Intuitive toxicology in the 21st century-Bridging the perspectives of the public and risk assessors in Europe.

Three decades ago, several articles on the subjectivity in chemical risk judgments (i.e., labeled "intuitive toxicology") measured the divide between the public and toxicologists with different backgrounds regarding the validity of predicting health effects based on in vivo studies. Similar divides with impacts on societal discourse and chemical risk assessment practices might exist concerning alternative toxicity testing methods (i.e., in vitro and in silico). However, studies to date have focused either on the public's views of in vivo or stem cell testing or on experts' views of in vivo testing and potential alternatives (i.e., toxicologists and medical students), which do not allow for a direct investigation of potential divides. To fill this knowledge gap, we conducted two online surveys, involving members of the German-speaking public in Switzerland and European human health risk assessors, respectively. This article presents the results of these two surveys regarding the divide in the public's and risk assessors' perspectives on risk assessment based on in vivo, in vitro, and in silico testing. Particularly, the survey with the risk assessors highlights that, beyond scientific and regulatory barriers, alternatives to in vivo testing may encounter individual hurdles, such as higher uncertainty associated with them. Understanding and addressing these hurdles will be crucial to facilitate the integration of new approach methodologies into chemical risk assessment practices as well as a successful transition toward next-generation risk assessment, bringing us closer to a fit-for-purpose and more efficient regulatory landscape.

Quantitative risk assessment of skin sensitising pesticides: Clinical and toxicological considerations.

Like many other consumer and occupational products, pesticide formulations may contain active ingredients or co-formulants which have the potential to cause skin sensitisation. Currently, there is little evidence they do, but that could just reflect lack of clinical investigation. Consequently, it is necessary to carry out a safety evaluation process, quantifying risks so that they can be properly managed. A workshop on this topic in 2022 discussed how best to undertake quantitative risk assessment (QRA) for pesticide products, including learning from the experience of industries, notably cosmetics, that already undertake such a process routinely. It also addressed ways to remedy the matter of clinical investigation, even if only to demonstrate the absence of a problem. Workshop participants concluded that QRA for skin sensitisers in pesticide formulations was possible, but required careful justification of any safety factors applied, as well as improvements to the estimation of skin exposure. The need for regulations to stay abreast of the science was also noted. Ultimately, the success of any risk assessment/management for skin sensitisers must be judged by the clinical picture. Accordingly, the workshop participants encouraged the development of more active skin health monitoring amongst groups most exposed to the products.

Use of the benchmark-dose (BMD) approach to derive occupational exposure limits (OELs) for genotoxic carcinogens: N-nitrosamines.

N-Nitrosamines are potent carcinogens and considered non-threshold carcinogens in various regulatory domains. However, recent data indicate the existence of a threshold for genotoxicity, which can be adequately demonstrated. This aspect has a critical impact on selecting the methodology that is applied to derive occupational exposure limits (OELs). OELs are used to protect workers potentially exposed to various chemicals by supporting the selection of appropriate control measures and ultimately reducing the risk of occupational cancer. Occupational exposures to nitrosamines occur during manufacturing processes, mainly in the rubber and chemical industry. The present study derives OELs for inhaled N-nitrosamines, employing the benchmark dose (BMD) approach if data are adequate and read-across for nitrosamines without adequate data. Additionally, benchmark dose lower confidence limit (BMDL) is preferred and more suitable point-of-departure (PoD) to calculate human health guidance values, including OEL. The lowest OEL (0.2 µg/m3 ) was derived for nitrosodiethylamine (NDEA), and nitrosopiperidine (NPIP) (OEL = 0.2 µg/m3 ), followed by nitrosopyrrolidine (NPYR) (0.4 µg/m3 ), nitrosodimethylamine (NDMA), nitrosodimethylamine (NMEA), and nitrosodipropylamine (NDPA) (0.5 µg/m3 ), nitrosomorpholine (NMOR) (OEL = 1 µg/m3 ), and nitrosodibutylamine (NDBA) (OEL = 2.5 µg/m3 ). Limits based on "non-threshold" TD50 slope calculation were within a 10-fold range. These proposed OELs do not consider skin absorption of nitrosamines, which is also a possible route of entry into the body, nor oral or other environmental sources. Furthermore, we recommend setting a limit for total nitrosamines based on the occupational exposure scenario and potency of components.

Exploring the Potential of ToxCast Data in Supporting Read-Across for Evaluation of Food Chemical Safety.

The intention of this study was to determine the utility of high-throughput screening (HTS) data, as exemplified by ToxCast and Tox21, for application in toxicological read-across in food-relevant chemicals. Key questions were addressed on the extent to which the HTS data could provide information enabling (1) the elucidation of underlying bioactivities associated with apical toxicological outcomes, (2) the closing of existing toxicological data gaps, and (3) the definition of the boundaries of chemical space across which bioactivity could reliably be extrapolated. Results revealed that many biological targets apparently activated within the chemical groupings lack, at this time, validated toxicity pathway associations. Therefore, as means of providing proof-of-principle, a comparatively well-characterized end point-estrogenicity-was selected for evaluation. This was facilitated through the preparation of two exploratory case studies, focusing upon groupings of paraben-gallates and pyranone-type compounds (notably flavonoids). Within both, the HTS data were seen to reflect estrogenic potencies in a manner which broadly corresponded to established structure-activity group relationships, with parabens and flavonoids displaying greater estrogen receptor affinity than benzoate esters and alternative pyranone-containing molecules, respectively. As such, utility in the identification of out-of-domain compounds was demonstrated, indicating potential for application in addressing point (3) as detailed above.

Approaches in metabolomics for regulatory toxicology applications.

Innovative methodological approaches are needed to conduct human health and environmental risk assessments on a growing number of marketed chemicals. Metabolomics is progressively proving its value as an efficient strategy to perform toxicological evaluations of new and existing substances, and it will likely become a key tool to accelerate chemical risk assessments. However, additional guidance with widely accepted and harmonized procedures is needed before metabolomics can be routinely incorporated in decision-making for regulatory purposes. The aim of this review is to provide an overview of metabolomic strategies that have been successfully employed in toxicity assessment as well as the most promising workflows in a regulatory context. First, we provide a general view of the different steps of regulatory toxicology-oriented metabolomics. Emphasis is put on three key elements: robustness of experimental design, choice of analytical platform, and use of adapted data treatment tools. Then, examples in which metabolomics supported regulatory toxicology outputs in different scenarios are reviewed, including chemical grouping, elucidation of mechanisms of toxicity, and determination of points of departure. The overall intention is to provide insights into why and how to plan and conduct metabolomic studies for regulatory toxicology purposes.

Bringing Chemistry to Medicine - The Contribution of Paracelsus to Modern Toxicology.

At the heart of Paracelsus' medical theory is the belief that all matter can be reduced to three basic elements: sulphur, mercury and salt. Their unique properties can be harnessed in the preparation of specific medicines. In this way, poisons can become medicines since it is the dose that determines toxicity.

Critical assessment and integration of separate lines of evidence for risk assessment of chemical mixtures.

Humans are exposed to multiple chemicals on a daily basis instead of to just a single chemical, yet the majority of existing toxicity data comes from single-chemical exposure. Multiple factors must be considered such as the route, concentration, duration, and the timing of exposure when determining toxicity to the organism. The need for adequate model systems (in vivo, in vitro, in silico and mathematical) is paramount for better understanding of chemical mixture toxicity. Currently, shortcomings plague each model system as investigators struggle to find the appropriate balance of rigor, reproducibility and appropriateness in mixture toxicity studies. Significant questions exist when comparing single-to mixture-chemical toxicity concerning additivity, synergism, potentiation, or antagonism. Dose/concentration relevance is a major consideration and should be subthreshold for better accuracy in toxicity assessment. Previous work was limited by the technology and methodology of the time, but recent advances have resulted in significant progress in the study of mixture toxicology. Novel technologies have added insight to data obtained from in vivo studies for predictive toxicity testing. These include new in vitro models: omics-related tools, organs-on-a-chip and 3D cell culture, and in silico methods. Taken together, all these modern methodologies improve the understanding of the multiple toxicity pathways associated with adverse outcomes (e.g., adverse outcome pathways), thus allowing investigators to better predict risks linked to exposure to chemical mixtures. As technology and knowledge advance, our ability to harness and integrate separate streams of evidence regarding outcomes associated with chemical mixture exposure improves. As many national and international organizations are currently stressing, studies on chemical mixture toxicity are of primary importance.

Consensus statement on the need for innovation, transition and implementation of developmental neurotoxicity (DNT) testing for regulatory purposes.

This consensus statement voices the agreement of scientific stakeholders from regulatory agencies, academia and industry that a new framework needs adopting for assessment of chemicals with the potential to disrupt brain development. An increased prevalence of neurodevelopmental disorders in children has been observed that cannot solely be explained by genetics and recently pre- and postnatal exposure to environmental chemicals has been suspected as a causal factor. There is only very limited information on neurodevelopmental toxicity, leaving thousands of chemicals, that are present in the environment, with high uncertainty concerning their developmental neurotoxicity (DNT) potential. Closing this data gap with the current test guideline approach is not feasible, because the in vivo bioassays are far too resource-intensive concerning time, money and number of animals. A variety of in vitro methods are now available, that have the potential to close this data gap by permitting mode-of-action-based DNT testing employing human stem cells-derived neuronal/glial models. In vitro DNT data together with in silico approaches will in the future allow development of predictive models for DNT effects. The ultimate application goals of these new approach methods for DNT testing are their usage for different regulatory purposes.

A quantitative risk assessment for skin sensitizing plant protection products: Linking derived No-Effect levels (DNELs) with agricultural exposure models.

Chemical skin sensitizers produce allergic contact dermatitis, which is one of the most frequent occupational diseases associated with chemical exposures. Skin exposure is the major route of exposure when using plant protection products (PPPs). Therefore, skin sensitization is an important factor to be addressed during the regulatory risk assessment of PPPs. The main regulatory decision criterion considered when performing risk assessment for skin sensitizers is the dose applied. The equally important criteria "potency of the substance" is insufficiently considered by two potency categories as potency may vary up to five orders of magnitude. "Frequency of exposure" to the skin sensitizer is not considered at all. Consequently, an improved risk assessment methodology is essential to adequately assess health risks from skin sensitizers, especially for agricultural operators using PPPs. A quantitative risk assessment (QRA) approach for addressing PPPs sensitizing potential is proposed here. This QRA combines a methodology to derive a substance-specific threshold for skin sensitizers, a Derived No-Effect Level (DNEL), and an agricultural exposure model used for assessing chronic health risks of PPPs. The proposed QRA for skin sensitizing PPPs is a clear improvement over current risk assessment to ensure the safe use of skin sensitizers in an occupational context.

Systems Toxicology: Real World Applications and Opportunities.

Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized from empirical end points to describing modes of action as adverse outcome pathways and perturbed networks. Toward this aim, Systems Toxicology entails the integration of in vitro and in vivo toxicity data with computational modeling. This evolving approach depends critically on data reliability and relevance, which in turn depends on the quality of experimental models and bioanalysis techniques used to generate toxicological data. Systems Toxicology involves the use of large-scale data streams ("big data"), such as those derived from omics measurements that require computational means for obtaining informative results. Thus, integrative analysis of multiple molecular measurements, particularly acquired by omics strategies, is a key approach in Systems Toxicology. In recent years, there have been significant advances centered on in vitro test systems and bioanalytical strategies, yet a frontier challenge concerns linking observed network perturbations to phenotypes, which will require understanding pathways and networks that give rise to adverse responses. This summary perspective from a 2016 Systems Toxicology meeting, an international conference held in the Alps of Switzerland, describes the limitations and opportunities of selected emerging applications in this rapidly advancing field. Systems Toxicology aims to change the basis of how adverse biological effects of xenobiotics are characterized, from empirical end points to pathways of toxicity. This requires the integration of in vitro and in vivo data with computational modeling. Test systems and bioanalytical technologies have made significant advances, but ensuring data reliability and relevance is an ongoing concern. The major challenge facing the new pathway approach is determining how to link observed network perturbations to phenotypic toxicity.

A framework for cumulative risk assessment in the 21st century.

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.

Problem formulation for risk assessment of combined exposures to chemicals and other stressors in humans.

When the human health risk assessment/risk management paradigm was developed, it did not explicitly include a "problem formulation" phase. The concept of problem formulation was first introduced in the context of ecological risk assessment (ERA) for the pragmatic reason to constrain and focus ERAs on the key questions. However, this need also exists for human health risk assessment, particularly for cumulative risk assessment (CRA), because of its complexity. CRA encompasses the combined threats to health from exposure via all relevant routes to multiple stressors, including biological, chemical, physical and psychosocial stressors. As part of the HESI Risk Assessment in the 21st Century (RISK21) Project, a framework for CRA was developed in which problem formulation plays a critical role. The focus of this effort is primarily on a chemical CRA (i.e., two or more chemicals) with subsequent consideration of non-chemical stressors, defined as "modulating factors" (ModFs). Problem formulation is a systematic approach that identifies all factors critical to a specific risk assessment and considers the purpose of the assessment, scope and depth of the necessary analysis, analytical approach, available resources and outcomes, and overall risk management goal. There are numerous considerations that are specific to multiple stressors, and proper problem formulation can help to focus a CRA to the key factors in order to optimize resources. As part of the problem formulation, conceptual models for exposures and responses can be developed that address these factors, such as temporal relationships between stressors and consideration of the appropriate ModFs.

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.

Systems toxicology: from basic research to risk assessment.

Systems Toxicology is the integration of classical toxicology with quantitative analysis of large networks of molecular and functional changes occurring across multiple levels of biological organization. Society demands increasingly close scrutiny of the potential health risks associated with exposure to chemicals present in our everyday life, leading to an increasing need for more predictive and accurate risk-assessment approaches. Developing such approaches requires a detailed mechanistic understanding of the ways in which xenobiotic substances perturb biological systems and lead to adverse outcomes. Thus, Systems Toxicology approaches offer modern strategies for gaining such mechanistic knowledge by combining advanced analytical and computational tools. Furthermore, Systems Toxicology is a means for the identification and application of biomarkers for improved safety assessments. In Systems Toxicology, quantitative systems-wide molecular changes in the context of an exposure are measured, and a causal chain of molecular events linking exposures with adverse outcomes (i.e., functional and apical end points) is deciphered. Mathematical models are then built to describe these processes in a quantitative manner. The integrated data analysis leads to the identification of how biological networks are perturbed by the exposure and enables the development of predictive mathematical models of toxicological processes. This perspective integrates current knowledge regarding bioanalytical approaches, computational analysis, and the potential for improved risk assessment.

The Clinical Toxicology Recommendations Collaborative: purpose, organization, and methodology.

INTRODUCTION: Scientific societies aim to provide a collective voice and unified stance on important issues. The Clinical Toxicology Recommendations Collaborative was formed in 2016 to develop evidence- and consensus-based recommendations for the management of patients exposed to common and/or serious poisonings for which the management is unclear or controversial. ORGANIZATION: The Clinical Toxicology Recommendations Collaborative is led jointly by the American Academy of Clinical Toxicology, the Asia Pacific Association of Medical Toxicology, and the European Association of Poison Centres and Clinical Toxicologists. The Governance Committee is chaired by a Past-President of one of these Societies and comprised of the six Presidents and Immediate Past-Presidents of the three Societies. A Steering Committee oversees the process of each project workgroup. METHODOLOGY: The overall process is guided by standards set forth by the Institute of Medicine for developing trustworthy guidelines and the Appraisal of Guidelines for Research and Evaluation Instrument. Systematic reviews are produced using the framework set in the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) methodology. Workgroup members jointly review the evidence and prepare statements on which they vote anonymously using a 9-point Likert scale. A two-round modified Delphi method is used to reach a consensus on clinical recommendations using the RAND/UCLA Appropriateness Method. Final recommendations are approved by unanimous consent of the workgroup and are expressed as both levels of evidence and strength of recommendations. LIMITATIONS: The major limitations of the Clinical Toxicology Recommendations Collaborative process centre around the amount and quality of evidence, the assessment of that evidence, and the voting of the panel. CONCLUSIONS: By using a transparent evidence- and consensus-based approach to produce systematic reviews and clinical recommendations, the Clinical Toxicology Recommendations Collaborative aims to create an international framework for clinical toxicology education and decision-making and foster positive change for the benefit of poisoned patients.

Dose ingested, vomiting, and outcome in patients ingesting a standard paraquat 20SL formulation.

BACKGROUND: FAO specifications for liquid paraquat dichloride SL formulations require the use of an emetic agent to stimulate vomiting within 30 min of ingestion. To date, there is no high-quality evidence of efficacy, despite use of the PP796 emetic since 1979. We first examined the validity of patients' self-reported dose of paraquat ingested by examining the relationship with blood paraquat concentration and time to death for patients ingesting the standard paraquat SL formulation in a Sri Lankan cohort. As a secondary outcome, we assessed whether ingestion resulted in vomiting within 30 min and whether vomiting was associated with good outcome. METHODS: Patients presenting with paraquat SL self-poisoning were prospectively studied in ten Sri Lankan hospitals in 2003-08. Data on reported dose ingested, incidence and timing of vomiting after ingestion, treatment received, plasma paraquat concentration, and outcome were collected prospectively on presentation to hospital. Time between ingestion and blood sampling was incorporated by covariate adjustment. RESULTS: 441 patients were recruited to the case series, presenting a median (IQR) of 3.0 (1.5-8.1] h post ingestion. Outcome was known for 435 patients of whom 322 (74.0%) died within 42 days, a median of 1.3 (0.6-4.4) days post ingestion. Median reported dose ingested was 15 to <30 mL. There was a highly significant linear trend between log plasma paraquat and reported dose ingested (p < .001); adjustment for the log of the time from ingestion to sampling further improved the model fit. Case fatality and median time to death also showed good agreement with estimated ingestion amount. 347/438 patients (79.2%) were stated to have vomited before reaching the study hospital with 300 (68.5%) vomiting within 30 min of ingestion; time to vomiting was unknown for a further 12 (2.7%). The proportion vomiting was strongly associated with reported dose ingested (p < .001); of note the proportion vomiting within 30 min only increased to 83.3% for the highest ingestion group. Patients vomiting within 30 min had higher plasma paraquat concentrations (p = .008), and higher hazard ratio in the adjusted Cox regression model of 2.01 (95% CI 1.45-2.77) compared to those who did not. Vomiting within 30 min was associated with a higher case fatality (241/295 [81.7%] vs 68/125 [54.4%], p < .001). Forty-three (47.3%) of the 91 patients who did not vomit before reaching hospital died (one had unknown outcome). CONCLUSION: Importantly, we found good agreement between reported dose ingested and plasma paraquat concentration, case fatality, and time to death, suggesting that the reported dose is a valid marker for the dose ingested. Vomiting occurred within 30 min for 68.5% of patients, exceeding the characteristics for a purported effective emetic in the FAO specifications. However, vomiting within 30 min was associated with approximately double the risk of death compared to those who did not vomit, larger paraquat ingestions, and higher blood paraquat concentrations. In addition, death occurred in many patients who did not vomit, and the proportion vomiting within 30 min only reached 82.1% for the highest ingested dose group. Overall, we found no evidence of benefit resulting from incorporation of the emetic, suggesting that the current FAO specification is not effective at preventing deaths after ingestion of the paraquat SL formulation.

Evaluating the food safety and risk assessment evidence-base of polyethylene terephthalate oligomers: A systematic evidence map.

BACKGROUND: The presence of polyethylene terephthalate (PET) oligomers in food contact materials (FCMs) is well-documented. Consumers are exposed through their migration into foods and beverages; however, there is no specific guidance for their safety evaluation. OBJECTIVES: This systematic evidence map (SEM) aims to identify and organize existing knowledge and associated gaps in hazard and exposure information on 34 PET oligomers to support regulatory decision-making. METHODS: The methodology for this SEM was recently registered. A systematic search in bibliographic and gray literature sources was conducted and studies evaluated for inclusion according to the Populations, Exposures, Comparators, Outcomes, and Study type (PECOS) framework. Inclusion criteria were designed to record hazard and exposure information for all 34 PET oligomers and coded into the following evidence streams: human, animal, organism (non-animal), ex vivo, in vitro, in silico, migration, hydrolysis, and absorption, distribution, metabolism, excretion/toxicokinetics/pharmacokinetics (ADME/TK/PK) studies. Relevant information was extracted from eligible studies and synthesized according to the protocol. RESULTS: Literature searches yielded 7445 unique records, of which 96 were included. Data comprised migration (560 entries), ADME/TK/PK-related (253 entries), health/bioactivity (98 entries) and very few hydrolysis studies (7 entries). Cyclic oligomers were studied more frequently than linear PET oligomers. In vitro results indicated that hydrolysis of cyclic oligomers generated a mixture of linear oligomers, but not monomers, potentially allowing their absorption in the gastrointestinal tract. Cyclic dimers, linear trimers and the respective smaller oligomers exhibit physico-chemical properties making oral absorption more likely. Information on health/bioactivity effects of oligomers was almost non-existent, except for limited data on mutagenicity. CONCLUSIONS: This SEM revealed substantial deficiencies in the available evidence on ADME/TK/PK, hydrolysis, and health/bioactivity effects of PET oligomers, currently preventing appropriate risk assessment. It is essential to develop more systematic and tiered approaches to address the identified research needs and assess the risks of PET oligomers.

Evaluating the food safety and risk assessment evidence-base of polyethylene terephthalate oligomers: Protocol for a systematic evidence map.

BACKGROUND: Polyethylene terephthalate (PET) oligomers are ubiquitous in PET used in food contact applications. Consumer exposure by migration of PET oligomers into food and beverages is documented. However, no specific risk assessment framework or guidance for the safety evaluating of PET oligomers exist to date. AIM: The aim of this systematic evidence map (SEM) is to identify and organize existing knowledge clusters and associated gaps in hazard and exposure information of PET oligomers. Research needs will be identified as an input for chemical risk assessment, and to support future toxicity testing strategies of PET oligomers and regulatory decision-making. SEARCH STRATEGY AND ELIGIBILITY CRITERIA: Multiple bibliographic databases (incl. Embase, Medline, Scopus, and Web of Science Core Collection), chemistry databases (SciFinder-n, Reaxys), and gray literature sources will be searched, and the search results will be supplemented by backward and forward citation tracking on eligible records. The search will be based on a single-concept PET oligomer-focused strategy to ensure sensitive and unbiased coverage of all evidence related to hazard and exposure in a data-poor environment. A scoping exercise conducted during planning identified 34 relevant PET oligomers. Eligible work of any study type must include primary research data on at least one relevant PET oligomer with regard to exposure, health, or toxicological outcomes. STUDY SELECTION: For indexed scientific literature, title and abstract screening will be performed by one reviewer. Selected studies will be screened in full-text by two independent reviewers. Gray literature will be screened by two independent reviewers for inclusion and exclusion. STUDY QUALITY ASSESSMENT: Risk of bias analysis will not be conducted as part of this SEM. DATA EXTRACTION AND CODING: Will be performed by one reviewer and peer-checked by a second reviewer for indexed scientific literature or by two independent reviewers for gray literature. SYNTHESIS AND VISUALIZATION: The extracted and coded information will be synthesized in different formats, including narrative synthesis, tables, and heat maps. SYSTEMATIC MAP PROTOCOL REGISTRY AND REGISTRATION NUMBER: Zenodo: https://doi.org/10.5281/zenodo.6224302.

The ethics of human volunteer studies involving experimental exposure to pesticides: unanswered dilemmas.

The controversy about the use of data from human volunteer studies involving experimental exposure to pesticides as part of regulatory risk assessment has been widely discussed, but the complex and interrelated scientific and ethical issues remain largely unresolved. This discussion paper, generated by authors who comprised a workgroup of the ICOH Scientific Committee on Rural Health, reviews the use of human experimental studies in regulatory risk assessment for pesticides with a view to advancing the debate as to when, if ever, such studies might be ethically justifiable. The discussion is based on three elements: (a) a review of discussion papers on the topic of human testing of pesticides and the positions adopted by regulatory agencies in developed countries; (b) an analysis of published and unpublished studies involving human testing with pesticides, both in the peer-reviewed literature and in the JMPR database; and (c) application of an ethical analysis to the problem. The paper identifies areas of agreement which include general principles that may provide a starting point on which to base criteria for judgements as to the ethical acceptability of such studies. However, the paper also highlights ongoing unresolved differences of opinion inherent in ethical analysis of contentious issues, which we propose should form a starting point for further debate and the development of guidelines to achieve better resolution of this matter.