PubMed | Sequani Ltd and University of Antwerp
Type: Journal Article | Journal: Journal of pharmacokinetics and pharmacodynamics | Year: 2016

The Gttingen minipig is the most commonly used pig breed in preclinical drug development in Europe and has recently also been explored for physiologically based pharmacokinetic modelling. To develop such a model, not only physiological data from adult animals but also data from juvenile animals are required, especially when using this model for paediatric drug development. Therefore, the aim of our study was to document body and organ weights (brain, heart, lungs, liver, gastrointestinal tract, spleen and kidney), lengths of the small and large intestines and pH values of the gastrointestinal tract in Gttingen minipigs from the foetal stage until the age of 5 months. Postnatal organ and body weights were fitted to regression models to find suitable equations that could be used to estimate organ weights as a function of body weight in the neonatal and juvenile Gttingen minipig. Most organs followed a non-linear growth curve during the first 5 months of life. In general, relative organ weights were the highest during the first week of life, during which the gastric pH was more alkaline than at 28 days of age.


PubMed | Sequani Ltd
Type: Journal Article | Journal: Toxicologic pathology | Year: 2015

The development process of myelination varies between region and species. Fully myelinated fibers are required if mammalian neural circuits are to function normally. Histology samples at staggered time points throughout the study were examined at days 4, 5, 7, 8, 10, 14, 17, 24, 37, and 44. We suggest that the development of myelin in the juvenile rodent brain can be conveniently separated into 3 phases. Evaluation of myelin basic protein-stained sections of the areas of brain that contain the elements of the developing limbic system over the sensitive period from postnatal day (PND) 14 to 34 may provide an insight into possible toxicity that may lead to cognition and learning issues in adults. We will hope to develop this notion further in the future. The precise chronology of the development of the blood-brain barrier in rats has yet to be established; thus, there is potential for significant exposure of the juvenile brain to chemicals that do not cross the blood-brain barrier in the adult. Thus, it is suggested that evaluation of myelin development should probably be extended to all new chemical entities intended for pediatric use, and not just those that are intended for central nervous system use.

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