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At least 541 records · Page 30Linked to original sources
PubMed2006

The molecular basis for ligand specificity in a mouse olfactory receptor: a network of functionally important residues.

Sequence differences between members of the mouse olfac-tory receptor MOR42 subfamily (MOR42-3 and MOR42-1) are likely to be the basis for variation in ligand binding preference among these receptors. We investigated the specificity of MOR42-3 for a variety of dicarboxylic acids. We used site-directed mutagenesis, guided by homology modeling and ligand docking studies, to locate functionally important residues. Receptors were expressed in Xenopus oocytes and assayed using high throughput electrophysiology. The importance of the Val-113 residue, located deep within the receptor, was analyzed in the context of interhelical interactions. We also screened additional residues predicted to be involved in ligand binding site, based on comparison of ortholog/paralog pairs from the mouse and human olfactory receptor genomes (Man, O., Gilad, Y., and Lancet, D. (2004) Protein Sci. 13, 240-254). A network of 8 residues in transmembrane domains III, V, and VI was identified. These residues form part of the ligand binding pocket of MOR42-3. C12 dicarboxylic acid did not activate the receptor in our functional assay, yet our docking simulations predicted its binding site in MOR42-3. Binding without activation implied that C12 dicarboxylic acid might act as an antagonist. In our functional assay, C12 dicarboxylic acid did indeed act as an antagonist of MOR42-3, in agreement with molecular docking studies. Our results demonstrate a powerful approach based on the synergy between computational predictions and physiological assays.

Animals↗
PubMed2004

The analysis of stress-induced duplex destabilization in long genomic DNA sequences.

We present a method for calculating predicted locations and extents of stress-induced DNA duplex destabilization (SIDD) as functions of base sequence and stress level in long DNA molecules. The base pair denaturation energies are assigned individually, so the influences of near neighbors, methylated bases, adducts, or lesions can be included. Sample calculations indicate that copolymeric energetics give results that are close to those derived when full near-neighbor energetics are used; small but potentially informative differences occur only in the calculated SIDD properties of moderately destabilized regions. The method presented here for analyzing long sequences calculates the destabilization properties within windows of fixed length N, with successive windows displaced by an offset distance d(o). The final values of the relevant destabilization parameters for each base pair are calculated as weighted averages of the values computed for each window in which that base pair appears. This approach implicitly assumes that the strength of the direct coupling between remote base pairs that is induced by the imposed stress attenuates with their separation distance. This strategy enables calculations of the destabilization properties of DNA sequences of any length, up to and including complete chromosomes. We illustrate its utility by calculating the destabilization properties of the entire E. coli genomic DNA sequence. A preliminary analysis of the results shows that promoters are associated with SIDD regions in a highly statistically significant manner, suggesting that SIDD attributes may prove useful in the computational prediction of promoter locations in prokaryotes.

Base Pairing↗
PubMed2003

Honeybee (Apis mellifera L.) mrjp gene family: computational analysis of putative promoters and genomic structure of mrjp1, the gene coding for the most abundant protein of larval food.

Mrjp1 gene belongs to the honeybee mrjp gene family encoding the major royal jelly proteins (MRJPs), secreted by nurse bees into the royal jelly. In this study, we have isolated the genomic clone containing the entire mrjp1 gene and determined its sequence. The mrjp1 gene sequence spans over 3038 bp and contains six exons separated by five introns. Seven mismatches between the mrjp1 gene sequence and two previously independently published cDNA sequences were found, but these differences do not lead to any change in the deduced amino acid sequence of MRJP1. With the aid of inverse polymerase chain reaction we obtained sequences flanking the 5' ends of other mrjp genes (mrjp2, mrjp3, mrjp4 and mrjp5). Putative promoters were predicted upstream of all mrjp genes (including mrjp1). The predicted promoters contain the TATA motif (TATATATT), highly conserved both in sequence and position. Ultraspiracle (USP) transcription factor (TF) binding sites in putative promoter regions and clusters of dead ringer TF binding sites upstream of these promoters were predicted computationally. We propose that USP, as a juvenile hormone (JH) binding TF, might possibly act as a mediator of mrjp expression in response to JH. Mrjp1's genomic locus is predicted to encode an antisense transcript, partially overlapping with five mrjp1 exons and entirely overlapping with the putative promoter and predicted transcriptional start point of mrjp1. This finding may shed light on the mechanisms of regulation of mrjps expression. Southern blot analysis of genomic DNA revealed that all so far known members of mrjp gene family (mrjp1, mrjp2, mrjp3, mrjp4 and mrjp5) are present as single-copy genes per haploid honeybee genome. Although MRJPs and the yellow protein of Drosophila melanogaster share a certain degree of similarity in aa sequence and although it has been shown that they share a common evolutionary origin, neither structural similarities in the gene organization, nor significant similarities between intron sequences of mrjp1 gene and fourteen yellow-like genes of D. melanogaster were found.

Animals↗
PubMed1996

Identification and characterization of a cDNA and the structural gene encoding the mouse epithelial membrane protein-1.

The PMP22/EMP/MP20 gene family includes four closely related proteins, peripheral myelin protein-22 (PMP22), epithelial membrane protein-1 (EMP-1), epithelial membrane protein-2 (EMP-2), and epithelial membrane protein-3 (EMP-3), which share amino acid identities ranging from 33 to 43%. In addition, the lens-specific membrane protein MP20 represents a more distant relative. Functionally, this family of proteins is likely to play important roles in the control of cell proliferation, cell differentiation, and cell death. In particular, mutations affecting the PMP22 gene are responsible for various hereditary peripheral neuropathies in humans and mice. We report the isolation and characterization of a mouse EMP-1 cDNA and the corresponding emp-1 gene. Mouse EMP-1 displays 93% amino acid identity to rat EMP-1 and 39% identity to mouse PMP22. The cDNA-predicted EMP-1 protein contains four putative membrane-associated domains and can be N-linked glycosylated in vitro. EMP-1 is encoded by a single-copy gene with the positions of introns exactly conserved between emp-1 and PMP22, corroborating the hypothesis that both genes belong to the same family. Computer-predicted structural domains of EMP-1 are partially mirrored by the exon/intron structure of emp-1. Most interestingly, exon 4, which covers the potential second transmembrane domain, a small intracellular loop, and half of the third transmembrane domain, encodes the most highly conserved regions between the EMP-1 and PMP22 proteins and is also remarkably conserved in the MP20 gene, indicating some shared functional significance for this module in the PMP22/EMP/MP20 family.

Amino Acid Sequence↗
PubMed1995

DNA curvature of the tobacco GRS repetitive sequence family and its relation to nucleosome positioning.

Recently, a highly repetitive DNA sequence family (GRS) from tobacco was described in our laboratory. These sequences were found to be localized predominantly in the pericentromeric heterochromatin of tobacco chromosomes. To test the hypothesis that these sequences play an important role in the formation of heterochromatin, we investigated the DNA curvature of the GRS sequences and its possible impact to the chromatin structure at these loci. Application of the nearest-neighbour wedge model of intrinsic DNA curvature for the GRS1 family member predicted two loci of curvature: a major bend at the 5' end of the sequence and a minor bend of opposite direction at the centre of the GRS1. The presence of the major and the minor loci of DNA curvature was studied experimentally using permutation analysis and site-directed mutagenesis. The experimental results were consistent with the computer predictions. We gave evidence that the described DNA curvature is also present in the entire GRS family. Genomic statistical sequencing showed the conservation of the major bend sequence determinants in the members of the GRS family. To investigate the chromatin structure at the GRS sequences, we determined the nucleosome positioning in vivo at these sequences using thermal cycle primer extension. A relation between the curvature pattern and the histone octamer position was observed: the major bend is excluded from the nucleosome surface to the linker region, while the minor bend is distributed along the core DNA. The suggestion is made that the sequences in the minor locus of curvature define the rotational setting of the nucleosome, and a possible role of the major bend as a factor, which defines the translational setting, is discussed.

Base Sequence↗
PubMed2005

Organolanthanide-mediated intermolecular hydroamination of 1,3-dienes: mechanistic insights from a computational exploration of diverse mechanistic pathways for the stereoselective hydroamination of 1,3-butadiene with a primary amine supported by an ansa-neodymocene-based catalyst.

The complete catalytic reaction course for the organolanthanide-mediated intermolecular hydroamination of 1,3-butadiene and n-propylamine by an archetypical [Me2Si(eta5-Me4C5)2NdCH(SiMe3)2] precatalyst was critically scrutinized by employing a reliable gradient-corrected DFT method. A free-energy profile of the overall reaction is presented that is based on the thorough characterization of all crucial elementary steps for a tentative catalytic cycle. A computationally verified, revised mechanistic scenario is proposed which is consistent with the experimentally derived empirical rate law and accounts for crucial experimental observations. It involves kinetically mobile reactant association/dissociation equilibria and facile, reversible intermolecular diene insertion into the Nd-amido bond, linked to turnover-limiting protonolysis of the eta3-butenyl-Nd functionality. The computationally predicted effective kinetics (Delta(tot) = 11.3 kcal mol(-1), Delta(tot) = -35.7 e.u.) are in reasonably good agreement with experimental data for the thoroughly studied hydroamination of alkynes. The thermodynamic and kinetic factors that determine the almost complete regio- and stereoselectivity of the mechanistically diverse intermolecular 1,3-diene hydroamination have been unraveled. The present computational study complements experiments because it allows, first, a more detailed understanding and a consistent rationalization of the experimental results for the hydroamination of 1,3-dienes and primary amines and, second, enhances the insights into general mechanistic aspects of organolanthanide-mediated intermolecular hydroamination.

Journal Article↗
PubMed2002

Exploring genetic regulatory networks in metazoan development: methods and models.

One of the foremost challenges of 21st century biological research will be to decipher the complex genetic regulatory networks responsible for embryonic development. The recent explosion of whole genome sequence data and of genome-wide transcriptional profiling methods, such as microarrays, coupled with the development of sophisticated computational tools for exploiting and analyzing genomic data, provide a significant starting point for regulatory network analysis. In this article we review some of the main methodological issues surrounding genome annotation, transcriptional profiling, and computational prediction of cis-regulatory elements and discuss how the power of model genetic organisms can be used to experimentally verify and extend the results of genomic research.

Animals↗
PubMed1998

Molecular and in vitro analysis of eight dengue type 2 viruses isolated from patients exhibiting different disease severities.

Potential genetic determinants of dengue virulence were studied by sequencing the entire genomes of eight dengue 2 virus strains isolated from patients exhibiting different disease severities during an epidemic season in northeastern Thailand in 1993. The isolates came from one dengue shock syndrome (ThNH-7/93), three dengue hemorrhagic fever, and four dengue fever patients. Phylogenetic analysis showed that the isolates belonged to the Southeast Asian genotype. The 3' noncoding regions showed distinctive secondary structures, with one specific structure for the isolate ThNH-7/93. Analysis of the predicted polyprotein showed several amino acid (aa) changes scattered mostly in the nonstructural region. Of 30 positions with aa changes, 7 were unique to the isolate ThNH-7/93 and 3 of those led to radical alterations in aa character. Several aa changes coincided with previous studies relating genome sequence and virulence. Minimal changes in computer-predicted protein secondary structures were observed. Infective particles in the inoculum for all isolates were approximately equal as measured by focus formation on BHK-21 cells, but this did not correlate with the number of plaques formed on LLC-MK2 cells. Isolates from patients that experienced secondary infection were shown to have significantly larger plaques than the isolates from primary infection patients.

Adolescent↗
PubMed2002

Advances in proteomic technologies.

Proteomics is a rapidly emerging set of key technologies that are being used to identify proteins and map their interactions in a cellular context. With the sequencing of the human genome, the scope of proteomics has shifted from protein identification and characterization to include protein structure, function and protein-protein interactions. Technologies used in proteomic research include two-dimensional gel electrophoresis, mass spectrometry, yeast two-hybrids screens, and computational prediction programs. While some of these technologies have been in use for a long time, they are currently being applied to study physiology and cellular processes in high-throughput formats. It is the high-throughput approach that defines and characterizes modern proteomics. In this review, we discuss the current status of these experimental and computational technologies relevant to the three major aspects of proteomics-characterization of proteomes, identification of proteins, and determination of protein function. We also briefly discuss the development of new proteomic technologies that are based on recent advances in analytical and biochemical techniques, engineering, microfabrication, and computational prowess. The integration of these advances with established technologies is invaluable for the drive toward a comprehensive understanding of protein structure and function in the cellular milieu.

Electrophoresis, Gel, Two-Dimensional↗
PubMed2003

Definitive angiographic detection of subarachnoid haemorrhage compared with laboratory assessment of intracranial bleed in CT-negative patients.

BACKGROUND: Between 2.5% and 5% of cases of subarachnoid haemorrhage (SAH) give negative results for computed tomography (CT) scanning. Recent UK guidelines make recommendations as to standardization of laboratory methodology for the detection of SAH in individuals with a negative CT scan. We have compared this approach with our routine assessment using first-order derivative spectrophotometry, a recently reported iterative computer prediction model and measurement of cerebrospinal fluid (CSF) ferritin concentration. All methods were judged against cerebral angiography as the definitive means of determining patient outcome. METHODS: Scanning spectrophotometry of CSF is necessary for both the UK guidelines and our in-house method. Absorbance measurements at 360, 405, 414 and 455 nm are required for the computer model. CSF ferritin concentration was measured using a serum method on a DPC Immulite 2000. This gave a value of <12 microg/L for normal CSF. Ethical approval and informed patient consent to additional investigation were obtained. RESULTS: The sensitivity and specificity for the UK guidelines method, derivative spectrophotometry (in-house), iterative computer model and CSF ferritin were, respectively: 0.8, 1.0; 0.9, 1.0; 0.9, 0.5; 1.0, 0.78. CONCLUSION: First-order derivative spectrophotometry had best concordance with angiography. Combination of this with CSF ferritin measurement may improve sensitivity, although the zero-order method recommended in the UK guidelines for the detection of an intracranial bleed is more amenable and has comparable performance.

Bilirubin↗
PubMed2002

Evolutionary computational methods to predict oral bioavailability QSPRs.

This review discusses evolutionary and adaptive methods for predicting oral bioavailability (OB) from chemical structure. Genetic Programming (GP), a specific form of evolutionary computing, is compared with some other advanced computational methods for OB prediction. The results show that classifying drugs into 'high' and 'low' OB classes on the basis of their structure alone is solvable, and initial models are already producing output that would be useful for pharmaceutical research. The results also suggest that quantitative prediction of OB will be tractable. Critical aspects of the solution will involve the use of techniques that can: (i) handle problems with a very large number of variables (high dimensionality); (ii) cope with 'noisy' data; and (iii) implement binary choices to sub-classify molecules with behavior that are qualitatively different. Detailed quantitative predictions will emerge from more refined models that are hybrids derived from mechanistic models of the biology of oral absorption and the power of advanced computing techniques to predict the behavior of the components of those models in silico.

Animals↗
PubMed2004

A computer model to predict the outcome and duration of ureteral or renal calculous passage.

PURPOSE: We developed a computer model to predict the outcome and the duration until passage of ureteral/renal calculi. MATERIALS AND METHODS: A retrospective, randomized study was performed of the outcome in 301 patients presenting to the emergency room for renal colic. Presenting characteristics of those diagnosed with a single calculus by computerized tomography were recorded for analysis. Predictors of stone passage and passage duration were identified and then used to create a logistic regression model. The algorithm was trained on 141 randomly selected patients and then tested on a separate 160 patients. Model accuracy was compared to predictions from 10 experienced urologists and 9 urology residents in 77 randomly selected patients. The model was tested further in 30 randomly selected patients at a private hospital to assess its general applicability. RESULTS: The model prediction accuracy in 160 patients was 86.3% for passage and 87.3% for duration (less or greater than 2 weeks). In the comparison group the model, the 10 experienced urologists and the 9 urology residents had an overall prediction accuracy of 88.3%, 70.5% (p = 0.006) and 72% (p = 0.007) for passage, and 87.1%, 71.6% (p = 0.007) and 81% (p = 0.075) for duration, respectively. Prediction accuracy was 93.3% for passage and 90.3% for duration when tested at a private hospital. CONCLUSIONS: Our model provides outcome and duration of passage predictions for patients presenting acutely in the emergency room with a single ureteral/renal calculus. It performs better than experienced urologists and urology residents. It can be applied to a private practice setting with equal accuracy.

Adolescent↗
PubMed2005

MULTIPRED: a computational system for prediction of promiscuous HLA binding peptides.

MULTIPRED is a web-based computational system for the prediction of peptide binding to multiple molecules (proteins) belonging to human leukocyte antigens (HLA) class I A2, A3 and class II DR supertypes. It uses hidden Markov models and artificial neural network methods as predictive engines. A novel data representation method enables MULTIPRED to predict peptides that promiscuously bind multiple HLA alleles within one HLA supertype. Extensive testing was performed for validation of the prediction models. Testing results show that MULTIPRED is both sensitive and specific and it has good predictive ability (area under the receiver operating characteristic curve A(ROC) > 0.80). MULTIPRED can be used for the mapping of promiscuous T-cell epitopes as well as the regions of high concentration of these targets--termed T-cell epitope hotspots. MULTIPRED is available at http://antigen.i2r.a-star.edu.sg/multipred/.

Computational Biology↗
PubMed2004

An evidence ontology for use in pathway/genome databases.

An important emerging need in Model Organism Databases (MODs) and other bioinformatics databases (DBs) is that of capturing the scientific evidence that supports the information within a DB. This need has become particularly acute as more DB content consists of computationally predicted information, such as predicted gene functions, operons, metabolic pathways, and protein properties. This paper presents an ontology for encoding the type of support and the degree of support for DB assertions, and for encoding the literature source in which that support is reported. The ontology includes a hierarchy of 35 evidence codes for modeling different types of wet-lab and computational evidence for the existence of operons and metabolic pathways, and for gene functions. We also describe an implementation of the ontology within the Pathway Tools software environment, which is used to query and update Pathway/Genome DBs such as EcoCyc, MetaCyc, and HumanCyc.

Computational Biology↗
PubMed2006

An efficient computational method for predicting rotational diffusion tensors of globular proteins using an ellipsoid representation.

We propose a new computational method for predicting rotational diffusion properties of proteins in solution. The method is based on the idea of representing protein surface as an ellipsoid shell. In contrast to other existing approaches this method uses principal component analysis of protein surface coordinates, which results in a substantial increase in the computational efficiency of the method. Direct comparison with the experimental data as well as with the recent computational approach (Garcia de la Torre; et al. J. Magn. Reson. 2000, B147, 138-146), based on representation of protein surface as a set of small spherical friction elements, shows that the method proposed here reproduces experimental data with at least the same level of accuracy and precision as the other approach, while being approximately 500 times faster. Using the new method we investigated the effect of hydration layer and protein surface topography on the rotational diffusion properties of a protein. We found that a hydration layer constructed of approximately one monolayer of water molecules smoothens the protein surface and effectively doubles the overall tumbling time. We also calculated the rotational diffusion tensors for a set of 841 protein structures representing the known protein folds. Our analysis suggests that an anisotropic rotational diffusion model is generally required for NMR relaxation data analysis in single-domain proteins, and that the axially symmetric model could be sufficient for these purposes in approximately half of the proteins.

Anisotropy↗
PubMed2004

Identifying estrogen receptor alpha target genes using integrated computational genomics and chromatin immunoprecipitation microarray.

The estrogen receptor alpha (ERalpha) regulates gene expression by either direct binding to estrogen response elements or indirect tethering to other transcription factors on promoter targets. To identify these promoter sequences, we conducted a genome-wide screening with a novel microarray technique called ChIP-on-chip. A set of 70 candidate ERalpha loci were identified and the corresponding promoter sequences were analyzed by statistical pattern recognition and comparative genomics approaches. We found mouse counterparts for 63 of these loci and classified 42 (67%) as direct ERalpha targets using classification and regression tree (CART) statistical model, which involves position weight matrix and human-mouse sequence similarity scores as model parameters. The remaining genes were considered to be indirect targets. To validate this computational prediction, we conducted an additional ChIP-on-chip assay that identified acetylated chromatin components in active ERalpha promoters. Of the 27 loci upregulated in an ERalpha-positive breast cancer cell line, 20 having mouse counterparts were correctly predicted by CART. This integrated approach, therefore, sets a paradigm in which the iterative process of model refinement and experimental verification will continue until an accurate prediction of promoter target sequences is derived.

Animals↗
PubMed1997

A carboxy-terminal processing protease gene is located immediately upstream of the invasion-associated locus from Bartonella bacilliformis.

A gene with homology to those encoding an unusual class of C-terminal processing proteases that flanks the invasion-associated locus ialAB of Bartonella bacilliformis has been identified. The 1302 bp gene, termed ctpA, is located immediately upstream of the ialA gene and encodes a predicted nascent product of 434 amino acids, producing a mature protein of 411 amino acid residues. The Bartonella CtpA appears to undergo autolysis in vitro, producing multiple products of 43-46 kDa, and a second group of products of 36-37 kDa. Production of CtpA in vivo gives a single product of 41.8 kDa. In addition to a computer-predicted N-terminal secretory signal sequence, the molecular mass difference in vivo versus in vitro indicates that CtpA is likely to be secreted and post-translationally modified. The full-length CtpA protein shows 30% identify to the CtpA protein of Synechocystis sp. 6803 (69% overall sequence similarity). The mature CtpA protein also has significant homology to the tail-specific protease (Tsp) of Escherichia coli, with 22% identify and 62% similarity to an internal region of the 660 amino acid Tsp. The CtpA protein does not appear to exhibit haemolysin, collagenase, or caseinase activity. The ctpA gene is conserved in all Bartonella species examined, as determined by hybridization analyses, but it was not found in Brucella abortus or E. coli. The ctpA gene does not directly affect the erythrocyte-invasion phenotype conferred by ialAB, but its homology to other stress-response processing proteases implies an important role in survival of this intracellular pathogen.

Amino Acid Sequence↗
PubMed2005

Use of the dog as non-rodent test species in the safety testing schedule associated with the registration of crop and plant protection products (pesticides): present status.

The results from a survey of the expert information that is publicly accessible on the use of the dog as test species during the regulatory evaluation of agricultural chemicals and pesticides are reported. Methods that are being used or considered in order to reduce the number of dogs used for this purpose are described. Regulatory evaluation aims at establishing threshold values for safe human exposure; it is based on no-observed-adverse-effect levels (NOELs) determined in animal studies. Current regulations require testing in two species, a rodent species (usually rat or mouse), and a non-rodent species (usually the dog). Subchronic (90-day) and chronic (12-month) repeated-dose feeding studies must be routinely conducted in dogs. This report first focuses on the results from a retrospective study analysing data on 216 pesticides kept on record by the Bundesinstitut für Risikobewertung, BfR (German Federal Institute for Risk Assessment), the competent regulatory authority in Germany. The study was sponsored and coordinated by SET, the German Foundation for the Promotion of Research on Replacement and Complementary Methods to Reduce Animal Testing (Stiftung zur Förderung der Erforschung von Ersatz-und Ergänzungsmethoden zur Einschränkung von Tierversuchen, Mainz) and conducted by the BfR. Since the data submitted for registration of a product is the property of the manufacturer, the study could only proceed with the collaboration of the German Association of Manufacturers of Agricultural Chemicals (Industrieverband Agrar, IVA). To ensure confidentiality, designated codes were used instead of the compounds' proper names when the study was published. The results support two major conclusions. The use of the dog for the testing of pesticides is indeed necessary because the dog has proved to be the most sensitive species for about 15% of the compounds examined. However, chronic studies are only of limited value since they only provide essential information that cannot be obtained in sub-chronic studies in about 5% of cases. These conclusions are supported by several retrospective analyses using data on pharmaceutical drugs carried out in the context of the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH). Over 90% of drugs elicited no toxic symptoms in 12-month studies in dogs in addition to those that had been recorded previously in studies conducted for 90 or 180 days in dogs and rats. Another approach comparing the results from pre-clinical animal studies with clinical studies noted that animal studies predicted about 70% of the effects observed in volunteers, and in about 94% of cases the effects occurred in animal studies lasting not more than one month. Furthermore, the report summarises the current methods under consideration that could refine or reduce the use of dogs in toxicity testing: industrial data sharing and harmonisation of guidelines, in vitro methods, human studies, computational prediction models, and integrated testing approaches. The integrated Agricultural Chemicals Safety Assessment (ACSA) testing scheme, which is currently being developed in an international project initiated by the International Life Sciences Institute (ILSI, USA), is of particular relevance, since an ambitious attempt is being made to design a new comprehensive test framework incorporating modern scientific approaches and covering most aspects of current regulatory testing requirements. The ACSA project has access to the pesticide database of the US EPA's Office of Pesticide Programs (OPP). Preliminary results have confirmed the two major conclusions from the joint SET/BfR study conducted in Germany. Taking these results into account, it is recommended that the regulatory requirement for 12-month studies to be routinely carried out in dogs should be abandoned. While 90-day studies should be conducted in both rats and dogs, chronic studies should only take place in rats. If the dog is more sensitive than the rat in the 90-day study, an additional safety factor to the NOEL value obtained in the chronic rat study should be applied in order to set the threshold for safe human exposure, instead of conducting a 12-month study in dogs. This safety factor may be calculated from chronic NOEL data available in several pesticide databases. Chronic tests using dogs would then only be required if the test compound belongs to a new class of chemicals that has never been tested before. Thus, the report concludes that, according to current scientific knowledge, the routine 12-month studies in dogs are no longer required for agricultural chemicals and pesticides, and international regulations should be changed accordingly. Active international support of such measures is welcomed, from both an economical and an animal welfare perspective.

Animal Testing Alternatives↗