Environmental risk assessment for new human pharmaceuticals in the European Union according to the draft guideline/discussion paper of January 2001

Since 1993, an environmental risk assessment (ERA) for a new drug application has been stipulated by EU Directive 93/39/EEC amending Directive 65/65/EEC. In early 2001, after several unpublished draft versions for an ERA guideline, a draft guideline/discussion paper for an ERA for non-GMO-containing drugs was published by the European Medicines Evaluation Agency (EMEA). The draft guideline describes a step-wise, tiered procedure for the ERA. The first tier consists of deriving a crude predicted environmental concentration (PEC) in the aquatic compartment for the active pharmaceutical ingredient (API) or its major metabolites, based on predicted amounts used and specific removal rates in sewage treatment or surface waters. If this crude PEC is <0.01 microg/l and no environmental concerns are apparent, no further assessment is deemed necessary. Else, in the second tier, a crude predicted no-effect level (PNEC) for the aquatic compartment is to be extrapolated by dividing the lowest 50% effect concentration from acute ecotoxicity tests with algae, daphnia or fish (EC(50), LC(50)) by an assessment factor (usually 1000). If the ratio PEC/PNEC is <1, no further assessment is deemed necessary. Lastly, in the third tier, further considerations on a case-by-case basis are needed. This may encompass refining the environmental fate information and thereby the PEC, considering further environmental compartments and their respective PECs (up to and including field studies), but also refining the PNEC. While the ERA addresses mainly the API, excipients of the formulated drug should be considered as well. In the ease of medicinal products, the benefit for patients has relative precedence over environmental risks, meaning that even in the ease of an unacceptable residual risk for new drugs after third tier considerations, prohibition of a new API is not taken into consideration. Instead, possible mitigating or precautionary safety measures may consist of specific product labelling (i.e. package leaflets for the patients regarding returning and proper disposal of unused medicines), restricted use through in-hospital or in-surgery administration under supervision only, or the recommendation of environmental analytical monitoring up to ecological field studies.     

Risk assessment of human antibiotics in Korean aquatic environment

In Korea, antibiotic usage has received a lot of attention from the public due to the increasing number of bacteria resistant to the currently used antibiotics. In this study based on FDA regulation and EU draft guideline, the most concerned antibiotics regarding their environmental risk in Korea were assessed and the refined predicted environmental concentration in surface water (PEC(surface water)) was obtained by applying a GIS-based KORea ECOlogical Risk assessment (KOREOCORisk) model. Thirteen antibiotics, which expected introductory concentration (EIC) greater than the trigger value (1.0μg/L), were chosen to assess ecological risk and the PEC/PNEC ratio exceeded 1.0 for amoxicillin, erythromycin and roxithromycin. The results in this study using conservative assumptions did not represent that there is a risk for acute toxic effects in the environment based on today's use of pharmaceuticals in Korea. However, the results do not exclude the potential for chronic environmental effects.     

A risk-based methodology for deriving quality standards for organic contaminants in sewage sludge for use in agriculture--Conceptual Framework

This paper describes a systematic methodology (Conceptual Framework) to derive quality standards for organic (anthropogenic) contaminants in sewage sludge added to agricultural land, in the context of revision of EU Sludge Directive 86/278/EEC and the broader Soil Thematic Strategy. The overall objective is to ensure, based on a risk assessment approach, a sustainable use of sludge over a long time horizon. ILSI-Europe's Conceptual Framework is in essence consistent with the EU Technical Guidance Document (TGD) for Environmental Risk Assessment of Chemicals in the soil compartment, or US-EPA's Sewage Sludge Use and Disposal Regulations, Part 503 Standards. A 'checklist' of different exposure pathways and transfer processes for organic contaminants needs to be considered, and the most sensitive relevant toxicological endpoint and its PNEC need to be identified. The additional complexity specific to deriving Sludge Quality Standards (SQS) is that the toxicity results may need-e.g., for (indirect) human toxicity-to be related back to maximum acceptable soil exposure levels (PEC(soil)). In turn, the latter need to be back-calculated to the maximum acceptable levels in sewage sludge (PEC(sludge)) at the time of application. Finally, for a sustainable sludge use, the exposure from repeated addition and potential chemical build-up over time (e.g., 100 years) needs to be assessed. The SQS may therefore vary with the (local) sludge application regime, and/or sludge pretreatment processes.     

Use of Terrestrial Model Ecosystem Data in Environmental Risk Assessment for Industrial Chemicals,Biocides and Plant Protection Products in the EU

Risk assessment approaches within the regulatory framework of the European Union (EU) based on single species tests were compared to those using data from terrestrial model ecosystems (TMEs). In a case study with the fungicide carbendazim, single species data led to ratios of the predicted environmental concentration (PEC) and predicted no effect concentration (PNEC) of above 1000, depending on available data and related assessment factors, indicating concern for the terrestrial environment. Considering the high degree of realism of the TME studies with multiple endpoints measured, but also residual uncertainty related to higher variability of endpoints, an assessment factor of 5 was applied on TME data. The most sensitive reliable endpoint was earthworm biomass. With the TME studies yielding slightly higher effect thresholds compared to laboratory data, and due to the lower assessment factor, the PEC/PNEC ratio was lowered to 5. This means that there would be concern for high application rates of carbendazim.     

Environmental risk assessment for the polycyclic musks, AHTN and HHCB. II. Effect assessment and risk characterisation

Reports of the polycyclic musks AHTN and HHCB in surface water and fish, primarily in Europe, have prompted studies of their environmental effects. These effects then are used, along with the predicted environmental concentrations in a risk assessment according to the approach developed under European Union Regulation 793/93, in line with the Technical Guidance Document for risk assessment of new and existing chemicals. In 72-h studies with algae (Pseudokirchneriella subcapitata), NOECs were 0.374 mg/l (AHTN) and 0.201 mg/l (HHCB). In 21-day reproductive tests with daphnia (Daphnia magna) NOECs were 0.196 (AHTN) and 0.111 mg/l (HHCB). In 21-day growth tests with bluegill sunfish (Lepomis macrochirus), NOECs were 0.067 (AHTN) and 0.068 mg/l (HHCB). And, finally 35-day early life stage tests with fathead minnows (Pimephales promelas) resulted in NOECs of 0.035 (AHTN) and 0.068 mg/l (HHCB). These results lead to Predicted No Effect Concentrations (PNEC) of 3.5 microg/l (AHTN) and 6.8 microg/l (HHCB) for aquatic organisms. For the soil compartment, 8-week studies with earthworms (Eisenia fetida) resulted in NOECs of 105 (AHTN) and 45 mg/kg (HHCB) and 4-week studies with springtails (Folsomia candida) resulted in a NOECs of 45 mg/kg for both substances. These values lead to a PNEC of 0.32 mg/kg dw for both materials. Using mammalian studies, PNECs for fish or worm eating predators of 10 mg/kg fw (AHTN) and 100 mg/kg fw (HHCB) can be derived. For sediment dwelling organisms, PNECs were derived by equilibrium partitioning using the aquatic PNECs. Comparing PNECs with the measured or predicted environmental exposures leads to risk characterisation ratios as follows: aquatic species: AHTN 0.086, HHCB 0.074; sediment organisms: AHTN 0.44, HHCB 0.064; soil organisms: AHTN 0.091, HHCB 0.10; fish eating predators: AHTN 0.012, HHCB 0.001; worm eating predators: AHTN 0.007, HHCB 0.001.     

Probabilistic environmental risk assessment of five nanomaterials (nano-TiO2, nano-Ag,nano-ZnO,CNT, and fullerenes)

The environmental risks of five engineered nanomaterials (nano-TiO₂, nano-Ag, nano-ZnO, CNT, and fullerenes) were quantified in water, soils, and sediments using probabilistic Species Sensitivity Distributions (pSSDs) and probabilistic predicted environmental concentrations (PECs). For water and soil, enough ecotoxicological endpoints were found for a full risk characterization (between 17 and 73 data points per nanomaterial for water and between 4 and 20 for soil) whereas for sediments, the data availability was not sufficient. Predicted No Effect Concentrations (PNECs) were obtained from the pSSD and used to calculate risk characterization ratios (PEC/PNEC). For most materials and environmental compartments, exposure and effect concentrations were separated by several orders of magnitude. Nano-ZnO in freshwaters and nano-TiO₂ in soils were the combinations where the risk characterization ratio was closest to one, meaning that these are compartment/ENM combinations to be studied in more depth with the highest priority. The probabilistic risk quantification allows us to consider the large variability of observed effects in different ecotoxicological studies and the uncertainty in modeled exposure concentrations. The risk characterization results presented in this work allows for a more focused investigation of environmental risks of nanomaterials by consideration of material/compartment combinations where the highest probability for effects with predicted environmental concentrations is likely.     

Environmental Risk Assessment of Pharmaceutical Mixtures: Demands,Gaps, and Possible Bridges

The ecotoxicological risk of pharmaceutical mixtures typically exceeds the risk of each individual compound, which calls specific attention to the fact that monitoring surveys routinely find complex pharmaceutical mixtures in various environmental compartments. However, although the body of evidence on the ecotoxicology of pharmaceutical mixtures is quite consistent, the current guidelines for the environmental risk assessment of pharmaceuticals often do not explicitly address mixture effects. Data availability and acceptable methods often limit such assessments. A tiered approach that begins with summing up individual risk quotients, i.e., the ratio between the predicted or measured environmental concentration and the predicted no effect concentration (PNEC) is therefore suggested in this paper, in order to improve the realism of the environmental risk assessment of pharmaceuticals. Additionally, the use of a mixture-specific assessment factor, as well as the classical mixture toxicity concepts of concentration addition and independent action is explored. Finally, specific attention is given to the exposure-based waiving of environmental risk assessments, as currently implemented in screening or pre-screening phases (tier 0 in Europe, categorical exclusion in the USA), since even low, individually non-toxic concentrations might combine to produce substantial mixture effects.     

Bilastine: an environmental risk assessment

Context: Bilastine is a new oral selective, non-sedating histamine H₁ antagonist for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. The European Medicines Agency requires an Environmental Risk Assessment (ERA) for all novel medicines for human use. Objective: To calculate the bilastine predicted environmental concentration in surface water (PEC_sw; phase I ERA), and to determine the effects of bilastine on aquatic systems (phase II [tier A]). Materials and methods: Bilastine PEC_sw was calculated using the maximum daily dosage (20?mg), assuming that all administered bilastine was released into the aquatic environment. A persistence, bioaccumulation and toxicity assessment was conducted using the log K_ow from the molecular structure. In phase II (tier A), a ready biodegradability test was performed, and bilastine’s potential toxicity to various aquatic and sediment-dwelling micro-organisms was evaluated. Results: Bilastine PEC_SW was calculated as 0.1?μg?L^?1, and the compound was not readily biodegradable. Bilastine had no significant effects on Chironomus riparius midges, or on the respiration rate of activated sludge. For green algae, the bilastine no observed effect concentration (NOEC) was 22?mg?L^?1; bilastine had no effect on zebra fish development, or on the reproduction rate of daphnids. Discussion: Bilastine NOEC values against zebra fish, algae, daphnids, and aerobic organisms in activated sludge were at least 130?000-fold greater than the calculated PEC_SW value. Conclusion: No environmental concerns exist from bilastine use in patients with allergic rhinoconjunctivitis or urticaria.     

Human health risk assessment of carbamazepine in surface waters of North America and Europe

A human health risk assessment was carried out for environmental exposures to carbamazepine (CBZ) and its major human metabolites, carbamazepine diol (CBZ-DiOH) and carbamazepine N-glucuronide (CBZ-N-Glu). Carbamazepine is an active pharmaceutical ingredient (API) used worldwide as a medicine for treating epileptic seizures and trigeminal neuralgia. Carbamazepine tends to be detected in surface water more frequently, and at relatively higher concentrations, than most other APIs.Predicted no effect levels (PNECs) for CBZ and its major human metabolites were developed for surface waters to be protective of human health from environmental exposures from drinking water and fish consumption. These PNECs were compared to both measured (MEC) and predicted (PEC) environmental concentrations for North America and Europe. PECs were calculated using the geo-referenced models PhATE? for North America and GREAT-ER for Europe.The combined PNEC for drinking water and fish consumption for CBZ is 226,000 ng/L. Ninetieth percentile MECs ranged from 150 to 220 ng/L, while 90th percentile PECs ranged from 333 to 658 ng/L. Calculated margins of safety (MOS) therefore range from 340 to 1500. MOS for the major metabolites are significantly higher. This assessment indicates that CBZ and its major metabolites have high MOS (?1) and thus should have no appreciable risk to human health through environmental exposures based on available human data.     

Exposure assessment and microcosm fate of selected selective serotonin reuptake inhibitors

The exposure and fate of selective serotonin reuptake inhibitors (SSRIs) was evaluated using modeled predicted environmental concentrations (PECs) according to the U.S. and the European Union (EU) guidelines and microcosm model ecosystems. According to the U.S. guidance, crude environmental introduction concentrations, the only SSRI that would require environmental assessment would be sertraline. However, the more conservative EU draft guidance PEC would require further assessment of all five SSRIs. Refined PECs developed using the U.S. and the EU guidelines along with estimates of removal by sewage treatment and receiving water dilution factors indicate that the U.S. methodology corresponds better to MEC data determined in the U.S. and Canada. Worst-case (99th centile) PECs for citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline were 30, 19, 30, 65, and 122 ng/L, respectively, using the U.S. methodology and 142, 182, 841, 144, and 575 ng/L, respectively, using the EU draft methodology. The dissipation of fluoxetine and fluvoxamine from the water column in aquatic microcosms was best described using a two-compartment model while sertraline followed a one-compartment model. Fluoxetine and fluvoxamine water concentrations initially dissipated with first phase half-lives of 3.8 and 1.8 days, respectively, but levelled off at concentrations around 10 microg/L with second phase half-lives of 76.7 and 59.3 days, respectively, not including those estimated as infinity. Sertraline dissipation tended toward the detection limit with a half-life of 3.4 days. Fluoxetine was found to be the most persistent followed by fluvoxamine and sertraline. Estimated log(K(OC)) values for all SSRIs were >4.3 indicating that SSRIs are expected to adsorb to sediment or sludge. Partitioning into other environmental compartments such as this may act as a reservoir from which SSRIs may be re-released into surface waters and indicates the potential susceptibility of benthos.     

Ecotoxicity and screening level ecotoxicological risk assessment of five antimicrobial agents: triclosan,triclocarban, resorcinol,phenoxyethanol and p‐thymol

Acute and chronic (or sub‐chronic) toxicity of five selected antimicrobial agents, including triclosan (TCS), triclocarban (TCC), resorcinol, phenoxyethanol and p‐thymol, was investigated using the conventional three‐aquatic‐organism battery. These compounds are widely used in cosmetics and other personal care products and their ecological risk has recently become a significant concern. As results of toxicity tests, TCS was found to be most strongly toxic for green algae [e.g. 72 h no observed effect concentration (NOEC) of 0.50 µg l^?1] among the selected compounds, followed by TCC, while TCC was more toxic or similar to TCS for Daphnia and fish (e.g. Daphnia 8 day NOEC of 1.9 µg l^?1). Having compared the predicted no effect concentration (PNEC) determined from the toxicity data with measured environmental concentrations (MEC), the preliminary ecological risk assessment of these five antimicrobials was conducted. The MEC/PNEC ratios of TCS and TCC were over 1 for some monitoring data, especially in urban streams with watershed areas without sewage service coverage, and their potential risk for green algae and Daphnia might be at a level of concern, although the contribution of TCS/TCC on the total toxicity of the those sites needs to be further investigated. For the three other antimicrobials, the maximum MEC/PNEC ratio for resorcinol was 0.1–1, but those for phenoxyethanol and p‐thymol were <0.1 and their risk to aquatic organisms is limited, although the additive effects with TCS, TCC and other antimicrobial agents, such as parabens, need to be further examined in future studies. Copyright © 2012 John Wiley & Sons, Ltd.     

Critical review on the Environmental Risk Assessment of medicinal products for human use in the centralised procedure

In this article we analyse the Environmental Risk Assessment (ERA) of 59 medicinal products for human use authorised in the EU through the centralised procedure between 2011 and 2012, to establish whether company submissions are compliant with the European Medicines Agency (EMA) guideline and complete in terms of data and study reports provided. The most frequent questions raised by EU regulatory authorities are described, together with an evaluation of the presence and quality of ERA-related information in published regulatory assessment documents. The results of this review show recent improvement in ERA-related data presented in regulatory assessment documents available to the public while also highlighting a need to develop further guidance on environmental issues in order to assist applicants improve their ERA dossiers and overcome current shortcomings.     

Tiered environmental risk assessment of methyltins from heat stabilizers in rigid PVC in Sweden

The methyltins, methyltin 2-ethylhexyl mercaptoacetate and methyltin-2-mercaptoethyloleate sulfide, are used as heat stabilizers in rigid PVC. The degradation products monomethyltintrichloride (MMTTC) and dimethyltindichloride (DMTDC) may leach from the PVC, and enter the environment. A risk assessment was executed for the use of these products in Sweden, with the double aim to (a) assess the potential environmental risks, and (b) explore the possibilities of a tiered risk assessment. An initial assessment was executed with EUSES 1.0. The initial assessment showed no significant environmental risks on a regional scale. On a local scale however, emissions from a sewage treatment plant to the surface water pose a potential risk for the near proximity. In a second tier, this critical exposure route was studied in more detail; an improved exposure scenario was drawn up; and an additional sorption experiment was performed. This refinement resulted in much lower predicted environmental concentrations (相似文献   

Assessment of environmental risks to groundwater ecosystems related to use of veterinary medicinal products

The current EU guidelines for the environmental risk assessment of veterinary pharmaceutical products (VMPs) in groundwater (GW) suggest an approach based on the comparison between the calculated concentration in GW (PEC_gw) and a threshold concentration of 0.1 μg/L. The latter is the upper limit of the concentration for pesticides in groundwater in the EU. If the calculated PEC_gw does not exceed the threshold, then the risk is considered acceptable. It is assumed that the concentration of 0.1 μg/L is by default safe for both humans and exposed GW organisms. On this basis, it is not clear whether the GW is recognized as an ecosystem or as a source of drinking water. Largely unrecognized biodiversity in GW is worthy of protection through the adoption of a more scientifically sound risk analysis, which should be based on the consideration of ecological criteria.Based on the evidence of their vulnerability, we propose that risk assessments of GW ecosystems should be a compulsory part of the overall risk assessment of VMPs (as well as pesticides, biocides and feed additives). Furthermore, we suggest the use of a risk quotient approach based on the PEC/PNEC ratio in which the PNEC is calculated including an additional safety factor of 10 to the calculated PNEC for surface water.     

Environmental risk assessment for excipients from galenical pharmaceutical production in wastewater and receiving water

Many different excipients are used in galenical pharmaceutical production, in addition to the active pharmaceutical ingredients. Excipients are little investigated regarding their environmental fate and impact, even though some of them are used in appreciable quantities. For 35 excipients used in galenical production at Roche Basle and Roche Kaiseraugst, both in Switzerland, in the years 2013 and 2014, the environmentally relevant properties were collated. A predicted environmental concentration (PEC) was calculated for the wastewater treatment plants (WWTPs) and the receiving water, the River Rhine for both sites, based on maximum daily losses of the single excipients to wastewater, derived by mass balance, and the site-specific dilution factor. Predicted no effect concentrations (PNECs) were derived for the WWTPs and the River Rhine. PECs and PNECs were compared for the WWTPs and the receiving water, in an environmental risk assessment. Additionally, to simulate a worst case scenario, certain galenical productions where given excipients are used in the highest amounts were assumed to take place in parallel on the same day, resulting in theoretical maximum excipient losses to wastewater. All PEC/PNEC risk characterisation ratios for the excipients currently used by Roche in Switzerland are well below 1 throughout. Together with the fact that based on biodegradability data many excipients will be removed in the WWTP, this indicates that the excipients currently used do not present a risk to the environment.     

Ethinyl Estradiol and Other Human Pharmaceutical Estrogens in the Aquatic Environment: A Review of Recent Risk Assessment Data

Interest in pharmaceuticals in the environment has increased substantially in recent years. Several studies in particular have assessed human and ecological risks from human pharmaceutical estrogens, such as 17α-ethinyl estradiol (EE2). Regulatory action also has increased, with the USA and other countries developing rules to address estrogens and other pharmaceuticals in the environment. Accordingly, the Center for Drug Evaluation and Research at the US Food and Drug Administration has conducted a review and analysis of current data on the long-term ecological exposure and effects of EE2 and other estrogens. The results indicate that mean-flow long-term predicted environmental concentrations (PECs) of EE2 in approximately 99% or more of US surface water segments downstream of wastewater treatment plants are lower than a predicted no-effect concentration (PNEC) for aquatic chronic toxicity of 0.1 ng/L. Exceedances are expected to be primarily in localized, effluent-dominated water segments. The median mean-flow PEC is more than two orders of magnitude lower than this PNEC. Similar results exist for other pharmaceutical estrogens. Data also suggest that the contribution of EE2 more broadly to total estrogenic load in the environment from all sources (including other human pharmaceutical estrogens, endogenous estrogens, natural environmental estrogens, and industrial chemicals), while highly uncertain and variable, appears to be relatively low overall. Additional data and a more comprehensive approach for data collection and analysis for estrogenic substances in the environment, especially in effluent-dominated water segments in sensitive environments, would more fully characterize the risks.     

Mediterranean countries impact on the implementation of Council Directive 91/414/EEC

For the implementation of the Framework Council Directive 91/414/EEC, participation of all member states (MS) is required. In the first round of the review program of plant protection products, Mediterranean countries have successfully performed their proportional work share for the central registration of the active substances and the national registration of the respective plant protection products. However, some issues of risk assessment, related to appropriate estimation of exposure, still require further refinement and adaptation to the Mediterranean conditions. Issues related to the estimation of agricultural worker exposure to plant protection products due to different agronomic practices and conditions, identified shortcomings in the consumer risk assessment related to different habits of the Mediterranean population and different needs of Mediterranean agriculture will be discussed. Finally, the possible effects of the Directive 91/414/EEC upon the plant protection of Mediterranean countries, due to the withdrawal from the market of a wide range of plant protection products is also a parameter that has to be considered.     

Human pharmaceuticals in US surface waters: a human health risk assessment

The detection of low levels of pharmaceuticals in rivers and streams, drinking water, and groundwater has raised questions as to whether these levels may affect human health. This report presents human health risk assessments for 26 active pharmaceutical ingredients (APIs) and/or their metabolites, representing 14 different drug classes, for which environmental monitoring data are available for the United States. Acceptable daily intakes (ADIs) are derived using the considerable data that are available for APIs. The resulting ADIs are designed to protect potentially exposed populations, including sensitive sub-populations. The ADIs are then used to estimate predicted no effect concentrations (PNECs) for two sources of potential human exposure: drinking water and fish ingestion. The PNECs are compared to measured environmental concentrations (MECs) from the published literature and to maximum predicted environmental concentrations (PECs) generated using the PhATE model. The PhATE model predictions are made under conservative assumptions of low river flow and no depletion (i.e., no metabolism, no removal during wastewater or drinking water treatment, and no instream depletion). Ratios of MECs to PNECs are typically very low and consistent with PEC to PNEC ratios. For all 26 compounds, these low ratios indicate that no appreciable human health risk exists from the presence of trace concentrations of these APIs in surface water and drinking water.     

Proposal of limit concentrations for skin irritation within the context of a new EEC directive on the classification and labeling of preparations

In this study, solvents belonging to different chemical families were tested for their irritating properties to the skin. The irritating potential of a chemical is expressed as its concentration in a nonirritant diluent beyond which irritation of the skin may be expected in the sense of EEC Directive 79/831/EEC. The substances were applied onto the shaved skin of rabbits by means of a modified Finn chamber for 4 hr. Afterward the exposure chamber was removed and the skin cleaned. Reading of erythema and edema was performed according to the scale of Draize at 1, 24, 48, and 72 hr after the removal of the patch. On the basis of the readings obtained the different dilutions of the organic solvents tested were classified as irritant or not according to the interpretation rules laid down in EEC Directive 83/467/EEC. On the basis of the structure-activity relationships found within each chemical family the irritation potential of the other members of the family could be derived via interpolation.