Pharmacokinetic, neurochemical, stereological and neuropathological studies on the potential effects of paraquat in the substantia nigra pars compacta and striatum of male C57BL/6J mice

AbstractThe pharmacokinetics and neurotoxicity of paraquat dichloride (PQ) were assessed following once weekly administration to C57BL/6J male mice by intraperitoneal injection for 1, 2 or 3 weeks at doses of 10, 15 or 25mg/kg/week. Approximately 0.3% of the administered dose was taken up by the brain and was slowly eliminated, with a half-life of approximately 3 weeks. PQ did not alter the concentration of dopamine (DA), homovanillic acid (HVA) or 3,4-dihydroxyphenylacetic acid (DOPAC), or increase dopamine turnover in the striatum. There was inconsistent stereological evidence of a loss of DA neurons, as identified by chromogenic or fluorescent-tagged antibodies to tyrosine hydroxylase in the substantia nigra pars compacta (SNpc). There was no evidence that PQ induced neuronal degeneration in the SNpc or degenerating neuronal processes in the striatum, as indicated by the absence of uptake of silver stain or reduced immunolabeling of tyrosine-hydroxylase-positive (TH+) neurons. There was no evidence of apoptotic cell death, which was evaluated using TUNEL or caspase 3 assays. Microglia (IBA-1 immunoreactivity) and astrocytes (GFAP immunoreactivity) were not activated in PQ-treated mice 4, 8, 16, 24, 48, 96 or 168h after 1, 2 or 3 doses of PQ.In contrast, mice dosed with the positive control substance, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 10mg/kg/dose×4 doses, 2h apart), displayed significantly reduced DA and DOPAC concentrations and increased DA turnover in the striatum 7 days after dosing. The number of TH+ neurons in the SNpc was reduced, and there were increased numbers of degenerating neurons and neuronal processes in the SNpc and striatum. MPTP-mediated cell death was not attributed to apoptosis. MPTP activated microglia and astrocytes within 4h of the last dose, reaching a peak within 48h. The microglial response ended by 96h in the SNpc, but the astrocytic response continued through 168h in the striatum.These results bring into question previous published stereological studies that report loss of TH+ neurons in the SNpc of PQ-treated mice. This study also suggests that even if the reduction in TH+ neurons reported by others occurs in PQ-treated mice, this apparent phenotypic change is unaccompanied by neuronal cell death or by modification of dopamine levels in the striatum

Phenological sensitivity to climate across taxa and trophic levels

Differences in phenological responses to climate change among species can desynchronise ecological interactions and thereby threaten ecosystem function. To assess these threats, we must quantify the relative impact of climate change on species at different trophic levels. Here, we apply a Climate Sensitivity Profile approach to 10,003 terrestrial and aquatic phenological data sets, spatially matched to temperature and precipitation data, to quantify variation in climate sensitivity. The direction, magnitude and timing of climate sensitivity varied markedly among organisms within taxonomic and trophic groups. Despite this variability, we detected systematic variation in the direction and magnitude of phenological climate sensitivity. Secondary consumers showed consistently lower climate sensitivity than other groups. We used mid-century climate change projections to estimate that the timing of phenological events could change more for primary consumers than for species in other trophic levels (6.2 versus 2.5–2.9 days earlier on average), with substantial taxonomic variation (1.1–14.8 days earlier on average)

Qualitative Impact Assessment of Land Management Interventions on Ecosystem Services (“QEIA”). Report-1: Executive Summary: QEIA Evidence Review & Integrated Assessment

The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten teams involving 45 experts drawn from the independent research community in a consistent series of Evidence Reviews covering the broad topics of: • Air quality • Greenhouse gas emissions • Soils • Water management • Biodiversity: croplands • Biodiversity: improved grassland • Biodiversity: semi-natural habitats • Biodiversity: integrated systems-based actions • Carbon sequestration • Cultural services (including recreation, geodiversity and regulatory services). It should be noted that this piece of work is just one element of the wider underpinning work Defra has commissioned to support the development of the ELM schemes

Qualitative impact assessment of land management interventions on Ecosystem Services (‘QEIA’). Report-2: Integrated Assessment

The focus of this project was to provide an expert-led, rapid qualitative assessment of land management interventions on Ecosystem Services (ES) proposed for inclusion in Environmental Land Management (ELM) schemes. This involved a review of the current evidence base for 741 land management actions on 33 Ecosystem Services and 53 Ecosystem Service indicators by ten expert teams drawn from the independent research community in a consistent series of ten Evidence Reviews covering the broad topics of; • Air quality • Greenhouse gas emissions • Soils • Water management • Biodiversity: croplands • Biodiversity: improved grassland • Biodiversity: semi-natural habitats • Biodiversity: integrated systems-based actions • Carbon sequestration • Cultural services (including recreation, geodiversity and regulatory services) These reviews were undertaken rapidly at Defra’s request by ten teams involving 45 experts who together captured more than 2,400 individual sources of evidence. This was followed by the Integrated Assessment (IA) reported here to provide a more accessible summary of these evidence reviews with a focus on capturing the actions with the greatest potential magnitude of change for the intended ES, and their potential co-benefits and trade-offs for the other ES

The EC/HO International Validation Study on Alternative Methods to the Draize Eye Irritation Test

This is the final report of the Management Team for a European Commission/British Home Office (EC/HO) validation study on alternatives to the Draize eye irritation test. The principal goal of the study was to established whether one or more of nine non-animal tests could be used to replace the Draize test for all severely irritating materials (or those belonging to specific classes) or the animal test completely for chemicals with or without regard to chemical class. Sixty chemicals were indipendently selected, coded and supplie, then the data obtained in 37 laboratories were analysed indipendently. The results of comparisons between 27 alternative test index scores and the Modified Maximum Avarage Scores (MMASs) obtained in the Draize eye test were compared. Tables of results showing Pearson's product moment correlation coefficients and Spearman's rank coefficients for each laboratory are provided, and correlation matrices of alternative test index scopres among the different groups of laboratories are shown for each endpoint.JRC.(EI)-Environment Institut

Validation - Lessons Learned from Practical Experience

With regard to the problems encountered and the experience gained in validation studies conducted in the past, suggestions have been made concerning criteria for the selection of the tests and laboratories to be included in a validation study, the selection and distribution of test chemicals, and procedures for the handing, analysis and interpretation of the resulting ddata. In particular, tests should have been developed to the extent that detailed protocols and standards operating procedures have been produced and evaluated. The laboratories should be chosen on the basis of evidence of their appropriate experience, competence and ability to comply with good laboratory practice (GLP) requirements. The choise of test chemicals depends primarily on the goals of the validation study and on the availability of reliable in vitro toxicity data of high quality. A biostatistician should be involved in the initial design of the validationstudy as well as in the analysis of the resulting data. The quality of the in vivo and in vitro data must be ensured, prior to determining the reproducibility and predictivity of the alternative test.JRC.(EI)-Environment Institut

Alternative Methods for Skin Irritation Testing. The Current Status.

The following have been reviewed: (a) structure-activity and structure property relationships for skin corrosion and irritation; (b) the use of pH and acid-alkaline reserve measurementsin predicting skin corrosivity; (c) IN VITRO tests for skin corrosion; (d) IN VITRO tests for skin irritation (keratinocyte cultures, organ cultures, and reconstituted human skin models); and (e) human patch tests for skin irritation. It was apparent that, although several promising candidate IN VITRO tests for skin irritation (for example, reconstituted human skin methods, and human and animal skin organ culture methods) were under development and evaluation, a test protocol, preliminary prediction model and supporting data on different types of chemicals were only available for a method employing EpiDerm TM. Thus, it is proposed that this EpiDerm TM test undergoes prevalidation during1998. In addition, since it was felt preferable to be able to include other IN VITRO tests in such a prevalidation study, it is recommended that a "challenge" be set to anyone interested in taking part. This involves submitting data on 10 test chemicals to ECVAM, obtained according to a standard protocol with a preliminary prediction model, for review.JRC.(EI)-Environment Institut

An Evaluation of the Proposed OECD Testing Strategy for Skin Corrosion.

Abstract not availableJRC.I-Institute for Health and Consumer Protection (Ispra