Read-across approaches: current applications and regulatory acceptance in Korea, Japan, and China.

The aim of this paper was to investigate the current status of read-across approaches in the Republic of Korea, Japan, and China in terms of applications and regulatory acceptance. In the Republic of Korea, over the last 6 years, approximately 8% of safety data records used for chemical registrations were based upon read-across, and a guideline published on the use of read-across results in 2017. In Japan, read-across is generally accepted for screening hazard classification of toxicological endpoints according to the Chemical Substances Control Law (CSCL). In China, read-across data, along with data from other animal alternatives are accepted as a data source for chemical registrations, but could be only considered when testing is not technically feasible. At present, read-across is not widely used for chemical registrations and regulatory acceptance of read-across may differ among countries in Asia. With consideration of the advantages and limitations of read-across, it is expected that read-across may soon gradually be employed in Asian countries. Thus, regulatory agencies need to prepare for this progression.

Integrating toxicokinetics into toxicology studies and the human health risk assessment process for chemicals: Reduced uncertainty, better health protection.

The database of practical examples where toxicokinetic (TK) data has benefitted all stages of the human health risk assessment process are increasingly being published and accepted. This review aimed to highlight and summarise notable examples and to describe the "state of the art" in this field. The overall recommendation is that for any in vivo animal study conducted, measurements of TK should be very carefully considered for inclusion as the numerous benefits this brings continues to grow, particularly during the current march towards animal free toxicology testing and ambitions to eventually conduct human health risk assessments entirely based upon non-animal methods.

Principles of dose-setting in toxicology studies: the importance of kinetics for ensuring human safety.

Regulatory toxicology seeks to ensure that exposures to chemicals encountered in the environment, in the workplace, or in products pose no significant hazards and produce no harm to humans or other organisms, i.e., that chemicals are used safely. The most practical and direct means of ensuring that hazards and harms are avoided is to identify the doses and conditions under which chemical toxicity does not occur so that chemical concentrations and exposures can be appropriately limited. Modern advancements in pharmacology and toxicology have revealed that the rates and mechanisms by which organisms absorb, distribute, metabolize and eliminate chemicals-i.e., the field of kinetics-often determine the doses and conditions under which hazard, and harm, are absent, i.e., the safe dose range. Since kinetics, like chemical hazard and toxicity, are extensive properties that depend on the amount of the chemical encountered, it is possible to identify the maximum dose under which organisms can efficiently metabolize and eliminate the chemicals to which they are exposed, a dose that has been referred to as the kinetic maximum dose, or KMD. This review explains the rationale that compels regulatory toxicology to embrace the advancements made possible by kinetics, why understanding the kinetic relationship between the blood level produced and the administered dose of a chemical is essential for identifying the safe dose range, and why dose-setting in regulatory toxicology studies should be informed by estimates of the KMD rather than rely on the flawed concept of maximum-tolerated toxic dose, or MTD.

The EU-ToxRisk method documentation, data processing and chemical testing pipeline for the regulatory use of new approach methods.

Hazard assessment, based on new approach methods (NAM), requires the use of batteries of assays, where individual tests may be contributed by different laboratories. A unified strategy for such collaborative testing is presented. It details all procedures required to allow test information to be usable for integrated hazard assessment, strategic project decisions and/or for regulatory purposes. The EU-ToxRisk project developed a strategy to provide regulatorily valid data, and exemplified this using a panel of > 20 assays (with > 50 individual endpoints), each exposed to 19 well-known test compounds (e.g. rotenone, colchicine, mercury, paracetamol, rifampicine, paraquat, taxol). Examples of strategy implementation are provided for all aspects required to ensure data validity: (i) documentation of test methods in a publicly accessible database; (ii) deposition of standard operating procedures (SOP) at the European Union DB-ALM repository; (iii) test readiness scoring accoding to defined criteria; (iv) disclosure of the pipeline for data processing; (v) link of uncertainty measures and metadata to the data; (vi) definition of test chemicals, their handling and their behavior in test media; (vii) specification of the test purpose and overall evaluation plans. Moreover, data generation was exemplified by providing results from 25 reporter assays. A complete evaluation of the entire test battery will be described elsewhere. A major learning from the retrospective analysis of this large testing project was the need for thorough definitions of the above strategy aspects, ideally in form of a study pre-registration, to allow adequate interpretation of the data and to ensure overall scientific/toxicological validity.

Internationalization of read-across as a validated new approach method (NAM) for regulatory toxicology.

Read-across (RAx) translates available information from well-characterized chemicals to a substance for which there is a toxicological data gap. The OECD is working on case studies to probe general applicability of RAx, and several regulations (e.g., EU-REACH) already allow this procedure to be used to waive new in vivo tests. The decision to prepare a review on the state of the art of RAx as a tool for risk assessment for regulatory purposes was taken during a workshop with international experts in Ranco, Italy in July 2018. Three major issues were identified that need optimization to allow a higher regulatory acceptance rate of the RAx procedure: (i) the definition of similarity of source and target, (ii) the translation of biological/toxicological activity of source to target in the RAx procedure, and (iii) how to deal with issues of ADME that may differ between source and target. The use of new approach methodologies (NAM) was discussed as one of the most important innovations to improve the acceptability of RAx. At present, NAM data may be used to confirm chemical and toxicological similarity. In the future, the use of NAM may be broadened to fully characterize the hazard and toxicokinetic properties of RAx compounds. Concerning available guidance, documents on Good Read-Across Practice (GRAP) and on best practices to perform and evaluate the RAx process were identified. Here, in particular, the RAx guidance, being worked out by the European Commission's H2020 project EU-ToxRisk together with many external partners with regulatory experience, is given.

Evaluating potential refinements to existing Threshold of Toxicological Concern (TTC) values for environmentally-relevant compounds.

The Toxic Substances Control Act (TSCA) mandates the US EPA perform risk-based prioritisation of chemicals in commerce and then, for high-priority substances, develop risk evaluations that integrate toxicity data with exposure information. One approach being considered for data poor chemicals is the Threshold of Toxicological Concern (TTC). Here, TTC values derived using oral (sub)chronic No Observable (Adverse) Effect Level (NO(A)EL) data from the EPA's Toxicity Values database (ToxValDB) were compared with published TTC values from Munro et al. (1996). A total of 4554 chemicals with structures present in ToxValDB were assigned into their respective TTC categories using the Toxtree software tool, of which toxicity data was available for 1304 substances. The TTC values derived from ToxValDB were similar, but not identical to the Munro TTC values: Cramer I ((ToxValDB) 37.3 c. f. (Munro) 30 µg/kg-day), Cramer II (34.6 c. f. 9.1 µg/kg-day) and Cramer III (3.9 c. f. 1.5 µg/kg-day). Cramer III 5th percentile values were found to be statistically different. Chemical features of the two Cramer III datasets were evaluated to account for the differences. TTC values derived from this expanded dataset substantiated the original TTC values, reaffirming the utility of TTC as a promising tool in a risk-based prioritisation approach.

Use cases, best practice and reporting standards for metabolomics in regulatory toxicology.

Metabolomics is a widely used technology in academic research, yet its application to regulatory science has been limited. The most commonly cited barrier to its translation is lack of performance and reporting standards. The MEtabolomics standaRds Initiative in Toxicology (MERIT) project brings together international experts from multiple sectors to address this need. Here, we identify the most relevant applications for metabolomics in regulatory toxicology and develop best practice guidelines, performance and reporting standards for acquiring and analysing untargeted metabolomics and targeted metabolite data. We recommend that these guidelines are evaluated and implemented for several regulatory use cases.

Workshop on the validation and regulatory acceptance of innovative 3R approaches in regulatory toxicology - Evolution versus revolution.

At a joint workshop organized by RIVM and BfR, international experts from governmental institutes, regulatory agencies, industry, academia and animal welfare organizations discussed and provided recommendations for the development, validation and implementation of innovative 3R approaches in regulatory toxicology. In particular, an evolutionary improvement of our current approach of test method validation in the context of defined approaches or integrated testing strategies was discussed together with a revolutionary approach based on a comprehensive description of the physiological responses of the human body to chemical exposure and the subsequent definition of relevant and predictive in vitro, in chemico or in silico methods. A more comprehensive evaluation of biological relevance, scientific validity and regulatory purpose of new test methods and assessment strategies together with case studies that provide practical experience with new approaches were discussed as essential steps to build up the necessary confidence to facilitate regulatory acceptance.

Scientific and Regulatory Policy Committee Points to Consider*: Review of Scientific and Regulatory Policy Committee Points to Consider: Review of Current Practices for Ultrastructural Pathology Evaluations in Support of Nonclinical Toxicology Studies.

Anatomic pathology and clinical pathology end points are standard components of almost every nonclinical general toxicity study conducted during the risk assessment of novel pharmaceuticals and chemicals. On occasion, an ultrastructural pathology evaluation using transmission electron microscopy (TEM) may be included in nonclinical toxicity studies. Transmission electron microscopy is most commonly used when a light microscopic finding may require further characterization that could inform on the pathogenesis and/or mechanism of action. Regulatory guidance do not address the use of TEM in general study designs nor whether these assessments should be performed in laboratories conducted in compliance with Good Laboratory Practices. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current practices on the use of TEM in nonclinical toxicity studies. The Working Group constructed a survey sent to members of societies of toxicologic pathology in the United States, Europe, Britain, and Japan, and responses were collected through the STP for evaluation by the Working Group. The survey results and regulatory context are discussed, as are "points to consider" from the collective experience of the Working Group. This survey indicates that TEM remains an essential diagnostic option for complementing toxicologic pathology evaluations. *This Points to Consider article is a product of a Society of Toxicologic Pathology (STP) Working Group commissioned by the Scientific and Regulatory Policy Committee (SRPC) of the STP. It has been reviewed and approved by the SRPC and Executive Committee of the STP but it does not represent a formal Best Practice recommendation of the Society; rather, it is intended to provide key "points to consider" in designing nonclinical studies or interpreting data from toxicity and safety studies intended to support regulatory submissions. The points expressed in this document are those of the authors and do not reflect views or policies of the employing institutions. Readers of Toxicologic Pathology are encouraged to send their thoughts on these articles or ideas for new topics to the Editor.

Nordic symposium on "toxicology and pharmacology without animal experiments-Will it be possible in the next 10 years?"

Toxicological and pharmacological information from human cells and tissues provides knowledge readily applicable to human safety assessment and to the efficacy assessment of pharmaceuticals. The 3R principle in animal studies includes the use of human material in the R of Replacement. The Reduction and Refinement Rs are related to animal use. Knowledge of the 3Rs and successful 3R methods are a prerequisite for the Reduction of animal experiments in the future. More collaboration among researchers using experimental animals and those working in vitro is necessary with mutual respect. The OECD Guidelines for the Testing of Chemicals have included the animal-free part of the 3Rs in guidances for the development and reporting of Adverse Outcome Pathways (AOPs), which is to be part of the Integrated Approaches to Testing and Assessment (IATA). The 3R centres established to help fulfil the Directive 2010/63/EU play an important role to promote the 3Rs and in the development of animal-free toxicology. Research centres in each Nordic country are founded upon solid research activities in cell and organ toxicity, including major EU programmes to promote 3Rs and implementation of good practices and methods broadly in all stakeholders of industry, regulators and academia. In the light of this, the Nordic Symposium on Toxicology and Pharmacology without Animal Experiments addressed more adopted/modified test guidelines or new test guidelines for new end-points, or hazard challenges, new in vitro 3D models, speeding up transfer of knowledge from research to regulation to understand AOP and towards IATA.

Endocrine Disruption: Current approaches for regulatory testing and assessment of plant protection products are fit for purpose.

The ongoing debate concerning the regulation of endocrine disruptors, has increasingly led to questions concerning the current testing of chemicals and whether this is adequate for the assessment of potential endocrine disrupting effects. This paper describes the current testing approaches for plant protection product (PPP) active substances in the European Union and the United States and how they relate to the assessment of endocrine disrupting properties for human and environmental health. This includes a discussion of whether the current testing approaches cover modalities other than the estrogen, androgen, thyroid and steroidogenesis (EATS) pathways, sensitive windows of exposure, adequate assessment of human endocrine disorders and wildlife species, and the determination of thresholds for endocrine disruption. It is concluded, that the scope and nature of the core and triggered data requirements for PPP active substances are scientifically robust to address adverse effects mediated through endocrine mode(s) of action and to characterise these effects in terms of dose response.

Strategies to improve the regulatory assessment of developmental neurotoxicity (DNT) using in vitro methods.

Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential. We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential.

Expertos, juicios y crimen: Pere Mata (1811-1877) y el veneno de María Bonamot / Experts, trials and crimes: Pere Mata (1811-1877) and Maria Bonamot's poison

El siglo XIX fue un periodo en el que se produjo un creciente interés por los venenos y los crímenes por envenenamiento a pesar de no ser formas habituales de homicidio. La nueva toxicología pretendía ofrecer herramientas para combatir este tipo de crímenes. Sin embargo, fueron precisamente los debates surgidos durante los procesos judiciales, los que ayudaron a configurar la toxicología del siglo XIX. Alejados de las pautas ofrecidas en los manuales y ante la necesidad de mostrar a un juez carente de formación en estas materias, la presencia o ausencia del veneno, los toxicólogos del siglo XIX pusieron en juego todas sus estrategias para vencer a otros expertos y convencer a los profanos. A mediados de 1844 se produjo en Madrid un caso de envenenamiento que llamó la atención tanto de la prensa médica como de la prensa periódica española. Dos factores contribuyeron a su popularidad: las fechas en las que se produjo (tan solo un año después de la creación de la cátedra de Medicina Legal en las Facultades de Madrid y Barcelona); y la participación como peritos de algunos de los personajes españoles más influyentes en la medicina legal y toxicología española como es el caso de Pere Mata i Fontanet (1811-1877). Pere Mata desempeñó una labor importante en los tres terrenos que contribuyeron decisivamente a la homogeneidad de la comunidad de toxicólogos: la formación universitaria, la literatura académica y la organización profesional. El análisis de un caso de envenenamiento como el que se desarrolla en este trabajo, permite considerar muchas de las cuestiones relacionadas con la toxicología en el siglo XIX: la constitución de una nueva disciplina académica, la creación de una comunidad de expertos, las controversias públicas y la gestión de las pruebas periciales en los tribunales

The XIXth century saw a growing interest in poisons and crimes by poison although these are not usual ways of murder. New technology aspired to offer tools to combat this type of crimes. However, it was precisely the debates that arose during trials that helped to configure XIXth century toxicology. Far from the guidelines offered in manuals and facing the need to demonstrate to a judge, lacking In training in these subjects the presence or absence of the poison, XIXth century toxicologists used all of their strategies to beat other experts and convince the layperson. In the middle of 1844 there was a case of poisoning in Madrid that caught the attention of both the medical press and the Spanish newspapers. Two factors contributed to its popularity: the date that it happened 8only a year after the creation of the chair of Forensic Medicine at the faculties in Madrid and Barcelona); and the participation as experts of some of the most influential Spaniards in forensic medicine and Spanish toxicology such as Pere Mata I Fontanet (1811-1877). Pere Mata carried out important work in the three fields which decisively contributed to the homogeneity of the community of toxicologists: university training, academic literature and the professional organization. The analysis of a case of poisoning as the one developed in this work permits the consideration of many issues related totoxicology in the XIXth century: the constitution of a new academic subject, the creation of a community of experts, public controversies and the management of expert evidence at trials

Framework for the quantitative weight-of-evidence analysis of 'omics data for regulatory purposes.

A framework for the quantitative weight-of-evidence (QWoE) analysis of 'omics data for regulatory purposes is presented. The QWoE framework encompasses seven steps to evaluate 'omics data (also together with non-'omics data): (1) Hypothesis formulation, identification and weighting of lines of evidence (LoEs). LoEs conjoin different (types of) studies that are used to critically test the hypothesis. As an essential component of the QWoE framework, step 1 includes the development of templates for scoring sheets that predefine scoring criteria with scores of 0-4 to enable a quantitative determination of study quality and data relevance; (2) literature searches and categorisation of studies into the pre-defined LoEs; (3) and (4) quantitative assessment of study quality and data relevance using the respective pre-defined scoring sheets for each study; (5) evaluation of LoE-specific strength of evidence based upon the study quality and study relevance scores of the studies conjoined in the respective LoE; (6) integration of the strength of evidence from the individual LoEs to determine the overall strength of evidence; (7) characterisation of uncertainties and conclusion on the QWoE. To put the QWoE framework in practice, case studies are recommended to confirm the relevance of its different steps, or to adapt them as necessary.

The implementation of medical monitoring programs following potentially hazardous exposures: a medico-legal perspective.

CONTEXT: Clinical toxicologists may be called upon to determine the appropriateness of medical monitoring following documented or purported exposures to toxicants in the occupational, environmental, and medical settings. METHODS: We searched the MEDLINE database using the Ovid® search engine for the following terms cross-referenced to the MeSH database: ("occupational exposures" OR "environmental exposures") AND ("physiologic monitoring" OR "population surveillance"). The titles and abstracts of the resulted articles were reviewed for relevance. We expanded our search to include non-peer-reviewed publications and gray literature and resources using the same terms as utilized in the MEDLINE search. There were a total of 48 relevant peer-reviewed and non-peer-reviewed publications. Publications excluded contained no information relevant to medical monitoring following potentially harmful toxicologic exposures, discussed only worker screening/surveillance and/or population biomonitoring, contained redundant information, or were superseded by more recent information. Approaches to medical monitoring: A consensus exists in the peer-reviewed medical literature, legal literature, and government publications that for medical monitoring to be a beneficial public health activity, careful consideration must be given to potential benefits and harms of the program. Characteristics of the exposure, the adverse human health effect, the screening test, and the natural history of the disease are important in determining whether an exposed population will reap a net benefit or harm from a proposed monitoring program. Broader interpretations of medical monitoring: Some have argued that medical monitoring programs should not be limited to exposure-related outcomes but should duplicate general preventive medicine efforts to improve public health outcomes although an overall reduction of morbidity, mortality and disability by modifying correctable risk factors and disease conditions. This broader approach is inconsistent with the targeted approach advocated by the Agency for Toxic Substances and Disease Registry and the United States Preventive Services Task Force and the bulk of the peer-reviewed medical literature. Medical monitoring in legal contexts: Numerous medical monitoring actions have been litigated. Legal rationales for allowing medical monitoring claims often incorporate some of the scientific criteria for the appropriateness of monitoring programs. In the majority of cases in which plaintiffs were awarded medical monitoring relief, plaintiffs were required to demonstrate both that the condition for which medical monitoring was sought could be detected early, and that early detection and treatment will improve morbidity and mortality. However, the treatment of medical monitoring claims varies significantly depending upon jurisdiction. Examples of large-scale, comprehensive medical monitoring programs: Large-scale, comprehensive medical monitoring programs have been implemented, such as the Fernald Medical Monitoring Program and the World Trade Center Health Program, both of which exceeded the scope of medical monitoring typically recommended in the peer-reviewed medical literature and the courts. The Fernald program sought to prevent death and disability due to non-exposure-related conditions in a manner similar to general preventive medicine. The World Trade Center Health Program provides comprehensive medical care for World Trade Center responders and may be viewed as a large-scale, federally--funded research effort, which distinguishes it from medical monitoring in a medico-legal context. Synthesis of public health approaches to medical monitoring: Medical monitoring may be indicated following a hazardous exposure in limited circumstances. General causation for a specific adverse health effect must be either established by scientific consensus through a formal causal analysis using a framework such as the Bradford-Hill criteria. The exposure must be characterized and must be of sufficient severity that the exposed population has a significantly elevated risk of an adverse health effect. Monitoring must result in earlier detection of the condition than would otherwise occur and must confer a benefit in the form of primary, secondary or tertiary prevention. Outcome tables may be of use in describing the potential benefits and harms of a proposed monitoring program. CONCLUSIONS: In the context of litigation, plaintiffs may seek medical monitoring programs after documented or putative exposures. The role of the clinical toxicologist, in this setting, is to evaluate the scientific justifications and medical risks and assist the courts in determining whether monitoring would be expected to result in a net public health benefit.