Concentrations of parabens in human breast tumours

Parabens are used as preservatives in many thousands of cosmetic, food and pharmaceutical products to which the human population is exposed. Although recent reports of the oestrogenic properties of parabens have challenged current concepts of their toxicity in these consumer products, the question remains as to whether any of the parabens can accumulate intact in the body from the long-term, low-dose levels to which humans are exposed. Initial studies reported here show that parabens can be extracted from human breast tissue and detected by thin-layer chromatography. More detailed studies enabled identification and measurement of mean concentrations of individual parabens in samples of 20 human breast tumours by high-pressure liquid chromatography followed by tandem mass spectrometry. The mean concentration of parabens in these 20 human breast tumours was found to be 20.6 +/- 4.2 ng g(-1) tissue. Comparison of individual parabens showed that methylparaben was present at the highest level (with a mean value of 12.8 +/- 2.2 ng g(-1) tissue) and represents 62% of the total paraben recovered in the extractions. These studies demonstrate that parabens can be found intact in the human breast and this should open the way technically for more detailed information to be obtained on body burdens of parabens and in particular whether body burdens are different in cancer from those in normal tissues. Copyright (C) 2004 John Wiley Sons, Ltd.

Technologies for biological containment of GM and Non-GM crops

International Perspective The development of GM technology continues to expand into increasing numbers of crops and conferred traits. Inevitably, the focus remains on the major field crops of soybean, maize, cotton, oilseed rape and potato with introduced genes conferring herbicide tolerance and/or pest resistance. Although there are comparatively few GM crops that have been commercialised to date, GM versions of 172 plant species have been grown in field trials in 31 countries. European Crops with Containment Issues Of the 20 main crops in the EU there are four for which GM varieties are commercially available (cotton, maize for animal feed and forage, and oilseed rape). Fourteen have GM varieties in field trials (bread wheat, barley, durum wheat, sunflower, oats, potatoes, sugar beet, grapes, alfalfa, olives, field peas, clover, apples, rice) and two have GM varieties still in development (rye, triticale). Many of these crops have hybridisation potential with wild and weedy relatives in the European flora (bread wheat, barley, oilseed rape, durum wheat, oats, sugar beet and grapes), with escapes (sunflower); and all have potential to cross-pollinate fields non-GM crops. Several fodder crops, forestry trees, grasses and ornamentals have varieties in field trials and these too may hybridise with wild relatives in the European flora (alfalfa, clover, lupin, silver birch, sweet chestnut, Norway spruce, Scots pine, poplar, elm, Agrostis canina, A. stolonifera, Festuca arundinacea, Lolium perenne, L. multiflorum, statice and rose). All these crops will require containment strategies to be in place if it is deemed necessary to prevent transgene movement to wild relatives and non-GM crops. Current Containment Strategies A wide variety of GM containment strategies are currently under development, with a particular focus on crops expressing pharmaceutical products. Physical containment in greenhouses and growth rooms is suitable for some crops (tomatoes, lettuce) and for research purposes. Aquatic bioreactors of some non-crop species (algae, moss, and duckweed) expressing pharmaceutical products have been adopted by some biotechnology companies. There are obvious limitations of the scale of physical containment strategies, addressed in part by the development of large underground facilities in the US and Canada. The additional resources required to grow plants underground incurs high costs that in the long term may negate any advantage of GM for commercial productioNatural genetic containment has been adopted by some companies through the selection of either non-food/feed crops (algae, moss, duckweed) as bio-pharming platforms or organisms with no wild relatives present in the local flora (safflower in the Americas). The expression of pharmaceutical products in leafy crops (tobacco, alfalfa, lettuce, spinach) enables growth and harvesting prior to and in the absence of flowering. Transgenically controlled containment strategies range in their approach and degree of development. Plastid transformation is relatively well developed but is not suited to all traits or crops and does not offer complete containment. Male sterility is well developed across a range of plants but has limitations in its application for fruit/seed bearing crops. It has been adopted in some commercial lines of oilseed rape despite not preventing escape via seed. Conditional lethality can be used to prevent flowering or seed development following the application of a chemical inducer, but requires 100% induction of the trait and sufficient application of the inducer to all plants. Equally, inducible expression of the GM trait requires equally stringent application conditions. Such a method will contain the trait but will allow the escape of a non-functioning transgene. Seed lethality (‘terminator’ technology) is the only strategy at present that prevents transgene movement via seed, but due to public opinion against the concept it has never been trialled in the field and is no longer under commercial development. Methods to control flowering and fruit development such as apomixis and cleistogamy will prevent crop-to-wild and wild-to-crop pollination, but in nature both of these strategies are complex and leaky. None of the genes controlling these traits have as yet been identified or characterised and therefore have not been transgenically introduced into crop species. Neither of these strategies will prevent transgene escape via seed and any feral apomicts that form are arguably more likely to become invasives. Transgene mitigation reduces the fitness of initial hybrids and so prevents stable introgression of transgenes into wild populations. However, it does not prevent initial formation of hybrids or spread to non-GM crops. Such strategies could be detrimental to wild populations and have not yet been demonstrated in the field. Similarly, auxotrophy prevents persistence of escapes and hybrids containing the transgene in an uncontrolled environment, but does not prevent transgene movement from the crop. Recoverable block of function, intein trans-splicing and transgene excision all use recombinases to modify the transgene in planta either to induce expression or to prevent it. All require optimal conditions and 100% accuracy to function and none have been tested under field conditions as yet. All will contain the GM trait but all will allow some non-native DNA to escape to wild populations or to non-GM crops. There are particular issues with GM trees and grasses as both are largely undomesticated, wind pollinated and perennial, thus providing many opportunities for hybridisation. Some species of both trees and grass are also capable of vegetative propagation without sexual reproduction. There are additional concerns regarding the weedy nature of many grass species and the long-term stability of GM traits across the life span of trees. Transgene stability and conferred sterility are difficult to trial in trees as most field trials are only conducted during the juvenile phase of tree growth. Bio-pharming of pharmaceutical and industrial compounds in plants Bio-pharming of pharmaceutical and industrial compounds in plants offers an attractive alternative to mammalian-based pharmaceutical and vaccine production. Several plantbased products are already on the market (Prodigene’s avidin, β-glucuronidase, trypsin generated in GM maize; Ventria’s lactoferrin generated in GM rice). Numerous products are in clinical trials (collagen, antibodies against tooth decay and non-Hodgkin’s lymphoma from tobacco; human gastric lipase, therapeutic enzymes, dietary supplements from maize; Hepatitis B and Norwalk virus vaccines from potato; rabies vaccines from spinach; dietary supplements from Arabidopsis). The initial production platforms for plant-based pharmaceuticals were selected from conventional crops, largely because an established knowledge base already existed. Tobacco and other leafy crops such as alfalfa, lettuce and spinach are widely used as leaves can be harvested and no flowering is required. Many of these crops can be grown in contained greenhouses. Potato is also widely used and can also be grown in contained conditions. The introduction of morphological markers may aid in the recognition and traceability of crops expressing pharmaceutical products. Plant cells or plant parts may be transformed and maintained in culture to produce recombinant products in a contained environment. Plant cells in suspension or in vitro, roots, root cells and guttation fluid from leaves may be engineered to secrete proteins that may be harvested in a continuous, non-destructive manner. Most strategies in this category remain developmental and have not been commercially adopted at present. Transient expression produces GM compounds from non-GM plants via the utilisation of bacterial or viral vectors. These vectors introduce the trait into specific tissues of whole plants or plant parts, but do not insert them into the heritable genome. There are some limitations of scale and the field release of such crops will require the regulation of the vector. However, several companies have several transiently expressed products in clinical and pre-clinical trials from crops raised in physical containment.

Quantitative analysis of mannitol polymorphs: FT-Raman spectroscopy

Mannitol is a polymorphic excipient which is usually used in pharmaceutical products as the beta form, although other polymorphs (alpha and delta) are common contaminants. Binary mixtures containing beta and delta mannitol were prepared to quantify the concentration of the beta form using FT-Raman spectroscopy. Spectral regions characteristic of each form were selected and peak intensity ratios of beta peaks to delta peaks were calculated. Using these ratios, a correlation curve was established which was then validated by analysing further samples of known composition. The results indicate that levels down to 2% beta could be quantified using this novel, non-destructive approach. Potential errors associated with quantitative studies using FT-Raman spectroscopy were also researched. The principal source of variability arose from inhomogeneities on mixing of the samples; a significant reduction of these errors was observed by reducing and controlling the particle size range. The results show that FT-Raman spectroscopy can be used to rapidly and accurately quantitate polymorphic mixtures.

Condensed tannins in extracts from European medicinal plants and herbal products

Medicinal plant materials are not usually analysed for condensed tannins (CT). Thirty commercially available European medicinal plants and herbal products were screened for CT and fourteen CT samples were analysed in detail. This is also the first comprehensive CT analysis of pine buds, walnut leaves, heather flowers and great water dock roots. Acetone/water extracts contained between 3.2 and 25.9 g CT/100 g of extract, had CT with mean degrees of polymerisation of 2.9 to 13.3, procyanidin/prodelphinidin ratios of 1.6/98.4 to 100/0 and cis/trans flavan-3-ol ratios of 17.7/82.3 to 97.3/2.7. The majority of samples contained procyanidins, four contained A-type linkages (blackthorn flowers, heather flowers, bilberry leaves and cowberry leaves) and one sample also had galloylated procyanidins (great water dock roots).

Dunford-Pettis properties, Hilbert spaces and projective tensor products

We study complete continuity properties of operators onto ℓ2 and prove several results in the Dunford–Pettis theory of JB∗-triples and their projective tensor products, culminating in characterisations of the alternative Dunford–Pettis property for where E and F are JB∗-triples.

Serving GODAE Data and Products to the Ocean Community

The Global Ocean Data Assimilation Experiment (GODAE [http:// www.godae.org]) has spanned a decade of rapid technological development. The ever-increasing volume and diversity of oceanographic data produced by in situ instruments, remote-sensing platforms, and computer simulations have driven the development of a number of innovative technologies that are essential for connecting scientists with the data that they need. This paper gives an overview of the technologies that have been developed and applied in the course of GODAE, which now provide users of oceanographic data with the capability to discover, evaluate, visualize, download, and analyze data from all over the world. The key to this capability is the ability to reduce the inherent complexity of oceanographic data by providing a consistent, harmonized view of the various data products. The challenges of data serving have been addressed over the last 10 years through the cooperative skills and energies of many individuals.

The GlobMODEL demonstrator: assimilation of new satellite products in an operational meteorological center

As part of its Data User Element programme, the European Space Agency funded the GlobMODEL project which aimed at investigating the scientific, technical, and organizational issues associated with the use and exploitation of remotely-sensed observations, particularly from new sounders. A pilot study was performed as a "demonstrator" of the GlobMODEL idea, based on the use of new data, with a strong European heritage, not yet assimilated operationally. Two parallel assimilation experiments were performed, using either total column ozone or ozone profiles retrieved at the Royal Netherlands Meteorological Institute (KNMI) from the Ozone Monitoring Instrument (OMI). In both cases, the impact of assimilating OMI data in addition to the total ozone columns from the SCanning Imaging Absorption spectroMeter for Atmospheric CartograpHY (SCIAMACHY) on the European Centre for Medium Range Weather Forecasts (ECMWF) ozone analyses was assessed by means of independent measurements. We found that the impact of OMI total columns is mainly limited to the region between 20 and 80 hPa, and is particularly important at high latitudes in the Southern hemisphere where the stratospheric ozone transport and chemical depletion are generally difficult to model with accuracy. Furthermore, the assimilation experiments carried out in this work suggest that OMI DOAS (Differential Optical Absorption Spectroscopy) total ozone columns are on average larger than SCIAMACHY total columns by up to 3 DU, while OMI total columns derived from OMI ozone profiles are on average about 8 DU larger than SCIAMACHY total columns. At the same time, the demonstrator brought to light a number of issues related to the assimilation of atmospheric composition profiles, such as the shortcomings arising when the vertical resolution of the instrument is not properly accounted for in the assimilation. The GlobMODEL demonstrator accelerated scientific and operational utilization of new observations and its results - prompted ECMWF to start the operational assimilation of OMI total column ozone data.

Organic pollutants in animal products

It is necessary to assess the contamination of animal products by pollutants in order to protect human health. This can be achieved by understanding the processes whereby contaminants are introduced into the food chain. Such contamination can arise from the atmospheric deposition on to crops and soil or via contaminated feed. These processes are described and quantified with particular reference to the deposition of organic pollutants onto pasture. The transfer of the contaminants from the fodder and feed to the animal is also described. Finally, these processes are put in context by the illustration of how they are used in regulatory exposure models.

Errors associated with the preparation of aseptic products in UK hospital pharmacies: lessons from the national aseptic error reporting scheme

Background Pharmacy aseptic units prepare and supply injectables to minimise risks. The UK National Aseptic Error Reporting Scheme has been collecting data on pharmacy compounding errors, including near-misses, since 2003. Objectives The cumulative reports from January 2004 to December 2007, inclusive, were analysed. Methods The different variables of product types, error types, staff making and detecting errors, stage errors detected, perceived contributory factors, and potential or actual outcomes were presented by cross-tabulation of data. Results A total of 4691 reports were submitted against an estimated 958 532 items made, returning 0.49% as the overall error rate. Most of the errors were detected before reaching patients, with only 24 detected during or after administration. The highest number of reports related to adult cytotoxic preparations (40%) and the most frequently recorded error was a labelling error (34.2%). Errors were mostly detected at first check in assembly area (46.6%). Individual staff error contributed most (78.1%) to overall errors, while errors with paediatric parenteral nutrition appeared to be blamed on low staff levels more than other products were. The majority of errors (68.6%) had no potential patient outcomes attached, while it appeared that paediatric cytotoxic products and paediatric parenteral nutrition were associated with greater levels of perceived patient harm. Conclusions The majority of reports were related to near-misses, and this study highlights scope for examining current arrangements for checking and releasing products, certainly for paediatric cytotoxic and paediatric parenteral nutrition preparations within aseptic units, but in the context of resource and capacity constraints.