Comparative physicochemical and pharmacokinetic profiles of inhaled beclomethasone dipropionate and budesonide

AbstractThe physicochemical and pharmacokinetic characteristics of BDP and budesonide are somewhat different, but the overall result is that both are well suited for use as inhaled corticosteroids. Both BDP and budesonide are metabolized primarily by the liver, with one of the metabolites of BDP, 17-BMP, having greater receptor affinity than either the parent compound or budesonide, which has no active metabolites. BDP has a lower water solubility than either 17-BMP or budesonide, which have similar water solubilities. Budesonide has lower oral bioavailability than BDP; however, it is generally reported to have a longer plasma half-life than either BDP or 17-BMP. The physicochemical and pharmacokinetic profiles of inhaled BDP and budesonide provide both compounds with a favourable ratio of topical to systemic effects and support their well-established role in the treatment of asthma. The device used to deliver an inhaled corticosteroid influences the lung deposition of the drug and selection of the device should be made with an understanding of the particular advantages and disadvantages of the device for each individual patient

The significance of sample mass in the analysis of steroid estrogens in sewage sludges and the derivation of partition coefficients in wastewaters

Optimization of an analytical method for determination of steroid estrogens, through minimizing sample size, resulted in recoveries >84%, with relative standard deviations <3% and demonstrated the significance of sample size on method performance. Limits of detection were 2.1–5.3 ng/g. Primary sludges had estrogen concentrations of up to one order of magnitude less than those found in biological sludges (up to 994 ng/g). However, partition coefficients were higher in primary sludges (except estriol), with the most hydrophobic compound (ethinylestradiol) exhibiting the highest Kp value, information which may be of value to those involved in modeling removal during wastewater treatment

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution

This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project “EuroMix” aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment

A Tiered Approach to Systemic Toxicity Testing for Agricultural Chemical Safety Assessment

Aproposal has been developed by the Agricultural Chemical Safety Assessment (ACSA) Technical Committee of the ILSI Health and Environmental Sciences Institute (HESI) for an improved approach to assessing the safety of crop protection chemicals. The goal is to ensure that studies are scientifically appropriate and necessary without being redundant, and that tests emphasize toxicological endpoints and exposure durations that are relevant for risk assessment. The ACSA Systemic Toxicity Task Force proposes an approach to systemic toxicity testing as one part of the overall assessment of a compound\u2019s potential to cause adverse effects on health. The approach is designed to provide more relevant data for deriving reference doses for shorter time periods of human exposure, and includes fewer studies for deriving longer term reference doses\u2014that is, neither a 12-month dog study nor a mouse carcinogenicity study is recommended. All available data, including toxicokinetics and metabolism data and life stages information, are taken into account. The proposed tiered testing approach has the potential to provide new risk assessment information for shorter human exposure durations while reducing the number of animals used and without compromising the sensitivity of the determination of longer term reference doses

Cumulative risk assessment of pesticide residues in food

There is increasing need to address the potential risks of combined exposures to multiple residues from pesticides in the diet. The available evidence suggests that the main concern is from dose addition of those compounds that act by the same mode of action. The possibility of synergy needs to be addressed on a case-by-case basis, where there is a biologically plausible hypothesis that it may occur at the levels of residues occurring in the diet. Cumulative risk assessment is a resource-intense activity and hence a tiered approach to both toxicological evaluation and intake estimation is recommended, and the European Food Safety Authority (EFSA) has recently published such a proposal. Where assessments have already been undertaken by some other authority, full advantage should be taken of these, subject of course to considerations of quality and relevance. Inclusion of compounds in a cumulative assessment group (CAG) should be based on defined criteria, which allow for refinement in a tiered approach. These criteria should include chemical structure, mechanism of pesticidal action, target organ and toxic mode of action. A number of methods are available for cumulating toxicity. These are all inter-related, but some are mathematically more complex than others. The most useful methods, in increasing levels of complexity and refinement, are the hazard index, the reference point index, the Relative Potency Factor method and physiologically based toxicokinetic modelling, although this last method would only be considered should a highly refined assessment be necessary. Four possible exposure scenarios are of relevance for cumulative risk assessment, acute and chronic exposure in the context of maximum residue level (MRL)-setting, and in relation to exposures from the actual use patterns, respectively. Each can be addressed either deterministically or probabilistically. Strategies for dealing with residues below the limit of detection, limit of quantification or limit of reporting need to be agreed. A number of probabilistic models are available, but some of there are geographically constrained due to the underlying datasets used in their construction. Guidance on probabilistic modelling needs to be finalised. Cumulative risk assessments have been performed in a number of countries, on organophosphate insecticides alone (USA) or together with carbamates (UK, DK, NL), triazines, chloroacetanilides, carbamates alone (USA), and all pesticides (DE). All identifiable assumptions and uncertainties should be tabulated and evaluated, at least qualitatively. Those likely to have a major impact on the outcome of the assessment should be examined quantitatively. In cumulative risk assessment, it is necessary, as in other risk assessments, for risk managers to consider what level Of Fisk would be considered "acceptable", for example what percentile of the population should be below the reference value. Criteria for prioritising CAGs for cumulative risk assessment include frequency of detection in monitoring programmes, high usage, high exposure relative to the reference value, large number of compounds (e.g. five or more) in a group