Human Relevance Assessments Research Articles

Mode of action analysis for fluxapyroxad-induced rat liver tumour formation: evidence for activation of the constitutive androstane receptor and assessment of human relevance

The fungicide fluxapyroxad (BAS 700 F) has been shown to significantly increase the incidence of liver tumours in male Wistar rats at dietary levels of 1500 and 3000 ppm and in female rats at a dietary level of 3000 ppm via a non-genotoxic mechanism. In order to elucidate the mode of action (MOA) for fluxapyroxad-induced rat liver tumour formation a series of in vivo and in vitro investigative studies were undertaken. The treatment of male and female Wistar rats with diets containing 0 (control), 50, 250, 1500 and 3000 ppm fluxapyroxad for 1, 3, 7 and 14 days resulted in a dose-dependent increases in relative weight at 1500 and 3000 ppm from day 3 onwards in both sexes, with an increase in relative liver weight being also observed in male rats given 250 ppm fluxapyroxad for 14 days. Examination of liver sections revealed a centrilobular hepatocyte hypertrophy in some fluxapyroxad treated male and female rats. Hepatocyte replicative DNA synthesis (RDS) was significantly increased in male rats given 1500 and 3000 ppm fluxapyroxad for 3 and 7 days and in female rats given 50–3000 ppm fluxapyroxad for 7 days and 250–3000 ppm fluxapyroxad for 3 and 14 days; the maximal increases in RDS in both sexes being observed after 7 days treatment. The treatment of male and female Wistar rats with 250–3000 ppm fluxapyroxad for 14 days resulted in significant increases in hepatic microsomal total cytochrome P450 (CYP) content and CYP2B subfamily-dependent enzyme activities. Male Wistar rat hepatocytes were treated with control medium and medium containing 1–100 μM fluxapyroxad or 500 μM sodium phenobarbital (NaPB) for 4 days. Treatment with fluxapyroxad and NaPB increased CYP2B and CYP3A enzyme activities and mRNA levels but had little effect on markers of CYP1A and CYP4A subfamily enzymes and of the peroxisomal fatty acid β-oxidation cycle. Hepatocyte RDS was significantly increased by treatment with fluxapyroxad, NaPB and 25 ng/ml epidermal growth factor (EGF). The treatment of hepatocytes from two male human donors with 1–100 μM fluxapyroxad or 500 μM NaPB for 4 days resulted in some increases in CYP2B and CYP3A enzyme activities and CYP mRNA levels but had no effect on hepatocyte RDS, whereas treatment with EGF resulted in significant increase in RDS in both human hepatocyte preparations. Hepatocytes from male Sprague-Dawley wild type (WT) and constitutive androstane receptor (CAR) knockout (CAR KO) rats were treated with control medium and medium containing 1–16 μM fluxapyroxad or 500 μM NaPB for 4 days. While both fluxapyroxad and NaPB increased CYP2B enzyme activities and mRNA levels in WT hepatocytes, only minor effects were observed in CAR KO rat hepatocytes. Treatment with both fluxapyroxad and NaPB only increased RDS in WT and not in CAR KO rat hepatocytes, whereas treatment with EGF increased RDS in both WT and CAR KO rat hepatocytes. In conclusion, a series of in vivo and in vitro investigative studies have demonstrated that fluxapyroxad is a CAR activator in rat liver, with similar properties to the prototypical CAR activator phenobarbital. A robust MOA for fluxapyroxad-induced rat liver tumour formation has been established. Based on the lack of effect of fluxapyroxad on RDS in human hepatocytes, it is considered that the MOA for fluxapyroxad-induced liver tumour formation is qualitatively not plausible for humans.

EFSA Workshop on in vitro comparative metabolism studies in regulatory pesticide risk assessment

The European Union (EU) pesticides Regulation established that in vitro comparative metabolism studies shall be performed. At present an Organisation for Economic Co-operation and Development (OECD) test guideline for this kind of studies is not available. The European Food Safety Authority (EFSA) Workshop on in vitro comparative metabolism studies in regulatory pesticide risk assessment discussed the use of these studies to identify human metabolites and to support the assessment of human relevance of chemical-mediated thyroid disruption. Discussions focused on the minimum amount of information that should be provided to satisfy the data requirement and should be included in the study protocols, the key elements to be considered for the interpretation of the studies outcome and how metabolism data can be used in a weight of evidence (WoE) approach for endocrine mediated mechanisms of toxicity. From the Workshop it became clear that a guidance document is needed on how to conduct and interpret these studies for the identification of human metabolites. The workshop outcome can be the foundation stone for developing such guidance. For supporting the assessment of human relevance of chemical-mediated thyroid disruption, the workshop outcome recommended that some mechanistic relevant key events should be measured to use this information as part of WoE approach.

Reproduce. Generalize. Extend. On Information Retrieval Evaluation without Relevance Judgments

The evaluation of retrieval effectiveness by means of test collections is a commonly used methodology in the information retrieval field. Some researchers have addressed the quite fascinating research question of whether it is possible to evaluate effectiveness completely automatically, without human relevance assessments. Since human relevance assessment is one of the main costs of building a test collection, both in human time and money resources, this rather ambitious goal would have a practical impact. In this article, we reproduce the main results on evaluating information retrieval systems without relevance judgments; furthermore, we generalize such previous work to analyze the effect of test collections, evaluation metrics, and pool depth. We also expand the idea to semi-automatic evaluation and estimation of topic difficulty. Our results show that (i) previous work is overall reproducible, although some specific results are not; (ii) collection, metric, and pool depth impact the automatic evaluation of systems, which is anyway accurate in several cases; (iii) semi-automatic evaluation is an effective methodology; and (iv) automatic evaluation can (to some extent) be used to predict topic difficulty.

Application of the comparison approach to open TG-GATEs: A useful toxicogenomics tool for detecting modes of action in chemical risk assessment

Mode of action information is one of the key components for chemical risk assessment as mechanistic insight leads to better understanding of potential adverse health effects of a chemical. This insight greatly facilitates assessment of human relevance and enhances the use of non-animal methods for risk assessment, as it ultimately enables extrapolation from initiating events to adverse effects. Recently, we reported an in vitro toxicogenomics comparison approach to categorize (non-)genotoxic carcinogens according to similarities in their proposed modes of action. The present study aimed to make this comparison approach generally applicable, allowing comparison of outcomes across different studies. The resulting further developed comparison approach was evaluated through application to toxicogenomics data on 18 liver toxicants in human and rat primary hepatocytes from the Open TG-GATEs database. The results showed sensible matches between compounds with (partial) overlap in mode of action, whilst matches for compounds with different modes of action were absent. Comparison of the results across species revealed pronounced and relevant differences between primary rat and human hepatocytes, underpinning that information on mode of action enhances assessment of human relevance. Thus, we demonstrate that the comparison approach now is generally applicable, facilitating its use as tool in mechanism-based risk assessment.

A framework for designing retrieval effectiveness studies of library information systems using human relevance assessments

PurposeThe purpose of this paper is to demonstrate how to apply traditional information retrieval (IR) evaluation methods based on standards from the Text REtrieval Conference and web search evaluation to all types of modern library information systems (LISs) including online public access catalogues, discovery systems, and digital libraries that provide web search features to gather information from heterogeneous sources.Design/methodology/approachThe authors apply conventional procedures from IR evaluation to the LIS context considering the specific characteristics of modern library materials.FindingsThe authors introduce a framework consisting of five parts: search queries, search results, assessors, testing, and data analysis. The authors show how to deal with comparability problems resulting from diverse document types, e.g., electronic articles vs printed monographs and what issues need to be considered for retrieval tests in the library context.Practical implicationsThe framework can be used as a guideline for conducting retrieval effectiveness studies in the library context.Originality/valueAlthough a considerable amount of research has been done on IR evaluation, and standards for conducting retrieval effectiveness studies do exist, to the authors’ knowledge this is the first attempt to provide a systematic framework for evaluating the retrieval effectiveness of twenty-first-century LISs. The authors demonstrate which issues must be considered and what decisions must be made by researchers prior to a retrieval test.

Mode of Action Associated With Development of Hemangiosarcoma in Mice Given Pregabalin and Assessment of Human Relevance

Pregabalin increased the incidence of hemangiosarcomas in carcinogenicity studies of 2-year mice but was not tumorigenic in rats. Serum bicarbonate increased within 24 h of pregabalin administration in mice and rats. Rats compensated appropriately, but mice developed metabolic alkalosis and increased blood pH. Local tissue hypoxia and increased endothelial cell proliferation were also confirmed in mice alone. The combination of hypoxia and sustained increases in endothelial cell proliferation, angiogenic growth factors, dysregulated erythropoiesis, and macrophage activation is proposed as the key event in the mode of action (MOA) for hemangiosarcoma formation. Hemangiosarcomas occur spontaneously in untreated control mice but occur only rarely in humans. The International Programme on Chemical Safety and International Life Sciences Institute developed a Human Relevance Framework (HRF) analysis whereby presence or absence of key events can be used to assess human relevance. The HRF combines the MOA with an assessment of biologic plausibility in humans to assess human relevance. This manuscript compares the proposed MOA with Hill criteria, a component of the HRF, for strength, consistency, specificity, temporality, and dose response, with an assessment of key biomarkers in humans, species differences in response to disease conditions, and spontaneous incidence of hemangiosarcoma to evaluate human relevance. Lack of key biomarker events in the MOA in rats, monkeys, and humans supports a species-specific process and demonstrates that the tumor findings in mice are not relevant to humans at the clinical dose of pregabalin. Based on this collective dataset, clinical use of pregabalin would not pose an increased risk for hemangiosarcoma to humans.

An evaluation of Bradfordizing Effects

The purpose of this paper is to apply and evaluate the bibliometric method Brad-fordizing for information retrieval (IR) experiments. Bradfordizing is used for generating core document sets for subject-specific questions and to reord result sets from distributed searches. The method will be applied and tested in a controlled scenario of scien-tific literature databases from Social and Political Sciences, Economics, Psy-chology and medical sci-ence (SOLIS, SoLit, USB Köln Opac, CSA Sociologi-cal s, World Affairs Online, Psyndex and Med-line) and 164 standardized topics. An evaluation of the method and its effects is carried out in two labora-tory-based information re-trieval experiments (CLEF and KoMoHe) using a con-trolled document corpus and human relevance as-sessments. The results show that Bradfordizing is a very robust method for re-ranking the main document types (journal articles and monographs) in today’s digital libraries (DL). The IR tests show that relevance distributions after re-ranking improve at a sig-nificant level if articles in the core are compared with articles in the succeeding zones. The items in the core are significantly more often assessed as relevant, than items in zone 2 (z2) or zone 3 (z3). The improvements between the zones are statis-tically significant based on the Wilcoxon signed-rank test and the paired T-Test.

Speech retrieval from unsegmented finnish audio using statistical morpheme-like units for segmentation, recognition, and retrieval

This article examines the use of statistically discovered morpheme-like units for Spoken Document Retrieval (SDR). The morpheme-like units ( morphs ) are used both for language modeling in speech recognition and as index terms. Traditional word-based methods suffer from out-of-vocabulary words. If a word is not in the recognizer vocabulary, any occurrence of the word in speech will be missing from the transcripts. The problem is especially severe for languages with a high number of distinct word forms such as Finnish. With the morph language model, even previously unseen words can be recognized by identifying its component morphs. Similarly in information retrieval queries, complex word forms, even unseen ones, can be matched to data after segmenting them to morphs. Retrieval performance can be further improved by expanding the transcripts with alternative recognition results from confusion networks . In this article, a novel retrieval evaluation corpus consisting of unsegmented Finnish radio programs, 25 queries and corresponding human relevance assessments was constructed. Previous results on using morphs and confusion networks for Finnish SDR are confirmed and extended to the unsegmented case. As previously, using morphs or base forms as index terms yields about equal performance but combination methods, including a new one, are found to work better than either alone. Using alternative morph segmentations of the query words is found to further improve the results. Lexical similarity-based story segmentation was applied and performance using morphs, base forms, and their combinations was compared for the first time.

A Mechanistic Interpretation of the Oncogenicity of Chlorothalonil in Rodents and an Assessment of Human Relevance

Chronic dietary treatment of rodents with the fungicide chlorothalonil causes an increased incidence of papillomas and carcinomas of the forestomach squamous epithelium (rats and mice, both sexes) and adenomas and carcinomas of the renal proximal tubule epithelium (rats, both sexes; mice, males only); the product elicits no tumorigenic response in dogs. As a result, chlorothalonil is classified by EPA as a Group B2 “probable human carcinogen.” However, chlorothalonil is not genotoxic and there is strong evidence that both the forestomach and renal tumors observed in rodents result from cytotoxicity followed by compensatory cell proliferation and hyperplasia. In the case of the forestomach, cytotoxicity results from sustained irritation of the squamous epithelium by chlorothalonil leading to inflammation, ulceration, and restorative hyperplasia. Cytotoxicity in the renal tubular epithelium is associated with formation of di- and trithiols that arise through the action of renal β-lyase on cysteine S-conjugates derived from the corresponding glutathione conjugates of chlorothalonil. Renal cytotoxicity and cell necrosis in rodents result from the ability of the di- and trithiols to inhibit kidney mitochondrial respiration and disrupt cellular integrity. There is strong evidence that this mechanism is not operative in other species such as dogs and monkeys. The progression from cytotoxicity to hyperplasia to neoplasia is becoming increasingly well-recognized as a threshold-based mechanism of carcinogenesis. Unless exposure is excessively prolonged or intense, the cytotoxic effects will be fully reversible. Furthermore, the effects observed in rodents are not appropriate for evaluating the potential human cancer risk from chlorothalonil. Humans do not possess an organ equivalent to the rodent forestomach and the rat is a poor model for evaluating potential human risk for the renal tumorigenicity of chlorothalonil. Humans are likely to be very much less sensitive than rats to the nephrotoxic effects of chlorothalonil. In view of the fact that the tumorigenic effects of chlorothalonil are mediated through a well-understood, nongenotoxic, threshold-based mechanisms of little or no relevance to humans, chlorothalonil should be a prime candidate for re-review under EPA's new risk assessment guidelines. Expert committees in both Europe and Canada have concluded that human risks to chlorothalonil should be evaluated by means of the NOEL/safety factor approach usually employed for noncarcinogenic materials.

Automatic term class construction using relevance—A summary of work in automatic pseudoclassification

Term classifications and thesauri can be used for many purposes in automatic information retrieval. Normally a thesaurus is generated manually by subject experts: alternatively, the associations between the terms can be obtained automatically by using the occurrence characteristics of the terms across the documents of a collection. A third possibility consists in taking into account user relevance assessments of certain documents with respect to certain queries in order to build term classes designed to retrieve the relevant documents and simultaneously to reject the nonrelevant documents. This last strategy, known as pseudoclassification, produces a user-dependent term classification. A number of pseudoclassification studies are summarized in the present report, and conclusions are reached concerning the effectiveness and feasibility of constructing term classifications based on human relevance assessments.