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1.
Integr Environ Assess Manag ; 20(3): 780-793, 2024 May.
Article in English | MEDLINE | ID: mdl-37563990

ABSTRACT

The European environmental risk assessment (ERA) of plant protection products follows a tiered approach. The approach for soil invertebrates currently consists of two steps, starting with a Tier 1 assessment based on reproduction toxicity tests with earthworms, springtails, and predatory mites. In case an unacceptable risk is identified at Tier 1, field studies can be conducted as a higher-tier option. For soil invertebrates, intermediate tiers are not implemented. Hence, there is limited possibility to include additional information for the ERA to address specific concerns when the Tier 1 fails, as an alternative to, for example, a field study. Calibrated intermediate-tier approaches could help to address risks for soil invertebrates with less time and resources but also with sufficient certainty. A multistakeholder workshop was held on 2-4 March 2022 to discuss potential intermediate-tier options, focusing on four possible areas: (1) natural soil testing, (2) single-species tests (other than standard species), (3) assessing recovery in laboratory tests, and (4) the use of assembled soil multispecies test systems. The participants acknowledged a large potential in the intermediate-tier options but concluded that some issues need to be clarified before routine application of these approaches in the ERA is possible, that is, sensitivity, reproducibility, reliability, and standardization of potential new test systems. The definition of suitable assessment factors needed to calibrate the approaches to the protection goals was acknowledged. The aims of the workshop were to foster scientific exchange and a data-driven dialog, to discuss how the different approaches could be used in the risk assessment, and to identify research priorities for future work to address uncertainties and strengthen the tiered approach in the ERA for soil invertebrates. This article outlines the background, proposed methods, technical challenges, difficulties and opportunities in the ERA, and conclusions of the workshop. Integr Environ Assess Manag 2024;20:780-793. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

2.
Article in English | MEDLINE | ID: mdl-37814916

ABSTRACT

Under current European Union regulation, the risks to aquatic organisms must be assessed for uses of plant protection products (PPPs) that may result in exposure to the environment. For herbicidal PPPs, aquatic macrophytes are often the most sensitive taxa. For some herbicidal modes of action, macrophytes may be affected only while they are actively growing. For the risk assessment, it is therefore useful to know whether application timings would result in surface water exposure during periods when aquatic macrophytes are actively growing (therefore potentially resulting in effects). Toxicity endpoints, which are based on studies with active growth, may be overconservative in cases where exposure of PPPs will not co-occur with active macrophyte growth. A comprehensive literature search was performed, using systematic and manual approaches, with the aim of identifying the main active growth period for macrophytes in natural freshwater bodies in climates relevant to the Central and Northern zones of the European Union. The results of the searches were screened initially to identify all potentially relevant references, for which a full evaluation was then performed. Reliability was assessed using the principles of the Klimisch scoring system. As part of the full evaluation, growth periods were identified for each macrophyte species studied. Finally, the extracted growth periods were considered together to determine an overall active growth period for aquatic macrophytes representative of the Central and Northern EU zones. Based on this literature review, the active growth period identified for most aquatic macrophyte species representative of the Central and Northern EU zones is April to September. Relating to the regulatory implication of these results, it may be possible to conclude a low risk for aquatic macrophytes if the predicted surface water exposure period for certain PPPs is demonstrated to be outside the periods of active growth. Integr Environ Assess Manag 2023;00:1-15. © 2023 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

3.
Sci Rep ; 13(1): 15843, 2023 09 22.
Article in English | MEDLINE | ID: mdl-37739987

ABSTRACT

Proteasomes are multi-subunit complexes that specialize in protein degradation. Cancer cells exhibit a heightened dependence on proteasome activity, presumably to support their enhanced proliferation and other cancer-related characteristics. Here, a systematic analysis of TCGA breast cancer datasets revealed that proteasome subunit transcript levels are elevated in all intrinsic subtypes (luminal, HER2-enriched, and basal-like/triple-negative) when compared to normal breast tissue. Although these observations suggest a pan-breast cancer utility for proteasome inhibitors, our further experiments with breast cancer cell lines and patient-derived xenografts (PDX) pointed to triple-negative breast cancer (TNBC) as the most sensitive subtype to proteasome inhibition. Finally, using TNBC cells, we extended our studies to in vivo xenograft experiments. Our previous work has firmly established a cytoprotective role for the transcription factor NRF1 via its ability to upregulate proteasome genes in response to proteasome inhibition. In further support of this notion, we show here that NRF1 depletion significantly reduced tumor burden in an MDA-MB-231 TNBC xenograft mouse model treated with carfilzomib. Taken together, our results point to TNBC as a particularly vulnerable breast cancer subtype to proteasome inhibition and provide a proof-of-principle for targeting NRF1 as a viable means to increase the efficacy of proteasome inhibitors in TNBC tumors.


Subject(s)
NF-E2-Related Factor 1 , Proteasome Endopeptidase Complex , Triple Negative Breast Neoplasms , Animals , Humans , Mice , Cytoplasm , Disease Models, Animal , Proteasome Endopeptidase Complex/genetics , Proteasome Inhibitors/pharmacology , Proteolysis , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , NF-E2-Related Factor 1/metabolism
4.
Pediatr Dermatol ; 40(2): 326-329, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36178265

ABSTRACT

Variegate porphyria (VP) is a rare subtype of porphyrias characterized by dysfunction of enzymes in the heme biosynthesis pathway leading to an accumulation of porphyrins and their precursors. The resulting buildup can manifest as neuropsychiatric symptoms and photosensitive blistering eruptions on sun-exposed skin. We report a case of VP in a 9-year-old girl with many confounding medical factors that warranted alternative explanations for her cutaneous lesions. VP has been reported infrequently in the pediatric population and is associated with more severe neuropsychiatric outcomes compared to adult-onset disease.


Subject(s)
Porphyria, Variegate , Porphyrias , Porphyrins , Child , Adult , Female , Humans , Porphyria, Variegate/diagnosis , Blister/diagnosis , Blister/etiology , Porphyrias/diagnosis , Porphyrias/metabolism , Skin/metabolism
5.
Environ Toxicol Chem ; 41(10): 2595-2602, 2022 10.
Article in English | MEDLINE | ID: mdl-35866471

ABSTRACT

Wild birds and mammals that feed in agricultural habitats are potentially exposed to pesticides through various routes. The European Food Safety Authority (EFSA) recently published a statement which concluded that the current EFSA risk assessment scheme for birds and mammals does not adequately cover bats (Chiroptera). In the present study, we take a more detailed look at the EFSA statement and assumptions made regarding direct (dermal) and indirect (dietary) exposure of bats to pesticides in terms of their realism and the potential implications for risk assessment outcomes. Regarding dietary exposure, errors in the residue per unit dose (RUD) values for flying insects (bat food), proposed in the EFSA bat statement, were identified and corrected. Lower RUD values based on a much broader data base are proposed. Using these more realistic RUD values, together with current assumptions regarding toxicity and exposure, the acute and long-term risk to bats appears to be within the range of those calculated for birds and ground-dwelling mammals under the current risk assessment scheme. Depending on the assumptions made, some uncertainties may remain and should be investigated further. According to the EFSA bat statement, dermal exposure of bats is the most significant route of exposure, resulting in the highest predicted daily doses. We demonstrated that the dermal exposure models in the EFSA bat statement predict much higher residues for bats than those measured for other flying organisms that have larger surface area to volume ratios, and thus would be expected to have the reverse relationship. We also illustrated that the amounts of spray liquid required to achieve the predicted dermal exposures of bats are implausibly high, with bats carrying an amount of spray liquid that exceeds their body weight many fold. It is recommended that a bat risk assessment framework should be based on realistic, sound science, allowing resources to be focused on those scenarios that are not already covered by the existing bird and mammal framework. Therefore, a quantitative risk assessment scheme should not be implemented until the many scientific uncertainties within the EFSA bat statement are addressed. Environ Toxicol Chem 2022;41:2595-2602. © 2022 Cambridge Environmental Assessments. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.


Subject(s)
Chiroptera , Pesticides , Animals , Birds , Dietary Exposure , Food Safety , Pesticides/analysis , Pesticides/toxicity , Risk Assessment
7.
Environ Sci Technol ; 56(7): 4029-4038, 2022 04 05.
Article in English | MEDLINE | ID: mdl-35302757

ABSTRACT

Efforts to understand macroplastic pollution have primarily focused on coastal and marine environments to the exclusion of freshwater, terrestrial, and urban ecosystems. To better understand macroplastics in the environment and their sources, a dual approach examining plastic input and leakage can be used. In this study, litter aggregation pathways at 40 survey sites with varying ambient population counts in the Ganges River Basin were surveyed in pre- and postmonsoon seasons. We examine active litter leakage using transect surveys of on-the-ground items, in conjunction with assessments of single-use plastic consumer products at the point of sale. We find that sites with low populations have a significantly higher number of littered items per 1,000 people than those with mid to high populations. Over 75% of litter items were plastics or multimaterial items containing plastic, and tobacco products and plastic food wrappers were the most recorded items. There was no significant variation of litter densities pre- and postmonsoon. Most single-use plastic consumer products were manufactured in-country, but approximately 40% of brands were owned by international companies. Stratified sampling of active litter input and consumer products provides a rapid, replicable snapshot of plastic use and leakage.


Subject(s)
Rivers , Waste Products , Ecosystem , Environmental Monitoring , Humans , Plastics , Waste Products/analysis
8.
Environ Pollut ; 269: 116160, 2021 Jan 15.
Article in English | MEDLINE | ID: mdl-33316501

ABSTRACT

The COVID-19 pandemic has resulted in an unprecedented surge of production, consumption, and disposal of personal protective equipment (PPE) including face masks, disposable gloves, and disinfectant wipes, which are often made of single use plastic. Widespread public use of these items has imposed pressure on municipalities to properly collect and dispose of potentially infectious PPE. There has been a lack of structured monitoring efforts to quantify the emerging trend of improperly disposed of PPE debris. In this study, we present a baseline monitoring survey to describe the spatial distribution of PPE debris during the COVID-19 pandemic from the metropolitan city of Toronto, Canada. Our objectives were to: (1) quantify PPE debris types among surveyed areas and; (2) identify PPE debris densities and accumulation of surveyed areas. A total of 1306 PPE debris items were documented, with the majority being disposable gloves (44%), followed by face masks (31%), and disinfecting wipes (25%). Of the face masks, 97% were designed for single use while only 3% were reusable. Of the surveyed locations, the highest daily average densities of PPE debris were recorded in the large and medium-sized grocery store parking lots and the hospital district (0.00475 items/m2, 0.00160 items/m2, and 0.00133 items/m2 respectively). The two surveyed residential areas had the following highest PPE densities (0.00029 items/m2 and 0.00027 items/m2), while the recreational trail had the lowest densities (0.00020 items/m2). Assuming a business-as-usual accumulation, an estimated 14,298 PPE items will be leaked as debris in just the surveyed areas annually. To facilitate proper disposal of PPE debris by the public we recommend development of municipal efforts to improve PPE collection methods that are informed by the described PPE waste pathways.


Subject(s)
COVID-19 , Personal Protective Equipment , Canada , Cities , Humans , Infectious Disease Transmission, Patient-to-Professional , Pandemics , Plastics , SARS-CoV-2
9.
PLoS One ; 15(12): e0242459, 2020.
Article in English | MEDLINE | ID: mdl-33264309

ABSTRACT

Rivers worldwide are now acting as major transport pathways for plastic pollution and discharge large quantities of waste into the ocean. Previous oceanographic modelling and current drifter data have been used to predict the movement and accumulation of plastic pollution in the marine environment, but our understanding of the transport and fate through riparian systems is still largely unknown. Here we undertook a proof of concept study by applying open source tracking technology (both GPS (Global Positing System) cellular networks and satellite technology), which have been successfully used in many animal movement studies, to track the movements of individual plastic litter items (500 ml PET (polyethylene terephthalate) drinks bottles) through the Ganges River system (known as the Ganga in India and the Padma and Meghna in Bangladesh, hereafter known as the Ganges) and the Bay of Bengal. Deployed tags were successfully tracked through the Ganges river system and into the Bay of Bengal marine system. The "bottle tags" were designed and built (e.g. shape, size, buoyancy) to replicate true movement patterns of a plastic bottle. The maximum distance tracked to date is 2845 km over a period of 94 days. We discuss lessons learnt from the development of these plastic litter tags, and outline how the potential widespread use of this open source technology has the ability to significantly increase understanding of the location of accumulation areas and the timing of large inputs of plastic pollution into the aquatic system. Furthermore, "bottle tags" may act as a powerful tool for stimulating social behaviour change, informing science-based policy, and as valuable educational outreach tools for public awareness.


Subject(s)
Plastics/analysis , Technology , Water Pollution/analysis , Bangladesh , Geography , Oceans and Seas , Rivers/chemistry
10.
Ecotoxicology ; 28(10): 1198-1209, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31696445

ABSTRACT

Wildlife can be exposed to chemicals in the environment from various anthropogenic sources. Ecotoxicity studies, undertaken to address the risks from potential exposure to chemicals, vary in their design e.g. duration of exposure, effect types and endpoints measured. Ecotoxicity studies measure biological responses to test item exposure. Responses can be highly variable, with limited opportunity for control of extrinsic sources of variability. It is critical to distinguish between treatment-related effects and background 'normal variability' when interpreting results. Historical control data (HCD) can be a valuable tool in contextualising results from single studies against previous studies performed under similar conditions. This paper discusses the case for better use of HCD in ecotoxicology assessments, illustrating with case studies the value and difficulties of using HCD in interpretation of results of standard and higher-tier study designs. HCD are routinely used in mammalian toxicology for human health assessments, but not directly in ecotoxicology. The possible reasons for this are discussed e.g., different data types, the potential to mask effects, and the lack of guidance. These concerns are real but not insurmountable and we would like to see organisations such as OECD, EFSA and USEPA develop guidance on the principles of HCD collection. Hopefully, this would lead to greater use of HCD and regulatory acceptance. We believe this is not only a scientifically valid approach but also an ethical issue that is in line with societally driven legal mandates to minimise the use of vertebrate testing in chemical regulatory decision making.


Subject(s)
Ecotoxicology/methods , Animals , Data Analysis , Risk Assessment/methods
11.
Sci Adv ; 4(6): eaat0131, 2018 06.
Article in English | MEDLINE | ID: mdl-29938223

ABSTRACT

The rapid growth of the use and disposal of plastic materials has proved to be a challenge for solid waste management systems with impacts on our environment and ocean. While recycling and the circular economy have been touted as potential solutions, upward of half of the plastic waste intended for recycling has been exported to hundreds of countries around the world. China, which has imported a cumulative 45% of plastic waste since 1992, recently implemented a new policy banning the importation of most plastic waste, begging the question of where the plastic waste will go now. We use commodity trade data for mass and value, region, and income level to illustrate that higher-income countries in the Organization for Economic Cooperation have been exporting plastic waste (70% in 2016) to lower-income countries in the East Asia and Pacific for decades. An estimated 111 million metric tons of plastic waste will be displaced with the new Chinese policy by 2030. As 89% of historical exports consist of polymer groups often used in single-use plastic food packaging (polyethylene, polypropylene, and polyethylene terephthalate), bold global ideas and actions for reducing quantities of nonrecyclable materials, redesigning products, and funding domestic plastic waste management are needed.

12.
Environ Toxicol Chem ; 36(3): 565-575, 2017 03.
Article in English | MEDLINE | ID: mdl-28234406

ABSTRACT

The use of plant protection products on agricultural crops can result in exposure of birds and mammals to toxic chemicals. In the European Union, the risks from such exposures are assessed under the current (2009) guidance document from the European Food Safety Authority (EFSA), designed to increase the realism of the theoretical risk assessments in comparison to its predecessor (SANCO/4145/2000). Since its adoption over 7 yr ago, many plant protection products have been evaluated successfully using the 2009 EFSA guidance document. However, there are still significant areas of improvement recommended for future revisions of this guidance. The present Focus article discusses experiences to date with the current scheme, including levels of conservatism in input parameters and interpretation by regulatory authorities together with proposals for how the guidance document could be improved when it is revised in the not too distant future. Several areas for which further guidance is recommended have been identified, such as the derivation of ecologically relevant bird and mammal reproductive endpoints and the use of modeling approaches to contextualize risk assessments. Areas where existing databases could be improved were also highlighted, including the collation of relevant focal species across Europe and expansion of the residue database for food items. To produce a realistic and useable guidance document in the future, it is strongly recommended that there is open and constructive communication between industry, regulatory authorities, and the EFSA. Such collaboration would also encourage harmonization between member states, thus reducing workloads for both industry and regulatory authorities. Environ Toxicol Chem 2017;36:565-575. © 2017 SETAC.


Subject(s)
Agrochemicals/toxicity , Birds/growth & development , Environmental Monitoring , Environmental Pollutants/toxicity , Reproduction/drug effects , Rodentia/growth & development , Animals , Crops, Agricultural/drug effects , Crops, Agricultural/growth & development , Environmental Monitoring/legislation & jurisprudence , Environmental Monitoring/methods , European Union , Food Safety , Government Regulation , Guidelines as Topic , Risk Assessment
13.
Brain Behav ; 6(2): e00425, 2016 02.
Article in English | MEDLINE | ID: mdl-27110447

ABSTRACT

INTRODUCTION: In the hyperacute phase of ischemic stroke, a 0° position is recommended to increase cerebral perfusion in nonhypoxic patients able to tolerate lying flat. However, use of 0° positioning is not uniformly applied in clinical practice, most likely due to concerns of aspiration pneumonia. We aimed to determine the risk of pneumonia associated with 0° head of bed positioning in acute stroke patients treated with thrombolytic therapy. METHODS: A retrospective descriptive study was conducted using prospectively collected, consecutive acute ischemic stroke patients treated with IVtPA whose head of bed was positioned at 0° for the first 24 h. Rates of hospital-acquired pneumonia were determined using a strict adjudication process to insure accuracy of pneumonia diagnoses. Quantitative characteristics were analyzed in SPSS to compare differences between "true" pneumonia cases and nonpneumonia cases. RESULTS: Twenty-four of 333 (7.2%) patients had mention the diagnosis of pneumonia in the registry and/or medical record. Of these cases, only 15 (4.5%) met evidence-based diagnostic criteria for hospital-acquired pneumonia. The 15 adjudicated cases had similar median admission NIHSS scores to nonpneumonia cases (10 vs. 9, respectively; P = ns), but were older (74 ± 15 vs. 64 ± 17 years; mean difference 9.889, 95 CI = 1.2-18.6; P = 0.026). A total of eight patients with pneumonia were intubated and mechanically ventilated, and one patient received bilevel positive airway pressure ventilation during the 0° positioning period. Pneumonia cases had significantly longer hospitalizations (14.5 ± 12 vs. 6.6 ± 9 days; mean difference 7.97, 95% CI = 1.1-14.8; P = 0.026) and higher median discharge mRS score (4 vs. 3: P = 0.003). CONCLUSIONS: Zero-degree head of bed positioning in the first 24 h following an acute ischemic stroke treated with IV-tPA was associated with acceptable rates of pneumonia. Rates for pneumonia may be further reduced by eliminating use of a 0° protocol in intubated/mechanically ventilated patients.


Subject(s)
Brain Ischemia/therapy , Head , Patient Positioning , Pneumonia/epidemiology , Stroke/therapy , Adult , Age Factors , Aged , Aged, 80 and over , Brain Ischemia/complications , Brain Ischemia/epidemiology , Fibrinolytic Agents/therapeutic use , Humans , Middle Aged , Patient Positioning/adverse effects , Pneumonia/complications , Prospective Studies , Recombinant Proteins/therapeutic use , Registries , Retrospective Studies , Risk , Stroke/complications , Stroke/epidemiology , Tissue Plasminogen Activator/therapeutic use
16.
Environ Sci Technol ; 43(20): 7916-23, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19921914

ABSTRACT

Hydrophobic contaminants accumulate within aquatic sediments, hence pelagic predators may have limited direct contact with such compounds, but can be exposed via their benthic prey (i.e., via dietary exposure). Here we examine the importance of feeding behaviors of both prey (sediment ingesters or noningesters) and predators (piercers or engulfers) in determining the extent of dietary exposure and toxic effects. A freshwater macroinvertebrate system was used, consisting of two predator species, a piercer (Notonecta glauca) and an engulfer (Ischnura elegans), and three prey species, a sediment noningester (Cloëon dipterum) and two sediment ingesters (Asellus aquaticus, Chironomus riparius). Predators were fed prey previously exposed to artificial sediment dosed with 30 microg/g of 14C benzophenone. The piercer predator accumulated more benzophenone from sediment ingester compared to sediment noningester prey, whereas the engulfer predator accumulated a similar concentration for all three prey species. Toxic effects, in terms of reduced feeding rate, were only observed with the engulfer feeding on sediment noningesters, probably due to the interaction between the narcotic mode of action of benzophenone and predator hunting strategy. The importance of dietary exposure in risk assessments may therefore depend on exposure pathways of prey, feeding behaviors of predators, and the contaminant's toxic mode of action.


Subject(s)
Benzophenones/metabolism , Feeding Behavior , Food Chain , Insecta/metabolism , Predatory Behavior , Animals , Carbon Radioisotopes , Environmental Pollutants/metabolism , Models, Biological
17.
Environ Toxicol Chem ; 28(11): 2449-57, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19572771

ABSTRACT

Ecological risk assessments tend to focus on contaminant effects on single species in isolation. However, additional effects from interactions between species (e.g., predator-prey interactions) may also occur in natural systems. The present study investigated the consequences of sublethal contaminant effects in prey on predator-prey interactions, particularly the interaction between prey behavioral changes and predation by predators with different hunting strategies. Ambush (Ischnura elegans Vander Linden [Insecta, Odonata]) and active (Notonecta glauca Linnaeus [Insecta, Heteroptera]) predator species were used in conjunction with three prey species (Asellus aquaticus Linnaeus [Crustacea, Isopoda], Cloion dipterum Linnaeus [Insecta, Ephemeroptera], and Chironomus riparius Meigen [Insecta, Diptera]). Immobilized prey demonstrated the importance of prey behavior for determining predation rates for both single- and multiple-prey species. Chironomus riparius was less responsive following exposure to cadmium, becoming more vulnerableto attack by the active but not the ambush predator. Some evidence was also observed for reduced general activity in C. dipterum following cadmium exposure. Sublethal exposure of prey did not affect the prey choice of active predators, possibly because of prey behavioral changes being insufficient to influence their relative availabilities. However, cadmium exposure of prey did alter their susceptibility to ambush predators. There was a reduced proportion of C. dipterum and an increased proportion of A. aquaticus in the diet of ambush predators, possibly because of reduced activity in C. dipterum affecting their relative encounter rates with predators. Sublethal exposures can therefore result in reduced prey survival that would not be predicted by single-species toxicity tests.


Subject(s)
Cadmium/toxicity , Environmental Monitoring , Insecta/metabolism , Predatory Behavior , Toxicity Tests , Animals , Ecology , Risk Assessment
18.
Adv Ther ; 25(2): 77-88, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18309465

ABSTRACT

INTRODUCTION: TobraDex ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.1%; Alcon Laboratories Inc, Fort Worth, Tex) is frequently used for inflammatory ocular conditions where a risk of bacterial ocular infection exists. A new formulation, TobraDex ST ophthalmic suspension (tobramycin 0.3%, dexamethasone 0.05%, Alcon), utilises a novel suspension technology to reduce viscosity and help prevent settling in the container. METHODS: A rabbit model that closely mimics the human eye and a clinical study with cataract patients was used to compare the pharmacokinetics and tissue permeability of TobraDex ST and TobraDex. An in-vitro model was used to assess the bactericidal activity using the rabbit tear concentrations of tobramycin 10 minutes after a single topical dose. RESULTS: Concentrations of both tobramycin and dexamethasone were greater in the tear film and ocular tissues of rabbits treated with TobraDex ST. There was an 8.3-fold increase in tobramycin concentration in the rabbit tear film 10 minutes after dosing with TobraDex ST compared with TobraDex. Concentrations of tobramycin and dexamethasone in ocular tissues from rabbits exposed to TobraDex ST were up to 12.5-fold greater relative to TobraDex. The in-vitro bactericidal activity (>99.9% kill, 3-log reduction) of TobraDex ST toward tobramycin-resistant and methicillin-resistant Staphylococcus aureus occurred in 90 minutes. TobraDex ST killed Streptococcus pneumoniae 3-log in 5 minutes. TobraDex had no activity toward tobramycin-resistant, methicillin-resistant S. aureus and required approximately 120 minutes for 3-log reduction of S. pneumoniae. In humans, the mean ratio of dexamethasone levels in the aqueous humour at 1 hour was 1.17 in favour of TobraDex ST. CONCLUSION: TobraDex ST demonstrated improved suspension formulation characteristics, enhanced pharmacokinetic distribution and improved bactericidal characteristics, and may provide a useful alternative as compared to TobraDex.


Subject(s)
Dexamethasone/pharmacokinetics , Methicillin-Resistant Staphylococcus aureus/drug effects , Ophthalmic Solutions/pharmacokinetics , Streptococcus pneumoniae/drug effects , Tobramycin/pharmacokinetics , Adult , Animals , Cataract/metabolism , Dexamethasone/pharmacology , Drug Combinations , Drug Resistance, Bacterial , Eye , Female , Humans , Male , Ophthalmic Solutions/pharmacology , Rabbits , Suspensions , Tears/chemistry , Tobramycin/pharmacology
19.
J Ocul Pharmacol Ther ; 23(4): 335-42, 2007 Aug.
Article in English | MEDLINE | ID: mdl-17803431

ABSTRACT

PURPOSE: The aim of this study was to establish a novel method to predict the human ocular penetration and distribution of topical antibiotics by using a controlled rabbit model that mimics the human eye with manual blinking and tear flow. METHODS: After anesthetizing the rabbits, a single dose of commercial antibiotic formulations was given with precision directly onto the cornea. This was followed by a 30-min controlled period applying manual blinking (4 blinks/min) and a supplementary tear flow (2 microL/min) that mimics the human eye. Tear samples were collected every 5 min and after euthanasia, conjunctival, aqueous humor, iris-ciliary body, and scleral samples were collected. The corneas were mounted in perfusion chambers to determine the level and continuing rate of release of the antibiotics, the levels of which were all determined using high-performance liquid chromatography analysis. RESULTS: U.S. formulations achieved conjunctival and corneal levels (µg/g) as follows: moxifloxacin, 6.6 +/- 0.3 and 50 +/- 5; tobramycin, 3.1 +/- 1.4 and 20 +/- 5; gentamicin, <2 and <2; levofloxacin, 1.5 +/- 0.3 and 19 +/- 2; gatifloxacin, 0.9 +/- 0.1 and 11 +/- 1; and trimethoprim, <0.1 and 2 +/- 1. Japan formulations achieved conjunctival and corneal levels as follows: levofloxacin 2.1 +/- 0.8 and 12 +/- 2; gatifloxacin, 2.2 +/- 0.9 and 7 +/- 1; ofloxacin, 1.6 +/- 0.5 and 7 +/- 1; and tosufloxacin, 0.7 +/- 0.1 and 1.5 +/- 0.3 (mean +/- standard error, n = 4). CONCLUSIONS: Moxifloxacin achieved the highest levels of antibiotic in ocular tissues. In the conjunctiva and cornea, the moxifloxacin level was 3-30 times the level of other fluoroquinolones, at least twice the level of the aminoglycosides, and 25 times the level of the antibacterial trimethoprim.


Subject(s)
Aminoglycosides/pharmacokinetics , Anti-Bacterial Agents/pharmacokinetics , Fluoroquinolones/pharmacokinetics , Ophthalmic Solutions/pharmacokinetics , Trimethoprim/pharmacokinetics , Administration, Topical , Animals , Blinking , Chromatography, High Pressure Liquid , Conjunctiva/metabolism , Cornea/metabolism , Female , Japan , Models, Animal , Rabbits , Species Specificity , Tears/metabolism , Tissue Distribution , United States
20.
Environ Sci Technol ; 41(5): 1783-9, 2007 Mar 01.
Article in English | MEDLINE | ID: mdl-17396674

ABSTRACT

Aquatic ecological risk assessment is primarily focused on aqueous exposure, but many hydrophobic contaminants bind to particulate material and accumulate in sediments. The risk posed by such contaminants is partially dependent on the importance of dietary exposure. Here, we describe the bioaccumulation of a highly hydrophobic compound (dioctadecyl-dimethyl ammonium chloride (DODMAC)) to four freshwater macroinvertebrates (i.e., Asellus aquaticus, Chironomus riparius, Gammarus pulex, Lumbriculus variegatus) and investigate the mechanistic basis for observed interspecific variation in bioaccumulation. Although more than 99.99% of DODMAC was sediment-bound, it was bioavailable to all four species via dietary exposure. Interspecific variation in bioaccumulation was apparent despite the lack of selective feeding and biotransformation potential and after normalization for body size and lipid content. Chironomus riparius had the highest lipid-normalized DODMAC concentration and L. variegatus had the lowest. Study species differed in factors affecting uptake (i.e., feeding rate) and absorption efficiency (i.e., gut passage time and gut surfactancy). Feeding rate did not explain interspecific variation in bioaccumulation, but bioaccumulation was enhanced by either high surfactancy and short gut passage time (e.g., G. pulex) or low surfactancy and long gut passage time (e.g., C. riparius). Risk assessment of hydrophobic contaminants should consider dietary exposure and the potential food chain effects of interspecific variation in bioaccumulation.


Subject(s)
Geologic Sediments/chemistry , Invertebrates/drug effects , Animals , Invertebrates/metabolism
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