Abstract-In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible models for predicting the toxicity of chemicals when little or no empirical data are available. In recent years, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. The objective of this research was to develop procedures that relate modes of acute toxic action in the fathead minnow (Pimephales promelas) to chemical structures and properties. An empirically derived database for diverse chemical structures of acute toxicity and corresponding modes of toxic action was developed through joint toxic action studies, the establishment of toxicodynamic profiles, and behavioral and dose-response interpretation of 96-h LC50 tests. Using the results from these efforts, as well as principles in the toxicological literature, approximately 600 chemicals were classified as narcotics (three distinct groups), oxidative phosphorylation uncouplers, respiratory inhibitors, electrophiles/proelectrophiles, acetylcholinesterase inhibitors, or central nervous system seizure agents. Using this data set, a computer-based expert system has been established whereby chemical structures are associated with likely modes of toxic action and, when available, corresponding QSARs.

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In the field of environmental toxicology, and especially aquatic toxicology, quantitative structure activity relationships (QSARs) have developed as scientifically-credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A basic and fundamental understanding of toxicological principles has been considered crucial to the continued acceptance and application of these techniques as biologically relevant. As a consequence, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. The assessment of a compound's likely mode of toxic action is critical for a correct QSAR selection; incorrect mode of action-based QSAR selections can result in 10- to 1000-fold errors in toxicity predictions. The establishment of toxicologically-credible techniques to assess mode of toxic action from chemical structure requires toxicodynamic knowledge bases that are clearly defined with regard to exposure regimes and biological models/endpoints and based on compounds that adequately span the diversity of chemicals anticipated for future applications. With such knowledge bases classification systems, including rule-based experts systems, have been established for use in predictive aquatic toxicology applications.

An ~80% decline in the eastern population of the monarch butterfly (Danaus plexippus) has prompted conservation efforts to increase summer reproductive success in the Midwest United States. Implementation of conservation practices will create a patchwork of milkweed (mainly Asclepias spp.) habitat within agricultural landscapes dominated by corn and soybean production. Since the monarch butterfly is a vagile species, reproductive success is, in part, a function of both the amount and spatial arrangement of habitat patches in a fragmented landscape. To inform conservation planning we developed a spatially-explicit, agentbased model for summer breeding, non-migratory female monarch butterfly movement and egg-laying on an Iowa, USA landscape. Our model employs a unique movement algorithm when monarch agents encounter habitat edges that incorporates monarch perceptual range to their host plant and spatial memory of previously visited habitat. These behavioral factors are rarely incorporated into animal movement algorithms; however, they can influence estimates of resource utilization. Model exploration assessed the distribution and density of eggs laid on a spatially-explicit 148,665 ha landscape comprised of 17 land cover classes with varying milkweed densities. Uncertainty analysis was undertaken by sampling 25 combinations of perceptual range, spatial memory, flight step length and flight directionality parameters from a total of 256 (44) possible combinations. Movement paths simulated with our new movement algorithm show preferential use of high density milkweed areas that would not be simulated using a correlated random walk. Increasing perceptual range caused a decrease in the area used by monarch agents and caused a skewed egg distribution where most eggs were laid in relatively few habitat patches. Increasing spatial memory caused an increase in the area used but decreased the median number of eggs laid in roadside habitat. Current national and regional monarch conservation goals assume a uniform distribution of milkweed in different land cover classes. Translating these goals into spatially-explicit, heterogeneous habitat patches is essential for predicting realized fecundity in the landscape. Our model provides the foundation to link national and regional monarch conservation goals to fine scale spatial configurations of habitat patches in defined landscapes.

Estimating the toxicity of reactive xenobiotics to aquatic organisms requires physicochemical descriptors of passive transport and chemical reactions with nucleophilic biological ligands. Herein, electrophiles whose toxic action is attributed to nucleophilic substitution (SN), Michael-type addition and Schiff-base formation were examined. Training sets for each molecular mechanism were generated through substructure search applied to chemicals in a fathead minnow (Pimephules promelus) database. Based on a delineation of compounds by a presumed molecular mechanism, relationships between modes of toxic action, potency (96-hour LC,, values) and mechanistically-appropriate quantum-chemica1 descriptors were explored. Monohalo-C(sp3) function which may give rise to S, reactivity was encountered in 35 compounds.The inclusion of E L , , , , a nonspecific electrophilicity descriptor, to the generic LC,, -hydrophobicity relation increased the explained variance from r' = 36% to 69%. Eighteen potential Michael-type acceptors, mainly acrylates, were identified by the presence of a localized CC double bond at an E, position to a polar group. Due to different modes of action, the toxic potency of these chemicals varies almost independently of hydrophobicity (? = 0.12). Two additional electronic descriptors that are consistent with the likely molecular mechanism provide a multivariate QSAR with ? = 0.78. Forty-five aldehydes and 3 formamides comprised the training set associated with probable Schiff-base mechanism of toxicity. The results suggest a marginal increase of toxic potency from that expected due to narcosis for more electrophilic carbonyl groups. Overall, it was concluded that regressions based on data sets that combine reactive chemicals with narcotics typically require an electronic descriptor in addition to hydrophobicity, even if the compounds all contain a common electrophilic moiety related to the putative specific reaction mechanism. However, without the generation of additional toxicity data from chemical sets that incorporate a broader range of electronic and steric character, it will likely remain extremely difficult to develop a quantitative ability to predict the potency of electrophilic compounds.

Establishment and maintenance of milkweed plants (Asclepias spp.) in agricultural landscapes of the north central United States are needed to reverse the decline of North America's eastern monarch butterfly (Danaus plexippus) population. Because of a lack of toxicity data, it is unclear how insecticide use may reduce monarch productivity when milkweed habitat is placed near maize and soybean fields. To assess the potential effects of foliar insecticides, acute cuticular and dietary toxicity of 5 representative active ingredients were determined: beta‐cyfluthrin (pyrethroid), chlorantraniliprole (anthranilic diamide), chlorpyrifos (organophosphate), and imidacloprid and thiamethoxam (neonicotinoids). Cuticular median lethal dose values for first instars ranged from 9.2 × 10–3 to 79 μg/g larvae for beta‐cyfluthrin and chlorpyrifos, respectively. Dietary median lethal concentration values for second instars ranged from 8.3 × 10–3 to 8.4 μg/g milkweed leaf for chlorantraniliprole and chlorpyrifos, respectively. To estimate larval mortality rates downwind from treated fields, modeled insecticide exposures to larvae and milkweed leaves were compared to dose–response curves obtained from bioassays with first‐, second‐, third‐, and fifth‐instar larvae. For aerial applications to manage soybean aphids, mortality rates at 60 m downwind were highest for beta‐cyfluthrin and chlorantraniliprole following cuticular and dietary exposure, respectively, and lowest for thiamethoxam. To estimate landscape‐scale risks, field‐scale mortality rates must be considered in the context of spatial and temporal patterns of insecticide use. Environ Toxicol Chem 2020;39:923–941. © 2020 SETAC

Recreating the structure of human tissues in the laboratory is valuable for fundamental research, testing interventions, and reducing the use of animals. Critical to the use of such technology is the ability to produce tissue models that accurately reproduce the microanatomy of the native tissue. Current artificial cell‐based skin systems lack thorough characterisation, are not representative of human skin, and can show variation. In this study, we have developed a novel full thickness model of human skin comprised of epidermal and dermal compartments. Using an inert porous scaffold, we created a dermal construct using human fibroblasts that secrete their own extracellular matrix proteins, which avoids the use of animal‐derived materials. The dermal construct acts as a foundation upon which epidermal keratinocytes were seeded and differentiated into a stratified keratinised epithelium. In‐depth morphological analyses of the model demonstrated very close similarities with native human skin. Extensive immunostaining and electron microscopy analysis revealed ultrastructural details such as keratohyalin granules and lamellar bodies within the stratum granulosum , specialised junctional complexes, and the presence of a basal lamina. These features reflect the functional characteristics and barrier properties of the skin equivalent. Robustness and reproducibility of in vitro models are important attributes in experimental practice, and we demonstrate the consistency of the skin construct between different users. In summary, a new model of full thickness human skin has been developed that possesses microanatomical features reminiscent of native tissue. This skin model platform will be of significant interest to scientists researching the structure and function of human skin.