Toxicity Thresholds Research Articles

Storms mobilize organophosphate esters, bisphenols, PFASs, and vehicle-derived contaminants to San Francisco Bay watersheds.

In urban to peri-urban watersheds such as those surrounding San Francisco Bay, stormwater runoff is a major pathway by which contaminants enter aquatic ecosystems. We evaluated the occurrence of 154 organic contaminants via liquid chromatography coupled to tandem mass spectrometry, including organophosphate esters (OPEs), bisphenols, per- and polyfluoroalkyl substances (PFASs), and a suite of novel urban stormwater tracers (SWCECs; i.e., vehicle-derived chemicals, pesticides, pharmaceuticals/personal care products, benzothiazoles/benzotriazoles). Time-averaged composite sampling focused on storms in highly developed watersheds over four wet seasons, with complementary sampling in less-urban reference watersheds, near-shore estuarine sites, and the open Bay. Of the targeted contaminants, 68 (21 SWCECs, 29 OPEs, 3 bisphenols, 15 PFASs) were detected in ≥10 of 26 urban stormwater samples. Median concentrations exceeded 500 ng L-1 for 1,3-diphenylguanidine, hexa(methoxymethyl)melamine, and caffeine, and exceeded 300 ng L-1 for 2-hydroxy-benzothiazole, 5-methyl-1H-benzotriazole, pentachlorophenol, and tris(2-butoxyethyl) phosphate. Median individual PFAS concentrations were <10 ng L-1, with highest concentrations for PFHxA (180 ng L-1), PFOA (110 ng L-1), and PFOS (81 ng L-1). In six of eight urban stormwater samples analyzed for 6PPD-quinone (a tire rubber-derived transformation product), concentrations exceeded coho salmon acute toxicity thresholds, suggesting (sub)lethal impacts for sensitive species. Observed concentrations were generally significantly higher in highly developed watersheds relative to reference watersheds, but not statistically different in near-shore estuarine sites, suggesting substantial transient exposure potential at stormwater outfalls or creek outflows. Results emphasized the role of stormwater in contaminant transport, the importance of vehicles/roadways as contaminant sources, and the value of monitoring broad multi-analyte contaminant suites to enable comprehensive source and toxicity evaluations.

Diuretic drug utilization in neonates: a French prescription database analysis.

Background: The use of diuretics is extremely common in infants cared for in neonatal wards, despite the lack of proven efficacy for many conditions. The main objective of this study was to assess the rate of diuretics exposure in a multicenter French cohort. The secondary objectives were to describe the evolution of this exposure over time, the indications, the prescription practices, and the exposure rates among centers. Methods: An observational study was conducted in 40 Level 3 French neonatal intensive care units using the same computerized order-entry system. Neonates hospitalized between January 2017 to December 2021 with a corrected age between 24 and 44weeks of gestation at admission were eligible. Results: A total of 86,032 patients were included. The exposure rate was 8.5%, more specifically 29.4% for children born at < 32weeks of gestation and 3.7% for neonates born at term. There was no significant variation over the study period, but the exposure ranged from 2.4% to 26.5% depending on the center. The main drugs prescribed were furosemide, spironolactone and dopamine with a diuretic purpose. The main indications were "fluid retention," and to a lesser extent "bronchopulmonary dysplasia" and "post-transfusion." For furosemide, the first exposure occurred in mean at 16.5 (±17.8) days of life, mean duration of exposure was 6.2 (±9.5) days, and the cumulative dose was in mean 10.7 (23.9) mg/kg. Conclusion: Diuretic prescription practices vary between centers. The administration of these drugs is often non-evidence based, doses and duration of treatment easily exceed toxic thresholds.

Nontoxic effects of thymol, carvacrol, cinnamaldehyde, and garlic oil on dung beetles: A potential alternative to ecotoxic anthelmintics.

The sustainability of the traditional extensive livestock sector will only be possible if healthy dung-decomposing insect communities are preserved. However, many current pharmaceutical anthelmintics are harmful to dung beetles, their presence can have a negative impact on biological systems. Phytochemical anthelmintics are an alternative to ecotoxic synthetic pharmaceutical anthelmintics, although ecotoxicological tests of their possible indirect effects on dung beetles are required to demonstrate their viability. In this study, the potential ecotoxicity of thymol, carvacrol, cinnamaldehyde and garlic oil (diallyl disulfide and diallyl trisulfide) were tested for the first time. Inhibition of antennal response was measured as a relevant parameter by obtaining relevant toxicity thresholds derived from concentration‒response curves, such as the IC50. All phytochemical compounds tested were demonstrated to be suitable alternative candidates to the highly ecotoxic compound ivermectin, considering their non-toxicity to nontarget organisms. Residues of the phytochemical antiparasitics found in cattle droppings were extremely low, even undetectable in the case of diallyl disulfide and diallyl trisulfide. Furthermore, our results showed that none of the phytochemical compounds have ecotoxic effects, even at extremely high concentrations, including those almost 1000 times higher than what is most likely to be found in dung susceptible to ingestion by dung beetles in the field. We can conclude that the four selected phytochemical compounds meet the requirements to be considered reliable alternatives to ecotoxic veterinary medicinal products, such as ivermectin.

Pesticide Mixtures in Surface Waters of Two Protected Areas in Southwestern Germany

Pesticides enter non-target surface waters as a result of agricultural activities and may reach water bodies in protected areas. We measured in southwestern Germany pesticide concentrations after heavy rainfalls in streams of a drinking water protection area near Hausen (Freiburg) and in the catchment of the Queich (Landau), which originates from the biosphere reserve Palatinate Forest. On average, 32 (n = 21) and 21 (n = 10) pesticides were detected per sample and event in the area of Hausen (n = 56) and in the Queich catchment (n = 17), respectively. The majority of pesticides detected in > 50% of all samples were fungicides, with fluopyram being detected throughout all samples. Aquatic invertebrates exhibited highest risks with 16.1% of samples exceeding mixture toxicity thresholds, whereas risks were lower for aquatic plants (12.9%) and fish (6.5%). Mixture toxicity threshold exceedances indicate adverse ecological effects to occur at half of sites (50%). This study illustrates the presence of pesticide mixtures and highlights ecological risks for aquatic organisms in surface waters of protected areas in Germany.

A first estimation of the role of penguin guano on copper cycling and organic speciation in Antarctic coastal waters

Cu is a vital micronutrient, but free Cu ions (Cu2+) in seawater, even at subnanomolar concentrations, can impede phytoplankton growth. Natural Cu complexation with organic ligands regulates Cu acquisition and, in most instances, reduces Cu2+ concentrations below toxic thresholds. Along the Antarctic coast, the sources and sinks of Cu and its associated ligands remain poorly defined. Despite the high productivity in the area, there are no studies on the role of trophic transfer in Cu cycling.This study explores penguin guano release of Cu and Cu ligands and its potential in neutralizing copper toxicity along the Antarctic coast. We collected guano in a Chinstrap penguin nesting location in the West coast of Deception Island and extracted its components into aqueous solution imitating natural processes. Copper concentration in guano was 0.4 mg (dry weight g)−1 constituting a potential toxic threat and showed biomagnification with respect to krill. Surface seawater samples collected from various locations varying in penguin activity, were analyzed to assess the potential influence of guano on the area. Visual examination and elevated levels of Al suggested that a substantial portion of guano was lithogenic. Consequently, only a modest 16 % of the total Cu present in guano could be extracted using mechanical methods. Notably, the concentrations of the extracted organic ligands were approximately 23 times higher than the concentrations of the extracted Cu. This significant presence of ligands effectively nullifies any potential toxicity that could have arisen from free Cu2+ ions. Guano ligands' conditional stability constants were lower than those in surface seawater suggesting phytoplankton exudation was the main ligand source in the area. Overall, guano acts as a key node for Cu cycling in coastal Antarctic waters but its deleterious potential is neutralized by ligands from krill digestion and the high background concentration of phytoplankton exudates.

Assessment of the impacts of GABA and AChE targeting pesticides on freshwater invertebrate family richness in English Rivers

Globally, riverine system biodiversity is threatened by a range of stressors, spanning pollution, sedimentation, alterations to water flow, and climate change. Pesticides have been associated with population level impacts on freshwater invertebrates for acute high-level exposures, but far less is known about the chronic impact of episodic exposure to specific classes of pesticides or their mixtures. Here we employed the use of the UK Environment Agency's monitoring datasets over 40 years (covering years 1980 to 2019) to assess the impacts of AChE (acetylcholinesterase) and GABA (gamma-aminobutyric acid) receptor targeting pesticides on invertebrate family richness at English river sites. Concentrations of AChE and GABA pesticides toxic to freshwater invertebrates occurred (measured) across 18 of the 66 river sites assessed. For one of the three river sites (all found in the Midlands region of England) where data recorded over the past 40 years were sufficient for robust modelling studies, both AChE and GABA pesticides associated with invertebrate family richness. Here, where AChE total pesticide concentrations were classified as high, 46 of 64 invertebrate families were absent, and where GABA total pesticide concentration were classified as high, 16 of 64 invertebrate families were absent. Using a combination of field evidence and laboratory toxicity thresholds for population relevant endpoints we identify families of invertebrates most at risk in the selected English rivers to AChE and GABA pesticides. We, furthermore, provide strong evidence that the absence of the invertebrate family Polycentropodidae (caddisfly) from one field site is due to exposure effects to AChE pesticides.

Occurrence and Health Risks of Organic Micropollutants in Tap Water in Dalian.

Organic micropollutants (OMPs) in tap water may pose risks to human health. Previous studies on the potential health risks of OMPs in tap water may have underestimated the potential health risks of OMPs due to their limited coverage in target pollutants and incomplete toxicity data. In this study, tap water samples were collected in 37 sampling sites in Dalian, China. More than 1,200 target pollutants were screened by combining screening analysis and target analysis. A total of 93 OMPs were detected, with concentration summation ranging from 157 to 1.7 × 104 ng/L among different sampling sites. A total of 17 OMPs (12 agrochemicals, 3 pharmaceuticals and personal care products, and 2 other compounds) were detected in over 80% of the sampling sites. Especially, imidacloprid, tebuconazole, and atrazine-desethyl were found in all the sampling sites. Computational toxicology models were adopted to predict the missing toxicity threshold values of the identified chemicals. Noncarcinogenic risks were estimated to be negligible among all the sampling sites, while carcinogenic risks at six sites were above 10-6 but below 10-4, indicating non-negligible risks. Griseofulvin contributed the most to the carcinogenic risk. This study offers valuable insights that can guide future initiatives to safeguard tap water safety.

Spatiotemporal Trends Spanning Three Decades Show Toxic Levels of Chemical Contaminants in Marine Mammals.

Despite their ban and restriction under the 2001 Stockholm Convention, persistent organic pollutants (POPs) are still widespread and pervasive in the environment. Releases of these toxic and bioaccumulative chemicals are ongoing, and their contribution to population declines of marine mammals is of global concern. To safeguard their survival, it is of paramount importance to understand the effectiveness of mitigation measures. Using one of the world's largest marine mammals strandings data sets, we combine published and unpublished data to examine pollutant concentrations in 11 species that stranded along the coast of Great Britain to quantify spatiotemporal trends over three decades and identify species and regions where pollutants pose the greatest threat. We find that although levels of pollutants have decreased overall, there is significant spatial and taxonomic heterogeneity such that pollutants remain a threat to biodiversity in several species and regions. Of individuals sampled within the most recent five years (2014-2018), 48% of individuals exhibited a concentration known to exceed toxic thresholds. Notably, pollutant concentrations are highest in long-lived, apex odontocetes (e.g., killer whales (Orcinus orca), bottlenose dolphins (Tursiops truncatus), and white-beaked dolphins (Lagenorhynchus albirostris)) and were significantly higher in animals that stranded on more industrialized coastlines. At the present concentrations, POPs are likely to be significantly impacting marine mammal health. We conclude that more effective international elimination and mitigation strategies are urgently needed to address this critical issue for the global ocean health.

Accumulation of livestock manure–derived heavy metals in the Hexi Corridor oasis agricultural alkaline soil and bioavailability to Chinese cabbage (Brassica pekinensis L.) after 4-year continuous application

Hexi Corridor is one of the most important base of vegetable producing areas in China. Livestock manure (LM) applied to agricultural field could lead to soil heavy metal (HM) pollution. Previous studies have focused on HM pollution following LM application in acidic polluted soils; however, fewer studies have been conducted in alkaline unpolluted soils. A 4–year field vegetable production experiment was conducted using pig manure (PM) and chicken manure (CM) at five application rates (0, 15, 30, 45, and 60 t ha−1) to elucidate potential risks of HMs in an alkaline unpolluted soil in the Hexi Corridor oasis agricultural area and HM uptake by Chinese cabbage. The results showed that LM application caused a significant build–up of Cu, Zn, Pb, Cd, and Ni content in topsoil by 30.6–99.7%, 11.4–51.7%, 1.4–31.3%, 5.6–44.9%, 14%–40.8%, respectively. The Cd, Cu, Zn could potentially exceed the soil threshold in next 8–65 years after 15–60 t ha−1 LM application. Under LM treatment, the soil DTPA–extractable Cu, Zn, Fe, the acid–extractable fraction of Cu, Zn, Fe, Cd, Ni, and the Oxidable fraction of Cu, Zn, Fe, Mn, Cd, Ni significantly increased, but the DTPA–extractable Pb, Cd, the acid–extractable fraction of Pb, and the reducible fraction of Cd significantly decreased. Cu and Zn could migrate to the deeper soil and relatively increase in DTPA–extracted Cu, Zn were found in 20–40 cm soil depth after LM application. The pH and SOM could influence the bioavailability of HMs in soil. The bioaccumulation factor and transfer factor (TF) values were <1 except Mn (TF > 1). HMs in leaf did not approach the threshold for HM toxicity due to the “dilution effect”. Recommend the type of manure was the PM and the annual PM application rate was 30 t ha−1 to ensure a 20–year period of clean production in alkaline unpolluted Fluvo–aqiuc vegetable soils.

Lithological controls on lake water biogeochemistry in Maritime Antarctica

Although the Antarctic lakes are of great importance for the climate and the carbon cycle, the lithological influences on the input of elements that are necessary for phytoplankton in lakes have so far been insufficiently investigated. To address this issue, we analyzed phytoplankton cell concentrations and chemical compositions of water samples from lakes, ponds and a stream on Fildes and Ardley Islands of King George Island in the South Shetland Archipelago. Furthermore, lake sediments, as well as soil and rock samples collected from the littoral zone were analyzed for their mineralogical/petrographic composition and pollutant contents of polycyclic aromatic hydrocarbons (PAHs). In addition, leaching experiments were carried out to with the lithologic samples to investigate the possible changes in pH, alkalinity, macronutrients (N, P, Si), micronutrients (e.g. Fe, Zn, Cu, Mn), anions (S, F, Br), and other cations (e.g. Na, K, Mg, Ca, Al, Ti, V, Cr, Co, Ni, As, Se, Pb, Sb, Mo, Ag, Cd, Sn, Ba, Tl, B). Our results showed that phytoplankton levels varied between 15 and 206 cells/mL. Chlorophyll-a concentrations showed high correlations with NH4, NO3. The low levels of PO4 (<0.001 mg/L) indicated a possible P-limitation in the studied lakes. The composition of rock samples ranged from basalt to trachybasalt with variable major oxide (e.g. SiO2, Na2O and K2O) contents and consist mainly quartz, albite, calcite, dolomite and zeolite minerals. The concentrations of total PAHs were below the toxic threshold levels (9.55–131.25 ng g−1 dw). Leaching experiments with lithologic samples indicated major increase in pH (up to 9.77 ± 0.02) and nutrients, especially PO4 (1.03 ± 0.04 mg/L), indicating a strong P-fertilization impact in increased melting scenarios. Whereas, toxic elements such as Pb, Cu, Cd, Al and As were also released from the lithology, which may reduce the phytoplankton growth.

Intraspecific and geographical variation in rodenticide exposure among common kestrels in Tenerife (Canary Islands)

This study assesses the impact of second-generation anticoagulant rodenticides (SGARs) on the common kestrel (Falco tinnunculus canariensis) in Tenerife, Canary Islands. The analysis of 390 liver samples over 19 years using HPLC-MS/MS showed that 93.1 % of kestrels were exposed to SGARs in this island. A notable shift in SGAR profiles was observed, with bromadiolone and flocoumafen decreasing, while brodifacoum levels increased sharply from 2018 onwards. Comparatively, Tenerife kestrels had a higher detection frequency of SGARs (93.1 %) than those in the rest of the islands of the archipelago (68.2 %), with median concentrations nearly double (∑AR = 180.9 vs 102.4 ng/g liver, P < 0.0001). Furthermore, on average, kestrels from Tenerife were found to have a higher number of different rodenticide compounds per individual. A Generalized Linear Model (GLM) analysis revealed that several factors contribute to the likelihood of SGAR exposure: being an adult kestrel, the enactment of legal restrictions on SGAR bait concentrations in 2018, higher livestock density, and greater human population density. These findings suggest that both bioaccumulation over the birds' lifespans and environmental factors related to human and agricultural activity are influencing the levels of SGARs detected. Alarmingly, 44.7 % of kestrels had SGAR levels above the toxicity threshold established for other raptor species (200 ng/g liver), signaling a high poisoning risk. This is despite EU regulations to protect wildlife, with our findings indicating an increase in both exposure rates and SGAR concentrations since these laws were enacted. The data highlight a critical environmental threat to endemic species on islands like Tenerife. The common kestrel, not considered globally endangered, is nonetheless facing regional threats from SGAR contamination. These results emphasize the urgent need for effective regulations to address the persistent and growing impact of SGARs on island biodiversity.

The Uptake of Rare Trace Elements by Perennial Ryegrass (Lolium perenne L.).

Technological development has increased the use of chemical elements that have hitherto received scant scientific attention as environmental contaminants. Successful management of these rare trace elements (RTEs) requires elucidation of their mobility in the soil-plant system. We aimed to determine the capacity of Lolium perenne (a common pasture species) to tolerate and accumulate the RTEs Be, Ga, In, La, Ce, Nd, and Gd in a fluvial recent soil. Cadmium was used as a reference as a well-studied contaminant that is relatively mobile in the soil-plant system. Soil was spiked with 2.5-283 mg kg-1 of RTE or Cd salts, representing five, 10, 20, and 40 times their background concentrations in soil. For Be, Ce, In, and La, there was no growth reduction, even at the highest soil concentrations (76, 1132, 10.2, and 874 mg kg-1, respectively), which resulted in foliar concentrations of 7.1, 12, 0.11, and 50 mg kg-1, respectively. The maximum no-biomass reduction foliar concentrations for Cd, Gd, Nd, and Ga were 0.061, 0.1, 7.1, and 11 mg kg-1, respectively. Bioaccumulation coefficients ranged from 0.0030-0.95, and increased Ce < In < Nd ≅ Gd < La ≅ Be ≅ Ga < Cd. Beryllium and La were the RTEs most at risk of entering the food chain via L. perenne, as their toxicity thresholds were not reached in the ranges tested, and the bioaccumulation coefficient (plant/soil concentration quotient) trends indicated that uptake would continue to increase at higher soil concentrations. In contrast, In and Ce were the elements least likely to enter the food chain. Further research should repeat the experiments in different soil types or with different plant species to test the robustness of the findings.

Golcadomide (GOLCA; CC-99282), a Novel CELMoD Agent, Plus R-CHOP in Patients (pts) with Previously Untreated Aggressive B-Cell Lymphoma (a-BCL): Safety and Efficacy Results from Phase 1b Dose Expansion

Introduction Up to 40% of pts with diffuse large B-cell lymphoma (DLBCL) relapse after first-line chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). CELMoD agents such as GOLCA potently degrade target proteins Ikaros/Aiolos, resulting in antiproliferative, apoptotic, and immunomodulatory activity. GOLCA preferentially distributes to tissues and lymphoid organs. In a phase 1 study, GOLCA demonstrated a manageable safety profile with promising clinical activity as monotherapy in relapsed/refractory non-Hodgkin lymphoma (Michot et al. Blood 2021). CC-220-DLBCL-001 (NCT04884035) is an ongoing open-label, multicenter, dose escalation and expansion trial to assess safety and preliminary efficacy of CELMoD agents + R-CHOP for untreated a-BCL. GOLCA demonstrated a manageable safety profile in the dose escalation phase (Munoz et al. ICML 2023 abstract 438); we report combined results from the GOLCA dose escalation and expansion phases. Methods Eligible pts were ≥ 18 years, had untreated a-BCL with measurable disease (Lugano 2014), ECOG performance status ≤ 2 and International Prognostic Index (IPI) score 0-5 (2-5 in dose expansion). Pts were treated with R-CHOP plus GOLCA in 21-day (D) cycles (C) for up to 6C, or until disease progression/unacceptable toxicity/study withdrawal/physician decision. During dose escalation, pts received GOLCA at dose levels (DL): 0.2 mg D1-7 (DL-1), 0.4 mg D1-7 (DL1), and 0.4 mg D1-10 (DL2). DL2 met the dose-limiting toxicity threshold and was not continued in the expansion phase. During dose expansion, pts were randomized 1:1 to R-CHOP plus GOLCA at DL-1 or DL1. The primary endpoint for the expansion phase was safety of GOLCA at the recommended phase 2 dose (DL1) (based on adverse events [AEs]); secondary endpoints included overall response rate (ORR) and complete metabolic response (CMR) rate (assessed at end of treatment [EoT] by PET-CT [Lugano 2014]). Circulating tumor DNA (ctDNA) was measured at C1D1, C2D1, C3D1, and EoT using the PhasED-Seq assay. Results Across escalation and expansion, 78 pts were treated (DL-1, n = 35; DL1, n = 37; DL2, n = 6). Median age was 63.0 years, 56.4% were male, most had high-intermediate/high IPI (3-5) score at diagnosis (64.1%), Ann Arbor stage III-IV disease (83.3%), and germinal center B cell as cell of origin (51.3%); 83.3% pts had DLBCL histology. At data extraction (May 25, 2023), across escalation and expansion, 38 pts had treatment ongoing, 31 completed treatment, and 35 continued to follow-up. A total of 3 pts discontinued due to AEs, 1 each at DL-1, DL1, and DL2. In the safety population (n = 78), median GOLCA relative dose intensity (RDI) was 99.4%; 82.1% of pts received RDI ≥ 85%. RDI for CHOP components was &amp;gt; 90%. A total of 73 (93.6%) pts had ≥ 1 treatment-emergent AE (TEAE); 70 (89.7%) pts had ≥ 1 TEAE considered related to GOLCA; 65 (83.3%) pts had ≥ 1 grade 3/4 TEAE, 62 (79.5%) pts had ≥ 1 grade 3/4 TEAE considered related to GOLCA. The most frequently occurring grade 3/4 TEAEs were neutropenia (76.9%) and thrombocytopenia (32.1%) ( Table). A total of 30 (38.5%) pts had serious TEAEs, most frequently febrile neutropenia (preferred term: 11 pts, 14.1%); 12 (15.4%) pts had serious TEAEs of infection or infestation (system organ class); 6 pts (7.7%) had venous thromboembolisms considered related to GOLCA (4 deep vein thrombosis, 1 superficial thrombosis, 1 pulmonary embolism). Treatment-related AEs leading to GOLCA dose reduction or discontinuation occurred in 11 (14.1%) pts and 6 (7.7%) pts, respectively. After a median follow-up time of 4.1 months (range 0.3-12.3) and among all treated pts with EoT response available, 21/25 had CMR; together, 14/14 pts who received GOLCA 0.4 mg (DL1 and DL2) achieved CMR at EoT ( Figure). Among efficacy-evaluable pts (n = 56), ORR was 91.1% (95% CI 80.4-97.0). Pts treated with GOLCA at DL-1 and DL1 who were ctDNA high-risk (≥ 2.5 log hGE/mL) responded to study treatment (CMR-PMR) and had early decreases in ctDNA (Kaplan et al. ASH 2023). Conclusions GOLCA demonstrated a manageable safety profile, showed good combinability with R-CHOP, and did not compromise delivery of curative treatment. Efficacy results and substantial ctDNA decrease indicate robust clinical activity in frontline DLBCL, with a high CMR rate at EoT, particularly among patients treated at DL1. Study support Bristol Myers Squibb.

Modelling and bifurcation analysis of spatiotemporal hormetic effects on pest control

A discrete hormetic Ricker model (HRM) of a population with instant pulse perturbation between two consecutive generations can generate hormetic effects. For example, analysis of complex three-parameter spaces with the intrinsic growth rate, intervention strength, and dose timing as parameters revealed hormetic biphasic dose and dose timing responses. These responses exhibited either a J-shaped or an inverted U-shaped pattern, yielding a homeostatic change or a catastrophic shift and hormetic effects in many parameter regions. However, whether it is pest control or the effectiveness of treatments of tumors with radiotherapy and/or chemotherapy, the phenomenon is linked to the size of the space in which the parameters are located. Thus, the occurrence of hormetic effects is associated with spatiotemporal heterogeneity. To show this, we have developed an integro-difference equation based on the HRM that can describe the complex dynamics and hormetic effects in pest populations in two-dimensional space. Our findings indicate that factors such as the spatial domain, spatial grid, the dosage, and timing of control applications, and the intrinsic growth rate of the pest can significantly affect the spatial and temporal characteristics of pest populations and diverse biological phenomena in two-dimensional space. In particular, under the same size of spatial domains (or the same number of spatial grids), the smaller the spatial grids (or the larger the spatial domain), the stronger the hormetic effects of low dose stimulation and high dose inhibition will be. These factors include larger maximum responses and higher toxic thresholds. Therefore, optimal pest control measures should not only rely on the efficiency of a pesticide and its application time but should also be based on the spatial domain and the designing of reasonable grid-based control strategies to avoid hormetic effects.

Hormetic and synergistic effects of cancer treatments revealed by modelling combinations of radio - or chemotherapy with immunotherapy

BackgroundRadio/chemotherapy and immune systems provide examples of hormesis, as tumours can be stimulated (or reduced) at low radio/chemical or antibody doses but inhibited (or stimulated) by high doses.MethodsInteractions between effector cells, tumour cells and cytokines with pulsed radio/chemo-immunotherapy were modelled using a pulse differential system.ResultsOur results show that radio/chemotherapy (dose) response curves (RCRC) and/or immune response curves (IRC) or a combination of both, undergo homeostatic changes or catastrophic shifts revealing hormesis in many parameter regions. Some mixed response curves had multiple humps, posing challenges for interpretation of clinical trials and experimental design, due to a fuzzy region between an hormetic zone and the toxic threshold. Mixed response curves from two parameter bifurcation analyses demonstrated that low-dose radio/chemotherapy and strong immunotherapy counteract side-effects of radio/chemotherapy on effector cells and cytokines and stimulate effects of immunotherapy on tumour growth. The implications for clinical applications were confirmed by good fits to our model of RCRC and IRC data.ConclusionsThe combination of low-dose radio/chemotherapy and high-dose immunotherapy is very effective for many solid tumours. The net benefit and synergistic effect of combined therapy is conducive to the treatment and inhibition of tumour cells.

Variability in methylmercury exposure across migratory terrestrial bird species: Influencing factors, biomagnification and potential risks

Despite China's considerable mercury (Hg) emissions, monitoring of methylmercury (MeHg) levels in its terrestrial environments remains limited. This study examined the occurrence and accumulation of MeHg in body feathers of 12 migratory terrestrial bird species originating from Siberia and northeastern China. Considerable variations in foraging habits and MeHg levels were observed among these species. Accipiters, including Eurasian and Japanese sparrowhawks (A. gularis and A. nisus) and northern goshawk (A. gentilis), along with insectivorous songbirds including grey-backed thrush (T. hortulorum) and orange-flanked bluetail (T. cyanurus), showed notable levels of MeHg (0.62–1.20 mg/kg). Up to 25 % of the individuals within these species were classified as low-risk based on feather Hg toxicity thresholds, while the remaining species fell into the no-risk category. Despite showing enriched δ15N, MeHg concentrations in short-eared and long-eared owls (A. flammeus and A. otus) were lower than in sparrowhawks. The herbivorous oriental turtle dove (S. orientalis) exhibited significantly lower MeHg levels compared to all other species. There was a significant positive correlation between MeHg concentrations and δ15N across species, highlighting the substantial biomagnification potential of MeHg within the terrestrial food web. Additionally, we found significantly higher MeHg levels in adults than juveniles in both sparrowhawk species. Our results demonstrate the effectiveness of utilizing migratory bird feathers for monitoring terrestrial Hg contamination, and underscore the importance of further assessment.

Application of biological early warning systems in wastewater treatment plants: Introducing a promising approach to monitor changing wastewater composition

Wastewater treatment plants (WWTPs) are a major source of micropollutants to surface waters. Currently, their chemical or biological monitoring is realized by using grab or composite samples, which provides only snapshots of the current wastewater composition. Especially in WWTPs with industrial input, the wastewater composition can be highly variable and a continuous assessment would be advantageous, but very labor and cost intensive. A promising concept are automated real-time biological early warning systems (BEWS), where living organisms are constantly exposed to the water and an alarm is triggered if the organism's responses exceed a harmful threshold of acute toxicity. Currently, BEWS are established for drinking water and surface water but are seldom applied to monitor wastewater. This study demonstrates that a battery of BEWS using algae (Chlorella vulgaris in the Algae Toximeter, bbe Moldaenke), water flea (Daphnia magna in the DaphTox II, bbe Moldaenke) and gammarids (Gammarus pulex in the Sensaguard, REMONDIS Aqua) can be adapted for wastewater surveillance. For continuous low-maintenance operation, a back-washable membrane filtration system is indispensable for adequate preparation of treated wastewater. Only minor deviations in the reaction of the organisms towards treated and filtered wastewater compared to surface waters were detected. After spiking treated wastewater with two concentrations of the model compounds diuron, chlorpyrifos methyl, and sertraline, the organisms in the different BEWS showed clear responses depending on the respective compound, concentration and mode of action. Immediate effects on photosynthetic activity of algae were detected for diuron exposure, and strong behavioral changes in water flea and gammarids after exposure to chlorpyrifos methyl or sertraline were observed, which triggered automated alarms. Different types of data analysis were applied to extract more information out of the specific behavioral traits, than only provided by the vendors algorithms. To investigate, whether behavioral movement changes can be linked to impact other endpoints, the effects on feeding activity of G. pulex were evaluated and results indicated significant differences between the exposures. Overall, these findings provide an important basis indicating that BEWS have the potential to act as alarm systems for pollution events in the wastewater sector.

SAT261 Hypervitaminosis A With Hypercalcemia Without Overtly Excessive Vitamin A Intake

Abstract Disclosure: C. Chiou: None. B. Greck: None. Background: Hypervitaminosis A (hypervitA) is an uncommon cause of hypercalcemia and is due to excessive intake of preformed vitamin A (vitA), i.e., retinoids, especially in emulsified form, a common preparation in supplement. In contrast, provitamin (carotenoids) does not cause hypervitA due to limit in absorption and conversion to vitA. The tolerable upper intake level (UL) and recommended dietary allowance (RDA) of vitA for adult are 3000 and 700 (female) - 900 (male) mcg retinoid activity equivalent (RAE) respectively. While daily intake of vitA &amp;gt; UL carries risk of chronic toxicity, there are reports of hypervitA with chronic intake of vitA below UL. VitA is mainly stored in hepatic stellate cells (HSC). Liver injury can induce HSC to transform, releasing vitA, and losing capacity of vitA storage. Renal insufficiency is known with higher vitA levels in blood. Potentially, the threshold of vitA toxicity from supplement is much less in conditions with hepatic and/or renal disease. Here we report a case without history of excessive vitA intake developed hypervitA in relatively short period of time after hospitalization while in the acute and long-term care unit. Clinical Case: A 57-year male was hospitalized for alcohol related pancreatitis. It was complicated by sepsis, multi-organ failure requiring respirator, parenteral nutrition and/or tube feeding. Mild hypercalcemia was noted 4 weeks after admission, initially intermittently, then persistently and progressively higher, peak of 12.6 mg/dL at 4 months after admission. Prior calcium levels were low or normal up to 6 years before admission. Evaluation of hypercalcemia found low i-PTH, low 1,25-D, hypercalciuria, negative serum protein electrophoresis, and normal PTH-related protein. VitA was surprisingly elevated at 137 [38-98] mcg/dL. Nutritional intake was reviewed. No history of excessive vitA intake. Patient was on total parenteral nutrition (TPN) and/or tube feeding most of time, the range and average of daily preformed vitA supplement from admission to onset of hypercalcemia were 0-1309 and 1006 mcg RAE respectively; while from onset to peak of hypercalcemia, 0-3327 and 1891 mcg RAE respectively. The maximal daily preformed vitA via TPN is 1000 mcg RAE. All preformed vitA in tube feeding is from original formula without extra addition. After discovery of hypervitA, feeding formula was changed to one containing much less preformed vitA, and hypercalcemia slowly improved. Conclusion: HypervitA can develop relatively easily with tube feeding and/or parenteral nutrition with average daily preformed vitA above RDA but way below UL in a susceptible patient. In patients with liver disease and/or renal insufficiency, careful selection of feeding formula and/or nutritional supplement regarding content of preformed vitA, and alert to potential development of hypervitA are advisable. Presentation: Saturday, June 17, 2023

Nickel ion release and surface analyses on instrument fragments fractured beyond the apex: a laboratory investigation

BackgroundTo analyse the changes in surface and nickel ion release characteristics of fractured root canal shaping instruments in a simulated body fluid environment.MethodsA total of 54 new instruments were studied. The instrument groups consisted of five different NiTi alloys and a stainless-steel alloy. To standardize instrument fracture, a torsional type of failure was created on each instrument. The fractured specimens of each instrument group were randomly divided into three static immersion subgroups of 1 h, 7-day, and 30-day (n = 3). Simulated body fluid (SBF) was prepared to mimic human blood plasma by Kokubo&Takadama protocol for ex situ static immersions at 37ºC. The surfaces were examined via scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy. To determine the quantitative ion release, the retrieved SBFs were analyzed using inductively coupled plasma mass spectrometry. Two-way ANOVA and Tukey post hoc tests sought the statistical significance of the nickel ion values(p < 0.05).ResultsIn 1 h of immersion, the newly formed structures, exhibiting mostly oxygen signals, were widespread and evident on NiTi surfaces. In contrast, fewer structures were detected on the SS surface in that subgroup. In 7 days of immersion, a tendency for a decrease in the density of the new structures was revealed in NiTi groups. The oxygen signals on NiTi group surfaces significantly increased, contrary to their decrease in SS. Signals of sodium, chlorine, and calcium were detected, indicating salt precipitates in groups. In 30 days of immersion, salt precipitates continued to form. The Ni-ion release values in all instrument groups presented significant differences in comparison to the SBF control in all immersion periods(p < 0.001). No significant differences were observed in immersion time periods or instrument groups(p > 0.05).ConclusionsWithin the limitations of the presented study, it was concluded that the fractured SS and NiTi root canal instruments release Ni ions in contact with body fluid. However, the Ni ion release values determined during the observation periods are lower than the critical toxic or allergic thresholds defined for the human body. This was due to the ionic dissolution cycle reaching a stable state from 1-hour to 30-day exposure to the body fluid of fractured instruments.

Cherenkov Radiation induced photodynamic therapy - repurposing older photosensitizers, and radionuclides

Context: Old-generation photosensitizers are minimally used in current photodynamic therapy (PDT) because they absorb in the UV/blue/green region of the spectrum where biological tissues are generally highly absorbing. The UV/blue light of Cherenkov Radiation (CR) from nuclear disintegration of beta-emitter radionuclides shows promise as an internal light source to activate these photosensitizers within tissue. Outline of the study: 1) radionuclide choice and Cherenkov Radiation, 2) Photosensitizer choice, synthesis and radiolabeling, 3) CR-induced fluorescence, 4) Verification of ROS formation, 5) CR-induced PDT with either free eosine and free CR emitter, or with radiolabelled eosin. Results: Cherenkov Radiation Energy Transfer (CRET) from therapeutic radionuclides (90Y) and PET imaging radionuclides (18F, 68Ga) to eosin was shown by spectrofluorimetry and in vitro, and was shown to result in a PDT process. The feasibility of CR-induced PDT (CR-PDT) was demonstrated in vitro on B16F10 murine melanoma cells mixing free eosin (λabs = 524 nm, ΦΔ 0.67) with free CR-emitter [18F]-FDG under their respective intrinsic toxicity levels (0.5 mM/8 MBq) and by trapping singlet oxygen with diphenylisobenzofuran (DPBF). An eosin-DOTAGA-chelate conjugate 1 was synthesized and radiometallated with CR-emitter [68Ga] allowed to reach 25 % cell toxicity at 0.125 mM/2 MBq, i.e. below the toxicity threshold of each component measured on controls. Incubation time was carefully examined, especially for CR emitters, in light of its toxicity, and its CR-emitting yield expected to be 3 times as much for 68Ga than 18F (considering their β particle energy) per radionuclide decay, while its half-life is about twice as small. Perspective: This study showed that in complete darkness, as it is at depth in tissues, PDT could proceed relying on CR emission from radionuclides only. Interestingly, this study also repurposed PET imaging radionuclides, such as 68Ga, to trigger a therapeutic event (PDT), albeit in a modest extent. Moreover, although it remains modest, such a PDT approach may be used to achieve additional tumoricidal effect to RIT treatment, where radionuclides, such as 90Y, are strong CR emitters, i.e. very potent light source for photosensitizer activation.