TKPlate 1.0: An Open-access platform for toxicokinetic and toxicodynamic modelling of chemicals to implement new approach methodologies in chemical risk assessment.

This publication is linked to the following EFSA Supporting Publications articles: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-8441/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-8440/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2023.EN-8437/full.

Artificial intelligence and real-world data for drug and food safety - A regulatory science perspective.

In 2013, the Global Coalition for Regulatory Science Research (GCRSR) was established with members from over ten countries (www.gcrsr.net). One of the main objectives of GCRSR is to facilitate communication among global regulators on the rise of new technologies with regulatory applications through the annual conference Global Summit on Regulatory Science (GSRS). The 11th annual GSRS conference (GSRS21) focused on "Regulatory Sciences for Food/Drug Safety with Real-World Data (RWD) and Artificial Intelligence (AI)." The conference discussed current advancements in both AI and RWD approaches with a specific emphasis on how they impact regulatory sciences and how regulatory agencies across the globe are pursuing the adaptation and oversight of these technologies. There were presentations from Brazil, Canada, India, Italy, Japan, Germany, Switzerland, Singapore, the United Kingdom, and the United States. These presentations highlighted how various agencies are moving forward with these technologies by either improving the agencies' operation and/or preparing regulatory mechanisms to approve the products containing these innovations. To increase the content and discussion, the GSRS21 hosted two debate sessions on the question of "Is Regulatory Science Ready for AI?" and a workshop to showcase the analytical data tools that global regulatory agencies have been using and/or plan to apply to regulatory science. Several key topics were highlighted and discussed during the conference, such as the capabilities of AI and RWD to assist regulatory science policies for drug and food safety, the readiness of AI and data science to provide solutions for regulatory science. Discussions highlighted the need for a constant effort to evaluate emerging technologies for fit-for-purpose regulatory applications. The annual GSRS conferences offer a unique platform to facilitate discussion and collaboration across regulatory agencies, modernizing regulatory approaches, and harmonizing efforts.

Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks.

The workshop titled "Application of evidence-based methods to construct mechanism-driven chemical assessment frameworks" was co-organized by the Evidence-based Toxicology Collaboration and the European Food Safety Authority (EFSA) and hosted by EFSA at its headquarters in Parma, Italy on October 2 and 3, 2019. The goal was to explore integration of systematic review with mechanistic evidence evaluation. Participants were invited to work on concrete products to advance the exploration of how evidence-based approaches can support the development and application of adverse outcome pathways (AOP) in chemical risk assessment. The workshop discussions were centered around three related themes: 1) assessing certainty in AOPs, 2) literature-based AOP development, and 3) integrating certainty in AOPs and non-animal evidence into decision frameworks. Several challenges, mostly related to methodology, were identified and largely determined the workshop recommendations. The workshop recommendations included the comparison and potential alignment of processes used to develop AOP and systematic review methodology, including the translation of vocabulary of evidence-based methods to AOP and vice versa, the development and improvement of evidence mapping and text mining methods and tools, as well as a call for a fundamental change in chemical risk and uncertainty assessment methodology if to be conducted based on AOPs and new approach methodologies (NAM). The usefulness of evidence-based approaches for mechanism-based chemical risk assessments was stressed, particularly the potential contribution of the rigor and transparency inherent to such approaches in building stakeholders' trust for implementation of NAM evidence and AOPs into chemical risk assessment.

Communicating to and engaging with the public in regulatory science.

This paper presents selected highlights from the 'Engaging with society' session of EFSA's third Scientific Conference 'Science, Food and Society' (Parma, Italy, 18-21 September 2018). The social dimension for scientific advisory bodies largely concerns science communication and public engagement. The political, economic and technological transformation of contemporary societies is challenging conventional structures and approaches in these areas. The disintermediation of communication and the proliferation of misinformation, it is argued, herald the onset of the post-truth society. A better understanding of the way individuals consume information today has led to the development of tools to guide mediators such as journalists and communication specialists in countering these trends. Public engagement can reinforce confidence in regulatory bodies and potentially contribute to the quality of the scientific process. Scientific advisory bodies in Europe have created strategies and mechanisms to engage the public that are designed to increase transparency and representativeness. To be effective, several engagement mechanisms are needed, although factors such as resource constraints, institutional culture and public/stakeholder attitudes may limit their development. In conclusion, a more vigorous role for social research is needed to place scientific risk assessment within broader socio-economic and political contexts. Social science expertise can help to define more impactful public information strategies and to explore the potential opportunities that engaged stakeholders and citizens can make to sustain and strengthen regulatory science.

The Emergence of Systematic Review in Toxicology.

The Evidence-based Toxicology Collaboration hosted a workshop on "The Emergence of Systematic Review and Related Evidence-based Approaches in Toxicology," on November 21, 2014 in Baltimore, Maryland. The workshop featured speakers from agencies and organizations applying systematic review approaches to questions in toxicology, speakers with experience in conducting systematic reviews in medicine and healthcare, and stakeholders in industry, government, academia, and non-governmental organizations. Based on the workshop presentations and discussion, here we address the state of systematic review methods in toxicology, historical antecedents in both medicine and toxicology, challenges to the translation of systematic review from medicine to toxicology, and thoughts on the way forward. We conclude with a recommendation that as various agencies and organizations adapt systematic review methods, they continue to work together to ensure that there is a harmonized process for how the basic elements of systematic review methods are applied in toxicology.

Meta-analytical equivalence studies on diagnostic tests for bovine brucellosis allowing assessment of a test against a group of comparative tests.

In the assessment of diagnostic tests the task may arise to show that a candidate test is non-inferior compared to a comparative (standard) test with regard to the diagnostic sensitivity or specificity. This setting is known as "one-sided equivalence" and has been applied to a single comparison between two diagnostic tests (Chen et al., 2003). Recently, the approach has been extended into a meta-analytical framework (EFSA, 2006), allowing for the difference between the sensitivity (or specificity) of two diagnostic tests to be estimated using information gathered through systematic literature review. Using this approach, confounding factors are adjusted by matching of parameter estimates on study population and preferred levels of the confounding factors. However, the power of this approach was found to be limited and therefore Markov chain Monte Carlo logistic regression (MCMCLR) models that allow adjustment for confounding variables have been developed (EFSA, 2006). We report here a refinement of the statistical inference based on the latter approach. The objective was to generate a posterior distribution of the meta-analytical difference statistic for the candidate test and a set of comparative tests. The algorithm for this purpose uses Monte Carlo sampling from the posterior distributions of sensitivity (or specificity) and, for each iteration, (i) identifies the least performant comparative test, (ii) establishes the difference statistics for this test and the candidate test and (iii) compares the difference statistic with a critical threshold value. The proportion of iterations in which the critical threshold was exceeded is then interpreted as the P-value for the one-sided equivalence test for the candidate versus the set of comparative tests. We illustrate and discuss the method using a case study on tests for bovine brucellosis.

Towards a new reference test for surra in camels.

Current serological diagnosis of Trypanosoma evansi infection in camels is based on the native variable antigen type RoTat 1.2. The goal of this study was to develop a novel serological diagnostic test based on a nonvariable protein and freed from the use of rats or mice for its production. An enzyme-linked immunosorbent assay using a recombinant extracellular domain of invariant surface glycoprotein 75 (ELISA/rISG75) was developed and tested on a collection of 184 camel sera. The results were compared to those obtained from three established antibody detection tests based on variable surface glycoprotein RoTat 1.2: an ELISA for T. evansi (ELISA/T. evansi), a card agglutination test for trypanosomiasis (CATT/T. evansi), and an immune trypanolysis (TL) assay. The ELISA/rISG75 and the ELISA/T. evansi showed a sensitivity of 94.6% (95% confidence interval [CI], 87.8 to 98.2%, at 19% positivity cutoff value) and 98.9% (95% CI, 94.1 to 99.8, at 12% positivity cutoff value), respectively. The ELISA/rISG75 had 100% specificity (CI, 95.9 to 100%), while the ELISA/T. evansi showed 98.9% specificity (CI, 95.9 to 100%). The ELISA/rISG75 demonstrated an almost perfect agreement with the TL assay, the CATT/T. evansi, and the ELISA/T. evansi, with kappa scores of at least 0.94. The ELISA/rISG75, having a performance comparable to that of the gold standard (the TL assay) and being independent of antigenic variation, may become a new reference test for surra in camels. It opens avenues for the diagnosis of T. evansi infections in other hosts as well as for the development of a pan-Trypanozoon test for detection of Trypanosoma brucei brucei, T. b. gambiense, T. b. rhodesiense, T. evansi, and T. equiperdum.

Defining output-based standards to achieve and maintain tuberculosis freedom in farmed deer, with reference to member states of the European Union.

Within the European Union (EU), detailed legislation has been developed for cattle, but not deer, to minimise disease risks associated with trade in animals and animal products. This legislation is expressed as input-based standards, providing a detailed outline of the activity required (for example, testing of animals and application of defined control measures), on the expectation that an adequate output (for example, confidence in freedom) will be achieved. Input-based standards are at odds with the increasing shift towards output-based standards, particularly in OIE rules governing international trade. In this paper, we define output-based standards to achieve and maintain freedom from tuberculosis (TB) in farmed deer, with reference to EU member states. After considering the probability of freedom achieved for cattle under existing EU legislation, we defined a 'free farmed deer holding' as one with a probability of freedom from infection of at least 99%. We then developed an epidemiological model of TB surveillance systems for deer holdings, incorporating different surveillance strategies, including combinations of diagnostic tests, and a variety of different scenarios relating to the potential for introduction of infection. A range of surveillance strategies were identified to achieve and maintain a free farmed deer holding, and worked examples are presented. The surveillance system sensitivity for varying combinations of screening and confirmatory tests in live animals, animals at slaughter and on-farm deaths is also presented. Using a single test at a single point in time, none of the TB tests routinely used in farmed deer is able to achieve an acceptable probability of TB freedom. If repeat testing were undertaken, an acceptable probability of TB freedom could be achieved, with differing combinations of the surveillance system sensitivity, frequency of testing and risk of introduction. The probability of introduction of infection through the importation of infected deer was influenced by the use of a pre-movement test (assumed 90% test sensitivity and negative test results), the TB prevalence in the source herd and the number of animals imported. A surveillance system sensitivity of at least 81% was achieved with different combinations of annual live animal surveillance and surveillance of animals at slaughter or on-farm deaths. This methodology has broad applicability and could also be extended to other diseases in both deer and other species with relevance to trade in animals and animal products.

Antimicrobial drug use and resistance in Europe.

Our study confronts the use of antimicrobial agents in ambulatory care with the resistance trends of 2 major pathogens, Streptococcus pneumoniae and Escherichia coli, in 21 European countries in 2000-2005 and explores whether the notion that antimicrobial drug use determines resistance can be supported by surveillance data at national aggregation levels. The data obtained from the European Surveillance of Antimicrobial Consumption and the European Antimicrobial Resistance Surveillance System suggest that variation of consumption coincides with the occurrence of resistance at the country level. Linear regression analysis showed that the association between antimicrobial drug use and resistance was specific and robust for 2 of 3 compound pathogen combinations, stable over time, but not sensitive enough to explain all of the observed variations. Ecologic studies based on routine surveillance data indicate a relation between use and resistance and support interventions designed to reduce antimicrobial drug consumption at a national level in Europe.

Evaluation of the micro-CATT, CATT/Trypanosoma brucei gambiense, and LATEX/T b gambiense methods for serodiagnosis and surveillance of human African trypanosomiasis in West and Central Africa.

OBJECTIVE: To evaluate the performance of serological tests using dried blood on filter-papers (micro-card agglutination test for trypanosomiasis (micro-CATT)) performed under field and laboratory conditions and using whole blood ((CATT/T.b. gambiense) (wb-CATT) and latex agglutination (LATEX/T.b. gambiense) (wb-LATEX)) for the serodiagnosis and surveillance of human African trypanosomiasis in West and Central Africa. METHODS: We evaluated the micro-CATT, wb-CATT and wb-LATEX methods in Côte d'Ivoire and the Central African Republic by screening 940 people. Sensitivity and specificity were calculated for each serological test; only patients with the confirmed presence of trypanosomes in the blood or lymph aspirate were considered true positives. Positive and negative predictive values were also calculated. FINDINGS: Each of the tests showed a lower sensitivity in the Central African Republic than in Côte d'Ivoire. CONCLUSION: The results confirmed the efficiency of the classic wb-CATT to detect sleeping sickness patients. The micro-CATT method can be used for human African trypanosomiasis surveillance if the test is performed on the same day as the blood collection, or if samples are stored at 4 degrees C. Otherwise, micro-CATT can be used when absolute sensitivity is not required. wb-LATEX should only be used for high-specificity screening.

Evaluation of an EDTA version of CATT/Trypanosoma brucei gambiense for serological screening of human blood samples.

CATT/Trypanosoma brucei gambiense, a direct card agglutination test designed for field surveys on human African trypanosomosis, is currently used with freshly collected heparinized blood samples. When testing serum samples, it has been observed earlier that, at lower sample dilutions, a complement-mediated inhibition phenomenon may cause false negative test results. This can be avoided by adding an anticomplementary agent such as di-sodium ethylenediaminetetraacetate dihydrate (EDTA) to the reaction. As the sensitivity of the blood assay might be improved in the same way, this possibility has been examined under both laboratory and field conditions, by adding EDTA to the test buffer or, as an anticoagulant, to the blood samples. The CATT-EDTA versions proved up to 7% more sensitive but also 1-2% less specific than the current test. CATT buffer supplemented with EDTA remained stable for at least 2 years at +45 degrees C.