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

Establishing Lagrangian connections between observations within air masses crossing the Atlantic during the International Consortium for Atmospheric Research on Transport and Transformation experiment

The ITCT-Lagrangian-2K4 (Intercontinental Transport and Chemical Transformation) experiment was conceived with an aim to quantify the effects of photochemistry and mixing on the transformation of air masses in the free troposphere away from emissions. To this end, attempts were made to intercept and sample air masses several times during their journey across the North Atlantic using four aircraft based in New Hampshire (USA), Faial (Azores) and Creil (France). This article begins by describing forecasts from two Lagrangian models that were used to direct the aircraft into target air masses. A novel technique then identifies Lagrangian matches between flight segments. Two independent searches are conducted: for Lagrangian model matches and for pairs of whole air samples with matching hydrocarbon fingerprints. The information is filtered further by searching for matching hydrocarbon samples that are linked by matching trajectories. The quality of these "coincident matches'' is assessed using temperature, humidity and tracer observations. The technique pulls out five clear Lagrangian cases covering a variety of situations and these are examined in detail. The matching trajectories and hydrocarbon fingerprints are shown, and the downwind minus upwind differences in tracers are discussed

Association of Accelerometry-Measured Physical Activity and Cardiovascular Events in Mobility-Limited Older Adults: The LIFE (Lifestyle Interventions and Independence for Elders) Study.

BACKGROUND:Data are sparse regarding the value of physical activity (PA) surveillance among older adults-particularly among those with mobility limitations. The objective of this study was to examine longitudinal associations between objectively measured daily PA and the incidence of cardiovascular events among older adults in the LIFE (Lifestyle Interventions and Independence for Elders) study. METHODS AND RESULTS:Cardiovascular events were adjudicated based on medical records review, and cardiovascular risk factors were controlled for in the analysis. Home-based activity data were collected by hip-worn accelerometers at baseline and at 6, 12, and 24 months postrandomization to either a physical activity or health education intervention. LIFE study participants (n=1590; age 78.9±5.2 [SD] years; 67.2% women) at baseline had an 11% lower incidence of experiencing a subsequent cardiovascular event per 500 steps taken per day based on activity data (hazard ratio, 0.89; 95% confidence interval, 0.84-0.96; P=0.001). At baseline, every 30 minutes spent performing activities ≥500 counts per minute (hazard ratio, 0.75; confidence interval, 0.65-0.89 [P=0.001]) were also associated with a lower incidence of cardiovascular events. Throughout follow-up (6, 12, and 24 months), both the number of steps per day (per 500 steps; hazard ratio, 0.90, confidence interval, 0.85-0.96 [P=0.001]) and duration of activity ≥500 counts per minute (per 30 minutes; hazard ratio, 0.76; confidence interval, 0.63-0.90 [P=0.002]) were significantly associated with lower cardiovascular event rates. CONCLUSIONS:Objective measurements of physical activity via accelerometry were associated with cardiovascular events among older adults with limited mobility (summary score >10 on the Short Physical Performance Battery) both using baseline and longitudinal data. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01072500

Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA

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

POTENTIAL OF VEGETATION MANAGEMENT FOR GROUND SQUIRREL CONTROL

Manipulation or alteration of habitat vegetation is used frequently with integrated pest management of certain vertebrate pest species. However, it has been less than satisfactory with ground squirrel species in many situations. Special plantings of tall grasses and broadleaf species were experimentally explored in an effort to make levee habitat less suitable for the California ground squirrel in the Sacramento Valley. The experimental plantings failed to achieve that objective for a variety of apparent or suspected reasons and, in fact, in some grass plots the number of ground squirrels increased over what was present prior to planting. Other problems associated with these experimental plantings, including aggressive tendencies of some species, are discussed

Adverse Outcome Pathway Bridge Building from Research to Regulation

The adverse outcome pathway (AOP) framework is a new way of generating knowledge from existing data for hazard assessment. Computational tools will help, especially with further development and adoption of data quality guidance

Perspective on Health Effects of Endocrine Disruptors with a Focus on Data Gaps

Screening for endocrine disrupting properties at the molecular and cellular level is developing rapidly, but can epidemiology bridge the gap to human health impact? Reviews by the World Health Organization and the United States Endocrine Society listed diseases which may be related to endocrine disrupting chemicals (EDCs). Much of the evidence relating these diseases to EDCs is from animal and epidemiological studies, many with significant weaknesses. What human health data sources are available? Some examples are provided from Nordic countries, Denmark, France, Switzerland, and the United States. Health register shortcomings are noted, including diagnostic criteria and "signal-to-noise" ratio (high background incidence rates). Issues with exposure assessment (human biomonitoring), data governance (FAIR principles), legislative hurdles, and patient consent are also illustrated. For all the above reasons, it is clear why generating reliable long-term data for human diseases putatively associated with EDCs has not yet been achieved and thus why it is difficult to bridge the gap between molecular/cellular/animal toxicity data and human health risks of EDCs. This will require international cooperation, sustained support, and public acceptance