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PubMed | L'Oréal, Episkin SA, CiToxLAB, VitroScreen and 3 more.
Type: Journal Article | Journal: Toxicology in vitro : an international journal published in association with BIBRA | Year: 2015

The U-SENS is a test method based on the human myeloid U937 cell line to assess the skin sensitisation potential of substances. To demonstrate its robustness, a multicentre validation study with four laboratories testing 24 coded substances has been conducted according to internationally agreed principles. The primary objective of the study was to enlarge the U-SENSs reproducibility database. Secondary objectives were to provide additional evidence on its transferability and its predictive capability. Reproducibility within laboratories was approximately 92%, while the reproducibility between laboratories was 87.5%. Predictivity for the 24 validation substances was high, with sensitivity, specificity and accuracy being on average at least 93.8%. Similar performances are obtained for 38 substances when combining the study results with those of an earlier multicentre study, as well as with an automated version of the U-SENS. With reliability and relevance similar to comparable non-animal skin sensitisation test methods, which have achieved regulatory acceptance, it is concluded that the U-SENS is a well reproducible and predictive test method. This profiles the U-SENS as a valuable addition to the suite of non-animal testing methods for skin sensitisation with the potential to significantly contribute to the development of integrated testing strategies.


PubMed | Prosensa, Glaxosmithkline, University of California at Davis and CiToxLab
Type: Journal Article | Journal: Toxicologic pathology | Year: 2015

Chronic administration of drisapersen, a 2-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration. Glomerulopathy occurred in both species with species-specific characteristics. Glomerular lesions in mice were characterized by progressive hyaline matrix accumulation, accompanied by the presence of renal amyloid and with subsequent papillary necrosis. Early changes involved glomerular endothelial hypertrophy and degeneration, but the chronic glomerular amyloid and hyaline alterations in mice appeared to be species specific. An immune-mediated mechanism for the glomerular lesions in mice was supported by early inflammatory changes including increased expression of inflammatory cytokines and other immunomodulatory genes within the renal cortex, increased stimulation of CD68 protein, and systemic elevation of monocyte chemotactic protein 1. In contrast, kidneys from monkeys given drisapersen chronically showed less severe glomerular changes characterized by increased mesangial and inflammatory cells, endothelial cell hypertrophy, and subepithelial and membranous electron-dense deposits, with ultrastructural and immunohistochemical characteristics of complement and complement-related fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a condition described in man and experimental animals to be linked to dysregulation of the alternative complement pathway. Thus, inflammatory/immune mechanisms appear critical to glomerular injury with species-specific sensitivities for mouse and monkey. The lower observed proinflammatory activity in humans as compared to mice and monkeys may reflect a lower risk of glomerular injury in patients receiving AON therapy.


Baumann A.,Bayer AG | Flagella K.,Genentech | Forster R.,CiToxLAB | de Haan L.,MedImmune | And 5 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

New challenges and opportunities in nonclinical safety testing of biologics were discussed at the 3rd European BioSafe Annual General Membership meeting in November 2013 in Berlin:. (i)Approaches to refine use of non-human primates in non-clinical safety testing of biologics and current experience on the use of minipigs as alternative non-rodent species.(ii)Tissue distribution studies as a useful tool to support pharmacokinetic/pharmacodynamic (PKPD) assessment of biologics, in that they provide valuable mechanistic insights at drug levels at the site of action.(iii)Mechanisms of nonspecific toxicity of antibody drug conjugates (ADC) and ways to increase the safety margins.(iv)Although biologics toxicity typically manifests as exaggerated pharmacology there are some reported case studies on unexpected toxicity.(v)Specifics of non-clinical development approaches of noncanonical monoclonal antibodies (mAbs), like bispecifics and nanobodies. © 2014 Elsevier Inc.


PubMed | MedImmune, Bayer AG, Pfizer, UCB Pharma and 4 more.
Type: Congresses | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2014

New challenges and opportunities in nonclinical safety testing of biologics were discussed at the 3rd European BioSafe Annual General Membership meeting in November 2013 in Berlin: (i)Approaches to refine use of non-human primates in non-clinical safety testing of biologics and current experience on the use of minipigs as alternative non-rodent species.(ii)Tissue distribution studies as a useful tool to support pharmacokinetic/pharmacodynamic (PKPD) assessment of biologics, in that they provide valuable mechanistic insights at drug levels at the site of action.(iii)Mechanisms of nonspecific toxicity of antibody drug conjugates (ADC) and ways to increase the safety margins.(iv)Although biologics toxicity typically manifests as exaggerated pharmacology there are some reported case studies on unexpected toxicity.(v)Specifics of non-clinical development approaches of noncanonical monoclonal antibodies (mAbs), like bispecifics and nanobodies.


Garg S.,University of Arkansas for Medical Sciences | Zheng J.,University of Arkansas for Medical Sciences | Wang J.,University of Arkansas for Medical Sciences | Authier S.,CIToxLAB | And 3 more authors.
Radiation Research | Year: 2016

Dysfunction of the intestinal epithelial barrier and leakage of luminal antigens and bacteria across the barrier have been linked to various human diseases. Intestinal permeability is regulated by intercellular structures, termed "tight junction" (Tj), which are disrupted after total-body irradiation (TBI). In this study, we investigated radiation-induced alterations in Tj-related proteins in the jejunum, ileum and colon of a non-human primate (NHP) model. NHPs were total-body irradiated with 6.7 and 7.4 Gy and intestines were procured at day 4, 7 and 12. Radiation exposure was found to induce significant increases in claudin-10 mRNA early (day 4) in all three gut segments and claudin-4 mRNA levels were repressed through day 12. TNF-alpha was highly induced in the jejunum and colon at early time points, but little induction was found in the ileum. Claudin-1 was induced only in the colon on day 4 postirradiation. Unlike the colon and jejunum, the ileum levels of claudin-7 were significantly downregulated through day 12 postirradiation. Western blot analysis revealed increased levels of claudin-2 on day 4 and of JAM-1 on day 7 postirradiation in all three gut segments. E-cadherin was downregulated on day 4 postirradiation in all segments, but remained reduced in the jejunum only until day 12. Taken together, these data suggest that exposure to radiation causes segment-specific alterations in the expression of Tj-related proteins. Interruption of Tjs may be a key factor contributing to injury to the intestinal mucosal barrier and increased intestinal permeability. © 2016 by Radiation Research Society.


Barrow P.C.,CiToxLAB | Reynaud L.,Ricerca Biosciences
Methods in Molecular Biology | Year: 2013

The regulatory toxicology report is an unusual document that requires a particular skill to write. The report must be clear, accurate, concise, and focused. A clear and direct writing style is required. The end-users of the report will hope to find the information they seek with as little effort as possible. Few, or none, will read the entire document. The author should aim to appease the user by obliging him to read as little text and turn as few pages as possible. This chapter gives tips and guidance on how to present the experimental data and write the narrative text in the final study report for a teratology study. © 2013 Springer Science+Business Media, LLC.


Barrow P.C.,CiToxLAB | Allais L.,Ricerca Biosciences
Methods in Molecular Biology | Year: 2013

Preventative and therapeutic vaccines are increasingly used during pregnancy and present special considerations for developmental toxicity testing. The various components of the vaccine formulation (i.e., protein or polysaccharide antigen, adjuvants, and excipients) need to be assessed for direct effects on the developing conceptus. In addition, possible adverse influences of the induced antibodies on fetal and/or postnatal development need to be evaluated. A guidance document on the preclinical testing of preventative and therapeutic vaccines for developmental toxicity was issued by the FDA in 2006. Preclinical studies are designed to assess possible influences of vaccines on pre- and postnatal development. The choice of model animal for these experiments is influenced by species differences in the timing and extent of the transfer of the induced maternal antibodies to the fetus. The cross-placental transport of maternal immunoglobulins generally only occurs in late gestation and tends to be greater in humans and monkeys than in non-primate species. For many vaccines, the rabbit shows a greater rate of prenatal transfer of the induced antibodies than rodents. For biotechnology-derived vaccines that are not immunogenic in lower species, nonhuman primates may be the only appropriate models. It may be advisable to test new adjuvants using the ICH study designs for conventional pharmaceuticals in addition to the developmental toxicity study with the final vaccine formulation. © 2013 Springer Science+Business Media, LLC.


PubMed | Tetrahedron and CiToxLAB
Type: | Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association | Year: 2015

L-Ergothioneine is a naturally occurring histidine-derived betaine (CAS No: 497-30-3) synthesized by bacteria and fungi, and found ubiquitously in plants and animals. It is present in many human foodstuffs. We evaluated the potential reproductive toxicity of L-Ergothioneine in Sprague-Dawley rats. L-Ergothioneine was administered at concentrations of 0.1, 0.3 or 0.9% in diet to F0 males (for 10 weeks before pairing and 3 weeks during pairing) and F0 females (for 13 weeks before pairing, during pairing and gestation, and until day 5 of lactation). Systemic exposure increased with dose-level, but not dose proportionally, suggesting saturation of uptake mechanisms. No clinical signs of toxicity were observed and there were no effects of L-Ergothioneine treatment on mating and reproductive performance or parameters of fertility. All animals mated within a similar number of days and pregnancy rates were uniformly high in control and treated groups. There were no effects of treatment with L-Ergothioneine on the duration of gestation, pre- and post-implantation losses, number of pups delivered and viability index, or on litter parameters (litter size, clinical signs, body weight or sex ratio) and the repartition of found dead/cannibalized pups. In conclusion, L-Ergothioneine was well tolerated and without adverse effects on the reproductive parameters evaluated.


Barrow P.C.,CiToxLAB | Spezia F.,CiToxLAB
Methods in Molecular Biology | Year: 2013

The developmental and reproductive toxicity testing (including teratogenicity) of new foods and food additives is performed worldwide according to the guidelines given in the FDA Redbook. These studies are not required for substances that are generally recognized as safe, according to the FDA inventory. The anticipated cumulated human exposure level above which developmental or reproduction studies are required depends on the structure-alert category. For food additives of concern, both developmental (prenatal) and reproduction (multigeneration) studies are required. The developmental studies are performed in two species, usually the rat and the rabbit. The reproduction study is generally performed in the rat. The two rat studies are preferably combined into a single experimental design, if possible. The test methods described in the FDA Redbook are similar to those specified by the OECD for the reproductive toxicity testing of chemicals. © 2013 Springer Science+Business Media, LLC.


Spezia F.,CiToxLAB | Barrow P.C.,CiToxLAB
Methods in Molecular Biology | Year: 2013

In Europe, the developmental toxicity testing (including teratogenicity) of new cosmetic ingredients is performed according to the Cosmetics Directive 76/768/EEC: only alternatives leading to full replacement of animal experiments should be used. This chapter presents the three scientifically validated animal alternative methods for the assessment of embryotoxicity: the embryonic stem cell test (EST), the micromass (MM) assay, and the whole embryo culture (WEC) assay. © 2013 Springer Science+Business Media, LLC.

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