The Historical Development of Animal Toxicity Testing

This paper traces the historical development of animal toxicity testing, from its ancient origins through the period of standardization following World War II. It explores the roots of toxicity testing in physiology and experimental medicine, drug development, and the detection and identification of poisons. The discussion then turns to the shift in focus from acute to chronic toxicity which occurred around the turn of the century. The controversy over the potential toxicity of preservatives and pesticide residues illustrates the evolution of toxicity testing in the early to middle part of the twentieth century, as well as the influence of political and economic factors on its development. The paper concludes with the emergence of standardized protocols for toxicity testing during and immediately following the Second World war

Wind tunnel pressurization and recovery system

The high density, low toxicity characteristics of refrigerant-12 (dichlorofluoromethane) make it an ideal gas for wind tunnel testing. Present limitations on R-12 emissions, set to slow the rate of ozone deterioration, pose a difficult problem in recovery and handling of large quantities of R-12. This preliminary design is a possible solution to the problem of R-12 handling in wind tunnel testing. The design incorporates cold temperature condensation with secondary purification of the R-12/air mixture by adsorption. Also discussed is the use of Freon-22 as a suitable refrigerant for the 12 foot wind tunnel

The multifocal pattern electroretinogram in chloroquine retinopathy

Purpose: Optimal screening for ocular toxicity caused by chloroquine and hydroxychloroquine is still controversial. With the multifocal pattern electroretinogram (mfPERG), a new electrophysiological technique has recently become available to detect early changes of ganglion cells. In this study this new technique is applied to a series of 10 patients seen consecutively receiving long-term chloroquine medication. Methods: In 10 patients receiving chloroquine medication, clinical examination, Amsler visual field testing and computerized color vision testing were performed. If toxicity was suspected, automated perimetry was carried out. In addition, in all patients conventional pattern electroretinogram (PERG) and mfPERG testing were performed. Results: On clinical examination 8 patients showed no chloroquine-associated maculopathy, while 2 patients did. Of these 2, only 1 reported abnormalities when viewing the Amsler chart, while automated perimetry showed typical, ring-like paracentral scotomas in both affected patients and color vision was significantly abnormal. In the normal patients, 4 of 8 had a mild color vision disturbance, which correlated to age-related macular changes. The amplitudes of the PERG and the central (approximately 10degrees) responses of the mfPERG were markedly reduced in chloroquine maculopathy, while the latencies were unchanged. The peripheral rings of mfPERG (ranging to 48degrees) were not affected by chloroquine toxicity. Both PERG and mfPERG were less affected by age-related macular changes. Conclusions: The reduction of PERG and central mfPERG responses in chloroquine maculopathy may help with the early detection of toxicity. Copyright (C) 2004 S. Karger AG, Basel

The use of simulated whole effluents in toxicity assessments: A review of case studies from reverse osmosis desalination plants

Seawater desalination is an increasingly common means to meet the demand for freshwater. Resulting wastewater discharges can, however, impact biota of the surrounding environment. Concern exists that interactive effects specific to the outputs of each desalination plant may result in unique impacts difficult to predict by studying existing plants or assessing the effects of individual chemicals found in waste streams. Given this, we highlight an alternative approach to assess potential toxicity of desalination outfalls. Specifically, we review three recent case studies from Australia in which simulated whole effluents were used in toxicity assessments before desalination plants were constructed. This approach enabled potential toxic effects of wastewater to be considered before the plants became operational and, in one case, even facilitated consideration of potential effects of different treatment processes and suppliers. As in many whole effluent toxicity assessments, the time required for testing and restricted range of species considered were limitations. Given the benefits of this method, however, the use of simulated whole effluents is a development that could facilitate an improved capacity to forecast impacts of proposed desalination plants

Toxicity of the pyrolysis products of spacecraft materials

A number of spacecraft construction materials are evaluated for the toxic effects of their thermodegradation products on rats. Pyrolysis toxicity testing of pyrolysate fumes establish carbon monoxide, carbon dioxide and hydrogen cyanide as the most common intoxicating agents. Generally, COHb levels of animals expiring in the test chamber suggest higher concentrations of CO are produced with larger samples of most materials

Bioavailability of pesticides in freshwater sediments

In ecological risk assessment standardized sediment toxicity tests are used to predict the hazard of chemicals for sediment-living organisms. Feeding is a prerequisite in these long-term tests to avoid starvation of test organisms. Therefore, added food particles may act as vectors for the test compound. The importance of food particles as vectors, however, is dependent on several factors, for example, sorption and major uptake routes. In this thesis, laboratory experiments on the importance of pesticide sorption and uptake routes for the bioavailability to the midge Chironomus riparius in sediment toxicity test setups were performed. A feeding selectivity study showed that larvae almost exclusively fed on added food particles, and highly neglected sediment particles. Additionally, experiments on the sorption of the insecticide lindane, showed that food and peat particles (used in artificial sediment) efficiently sorbed lindane (>95% after 48 h). The binding strength of lindane was weak, facilitating particulate uptake. However, the uptake from dissolved lindane was higher than the uptake from particles. From this we concluded that toxicity may be underestimated in spiked-sediment scenarios, where hydrophobic pesticides sorb to the sediment and larvae to a large extent feed on uncontaminated food particles. Conversely, in a spiked-water scenario, the food particles may act as vector, resulting in a facilitated particulate uptake, in addition to the uptake from water. Sediment organic matter affects sorption, and thus bioavailability of pesticides. Pyrethroid toxicity was much higher in artificial sediment than in a natural sediment, indicating the simplicity and shortcomings of using artificial sediments. Interestingly, the sediment quality highly affected bioavailability in spiked-water. For example, C. riparus larvae in sediments with low organic matter content and exposed to spiked-water pyrethroids, showed lower survival, slower development, and increased adult size, than those in sediments with higher organic matter. The pyrethroid deltamethrin, showed an LC50-value (28 d) for C. riparius larvae in artificial sediment of 16 pg/L and 11 µg/kg for water- and sediment exposures, respectively, i.e. toxic effects occurred at concentrations lower than the detection limits for high-tech analytical methods. This thesis contributes to a wider understanding of processes affecting bioavailability in freshwater sediments, and in particular in standardized sediments used in toxicity testing. The understanding of test compound sorption and bioavailability is crucial for sound interpretations of toxicity tests and for the general credibility of such tests

Opportunities for improving the efficiency of paediatric HIV treatment programmes

Objectives: To conduct two economic analyses addressing whether to: routinely monitor HIV-infected children on antiretroviral therapy (ART) clinically or with laboratory tests; continue or stop cotrimoxazole prophylaxis when children become stabilized on ART. Design and methods: The ARROW randomized trial investigated alternative strategies to deliver paediatric ART and cotrimoxazole prophylaxis in 1206 Ugandan/Zimbabwean children. Incremental cost-effectiveness and value of implementation analyses were undertaken. Scenario analyses investigated whether laboratory monitoring (CD4 tests for efficacy monitoring; haematology/biochemistry for toxicity) could be tailored and targeted to be delivered cost-effectively. Cotrimoxazole use was examined in malaria-endemic and non-endemic settings. Results: Using all trial data, clinical monitoring delivered similar health outcomes to routine laboratory monitoring, but at a reduced cost, so was cost-effective. Continuing cotrimoxazole improved health outcomes at reduced costs. Restricting routine CD4+ monitoring to after 52 weeks following ART initiation and removing toxicity testing was associated with an incremental cost-effectiveness ratio of $6084 per quality-adjusted life-year (QALY) across all age groups, but was much lower for older children (12+ years at initiation; incremental cost-effectiveness ratio =$769/QALY). Committing resources to improve cotrimoxazole implementation appears cost-effective. A healthcare system that could pay $600/QALY should be willing to spend up to$12.0 per patient-year to ensure continued provision of cotrimoxazole. Conclusion: Clinically driven monitoring of ART is cost-effective in most circumstances. Routine laboratory monitoring is generally not cost-effective at current prices, except possibly CD4 testing amongst adolescents initiating ART. Committing resources to ensure continued provision of cotrimoxazole in health facilities is more likely to represent an efficient use of resources

Polyethylene Glycol Epirubicin-Loaded Transcatheter Arterial Chemoembolization Procedures Utilizing a Combined Approach with 100 and 200 μm Microspheres: A Promising Alternative to Current Standards

PURPOSE:To report clinical effectiveness, toxicity profile, and prognostic factors of combined 100 μm ± 25 and 200 μm ± 50 epirubicin-loaded polyethylene glycol (PEG) microsphere drug-eluting embolic transcatheter arterial chemoembolization protocol in patients with hepatocellular carcinoma. MATERIALS AND METHODS: In this prospective, single-center, single-arm study with 18 months of follow-up, 36 consecutive patients (mean age 69.9 y ± 10.8; 26 men, 10 women; 54 naïve lesions) were treated. Embolization was initiated with 100 μm ± 25 microspheres, and if stasis (10 heart beats) was not achieved, 200 μm ± 50 microspheres were administered. Each syringe (2 mL) of PEG microsphere was loaded with 50 mg of epirubicin. Results were evaluated using Modified Response Evaluation Criteria In Solid Tumors with multidetector computed tomography/magnetic resonance imaging at 1, 3-6, 9-12, and 15-18 months. Toxicity profile was assessed by laboratory testing before and after the procedure. Complications were recorded. Postembolization syndrome (PES) was defined as onset of fever/nausea/pain after the procedure. Patient/lesion characteristics and treatment results were correlated with predicted outcome using regression analysis. Child-Pugh score was A in 86.1% of patients (31/36) and B in 13.9% (5/36). RESULTS: In 10 of 21 lesions, < 2 cm in diameter (47.5%) stasis was achieved with 100 μm ± 25 microspheres only, whereas all other lesions required adjunctive treatment with 200 μm ± 50 microspheres. Reported adverse events were grade 1 acute liver bile duct injury (3/39 cases, 7.7%) and PES (grade 2; 3/39 cases, 7.7%). Complete response (CR) at 1, 3-6, 9-12, and 15-18 months was 61.1%, 65.5%, 63.63%, and 62.5%. Objective response (CR + partial response) at 1, 3-6, 9-12, and 15-18 months was 83.3%, 65.85%, 63.63%, and 62.5%. No single factor (laboratory testing, etiology, patient status, hepatic status, tumor characteristics, administration protocol) predicted outcomes except for albumin level at baseline for CR (P < .05, odds ratio = 1.09). CONCLUSIONS: The combined microsphere sizing strategy was technically feasible and yielded promising results in terms of effectiveness and toxicity