Cross-Species Extrapolation of Biological Data to Guide the Environmental Safety Assessment of Pharmaceuticals-The State of the Art and Future Priorities.

The extrapolation of biological data across species is a key aspect of biomedical research and drug development. In this context, comparative biology considerations are applied with the goal of understanding human disease and guiding the development of effective and safe medicines. However, the widespread occurrence of pharmaceuticals in the environment and the need to assess the risk posed to wildlife have prompted a renewed interest in the extrapolation of pharmacological and toxicological data across the entire tree of life. To address this challenge, a biological "read-across" approach, based on the use of mammalian data to inform toxicity predictions in wildlife species, has been proposed as an effective way to streamline the environmental safety assessment of pharmaceuticals. Yet, how effective has this approach been, and are we any closer to being able to accurately predict environmental risk based on known human risk? We discuss the main theoretical and experimental advancements achieved in the last 10 years of research in this field. We propose that a better understanding of the functional conservation of drug targets across species and of the quantitative relationship between target modulation and adverse effects should be considered as future research priorities. This pharmacodynamic focus should be complemented with the application of higher-throughput experimental and computational approaches to accelerate the prediction of internal exposure dynamics. The translation of comparative (eco)toxicology research into real-world applications, however, relies on the (limited) availability of experts with the skill set needed to navigate the complexity of the problem; hence, we also call for synergistic multistakeholder efforts to support and strengthen comparative toxicology research and education at a global level. Environ Toxicol Chem 2024;43:513-525. © 2023 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Computed tomography chest imaging offers no advantage over chest X-ray in the initial assessment of gestational trophoblastic neoplasia.

BACKGROUND: The International Federation of Gynaecology and Obstetrics (FIGO) score identifies gestational trophoblastic neoplasia (GTN) patients as low- or high-risk of single-agent chemotherapy resistance (SACR). Computed tomography (CT) has greater sensitivity than chest X-ray (CXR) in detecting pulmonary metastases, but effects upon outcomes remain unclear. METHODS: Five hundred and eighty-nine patients underwent both CXR and CT during GTN assessment. Treatment decisions were CXR based. The number of metastases, risk scores, and risk category using CXR versus CT were compared. CT-derived chest assessment was evaluated as impact upon treatment decision compared to patient outcome, incidence of SACR, time-to-normal human chorionic gonadotrophin hormone (TNhCG), and primary chemotherapy resistance (PCR). RESULTS: Metastasis detection (p < 0.0001) and FIGO score (p = 0.001) were higher using CT versus CXR. CT would have increased FIGO score in 188 (31.9%), with 43 re-classified from low- to high-risk, of whom 23 (53.5%) received curative single-agent chemotherapy. SACR was higher when score (p = 0.044) or risk group (p < 0.0001) changed. Metastases on CXR (p = 0.019) but not CT (p = 0.088) lengthened TNhCG. Logistic regression analysis found no difference between CXR (area under the curve (AUC) = 0.63) versus CT (AUC = 0.64) in predicting PCR. CONCLUSIONS: CT chest would improve the prediction of SACR, but does not influence overall treatment outcome, TNhCG, or prediction of PCR. Lower radiation doses and cost mean ongoing CXR-based assessment is recommended.

A prospective, matched comparison of ultra-low and standard-dose computed tomography for assessment of renal colic.

OBJECTIVE: To determine the diagnostic accuracy of ultra-low-dose computed tomography (ULDCT) compared with standard-dose CT (SDCT) in the evaluation of patients with clinically suspected renal colic, in addition to secondary features (hydroureteronephrosis, perinephric stranding) and additional pathological entities (renal masses). PATIENTS AND METHODS: A prospective, comparative cohort study was conducted amongst patients presenting to the emergency department with signs and symptoms suggestive of renal or ureteric colic. Patients underwent both SDCT and ULDCT. Single-blinded review of the image sets was performed independently by three board-certified radiologists. RESULTS: Among 21 patients, the effective radiation dose was lower for ULDCT [mean (SD) 1.02 (0.16) mSv] than SDCT [mean (SD) 4.97 (2.02) mSv]. Renal and/or ureteric calculi were detected in 57.1% (12/21) of patients. There were no significant differences in calculus detection and size estimation between ULDCT and SDCT. A higher concordance was observed for ureteric calculi (75%) than renal calculi (38%), mostly due to greater detection of calculi of <3 mm by SDCT. Clinically significant calculi (≥3 mm) were detected by ULDCT with high specificity (97.6%) and sensitivity (100%) compared to overall detection (specificity 91.2%, sensitivity 58.8%). ULDCT and SDCT were highly concordant for detection of secondary features, while ULDCT detected less renal cysts of <2 cm. Inter-observer agreement for the ureteric calculi detection was 93.9% for SDCT and 87.8% for ULDCT. CONCLUSION: ULDCT performed similarly to SDCT for calculus detection and size estimation with reduced radiation exposure. Based on this and other studies, ULDCT should be considered as the first-line modality for evaluation of renal colic in routine practice.

Single use versus reusable digital flexible ureteroscopes: A prospective comparative study.

OBJECTIVES: To compare the performance and surgical outcomes of two different single-use digital flexible ureteroscopes with a reusable video flexible ureteroscope. METHODS: Patients undergoing retrograde flexible ureteroscopy at Nepean Hospital, Sydney, Australia, were included in this study. Three different flexible ureteroscopes were used in this study: (i) single-use digital LithoVue (Boston Scientific, Marlborough, MA, USA); (ii) single-use digital PU3022A (Pusen, Zhuhai, China); and (iii) reusable digital URF-V2 (Olympus, Tokyo, Japan). Visibility and maneuverability was rated on a 5-point Likert scale by the operating surgeon. Operative outcomes and complications were collected and analyzed. RESULTS: A total of 150 patients were included in the present study. Of these, 141 patients had ureteroscopy for stone treatment, four for endoscopic combined intrarenal surgery and five for diagnostic/tumor treatment. There were 55 patients in the LithoVue group, 31 in the PU3022A group and 64 patients in the Olympus URF-V2 group. The URF-V2 group had higher visibility scores than both the single-use scopes and higher maneuverability scores when compared with the PU3022A. The LithoVue had higher visibility and maneuverability scores when compared with the PU3022A. There were no differences in operative time, rates of relook flexible ureteroscopes, scope failure or complication rates observed. CONCLUSIONS: Single-use digital flexible ureteroscopes have visibility and maneuverability profiles approaching that of a reusable digital flexible ureteroscope. Single-use flexible ureteroscopes achieve similar clinical outcomes to the more expensive reusable versions.

Systematic review of health-related quality of life and patient-reported outcome measures in gestational trophoblastic disease: a parallel synthesis approach.

Gestational trophoblastic disease is a rare complication of pregnancy that can develop into cancer. Medical outcomes of gestational trophoblastic disease are well researched, but the effect of the disease on health-related quality of life (HRQOL) requires attention if care is to be improved. This systematic review was designed to establish the effect of gestational trophoblastic disease and its treatment on HRQOL and to identify the appropriateness of HRQOL measures. Quantitative studies found HRQOL in long-term survivors of gestational trophoblastic disease to be at or above population norms. The disease had a negative effect on HRQOL for patients who experienced physical, psychological, and social sequelae related to the condition. Clinically significant levels of anxiety, depression, sexual dysfunction, and fertility-related distress were found in these patients. The results should be treated with caution because the evidence base was limited to small heterogeneous samples, data were retrospective, and a range of measures was used. Within qualitative studies on HRQOL for survivors of gestational trophoblastic disease, new conditions emerged, including nerve damage, fatigue, amenorrhoea, and grief. These areas are not captured in existing patient-reported outcome measures, and the content might not be valid for this population. Further qualitative research might lead to the development of a specific patient-reported outcome measure for gestational trophoblastic disease, providing reliable, meaningful, and valid assessments, and allowing longitudinal data to be obtained.

Evolution of a Teenage and Young Adult Service, in Sheffield, U.K., for Patients with Gestational Trophoblastic Neoplasia.

OBJECTIVE: To describe the evolution of a teenage and young adult (TYA) service for patients with gestational trophoblastic neoplasia (GTN). BACKGROUND: Since its opening in 2002 the TYA unit has demonstrated its effectiveness and ability to care for GTN patients, offering additional emotional assessment and meeting the specific needs that many young GTN patients have. Patients using the TYA unit were identified from the Centre's databases, and individual records were scrutinized for demographics, clinical presentation, barriers to care, compliance, and specific needs. RESULTS: Of the 121 GTN patients who have utilized the facilities, there were 94 complete moles, 11 choriocarcinomas, 3 placental site trophoblastic tumors, 1 twin molar pregnancy, and 4 with persistent unexplained hCG elevation. Presenting with a complicated social background was identified as a barrier to care in 8 patients. In addition to patients, 40 relatives and 12 infants have also utilized the facilities. A total of 33% of patients and carers had social work input and/or refer-ral to psychology services. CONCLUSION: The bespoke service and care offered to TYA patients is appropriate and should be considered the gold standard for young patients, enabling them to cope with their unique challenges during diagnosis and treatment.

The Role of Computed Tomography Scanning of the Thorax in the Initial Assessment of Gestational Trophoblastic Neoplasia.

OBJECTIVE: The aim of this study was to determine whether lesions found on computed tomography (CT) imaging of the thorax would affect FIGO (International Federation of Gynecology and Obstetrics) 2000 risk score and/or alter clinical management. METHODS: The Sheffield Trophoblastic Disease database was searched for all new patients registered for staging/scoring investigations between January 1, 2006, and June 30, 2010. The FIGO 2000 score was noted and then recalculated using information from CT scan reports. Where a change of risk score would have affected a patient's management, the case notes were further reviewed. RESULTS: 191 patients had undergone both modalities of imaging. Using standard FIGO scoring, 169 and 22 patients were noted to be at low and high risk, respectively. Using information from CT imaging, only a further 20 patients would have been reclassified as high risk. Fifteen of these "new" high-risk patients required salvage treatment with intravenous chemotherapy; all were cured. CONCLUSIONS: With no potential advantage in terms of patient outcome and significantly increased radiation dose, there is little justification for routine CT imaging of the thorax in the initial assessment of new patients with gestational trophoblastic neoplasia.

A multi-endpoint in vivo larval zebrafish (Danio rerio) model for the assessment of integrated cardiovascular function.

INTRODUCTION: Despite effective in vitro preclinical strategies to identify cardiovascular (CV) liabilities, there remains a need for early functional assessment prior to complex in vivo mammalian models. The larval zebrafish (Danio rerio, Zf) has been suggested for this role: previous data suggest that cardiac electrophysiology and vascular ultrastructure are comparable with mammals, and also indicate responsiveness of individual Zf CV system endpoints to some functional modulators. Little information is, however, available regarding integrated functional CV responses to drug treatment. Consequently, we developed a novel larval Zf model capable of simultaneous quantification of chronotropic, inotropic and arrhythmic effects, alongside measures of blood flow and vessel diameter. METHODS: Non-invasive video analysis of the heart and dorsal aorta of anaesthetized and agarose-embedded larval ZF was used to measure multiple cardiovascular endpoints, simultaneously, following treatment with a range of functional modulators of CV physiology. RESULTS: Changes in atrial and ventricular beat frequencies were detected in response to acute treatment with cardio-stimulants (adrenaline and theophylline), and negative chrono/inotropes (cisapride, haloperidol, terfenadine and verapamil). Arrhythmias were also observed including terfenadine-induced 2:1 atrial-ventricular (A-V) block, a previously proposed hERG surrogate measure. Significant increases in blood flow were detected in response to adrenaline and theophylline exposure; and decreases after cisapride, haloperidol, terfenadine, and verapamil treatment. Using dorsal aorta (DA) blood flow and ventricular beat rate, surrogate stoke volumes were also calculated for all compounds. DISCUSSION: These data support the use of this approach for CV function studies. Moreover the throughput and compound requirements (approximately 3 compounds/person effort/week and <10 mg) make our approach potentially suitable for higher throughput drug safety and efficacy applications, pending further assessment of ZF-mammalian pharmacological comparability.

A European perspective on alternatives to animal testing for environmental hazard identification and risk assessment.

Tests with vertebrates are an integral part of environmental hazard identification and risk assessment of chemicals, plant protection products, pharmaceuticals, biocides, feed additives and effluents. These tests raise ethical and economic concerns and are considered as inappropriate for assessing all of the substances and effluents that require regulatory testing. Hence, there is a strong demand for replacement, reduction and refinement strategies and methods. However, until now alternative approaches have only rarely been used in regulatory settings. This review provides an overview on current regulations of chemicals and the requirements for animal tests in environmental hazard and risk assessment. It aims to highlight the potential areas for alternative approaches in environmental hazard identification and risk assessment. Perspectives and limitations of alternative approaches to animal tests using vertebrates in environmental toxicology, i.e. mainly fish and amphibians, are discussed. Free access to existing (proprietary) animal test data, availability of validated alternative methods and a practical implementation of conceptual approaches such as the Adverse Outcome Pathways and Integrated Testing Strategies were identified as major requirements towards the successful development and implementation of alternative approaches. Although this article focusses on European regulations, its considerations and conclusions are of global relevance.

Assessment of fracture healing after minimally invasive plate osteosynthesis or open reduction and internal fixation of coexisting radius and ulna fractures in dogs via ultrasonography and radiography.

OBJECTIVE: To evaluate fracture healing after minimally invasive plate osteosynthesis (MIPO) or open reduction and internal fixation (ORIF) of coexisting radius and ulna fractures in dogs via ultrasonography and radiography. DESIGN: Prospective cohort study. ANIMALS: 16 dogs with radius-ulna fractures that underwent MIPO (n = 9; 2 dogs were subsequently not included in the analyses because of incomplete follow-up information) or ORIF (7). PROCEDURES: Dogs in the 2 treatment groups were matched by age, body weight, and configuration of the fractures. Fracture healing was evaluated with ultrasonography, power Doppler ultrasonography, and radiography every 3 to 4 weeks until healing was complete; a semiquantitative score based on the number of Doppler signals was used to characterize neovascularization, and subjective B-mode ultrasonographic and radiographic scores were assigned to classify healing. RESULTS: Fractures in dogs that underwent MIPO healed in significantly less time than did fractures in dogs that underwent ORIF (mean ± SD; 30 ± 10.5 days and 64 ± 10.1 days, respectively). Radiography revealed that fractures in dogs that underwent MIPO healed with significantly more callus formation than did fractures in dogs that underwent ORIF. Although Doppler ultrasonography revealed abundant vascularization in fractures that were healing following MIPO, no significant difference in neovascularization scores was found between groups. CONCLUSIONS AND CLINICAL RELEVANCE: For dogs with radius-ulna fractures, data indicated that bridging osteosynthesis combined with a minimally invasive approach contributed to rapid healing after MIPO. The MIPO technique may offer some clinical advantage over ORIF, given that complete radius-ulna fracture healing was achieved in a shorter time with MIPO.

Radiographic quantitative assessment of cranial tibial subluxation before and after tibial plateau leveling osteotomy in dogs.

OBJECTIVE: To determine the influence of stifle joint flexion angle, cranial cruciate ligament (CrCL) integrity, tibial plateau leveling osteotomy (TPLO), and cranial tibial subluxation on the distance between the location of the origin and insertion of the CrCL (CrCL(d)) in dogs. SAMPLES: 4 pairs of pelvic limbs from adult dog cadavers weighing 23 to 34 kg. Procedures-Mediolateral projection radiographs of each stifle joint were obtained with the joint flexed at 90°, 105°, 120°, 135°, and 150°. Radiopaque markers were then placed at the sites of origin and insertion of the CrCL. Afterward, radiography was repeated in the same manner, before and after CrCL transection, with and without TPLO. Following CrCL transection, radiographs were obtained before and after inducing overt cranial tibial subluxation. Interobserver variation in measuring the CrCL(d) without fiduciary markers was assessed. The effect of CrCL integrity, cranial tibial subluxation, flexion angle, and TPLO on CrCL(d) was also determined. RESULTS: Interobserver agreement was strong, with an intraclass correlation coefficient of 0.859. The CrCL(d) was significantly shorter (< 1 mm) at 90° of flexion; otherwise, flexion angle had no effect on CrCL(d). Cranial tibial subluxation caused a 25% to 40% increase in CrCL(d). No effect of TPLO on CrCL(d) was found, regardless of CrCL integrity, forced stifle joint subluxation, or flexion angle. CONCLUSIONS AND CLINICAL RELEVANCE: Overt cranial tibial subluxation in CrCL-deficient stifle joints can be detected on mediolateral projection radiographs by comparing CrCL(d) on neutral and stressed joint radiographs at joint angles between 105° and 150°, regardless of whether a TPLO has been performed.

Using data from drug discovery and development to aid the aquatic environmental risk assessment of human pharmaceuticals: concepts, considerations, and challenges.

Over recent years, human pharmaceuticals have been detected in the aquatic environment. This, combined with the fact that many are (by design) biologically active compounds, has raised concern about potential impacts in wildlife species. This concern was realized with two high-profile cases of unforeseen environmental impact (i.e., estrogens and diclofenac), which have led to a flurry of work addressing how best to predict such effects in the future. One area in which considerable research effort has been made, partially in response to regulatory requirements, has been on the potential use of preclinical and clinical pharmacological and toxicological data (generated during drug development from nonhuman mammals and humans) to predict possible effects in nontarget, environmentally relevant species: so-called read across. This approach is strengthened by the fact that many physiological systems are conserved between mammals and certain environmentally relevant species. Consequently, knowledge of how a pharmaceutical works (the "mode-of-action," or MoA) in nonclinical species and humans could assist in the selection of appropriate test species, study designs, and endpoints, in an approach referred to as "intelligent testing." Here we outline the data available from the human drug development process and suggest how this might be used to design a testing strategy best suited to the specific characteristics of the drug in question. In addition, we review published data that support this type of approach, discuss the potential pitfalls associated with read across, and identify knowledge gaps that require filling to ensure accuracy in the extrapolation of data from preclinical and clinical studies, for use in the environmental risk assessment of human pharmaceuticals.

Chronic effects assessment and plasma concentrations of the beta-blocker propranolol in fathead minnows (Pimephales promelas).

The presence of many human pharmaceuticals in the aquatic environment is now a worldwide concern, yet little is known of the chronic effects that these bioactive substances may be having on aquatic organisms. Propranolol, a non-specific beta adrenoreceptor blocker (beta-blocker), is used to treat high blood pressure and heart disease in humans. Propranolol has been found in surface waters worldwide at concentrations ranging from 12 to 590ng/L. To test the potential for ecologically relevant effects in fish in receiving waters, short-term (21 days) adult reproduction studies were conducted, in which fathead minnows were exposed to nominal concentrations of propranolol hydrochloride [CAS number 318-98-9] ranging from 0.001 to 10mg/L (measured concentrations typically from 78 to 130%). Exposure of fish to 3.4mg/L (measured) over 3 days caused 100% mortality or severe toxicity requiring euthanasia. The most sensitive endpoints from the studies were a decrease in hatchability (with regard to the number of days to hatch) and a concentration-related increase in female gonadal somatic index (GSI), giving LOEC(hatchability) and LOEC(female GSI) values of 0.1mg/L. Concentration-related decreases in weights of male fish were also observed, with LOEC(male wet weight value) of 1.0mg/L, and the LOEC(reproduction) value was 1.0mg/L. Collectively, these data do not suggest that propranolol was acting as a reproductive toxin. Plasma concentrations of propranolol in male fish exposed to nominal concentrations of 0.1 and 1.0mg/L were 0.34 and 15.00mg/L, respectively, which constitutes 436 and 1546% of measured water concentrations. These compare with predicted concentrations of 0.07 and 0.84mg/L, and thus to a degree support the use of partition coefficient models for predicting concentrations in plasma in fish. In addition, propranolol plasma concentrations in fish exposed to water concentrations of 0.1 and 1.0mg/L were greater than the human therapeutic plasma concentration and hence these data very strongly support the fish plasma model proposed by Huggett et al. [Huggett, D.B., Cook, J.C., Ericson, J.F., Williams, R.T., 2003a. A theoretical model for utilizing mammalian pharmacology and safety data to prioritize potential impacts of human pharmaceuticals to fish. Hum. Ecol. Risk Assess. 9, 1789-1799].

Approaches to seizure risk assessment in preclinical drug discovery.

Assessment of seizure risk traditionally occurs late in the drug discovery process using low-throughput, resource intensive in vivo assays. Such approaches do not allow sufficient time to mitigate risk by influencing chemical design. Early identification using cheaper, higher throughput assays with lower animal and compound requirements would be preferable. Here we review the current techniques available to assess this issue and describe how they may be combined in a rational step-wise cascade allowing more effective assessment of seizure risk.

Zebrafish assays as early safety pharmacology screens: paradigm shift or red herring?

The recent flurry of interest in the potential use of the zebrafish (Danio rerio) in Drug Discovery has also led to the development of a range of assays purported to be useful as early screens in safety pharmacology. The purpose of this commentary is to take stock of the available zebrafish assays in the context of alternative mammalian cell-based assays, and of the validation outcomes to date. In addition, we report the results of a recent survey of the membership of the Safety Pharmacology Society regarding their views on zebrafish assays. The survey data indicate that the preferred way forward would be a collaborative effort between the pharmaceutical/biotechnology industry (as potential/eventual customers), and the zebrafish contract research companies (as suppliers), alongside expert input from academia and regulatory authorities.