BioMath GmbH

Rostock, Germany

BioMath GmbH

Rostock, Germany

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PubMed | European Center for Ecotoxicology and Toxicology of Chemicals, Public Health England, University of Leipzig, Dow AgroSciences and 14 more.
Type: | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2016

The European Centre for the Ecotoxicology and Toxicology of Chemicals (ECETOC) organised a workshop to discuss the state-of-the-art research on noncoding RNAs (ncRNAs) as biomarkers in regulatory toxicology and as analytical and therapeutic agents. There was agreement that ncRNA expression profiling data requires careful evaluation to determine the utility of specific ncRNAs as biomarkers. To advance the use of ncRNA in regulatory toxicology, the following research priorities were identified: (1) Conduct comprehensive literature reviews to identify possibly suitable ncRNAs and areas of toxicology where ncRNA expression profiling could address prevailing scientific deficiencies. (2) Develop consensus on how to conduct ncRNA expression profiling in a toxicological context. (3) Conduct experimental projects, including, e.g., rat (90-day) oral toxicity studies, to evaluate the toxicological relevance of the expression profiles of selected ncRNAs. Thereby, physiological ncRNA expression profiles should be established, including the biological variability of healthy individuals. To substantiate the relevance of key ncRNAs for cell homeostasis or pathogenesis, molecular events should be dose-dependently linked with substance-induced apical effects. Applying a holistic approach, knowledge on ncRNAs, omics and epigenetics technologies should be integrated into adverse outcome pathways to improve the understanding of the functional roles of ncRNAs within a regulatory context.


Schmidt K.,biovativ GmbH | Schmidt K.,BioMath GmbH | Hoflich C.,University of Rostock | Bruch M.,University of Rostock | And 17 more authors.
Journal fur Kulturpflanzen | Year: 2011

Geneticall y mo dified (GM) plants have to be analyzed for their potential impacts on the environment and on human or animal health before authorisation by the EU. The approval process currently refers to a conglomeration of diverse analytical methods and is intensive in time and costs. The intention of BioOK as a multidisciplinary scientific network is the development of tailor-made approaches for GM plants based on a cause-effect hypothesis to obtain an effective and qualified risk assessment system. The research activity of BioOK aims to renew the current approval process. It is based on a modular system covering all aspects of risk assessment: molecular characterisation, compound analysis, agronomic traits, target and non-target organisms, soil and micro organisms, toxicology, allergenicity and post-market monitoring, each module containing several test methods. The renewal of the risk assessment procedure intended by BioOK consists of two phases: first the optimization of test methods and second the establishment of a decision support system (DSS) based on baselines, indicators and thresholds developed for each of the methods. Optimized test methods have been developed mainly during the first phase: For compound analysis methods have been developed to ease the analysis of substantial equivalence of the events by GC-MS, LC-MS and HPLC/RI. A newly introduced testing scheme for the detection of potential effects of GM plants on soil combines an in-vitro system to collect rhizodeposits from plants grown under controlled environmental conditions and the corresponding bulk soil, and their characterisation by untargeted and highly sensitive molecular-chemical screening and fingerprinting technique. A novel in vitro system simulating the transport of substances from the gut into the blood that detects the risk of incorporation in human or animal at an early time point was developed. In order to increase the effectiveness and reproducibility of the sampling procedure we developed a valid defined sampling scheme. Finally, complementing the actual General Surveillance methodology, an approach for a Europe-wide case specific monitoring referring to cause-effect scenarios was developed. The second phase concentrates on the development of a Decision Support System (DSS). A computer-based system will implement and merge all standardized methods in a decision tree system following decision rules defined by baseline and thresholds for indicators.


Zeljenkova D.,Slovak Medical University | Alacova R.,Slovak Medical University | Ondrejkova J.,Slovak Medical University | Ambrusova K.,Slovak Medical University | And 34 more authors.
Archives of Toxicology | Year: 2016

The GRACE (GMO Risk Assessment and Communication of Evidence; www.grace-fp7.eu) project was funded by the European Commission within the 7th Framework Programme. A key objective of GRACE was to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of a 1-year feeding trial with a GM maize MON810 variety, its near-isogenic non-GM comparator and an additional conventional maize variety are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 452. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after a chronic exposure. © 2016 The Author(s)


Schmidt K.,BioMath GmbH | Schmidtke J.,BioMath GmbH | Schmidt P.,BioMath GmbH | Schmidt P.,University of Hohenheim | And 5 more authors.
Archives of Toxicology | Year: 2016

The data of four 90-day feeding trials and a 1-year feeding trial with the genetically modified (GM) maize MON810 in Wistar Han RCC rats performed in the frame of EU–funded project GRACE were analysed. Firstly, the data obtained from the groups having been fed the non–GM maize diets were combined to establish a historical control data set for Wistar Han RCC rats at the animal housing facility (Slovak Medical University, Bratislava, Slovakia). The variability of all parameters is described, and the reference values and ranges have been derived. Secondly, the consistency of statistically significant differences found in the five studies was analysed. In order to do so, the body weight development, organ weight, haematology and clinical biochemistry data were compared between the studies. Based on the historical control data, equivalence ranges for these parameters were defined, and the values measured in the GM maize–fed groups were compared with these equivalence ranges. Thirdly, the (statistical) power of these feeding studies with whole food/feed was assessed and detectable toxicologically relevant group differences were derived. Linear mixed models (LMM) were applied, and standardized effect sizes (SES) were calculated in order to compare different parameters as well as to provide an overall picture of group and study differences at a glance. The comparison of the five feeding trials showed a clear study effect in the control data. It also showed inconsistency both in the frequency of statistically significant differences and in the difference values between control and test groups. © 2016 The Author(s)


Zeljenkova D.,Slovak Medical University | Ambrusova K.,Slovak Medical University | Bartusova M.,Slovak Medical University | Kebis A.,Slovak Medical University | And 30 more authors.
Archives of Toxicology | Year: 2014

The GMO Risk Assessment and Communication of Evidence (GRACE; www.grace-fp7.eu) project is funded by the European Commission within the 7th Framework Programme. A key objective of GRACE is to conduct 90-day animal feeding trials, animal studies with an extended time frame as well as analytical, in vitro and in silico studies on genetically modified (GM) maize in order to comparatively evaluate their use in GM plant risk assessment. In the present study, the results of two 90-day feeding trials with two different GM maize MON810 varieties, their near-isogenic non-GM varieties and four additional conventional maize varieties are presented. The feeding trials were performed by taking into account the guidance for such studies published by the EFSA Scientific Committee in 2011 and the OECD Test Guideline 408. The results obtained show that the MON810 maize at a level of up to 33 % in the diet did not induce adverse effects in male and female Wistar Han RCC rats after subchronic exposure, independently of the two different genetic backgrounds of the event. © 2014, The Author(s).


Schmidt K.,BioMath GmbH | Schmidtke J.,BioMath GmbH | Kohl C.,Julius Kuhn Institute | Wilhelm R.,Julius Kuhn Institute | And 3 more authors.
Archives of Toxicology | Year: 2016

In this paper, we compare the traditional ANOVA approach to analysing data from 90-day toxicity studies with a more modern LMM approach, and we investigate the use of standardized effect sizes. The LMM approach is used to analyse weight or feed consumption data. When compared to the week-by-week ANOVA with multiple test results per week, this approach results in only one statement on differences in weight development between groups. Standardized effect sizes are calculated for the endpoints: weight, relative organ weights, haematology and clinical biochemistry. The endpoints are standardized, allowing different endpoints of the same study to be compared and providing an overall picture of group differences at a glance. Furthermore, in terms of standardized effect sizes, statistical significance and biological relevance are displayed simultaneously in a graph. © 2015, The Author(s).


PubMed | Julius Kuhn Institute, Wageningen University, BioMath GmbH and University of Veterinary Medicine Hannover
Type: Journal Article | Journal: Archives of toxicology | Year: 2016

In this paper, we compare the traditional ANOVA approach to analysing data from 90-day toxicity studies with a more modern LMM approach, and we investigate the use of standardized effect sizes. The LMM approach is used to analyse weight or feed consumption data. When compared to the week-by-week ANOVA with multiple test results per week, this approach results in only one statement on differences in weight development between groups. Standardized effect sizes are calculated for the endpoints: weight, relative organ weights, haematology and clinical biochemistry. The endpoints are standardized, allowing different endpoints of the same study to be compared and providing an overall picture of group differences at a glance. Furthermore, in terms of standardized effect sizes, statistical significance and biological relevance are displayed simultaneously in a graph.


PubMed | Julius Kuhn Institute, Wageningen UR Biometris, BioMath GmbH and University of Veterinary Medicine Hannover
Type: | Journal: Archives of toxicology | Year: 2016

The data of four 90-day feeding trials and a 1-year feeding trial with the genetically modified (GM) maize MON810 in Wistar Han RCC rats performed in the frame of EU-funded project GRACE were analysed. Firstly, the data obtained from the groups having been fed the non-GM maize diets were combined to establish a historical control data set for Wistar Han RCC rats at the animal housing facility (Slovak Medical University, Bratislava, Slovakia). The variability of all parameters is described, and the reference values and ranges have been derived. Secondly, the consistency of statistically significant differences found in the five studies was analysed. In order to do so, the body weight development, organ weight, haematology and clinical biochemistry data were compared between the studies. Based on the historical control data, equivalence ranges for these parameters were defined, and the values measured in the GM maize-fed groups were compared with these equivalence ranges. Thirdly, the (statistical) power of these feeding studies with whole food/feed was assessed and detectable toxicologically relevant group differences were derived. Linear mixed models (LMM) were applied, and standardized effect sizes (SES) were calculated in order to compare different parameters as well as to provide an overall picture of group and study differences at a glance. The comparison of the five feeding trials showed a clear study effect in the control data. It also showed inconsistency both in the frequency of statistically significant differences and in the difference values between control and test groups.


Nausch H.,University of Rostock | Sautter C.,ETH Zurich | Broer I.,University of Rostock | Schmidt K.,BioMath GmbH
Current Opinion in Biotechnology | Year: 2015

Field trails are indispensable for the scientific analysis of risks and potential benefits of genetically modified plants (GMP). The dramatic reduction of field trials in the European Union (EU) coincides with increasing safety demands, decreases in funding, and changes in the European directives. In parallel, opposition from non-governmental organizations (NGOs) has grown, and public acceptance has decreased. The cultivation of events approved by the EU is still allowed in principle, nevertheless, at least in Germany, there is a de facto moratorium on cultivation. In Switzerland, where development was much more hesitant compared to Germany, field trials are now possible, and a protected site has been established by the government. Public acceptance for scientific trials in Switzerland has risen, despite the continued moratorium on the cultivation based on a referendum. © 2015 Elsevier Ltd.


Mikschofsky H.,University of Rostock | Heilmann E.,University of Rostock | Schmidtke J.,BioMath GmbH | Schmidt K.,BioMath GmbH | And 3 more authors.
Plant Molecular Biology | Year: 2011

The production of plant-derived pharmaceuticals essentially requires stable concentrations of plant constituents, especially recombinant proteins; nonetheless, soil and seasonal variations might drastically interfere with this stability. In addition, variability might depend on the plant organ used for production. Therefore, we investigated the variability in plant constituents and antigen expression in potato plants under greenhouse and field growth conditions and in leaves compared to tubers. Using potatoes expressing VP60, the only structural capsid protein of the rabbit haemorrhagic disease virus (RHDV), CTB, the non-toxic B subunit (CTB) of the cholera toxin (CTA-CTB5) and the marker protein NPTII (neomycinphosphotransferase) as a model, we compare greenhouse and field production of potato-derived antigens. The influence of the production organ turned out to be transgene specific. In general, yield, plant quality and transgene expression levels in the field were higher than or similar to those observed in the greenhouse. The variation (CV) of major plant constituents and the amount of transgene-encoded protein was not influenced by the higher variation of soil properties observed in the field. Amazingly, for specific events, the variability in the model protein concentrations was often lower under field than under greenhouse conditions. The changes in gene expression under environmental stress conditions in the field observed in another event do not reduce the positive influence on variability since events like these should excluded from production. Hence, it can be concluded that for specific applications, field production of transgenic plants producing pharmaceuticals is superior to greenhouse production, even concerning the stability of transgene expression over different years. On the basis of our results, we expect equal or even higher expression levels with lower variability of recombinant pharmaceuticals in the field compared to greenhouse production combined with approximately 10 times higher tuber yield in the field. © 2011 Springer Science+Business Media B.V.

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