Proposal for regulatory risk mitigation measures for human pharmaceutical residues in the environment.

Environmental risks of human pharmaceutical products should be made transparent and mitigated as far as possible. We propose to apply a risk mitigation scheme to the marketing authorisation of human medicinal products which is pragmatic and tailored, and thus will not increase the burden to regulators and industry too much. This scheme takes into account increasing knowledge and accuracy of the environmental risk estimates, applying preliminary risk mitigation when risks are determined based on model estimates, and definitive, more strict and far-reaching risk mitigation when risks are based on actual measured environmental concentrations. Risk mitigation measures should be designed to be effective, proportional, easy to implement, and in line with current (other) legislation, as well as not being a burden to the patient/health care professionals. Furthermore, individual risk mitigation measures are proposed for products showing environmental risks, while general risk mitigation measures can be applied to all products to reduce the overall burden of pharmaceuticals in the environment. In order to effectively mitigate risk, linking marketing authorisation legislation to environmental legislation is essential.

Improving the regulatory environmental risk assessment of human pharmaceuticals: Required changes in the new legislation.

One of the flagship actions of the Pharmaceutical Strategy for Europe is to address environmental challenges associated with pharmaceutical use. This includes strengthening the Environmental Risk Assessment (ERA) at marketing authorisation (MA) of pharmaceuticals, and revision of the pharmaceutical legislation where needed. The overall aim of an ERA should be to enable comprehensive and effective identification and management of environmental risks of pharmaceuticals without affecting the availability of pharmaceuticals to patients. As experts in the evaluation of ERAs of human medicinal products submitted by pharmaceutical industries (Applicants), we have summarized the current status of the ERA and suggest legislative changes to improve environmental protection without affecting availability. Six regulatory goals were defined and discussed, including possible ways forward: 1) mandatory ERAs in accordance to the EMA guideline at the time of the MA, 2) enforcement of risk mitigation measures including re-evaluation of the ERA, 3) facilitated exchange of environmental data between pharmaceutical and environmental legislations, 4) substance-based assessments, 5) transparency of data, and 6) a catching-up procedure for active pharmaceutical ingredients that lack an ERA. These legislative proposals can be considered as prerequisites for a harmonised assessment and effective management of environmental risks and hazards of human pharmaceuticals.

Evaluation of the Daphnia magna reproduction test for detecting endocrine disruptors.

The Daphnia 21 d reproduction test is considered as a comprehensive and decisive test in the OECD Conceptual Framework for testing and assessment of endocrine disrupting chemicals (EDCs). However, how to interpret results of the Daphnia 21 d reproduction test for identification, risk assessment and testing strategy of EDCs remains an unsolved issue. This study analysed a total number of 135 published studies encompassing 86 known EDCs and non-EDCs with different modes of action. Our results show that the majority of effects on apical endpoints (survival, molting, growth, time to reproductive maturity, brood size, the number of broods, and the total number of offspring) do not seem to be EDC-specific. In contrast, the endpoint sex ratio is likely specific to juvenile hormones and their mimics. Variability is quantified for three most reported endpoints survival, the total number of offspring and sex ratio. Quantification of the endpoint sensitivity shows that the sensitivity of the sex ratio is lower than that of the total number of offspring. The Daphnia 21 d reproduction test gives insufficient information to conclude if a substance is an EDC or not. EDCs that are potent in assays in vitro may not be potent in the Daphnia 21 d reproduction test. We conclude that the Daphnia 21 d reproduction test is important for deriving No Observed Effect Concentrations for risk assessment but may produce false negatives in identification of EDCs when used on its own. A targeted testing strategy for selection of species, tests, and endpoints is suggested for identifying EDCs.

Development of a framework based on an ecosystem services approach for deriving specific protection goals for environmental risk assessment of pesticides.

General protection goals for the environmental risk assessment (ERA) of plant protection products are stated in European legislation but specific protection goals (SPGs) are often not precisely defined. These are however crucial for designing appropriate risk assessment schemes. The process followed by the Panel on Plant Protection Products and their Residues (PPR) of the European Food Safety Authority (EFSA) as well as examples of resulting SPGs obtained so far for environmental risk assessment (ERA) of pesticides is presented. The ecosystem services approach was used as an overarching concept for the development of SPGs, which will likely facilitate communication with stakeholders in general and risk managers in particular. It is proposed to develop SPG options for 7 key drivers for ecosystem services (microbes, algae, non target plants (aquatic and terrestrial), aquatic invertebrates, terrestrial non target arthropods including honeybees, terrestrial non-arthropod invertebrates, and vertebrates), covering the ecosystem services that could potentially be affected by the use of pesticides. These SPGs need to be defined in 6 dimensions: biological entity, attribute, magnitude, temporal and geographical scale of the effect, and the degree of certainty that the specified level of effect will not be exceeded. In general, to ensure ecosystem services, taxa representative for the key drivers identified need to be protected at the population level. However, for some vertebrates and species that have a protection status in legislation, protection may be at the individual level. To protect the provisioning and supporting services provided by microbes it may be sufficient to protect them at the functional group level. To protect biodiversity impacts need to be assessed at least at the scale of the watershed/landscape.

PBT assessment using the revised annex XIII of REACH: a comparison with other regulatory frameworks.

There is no uniform Persistent, Bioaccumulative, Toxic (PBT) or very Persistent, very Bioaccumulative (vPvB) assessment of chemicals in Europe, as the various regulatory frameworks use only limited or dissimilar PBT assessments, or none at all. The European REACH Regulation requires a PBT/vPvB assessment for all chemical substances that are produced within or imported into the EU in amounts exceeding 10 tonnes per year, using the criteria as described in REACH Annex XIII. However, not all substances on the EU market need to be screened according to these criteria under REACH. For a number of substances, such as those imported or produced in lower volumes, there is no REACH requirement, and for human and veterinary medicinal products, biocides, plant protection products, and food and feed additives, other EU legislation is in force to regulate their marketing and use. Compounds may also be screened for PBT properties within international agreements, such as the Oslo Paris Convention (OSPAR), the IMO Ballast Water Management Convention, the UNECE POP Protocol, and the UNEP Stockholm Convention on Persistent Organic Pollutants (POPs), which all have their own set of PBT or POP criteria. This study compares the PBT/vPvB assessment under REACH with PBT or POP assessments performed within other regulatory frameworks. Attention is paid to the process of PBT/vPvB/POP identification and which legislative steps can be taken if the PBT/vPvB/POP status is assigned. In addition to the different PBT or POP criteria of the various frameworks, descriptions of these criteria and approaches for application of weight of evidence also vary. Some EU frameworks still refer to the criteria in the former Technical Guidance Documents (TGD) of 2003, which preceded REACH. Although differences between the old TGD criteria and those in the REACH Annex XIII are small, this does cause dissimilarities among the frameworks. The risk management follow-up of a PBT or vPvB identification, which may include a socio economic analysis, also depends on the legal framework and the specific conditions under which a substance is used. Irrespective of the framework in which a substance is used, individual European Member States may propose a substance evaluation for PBT or vPvB identification under REACH. However, authorization is only possible for uses of PBT substances that are not covered by their regular framework but are registered under REACH. How socio-economic criteria should be weighed against PBT/vPvB properties and environmental risks in authorizing or restricting the use of PBT/vPvB substances is often not specified. Thus, although the goal of restricting or banning the use of PBT/vPvB substances is shared among all EU-based regulatory frameworks, there are many differences in how to achieve this goal. These differences create a challenge to harmonize the PBT/vPvB assessment of substances, not only regarding technical criteria, but also regarding regulatory follow-up.

Fish embryo toxicity of carbamazepine, diclofenac and metoprolol.

Frequently measured pharmaceuticals in environmental samples were tested in fish embryo toxicity (FET) tests with Danio rerio, based on the draft OECD test protocol. In this FET test 2-h-old zebrafish embryos were exposed for 72 h to carbamazepine, diclofenac and metoprolol to observe effects on embryo mortality, gastrulation, somite formation, tail movement and detachment, pigmentation, heartbeat, malformation of head, otoliths and heart, scoliosis, deformity of yolk, and hatching success at 24, 48 and 72 h. We found specific effects on growth retardation above 30.6 mg/l for carbamazepine, on hatching, yolk sac and tail deformation above 1.5mg/l for diclofenac, and on scoliosis and growth retardation above 12.6 mg/l for metoprolol. Scoring all effect parameters, the 72-h-EC(50) values were: for carbamazepine 86.5mg/l, for diclofenac 5.3mg/l and for metoprolol 31.0mg/l (mean measured concentrations). In conclusion, our results for carbamazepine and metoprolol are in agreement with other findings for aquatic toxicity, and also fish embryos responded in much the same way as rat embryos did. For diclofenac, the FET test performs comparably to Early Life Stage testing.

Field studies in pesticide registration: questioning the answers.

The principal conclusion of a workshop in October 2005 at RIVM (Bilthoven, The Netherlands) on the assessment of field studies with pesticides for authorization is that the lack of a definition of acceptability of effects is recognized as a problem by all stakeholders: Industry, risk assessors, and regulators. Because of this lack of definition in the legislation, it is unclear what critical effect values should be assessed in field studies. Despite the extensive documentation on field study performance, the decision making is not based on justifiable scientific opinions or publicly shared values but on technical limitations of the test design instead. In the workshop, research was identified that should result in a scientific basis for value judgments applied in decision making.

Assessment of persistency and bioaccumulation in pesticide registration frameworks within the Organization for Economic Cooperation and Development.

This article describes the results of a survey conducted in 2003 on methods used by different member countries within the Organization for Economic Cooperation and Development (OECD) to evaluate persistent and bioaccumulative pesticides. The objectives were to establish the differences in taking persistence (P) and bioaccumulation (B) into account in the decision-making process and to establish the influence of the assessors' subjectivity to data interpretation and data selection. Fifteen countries participated in the survey, which generated a vast amount of information on decision making, risk assessment, risk classification, and data treatment. Survey results indicated clear differences in approaches to the use of P, B, and toxicity (T) information in scientific risk assessment. Using the same data for 2 different pesticides, several OECD member countries responded differently in classifying both substances as P, B, and T. Differences in regulatory decision-making were also apparent because, based on identical classifications, several OECD member countries adopted different decisions on pesticide registration; recommendations were based, with respect to technical guidance, on data handling, training of assessors, and handling of uncertainty in risk assessment.

Validation of the exposure assessment for veterinary medicinal products.

Under the EU Directive 2004/28/EC, an environmental risk assessment of new veterinary medicinal products is required. Given the nature of risk assessment for new applications, there is a need to model exposure concentrations. Critical evaluations are essential to ensure that the use of models by regulators does not result in the propagation of misleading information. The empirical validations of soil exposure models, previously discussed in this journal, indicate that it is impossible to analyse the contribution of every model parameter to the variability in the predictions. In particular, the prediction of the slurry concentration is challenged by uncertainties concerning dilution, mixing and dissipation of residues. Surface water and groundwater models generated highly deviating results compared to the field results, questioning the usefulness of the available screening models. Animal husbandry, slurry handling and environmental conditions throughout Europe are considered in order to define realistic worst case scenarios, to be used in conjunction with distribution models for the environmental risk assessment of veterinary medicinal products at registration. Given the variability in manure management practice throughout Europe, a deterministic approach for the manure-to-soil model was selected. Both worst case and best case scenario were developed. Several modelling assumptions applied in the surface water exposure model for fish nursery effluent were validated against newly available data. Since the available data give no proof that a settling tank contributes to the removal of pesticides from waste water, it is recommended for risk assessment purposes to consider the contribution of the settling tank to removal of pesticides and medicines to be negligible. Surface water dilution factors may be considered to be rather small, a factor of 2, for low flow situations.

European medicines and feed additives regulation are not in compliance with environmental legislation and policy.

Environmental legislations for water and soil aim at the protection of quality of these compartments. This legislation has major consequences for product registration, amongst others the setting of environmental quality standards. A thorough risk assessment at registration of all products is crucial for the proper operationalisation of the environmental policy. A regulatory problem arises when the registration procedure is harmonised at a European level by the communautarian authority, while the authorities at the national level are responsible for maintaining the desired environmental quality. This problem can be tackled in two ways: firstly, the environmental risk assessment (ERA) should be based on common principles based on EU regulations and policy that steer the national authorities; secondly, the ERA should be developed under the supervision of competent authorities. Both options are not reflected in the forging of the ERA for medicines and feed additives. The formalisation of the contents and the procedure is not transparent nor open to input by scientists and other interested parties; the formalisation has no legal status, and European legislation cannot provide common protection goals in a global setting. The VICH Phase I and the EMEA Phase II guidance do not contain all communautarian environmental quality criteria, nor clear acceptability standards, nor harmonised methodology. Assessments are not made for all products, and the decision-making principles and practical procedures are not operational. It is therefore unlikely that any result of an ERA can be taken into consideration at registration, which undermines the legitimacy of the process. Both applicants and assessors are uncertain how to perform the risk assessment. The current developments may ultimately not only compromise product availability but also fail to protect the environment.