Screening Proteins That Interact With AcHog1 and the Functional Analysis of AcSko1 in Aspergillus cristatus.

Aspergillus cristatus is a dominant fungus formed during the "flowering" process of Fuzhuan brick tea. Previous research has established that the sporulation of Aspergillus nidulans, a model organism of filamentous fungi, is regulated by light. However, the sporulation of A. cristatus is dependent on osmotic stress. In a previous study, we used pull-down and mass spectrometry to identify proteins that interacted with AcHog1 in A. cristatus when cultured under different conditions of osmotic stress. In the present study, we analyzed the proteins we identified previously to investigate their functional role. The AA1E3BER4 protein was located downstream of Hog1 in the HOG branch pathway and was identified that was regulated by AcHog1. Furthermore, yeast two-hybrid analysis showed that AA1E3BER4 interacted with AcHog1. In addition, we knocked out and complemented the Acsko1 gene encoding the AA1E3BER4 protein. We found that the number of sexual and asexual spores were downregulated by 3.81- and 4.57-fold, respectively, in the ΔAcsko1 strain. The sensitivity of the ΔAcsko1 strain to sorbitol and sucrose, as regulators of osmotic stress, increased, and the sensitivity to high sucrose was higher than that of sorbitol. Acsko1 also regulated the response of A. cristatus to oxidative stress, Congo red, and SDS (sodium dodecyl sulfate). In addition, the deletion of Acsko1 significantly increased the pigment of the ΔAcsko1 strain. This is the first study to report the role of the sko1 gene in oxidative stress, stress-induced damage to the cell wall, and pigment in Aspergillus cristatus.

Predicting nonlinear relationships between external and internal concentrations with physiologically based pharmacokinetic modeling.

Although external concentrations are more readily quantified and often used as the metric for regulating and mitigating exposures to environmental chemicals, the toxicological response to an environmental chemical is more directly related to its internal concentrations than the external concentration. The processes of absorption, distribution, metabolism, and excretion (ADME) determine the quantitative relationship between the external and internal concentrations, and these processes are often susceptible to saturation at high concentrations, which can lead to nonlinear changes in internal concentrations that deviate from proportionality. Using generic physiologically-based pharmacokinetic (PBPK) models, we explored how saturable absorption or clearance influence the shape of the internal to external concentration (IEC) relationship. We used the models for hypothetical chemicals to show how differences in kinetic parameters can impact the shape of an IEC relationship; and models for styrene and caffeine to explore how exposure route, frequency, and duration impact the IEC relationships in rat and human exposures. We also analyzed available plasma concentration data for 2,4-dichlorophenoxyacetic acid to demonstrate how a PBPK modeling approach can be an alternative to common statistical methods for analyzing dose proportionality. A PBPK modeling approach can be a valuable tool used in the early stages of a chemical safety assessment program to optimize the design of longer-term animal toxicity studies or to interpret study results.

The role of Acpbs2 in the asexual sporulation, stress response and carbon metabolism of Aspergillus cristatus.

Aspergillus cristatus is the dominant fungus during the fermentation of Fuzhuan brick tea, hypotonic conditions only induced its sexual development to produce ascospores, while hypertonic conditions only induced its asexual development to produce conidia, indicating that osmotic stress can regulate spore production in A. cristatus. However, the underlying regulatory mechanism is unclear. In this study, the roles of Acpbs2, which is homologous to pbs2 from Saccharomyces cerevisiae, in sporulation, stress responses, the color of colonies, and carbon metabolism were explored in A. cristatus. Deletion mutants of Acpbs2 were obtained by homologous recombination. The time required to produce conidia was delayed, and the number of conidia produced was significantly reduced in hypertonic media in ΔAcpbs2 by phenotypic observations, indicating that Acpbs2 plays a positive role in asexual development. Stress sensitivity tests showed that the order of the sensitivity of ΔAcpbs2 to different osmotic regulators was 3 M NaCl > 3 M sucrose > 3 M sorbitol. Moreover, the deletion mutants were sensitive to high oxidative stress. The growth of the Acpbs2 deletion mutant was inhibited under alkaline-pH stress, indicating that Acpbs2 is involved in high pH stress tolerance. Additionally, compared with the wild type, the colony color of the Acpbs2 deletion mutant became lighter. All the above developmental defects were reversed by the reintroduction of the Acpbs2 gene in ΔAcpbs2. Transcriptome data showed that Acpbs2 regulated the expression of several genes related to conidial development, osmotic stress, oxidative stress, and carbon metabolism. More importantly, the interaction between Acpbs2 and its downstream gene Achog1 was verified by yeast two-hybrid assays. We speculated that this interaction might regulate the osmotic stress response, the oxidative stress response, and asexual sporulation in A. cristatus, which will be one of the focuses of our future research.

Metabolomics integrated with transcriptomics reveals the changes during developmental stages in Shiraia bambusicola.

Shiraia bambusicola is a fungus with high economic value widely used in medicine, agriculture, and food. We wished to understand the genes and metabolites changes involved in the different developmental stages of S. bambusicola. So, to reveal key genes and metabolites in the main active metabolite, the  were analyzed in different developmental stages of S. bambusicola fruiting body. A total of 29,137 Unigenes were annotated. In the whole growth process, differentially expressed genes were involved in the pathways of cytochrome P450, transcription factors, transporters, and so on, while in the early stage of growth, genes enriching to synthesis pathways of basic substances. In the middle stage of growth, genes with more prominent changes were involved in the pathways of the cell cycle, cancer mechanisms, and aminobenzoate degradation; in the later stage of growth, differentially expressed genes that enriched synthesis pathways of secondary metabolites. A total of 612 metabolites were detected from different growth stages of S. bambusicola. Among them, coumarins, alkaloids, rutin, liquiritigenin, quercetin, and other medically relevant metabolites were detected for the first time. We have identified 31 secondary metabolites,  relevantly only accumulated in the early and middle stage, but not detected in the later stage, such as flavonols, coumarins, nucleotides and its derivates and hydroxycinnamoyl derivatives. The differential genes and metabolites of the same group were enriched in 127 pathways, and more significantly in ubiquinone and other terpenoid quinone biosynthesis, phenylalanine metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, and phenylpropanoid biosynthesis. The correlation networks of several significantly enriched pathways were analyzed, and the relationships within and between these pathways, genes, and metabolites, were analyzed. The synthetic pathway of hypocrellin has been speculated upon. We believe that hypocrellin is synthesized in S. bambusicola via the shikimic acid pathway followed by phenylalanine, tyrosine, and tryptophan biosynthesis pathway, then the ubiquinone and other terpenoid quinone biosynthesis pathway, and finally a series of polymerization and modification reactions. Several genes and metabolites involved in the biosynthesis of hypocrellin have been identified. This study provides a reference for further research on S. bambusicola, by providing a basis for its use and development.

Denoising of an ultraviolet light received signal based on improved wavelet transform threshold and threshold function.

In this paper, the wavelet transform algorithm is used to reduce the noise of ultraviolet (UV) light received signals. An improved calculation method of the wavelet thresholds and a new threshold function are proposed. The new threshold function avoids the discontinuity of the traditional hard threshold function. It can also avoid the constant deviation caused by the traditional soft threshold function. The improved threshold calculation method takes into account the effect of the wavelet decomposition level, and the simulation results show the effectiveness of the proposed method. Compared with other methods, the method proposed in this paper can obtain a better denoising effect.

Incorporating human exposure information in a weight of evidence approach to inform design of repeated dose animal studies.

Human health risks from chronic exposures to environmental chemicals are typically estimated from potential human exposure estimates and dose-response data obtained from repeated-dose animal toxicity studies. Various criteria are available for selecting the top (highest) dose used in these animal studies. For example, toxicokinetic (TK) and toxicological data provided by shorter-term or dose range finding studies can be evaluated in a weight of evidence approach to provide insight into the dose range that would provide dose-response data that are relevant to human exposures. However, there are concerns that a top dose resulting from the consideration of TK data may be too low compared to other criteria, such as the limit dose or the maximum tolerated dose. In this paper, we address several concerns related to human exposures by discussing 1) the resources and methods available to predict human exposure levels and the associated uncertainty and variability, and 2) the margin between predicted human exposure levels and the dose levels used in repeated-dose animal studies. A series of case studies, ranging from data-rich to data-poor chemicals, are presented to demonstrate that expected human exposures to environmental chemicals are typically orders of magnitude lower than no-observed-adverse-effect levels/lowest-observed-adverse-effect levels (NOAELs/LOAELs) when available (used as conservative surrogates for top doses). The results of these case studies support that a top dose based, in part, on TK data is typically orders of magnitude higher than expected human exposure levels.

Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment.

Top dose selection for repeated dose animal studies has generally focused on identification of apical endpoints, use of the limit dose, or determination of a maximum tolerated dose (MTD). The intent is to optimize the ability of toxicity tests performed in a small number of animals to detect effects for hazard identification. An alternative approach, the kinetically derived maximum dose (KMD), has been proposed as a mechanism to integrate toxicokinetic (TK) data into the dose selection process. The approach refers to the dose above which the systemic exposures depart from being proportional to external doses. This non-linear external-internal dose relationship arises from saturation or limitation of TK process(es), such as absorption or metabolism. The importance of TK information is widely acknowledged when assessing human health risks arising from exposures to environmental chemicals, as TK determines the amount of chemical at potential sites of toxicological responses. However, there have been differing opinions and interpretations within the scientific and regulatory communities related to the validity and application of the KMD concept. A multi-stakeholder working group, led by the Health and Environmental Sciences Institute (HESI), was formed to provide an opportunity for impacted stakeholders to address commonly raised scientific and technical issues related to this topic and, more specifically, a weight of evidence approach is recommended to inform design and dose selection for repeated dose animal studies. Commonly raised challenges related to the use of TK data for dose selection are discussed, recommendations are provided, and illustrative case examples are provided to address these challenges or refute misconceptions.

Characterizing the role of the zinc finger transcription factor AcrpnR in governing development in Aspergillus cristatus.

Filamentous fungi reproduce sexually or asexually, and the developmental processes are strictly regulated by a variety of transcription factors. In this study, we characterized a zinc finger transcription factor, called AcrpnR, in Aspergillus cristatus (GME2916). The ∆AcrpnR strain exhibited decreased asexual reproduction and increased cleistothecium production. The complementation strain showed restoration of these phenotypic differences. Overexpression of AcrpnR resulted in enhanced asexual development and delayed and inhibited sexual reproduction, suggesting that AcrpnR is required for proper asexual and sexual development in A. cristatus. In addition, AcrpnR positively regulated the expression of genes of the central regulatory pathway of conidiation and negatively regulated the expression of sex-related genes. Overall, these results demonstrate that AcrpnR is essential for maintaining a balance between asexual and sexual development.

A Systematic Review of Published Physiologically-based Kinetic Models and an Assessment of their Chemical Space Coverage.

Across multiple sectors, including food, cosmetics and pharmaceutical industries, there is a need to predict the potential effects of xenobiotics. These effects are determined by the intrinsic ability of the substance, or its derivatives, to interact with the biological system, and its concentration-time profile at the target site. Physiologically-based kinetic (PBK) models can predict organ-level concentration-time profiles, however, the models are time and resource intensive to generate de novo. Read-across is an approach used to reduce or replace animal testing, wherein information from a data-rich chemical is used to make predictions for a data-poor chemical. The recent increase in published PBK models presents the opportunity to use a read-across approach for PBK modelling, that is, to use PBK model information from one chemical to inform the development or evaluation of a PBK model for a similar chemical. Essential to this process, is identifying the chemicals for which a PBK model already exists. Herein, the results of a systematic review of existing PBK models, compliant with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) format, are presented. Model information, including species, sex, life-stage, route of administration, software platform used and the availability of model equations, was captured for 7541 PBK models. Chemical information (identifiers and physico-chemical properties) has also been recorded for 1150 unique chemicals associated with these models. This PBK model data set has been made readily accessible, as a Microsoft Excel® spreadsheet, providing a valuable resource for those developing, using or evaluating PBK models in industry, academia and the regulatory sectors.

PBPK model reporting template for chemical risk assessment applications.

Physiologically-based pharmacokinetic (PBPK) modeling analysis does not stand on its own for regulatory purposes but is a robust tool to support drug/chemical safety assessment. While the development of PBPK models have grown steadily since their emergence, only a handful of models have been accepted to support regulatory purposes due to obstacles such as the lack of a standardized template for reporting PBPK analysis. Here, we expand the existing guidances designed for pharmaceutical applications by recommending additional elements that are relevant to environmental chemicals. This harmonized reporting template can be adopted and customized by public health agencies receiving PBPK model submission, and it can also serve as general guidance for submitting PBPK-related studies for publication in journals or other modeling sharing purposes. The current effort represents one of several ongoing collaborations among the PBPK modeling and risk assessment communities to promote, when appropriate, incorporating PBPK modeling to characterize the influence of pharmacokinetics on safety decisions made by regulatory agencies.

A simple locally active memristor and its application in HR neurons.

This paper proposes a simple locally active memristor whose state equation only consists of linear terms and an easily implementable function and design for its circuit emulator. The effectiveness of the circuit emulator is validated using breadboard experiments and numerical simulations. The proposed circuit emulator has a simple structure, which not only reduces costs but also increases its application value. The power-off plot and DC V-I Loci verify that the memristor is nonvolatile and locally active, respectively. This locally active memristor exhibits low cost, easy physical implementation, and wide locally active region characteristics. Furthermore, a neural model composed of two 2D HR neurons based on the proposed locally active memristor is established. It is found that complicated firing behaviors occur only within the locally active region. A new phenomenon is also discovered that shows coexisting position symmetry for different attractors. The firing pattern transition is then observed via bifurcation analysis. The results of MATLAB simulations are verified from the hardware circuits.

A weight of evidence approach to investigate potential common mechanisms in pesticide groups to support cumulative risk assessment: A case study with dinitroaniline pesticides.

In 2016, the United States Environmental Protection Agency's (EPA) Office of Pesticide Programs published guidelines for establishing candidate common mechanism groups (CMGs) for cumulative risk assessment (CRA) weight-of-evidence-based screenings. A candidate CMG is a group of chemicals that may share similar structure, apical endpoints, and/or mechanistic data that suggest the potential for a common mechanism of toxicity among them. Here, a weight-of-evidence approach is presented to establish candidacy of a CMG for a group of nine dinitroaniline pesticides. This approach involves review of available in vivo toxicity information and literature to determine mode of action, along with analyses of in vitro toxicity data and chemical structure. Despite structural similarity among some dinitroanilines and some shared target organs identified through toxicity observed in in vivo studies, there were no consistencies among groups, suggesting lack of a common mechanism when all analyses are considered together. For example, two structurally similar compounds with thyroid/liver in vivo effects were not found active in any Toxicity Forecaster (ToxCast) in vitro assays. The weight-of-evidence is insufficient to support the testable hypothesis that dinitroanilines could form a CMG, and highlights the importance of establishing a consensus among multiple lines of evidence prior to CRA.

Comparative transcriptome analysis of the calcium signaling and expression analysis of sodium/calcium exchanger in Aspergillus cristatus.

Aspergillus cristatus develops into various stages under different Na concentrations: the sexual stage in 0.5 M NaCl and asexual development stage in 3 M NaCl. In order to explore whether the Ca2+ signaling pathway in A. cristatus responded to the changes in the salt stress, we analyzed the gene expression levels in A. cristatus respectively cultured in 0.5 M NaCl and 3 M NaCl. According to the BLAST analysis results, we identified 25 Ca2+ -signaling proteins in A. cristatus. The expression levels of most genes involved in the Ca2+ -signaling pathway in A. cristatus cultured in different salt concentrations showed significant differences, indicating that the Ca2+ signaling pathway was involved in the response to the changes in the salt stress. In yeasts, only calcium ion influx proteins were reported to be involved in the response to the changes in the salt stress. So far, the protein for the exchanger of calcium/sodium ions has not been reported. Therefore, we obtained the sodium/calcium exchanger (termed NCX) proteins from the KEGG Database. The ncx gene of A. cristatus was cloned and characterized. The full length of ncx gene is 3055 bp, including a 2994-bp open reading frame encoding 994 amino acids. The expression levels of ncx in the sexual development stage and asexual development stage were respectively ∼8.94 times and ∼2.57 times of that in the hyphal formation stage. Therefore, we suggested that ncx gene was up-regulated to resist the sodium stress. The study results provide the basis for further exploring the Ca2+ -signaling mechanism and ion exchanger mechanism.

Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction.

Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-vetted models can be a great resource for the construction of models pertaining to new chemicals. A PBPK knowledgebase was compiled and developed from existing PBPK-related articles and used to develop new models. From 2,039 PBPK-related articles published between 1977 and 2013, 307 unique chemicals were identified for use as the basis of our knowledgebase. Keywords related to species, gender, developmental stages, and organs were analyzed from the articles within the PBPK knowledgebase. A correlation matrix of the 307 chemicals in the PBPK knowledgebase was calculated based on pharmacokinetic-relevant molecular descriptors. Chemicals in the PBPK knowledgebase were ranked based on their correlation toward ethylbenzene and gefitinib. Next, multiple chemicals were selected to represent exact matches, close analogues, or non-analogues of the target case study chemicals. Parameters, equations, or experimental data relevant to existing models for these chemicals and their analogues were used to construct new models, and model predictions were compared to observed values. This compiled knowledgebase provides a chemical structure-based approach for identifying PBPK models relevant to other chemical entities. Using suitable correlation metrics, we demonstrated that models of chemical analogues in the PBPK knowledgebase can guide the construction of PBPK models for other chemicals.

Comparative Transcriptome Sequence Analysis of Sporulation-Related Genes of Aspergillus cristatus in Response to Low and High Osmolarity.

Aspergillus cristatus undergoes sexual and asexual development under conditions of low and high osmotic pressure, respectively. In this study, the expression levels of 107 genes associated with sexual and asexual development were analysed under conditions of low and high osmotic pressure by RNA sequencing. The results showed that 37 genes were up-regulated and other genes were down-regulated under conditions of high osmotic pressure, with most of the up-regulated genes associated with asexual development and most down-regulated genes associated with sexual development. These results suggest that osmotic pressure regulated sexual and asexual development of A. cristatus by controlling the expression levels of key genes. Meanwhile, there were differences in the expression levels of key genes associated with the regulation of sexual and asexual development between A. cristatus and Aspergillus nidulans. Moreover, we verified the reliability of the results by quantitative real-time polymerase chain reaction analysis of some key genes. In this study, the relationship between sporulation-related genes and osmotic pressure at the transcriptome level were analysed, which indicated that A. cristatus was a useful model organism for the study of osmotic pressure regulation on sexual and asexual development.

Investigating the state of physiologically based kinetic modelling practices and challenges associated with gaining regulatory acceptance of model applications.

Physiologically based kinetic (PBK) models are used widely throughout a number of working sectors, including academia and industry, to provide insight into the dosimetry related to observed adverse health effects in humans and other species. Use of these models has increased over the last several decades, especially in conjunction with emerging alternative methods to animal testing, such as in vitro studies and data-driven in silico quantitative-structure-activity-relationship (QSAR) predictions. Experimental information derived from these new approach methods can be used as input for model parameters and allows for increased confidence in models for chemicals that did not have in vivo data for model calibration. Despite significant advancements in good modelling practice (GMP) for model development and evaluation, there remains some reluctance among regulatory agencies to use such models during the risk assessment process. Here, the results of a survey disseminated to the modelling community are presented in order to inform the frequency of use and applications of PBK models in science and regulatory submission. Additionally, the survey was designed to identify a network of investigators involved in PBK modelling and knowledgeable of GMP so that they might be contacted in the future for peer review of PBK models, especially in regards to vetting the models to such a degree as to gain a greater acceptance for regulatory purposes.

Comparative genomic and transcriptomic analyses of the Fuzhuan brick tea-fermentation fungus Aspergillus cristatus.

BACKGROUND: Aspergillus cristatus is the dominant fungus involved in the fermentation of Chinese Fuzhuan brick tea. Aspergillus cristatus is a homothallic fungus that undergoes a sexual stage without asexual conidiation when cultured in hypotonic medium. The asexual stage is induced by a high salt concentration, which completely inhibits sexual development. The taxon is therefore appropriate for investigating the mechanisms of asexual and sexual reproduction in fungi. In this study, de novo genome sequencing and analysis of transcriptomes during culture under high- and low-osmolarity conditions were performed. These analyses facilitated investigation of the evolution of mating-type genes, which determine the mode of sexual reproduction, in A. cristatus, the response of the high-osmolarity glycerol (HOG) pathway to osmotic stimulation, and the detection of mycotoxins and evaluation of the relationship with the location of the encoding genes. RESULTS: The A. cristatus genome comprised 27.9 Mb and included 68 scaffolds, from which 10,136 protein-coding gene models were predicted. A phylogenetic analysis suggested a considerable phylogenetic distance between A. cristatus and A. nidulans. Comparison of the mating-type gene loci among Aspergillus species indicated that the mode in A. cristatus differs from those in other Aspergillus species. The components of the HOG pathway were conserved in the genome of A. cristatus. Differential gene expression analysis in A. cristatus using RNA-Seq demonstrated that the expression of most genes in the HOG pathway was unaffected by osmotic pressure. No gene clusters associated with the production of carcinogens were detected. CONCLUSIONS: A model of the mating-type locus in A. cristatus is reported for the first time. Aspergillus cristatus has evolved various mechanisms to cope with high osmotic stress. As a fungus associated with Fuzhuan tea, it is considered to be safe under low- and high-osmolarity conditions.

Adverse Outcome Pathways-Organizing Toxicological Information to Improve Decision Making.

The number of chemicals for which environmental regulatory decisions are required far exceeds the current capacity for toxicity testing. High-throughput screening commonly used for drug discovery has the potential to increase this capacity. The adverse outcome pathway (AOP) concept has emerged as a framework for connecting high-throughput toxicity testing (HTT) and other results to potential impacts on human and wildlife populations. As a result of international efforts, the AOP development process is now well-defined and efforts are underway to broaden the participation through outreach and training. One key principle is that AOPs represent the chemical-agnostic portions of pathways to increase the generalizability of their application from early key events to overt toxicity. The closely related mode of action framework extends the AOP as needed when evaluating the potential risk of a specific chemical. This in turn enables integrated approaches to testing and assessment (IATA), which incorporate results of assays at various levels of biologic organization such as in silico; HTT; chemical-specific aspects including absorption, distribution, metabolism, and excretion (ADME); and an AOP describing the biologic basis of toxicity. Thus, it is envisaged that provision of limited information regarding both the AOP for critical effects and the ADME for any chemical associated with any adverse outcome would allow for the development of IATA and permit more detailed AOP and ADME research, where higher precision is needed based on the decision context.

Evaluating the Impact of Uncertainties in Clearance and Exposure When Prioritizing Chemicals Screened in High-Throughput Assays.

The toxicity-testing paradigm has evolved to include high-throughput (HT) methods for addressing the increasing need to screen hundreds to thousands of chemicals rapidly. Approaches that involve in vitro screening assays, in silico predictions of exposure concentrations, and pharmacokinetic (PK) characteristics provide the foundation for HT risk prioritization. Underlying uncertainties in predicted exposure concentrations or PK behaviors can significantly influence the prioritization of chemicals, though the impact of such influences is unclear. In the current study, a framework was developed to incorporate absorbed doses, PK properties, and in vitro dose-response data into a PK/pharmacodynamic (PD) model to allow for placement of chemicals into discrete priority bins. Literature-reported or predicted values for clearance rates and absorbed doses were used in the PK/PD model to evaluate the impact of their uncertainties on chemical prioritization. Scenarios using predicted absorbed doses resulted in a larger number of bin misassignments than those scenarios using predicted clearance rates, when comparing to bin placement using literature-reported values. Sensitivity of parameters on the model output of toxicological activity was examined across possible ranges for those parameters to provide insight into how uncertainty in their predicted values might impact uncertainty in activity.

Conceptual Framework To Extend Life Cycle Assessment Using Near-Field Human Exposure Modeling and High-Throughput Tools for Chemicals.

Life Cycle Assessment (LCA) is a decision-making tool that accounts for multiple impacts across the life cycle of a product or service. This paper presents a conceptual framework to integrate human health impact assessment with risk screening approaches to extend LCA to include near-field chemical sources (e.g., those originating from consumer products and building materials) that have traditionally been excluded from LCA. A new generation of rapid human exposure modeling and high-throughput toxicity testing is transforming chemical risk prioritization and provides an opportunity for integration of screening-level risk assessment (RA) with LCA. The combined LCA and RA approach considers environmental impacts of products alongside risks to human health, which is consistent with regulatory frameworks addressing RA within a sustainability mindset. A case study is presented to juxtapose LCA and risk screening approaches for a chemical used in a consumer product. The case study demonstrates how these new risk screening tools can be used to inform toxicity impact estimates in LCA and highlights needs for future research. The framework provides a basis for developing tools and methods to support decision making on the use of chemicals in products.