Antimicrobial Agents with Improved Clinical Efficacy versus Their Persistence in the Environment: Synthetic 4-Quinolone As an Example

There is increasing concern about the effects of pharmaceutical agents in the environment. The use of synthetic 4-quinolone compounds is rapidly increasing: newer and more complex analogues are being developed by the pharmaceutical industry to meet clinical and veterinary needs. This review aims at stimulating the need to consider the fate of pharmaceuticals in the environment as part of overall drug design and development. Currently, regulatory action is triggered if the predicted environmental concentration exceeds an arbitrarily set value, whereas in some countries, there are no regulations at all. By extension, from a clinical perspective, enviropharmacokinetics and enviropharmacodynamics are proposed to quantify the risk to organisms in the environment in a more realistic fashion that is reflective of concentrations at which hazardous effects are observable on such organisms. Such a new approach integrates our knowledge to address ecosystems and related health problems in a more holistic fashion, thus linking public health, environmental degradation, and ecology. Its success requires more collaboration in research and development of newer antibiotics, with their ultimate fate in the environment being central, to bolster the already existing aspirations of controlling the rapid emergence of resistance.     

Current and future needs for developmental toxicity testing

A review is presented of the use of developmental toxicity testing in the United States and international regulatory assessment of human health risks associated with exposures to pharmaceuticals (human and veterinary), chemicals (agricultural, industrial, and environmental), food additives, cosmetics, and consumer products. Developmental toxicology data are used for prioritization and screening of pharmaceuticals and chemicals, for evaluating and labeling of pharmaceuticals, and for characterizing hazards and risk of exposures to industrial and environmental chemicals. The in vivo study designs utilized in hazard characterization and dose-response assessment for developmental outcomes have not changed substantially over the past 30 years and have served the process well. Now there are opportunities to incorporate new technologies and approaches to testing into the existing assessment paradigm, or to apply innovative approaches to various aspects of risk assessment. Developmental toxicology testing can be enhanced by the refinement or replacement of traditional in vivo protocols, including through the use of in vitro assays, studies conducted in alternative nonmammalian species, the application of new technologies, and the use of in silico models. Potential benefits to the current regulatory process include the ability to screen large numbers of chemicals quickly, with the commitment of fewer resources than traditional toxicology studies, and to refine the risk assessment process through an enhanced understanding of the mechanisms of developmental toxicity and their relevance to potential human risk. As the testing paradigm evolves, the ability to use developmental toxicology data to meet diverse critical regulatory needs must be retained.     

Assessing the exposure risk and impacts of pharmaceuticals in the environment on individuals and ecosystems

The use of human and veterinary pharmaceuticals is increasing. Over the past decade, there has been a proliferation of research into potential environmental impacts of pharmaceuticals in the environment. A Royal Society-supported seminar brought together experts from diverse scientific fields to discuss the risks posed by pharmaceuticals to wildlife. Recent analytical advances have revealed that pharmaceuticals are entering habitats via water, sewage, manure and animal carcases, and dispersing through food chains. Pharmaceuticals are designed to alter physiology at low doses and so can be particularly potent contaminants. The near extinction of Asian vultures following exposure to diclofenac is the key example where exposure to a pharmaceutical caused a population-level impact on non-target wildlife. However, more subtle changes to behaviour and physiology are rarely studied and poorly understood. Grand challenges for the future include developing more realistic exposure assessments for wildlife, assessing the impacts of mixtures of pharmaceuticals in combination with other environmental stressors and estimating the risks from pharmaceutical manufacturing and usage in developing countries. We concluded that an integration of diverse approaches is required to predict ‘unexpected’ risks; specifically, ecologically relevant, often long-term and non-lethal, consequences of pharmaceuticals in the environment for wildlife and ecosystems.     

Exposure Assessment of Pharmaceuticals and Their Metabolites in the Aquatic Environment: Application to the French Situation and Preliminary Prioritization

Low levels of pharmaceuticals have been detected in many countries in surface waters. As a wide range of pharmaceuticals can reach aquatic environments, a selection of molecules to survey is the first step before implementing a monitoring program. We used a simple equation to calculate Predicted Environmental Concentrations (PECs), adapted from the European Medicine Agency model used for the Environmental Risk Assessment (ERA) of human pharmaceutical. Excretion fractions for pharmaceuticals were determined for 76 compounds. Using year 2004 French drug consumption data, we determined aquatic PECs for 112 parent molecules and several metabolites. Considering excretion fractions of pharmaceuticals can lead to drastically reduce predicted concentrations reaching the aquatic environment and help to target environmentally relevant pharmaceuticals and metabolites. Calculated PECs using the described methodology are consistent with French field measurements. The simple model for calculating PECs can be used as a valuable estimation of the exposure. Risk quotient ratios were also calculated. Due to the lack of ecotoxicological data, the use of PEC/PNEC ratios is not enough informative to prioritize pharmaceuticals likely to pose a risk for surface waters. Alternative ways to prioritize risk to pharmaceuticals, combining PEC, pharmacological, and ecotoxicological data available from the literature, should be implemented.     

Prioritization of Veterinary Medicines in China's Environment

Large amounts of veterinary medicines are widely used as therapeutic drugs and feed additives (growth promoters) in China, the environmental presence of which possibly poses challenges to the environment and human health. Therefore, it is important to list the veterinary medicines that are considered to be of relatively high priority in China for environmental management. In this study, a three-stage prioritization scheme was applied to veterinary medicines in China. In Stage I, exposure assessment was conducted based on usage amounts and the possibility of entering the environment. In Stage II, the ecotoxicity and human health effects of compounds having a high potential to enter the environment were assessed. In Stage III, considering both the results of Stages I and II, veterinary medicines were assigned into four priority classifications. Using the approach, 38 compounds were assigned to “H,” 7 compounds to “M,” 2 compounds to “L,” and 22 compounds to “VL.” Among the top-ranked compounds, antibiotics, endoparasiticides, and aquacultural medicines accounted for 57.9%, 28.9%, and 10.5%, respectively. Insecticides used widely in China's aquaculture need to be taken into account due to their high priority rank. This is the first study on the prioritization of veterinary pharmaceuticals in China.     

Microbial Content of Nonsterile Therapeutic Agents Containing Natural or Seminatural Active Ingredients

The relationship was investigated between various chemical or pharmaceutical production processes and the extent of microbial contamination, of natural origin, of the resulting products. The products contained active ingredients of vegetable, enzymatic, or animal origin. It was concluded that (i) vegetable products practically free from microbes can be produced if the proper manufacturing steps are taken; (ii) sterilization of the media used to manufacture antibiotics, etc., produces products with little contamination; and (iii) products containing extracts of animal organs require careful refrigeration and addition of preservatives to produce acceptable levels of microbial contamination.     

Harmonization of regulations for invertebrate biocontrol agents in Europe: progress,problems and solutions

The use of non‐native invertebrate biological control agents (IBCAs) in Europe is not covered by a Directive equivalent to that which regulates biocontrol with microorganisms or the genetic modification of crop plants. Regulation is at the discretion of individual member states and largely derived from national legislation on pesticides, plant health or environmental protection. There is no EU country with regulation of IBCAs that requires information on the microbial symbiont content of candidate species, and in the absence of horizontal transfer under natural conditions, this policy is unlikely to change. Although there have been few reported negative effects linked to the import and release of IBCAs, a number of countries have introduced or revised their regulatory frameworks in recent years. This article reviews major developments in the regulation and environmental risk assessment (ERA) of IBCAs in Europe over the last 10 years including: the fragmented pattern of regulation between countries, variation in information requirements for release licences, format and methods of ERA for different taxonomic groups of IBCAs, use and updating of the European Plant Protection Organisation Positive List, sources of expert advice on ERA data, communication between IBCA regulators, and options for the provision of international leadership to coordinate regulatory and ERA‐related issues with IBCA‐based biocontrol in Europe.     

Pharma-Planta: road testing the developing regulatory guidelines for plant-made pharmaceuticals

Significant advances over the last few years have seen plant-made pharmaceuticals (PMPs) move from the exploratory research phase towards clinical trials, with the first commercial products for human use expected to reach the market by 2009. Europe has yet to witness the commercial application of PMP technology, although at least one product has begun phase II clinical trials with others following close behind. These emerging products are set to challenge the complex and overlapping regulations that currently govern GM plants and ‘conventional’ pharmaceutical production. The areas of responsibility are being mapped out between the different EU regulatory agencies, with specific guidelines currently being drawn up for the regulation of PMPs. This article discusses issues surrounding the development of robust risk-assessment and risk-management practices based on health and environmental impact, while working with EU regulatory authorities to ensure appropriate regulatory oversight.     

Protection goals in environmental risk assessment: a practical approach

Policy protection goals are set up in most countries to minimise harm to the environment, humans and animals caused by human activities. Decisions on whether to approve new agricultural products, like pesticides or genetically modified (GM) crops, take into account these policy protection goals. To support decision-making, applications for approval of commercial uses of GM crops usually comprise an environmental risk assessment (ERA). These risk assessments are analytical tools, based on science, that follow a conceptual model that includes a problem formulation step where policy protection goals are considered. However, in most countries, risk assessors face major problems in that policy protection goals set in the legislation are stated in very broad terms and are too ambiguous to be directly applicable in ERAs. This means that risk assessors often have to interpret policy protection goals without clear guidance on what effects would be considered harmful. In this paper we propose a practical approach that may help risk assessors to translate policy protection goals into unambiguous (i.e., operational) protection goals and to establish relevant assessment endpoints and risk hypotheses that can be used in ERAs. Examples are provided to show how this approach can be applied to two areas of environmental concern relevant to the ERAs of GM crops.     

药物类新污染物的微生物降解机制研究进展

环境微生物作为自然界中主要的分解者蕴含着丰富的遗传和代谢多样性,在有机污染物降解中发挥着重要作用。药物被持续不断地释放到环境中,其环境暴露、环境风险和对人体健康的潜在影响已得到广泛关注。研究药物在环境中的微生物降解过程对于药物的环境命运、药物的环境风险评估和药物污染去除技术的开发等具有重要价值。本文重点综述了目前环境中常检出药物的微生物降解途径及其分子机理,总结了目前药物微生物降解研究领域的进展,最后探讨了药物的微生物降解领域未来的研究趋势。     

Veterinary antibiotics in the aquatic and terrestrial environment

The fate of antibiotics in the environment, and especially antibiotics used in animal husbandry, is subject to recent studies and the issue of this review. The assumed quantity of antibiotics excreted by animal husbandry adds up to thousands of tonnes per year. Administered medicines, their metabolites or degradation products reach the terrestrial and aquatic environment by the application of manure or slurry to areas used agriculturally, or by pasture-reared animals excreting directly on the land, followed by surface run-off, driftage or leaching in deeper layers of the earth. The scientific interest in antimicrobially active compounds in manure and soil, but also in surface and ground water, has increased during the last decade. On the one side, scientific interest has focused on the behaviour of antibiotics and their fate in the environment, on the other hand, their impact on environmental and other bacteria has become an issue of research. Analytical methods have now been developed appropriately and studies using these new techniques provide accurate data on concentrations of antimicrobial compounds and their residues in different organic matters. Some antibiotics seem to persist a long time in the environment, especially in soil, while others degrade very fast. Not only the fate of these pharmaceuticals but their origin as well is an object of scientific interest. Besides human input via wastewater and other effluents, livestock production has been recognised as a source of contamination. One main concern with regard to the excessive use of antibiotics in livestock production is the potential promotion of resistance and the resulting disadvantages in the therapeutic use of antimicrobials. Since the beginning of antibiotic therapy, more and more resistant bacterial strains have been isolated from environmental sources showing one or multiple resistance. There have been several attempts to use antibiotic resistance patterns in different bacteria as indicators for various sources of faecal pollution. This review gives an overview of the available data on the present use of veterinary antibiotics in agriculture, on the occurrence of antibiotic compounds and resistant bacteria in soil and water and demonstrates the need for further studies.     

Evaluation of “Classic” and Emerging Contaminants Resulting from the Application of Biosolids to Agricultural Lands: A Review

The presence of detectable amounts of contaminants in treated sewage sludge (concentrations μg/kg – mg/kg) has led to concerns that land applications of biosolids may result in an accumulation of contaminants in the soil and their subsequent translocation through the food chain. Despite advances in wastewater management (e.g., anaerobic, thermophilic, and mesophilic digestion), many compounds and their metabolites remain intact following treatment. This review looks at the main risk factors relating to the occurrence of “classic” (persistent organic pollutants [POPs]) and emerging pollutants (pharmaceuticals and personal care products) in biosolids. Relevant EU legislation and risk assessment strategies for the control of emerging contaminants are also considered. Organic pollutants regulated under the Stockholm Convention on POPs along with PPCPs were identified as contaminants of concern based on the risk factors: persistence, bioaccumulation, and toxicity (PBT). PPCPs were recognized as being of particular concern as their high transformation/removal rates are compensated by their continuous introduction into the environment. This study highlights the growing concern in relation to emerging contaminants in biosolids and highlights risk assessment strategies that can be used to characterize potential human/environmental risks.     

Ecological Risk Assessment for Terrestrial Ecosystems: The Summary of Discussions and Recommendations from the Adelaide Workshop (April 2004)

The Ecological Risk Assessment (ERA) workshop focused on the anthropogenic contaminants in the terrestrial environment, addressing various components of the ERA process. These included sources, exposure pathways, bioavailability, and toxicity to receptor organisms as well as risk communication. It was concluded that although the overseas experience on ERA for terrestrial ecosystems (e.g., International Standards or guidelines from the European Union and the United States) is very useful, it is not directly applicable to Australia due to the differences in receptor organisms, contaminants, soil, and environmental conditions. Workshop discussions stressed on the need for making ERA locally relevant (in terms of choice of receptor organisms, sampling strategy, and bioavailability considerations). The workshop discussions highlighted the need of better appreciation of both the similarities and the clear differences between aquatic and terrestrial ERAs. The availability of reliable data, problems with databases, estimation of bioavailability, and extrapolations from laboratory to field were noted among the key limitations. ERA—being inherently complex and involving a range of environmental compartments, target receptor, and exposure pathways—at a minimum requires a multidisciplinary approach to address the complexities. Bringing a multidisciplinary team together often proves a major challenge in ERA. The delegates called for continued efforts in this area and formation of a network or working group in Australia.     

Sources,impacts and trends of pharmaceuticals in the marine and coastal environment

There has been a significant investment in research to define exposures and potential hazards of pharmaceuticals in freshwater and terrestrial ecosystems. A substantial number of integrated environmental risk assessments have been developed in Europe, North America and many other regions for these situations. In contrast, comparatively few empirical studies have been conducted for human and veterinary pharmaceuticals that are likely to enter coastal and marine ecosystems. This is a critical knowledge gap given the significant increase in coastal human populations around the globe and the growth of coastal megacities, together with the increasing importance of coastal aquaculture around the world. There is increasing evidence that pharmaceuticals are present and are impacting on marine and coastal environments. This paper reviews the sources, impacts and concentrations of pharmaceuticals in marine and coastal environments to identify knowledge gaps and suggests focused case studies as a priority for future research.     

A Preliminary Canadian Environmental Emissions Inventory for Endogenous and Retail Pharmaceutical Estrogens

Pharmaceuticals and personal care products (PPCPs), including estrogen pharmaceuticals, have been an environmental concern for well more than a decade, but no environmental emissions inventory for Canada has yet been published. Endogenous estrogens cannot be distinguished from the equivalent pharmaceutical estrogens in the environment. Therefore, data were compiled to estimate total environmental emissions of endogenous and retail pharmaceutical estrogens by the Canadian population for year 2007. Approximately 1,700 kg of pharmaceutical estrogens were dispensed through retail pharmacies in Canada in 2007. Of this amount, total environmental emissions were estimated to be approximately 730 kg, half to surface water via municipal sewage outfalls (> 90% via sewage treatment plants providing primary, secondary, or tertiary treatment), and half to the soil vadose zone and (potentially) groundwater via in situ sewage treatment systems. Approximately 960 kg of endogenous estrogens were excreted by the Canadian population, with about 420 kg reaching the environment, again approximately half to each of surface water and soil/groundwater. In situ sewage treatment may deliver an equivalent load of estrogens to the environment as do sewage treatment plants, despite servicing only 22% of the Canadian population.     

Indirect Effects of Antibiotics in the Aquatic Environment: A Laboratory Study on Detritivore Food Selection Behavior

With regard to possible detrimental effects of human and veterinary antibiotics in the aquatic environment, most research in this field assesses direct impacts of pharmaceuticals on vertebrate or invertebrate test organisms. Another related area of concern is the possible development of antibiotic-resistant bacteria by introducing antimicrobials into the aquatic compartment. However, indirect effects of antibacterials on the trophic cascade have rarely been investigated. This study contributes with an example of how indirect effects of antibiotics on leaf litter decay can be measured and to what extent shredder organisms might be affected. Results from food-selection experiments using Gammarus pulex (Amphipoda) demonstrated clear preferences for leaves conditioned in the absence versus those conditioned in the presence of two antibiotics, oxytetracycline and sulfadiazine. Although this result suggested that microbial and fungal colonisation during leaf litter conditioning might be adversely affected in the antibiotic-treated groups, analyses of total carbon and nitrogen content of conditioned leaf discs did not reveal differences among the treatments.     

Using anticipatory life cycle assessment to enable future sustainable construction

The built environment is the largest single emitter of CO₂ and an important consumer of energy. Much research has gone into the improved efficiency of building operation and construction products. Life Cycle Assessment (LCA) is commonly used to assess existing buildings or building products. Classic LCA, however, is not suited for evaluating the environmental performance of developing technologies. A new approach, anticipatory LCA (a‐LCA), promises various advantages and can be used as a design constraint during the product development stage. It helps overcome four challenges: (i) data availability, (ii) stakeholder inclusion, (iii) risk assessment, and (iv) multi‐criteria problems. This article's contribution to the line of research is twofold: first, it adapts the a‐LCA approach for construction‐specific purposes in theoretical terms for the four challenges. Second, it applies the method to an innovative prefabricated modular envelope system, the CleanTechBlock (CTB), focusing on challenge (i). Thirty‐six CTB designs are tested and compared to conventional walls. Inclusion of technology foresight is achieved through structured scenario analysis. Moreover, challenge (iv) is tackled through the analysis of different environmental impact categories, transport‐related impacts, and thickness of the wall assemblies of the CTB. The case study results show that optimized material choice and product design is needed to reach the lowest environmental impact. Methodological findings highlight the importance of context‐specific solutions and the need for benchmarking new products.     

Leveraging existing data for prioritization of the ecological risks of human and veterinary pharmaceuticals to aquatic organisms

Medicinal innovation has led to the discovery and use of thousands of human and veterinary drugs. With this comes the potential for unintended effects on non-target organisms exposed to pharmaceuticals inevitably entering the environment. The impracticality of generating whole-organism chronic toxicity data representative of all species in the environment has necessitated prioritization of drugs for focused empirical testing as well as field monitoring. Current prioritization strategies typically emphasize likelihood for exposure (i.e. predicted/measured environmental concentrations), while incorporating only rather limited consideration of potential effects of the drug to non-target organisms. However, substantial mammalian pharmacokinetic and mechanism/mode of action (MOA) data are produced during drug development to understand drug target specificity and efficacy for intended consumers. An integrated prioritization strategy for assessing risks of human and veterinary drugs would leverage available pharmacokinetic and toxicokinetic data for evaluation of the potential for adverse effects to non-target organisms. In this reiview, we demonstrate the utility of read-across approaches to leverage mammalian absorption, distribution, metabolism and elimination data; analyse cross-species molecular target conservation and translate therapeutic MOA to an adverse outcome pathway(s) relevant to aquatic organisms as a means to inform prioritization of drugs for focused toxicity testing and environmental monitoring.     

Applicability of indicator monitoring to ecological risk assessment

Although ecological risk assessment (ERA) and environmental monitoring would seem to be potentially complimentary activities, they have been disjunct in practice. This is because of differences in goals and products. Environmental monitoring determines status and trends in indicators to determine whether the environment is improving. ERA estimates effects of stressors on endpoint attributes to support decision making. Indicators are, by definition, indicative of some unmeasured condition. Assessment endpoints are valued properties of the environment that are susceptible to stressors of concern. Indicators are justified by the logic of the monitoring program, which may be self-referential. Assessment endpoints are justified by their potential susceptibility and by environmental policies and public values. Indicators are often expressed in terms of indices or scores that obscure the actual condition of the environment. Because assessment endpoints must be clear to decision makers and the public, they require real units of actual environmental properties. Monitoring programs are peripherally concerned about causal relationships, while risk assessment is devoted to elucidating causal relationships. As a result, risk assessments may use the results of monitoring studies, but only after disaggregating the indicators to their components and choosing those that are appropriate. Monitoring programs could be more useful if they used a risk-based approach to address important problems rather than simply tracking indicators.