Prolonged fecal elimination of isoxazoline antiparasitic drugs in dogs and cats: is there a risk for nontarget species?

Understanding a drug's plasma half-life is essential in guiding dosage regimens and optimizing therapeutic outcomes, particularly in the early stages of drug development. By using published pharmacokinetic data from Food Animal Residue Avoidance Databank, we collected 560 data points of plasma half-lives for different drugs in dogs following intravenous administration. The dataset was then preprocessed and the mean elimination half-life for each drug was selected in the final clean dataset for model training and testing. Five types of chemical descriptors and four types of supervised machine learning (ML) algorithms were employed to build ML-empowered Quantitative Structure-Activity Relationship (QSAR) models. Model performances were assessed by determination coefficient (R2) and root mean square error values. The results showed that the Deep Neural Networks model with all-combined descriptor type had the best performance with R2 = 0.80 for the fivefold cross-validation set and R2 = 0.57 for the testing set. Furthermore, the applicability domains of the well-trained models are shown via Williams plots. This study reports an ML-based QSAR tool in predicting the elimination half-lives of drugs in dogs based on only chemical structures. This approach can be used to support drug development in dogs and provides a basis for potential interspecies extrapolation.

BackgroundThe overall aim of the interdisciplinary research project “PharmCycle” is to reduce the contamination of the aquatic environment with antibiotics by developing sustainable antibiotics, improving the environmental risk assessment of antibiotics, and reducing the discharges of antibiotics in the wastewater outlet. An overview of the holistic approach and first results are given.ResultsThe first step is to design sustainable antibiotics, which are effective against target organisms but, after their use, are less toxic, and are rapidly and completely degradable. To develop sustainable antibiotics, two different approaches (subprojects) are applied within PharmCycle: First, a re-design of the existing antibiotics with chemical and in silico methods (“Benign by Design”). Second, sustainable peptide-based antibiotics are produced with biotechnological methods. In the second step, the environmental risk assessment for antibiotics in the framework of the authorization process and for monitoring purposes is improved. There is a lack of data for the environmental risk assessment of antibiotics on the European market. With more transparency of these data, the environmental risk assessment for active substances and for the class of antibiotics can be improved. The aim is to increase the data availability by applying the Aarhus convention and by providing legal access to environmental information. Beside other shortages in the environmental risk assessment required by the European legislation, the effects of antibiotics directly applied in marine aquacultures are not assessed by marine prokaryotic test systems. Therefore, a marine cyanobacteria test was developed, which is more sensitive to selected priority antibiotics than the marine eukaryotic algae test (DIN EN ISO 10253) required by the European Medicines Agency. Marine cyanobacteria are of high importance for the nitrogen cycle and primary production. Moreover, they seem to play an important role with respect to climate change. To reduce the emission of antibiotics used as human pharmaceutical products to the aquatic environment, the third step focusses on the main pathway, the wastewater. Investigations to improve the wastewater treatment of priority antibiotics and sustainable antibiotics are conducted by a combination of methods: activated sludge units, activated carbon adsorption, and membrane filtration systems.ConclusionsWith the aim of improving the environmental risk assessment of antibiotics and to reduce the emission of antibiotics to the aquatic environment, an interdisciplinary approach is applied which includes the analysis of the German, European, and international law and the development of new legal instruments.

Pharmaceutical regulation of genetically modified organisms (GMOs) is one of the critical issues for developing viral vector-based medicines. In this perspective, we introduce the recent improvement of regulatory operations in GMOs like viral vector-based products in Japan by comparing those in the United States and the European Union. The recent advancements in genetic modification and editing techniques have accelerated the development of advanced-therapy medicinal products using genetically modified viral vectors and cells.1 Despite the increase in use of GMOs/living modified organisms (LMOs) in medicine, the potential risk of GMOs/LMOs on the environment is a concern. To address internationally the environmental issues related to biological diversity, including the usage of GMOs/LMOs, 196 nations as of 2021 have concluded or signed the Convention on Biological Diversity (CBD), which is the first global agreement to cover all aspects of biological diversity. The Cartagena Protocol based on CBD aims to ensure the safe handling, transport, and use of GMOs/LMOs, produced by modern biotechnology, which may have an impact on biological diversity. The Cartagena Protocol was entered into force on September 11, 2003. The Cartagena Protocol requires the parties to consider the necessity of the standard of handling of GMOs/LMOs and, if necessary, to establish the standard. The EU countries had already established domestic laws based on Directive 2001/18/EC that addressed the handling of GMOs/LMOs for medical use before the establishment of the Cartagena Protocol. Therefore, the EU countries did not have to take any additional actions to regulate the handling of GMOs/LMOs for pharmaceuticals. In 2003, the Japanese government established the Act on the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms,2 known as the Cartagena Act, for the handling of the GMOs/LMOs. This Act is similar to Directive 2001/18/EC and the domestic laws established in the EU countries. In contrast to the European Union and Japan, the United States is one of the few countries that have not signed the CBD and the Cartagena Protocol. The United States enacted one specific environmental law named the National Environmental Policy Act of 1969 (NEPA) that regulates all kinds of environmental assessments. For initiating clinical trials, developers should submit appropriate clinical trial-related applications (investigational new drug (IND) application in the United States, clinical trial application (CTA) in the European Union, and clinical trial notification (CTN) in Japan) to each regulatory agency. In the European Union and Japan, approval of the usage of the GMOs/LMOs in the clinical trials is also mandatory before starting clinical trials (Figure 1). The objective of the EU domestic laws is to protect humans and the environment when carrying out deliberate release of GMOs/LMOs into the environment. Thus, developers (academia and/or industry) planning clinical trials in the EU countries should submit an environmental risk assessment (ERA) of each GMO to each country where the clinical trial will be conducted. In Japan, the Cartagena Act has two types of GMO/LMO regulations, the deliberate release, with GMO/LMO-specific rules for usage (Type-1 Use Regulation (T-1R)) and containment use for closed production sites and laboratories (Type-2 Use Regulation (T-2R)). Clinical trials are within the scope of T-1R, therefore developers planning to conduct clinical trials in Japan should submit an ERA and the T-1R application for GMOs/LMOs. In the United States, the submission of an ERA is not required for IND applications. However, when GMOs/LMOs may affect the quality of the environment, the US Food and Drug Administration (FDA) will request an ERA during the review process of the IND (the Title 21 of the Code of Federal Regulations (CFR) 25.21 and 25.31). In both the European Union and the United States, applicants should submit an ERA result of GMOs/LMOs when applying for marketing authorization, and the FDA or European Medicines Agency (EMA) reviews the appropriateness of the usage of drugs in clinical practice based on the ERA result (Figure 1). In Japan, the resubmission of an ERA is not mandatory when applying for marketing authorization. If developers obtain new data that indicates the environmental risk is lower than expected, resubmission is acceptable at any time to relax the T-1R. Some clinical researchers in Japan recently commented that the Cartagena Act delays the development of medicines containing GMOs/LMOs when compared to that of the medicines regulated by the similar laws in the European Union and the United States.3 But the regulatory framework of Japan is not significantly different from that of at least the European Union (Figure 1). The Pharmaceuticals and Medical Devices Agency (PMDA) is the Japanese regulatory agency responsible for a scientific review of new drug applications and Cartagena Act-related applications. The PMDA believed that such opinions came from the differences between the scheme of the Cartagena Act implementation and the procedure of actual development of drugs, and a lack of information on the Cartagena Act applications among academia. To solve these problems, since 2019, the Ministry of Health, Labor, and Welfare and the PMDA have started to improve the implementation of the Cartagena Act to ensure faster development of drugs (Table 1). The first improvement made in 2019 was the establishment of the PMDA official consultations to address specific measures of the Cartagena Act. The consultations for the Cartagena Act were the first established at the PMDA for the environmental law, and the developers can officially discuss the Cartagena Act-related matters with the PMDA since the establishment. It takes < 3 months to complete the official consultations and for official minutes to be published. The applicant can then submit the T-1R application as soon as the issues pointed out in the consultations are resolved. The administrative processing time after the submission is officially < 6 months, and the median actual administrative processing time and total processing time in 2021 were ~ 2.7 months and < 5 months, respectively. Section 42 of the German Drug law indicates that the evaluation period of CTA for trials dealing with GMOs/LMOs is 90 days after receiving the application conforming to the regulations. Thus, the actual administrative processing time before starting clinical trials is similar between Japan and the European Union. Since 2021, the parallel application of CTN and T-1R is acceptable. Now, developers should receive the approval of the T-1R application before at least the first patient enrollment of the clinical trial in Japan. In the European Union, several countries, such as France, accept the parallel application of CTA and ERA, but some countries, such as Poland, demand the approval of usage of the GMOs in the clinical trials before submitting a CTA.4 The PMDA has published a considerable number of instructions, such as the specific descriptions of ERA for adeno-associated virus (AAV) vectors,5 to provide information about the Cartagena Act to future applicants. The specific ERA for AAV vectors includes the general information and prior knowledge about AAVs and the general principles of risk assessment for AAV vectors. The European Commission has also published specific ERA for AAV in June 2022.6 These instructions and specific descriptions will significantly reduce the burden on applicants and regulators in Japan. Because the ERA submission is not mandatory when applying for marketing authorization, the regulation of the development of gene therapy products in Japan is not more time-consuming than that in the European Union and the United States. No funding was received for this work. The authors declared no competing interests for this work.

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Invasive rat species have negatively affected island ecosystems contributing to the decline and extinction of many endemic species. The eradication of rodents on islands can leads to restoration of native ecosystems. Anticoagulant rodenticides (ARs) have been an effective tool for rat eradication on many oceanic island systems (Wilmer et al 2007). The Hawaiian Islands, USA have used first generation AR, diphacinone (DPN), for pest and rodent control. Rodent populations, found on the Hawaiian Islands, have not only caused the extinction small shorebird and plant populations but have also been in direct competition for resources. ARs, in the form of a bait pellet containing 0.005% DPN, have been aerially and hand broadcast across the islands. Aerial broadcasting via helicopter has allowed for remote islands with uneven and dangerous terrain. Successful Hawaiian rodent eradications have occurred on Kure Atoll, Mokoli'i Island, and Mokapu Island. Lehua Island, a remote and uninhabited island near Ni'ihau, successfully eradicated rabbits in 2006 but was unable to eradicate the rodent population via aerial broadcasting of DPN in 2009. Following this attempt in 2009, a fish mortality event was reported on Ni'ihau and a dead whale calf also was found around the same time. Analysis of the affected fish were done and found no rodenticide in tissues. Despite these results, concerns of AR exposure to non-target species such as fish were voiced by the public. To determine AR effects on coral reef fish found in Hawaii, U.S. Geological Survey was asked to address their sensitivity as a prerequisite of another DPN aerial broadcast over Lehua Island. In December 2016, we presented our preliminary findings, which were used in the planning processes of an aerial broadcast which was conducted in August 2017. My dissertation research used acute toxicity testing, tissue analysis, and pharmacokinetics to determine the relative sensitivity of fish species to ARs. The primary objectives for my dissertation were (1) determine the median lethal dose (LD50) of three common ARs in four fish species. (2) Assess AR concentrations in fish tissues over time, effects on clotting, and AR half-lives in fish tissue. and (3) Evaluate diphacinone concentrations in coral reef fish species muscle and liver pre and post-aerial broadcasting. Direct toxicity to ARs does not appear to be a primary concern as not only did fish in this study refuse to eat rodenticide dosed bait pellets in the lab aquaria but in comparison to target and non-target species, they appear to be less sensitive. Exposure to ARs delays clotting in fish species. There is a lag-time of effects to clotting time (up to 24 hours) but clotting times return to baseline or control values between 5-7 days post dosing. DPN and BROD half-lives in fish tissues, plasma, muscle, and liver were fairly rapid. DPN and BROD half-lives in plasma were longer than half-lives in muscle and the target organ, liver. I found no detectable or quantifiable amount of DPN in the sixteen species of coral reef fish liver and muscles samples examined from Lehua Island, Hawaii. Overall, these studies suggest that the use of rodenticides near waterways with a possibility of accidental exposure to fish species, should have little to no effect on fish communities.

Chapter 3 - Prioritization: Selection of Environmentally Occurring Pharmaceuticals to Be Monitored

Innocuousness and safety of classical swine fever marker vaccine candidate CP7_E2alf in non-target and target species

Potentialities of total reflection X-ray fluorescence spectrometry in environmental contamination: Hair of owned dogs as sentinel of arsenic exposure

It is essential to assess the environmental risk that Bt maize may hold and to study its effect on species assemblages that fulfil a variety of ecosystem functions. Environmental risk assessment can be improved through the use of an ecological model which can be applied to a specific environment, so that local species can be classified functionally and prioritized to identify potential test species. Although the stem borers, Busseola fusca (Lepidoptera: Noctuidae), and Chilo partellus (Lepidoptera: Crambidae), are the target species of Bt maize in South Africa various other Lepidoptera species are also directly exposed to Bt toxin. In this paper an ecological approach was followed for selection of non-target Lepidoptera species for ecological risk assessment of Bt maize, using data collected over a two-year period on Lepidoptera biodiversity on maize. Nine primary non-target lepidopterous consumers were identified. A selection matrix was developed in which each species was ranked for its maximum potential exposure to Bt toxin by assessing its occurrence, abundance, presence and linkage to other host plants in the maize ecosystem. Non-target Lepidoptera most likely to be affected were identified and prioritized for future testing and inclusion in risk assessments. Several non-target species were prioritized for their close association with maize, general occurrence in the maize-growing regions and their potential for economic damage should they become secondary pests. Through use of the selection matrix, knowledge gaps were identified for future research and guidance for the design of ecologically realistic experiments. Non-target species populations with the highest maximum potential exposure to Bt toxin are Sesamia calamistis (Hampson) (Lepidoptera: Noctuidae), Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) and Acantholeucania loreyi (Duponchel) (Lepidoptera: Noctuidae). Eublemma gayneri (Rothschild) (Lepidoptera: Noctuidae) can be considered to be a ‘value unknown’ species in the wild. Because of their sporadic occurrence, Agrotis segetum (Denis & Schiffermüller) (Lepidoptera: Noctuidae) and Spodoptera exigua (Hübner) (Lepidoptera: Noctuidae) are considered to be of lesser importance than H. armigera and A. loreyi, but should also be considered during pre-and post-release monitoring.

Pharmaceutical residues can harm the environment. Therefore any Marketing Authorisation Application (MAA) for a medicinal product for human use shall be accompanied by an "indication of any potential risks presented by the medicinal product for the environment" according to Article 8(3)(g) of the Directive 2001/83/EC. Since 2006 a guideline document from the European Medicines Agency (EMA, formerly EMEA) is available for this task, which is now called the "Environmental Risk Assessment" (ERA). Recently the EMA released a draft revision of an updated ERAguideline. The present paper provides a summary of the intended innovation. A number of options have been discontinued, but some of them cannot be easily recognised, even though they are potentially affecting the MAA and its costs in a relevant way. A new specifically tailored experimental testing course for antibiotics and a secondary poisoning assessment is introduced. The selectionof required study types is altered and the environmental fate evaluation is adapted to the scientific progress. In the recent situation it is suggested that marketing authorisation applicants may reconsider the conduct of water/sediment studies for substances not requiring these according to the guideline revision. The new tailored testing approach for antibiotics avoids any vertebrate use, because it demands no fish study, therefore it may be applied henceforth. If the new prescriptions are not yet in force at the point in time of the MAA submission, appropriate waivers should be stated in the ERA. No further HPLC-study types and acute earthworm toxicity tests should be performed, since the guideline update draft does not accept them. In preclinical toxicity and pharmacokinetic studies, additional data gathering on metabolites should be considered in order to avoid unnecessary leaflet warnings. The cost for ERA may change significantly, with a tendency to increase for generic pharmaceutical MAA, but with a possible reduction for substances of low environmental concern. Earlier consideration of ERA in the drug development process is recommended.

A critical evaluation of different parameters for estimating pharmaceutical exposure seeking an improved environmental risk assessment

rVSVΔG-ZEBOV-GP is a live, attenuated, recombinant vesicular stomatitis virus (rVSV)-based vaccine for the prevention of Ebola virus disease caused by Zaire ebolavirus. As a replication-competent genetically modified organism, rVSVΔG-ZEBOV-GP underwent various environmental evaluations prior to approval, the most in-depth being the environmental risk assessment (ERA) required by the European Medicines Agency. This ERA, as well as the underlying methodology used to arrive at a sound conclusion about the environmental risks of rVSVΔG-ZEBOV-GP, are described in this review. Clinical data from vaccinated adults demonstrated only infrequent, low-level shedding and transient, low-level viremia, indicating a low person-to-person infection risk. Animal data suggest that it is highly unlikely that vaccinated individuals would infect animals with recombinant virus vaccine or that rVSVΔG-ZEBOV-GP would spread within animal populations. Preclinical studies in various hematophagous insect vectors showed that these species were unable to transmit rVSVΔG-ZEBOV-GP. Pathogenicity risk in humans and animals was found to be low, based on clinical and preclinical data. The overall risk for non-vaccinated individuals and the environment is thus negligible and can be minimized further through defined mitigation strategies. This ERA and the experience gained are relevant to developing other rVSV-based vaccines, including candidates under investigation for prevention of COVID-19.

Preface. Workshop Summary. Strategies and Risk Assessment. Environmental Contamination and Remediation Practices at Former and Active Military Bases. German Experiences B.-A. Szelinski. General Environmental Situation, Risk Assessment and Remediation of Former Military Sites in East Germany V. Ermisch, P. Schuldt. Current and Future Research and Development Projects of the Federal Ministry for the Environment on Contaminated Military Sites S. Reppe. Environmental Risk Assessment and Management in Evaluation of Contaminated Military Sites. A Canadian Approach K.J. Reimer, B.A. Zeeb. Swedish Guidance on the Procedure for the Investigation and Risk Classification of Urban and Industrially Contaminated Areas D. Fredriksson. Environmental Situation and Remediation Plans of Military Sites in Latvia D. Hadonina. Strategy for Investigations and Remediation of a Polluted Norwegian Naval Base A. Johnsen. Chemical Aspects of Environmental Contamination at Military Sites S. Neffe. US Environmental Protection Agency's Baltic Technical Assistance Program: from Capacity Building to Environmental Security V.J. Saulys. Mathematical Modelling. Results of Mass Transport Modelling at some Wellfields and Former Soviet Military Bases in Lithuania M. Gregorauskas. Mass Transport Modelling in Groundwater Studies. Achievements of Latvian Scientists A. Spalvins. GIS and Mathematical Modelling for the Assessment of Vulnerability and Geographical Zoning for Groundwater Management and Protection J.P. Lobo-Ferreira. Modelling of Oil and Chlorinated Hydrocarbons in Saturated and Unsaturated Zones at the Military Base in Milovice V. Benes, V. Elias. Analysis and Monitoring. How to Map Hydrocarbon Contamination of Groundwater Without Analysing for Organics.A Study of Oil Contamination of Soil and Groundwater at Viestura Prospekts Former Military Fuel Storage Depot, Riga, Latvia D. Banks, et al. Monitoring a Diesel Spill at Skoddebergvatn Military Site in Northern Norway A. Misund. Impact of Military Contamination on Quality of Potable Water Resources V. Juodkazis, B. Paustys. Bioassays Used for Detection of Ecotoxicity at Contaminated Areas B. Rojiekova, et al. Compatibility of Groundwater Sampling and Laboratory Techniques. Some Practical Aspects of Investigations at Military Sites S. Janulevieius. Remediation Techniques. Advanced Methods for the In-Situ Remediation of Contaminated Soil and Groundwater J.A. Pezzullo. Groundwater Contamination Clean Up -- Reality or Illusion? B. Madsen. Remediation Practice at a Former Missile Base in Latvia H. Whittaker, et al. Implications of Selected Bacterial Strains for Contaminations of Oil Pollutants in Soil and Water S. Grigiskis, V. Cipinyte. Remediation of Soil and Groundwater at Air Bases Polluted with Oil, Chlorinated Hydrocarbons and Combat Chemicals J. Svoma, F. Hereik. Remedial Technologies Applied at Sliac -- Vlkanova, a Former Soviet Military Installation E. Fatulova. Remediation of Polluted Environment at Naval Ports of the Baltic Sea O. Tammemae. A Proposal for a Decision Flow Chart for the Selection of Technologies for the Rehabilitation of Polluted Aquifers T.E. Leitao. Investigation and Remediation of Former Military Fuel Storage of Valciunaia (Lithuania) N. Seirys. Dumped Ammunition in Mine Shafts J.G. Holme, et al. Nuclear Accidents and Radionuclide Transport M. Krosshavn, F. Fonnum. Migration Processes of Radio

Simple SummaryThe cat flea Ctenocephalides felis felis is the most important pest of domesticated cats and dogs worldwide. This review covers the recent advancements in the control of cat fleas. Over the years, there has been an interest in using ecologically friendly approaches to control fleas. To date, no biological, natural, or cultural means have been discovered that mitigate flea infestations. The recent registration of novel topical and oral therapies promises a new revolution in the control of fleas and ticks and the diseases associated with them.With the advent of imidacloprid and fipronil spot-on treatments and the oral ingestion of lufenuron, the strategies and methods to control cat fleas dramatically changed during the last 25 years. New innovations and new chemistries have highlighted this progress. Control strategies are no longer based on the tripartite approach of treating the pet, the indoor environment, and outdoors. The ability of modern therapies to break the cat flea life cycle and prevent reproduction has allowed for the stand-alone treatments that are applied or given to the pet. In doing so, we have not only controlled the cat flea, but we have prevented or reduced the impact of many of the diseases associated with ectoparasites and endoparasites of cats and dogs. This review provides an update of newer and non-conventional approaches to control cat fleas.

Environmental Risk Assessment (ERA) of diclofenac and ibuprofen: A public health perspective

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