Comprehensive framework for human health risk assessment of nanopesticides

Nanopesticides are not only in an advanced state of research and development but have started to appear on the market. Industry and regulatory agencies need a consolidated and comprehensive framework and guidance for human health risk assessments. In this perspective we develop such a comprehensive framework by exploring two case studies from relevant product types: an active ingredient delivered with a nanocarrier system, and a nanoparticle as an active ingredient. For a nanocarrier system, three entities are tracked during the assessment: the nanocarrier–active ingredient complex, the empty nanocarrier remaining after the complete release of the active ingredient, and the released active ingredient. For the nanoparticle of pure active ingredient, only two entities are relevant: the nanoparticle and the released ions. We suggest important adaptations of the existing pesticide framework to determine the relevant nanopesticide entities and their concentrations for toxicity testing. Depending on the nature of the nanopesticides, additional data requirements, such as those pertaining to durability in biological media and potential for crossing biological barriers, have also been identified. Overall, our framework suggests a tiered approach for human health risk assessment, which is applicable for a range of nanopesticide products to support regulators and industry in making informed decisions on nanopesticide submissions. Brief summaries of suitable methods including references to existing standards (if available) have been included together with an analysis of current knowledge gaps. Our study is an important step towards a harmonized approach accepted by regulatory agencies for assessing nanopesticides

HBO1 is required for the maintenance of leukaemia stem cells.

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)1. Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings

Adsorption and degradation of four acidic herbicides in soils from southern Spain

8 pages, 3 figures, 6 tables, 35 references.BACKGROUND: Pesticide degradation and adsorption in soils are key processes determining whether pesticide use will have any impact on environmental quality. Pesticide degradation in soil generally results in a reduction in toxicity, but some pesticides have breakdown products that are more toxic than the parent compound. Adsorption to soil particles ensures that herbicide is retained in the place where its biological activity is expressed and also determines potential for transportation away from the site of action. Degradation and adsorption are complex processes, and shortcomings in understanding them still restrict the ability to predict the fate and behaviour of ionisable pesticides. This paper reports the sorption and degradation behaviour of four acidic pesticides in five soils from southern Spain. Results are used to investigate the influence of soil and pesticide properties on adsorption and degradation as well as the potential link between the two processes. RESULTS: Adsorption and degradation of four acidic pesticides were measured in four soils from Spain characterised by small organic matter (OM) contents (0.3-1.0%) and varying clay contents (3-66%). In general, sorption increased in the order dicamba < metsulfuron-methyl < 2,4-D < flupyrsulfuron-methyl-sodium. Both OM and clay content were found to be important in determining adsorption, but relative differences in clay content between soils were much larger than those in OM content, and therefore clay content was the main property determining the extent of herbicide adsorption for these soils. pH was negatively correlated with adsorption for all compounds apart from metsulfuron-methyl. A clear positive correlation was observed for degradation rate with clay and OM content (P < 0.01), and a negative correlation was observed with pH (P < 0.01). The exception was metsulfuron-methyl, for which degradation was found to be significantly correlated only with soil bioactivity (P < 0.05). CONCLUSIONS: Both OM and clay content were found to be important in determining adsorption, but relative differences in clay content between soils were much larger than those in OM content, and therefore clay content was the main property determining the extent of herbicide adsorption for soils of this type. pH was negatively correlated with adsorption for all compounds apart from metsulfuron-methyl. The contrasting behaviour shown for these four acidic pesticides indicates that chemical degradation in soil is more difficult to predict than adsorption. Most of the variables measured were interrelated, and different behaviours were observed even for compounds from the same chemical class and with similar structures.This work was conducted with the financial support of the Spanish Ministry of Education and Science.Peer Reviewe

Impacts of (Nano)formulations on the Fate of an Insecticide in Soil and Consequences for Environmental Exposure Assessment

The development of nanopesticides has recently received an increased level of attention. However, there are very few data about the environmental fate of these new products, and it is not known whether nanoformulations can be evaluated within the current pesticide regulatory framework. Sorption and degradation parameters of the insecticide bifenthrin were measured in two soils for (i) the pure active ingredient, (ii) three nanoformulations, and (iii) a commercially available formulation. In most cases, fate parameters derived for the nanopesticides were significantly different from those derived for the pure active ingredient (factors of up to 10 for sorption and 1.8 for degradation), but discrepancies were not easy to relate to the characteristics of the nanocarriers. In some cases, differences were also observed between the commercial formulation and the pure active ingredient (factors of up to 1.4 for sorption and 1.7 for degradation). In the regulatory context, the common assumption that formulations do not influence the environmental fate of pesticide active ingredients after application seems therefore not always adequate. In the absence of direct measurement, an inverse modeling approach was successfully applied to evaluate the durability of the formulations in soil (release half-life ranged between 11 and 74 days). Predicted groundwater concentrations very much depended on the modeling approach adopted but overall suggest that the nanoformulations studied could reduce losses to groundwater

Sorption to soil, biochar and compost: is prediction to multicomponent mixtures possible based on single sorbent measurements?

Amendment with biochar and/or compost has been proposed as a strategy to remediate soil contaminated with low levels of polycyclic aromatic hydrocarbons. The strong sorption potential of biochar can help sequestering contaminants while the compost may promote their degradation. An improved understanding of how sorption evolves upon soil amendment is an essential step towards the implementation of the approach. The present study reports on the sorption of pyrene to two soils, four biochars and one compost. Detailed isotherm analyzes across a wide range of concentration confirmed that soil amendments can significantly increase the sorption of pyrene. Comparisons of data obtained by a classical batch and a passive sampling method suggest that dissolved organic matter did not play a significant role on the sorption of pyrene. The addition of 10% compost to soil led to a moderate increase in sorption (<2-fold), which could be well predicted based on measurements of sorption to the individual components. Hence, our result suggest that the sorption of pyrene to soil and compost can be relatively well approximated by an additive process. The addition of 5% biochar to soil (with or without compost) led to a major increase in the sorption of pyrene (2.5–4.7-fold), which was, however, much smaller than that suggested based on the sorption measured on the three individual components. Results suggest that the strong sorption to the biochar was attenuated by up to 80% in the presence of soil and compost, much likely due to surface and pore blockage. Results were very similar in the two soils considered, and collectively suggest that combined amendments with compost and biochar may be a useful approach to remediate soils with low levels of contamination. Further studies carried out in more realistic settings and over longer periods of time are the next step to evaluate the long term viability of remediation approaches based on biochar amendments

Fate of Biodegradable Engineered Nanoparticles Used in Veterinary Medicine as Delivery Systems from a One Health Perspective

The field of veterinary medicine needs new solutions to address the current challenges of antibiotic resistance and the need for increased animal production. In response, a multitude of delivery systems have been developed in the last 20 years in the form of engineered nanoparticles (ENPs), a subclass of which are polymeric, biodegradable ENPs, that are biocompatible and biodegradable (pbENPs). These platforms have been developed to deliver cargo, such as antibiotics, vaccines, and hormones, and in general, have been shown to be beneficial in many regards, particularly when comparing the efficacy of the delivered drugs to that of the conventional drug applications. However, the fate of pbENPs developed for veterinary applications is poorly understood. pbENPs undergo biotransformation as they are transferred from one ecosystem to another, and these transformations greatly affect their impact on health and the environment. This review addresses nanoparticle fate and impact on animals, the environment, and humans from a One Health perspective

Predicting the Sorption of Aromatic Acids to Noncarbonized and Carbonized Sorbents

Approaches based on the octanol–water partition coefficient are commonly used to describe sorption of neutral organic compounds in environmental systems, but they are not suitable for organic acids, which can dissociate to form anions. We here investigate the applicability of an alternative approach based on the pH-dependent distribution ratio (<i>D</i>_OW) to describe sorption of aromatic acids to sorbents representing different degrees of carbonization. Sorption isotherms for four structurally similar acids ((2,4-dichlorophenoxy)­acetic acid (2,4-D), 4-chloro-2-15 methylphenoxy)­acetic acid (MCPA), 4-(2,4-dichlorophenoxy)­butanoic16 acid (2,4-DB), and 5-chloro-2-(2,4-dichlorophenoxy)­phenol (triclosan)) were measured for 15 sorbents: fresh and carbonized wood shavings, pig manure, sewage sludge, carbon nanotubes, and activated carbon. Dissociation greatly affected the sorption of all acids. Sorption coefficients measured in the high pH range indicated that sorption of the anions ranged over several orders of magnitude and should not be neglected. Sorption trends for all sorbates and carbonized sorbents could be very well described by a single regression equation that included <i>D</i>_OW of the sorbate and the specific surface area of the sorbent (<i>R</i>² > 0.89)

How Redox Conditions and Irradiation Affect Sorption of PAHs by Dispersed Fullerenes (nC60)

Surface properties, dispersion state, and sorption behavior of carbon-based nanomaterials will change after being released into the environment. To study these processes, five different scenarios were considered to probe the impact of changes in surface properties of dispersed fullerenes (nC60) on their sorption potential due to irradiation and presence of oxygen. Sorption isotherms of pyrene by nC60 were determined at environmentally relevant concentrations applying a passive sampling method. Isotherms of all dispersion scenarios were best fit with the Dubinin–Ashthakov model. Sorption was strongest for nC60 kept under anoxic condition. Both the presence of oxygen and irradiation significantly decreased the sorption capacity of nC60, while commercially available polyhydroxy fullerenes had the smallest sorption. In addition, competition for sorption sites was never observed in multiple sorbate experiments with four polycyclic aromatic hydrocarbons at small concentration. A strong relationship between sorption coefficients and hydrophobic properties of sorbates suggests that hydrophobic interactions are of major importance. The results emphasize that aging of released fullerenes results in a reduced strength of interactions with nonpolar compounds and, thus, reduces the impact on the environmental transport of hydrophobic pollutants