Proposal for a National Blueprint Framework to Monitor Progress on Water-Related Sustainable Development Goals in Europe.

The 17 Sustainable Development Goals (SDGs) underpinned by 169 targets presents national governments with huge challenges for implementation. We developed a proposal for a National Blueprint Framework (NBF) with 24 water-related indicators, centered on SDG 6 (clean water and sanitation for all), each with a specific target. We applied the NBF to 28 EU Member States (EU-28) and conclude that: (1) The current SDG 6 indicators are useful for monitoring progress toward water-related targets but their usefulness can be improved by focusing more on their practical implementation. (2) The extension of SDG 6 with complementary indicators (e.g. for the circular economy of water) and quantitative policy targets is urgently needed. This will benefit the communication process and progress at the science-policy interface. (3) SDG indicators can be improved in a SMART (specific, measurable, achievable, relevant, and time-bound) manner and by setting clear policy targets for each indicator, allowing for measuring distance-to-targets. This allows country-to-country comparison and learning, and accelerates the SDG implementation process. (4) We propose 24 water-related indicators centered on SDG 6, with complementary indicators including quantitative policy targets. The approach is doable, easily scalable, and flexibly deployable by collecting information for the EU-28. (5) Main gaps in the EU-28 are observed for water quality, wastewater treatment, nutrient, and energy recovery, as well as climate adaptation to extreme weather events (heat, droughts, and floods). (6) The framework was less successful for non-OECD countries due to lack of data and EU-centric targets for each indicator. This needs further research.

REACH, non-testing approaches and the urgent need for a change in mind set.

The objectives of REACH cannot be achieved under the current risk assessment approach. A change in mind set among all the relevant stakeholders is needed: risk assessment should move away from a labor-intensive and animal-consuming approach to intelligent and pragmatic testing, by combining exposure and hazard data effectively and trying to group chemicals (category approaches). The focus should be on reducing the overall uncertainties of 30,000 chemicals while acknowledging the existence of the uncertainty paradox: reducing uncertainty in the assessment of individual chemicals following the classical chemical-by-chemical approach as we have in previous decades will result in a prolongation of uncertainty for the entire group of 30,000 chemicals as a whole. With the first REACH registration deadline (2010) rapidly approaching, a mind set change is urgently needed. We can speed up the regulatory acceptance process, starting with the maximum use of currently available exposure and hazard data, tools and models. Optimal use should also be made of experimental exposure and hazard data generated under REACH. Only such an approach will make it possible to obtain a sufficient level of information within the time frame of REACH. A much more intensive dialogue between stakeholders is necessary.

On-the-road driving performance after use of the antihistamines mequitazine and l-mequitazine, alone and with alcohol.

OBJECTIVE: Previous studies demonstrated that mequitazine produces mild sedation after single doses. Its enantiomer, l-mequitazine, has a stronger potency for the H1 receptor. The aim of the current study was to assess the effects of l-mequitazine and mequitazine, alone and with alcohol, on driving. METHODS: Twenty-five healthy volunteers were treated with l-mequitazine 2.5, 5.0 and 10 mg, mequitazine 10 mg and placebo, alone and in combination with alcohol in a double-blind crossover design. Driving performance was assessed using the standardized highway driving test in normal traffic. Its primary measure is the Standard Deviation of the Lateral Position (SDLP). Secondary measures consisted of an auditory word learning test during driving, and subjective measures of driving performance. RESULTS: L-mequitazine 2.5 and 5.0 mg showed no effect on SDLP in the highway driving test, while SDLP significantly increased after l-mequitazine 10 mg (alone +1.59 cm; with alcohol +1.41 cm) and mequitazine 10 mg (with alcohol +1.17 cm). Alcohol significantly impaired all performance measures (SDLP +2.63 cm) but did not interact with the effects of treatment. Subjective measures indicated that participants were aware of the impairing effects of alcohol, but not of l-mequitazine and mequitazine. CONCLUSION: L-mequitazine can be considered safe to drive in dosages of 2.5 and 5.0 mg. L-mequitazine 10 mg led to mild driving impairment. Alcohol impaired all performance measures and added to the effects of l-mequitazine and mequitazine.

Summary of a workshop on regulatory acceptance of (Q)SARs for human health and environmental endpoints.

The "Workshop on Regulatory Use of (Q)SARs for Human Health and Environmental Endpoints," organized by the European Chemical Industry Council and the International Council of Chemical Associations, gathered more than 60 human health and environmental experts from industry, academia, and regulatory agencies from around the world. They agreed, especially industry and regulatory authorities, that the workshop initiated great potential for the further development and use of predictive models, that is, quantitative structure-activity relationships [(Q)SARs], for chemicals management in a much broader scope than is currently the case. To increase confidence in (Q)SAR predictions and minimization of their misuse, the workshop aimed to develop proposals for guidance and acceptability criteria. The workshop also described the broad outline of a system that would apply that guidance and acceptability criteria to a (Q)SAR when used for chemical management purposes, including priority setting, risk assessment, and classification and labeling.

Uptake, distribution and retention of zineb and ziram in rainbow trout (Salmo gairdneri).

In short-term static bioaccumulation experiments with 14C-labelled zinc ethylenebisdithiocarbamate (zineb) and zinc dimethyldithiocarbamate (ziram) both compounds were rapidly disseminated through the tissues. Whole-body accumulation was low, with bioconcentration factors less than 100. Whole-body elimination was rapid with 45% and 25% of the initial radioactivity from ziram and zineb, respectively, being retained by the end of the 16-day depuration period. Pigmented tissues appeared to be major distribution sites as well. This may be related to the affinity of the compounds and/or their degradation products to melanin or to complexation with phenoloxidase, a copper-containing enzyme involved in melanin synthesis. Autoradiography also revealed a high labelling of thyroid follicles. The results show that dithiocarbamates are selectively localized in various tissues, reported to be the target organs for their toxic action. The observed differences in toxicokinetics between zineb and ziram may, in part, explain the differences in toxicity to fish between ethylenebisdithiocarbamates and dialkyldithiocarbamates.

The application of QSARs, extrapolation and equilibrium partitioning in aquatic effects assessment for narcotic pollutants.

QSAR estimates of toxicity of relatively unreactive organic chemicals for 19 species of bacteria, algae, fungi, protozoans, coelenterates, rotifers, molluscs, crustaceans, insects, fish and amphibians were used to predict 'no-effect-levels' (NELs) at the ecosystem level by means of a recently developed extrapolation model. Equilibrium-partitioning theory for sediment and water was used to derive NELs for aquatic sediments. A simple table is given from which NELs for water and sediments can be predicted on the basis of only the octanol-water partition coefficient and molecular weight.

Classifying environmental pollutants: Part 3. External validation of the classification system.

In order to validate a classification system for the prediction of the toxic effect concentrations of organic environmental pollutants to fish, all available fish acute toxicity data were retrieved from the ECETOC database, a database of quality-evaluated aquatic toxicity measurements created and maintained by the European Centre for the Ecotoxicology and Toxicology of Chemicals. The individual chemicals for which these data were available were classified according to the rulebase under consideration and predictions of effect concentrations or ranges of possible effect concentrations were generated. These predictions were compared to the actual toxicity data retrieved from the database. The results of this comparison show that generally, the classification system provides adequate predictions of either the aquatic toxicity (class 1) or the possible range of toxicity (other classes) of organic compounds. A slight underestimation of effect concentrations occurs for some highly water soluble, reactive chemicals with low log K(ow) values. On the other end of the scale, some compounds that are classified as belonging to a relatively toxic class appear to belong to the so-called baseline toxicity compounds. For some of these, additional classification rules are proposed. Furthermore, some groups of compounds cannot be classified, although they should be amenable to predictions. For these compounds additional research as to class membership and associated prediction rules is proposed.

Uniform system for the evaluation of substances. I. Principles and structure.

In April 1994, the first version of the Uniform System for the Evaluation of Substances (USES 1.0) was launched to comply with an action point of the Netherlands National Environmental Policy Plan. USES is a tool for the rapid, quantitative assessment of the hazards and risks of chemical substances, including new substances, existing substances, agricultural pesticides and biocides. It was developed to be applied as a decision-support system by the central government, by industry and institutes in the private sector and by international fora. Since hazard and risk assessment must be transparent to all users and easy to perform, USES 1.0 is well documented and available as a computer program. An overview of this system will be presented including its objectives, the national and international framework, the general principles involved, as well as the structure and the content of the models used.

Evaluation of EU risk assessments existing chemicals (EC Regulation 793/93).

An evaluation was performed on the first group (41) of completed risk assessments for chemicals of the EU priority lists (Existing Chemicals; EC Regulation 793/93). The evaluation focussed on the conclusions of the risk assessments. The EU risk assessment process detected a high number of substances of concern. Furthermore priority chemicals may pose potential risks to the whole range of protection goals of the risk assessment. The predictability of the risk assessments for priority chemicals was investigated. Our a priori knowledge on possible risks of priority chemicals is found to be poor, especially for consumers. Both for environment and human health the potential risks were linked with a broad spectrum of use patterns. It is concluded that no industry category can in advance be excluded from performing risk assessments. For a great number of chemicals, additional testing was found to be needed to finalize the risk assessment. This evokes questions about the completeness of the current base-set, but also about the suitability of some of the submitted human health tests that should initially fulfil the base-set needs. The results of this evaluation are useful for ongoing discussions on risk assessment processes for chemicals.

Risk assessment and management of new and existing chemicals.

An evaluation was made of the recently developed risk assessment methodologies for new and existing chemicals in the European Communities. The evaluation also included the methodologies to prioritize chemicals and procedures for risk management, i.e., the (draft) guidance document for the development of strategies for risk reduction. The way in which chemicals are prioritized is accepted with only very few comments. Clear progress has been made in the development and harmonization of risk assessment methodologies and the application of estimation methodologies. Nevertheless, improvements are necessary for the estimation of consumer and occupational exposure, the derivation, use and transparency of assessment factors for chemicals and classes of chemicals based on the mode of toxic action, environmental exposure models and their validation and relation with monitoring data. As far as risk management is concerned it was recommended to improve the integration of the myriad of directives and regulations, to clarify definitions, to provide clear guidance on the determination and weighing of advantages and implications of risk reduction measures and to develop tools, including voluntary agreements, to speed up the slow chemical-by-chemical approach.

The role of the European centre for the validation of alternative methods (ECVAM) in the validation of (Q)SARs.

Under the current chemicals legislation, the regulatory use of structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs), collectively referred to as (Q)SARs, for the assessment of chemicals is limited, partly due to concerns about the extent to which (Q)SAR estimates can be relied upon. On 29 October 2003, the European Commission adopted a legislative proposal that foresees the introduction of a new regulatory system for chemicals called REACH (Registration, Evaluation, and Authorisation of Chemicals), which will impose equivalent information requirements on both new and existing chemicals. For reasons of practicality, cost-effectiveness and animal welfare, it is envisaged that (Q)SARs will play an important role in the assessment of some 30,000 existing chemicals for which further information may be required under the REACH system. It will therefore be essential that the (Q)SAR models used will produce reliable estimates. To overcome the barriers in the acceptance of (Q)SARs for regulatory purposes, it is widely acknowledged that there needs to be international agreement on the principles of (Q)SAR validation, and that the process of (Q)SAR validation should be managed by independent organisations, with a view to providing independent advice to the regulators who make decisions on the acceptability of (Q)SARs. The European Centre for the Validation of Alternative Methods (ECVAM), which is part of the European Commission's Joint Research Centre (JRC), has a well-established role in providing independent scientific and technical advice to European policy makers. This paper describes progress made at an international level regarding the principles of validation, and explains the role of ECVAM regarding the practical validation of (Q)SARs.

The prospects for using (Q)SARs in a changing political environment--high expectations and a key role for the European Commission's joint research centre.

Recent policy developments in the European union (EU) and within the Organisation for Economic Cooperation and Development (OECD) have placed increased emphasis on the use of structure-activity relationships (SARs) and quantitative structure-activity relationships (QSARs), collectively referred to as (Q)SARs, within various regulatory programmes for the assessment of chemicals and products. The most significant example within the EU is the European commission's proposal (of 29 October 2003) to introduce a new system for managing chemicals (called REACH), which calls for an increased use of (Q)SARs and other non-animal methods, especially for the assessment of low production volume chemicals. Another development within the EU is the Seventh Amendment to the Cosmetics Directive, which foresees the phasing out of animal testing on cosmetics, combined with the imposition of marketing bans on cosmetics that have been tested on animals after certain deadlines. At the same time, the Existing Chemicals programme within the OECD is investigating ways of increasing the use of chemical category approaches, which depend heavily on the use of (Q)SARs, activity-activity relationships and read-across. Such developments are placing an enormous challenge on industry, regulatory bodies, and on the European commission's Joint Research Centre (JRC), which is responsible for providing independent scientific advice to policy makers in the European Commission and the Member States. This paper reviews the different scientific and regulatory purposes for which reliable (Q)SARs could be used, and describes the current work of the JRC in providing scientific support for the development, validation and implementation of (Q)SARs.

Application of QSARs in risk management of existing chemicals.

QSAR-estimates of aquatic toxicity of relatively unreactive (narcosis-type) organic chemicals for 19 species were used to predict "no-effect-levels" (NELs) at the ecosystem level by means of several extrapolation models which were recently discussed by the Organisation for Economic Cooperation and Development (OECD). It appeared that the differences between the numerical results of these extrapolation methods, despite their different statistical assumptions, were small. Equilibrium-partitioning theory for sediment and water as well as biota and water was used to derive NELs for aquatic sediments and whole-body residues. Simple equations are given, from which NELs for water, and subsequently for sediments and whole-body residues, can be predicted on the basis of only the octanol-water partition coefficient. Actual application of the models presented absolutely requires the availability of methods to recognize chemicals that act by the unspecific mechanism of narcosis. To this end, a classification scheme, based on molecular structure, was developed. This classification scheme was applied to the approximately 2000 so-called High Production Volume Chemicals (HPVCs) listed in Annex 1 of the Council Regulation on the Evaluation and the Control of the Environmental Risks of Existing Chemicals of the European Communities. From the classification of these 2000 HPVCs it is concluded that, for a large portion of all existing chemicals, reliable QSAR estimates of aquatic toxicity can be made; this considerably speeds up the process of priority setting and risk assessment of existing chemicals. The validity of this (dual) approach was tested by a comparison of estimated NELs with actual FCC values for all compounds from the US-EPA Water Quality Guidelines list that classify as narcosis-type compounds. This comparison shows that for many existing chemicals QSARs may be used to derive quality guidelines for water, aquatic sediments and residues in aquatic biota.

Use of the Threshold of Toxicological Concern (TTC) approach for deriving target values for drinking water contaminants.

Ongoing pollution and improving analytical techniques reveal more and more anthropogenic substances in drinking water sources, and incidentally in treated water as well. In fact, complete absence of any trace pollutant in treated drinking water is an illusion as current analytical techniques are capable of detecting very low concentrations. Most of the substances detected lack toxicity data to derive safe levels and have not yet been regulated. Although the concentrations in treated water usually do not have adverse health effects, their presence is still undesired because of customer perception. This leads to the question how sensitive analytical methods need to become for water quality screening, at what levels water suppliers need to take action and how effective treatment methods need to be designed to remove contaminants sufficiently. Therefore, in the Netherlands a clear and consistent approach called 'Drinking Water Quality for the 21st century (Q21)' has been developed within the joint research program of the drinking water companies. Target values for anthropogenic drinking water contaminants were derived by using the recently introduced Threshold of Toxicological Concern (TTC) approach. The target values for individual genotoxic and steroid endocrine chemicals were set at 0.01 µg/L. For all other organic chemicals the target values were set at 0.1 µg/L. The target value for the total sum of genotoxic chemicals, the total sum of steroid hormones and the total sum of all other organic compounds were set at 0.01, 0.01 and 1.0 µg/L, respectively. The Dutch Q21 approach is further supplemented by the standstill-principle and effect-directed testing. The approach is helpful in defining the goals and limits of future treatment process designs and of analytical methods to further improve and ensure the quality of drinking water, without going to unnecessary extents.

Effects of chemical stress on the population dynamics of Daphnia magna: a comparison of two test procedures.

Ten substances were tested to compare two methods that can be used in chronic toxicity studies with the Cladoceran Daphnia magna. In semistatic experiments with cohorts (life-table studies) survival appeared to be a dominant factor in exponential population growth. Specific inhibition of reproduction as a result of toxic stress was observed only in tests with bromide and 2,4-dichloroaniline. For some substances (cadmium, bichromate, metavanadate, and bromide) individual growth (carapace length) was found to be a sensitive parameter. In intermittent-flow experiments with small expanding populations the yield (carrying capacity) proved to be a highly sensitive parameter, probably owing to the fact that in these tests populations grow logistically, i.e., become additionally stressed by food limitation. Chemically induced reductions in food ingestion and conversion efficiency may thus become very predominant. In view of the place of these crustaceans in the food web such reductions in the carrying capacity would seem to be of great ecotoxicological importance.

Fish embryos as teratogenicity screens: a comparison of embryotoxicity between fish and birds.

Early life stage (ELS) toxicity experiments were carried out with zebra fish (Brachydanio rerio) and rainbow trout (Salmo gairdneri) and 10 chemicals used in the rubber industry. Several of these chemicals appeared to be teratogenic. A good correlation (r = 0.95) was found between the 7-day EC50 for zebra fish and the 60-day EC50 for rainbow trout for total embryotoxicity (embryolethality and malformations). The S. gairdneri test appeared to be slightly more sensitive than the test with B. rerio. It is therefore concluded that this short-term test is a good alternative for the long-term test with S. gairdneri. A remarkably good correlation (r = 0.90) was found between the ED50 for chicken embryotoxicity reported in the literature and the EC50 for embryotoxicity for both zebra fish and rainbow trout. This may, among other things, be explained by similarities in embryonic development and the absence of maternal and placental metabolism of the toxicants in tests with eggs of both fish and birds. It may therefore be concluded that both the short-term ELS test with B. rerio and the chicken egg test have the same predictive power for mammalian teratogenicity; i.e., both are suitable screening tests for direct-acting teratogens.

The use of cohorts and populations in chronic toxicity studies with Daphnia magna: a cadmium example.

Two semistatic life table experiments with Daphnia magna were carried out on reconstituted and Lake IJssel water. The "nontoxic concentrations" for cadmium with respect to the intrinsic rate of natural increase, derived from age-specific survival and fecundity were 1 and 3.2 micrograms/liter, respectively. Body length appeared to be a sensitive parameter. A third intermittent-flow experiment was started with small, exponentially growing populations. These populations had a stable age distribution, were composed of cohorts of different ages and showed an almost perfect logistic growth. Cadmium was shown to reduce the upper numerical limit (carrying capacity) for D. magna and was inversely related to this parameter: log Y = 2.85 -0.20 log [Cd]; r = -0.99. A "nontoxic concentration" could not be established. Based on the "background" concentration of cadmium, a freshwater quality criterion of 0.1 microgram/liter is proposed. The results are used to discuss several shortcomings of the current methods. Finally it is stated that the introduction of the concepts of population dynamics in reproduction tests with D. magna is a realistic step towards ecotoxicology.

Improvements in creatinine methodology: a critical assessment.

A large evaluation study, analytical as well as clinical, was performed on four published improvements for the determination of creatinine in serum. Two of the methods were based on the Jaffé reaction, the other two were enzymatic methods. Analytically, all four methods showed a similar performance. In the analysis of numerous specimens from advanced care departments, however, the methods performed differently. The two enzymatic procedures scored better than the two Jaffé methods, when compared with an HPLC-based reference method. However, even the best methods produced outliers and a larger scatter than that obtained with "normal" specimens.

Ecotoxicological effects assessment: a comparison of several extrapolation procedures.

In the future, extrapolation procedures will become more and more important for the effect assessment of compounds in aquatic systems. For achieving a reliable method these extrapolation procedures have to be evaluated thoroughly. As a first step three extrapolation procedures are compared by means of two sets of data, consisting of (semi)chronic and acute toxicity test results for 11 aquatic species and 8 compounds. Because of its statistical basis the extrapolation procedure of Van Straalen and Denneman is preferred over the procedures of the EPA and Stephan et al. The results of the calculations showed that lower numbers of toxicity data increase the chance of underestimating the risk of a compound. Therefore it is proposed to extend the OECD guidelines for algae, Daphnia, and fish with chronic (aquatic) toxicity tests for more species of different taxonomic groups.