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Measuring adverse effects on honey bees and their colonies requires a suitable methodology. For example, due to the large number of bees in a hive and the foraging activity, measuring the mortality of individuals is a difficult task that has not yet been adequately addressed. Knowing the natural daily mortality rate of a bee colony would be of great benefit in assessing whether and to what extent external influences and stress factors affect mortality. More precise mortality data could in turn help refining specific protection goals for regulatory purpose. The European Food Safety Authority recently published a document that estimated such mortality rates based on a systematic literature review, but none of these rates were assessed from continuous monitoring of colonies. Currently, bee mortality is routinely evaluated with various types of dead bee traps that prevent deceased bees from being removed from the colony. Both the literature review and the dead bee traps are relevant to regulatory risk assessment, but in our opinion are not describing the total mortality. Bee counters capable of precisely determining daily loss rates meet the above points and combine them with generating automated and continuous monitoring data. Lately, the field has gained a lot of importance in research and technological advances offer new possibilities in regulatory risk assessment. We will highlight these possibilities and discuss their future application in practice. [ABSTRACT FROM AUTHOR]

There is a regulatory need for crop development dates to assess current default values used within chemical exposure assessments as well as to justify refinements within risk assessments. However, a readily available pan‐European crop phenology database covering key FOrum for the Co‐ordination of pesticide fate models and their USe (FOCUS) crops and scenarios to meet this need is not currently available. Therefore, we describe the development of a harmonized, pan‐European, CropLife Europe Crop Development Database (C2D2), that is fully aligned with this regulatory requirement utilizing efficacy trials data generated for regulatory submissions when registering plant protection products under Regulation (EU)1107/2009. Evaluation of C2D2 against an independent data set showed good agreement for equivalent time periods, crop growth stages, and geographical regions. We illustrate how this database can be used to evaluate existing default crop development dates mandated by regulatory agencies for use within exposure assessments. Despite the large data set compiled and the geographical coverage of C2D2, not all FOCUSsw/gw scenarios have sufficient data to facilitate comparison, with less significant scenarios, like FOCUSgw Porto, being underrepresented. For those scenarios with sufficient data, clear differences between C2D2 and crop development dates assumed in the FOCUS modeling framework (using the AppDate tool) are often indicated over many growth stages, suggesting that amendment of the existing representation of crop development within the risk assessment process may be required. C2D2 is freely available under a Creative Commons license to facilitate innovation in exposure science to allow for more accurate and realistic risk assessment leading to enhanced crop and environmental protection. Integr Environ Assess Manag 2024;20:1060–1074. © 2023 CropLife Europe (Corteva Agriscience) and The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). Key Points: A freely available, harmonized, pan‐European crop development database (CropLife Europe Crop Development Database [C2D2]) has been developed by CropLife Europe for use in regulatory chemical exposure assessments by collating and harmonizing efficacy trials data generated for regulatory submissions when registering plant protection products.C2D2 comprises a wide range of crops (combinable, root, vegetable, top fruit, soft fruit), spans two decades (2000–2020), and covers 30 countries facilitating comparison with current regulatory scenarios, which suggests that amendment of the existing representation of crop development may be required.Evaluation of C2D2 against an independent data set from Germany for equivalent time periods and crop growth stages showed good agreement, promoting its use in exposure science innovation to allow for more accurate and realistic risk assessment leading to enhanced crop and environmental protection.C2D2 holds significant opportunities for future development of crop models to improve estimates and timing of chemical exposure, not only for use in chemical fate and transport models but also for nontarget organism, for example, pollinators, effect, and risk assessment. [ABSTRACT FROM AUTHOR]

Human cell-based test methods can be used to evaluate potential hazards of mixtures and products of petroleum refining ("unknown or variable composition, complex reaction products, or biological materials" substances, UVCBs). Analyses of bioactivity and detailed chemical characterization of petroleum UVCBs were used separately for grouping these substances; a combination of the approaches has not been undertaken. Therefore, we used a case example of representative high production volume categories of petroleum UVCBs, 25 lower olefin substances from low benzene naphtha and resin oils categories, to determine whether existing manufacturing-based category grouping can be supported. We collected two types of data: nontarget ion mobility spectrometry-mass spectrometry of both neat substances and their organic extracts and in vitro bioactivity of the organic extracts in five human cell types: umbilical vein endothelial cells and induced pluripotent stem cell-derived hepatocytes, endothelial cells, neurons, and cardiomyocytes. We found that while similarity in composition and bioactivity can be observed for some substances, existing categories are largely heterogeneous. Strong relationships between composition and bioactivity were observed, and individual constituents that determine these associations were identified. Overall, this study showed a promising approach that combines chemical composition and bioactivity data to better characterize the variability within manufacturing categories of petroleum UVCBs. [ABSTRACT FROM AUTHOR]

The predominantly animal-centric approach of chemical safety assessment has increasingly come under pressure. Society is questioning overall performance, sustainability, continued relevance for human health risk assessment and ethics of this system, demanding a change of paradigm. At the same time, the scientific toolbox used for risk assessment is continuously enriched by the development of “New Approach Methodologies” (NAMs). While this term does not define the age or the state of readiness of the innovation, it covers a wide range of methods, including quantitative structure–activity relationship (QSAR) predictions, high-throughput screening (HTS) bioassays, omics applications, cell cultures, organoids, microphysiological systems (MPS), machine learning models and artificial intelligence (AI). In addition to promising faster and more efficient toxicity testing, NAMs have the potential to fundamentally transform today’s regulatory work by allowing more human-relevant decision-making in terms of both hazard and exposure assessment. Yet, several obstacles hamper a broader application of NAMs in current regulatory risk assessment. Constraints in addressing repeated-dose toxicity, with particular reference to the chronic toxicity, and hesitance from relevant stakeholders, are major challenges for the implementation of NAMs in a broader context. Moreover, issues regarding predictivity, reproducibility and quantification need to be addressed and regulatory and legislative frameworks need to be adapted to NAMs. The conceptual perspective presented here has its focus on hazard assessment and is grounded on the main findings and conclusions from a symposium and workshop held in Berlin in November 2021. It intends to provide further insights into how NAMs can be gradually integrated into chemical risk assessment aimed at protection of human health, until eventually the current paradigm is replaced by an animal-free “Next Generation Risk Assessment” (NGRA).

In this study, 129 exposure situations (ESs) with six or more measured inhalation exposures to dust from solids or vapour from liquids in occupational settings were compared with modelled European Centre of Ecotoxicology and Toxicology of Chemicals (ECETOC) targeted risk assessment tool, version 3 (TRAv3) estimates. The measurement data were extracted from previously published studies examining TRAv3 performance and pooled into a curated database. The comparison exercise focussed on the vapour exposure scenarios, as there were too few dust scenarios for a meaningful analysis of any required model corrections. A group of experts in the exposure modelling field retrieved and reviewed the input parameters used in these ESs. Where considered appropriate, modifications were applied to better match the input parameter definitions and the scope of applicability of the TRAv3. Differences and mean absolute error (MAE) were calculated between the log-transformed modelled exposure value and the 75th percentile of each measured data set and regression analysis was performed. The results indicated that the TRAv3 overestimated 80% of the measured data sets. Both over- and underestimations were mostly by factors 1–5. The calculated MAE for liquids was 0.7, indicating that on average the difference between the 75th percentile and the TRAv3 estimate was less than one order of magnitude. A multiple linear regression showed that some input parameters such as medium volatility, certain process categories (PROC), industrial setting, and the presence of local exhaust ventilation are associated with underestimations. The results of the regression analysis can be used by TRAv3 users to review the degree of over- or underestimation in their current exposure assessments, compared to the curated database. Although multiple linear regression is an appropriate methodology to characterize the TRAv3's performance, more data sets are still needed in view of some remaining data gaps. Nevertheless, the results of the current analysis are being used by ECETOC to further develop the tool as a suitably conservative screening tool for use in REACH chemical safety assessment of occupational exposure to chemicals. [ABSTRACT FROM AUTHOR]

The United States Environmental Protection Agency (EPA) regulates chemical manufacture, import, processing, distribution, use, and disposal under the 2016 amended Toxic Substances Control Act (TSCA) for the purposes of protecting the public and sensitive populations—including workers—from chemical exposure risk. The publication of several TSCA risk evaluations provided a unique opportunity to evaluate the evolving regulatory approach for assessing the dermal exposure pathway in occupational settings. In this analysis, the occupational dermal exposure assessment methods employed in several TSCA risk evaluations were assessed. Specifically, a methodology review was conducted for the occupational dermal scenarios of manufacturing and feedstock use in the risk evaluations of three chlorinated organic chemicals: trichloroethylene, carbon tetrachloride, and perchloroethylene. Additionally, alternative exposure estimates were generated using the exposure model IH SkinPermTM. The review and alternative exposure analyses indicate that the current TSCA modeling approach may generate total dermal absorbed doses for chlorinated chemical manufacturing and feedstock use scenarios that are 2- to 20-fold higher than those generated by IH SkinPerm. Best-practice recommendations developed in the methodology review support a tiered, integrated approach to dermal exposure assessment that emphasizes collecting qualitative data; employing validated, peer-reviewed models that align with current industrial practices; and gathering empirical sampling data where needed. Collaboration among industry, EPA, and other stakeholders to share information and develop a standard approach to exposure assessment under TSCA would improve the methodological rigor of, and increase confidence in, the risk evaluation results. [ABSTRACT FROM AUTHOR]

Before plant protection product (PPP) marketing authorization, a risk assessment for nontarget soil organisms (e.g., earthworms) is required as part of Regulation (EC) No. 1107/2009. Following a stepwise approach, higher tier earthworm field studies are needed if they cannot demonstrate low long‐term risk based on laboratory studies. The European guidance for terrestrial ecotoxicology refers to ISO guideline 11268‐3 as a standard to conduct earthworm field studies. Assessment of such studies may be challenging, as no European harmonized guidance is available to properly analyze the accuracy, representativeness, and appropriateness of experimental designs, as well as the statistical analysis robustness of results and their scientific reliability. Following the ISO guideline 11268‐3, a field study was performed in 2016–2017 (Versailles, France). An assessment of the first year of this field study was performed in agreement with the quality criteria provided in 2006 in the guidance document published by de Jong and collaborators and recommendations by Kula and collaborators that allows describing the protocol and results of earthworm field studies. Not only did we underline the importance of a detailed analysis of raw data on the effects of pesticides on earthworms in field situations, but we also provided recommendations to harmonize protocols for assessing higher tier field studies devoted to earthworms to advance a better assessment of PPP fate and ecotoxicity. In particular, we provided practical field observations related to the study design, pesticide applications, and earthworm sampling. Concurrently, in addition to the conventional earthworm community study, we propose carrying out an assessment of soil function (i.e., organic matter decomposition, soil structuration, etc.) and calculating diversity indices to obtain information about earthworm community dynamics after the application of PPPs. Finally, through field observations, any relevant observation of external and/or internal recovery should be reported. Integr Environ Assess Manag 2023;19:254–271. © 2022 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC). KEY POINTS: The de Jong guidance and the recommendations provided by Kula and collaborators are used to assess an earthworm field study performed following the ISO 11268‐3 guideline of 2014.Recommendations are provided to harmonize protocol on assessing higher tier field studies devoted to earthworms for a better assessment of plant protection products fate and ecotoxicity. [ABSTRACT FROM AUTHOR]

Systematic review has become the preferred approach to addressing causality and informing regulatory and other decision-making processes, including chemical risk assessments. While advocates of systematic reviews acknowledge that they hold great potential for increasing objectivity and transparency in assessments of chemicals and human health risks, standardizing and harmonizing systematic review methods have been challenging. This review provides a brief summary of the development of systematic review methods and some of the frameworks currently in use in the US and Europe. We also provide an in-depth evaluation and comparison of two “competing” US EPA systematic review frameworks, informed by the constructively critical recommendations from the US National Academies of Science, Engineering and Medicine. We conclude with suggestions for moving forward to harmonize systematic review methods, as we believe that further criticism of individual available frameworks likely will be unproductive. Specifically, we issue a call to action for an international collaboration to work toward a blueprint that embraces the most scientifically critical elements common to most systematic review frameworks, while necessarily accommodating adaptations for specific purposes. Despite the array of available systematic review methods, it is clear that there is a shared goal and desire to promote objective assessment and synthesis of scientific evidence informing globally important issues regarding disease causality and human health risk evaluation.

Human cell-based test methods can be used to evaluate potential hazards of mixtures and products of petroleum refining (“unknown or variable composition, complex reaction products, or biological materials” substances, UVCBs). Analyses of bioactivity and detailed chemical characterization of petroleum UVCBs were used separately for grouping these substances; a combination of the approaches has not been undertaken. Therefore, we used a case example of representative high production volume categories of petroleum UVCBs, 25 lower olefin substances from low benzene naphtha and resin oils categories, to determine whether existing manufacturing-based category grouping can be supported. We collected two types of data: nontarget ion mobility spectrometry-mass spectrometry of both neat substances and their organic extracts and in vitro bioactivity of the organic extracts in five human cell types: umbilical vein endothelial cells and induced pluripotent stem cell-derived hepatocytes, endothelial cells, neurons, and cardiomyocytes. We found that while similarity in composition and bioactivity can be observed for some substances, existing categories are largely heterogeneous. Strong relationships between composition and bioactivity were observed, and individual constituents that determine these associations were identified. Overall, this study showed a promising approach that combines chemical composition and bioactivity data to better characterize the variability within manufacturing categories of petroleum UVCBs.

In this article, we have responded to the key statements in the article by Koivisto et al. (2022) that were incorrect and considered to be a biased critique on a subset of the exposure models used in Europe (i.e. ART and Stoffenmanager®) used for regulatory exposure assessment. We welcome scientific discussions on exposure modelling (as was done during the ISES Europe workshop) and criticism based on scientific evidence to contribute to the advancement of occupational exposure estimation tools. The tiered approach to risk assessment allows various exposure assessment models from screening tools (control/hazard banding) through to higher-tiered approaches. There is a place for every type of model, but we do need to recognize the cost and data requirements of highly bespoke assessments. That is why model developers have taken pragmatic approaches to develop tools for exposure assessments based on imperfect data. We encourage Koivisto et al. to focus on further scientifically robust work to develop mass-balance models and by independent external validations studies, compare these models with alternative model tools such as ART and Stoffenmanager®. [ABSTRACT FROM AUTHOR]

RIVM convened a workshop on the use of New Approach Methodologies (NAMs) for the ad hoc human health risk assessment of food and non-food products. Central to the workshop were two case studies of marketed products with a potential health concern: the botanical Tabernanthe iboga which is used to facilitate mental or spiritual insight or to (illegally) treat drug addiction and is associated with cardiotoxicity, and dermal creams containing female sex hormones, intended for use by perimenopausal women to reduce menopause symptoms without medical supervision. The workshop participants recognized that data from NAM approaches added valuable information for the ad hoc risk assessment of these products, although the available approaches were inadequate to derive health-based guidance values. Recommendations were provided on how to further enhance and implement NAM approaches in regulatory risk assessment, specifying both scientific and technical aspects as well as stakeholder engagement aspects. • New Approach Methodologies (NAMs) are growing, and new technologies move away from in vivo methods. • NAMs may be used for ad hoc risk assessment of borderline products. • Extrapolation from in silico and in vitro to in vivo is the major challenge using NAMs. • A NAM-based approach for risk assessment should be protective for sensitive groups. • The pathway of regulatory acceptance of NAMs involves several stages and different stakeholders. [ABSTRACT FROM AUTHOR]

In vivo skin sensitization assays have to be provided by applicants to the competent authorities in the European Union for the approval of active substances (AS) in pesticides. This study aimed to test the practicability of in silico predictions for AS by freely available (Q)SAR tools to evaluate their use as a time- and cost-effective alternative to animal testing in the context of the 3R concept. Predictions of skin sensitization for 48 selected sensitizing and non-sensitizing AS by the software programs CAESAR, Toxtree, OECD (Q)SAR Toolbox, CASE Ultra, Leadscope and SciQSAR were collected and compared. Different data evaluation methodologies (score definition, mean, weighted mean, threshold score definition) were applied to optimize the predictions. The calculation methods were internally cross-validated and further validated with an additional validation set of 80 AS. Although the presented calculation methodologies are not suitable as a stand-alone method, this study has shown weaknesses and strengths of some prominent (Q)SAR programs and diverse combinatorial options in the prediction of skin sensitization by pesticidal AS. The present study will help to foster discussions on in silico alternatives to animal testing in the pesticide area. [ABSTRACT FROM AUTHOR]

Honeybees have world-wide importance as crop pollinators. To ensure their persistence in agricultural systems, statistically robust field trials of plant protection products are vital., We consider the implications of regulations from the European Food Safety Authority that require the detection of a 7% effect size change in bee colony sizes under field conditions., Based on a power analysis, we argue that the necessary levels of replication (68 replicates) may pose practical constraints to field testing., Policy implications. Regulatory studies benefit from data sources collated over a range of spatial scales, from laboratory to landscapes. Basing effect size thresholds solely on expert judgement, as has been done, may be inappropriate. Rather, definition through experimental or simulation studies that assess the biological consequences of changes in colony size for bee populations is required. This has implications for regulatory bodies outside the European Union. [ABSTRACT FROM AUTHOR]

The increasing use of multi-walled carbon nanotubes (MWCNTs) in consumer products and their potential to induce adverse lung effects following inhalation has lead to much interest in better understanding the hazard associated with these nanomaterials (NMs). While the current regulatory requirement for substances of concern, such as MWCNTs, in many jurisdictions is a 90-day rodent inhalation test, the monetary, ethical, and scientific concerns associated with this test led an international expert group to convene in Washington, DC, USA, to discuss alternative approaches to evaluate the inhalation toxicity of MWCNTs. Pulmonary fibrosis was identified as a key adverse outcome linked to MWCNT exposure, and recommendations were made on the design of an in vitro assay that is predictive of the fibrotic potential of MWCNTs. While fibrosis takes weeks or months to develop in vivo, an in vitro test system may more rapidly predict fibrogenic potential by monitoring pro-fibrotic mediators (e.g., cytokines and growth factors). Therefore, the workshop discussions focused on the necessary specifications related to the development and evaluation of such an in vitro system. Recommendations were made for designing a system using lung-relevant cells co-cultured at the air-liquid interface to assess the pro-fibrogenic potential of aerosolized MWCNTs, while considering human-relevant dosimetry and NM life cycle transformations. The workshop discussions provided the fundamental design components of an air-liquid interface in vitro test system that will be subsequently expanded to the development of an alternative testing strategy to predict pulmonary toxicity and to generate data that will enable effective risk assessment of NMs. [ABSTRACT FROM AUTHOR]

In 2007, the U.S. National Research Council (NRC) published a groundbreaking report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The purpose of this report was to develop a long-range strategic plan to update and advance the way environmental agents are tested for toxicity. The vision focused on the identification of critical perturbations of toxicity pathways that lead to adverse human health outcomes using modern scientific tools and technologies. This review describes how emerging scientific methods will move the NRC vision forward and improve the manner in which the potential health risks associated with exposure to environmental agents are assessed. The new paradigm for toxicity testing is compatible with the widely used four-stage risk assessment framework originally proposed by the NRC in 1983 in the so-called Red Book. The Nrf2 antioxidant pathway provides a detailed example of how relevant pathway perturbations will be identified within the context of the new NRC vision for the future of toxicity testing. The implications of the NRC vision for toxicity testing for regulatory risk assessment are also discussed. [ABSTRACT FROM AUTHOR]

Abstract: U.S. EPA’s Supplemental Guidance in 2005 documented their procedure for incorporating age-dependent adjustment factors (ADAFs) into lifetime excess risk calculations. EPA’s first attempt to implement an ADAF when the dose–response model had a cumulative dose metric was for ethylene oxide and that attempt () failed to successfully follow EPA’s own guidelines. The failure suggested that the incorporation of ADAFs would increase the lifetime excess risk for ethylene oxide by approximately 66%. However, if the procedure in the guidelines were followed correctly, then the increase would have only been 0.008% or approximately 8,000 fold less. Because cumulative exposure is a common dose metric in dose–response models of epidemiological data, a correct implementation of the guidelines is of widespread importance. [Copyright &y& Elsevier]

Abstract: In US EPA’s evaluation of ethylene oxide (EO) in 2006, the calculation of the excess risk of lymphohematopoietic (LH) cancer incidence was flawed. The calculation was inappropriately based on an exposure-response model for LH mortality instead of LH incidence. This is especially inappropriate for EO because EO exposure may not increase LH incidence except at high doses. The observed increases in LH mortality with EO exposure in males in the NIOSH epidemiology study, although not statistically significant, can be explained at all but the highest doses by exposure-dependent changes in the survival time between LH onset and LH mortality without any changes in LH incidence. Furthermore, EPA’s life-table calculations of excess risk of incidence used formulas that are only appropriate for mortality. All of these concerns strongly suggest that EPA should limit their excess risk calculations to mortality unless they have data from an epidemiology study of incidence from which to derive an exposure-response model. What excess risks are calculated and how they are calculated is important for a scientifically-defensible regulatory assessment of EO and other substances. [Copyright &y& Elsevier]

Dermal exposure needs to be addressed in regulatory risk assessment of chemicals. The models used so far are based on very limited data. The EU project RISKOFDERM has gathered a large number of new measurements on dermal exposure to industrial chemicals in various work situations, together with information on possible determinants of exposure. These data and information, together with some non-RISKOFDERM data were used to derive default values for potential dermal exposure of the hands for so-called ‘TGD exposure scenarios’. TGD exposure scenarios have similar values for some very important determinant(s) of dermal exposure, such as amount of substance used. They form narrower bands within the so-called ‘RISKOFDERM scenarios’, which cluster exposure situations according to the same purpose of use of the products. The RISKOFDERM scenarios in turn are narrower bands within the so-called Dermal Exposure Operation units (DEO units) that were defined in the RISKOFDERM project to cluster situations with similar exposure processes and exposure routes. Default values for both reasonable worst case situations and typical situations were derived, both for single datasets and, where possible, for combined datasets that fit the same TGD exposure scenario. The following reasonable worst case potential hand exposures were derived from combined datasets: (i) loading and filling of large containers (or mixers) with large amounts (many litres) of liquids: 11 500 mg per scenario (14 mg cm−2 per scenario with surface of the hands assumed to be 820 cm2); (ii) careful mixing of small quantities (tens of grams in <1l): 4.1 mg per scenario (0.005 mg cm−2 per scenario); (iii) spreading of (viscous) liquids with a comb on a large surface area: 130 mg per scenario (0.16 mg cm−2 per scenario); (iv) brushing and rolling of (relatively viscous) liquid products on surfaces: 6500 mg per scenario (8 mg cm−2 per scenario) and (v) spraying large amounts of liquids (paints, cleaning products) on large areas: 12 000 mg per scenario (14 mg cm−2 per scenario). These default values are considered useful for estimating exposure for similar substances in similar situations with low uncertainty. Several other default values based on single datasets can also be used, but lead to estimates with a higher uncertainty, due to their more limited basis. Sufficient analogy in all described parameters of the scenario, including duration, is needed to enable proper use of the default values. The default values lead to similar estimates as the RISKOFDERM dermal exposure model that was based on the same datasets, but uses very different parameters. Both approaches are preferred over older general models, such as EASE, that are not based on data from actual dermal exposure situations. [ABSTRACT FROM AUTHOR]

Exposure assessors involved in regulatory risk assessments often need to estimate a reasonable worst-case full-shift exposure level from very limited exposure information. Full-shift exposure data of very high quality are rare. A full-shift value can also be calculated from (short term) task based values, either derived from measured data or from models. The most simple option is to use the task based exposure levels as the full-shift value. A second option is to calculate a time-weighted average (TWA), using (reasonable worst case) estimates of the duration and the exposure level of the relevant tasks. The third option is to use a Monte Carlo analysis with estimated input distributions for exposure level and duration of exposure. If an estimated distribution of respiratory volume is also included, this leads to a distribution of inhaled amounts. The 90th percentile of such a distribution is generally substantially lower than the fixed point estimates calculated using high end values for each parameter. This technique can thus prevent unnecessary conservative estimates in risk assessment. The output distribution can also be used as valuable input to the risk management process, because it provides information on probabilities of exposure levels, that can influence the cost-benefit analysis of the risk management process. Finally, the sensitivity analysis of Monte Carlo simulation can give guidance for further studies to increase the accuracy of the exposure assessment. [ABSTRACT FROM AUTHOR]

Recent advances in understanding of biological mechanisms and adverse outcome pathways for many exposure-related diseases show that certain common mechanisms involve thresholds and nonlinearities in biological exposure concentration-response (C-R) functions. These range from ultrasensitive molecular switches in signaling pathways, to assembly and activation of inflammasomes, to rupture of lysosomes and pyroptosis of cells. Realistic dose-response modeling and risk analysis must confront the reality of nonlinear C-R functions. This paper reviews several challenges for traditional statistical regression modeling of C-R functions with thresholds and nonlinearities, together with methods for overcoming them. Statistically significantly positive exposure-response regression coefficients can arise from many non-causal sources such as model specification errors, incompletely controlled confounding, exposure estimation errors, attribution of interactions to factors, associations among explanatory variables, or coincident historical trends. If so, the unadjusted regression coefficients do not necessarily predict how or whether reducing exposure would reduce risk. We discuss statistical options for controlling for such threats, and advocate causal Bayesian networks and dynamic simulation models as potentially valuable complements to nonparametric regression modeling for assessing causally interpretable nonlinear C-R functions and understanding how time patterns of exposures affect risk. We conclude that these approaches are promising for extending the great advances made in statistical C-R modeling methods in recent decades to clarify how to design regulations that are more causally effective in protecting human health. • Many causal dose-response relationships involve thresholds and nonlinearities in signaling pathways and responses. • Realistic risk assessment must deal with nonlinear exposure concentration-response (C-R) functions. • This raises challenges for traditional statistical C-R modeling, including modeling confounding, errors, and interactions. • These challenges imply that regression coefficients may not predict how reducing exposure would reduce risk. • Causal Bayesian networks, dynamic simulation models, and nonparametric regression modeling can help. [ABSTRACT FROM AUTHOR]

Compared with nutrient levels and habitat degradation, the importance of agricultural pesticides in surface water may have been underestimated due to a lack of comprehensive quantitative analysis. Increasing pesticide contamination results in decreasing regional aquatic biodiversity, i.e., macroinvertebrate family richness is reduced by ∼30% at pesticide concentrations equaling the legally accepted regulatory threshold levels (RTLs). This study provides a comprehensive metaanalysis of 838 peer-reviewed studies (>2,500 sites in 73 countries) that evaluates, for the first time to our knowledge on a global scale, the exposure of surface waters to particularly toxic agricultural insecticides. We tested whether measured insecticide concentrations (MICs; i.e., quantified insecticide concentrations) exceed their RTLs and how risks depend on insecticide development over time and stringency of environmental regulation. Our analysis reveals that MICs occur rarely (i.e., an estimated 97.4% of analyses conducted found no MICs) and there is a complete lack of scientific monitoring data for ∼90% of global cropland. Most importantly, of the 11,300 MICs, 52.4% (5,915 cases; 68.5% of the sites) exceeded the RTL for either surface water (RTLSW) or sediments. Thus, the biological integrity of global water resources is at a substantial risk. RTLSW exceedances depend on the catchment size, sampling regime, and sampling date; are significantly higher for newer-generation insecticides (i.e., pyrethroids); and are high even in countries with stringent environmental regulations. These results suggest the need for worldwide improvements to current pesticide regulations and agricultural pesticide application practices and for intensified research efforts on the presence and effects of pesticides under real-world conditions.

Proper use information is necessary to do exposure modelling in the scope of regulatory risk assessments. The legal regime under which the regulatory risk assessment is done influences the need for use information. Different legal regimes lead to more or less possibilities for authorities to define the exposure scenario to be assessed and the data to be presented by the industrial parties involved. The more information is required by the regulations, the less use information has to be gathered or guessed at by the regulatory exposure assessor. The value of use information is further determined by the scope of the assessment. A very conservative first tier (screening) assessment requires little information, whereas a detailed assessment of actual risks requires accurate use information. The scientific knowledge and available models limit the benefits of use information. Interesting use information has little value if there are no methods to account for the information in the exposure assessment, e.g. if relations between possible exposure determinants and exposure levels are unknown. The need for use information will further be dependent on the analysis of costs (of gathering data) versus benefits (increase in quality of the assessment). Many choices regarding the need for use information depend on policy choices by decision-makers. These decision-makers again depend on proper scientific information to make informed choices. [ABSTRACT FROM PUBLISHER]

An analysis was conducted on a cohort of Chinese pottery workers to estimate the exposure-response relationship between respirable crystalline silica dust exposure and the incidence of radiographically diagnosed silicosis, and to estimate the long-term risk of developing silicosis until the age of 65. The cohort comprised 3,250 employees with a median follow-up duration of around 37 years. Incident cases of silicosis were identified via silicosis registries (Chinese X-ray stage I, similar to International Labor Organisation classification scheme profusion category 1/1). Individual exposure to respirable crystalline silica dust was estimated based on over 100,000 historical dust measurements. The association between dust exposure, incidence and long-time risk of silicosis was quantified by Poisson regression analysis adjusted for age and smoking. The risk of silicosis depended not only on the cumulative respirable crystalline silica dust exposures, but also on the time-dependent respirable crystalline silica dust exposure pattern (long-term average concentration, highest annual concentration ever experienced and time since first exposure). A long-term "excess" risk of silicosis of approximately 1.5/1,000 was estimated among workers with all annual respirable crystalline silica dust concentration estimates less than 0.1 mg/m(3), using the German measurement strategy. This study indicates the importance of proper consideration of exposure information in risk quantification in epidemiological studies.