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Regulate to reduce chemical mixture risk
Abstract
Humans and wildlife are continuously exposed to multiple chemicals from different sources and via different routes, both simultaneously and in sequence. Scientific evidence for heightened toxicity from such mixtures is mounting, yet regulation is lagging behind. Ensuring appropriate regulation of chemical mixture risks will require stronger legal stimuli as well as close integration of different parts of the regulatory systems in order to meet the data and testing requirements for mixture risk assessment.
... Due to the wide use of chemicals and as proven by numerous scientific monitoring studies, the environment, humans and wildlife are continuously exposed not to single but to multiple chemicals from different sources and via different routes, both simultaneously and in sequence e.g., [5][6][7][8][9][10]. This extend of co-exposure has profound yet only rudimentarily understood consequences for living organisms, ecosystems and biodiversity [11]. ...
... This extend of co-exposure has profound yet only rudimentarily understood consequences for living organisms, ecosystems and biodiversity [11]. Complex mixtures of chemicals (see Infobox of Fig. 1) can cause joint "combination effects" even if the predicted single substances' effects or risks are below the regulatory accepted "safe" thresholds (i.e., Risk Characterization Ratio below 1 [5,[12][13][14][15] (see also next chapter). ...
... In order to scrutinize the possible impact of a MAF, ECHA analyzed chemical safety reports of selected substances and modelled risk characterization ratios for certain use categories. The question was whether a MAF in different magnitudes (2,5,20,50) would be "adsorbed" without any changes (no revision) and/or lead to refinements of the respective chemical safety assessments (i.e., PEC estimation, use of monitoring data, refinement of PNEC) and/or risk reduction measures (additional risk management measures, withdraw use). Indicative results were presented during stakeholder workshops and in an associated background document [21]. ...
There is indisputable evidence that the environment, humans and wildlife are continuously exposed not to single but to multiple chemicals from different sources. Exposure to these mixtures can lead to combined risks not yet sufficiently addressed in any of the European chemical legislations. Under the REACH regulation for industrial chemicals, specific environmental mixture assessments are challenged by a lack of data on toxicity, use and exposures and the communication of data along the supply chain. Within the Chemicals Strategy for Sustainability the European Commission proposed to introduce (a) mixture allocation factor(s) (MAF) as regulatory management tool to reduce exposures, effects and potential risks of unintentional mixtures. The MAF is proposed to be applied as default value within the chemical safety assessments undertaken by companies under REACH. Here, we critically review the relevant literature discussing the conceptual background of the MAF and approaches to derive its magnitude. The analysis focuses on the environment and key issues for an implementation in regulatory practise together with remaining uncertainties and needs for possible ways forward. At this stage introducing a MAF in REACH Annex I appears the most pragmatic and immediately implementable measure to address risks from unintentional mixtures in the environment. A so-called MAFceiling appears as the preferred option of policy makers, since it would only affect relevant substances close to their respective risk threshold. While the magnitude of a MAF will be decided politically, the choice of methods and assumptions to derive its size should be clear and transparent, build on the available scientific evidence and take account for uncertainties. A MAF will be most effective reducing environmental releases and exposure levels if risk mitigation measures are implemented in practise. Its socioeconomic impacts and costs need to be assessed in a balanced way together with the benefits for the environment, society, and for companies—also in comparison to the efforts needed for specific mixture risk assessments. In the future and with the experiences gathered in practise, a discussion is needed on how to assess and regulate unintentional mixtures across different pieces of chemicals legislation to consider the true exposure situation and ensure harmonisation.
... Since simultaneous exposure to many phthalates is probable and many phthalates have been shown to have a cumulative effect (Conley et al., 2021;Howdeshell et al., 2008;Hannas et al., 2011), a risk assessment was carried out for a mixture of five selected reprotoxic phthalates (DEHP, DnBP, DiBP, BBzP, DiNP) using the hazard index (HI) approach . Mixture risk assessment was also previously addressed by Kortenkamp and Faust (2018), Kortenkamp and Koch (2020) and Apel et al. (2020b). As toxicity reference values consolidated HBM-GV GenPop for BBzP, DEHP, DiBP and DnBP have been chosen and for DiNP a provisional HBM-GV GenPop for the purpose of the MRA alone (pHBM-GV GenPop-MRA ) was established based on a common anti-androgenic endpoint (for details see Lange et al., 2022). ...
... These results clearly show that the inclusion of mixture RAs in current regulatory practice is imperative. Conventions for the integration of mixture effects into regulatory RAs are essential, e.g., through a mixture assessment factor (MAF) (e.g., Kortenkamp and Faust, 2018;Backhaus, T., 2022;Escher et al., 2022;Nikolopoulou et al., 2023). ...
... But in an environmental sample the mixture of all substancesand not only a few substances of interest -contributes to overall ecotoxicity. Thus, applying ecotoxicological tests is seen as a valuable complemental method to chemical analysis, making it possible to include and evaluate the overall toxicity of all bioavailable substances in a mixture [3][4][5]. At the same time, the sample volumes for the different tests are often restricted, as obtaining and preparing water samples for monitoring is elaborate and costly. ...
International standard test guidelines for the ecotoxicological characterisation of various substances use organisms such as algae, daphnids and fish embryos. These guidelines recommend or use relatively high volumes of water for the process of testing, for example, 200 mL for a complete dose–response relationship in a daphnia assay. However, for various samples such as concentrated extracts from environmental monitoring or leachates from microplastic ageing experiments, the amount of available sample volume is limited, that is, rather in the range of 10–50 mL/biotest. Using the exposure volumes as recommended in test guidelines would not allow to test a range of different concentrations or to repeat tests or use multiple different organismic bioassays. Lower media volumes would allow the testing of more samples (more concentrations per sample, more test repetitions for statistical robustness, etc.) but it may also decrease the possible number of organisms tested in the same volume. Here, we aimed at reducing the test volumes in the acute daphnia assay (using a maximum of 30 mL for a complete dose–response relationship) without impacting animals’ sensitivity towards toxicants. A literature review on existing miniaturisation approaches was used as a starting point. Subsequently, assays employing conventional as well as reduced test volumes were compared for 16 selected test substances with a diverse spectrum of lipophilicity. Results showed that there are differences in EC50 between the two approaches, but that these differences were overall only within a range of a factor of two to three. Further, by retrieving EC50 values for the genus Daphnia and 16 test substances from the United States Environmental Protection Agency database, we demonstrated that our results are well in line with the general differences in sensitivities.
... This will ensure a more accurate and comprehensive understanding of the existing environmental conditions. While this study reports on individual UV-filter and PAH compounds, the additive effects of complex mixture of chemicals present in these environments requires consideration in terms of additive toxicity effects (Kortenkamp & Faust, 2018). Therefore, understanding and mitigating the impact of these substances on our environment and the organisms within it is of great importance. ...
Water reservoirs and lakes are gaining popularity for recreation activities as populations increase, and green spaces become in high demand. However, these activities may cause contamination to critical water resources. This study investigates the impact of recreational activities on the presence and concentration of polycyclic aromatic hydrocarbons (PAHs) and ultraviolet (UV) filters in drinking water reservoirs in Southeast Queensland, Australia. Polydimethylsiloxane passive samplers were used to monitor 14 lakes over a three-year period, focusing on seasonal variations and the influence of recreational activities such as petrol-powered boating and swimming. A total of 15 PAHs and 6 UV-filters were detected, with chrysene (97%) and octyl salicylate (34%) being the most prevalent PAH and UV-filter, respectively. Polycyclic aromatic hydrocarbons levels were statistically significantly higher in lakes permitting petrol-powered boating, especially during summer (p = 0.005 to 0.05). Lake Maroon and Lake Moogerah were the only sites that showed significantly higher PAH levels in summer (3.9 ± 1.1 and 4.0 ± 1.2 ng L−1 respectively) compared to winter (1.6 ± 0.61 and 1.5 ± 0.84 respectively). UV-filters were generally detected in higher levels in lakes allowing swimming, with Lake Moogerah and Lake Sommerset measuring UV-filter concentrations of 20 ± 4.1 and 20 ± 11 ng L−1 in summer, respectively. Other lakes that do not permit swimming, such as Lake Maroon and Lake Samsonvale, also exhibited elevated UV-filter levels, suggesting illegal swimming. These findings highlight the complexity of PAH and UV-filter presence, influenced by multiple factors including lake size, recreational activity type, and seasonal variations. The levels of individual PAHs and UV-filters in this study were below established freshwater guidelines. However, when considering their bioaccumulation potential and mixture toxicity, mitigating the impact of these substances on our environment and the organisms within it should be of priority.
... Implications. Chemical regulation in the United States typically considers risks associated with individual toxicants rather than the complex mixtures present in wastewater effluent or the environment (47). This poses a challenge for regulating PFAS, pharmaceuticals, and other organofluorine compounds because there are potentially tens of thousands of these chemicals in commerce (2). ...
Wastewater receives per- and polyfluoroalkyl substances (PFAS) from diverse consumer and industrial sources, and discharges are known to be a concern for drinking water quality. The PFAS family includes thousands of potential chemical structures containing organofluorine moieties. Exposures to a few well-studied PFAS, mainly perfluoroalkyl acids (PFAA), have been associated with increased risk of many adverse health outcomes, prompting federal drinking water regulations for six compounds in 2024. Here, we find that the six regulated PFAS (mean = 7 to 8%) and 18 measured PFAA (mean = 11 to 21%) make up only a small fraction of the extractable organofluorine (EOF) in influent and effluent from eight large municipal wastewater treatment facilities. Most of the EOF in influent (75%) and effluent (62%) consists of mono- and polyfluorinated pharmaceuticals. The treatment technology and sizes of the treatment facilities in this study are similar to those serving 70% of the US population. Despite advanced treatment technologies, the maximum EOF removal efficiency among facilities in this work was <25%. Extrapolating our measurements to other large facilities across the United States results in a nationwide EOF discharge estimate of 1.0 to 2.8 million moles F y ⁻¹ . Using a national model that simulates connections between wastewater discharges and downstream drinking water intakes, we estimate that the sources of drinking water for up to 23 million Americans could be contaminated above regulatory thresholds by wastewater-derived PFAS alone. These results emphasize the importance of further curbing ongoing PFAS sources and additional evaluations of the fate and toxicity of fluorinated pharmaceuticals.
... Besides, concentration addition, the most widely used concept to determine the effects of chemical mixtures, depends on the data of single chemicals. However, neither exposure nor toxicity data are generally available (Kortenkamp & Faust, 2018). Only a relatively small subset of the chemicals used have been sufficiently characterized their potential for human or ecological toxicity (Judson et al., 2009). ...
Environmental exposures to volatile organic compound (VOC) mixtures have received increasing attention, yet the risks are under studied. This study aimed to explore the risks of combined exposures to several commonly detected VOCs and to draw attention to the necessity of studying long-term and low-concentration environmental exposure patterns. In this study, we examined the effects of long-term and low-concentration exposures to VOCs like 1,2-dichlorobenzene, benzene, toluene and formaldehyde either alone or in combination on D. melanogaster mortality. A quantitative relationship was established between 1,2-dichlorobenzene concentration and mortality. Additionally, 1,2-dichlorobenzene was more toxic than toluene, and males were more sensitive to 1,2-dichlorobenzene. In cocktail, 1,2-dichlorobenzene + benzene, 1,2-dichlorobenzene acted as an antagonist and interaction type may depend on component concentration. Antagonistic interaction was also found in twice mixture of toluene + benzene + formaldehyde and the degree of antagonism decreased with increasing concentrations of formaldehyde + benzene. The observed interactions and variations in their type or degree relative to mixture component concentrations may be attributed to inter-component metabolic interference and metabolic saturation.
... Toxicology 511 (2025) 154037 co-occurring contaminants could provide an in-depth grasp of the metabolic changes and/or biologic events that occur during realistic e-waste exposure scenarios (Eze and Vinken, 2024). The effects of the chemical mixture can occur and could be greater when each chemical in the mixture is even present at levels below the no-observed adverse effect level (Kortenkamp and Faust, 2018;Thrupp et al., 2018). If dose-response and mode-of-action data for the entire mixture are available, the likely toxicity of a new mixture can be determined using data from similar mixtures (Hayes et al., 2019). ...
... As such, heavy metals, pesticides, persistent organic pollutants (POPs), plastic additives or a combination of them accumulate on MPs making up complex toxic mixtures (Cao et al. 2021;Lynch et al. 2022;Verla et al. 2019). Notably, recent evidence suggests that pollutants within such mixtures may enhance the toxicity of MPs, even when their individual concentrations are below their respective effect thresholds (Escher et al. 2020;Kortenkamp and Faust 2018). It is now well establish that the composition of contaminants on beached MPs can vary significantly, depending on factors such as polymer type, weathering, and local environmental conditions, often resulting in high spatial variability (Fisner et al. 2013;Ogata et al. 2009;Taniguchi et al. 2016;Vedolin et al. 2018). ...
Microplastics are ubiquitous in the world’s oceans and pose serious environmental concerns, including their ingestion and the release of potentially toxic mixtures of intrinsic and extrinsic chemical compounds (i.e. leachates; MPLs). Mussels, as key intertidal bioengineers and filter-feeders are particularly susceptible to both exposure pathways. While the effects of microplastic ingestion have been widely investigated, research on the impacts of MPLs has only recently begun. This study examined the influence of MPLs derived from beached pellets collected in two separate regions, namely France and Portugal, on the respiration rates of two key ecosystem engineers, Mytilus edulis and Mytilus galloprovincialis. Possibly due to distinct mixtures of leached chemicals, unlike Portuguese-MPLs, exposure to French-MPLs significantly decreased the respiration rate of both mussel species. This research provides new insights into the physiological impacts of MPLs on bioengineer species, highlighting the importance of MP source and potential cascading effects at the ecosystem level. While we reported significant effects on mussel respiration after acute MPL exposure, future research should investigate long-term impacts and potential detoxification mechanisms to clarify the effects of MPs on mussel physiological performance and their potential consequences on specie fitness.
... Given these deciencies, there is increased scientic and regulatory interest to improve the hazard and risk characterization of real-world environmental samples that tend to exist as complex mixtures. 2,3 In contrast to approaches strictly reliant on chemical measures, effect-based methods (EBM) interrogate responses in biological systems following exposure to environmental samples. 4 To date there has been a focus on bioanalytical tests that characterize apical measures in exposed sh, invertebrate, and algae, as well as in in vitro assays designed to interrogate specic mode of action such as endocrine disruption. ...
Effect-based methods (EBM) are of growing interest in environmental monitoring programs. Few EBM have incorporated transcriptomics even though these provide a wealth of biological information and can be modeled to yield transcriptomic points of departure (tPODs). The study objectives were to: (A) characterize cytotoxic effects of soil extracts on the rainbow trout RTgill-W1 and the human Caco-2 cell lines; (B) measure gene expression changes and calculate tPODs; and (C) compare in vitro responses to available measures of plastic-related compounds and metals. Extracts were prepared from 35 soil samples collected at the Agbogbloshie E-waste site (Accra, Ghana). Cells were exposed to six soil concentrations (0.3 to 9.4 mg dry weight of extract (eQsed) per mL). Many samples caused cytotoxicity with RTgill cells being more sensitive than Caco-2 cells. Eleven samples were analyzed for transcriptomics in both cell lines, with responses measured in all samples (52 to 5925 differentially expressed genes) even in the absence of cytotoxicity. In RTgill cells there was concordance between cytotoxic measures in tPOD values (spearman = 0.85). Though trends between in vitro measures and contaminant data were observed, more work is needed in this area before definitive conclusions are drawn. Nonetheless, this study helps support ongoing efforts in establishing alternative testing strategies (e.g., alternative to animal methods; toxicogenomics) for the assessment of complex environmental samples.
... Currently, European ground-and surface water monitoring focuses on chemical analyses (European water framework directory (WFD) and its daughter regulations). As usually not all substances in an environmental sample are analysed, but the mixture of all substances contributes to overall ecotoxicity, applying ecotoxicological tests is seen as a valuable supplemental method to chemical analysis, allowing to include the overall toxicity of all bioavailable substances in a mixture (3)(4)(5). At the same time, the sample volumes for the different tests are often restricted as obtaining and preparing water samples for monitoring is elaborate and costly. ...
... However, humans constantly encounter a variety of chemical mixtures including pesticides, household chemicals, cosmetics, food additives, among others. These chemicals are often introduced simultaneously and their combined effects, both on somatic and reproductive health, are currently understudied (Walker et al., 2021;Kortenkamp and Faust, 2018). How important adequate toxicologic evaluation of mixtures is for reproductive safety can be seen, for example, by a study from Conley et al. (2021), who observed male reproductive congenital defects after in utero exposure to a mixture of antiandrogenic chemicals at less than half of the NOAEL, delayed Considerations for designing studies for male reproductive toxicity testing. ...
Reproductive toxicology testing is essential to safeguard public health of current and future generations. Traditional toxicological testing of male reproduction has focused on evaluating substances for acute toxicity to the reproductive system, with fertility assessment as a main endpoint and infertility a main adverse outcome. Newer studies in the last few decades have significantly widened our understanding of what represents an adverse event in reproductive toxicology, and thus changed our perspective of what constitutes a reproductive toxicant, such as endocrine disrupting chemicals that affect fertility and offspring health in an intergenerational manner. Besides infertility or congenital abnormalities, adverse outcomes can present as increased likelihood for various health problems in offspring, including metabolic syndrome, neurodevelopmental problems like autism and increased cancer predisposition, among others. To enable toxicologic studies to accurately represent the population, toxicologic testing designs need to model changing population characteristics and exposure circumstances. Current trends of increasing importance in human reproduction include increased paternal age, with an associated decline of nicotinamide adenine dinucleotide (NAD), and a higher prevalence of obesity, both of which are factors that toxicological testing study design should account for. In this perspective article, we highlighted some limitations of standard testing protocols, the need for expanding the assessed reproductive endpoint by including genetic and epigenetic sperm parameters, and the potential of recent developments, including mixture testing, novel animal models, in vitro systems like organoids, multigenerational testing protocols, as well as in silico modelling, machine learning and artificial intelligence.
... Iron oxide is a non-carcinogenic compound for humans, based on International Agency for Research on Cancer (IARC) reports (Tomatis et al. 1978). However simultaneous exposure to airborne chemicals could have complicated outcomes (Alabi et al. 2021;Kortenkamp and Faust 2018;Thrupp et al. 2018). For example, co-exposure to iron and other substances showed different toxicities than from a single exposure to either (Guo et al. 2009;Zhang et al. 2018;Yousef et al. 2019;Rafieepour et al. 2021). ...
... Due to the persistence and high bioaccumulation potential of many legacy substances, the blood exposome of chemical compounds is dominated by a range of persistent organic pollutants (POPs) Stockholm Convention, 2019), including perfluoroalkyl substances (PFAS), organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) (Rappaport et al., 2014;Stockholm Convention, 2019). The health impacts of such complex exposures are difficult to predict from single-compound toxicology studies, as they do not reflect realistic exposure scenarios (Cordova et al., 2023;Escher et al., 2020;Kortenkamp and Faust, 2018). Exposure to POP mixtures may result in additive effects, but can also result in synergism or antagonism, depending on the compounds and their concentrations (Bopp et al., 2019;Kortenkamp, 2007;Pierozan et al., 2023;Rainey et al., 2017). ...
Chemical risk assessments typically focus on single substances, often overlooking real-world co-exposures to chemical mixtures. Mixture toxicology studies using representative mixtures can reveal potential chemical interactions, but these do not account for the unique chemical profiles that occur in the blood of diverse individuals. Here we used the H295R steroidogenesis assay to screen personalized mixtures of 24 persistent organic pollutants (POPs) for cytotoxicity and endocrine disruption. Each mixture was reconstructed at a human exposure relevant concentration (1×), as well as at 10- and 100-fold higher concentration (10×, 100×) by acoustic liquid handling based on measured blood concentrations in a Swedish cohort. Among the twelve mixtures tested, nine mixtures decreased the cell viability by 4–18%, primarily at the highest concentration. While the median and maximum mixtures based on the whole study population induced no measurable effects on steroidogenesis at any concentration, the personalized mixture from an individual with the lowest total POPs concentration was the only mixture that affected estradiol synthesis (35% increase at the 100× concentration). Mixtures reconstructed from blood levels of three different individuals stimulated testosterone synthesis at the 1× (11–15%) and 10× concentrations (12–16%), but not at the 100× concentration. This proof-of-principle personalized toxicity study illustrates that population-based representative chemical mixtures may not adequately account for the toxicological risks posed to individuals. It highlights the importance of testing a range of real-world mixtures at relevant concentrations to explore potential interactions and non-monotonic effects. Further toxicological studies of personalized contaminant mixtures could improve chemical risk assessment and advance the understanding of human health, as chemical exposome data become increasingly available.
... Despite serving as a barrier of protection, our skin can absorb some of the chemicals in these items, allowing them to interact with the systems in our bodies. There are numerous effects (101). ...
Over the past three decades, the popularity of cosmetic and personal care products has skyrocketed, largely driven by social media influence and the propagation of unrealistic beauty standards, especially among younger demographics. These products, promising enhanced appearance and self-esteem, have become integral to contemporary society. However, users of synthetic, chemical-based cosmetics are exposed to significantly higher risks than those opting for natural alternatives. The use of synthetic products has been associated with a variety of chronic diseases, including cancer, respiratory conditions, neurological disorders, and endocrine disruption. This review explores the toxicological impact of beauty and personal care products on human health, highlighting the dangers posed by various chemicals, the rise of natural ingredients, the intricate effects of chemical mixtures, the advent of nanotechnology in cosmetics, and the urgent need for robust regulatory measures to ensure safety. The paper emphasizes the necessity for thorough safety assessments, ethical ingredient sourcing, consumer education, and collaboration between governments, regulatory bodies, manufacturers, and consumers. As we delve into the latest discoveries and emerging trends in beauty product regulation and safety, it is clear that the protection of public health and well-being is a critical concern in this ever-evolving field.
... Multiple violations of trace elements (Mn, As, U, Pb, and Mo) are very common concurrently in the groundwater samples in the rift floor section of ZLB. This simultaneous occurrence of toxic elements could pose a further threat to human health through their mixture products (Bopp et al. 2018;Kortenkamp and Faust 2018). A mixture risk assessment is not considered in this work; however, the result suggests that groundwater of the study area possibly causes health concerns for the people consuming directly without any treatment from the groundwater sources. ...
The Ethiopian Rift Valley (ERV) is characterized by arid and semi-arid climate with groundwater as the most important water resource used for drinking and irrigation purposes. However, in the region, people are suffering from severe water scarcity exacerbated by climate effect. Besides water availability, endemic water quality issues are critical and affect the suitability of the water and human health risks. The present study evaluates the suitability of groundwater for drinking and agricultural purposes in the Ziway Lake Basin (ZLB) of the ERV. Groundwater used for drinking contains multiple inorganic contaminants in levels that surpass the World Health Organization recommended limits. The most frequent of these violations were for Na+, K+, HCO3−, F− and few samples for Mn, As, U, Pb and Mo. The modeled Drinking Water Quality Index (DWQI) values of the groundwater show wide variation ranging from 12.7 (Excellent category) to 714 (Unsuitable category) with mean value of 94. Likewise, Irrigation Water Quality Index (IWQI) computed by considering EC, SAR, Na%, RSC and PI of the groundwater varies from 13.2 to 520 with a mean value of 106. Both DWQI and IWQI values suggest that groundwater is generally of Excellent quality for drinking and irrigation use in the headwater regions of the ZLB and progressively becomes extremely Unsuitable toward the rift floor. The exceptionally high DWQI values to the west of Lake Ziway is mainly associated with the co-occurrence of multiple toxic elements from a groundwater from the Quaternary sediments and rhyolitic volcanic aquifers.
... Human exposure to chemicals in the environment will almost always be to complex mixtures of chemicals from different sources, among which are food, water, air, consumer products, and other media and sources [2,26,27]. Exposures may contain genotoxic compounds and/or compounds with capacity to modify genotoxic agents responses [28,29]. These genotoxic events can be related to early biologic effects and/or altered structure/function which constitute the biomarkers of effect. ...
... Even though the concentration of individual pesticides in surface waters may still be low or even below their guidelines, one should note that the co-occurrence of pesticides can be more toxic due to synergistic or additive effects. 29 Furthermore, many of their transformation products exhibit equal or greater persistence/toxicity in the environment, such as desethylatrazine (DEA) and metolachlor ethanesulfonic acid (metolachlor ESA). 30,31 It is therefore essential to monitor the occurrence of pesticides and their transformation products in waters and assess the potential risks they pose to ecosystems and human health. ...
The objective of this study was to investigate the occurrence, spatial distribution, and ecotoxicological risk of pesticides and transformation products in surface waters of western Montérégie (Quebec, Canada). A total of 29 samples were collected from 11 rivers during the summers of 2019 and 2021, and the samples were analyzed for 48 pesticides and 8 transformation products. The downstream data were used to assess the ecotoxicological risks based on Quebec's acute or chronic aquatic life criterion (AALC or CALC). Overall, 9 herbicides (glyphosate, S-metolachlor, 2,4-D, metribuzin, atrazine, MCPA, prometryn, dimethenamid, simazine), 3 insecticides (clothianidin, imidacloprid, chlorantraniliprole), and 4 fungicides (azoxystrobin, fluxapyroxad, tebuconazole, carbendazim) were detected at all sampling sites, demonstrating their widespread use in western Montérégie. Glyphosate (87–4095 ng L⁻¹), S-metolachlor (6–2519 ng L⁻¹), and 2,4-D (6–1094 ng L⁻¹) were identified as the most abundant pesticides in surface water. Furthermore, 6 pesticide transformation products (metolachlor ESA, AMPA, metolachlor OA, desethylatrazine, atrazine-2-hydroxy, desisopropylatrazine) were detected at all sampling sites. The concentration of transformation products accounted for 51% on average of the total concentration, demonstrating the abundance of transformation products in surface waters. Neonicotinoids exhibited the highest ecotoxicological risk in the surface water samples with an average CALC risk quotient of 28 for 2019 and 12 for 2021, respectively. The present study offers insights into pesticides occurrence and their ecological impacts on surface waters of western Montérégie and allows for supporting future pesticide management and ecotoxicological risk mitigation strategies.
... Therefore, the risks associated with mixtures should not be overlooked during detection. The quantity and composition of contaminants change over time, and certain compounds may display toxicity even below their individual effect thresholds or analytical detection limits [18]. For, example, Carina et al. discovered significant temporal variations in the distribution of E2 in the northern South China Sea [19], and E2 was also found to undergo transformation into E1 in soil [20]. ...
Background
The gaps between estrogenic effect and its effect-active compounds exist frequently due to a large number of compounds that have been reported to induce this effect and the occurrence of pollutants in environments as mixtures. Therefore, identifying the estrogen-active compounds is of importance for environmental management and pollution treatment. In the current study, the effect-directed analysis (EDA) and non-targeted screening (NTS) were integrated to identify the estrogen-active compounds in soils of the rural area with different socioeconomic types (industrial, farming and plantation village) in Northeast China.
Results
The cytotoxicity results indicated that the industrial and farming villages showed cytotoxic effects. The detection rates of estrogenic effects for samples of winter and summer were 100% and 87%, respectively. Of which, the effects were found to be stronger in summer than in winter, with significant difference observed from the farming village (0.1–11.3 EEQ μg/kg dry weight). A total of 159 chemicals were detected by NTS. By integrating EDA, triphenyl phosphate (TPhP) and indole were successfully identified from a raw sample and its fraction, explaining up to 19.31% of the estrogen activity.
Conclusions
The present study demonstrates that the successful identification of seven estrogen-active compounds in rural areas of northeastern China can be achieved through the combination of effect-directed analysis (EDA) and non-targeted screening (NTS). This finding is beneficial for risk monitoring and pollution management.
... Concerns about the combined effect of exposure to chemicals in mixtures have been widely acknowledged (Drakvik et al., 2020;European Commission, 2012;Kortenkamp and Faust, 2018). Despite these concerns, hazard assessment of individual compounds remains predominant, and a greater examination of chemical mixtures is needed (Bopp et al., 2019;Escher et al., 2022;Heys et al., 2016). ...
The presence of aniline, a toxic aromatic amine, has been recorded in different industrial wastewaters. This study aims to investigate the transport of charged and neutral aniline species in aqueous solutions through hydrophobic and ion-exchange membranes (IEMs). Hydrophobic polyoctylmethylsiloxane (POMS) and polydimethylsiloxane (PDMS) membranes and cationic (CEMs) and anionic (AEMs) exchange membranes were tested using diffusion cells and electrodialysis (ED). Diffusion experiments showed that neutral aniline removal reached 90% with POMS and 100% with PDMS due to the concentration gradient between feed (pH = 10) and receiving (pH = 3) solutions. For IEMs, neutral aniline exhibited a faster transport than charged species, with neutral-to-charged transport ratios of 6.6:1 for AEMs and 3.2:1 for CEMs, type I. During ED experiments, an external electric potential increased the charged aniline transport, achieving higher initial fluxes (124.7 mmol·m2·h−1 at pH 4) compared to neutral aniline (43.6 and 53.2 mmol·m2·h−1 for AEMs and CEMs, type I). ED also demonstrated that charged aniline can be removed up to 97% using IEMs. These findings demonstrate the effectiveness of hydrophobic and IEMs in removing aniline, providing insights into its transport mechanism, contributing to the optimization of membrane technologies in treating industrial wastewater effluents, and environmental sustainability.
Organophosphate and pyrethroid pesticides are common contaminants in cannabis. Due to the status of cannabis as an illicit Schedule I substance at the federal level, there are no unified national guidelines in the U.S. to mitigate the health risk of pesticide exposure in cannabis. Here, we examined the change in the state-level regulations of organophosphate and pyrethroid pesticides in cannabis. The medians of pyrethroid and organophosphate pesticides specified by each state-level jurisdiction increased from zero pesticide in 2019 to 4.5 pyrethroid and 7 organophosphate pesticides in 2023, respectively. Next, we evaluated the potential connections between pyrethroids, organophosphates, cannabinoids, and Parkinson’s disease using the Comparative Toxicogenomics Database (CTD). Eleven pyrethroids, 30 organophosphates, and 14 cannabinoids were associated with 95 genes to form 3,237 inferred and curated Chemical-Gene-Phenotype-Disease tetramers. Using a behavioral repulsion assay with the whole organism model Caenorhabditis elegans, we examined the effect of cannabinoids and insecticides on depleting dopamine synthesis. Exposure to chlorpyrifos and permethrin, but not Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), results in dose-dependent effects on 1-nonanol repulsive behaviors in C. elegans, indicating dopaminergic neurotoxicity (p < 0.01). Dose-dependent effects of chlorpyrifos are different in the presence of Δ9-THC and CBD (p < 0.001). As a proof of concept, this study demonstrated how to use new approach methodologies such as C. elegans and the CTD to inform further testing and pesticide regulations in cannabis by chemical class.
Pesticide active ingredients (PAIs) are regularly detected in the rivers, creeks, wetlands, and inshore waterways that discharge to the Great Barrier Reef (GBR) lagoon. Pesticide active ingredients detected above ecologically protective concentrations may pose a hazard and risk to aquatic species. The ability to assess this hazard and risk is reliant on the availability of water quality guidelines, which are only available for a limited number of PAIs detected in GBR catchment waterways. Unendorsed guideline values, known as ecotoxicity threshold values (ETVs) were developed in part one of this study for active ingredients in two fungicides (4-hydroxychlorothalonil (fungicide degradate) and carbendazim) and two insecticides (dimethoate and methoxyfenozide) that are commonly detected in GBR catchment waterways. In the current study, the hazard and risk posed by these PAIs was assessed by comparing the ETVs to environmental monitoring data from the Great Barrier Reef Catchment Loads Monitoring Program. Exceedances of the concentrations that should protect 99 % of aquatic species (i.e., PC99) were observed for all four pesticides. Detected concentrations of 4-hydroxychlorothalonil, carbendazim and methoxyfenozide exceeded the PC95 ETV, however no exceedances of the PC95 were observed for dimethoate. The hazard quotient (HQ) method was used to identify high hazard sites across the GBR catchment area. In total, six sites were identified as having concentrations that exceeded the PC95 ETVs. For 4-hydroxychlorothalonil, the risk to aquatic species based on the 95th percentile concentrations ranged from 3 to 13 %, 1 to 8 %for carbendazim and 2 to 8 % for methoxyfenozide. Detected concentrations of carbendazim were two orders of magnitude higher than concentrations that are reported to induce behavioural effects in some fish species. Considering that detected concentrations of three of the four PAIs individually pose a potential risk to aquatic species, their contributions to pesticide mixture toxicity should be further assessed.
Emerging evidence reveals that low doses of stress stimulate, and high doses suppress, organism responses - a phenomenon known as hormesis. Here, we propose a framework for harnessing hormesis principles to optimize agrochemical use and mitigate pollution. We discuss how hormesis can be applied in agrochemical context and highlight challenges and needs beyond scientific research, offering a perspective for sustainable environmental solutions.
Persistent organic pollutants (POPs) affect human health through the aryl hydrocarbon receptor (AhR) pathway and are implicated in mitochondrial dysfunction. Using data from the PIVUS study, we investigated the associations of serum AhR ligand (POP)-mediated luciferase activity (AhRL), mitochondrial ATP production inhibiting substances (MIS-ATP), and those affecting reactive oxygen species (MIS-ROS) with several metabolic syndrome (MetS) and cardiopulmonary function parameters. These include insulin resistance (HOMA-IR), inflammation, oxidative stress, and cardiopulmonary variables (FVC, FEV1, LV-EF, CCA distensibility). MIS-ATP showed significant correlations with HOMA-IR and pulmonary functions, indicating its direct impact of MIS-ATP on metabolic and pulmonary health. MIS-ROS correlated with oxidative stress markers and CCA distensibility, suggesting a role in systemic inflammatory responses. This study highlights the intricate relationships between environmental pollutant mixture and cardiopulmonary health in MetS as indicated by biomarkers of POP exposure in the elderly population, suggesting POP exposure may influence MetS onset and progression through mitochondrial dysfunction.
Exposure to hazardous chemicals in consumer products poses significant risks to personal health and the environment, and the combined effects may be negative even if each individual exposure is low. This necessitates informed and effective policies for risk reduction.
This systematic review aims to identify and analyse existing evidence on how consumer preferences, product use, and product disposal are affected by information on harmful chemicals in consumer products and by price interventions. The review is conducted according to the PRISMA 2020 guidelines, synthesises forty-eight scientific articles on the relationship between information and consumer responses. No corresponding studies on the effects of price interventions were found. A large share of the identified articles focused on household chemicals, where warning labels are common, while less has been published on “everyday products” where the presence of hazardous chemicals is less clear to consumers. Effects of information on hazardous chemicals on consumer behaviour are highly contextual and dependent on the type of product, consumer behaviour and what kind of label is used. Warning symbols are effective in communicating a general warning of a potential danger, although consumers often misinterpret specifics regarding the exact nature of that danger or what means should be taken to minimise it. Informational texts are more informative but are also often missed or quickly forgotten. Consumer willingness to pay for safer products is generally positive but low. Additional research on how consumers react to information and price signals on chemical hazards is needed to improve policy design.
Güilt-Oumrait et al. leveraged data from the Human Early Life Exposome project, one of the most extensive population-based, early-life exposome cohorts available. The authors found that
elevated maternal prenatal exposure to 4 families of persistent environmental chemicals—metals, organochlorine compounds, polybrominated diphenyl ethers, and perfluoroalkyl substances (PFAS) — was associated with a significant increased risk of MetS in children aged 6 to 11 years.1 Drawing from preharmonized data amalgamated across 6 European mother-child cohorts, the study also integrated a panel of metabolic markers measured in children’s serum and urine. Results from the biomarker analysis added further support to the biological plausibility of the primary associations.
This research stands out as one of the most comprehensive endeavors delving into early-life environmental origins of metabolic risk, further bolstering prior toxicological and epidemiological
evidence in this area. In this commentary we put this work in context and discuss the implications for the field, including the available evidence to reduce the accumulated body burden of persistent chemicals and/or ways in which their adverse effects could be mitigated. Only by successfully addressing this challenge will we be fully equipped to break the cycle of accumulated exposure to persistent chemicals and their adverse multigenerational
metabolic and developmental health effects.
PBAT-modified starch blended film are thermoplastic biodegradable materials with good properties and a wide range of applications. In this study, L-02 cells were used as an in vitro toxicity evaluation system for risk assessment of PBAT-modified starch films with migration studies obtained in different food simulants. Determination of total migration and organic matter revealed that the results were in accordance with the standard except for the total organic matter under 95% (v/v) ethanol food simulant which exceeded the standard. The CCK-8 assay showed that these compounds affect the cell viability of L-02 cells. It was observed that the compounds made the cells express increased AST, ALT, TNF-α, IL-6, IL-1β, and ROS, and decreased SOD, GSH, and ATP. In addition, we explored the effect of migration in PBAT-modified starch composites on protein and gene expression levels in L-02 cells using a transcriptomic approach and found that the AMPK signaling pathway was affected. The expression of AMPK signaling pathway-related proteins was detected by Western Blot, and the expression levels of p-AMPK/AMPK were found to be upregulated, and those of p-mTOR/mTOR, SIRT1, PGC-1α, NRF1 and TFAM were downregulated. The above data suggest that the compounds migrating into the PBAT-modified starch film when exposed to food may induce oxidative stress and inflammation in hepatocytes, and may cause damage to hepatocytes through the AMPK pathway.
BACKGROUND:
Through the food and water they ingest, the air they breathe, and the consumer products with which they interact at home and at work, humans are exposed to tens of thousands of chemicals, many of which have not been evaluated to determine their potential toxicities. Furthermore, while current chemical testing tends to focus on individual chemicals, the exposures that people actually experience involve mixtures of chemicals. Unfortunately, the number of mixtures that can be formed from the thousands of environmental chemicals is enormous, and testing all of them would be impossible.
OBJECTIVES:
We seek to develop and demonstrate a method for identifying those mixtures that are most prevalent in humans.
METHODS:
We applied frequent itemset mining, a technique traditionally used for market basket analysis, to biomonitoring data from the 2009–2010 cycle of the continuous National Health and Nutrition Examination Survey (NHANES) to identify combinations of chemicals that frequently co-occur in people.
RESULTS:
We identified 90 chemical combinations consisting of relatively few chemicals that occur in at least 30% of the U.S. population, as well as three supercombinations consisting of relatively many chemicals that occur in a small but nonnegligible proportion of the U.S. population.
CONCLUSIONS:
We demonstrated how FIM can be used in conjunction with biomonitoring data to narrow a large number of possible chemical combinations down to a smaller set of prevalent chemical combinations.
Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.
The risk posed by complex chemical mixtures in the environment to wildlife and humans is increasingly debated, but has been
rarely tested under environmentally relevant scenarios. To address this issue, two mixtures of 14 or 19 substances of concern
(pesticides, pharmaceuticals, heavy metals, polyaromatic hydrocarbons, a surfactant, and a plasticizer), each present at its
safety limit concentration imposed by the European legislation, were prepared and tested for their toxic effects. The effects
of the mixtures were assessed in 35 bioassays, based on 11 organisms representing different trophic levels. A consortium of
16 laboratories was involved in performing the bioassays. The mixtures elicited quantifiable toxic effects on some of the
test systems employed, including i) changes in marine microbial composition, ii) microalgae toxicity, iii) immobilization
in the crustacean Daphnia magna, iv) fish embryo toxicity, v) impaired frog embryo development, and vi) increased expression on oxidative stress-linked reporter
genes. Estrogenic activity close to regulatory safety limit concentrations was uncovered by receptor-binding assays. The results
highlight the need of precautionary actions on the assessment of chemical mixtures even in cases where individual toxicants
are present at seemingly harmless concentrations.
Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment.
The way in which mixture risk assessment (MRA) should be included in chemical risk assessment is a current topic of debate. We used data from 67 recent pesticide evaluations to build a case study using Hazard Index calculations to form risk estimates in a tiered MRA approach in line with a Framework proposed by WHO/IPCS. The case study is used to illustrate the approach and to add detail to the existing Framework, and includes many more chemicals than previous case studies.
A low-tier MRA identified risk as being greater than acceptable, but refining risk estimates in higher tiers was not possible due to data requirements not being readily met. Our analysis identifies data requirements, which typically expand dramatically in higher tiers, as being the likely cause for an MRA to fail in many realistic cases. This forms a major obstacle to routine implementation of MRA and shows the need for systematic generation and collection of toxicological data. In low tiers, hazard quotient inspection identifies chemicals that contribute most to the HI value and thus require attention if further refinement is needed. Implementing MRA requires consensus on issues such as scope setting, criteria for performing refinement, and decision criteria for actions.
Today's chemical exposures are characterised by a widely spread blanket of contamination composed of myriads of chemicals, many of them endocrine disrupters, all at rather low levels. With their focus on considering single chemicals one by one, the approaches used by regulatory bodies worldwide for safety assessments of chemicals cannot keep up with these pollution patterns. A substantial challenge lies in the assessment of combination effects from large numbers of endocrine disrupters and other chemicals, all at low doses. We retrace the development of experimental and conceptual approaches required for assessing low dose mixtures, with an emphasis on work with endocrine disrupting chemicals. We find that nearly 20 years of research has produced good evidence for combination effects at levels around experimental thresholds. One obstacle in deciding on the relevance of this evidence is incomplete information about the range of endocrine-disrupting chemicals that make up combined exposures. These knowledge gaps need to be closed urgently, as is currently discussed under the heading of exposome research.
The toxicity of eight complex mixtures of chemicals with different chemical structures and toxicological modes of action (narcotics, polar narcotics, herbicides, insecticides, fungicides) was tested on the luminescent bacterium Vibrio fischeri. There were maximum 84 individual chemicals in the mixtures. Suitable statistical approaches were applied for the comparison between experimental results and theoretical predictions. The results demonstrated that the two models of Concentration Addition (CA) and Independent Action (IA) are suitable to explain the effect of the mixtures.Even extremely lower concentrations of individual chemicals contributed to the effect of the mixtures. Synergistic effects were not observed in any of the tested mixtures. In particular, the CA approach well predicted the effects of six out of eight mixtures and slightly overestimated the effects of the remaining two mixtures. Therefore, the CA model can be proposed as a pragmatic and adequately protective approach for regulatory purposes.
There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.
The detection of drugs in drinking water sources has raised questions related to safety. In the absence of regulatory or other official guidance, water utilities are faced with a problem of which drugs should be monitored and the detection limits that should be required. The US FDA summarizes data required for drug approval and post marketing adverse reaction reporting. The use of these data as a means of arriving at concentrations in water where adverse health effects are minimal or non-existent was explored. The minimum therapeutic dose was assumed an appropriate point of departure. Appropriate uncertainty factors could be applied depending upon the qualitative and quantitative nature of the data that are available. Assumptions inherent in US FDA's approval of drugs for use in subsets of the population relative to the broader concerns that arise for exposures of the entire population had to be considered. Additional questions are; whether the drug under consideration is carcinogenic, carries pregnancy and lactation warnings, approval for limited vs. chronic use, exposures to multiple compounds that could act in additive or synergistic ways, and the seriousness of toxicities that are observed. Aside from these considerations, a combined uncertainty factor of 1000 appeared adequate.
A review that focuses on small molecules and does not treat the large and growing design, testing, and use of biodegradable polymers is presented. The effects of chemical chemical structure and environmental variables on biodegrability, with emphasis on generalizations that can be applied in chemical design is also discussed. The chemicals that are reviewed include alkylbenzene sulfonates, dialkyl quaternaries, chelants/ sequestrants, drilling base fluids, vegetable oil-based functional fluids, ionic liquids, antiseptic/disinfectants, musk fragrances, gasoline oxygenates, and alkylphenol ethoxylates. Since all computer models only represent approximations of imperfect underlying data, predictive models based on rules of thumb provide a convenient way for chemists in research and development to easily compare alternatives.
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Regulate to reduce chemical mixture risk