Antimicrobial peptide DvAMP combats carbapenem-resistant Acinetobacter baumannii infection.

Carbapenem-resistant Acinetobacter baumannii (CRAB), an important opportunistic pathogen, is a major cause of healthcare-associated infections. The polymyxins (colistin and polymyxin B) are the last line of defense in the treatment of CRAB infections, and there is an urgent need to develop novel alternative therapeutic strategies. In this study, we found that the antimicrobial peptide DvAMP exhibited satisfactory antibacterial and antibiofilm activity against CRAB. In addition, DvAMP showed tolerable stability in salt ions and serum and exhibited low toxicity in vivo. Investigation of the underlying mechanism demonstrated that DvAMP disrupts cell membrane structural integrity and specifically binds to exogenous lipopolysaccharides (LPS) and phospholipids (PG/CL), resulting in increased membrane permeability and dissipating proton motive force (PMF), further reducing intracellular ATP levels and inducing ROS accumulation, leading to bacterial death. Furthermore, DvAMP therapy efficiently improved survival rates and decreased the bacterial load in the lungs of mice in a mouse pneumonia model, showing that DvAMP administration reduced CRAB susceptibility to lung infection. These results indicate that the peptide DvAMP is a promising alternative therapeutic agent to combat CRAB infection.

Temporal and spatial distribution of soil water repellency in grassland soils and its relation to soil moisture, hydrophobic matter, and particle size.

In grassland soils, soil water repellency (SWR) may be one of the triggers of soil erosion and degradation as it can reduce water infiltration and penetration into the soil. Few studies were focusing on the evaluation of soil hydro-physical properties, such as hydrophobicity, and their relation to soil moisture, hydrophobic matter, and particle size in grassland soils. In this study, 800 soil samples were collected from the Xilingol grassland in Inner Mongolia, China, using the water droplet penetration time (WDPT) test to evaluate water repellency and we aimed to investigate the temporal and spatial distribution of SWR in grassland soils using the Kriging and Inverse Distance Weighting (IDW) interpolation methods and determine the physical-chemical properties that trigger the SWR. The results showed that the grassland soils in the studied area were slightly water-repellent and a few portions of the area exhibited strong water-repellency. In April, areas of soils with a depth of 0-5 cm and slight to strong SWR accounted for 80 % of the total studied area, of which 5 % had strong water repellency. Moreover, in August, 90 % of the studied area consisted of soils with slight to strong SWR, of which 60 % accounted for soils with strong SWR. With a soil water content of 10.95 %, the SWR reached its peak, with an average value of 60.32 s. The SWR was positively correlated with total N, available N, and soil organic matter (SOM) contents, and therein the hydrophobic acid matter and the hydrophobic basic matter content had a positive contribution to SWR, and the hydrophilic basic matter and the hydrophilic acidic matter had a negative contribution on SWR. In addition, SWR was found to be negatively related to the soil particle size (r = -0.672). A slight SWR was also observed in the majority of the studied area, particularly in the topsoil and fine soils, especially during the monsoon period; hence, SWR must be also considered to reduce the risk of occurrence of soil erosion and degradation in grasslands.

The impaired swim bladder via ROS-mediated inhibition of the Wnt / Hedgehog pathway in zebrafish embryos exposed to eight toxic chemicals and binary chemical mixtures.

To comprehensively explore the potential toxicity of aquatic organisms exposed to chlorinated or brominated flame retardants (BFRs) and metals mixtures, it is necessary to find a common pathway to relate local toxic targeted sites or organs. A key challenge in environmental risk assessment (ERA) is how to clarify the same or different sites or organs of toxic action in a species after exposure to individual chemicals or chemical mixtures. In this study, zebrafish embryo was used to evaluate the sub-lethal toxicity (swim bladder damage) of tris(2,3-dibromo propyl) isocyanurate (TBC), chlorinated paraffins (CPs), hexabromocyclododecane (HBCD), Cu, Cd, Pb, Ag, and Zn through optical microscopy methods, and corresponding sub-lethal molecular levels (inflammation-related enzymes [deiodinase (DIO) enzymes] and transcriptional levels of key genes) in fish through quantitative real-time PCR (qRT-PCR). The tested chemicals all caused failed inflation of the swim bladder, as indicated by activity inhibition of type 2 iodothyronine deiodinase enzyme. Following embryonic exposure to respective TBC + Cu, HBCD + TBC, and Cd + Pb mixtures, as the concentration of the respective Cu, TBC, and Pb increased, the deformity of the swim bladder increased, as also indicated by activity inhibition of type 2 iodothyronine deiodinase enzyme. Additionally, eight chemicals down-regulated Wnt (wnt3, wnt9b, fzd3b, wnt1, fzd5, and fdz1) signaling pathways, which were neurotoxic responses to individual chemical treatments and Hedgehog (ihh, shh, ptc1 and ptc2) signaling pathways. Moreover, excessive ROS induced by eight chemicals effectively induced defects in the swim bladder and Wnt/Hedgehog signaling, which also be proved in respective TBC + Cu, HBCD + TBC, and Cd + Pb mixture treatments. Our results first revealed that eight chemicals caused swim bladder developmental defects via ROS-mediated inhibition of the Wnt and Hedgehog pathways, which revealed the common targeted sites or organs (swim bladders) for further studying the toxic mechanisms underlying the chemical mixtures.

Particle size-dependent effects of silver nanoparticles on swim bladder damage in zebrafish larvae.

Particle size-dependent biological effects of silver nanoparticles (AgNPs) are of great interest; however, the mechanism of action of silver ions (Ag+) released from AgNPs concerning AgNP particle size remains unclear. Thus, we evaluated the influence of particle size (20, 40, 60, and 80 nm) on the acute 96-h bioaccumulation and toxicity (swim bladder damage) of AgNPs in zebrafish (Danio rerio) larvae, with a focus on the mechanism of action of Ag+ released from differently sized AgNPs. The 40- and 60-nm AgNPs were more toxic than the 20- and 80-nm versions in terms of inflammation and oxidative damage to the swim bladder, as indicated by inhibition of type 2 iodothyroxine deiodinase enzyme activity, mitochondrial injury, and reduced 30-50% adenosine triphosphate content. Furthermore, up-regulation and down-regulation of swim bladder development-related gene expression was not observed for pbx1a and anxa5, but up-regulation expression of shha and ihha was observed with no statistical significance. That 20-nm AgNPs were less toxic was attributed to their rapid elimination from larvae in comparison with the elimination of 40-, 60-, and 80-nm AgNPs; thus, less Ag+ was released in 20-nm AgNP-exposed larvae. Failed inflation of swim bladders was affected by released Ag+ rather than AgNPs themselves. Overall, we reveal the toxicity contribution of Ag+ underlying the observed size-dependent effects of AgNPs and provide a scientific basis for comprehensively assessing the ecological risk and biosafety of AgNPs.

Effect of dissolved organic matter on the bioavailability and toxicity of cadmium in zebrafish larvae: Determination based on toxicokinetic-toxicodynamic processes.

The presence of dissolved organic matter (DOM) strongly influences the bioavailability of metals in aquatic environments; however, the association between the binding activities and the concentrations of DOM compositions is not well documented, leading to uncertainties in metal toxicity assessment. We creatively quantify the mitigation and acceleration effects of DOM compositions on cadmium (Cd) bioaccumulation and toxicity in zebrafish larvae using abiotic ligand (ABLs) and biotic ligand (BLs) in a toxicokinetic-toxicodynamic (TK-TD) model. The BL-TK-TD model could accurately predict the protective effect of fulvic acid while overestimating the complexing capacity of citric acid. The model also could successfully simulate the protective effects of native DOM in most cases from 32 natural water bodies in China. The observed LC50 values of Cd showed a peak effect for the native DOM fraction comprising hydrophilic acidic contents (3.55 ± 0.44 mg L - 1) in natural water from 32 sites. The BL-TK-TD model provides practically useful information to identify the effect of different DOM compositions on metal bioavailability and toxicity in aquatic environments and guides future water management policies aimed at controlling aquatic heavy metal pollution.

Bioavailability and toxicity of silver nanoparticles: Determination based on toxicokinetic-toxicodynamic processes.

Determining the bioavailability and toxicity mechanism of silver nanoparticles (AgNPs) is challenging as Ag+ is continuously released by external or internal AgNP dissolution in the actual exposure system (regardless of the laboratory or the natural environment). Here a novel pulsed-gradient Ag+ (AgNO3) exposure was conducted with zebrafish (Danio rerio) larvae to simulate dissolved gradient concentrations of Ag+ from polyvinylpyrrolidone (PVP)-coated AgNPs. The accumulation and toxicity of the pulsed-gradient Ag+ (AgNO3) and, in the meantime, the released Ag+ from PVP-AgNPs were predicted using a toxicokinetic-toxicodynamic (TK-TD) model with obtained Ag+ parameters. In order to further understand the possible mechanism of PVP-AgNP releasing Ag+ in the body, subcellular fractions (S9) of zebrafish were also used to incubate with AgNPs in vitro to mimic the realistic in vivo scenarios. In the TK process, in vivo analysis showed that AgNPs released around twice as many Ag+ into the body than were detected with a single Ag+ pulse-exposure system; this was supported by evidence that subcellular S9 fractions might cause the PVP-AgNPs to lose the capping agent and favor Ag+ release. In the TD process, toxicity (survival rate) was predicted by the total bodily Ag(I) concentration, suggesting that AgNP toxicity in larvae was mainly due to gradually released Ag+ rather than AgNPs themselves. This study helps clarify the role of Ag+ in AgNP toxicity and offers a novel framework by which to investigate the toxicity of metal nanoparticles and corresponding metal ions in biological systems.

Role of Toxicokinetic and Toxicodynamic Parameters in Explaining the Sensitivity of Zebrafish Larvae to Four Metals.

Given the persistence and toxic potencies of metal contaminants in ecosystems, animals, and human beings, they are considered to be hazardous global pollutants. While the lethality of metal toxicities (e.g., LC50) can significantly vary, even within the same species, the underlying mechanisms are less well-understood. In this study, we developed a subcellular two-compartment toxicokinetic-toxicodynamic (TK-TD) model for zebrafish larvae when exposed to four metals (cadmium, lead, copper, and zinc) to reveal whether differences in metal toxicity (LC50 values) were dominated by the TK or TD processes. Results showed that the subcellular TK and TD parameters of the four metals were significantly different, and the bioconcentration factor (BCF) value of copper was higher than those of the other metals. We also found that the TD parameter internal threshold concentration (CIT) was significantly positively correlated to the LC50 values (R2 = 0.7), suggesting a dominant role of TD processes in metal toxicity. Furthermore, the combined parameter CIT/BCF for a metal-sensitive fraction (BCFMSF), which linked exposure to effects through the TK-TD approach, explained up to 89% of the variation in toxicity to the four metals. The present study suggests that the observed variation in toxicity of these four metals was mainly determined by TD processes but that TK processes should not be ignored, especially for copper.

Trophic transfer of heavy metals in the marine food web based on tissue residuals.

Trophic transfer of metals has been well researched in aquatic food webs; however, most studies have examined the presence of metal residuals in the entire body of marine organisms and but not in specific tissues. In this study, we determined the concentrations of Cu, Cr, Pb, Zn, Cd, and Ni in various organs of 17 marine species, including crustaceans, gastropods, bivalves, and fishes, with different trophic levels (TLs), which were collected from the Liaodong Bay, China, in July 2019. Results showed that the liver, gill, and muscle tissues of marine species are ideal indicators for analyzing Cu, Cr, Pb, Zn, Cd, and Ni contamination in marine environments. When the entire bodies of these marine species were considered, a bio-dilution in Cu, Cr, Pb, Zn, Cd, and Ni was observed in the studied food web. In contrast, the metal tissue-specific bio-magnification in the entire studied food web showed different results. In the liver and gill tissues, negative correlations were found between the concentrations of cadmium and TLs, while copper bio-dilution was also observed in gill tissue. In the muscle tissues, Cu, Pb, and Ni showed bio-dilution and trophic magnification factors of Cu, Pb, and Ni ranged from 0.44 to 0.73. This study highlights the importance of tissue-specific considerations to obtain further accurate information on metal trophodynamics and trophic transfers in marine food webs, thereby enhancing the risk assessment of many elements in wildlife and human health.

DNA methylation and gene expression alterations in zebrafish embryos exposed to cadmium.

An unexplored attributing molecular mechanism of Cd toxicity is interference with the epigenetic machinery, such as DNA methylation, processes that are crucial for early fetal development. In order to investigate the effects of Cd on the expression of metallothionein (MT) and Dnmts transcripts, markers of DNA methylation, and signaling pathway gene expression, zebrafish embryos were exposed during 24 hours post-fertilization (starting at maximum 8-cell stage) to 0.0089, 0.089, and 0.89 µM Cd. The results showed that the Cd accumulation in zebrafish embryo reached a stable level after 12 hpf, and the Cd accumulation at individual time points was significantly different among different concentration groups. MT mRNA fold was significantly positive with the Cd content in embryos. We observed that the expression level of DNA methyltransferase (Dnmts) in the 0.089 µM Cd exposure group was significantly up-regulated. Dnmt1 expression was significantly up-regulated in the 0.89 µM Cd exposure group, and Dnmt3s expression and global methylation levels were significantly down-regulated. Cd up-regulated ErbB-3 gene expression, down-regulated ErbB-4 gene expression, and neutralized ErbB-1 gene expression. Cd activated Ca2+, MAPK-JUK, p38 MAP kinase, PI3K-AKT, and VEGF signaling pathway genes, indicating these pathway genes related to Cd exposure level. The results are helpful to clarify the molecular mechanism of DNA methylation in zebrafish embryo under metal pressure and further interference with the epigenetic machinery.

Assessment of the transfer of heavy metals in seawater, sediment, biota samples and determination the baseline tissue concentrations of metals in marine organisms.

The majority of tissue-specific environmental quality standards (EQSs) considering metal tolerance are prior to the chemical-specific EQSs in aquatic organisms. However, metal baseline levels in marine organisms were very scarce. We explored the correlation between Hg, Cd, Pb, Cu, and Zn concentrations in water or sediments and those metal concentrations in marine organisms (crustacean, mollusc, and fish) by generalized additive models (GAMs) and executed a meta-analysis of Hg, Cd, Pb, Cu, and Zn contents in those three organisms by implementing cumulative frequency distribution analysis of individual metal distribution in a heavy metal-contaminated semi-enclosed Bay, China. Results showed that the average contents of Hg, Cd, Pb, Cu, and Zn were 0.042±0.01, 0.38±0.22, 1.72±0.65, 3.61±1.01, and 16.08±6.33 µg/L in water; 0.064±0.02, 0.42±0.04, 20.54±7.76, 28.97±3.90, and 96.74±35.11 µg/g dw in sediment; and 0.0049±0.0028, 0.52±0.28, 0.24±0.15, 11.05±6.95, and 21.12±4.47 µg/g dw in crustacean, 0.015±0.0087, 0.24±0.17, 0.08±0.02, 0.37±0.35, and 10.62±6.79 µg/g dw in mollusc; and 0.0038±0.0028, 0.065±0.05, 0.32±0.19, 2.01±0.59, and 16.04±4.97 µg/g dw in fish. The mercury content in mollusc presented a negative correlation with mercury content in sediment, while the content of other metals (Cd, Pb, Cu, and Zn) in organisms showed positive correlations with the content of those metals in water or sediment. We further obtained tissue-baseline-C5% in crustacean, mollusc, and fish which were 1.191, 3.341, and 0.014 µg/g dw for Cu; 0.013, 0.072, and 0.033 µg/g dw for Cd, 0.015, 0.027, and 0.052 µg/g dw for Pb; 9.515, 14.422, and 0.056 µg/g dw for Zn; and 0.0009, 0.004, and 0.0035 µg/g dw for Hg, respectively. However, there were no obvious relationships of the 4d-NOEC in laboratory toxicity tests with C5%, as well as C50% and 4d-LC50 or tolerance index a for Cu, Cd, Pb, Zn, and Hg in organisms. Our results pointed out the controversy of laboratory sensitive species toxicity results for deriving chemical-specific EQSs with field studies. We advocated to set up the metal concentration baselines in aquatic organisms and further served the tissue-specific EQSs, which are essential basis for geochemical recordings, bio-monitoring, and semi-enclosed bay management in the world.

Understanding the effects of metal pre-exposure on the sensitivity of zebrafish larvae to metal toxicity: A toxicokinetics-toxicodynamics approach.

Organisms are increasingly tolerant to metal toxicity in the natural ecosystems, which did not match the results of the environmental risk assessment (ERA) of metals based on toxicity data from organisms in the laboratory. Studies have described the effects of pre-exposure to metals on metal toxicity tolerance in terms of the toxicokinetic (TK) process; however, the toxicodynamic (TD) process may be more susceptible to metal pre-exposure. Therefore, to determine whether pre-exposure to low concentrations of silver (Ag) or cadmium (Cd) affects the metal TK and TD processes of zebrafish (Danio rerio) larvae, we investigated four TK-TD model parameters that control tolerance and sensitivity to metal toxicity on the survival. Our results showed that the killing rate (ks) of larvae exposed to high Cd concentrations was significantly lower following pre-exposure to 10 µg/L Cd than that of larvaenot pre-exposed. However, the ks for high Ag concentrations was significantly higher in zebrafish larvae following pre-exposure to 2 µg/L Ag than in larvae not pre-exposed. In other words, a one-day pre-exposure to 2 µg/L Ag rendered the larvae more sensitive to Ag during a subsequent 4-day exposure to higher Ag concentrations, whereas a one-day pre-exposure to 10 µg/L Cd rendered the larvae more tolerance to Cd during a subsequent 4-day exposure to higher Cd concentrations. Our results further the current understanding of toxic metal tolerance mechanisms, both in TK and TD processes, and they will guide future laboratory studies to assess actual pre-exposure scenarios that occur in natural environments. Thus, our study can help reduce uncertainty in testing and improve ecological management concerning metal risk assessments.

A biological characteristic extrapolation of compound toxicity for different developmental stage species with toxicokinetic-toxicodynamic model.

Intraspecific difference in toxicity brings uncertainty to ecological risk assessment (ERA) and water quality criteria (WQC) of chemicals. Here, we compared intraspecies sensitivity to toxicants for Mesocyclops leuckarti of which toxicity data was obtained from published literatures, and zebrafish Danio rerio of which toxicity data was done in this study). Due to the internal concentration of chemicals not measured, simplified toxicokinetic-toxicodynamic (TK-TD) models were used, and we investigated whether TK-TD parameters estimated by Bayesian method might represent the differences in sensitivity between life-stages of 2 species. The results demonstrated that the difference in TK-TD parameters (background mortality m0, no effect concentration NEC, the killing rate ks, and the dominant rate kd) could represent the toxicity difference between life-stages of individual species. The TK-TD model could predict toxicity in individual species (Cyprinus carpio L., Enchytraeus crypticus, Folsomia candida, Hyalella Azteca) exposed to different chemical concentrations and successfully extrapolate toxicity between different life stages of Mesocyclops leuckarti and Danio rerio by scaling several TK-TD parameters. The modified TK-TD model on the extrapolation toxicity of chemicals between life stages for species could be useful for the ERA and for deriving and revising WQC for chemicals.

Predicting copper toxicity in zebrafish larvae under complex water chemistry conditions by using a toxicokinetic-toxicodynamic model.

Multiple water chemistry parameters influence metal toxicity in natural waters and accurate quantification of those influences may accelerate the development of site-specific water quality criteria (WQC) and further execute metal risk assessment for better protection of aquatic biota. Here, we investigated the effects of water chemistry parameters on copper (Cu) toxicity of larval zebrafish (Danio rerio) and then incorporated the effects of key parameters in a Toxicokinetic and Toxicodynamic (TK-TD) model. Further, the proposed TK-TD model was used to predict Cu toxicity in laboratory artificial waters as well as natural water samples. The predictive performance of the TK-TD model was evaluated in comparison to the biotic ligand model (BLM). The results showed that increasing Ca, Mg, pH, and fulvic acid (FA) levels significantly mitigated Cu toxicity in larvae, while K and Na levels had no significant effect on Cu toxicity. A predictive TK-TD model based on these data described 91 % of Cu accumulation and 87 % of survival of larvae exposed to Cu under 0, 2.5, 5, 10 mg/L FA. Compared with BLM, TK-TD model predicted better Cu accumulation and toxicity for an independent dataset in low DOC concentration (<10.95 mg L-1) of 9 sites in Haihe river (Tianjin, China) media during 96 h exposure. The BLM under-predicted the acute Cu toxicity to larvae when compared with observed values. In high DOC concentration (13.12-17.78 mg L-1) among three field sites, BLM and TK-TD model both under-predicted the acute Cu toxicity to larvae when compared with observed values. Our research provides a TK-TD approach for predicting Cu toxicity under complex water chemistry conditions and deriving Cu-WQC in different scenarios where there exist limits for using the BLM.

Different decreasing rates of chemical threshold concentrations can be explained by their toxicokinetic and toxicodynamic characteristics.

To protect ecosystems, threshold concentrations (e.g., HC5) for chemicals are often derived using the toxicity data obtained at fixed times. Since the toxicity (e.g., LC50) usually decreases with exposure time, the threshold concentrations are expected to be time-dependent, giving rise to the uncertainty in the chemical environmental criteria. Here, using the LC50 data with at least 3 different exposure durations (24, 48 and 96 h) for compounds, we explored the time evolutions of HC5 across 20 chemicals. Results showed that all chemical's HC5 decreased with time, but their decreasing rates of HC5 (k) are significantly different: for some chemicals the k are lower than 0.001 (e.g., methoxychlor and dieldrin), while for some chemicals the k are higher than 0.05 (e.g., PCP and aldicarb). Furthermore, we found that k is negatively related to the bioconcentration factors (BCF), and positively related to the damage recovery rates (kR). Our work demonstrated that time is an important source of the ecological threshold uncertainty, and this uncertainty is associated with chemical-specific toxicokinetic and toxicodynamic characteristics. We recommend that to effectively protect the ecological communities, higher assessment factor should be adopted in deriving the acute environmental criteria for these chemicals with high BCF and low kR, fluoranthene and diazinon.

Different factors determined the toxicokinetics of organic chemicals and nanomaterials exposure to zebrafish (Danio Rerio).

Little is known about how the chemical properties (molecular structure, such as the hydrophobic and hydrophilic end group for organic chemical, and particle size for nanomaterials (NMs)) quantitatively affect the toxicokinetics (TK) in organisms especially in short-term, single-species studies. A novel method based on a first-order one compartment TK model which described the monophasic uptake pattern and two-compartment TK model which adequately described the biphasic metabolism pattern was used to determine the bioconcentration and TK rate constants of organic compounds (n = 17) and nanomaterials (NMs, n = 7) in zebrafish. For both one and two compartment model, the uptake (kin) and elimination (kout) rate constants were fitted using a one- and two-compartment first-order kinetic model, and bioconcentration factors (BCF) and 95% depuration times (t95) for all tested chemicals were calculated, respectively. The results showed that there was significant difference in TK parameters kin, kout, and BCF between organic chemicals and nano metal oxides. For organic compounds, significant correlations were found between the kin and BCF and the octanol-water partition coefficient (Kow) and molecular mass. For nano metal oxides, there was a significant negative correlation between the kin or BCF and particle size, but a positive correlation between kin and Zeta potential of nanoparticles and also a significant positive correlation between kout and particle size or specific surface area. Those findings indicated that NMs particle size does matter in biological influx and efflux processes. Our results suggest that the TK process for organic compound and NMs are correlated by different chemical properties and highlight that the Kow, the absorption kin, metabolism k12 and k21, elimination rate kout, and all the parameters that enable the prediction and partitioning of chemicals need to be precisely determined in order to allow an effective TK modeling. It would therefore appear that the TK process of untested chemicals by a fish may be extrapolated from known chemical properties.

Comparison of the General Threshold Model of Survival and Dose-Response Models in Simulating the Acute Toxicity of Metals to Danio rerio.

We exposed zebrafish (Danio rerio) to different concentrations of lead and cadmium, and monitored them for survival at 24, 48, 72, and 96 h. Metal toxicity was predicted and compared using the dose-response and general threshold survival models in terms of required data sets, fit performance, and applicability. Environ Toxicol Chem 2019;38:2169-2177. © 2019 SETAC.

Toxicokinetic-toxicodynamic modeling of cadmium and lead toxicity to larvae and adult zebrafish.

Toxicity of hazard materials to organism is different between larvae and adult zebrafish. However, this different effect was seldom considered in toxicological modeling. Here, we measured Cd and Pb toxicity for larvae and adult zebrafish (Danio rerio) and assessed whether metal toxicity can be better simulated by the one-compartment or two-compartment toxicokinetic (TK) and toxicodynamic (TD) models with assumption of stochastic death (SD) and individual tolerance (IT), respectively. Results showed that, for larvae, the one-compartment model generally fitted the observed accumulation and survival better than two-compartment model. In contrast, for adult, the two-compartment model simulation satisfied the observed accumulation and survival better than one-compartment model. In addition, both the SD and the IT models generally described the Cd or Pb toxicity well, although the IT model predictions were slightly better than the SD model in adult fish, the opposite phenomenon was observed in larvae. Our results suggested that variations in both TK and TD parameters might be needed to quantify the toxicity sensitivity in larvae and adult zebrafish, and accounting these variations in mechanistic toxicological effect models (e.g. TK-TD) will allow more accurate predictions of hazard materials effects to organisms.

Physiologically based toxicokinetic and toxicodynamic (PBTK-TD) modelling of Cd and Pb exposure in adult zebrafish Danio rerio: Accumulation and toxicity.

Accurately predicting the accumulation and toxicity of metals in organisms is a challenging work in ecotoxicology. Here, we developed and validated a physiologically based toxicokinetic and toxicodynamic (PBTK-TD) model for adult zebrafish exposed to Cd and Pb. The model included the gill, liver, intestine, gonad, carcass, and brain, which were linked by blood circulation in the PBTK process and by dynamic relationships between the target organ concentrations and mortality in the TD process. Results showed that the PBTK sub-model can accurately describe and predict the uptake, distribution and disposition kinetics of Cd and Pb in zebrafish. The exchange rates and the accumulation of the metals in the organs were significantly different. For Cd, the highest exchange rate was between blood and liver, and the greatest accumulation of Cd occurred in the liver. For Pb, the greatest accumulation occurred in the gill. The TD sub-model further indicated that metal concentrations in the gill may effectively act as more suitable indicator of Cd and Pb toxic effect than whole body or other organs. The proposed PBTK-TD model is helpful to understanding the fundamental processes by which zebrafish regulate the uptake and disposition of metal and to quantitatively predicting metal toxicity.

Predicting the toxic effects of Cu and Cd on Chlamydomonas reinhardtii with a DEBtox model.

Predicting the sublethal effects of pollutants to aquatic organism is essential in realistic chemical risk assessment. However, only a few dynamics models for sublethal endpoints are available. Here, we investigated the toxic effects of the essential metal Cu and the nonessential metal Cd on Chlamydomonas reinhardtiiunder both single and combined exposure, compared the effectiveness of different effect endpoints as toxic effect factors, and developed a Dynamic Energy Budget toxicology (DEBtox) model to predict the sublethal effects of Cu and Cd on C. reinhardtii. The results showed that the chlorophyll fluorescence parameter is a better toxic effect indicator than others for short-term exposure (<24 h), while algal cell growth is preferred for long-term exposure (2-6 days). The developed DEBtox model could successfully predict single metal toxicity to C. reinhardtii, while the combined metal DEBtox model slightly overestimates the joint toxicity of Cu-Cd due to the antagonistic effect of Cu-Cd on C. reinhardtii. This study is helpful to understanding and better predictions of metal sublethal toxic effects on aquatic organisms.

Predicting the survival of zebrafish larvae exposed to fluctuating pulses of lead and cadmium.

Aquatic organisms are often exposed to time-varied concentrations of contaminants due to pulsed inputs in natural water. Traditional toxicology experiments are usually carried out in a constant exposure pattern, which is inconsistent with the actual environment. In this study, a refined toxicokinetic-toxicodynamic (TK-TD) model was used to study the toxic effects of Pb and Cd on zebrafish larvae under three pulse exposures with 2, 4, and 6 h, respectively. The parameter sensitivity analysis showed that JM, max had the greatest impact on the output of the model. Cd or Pb pulse exposure resulted in less death than constant exposure at the same time-weighted average (TWA) concentrations. Survival fraction in larvae under 6 h interval between two pulses of Pb or Cd was larger than that under 2 h and 4 h interval. Toxicity under constant exposure of Cd or Pb was greater than that under 2, 4, and 6 h interval pulse exposure because the cumulative Cd or Pb concentration in the body under constant exposure was greater than that under pulse exposure. The results also showed that the stochastic death (SD) model was more suitable than the individual tolerance (IT) model for predicting the survival fraction of larvae under pulse exposure to Pb and Cd, which was indicated by higher R2 (0.670-0.940) in SD model than that (0.588-0.861) in IT model. Our model provides approaches for laboratory toxicity testing and modeling approaches for addressing the toxicity of heavy metal pulsed exposure.