Eyes to the Future: Approaches To Assess Pesticide Impact on

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Chapter 10

Eyes to the Future: Approaches To Assess Pesticide Impact on Surface Waters in a Changing Climate Simone Hasenbein,1 Erika B. Holland,2 and Richard E. Connon*,3 1Aquatic Systems Biology Unit, Department of Ecology and Ecosystem Management, Technical University of Munich, 85354 Freising, Germany 2Department of Biological Sciences, California State University of Long Beach, Long Beach, California 90840, United States 3School of Veterinary Medicine, Department of Anatomy, Physiology and Cell Biology, University of California at Davis, Davis, California 95616, United States *E-mail: [email protected].

Global climate change (GCC) is a major threat to global biodiversity that will put many species at risk. Understanding species responses to combined effects between GCC and increased pesticide use requires an interdisciplinary perspective, combining molecular, physiological, and ecological approaches. A recent “Letter to the Editor” by Stewart (Stewart, A. J. Ecotoxicology: It’s Time for a Hard Re-Look. Environ. Toxicol. Chem. 2018, 37, 9–10) highlighted the need to re-evaluate the way in which ecotoxicological studies are conducted, indicating that the next generation of ecotoxicologists will need to reshape and advance the field to incorporate the following concerns: rapidly changing environmental conditions associated with GCC, the current and rapidly developing suite of tools and approaches available to determine toxicological effects, and the many computational advances that can be used toward predicting chemicals’ distribution and fate, as well as modeling physiological and population level effects. This chapter further stresses the importance of this reevaluation toward developing a stronger, more effective, collaborative, and multidisciplinary field to

© 2019 American Chemical Society Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

provide quantitative and qualitative data that can adequately be used in pesticide regulation. Further integration and collaboration among researchers, regulators, environmental managers, and stakeholders are needed nationally and globally to adequately address the ever-changing and predicted increased use of pesticides, particularly in light of GCC.

Introduction Global climate change (GCC) represents a key threat to aquatic biodiversity due to altered habitats resulting from changes in thermal regimes, salinity, pH, precipitation, and stratification of aquatic systems worldwide (1–4). Changes in these abiotic stressors will likely lead to large and deleterious impacts, causing severe physiological stress, species decline, and potential extirpation (5, 6). Decline of endangered and threatened species, and those with limited distributions, will particularly be intensified (7–10). As climates change, it is predicted that pesticide use will increase to combat insect pests and diseases (11), further affecting nontarget organisms in sensitive aquatic habitats. The concentration of pesticides present in terrestrial and aquatic environments, such as metals and persistent organic pollutants, will also continue to increase (12) due to continued production and use. Additionally, climate change is predicted to alter atmospheric deposition and surface runoff, leading to altered pesticide global movement (13). Studies predict that the latitudinal and longitudinal ranges of several insect pests and weeds will be expanded or shifted (13, 14), leading to the need for even greater pesticide applications (15). For example, forecast sea level rise, increased storm frequency and intensity, coastal flooding, and increased temperatures are predicted to cause increases in mosquito populations and vector-borne diseases (16), which will require enhanced abatement programs. These predictions together with the altered GCC patterns highlight the need to start addressing pesticide use in light of a changing climate. Stressors associated with GCC and other anthropogenic threats, such as water pollution, will likely produce confounding impacts in nontarget species, leading to additive, synergistic (more severe) or antagonistic (less severe) effects, where detrimental synergistic effects on aquatic ecosystems are predicted. Specifically, Hooper et al. (12) have postulated that pesticides are expected to interact with GCC stressors and affect organisms in two ways, causing: (1) “toxicant-induced climate susceptibility,” where pesticide exposure weakens the organisms’ ability to acclimate to altered environments; and (2) “climate-induced toxicant sensitives,” where changes in environmental parameters alter organisms’ tolerance to pesticide exposure. It is likely that these interactive effects are highly species-specific, associated with seasonality and life cycles of species in question, as well as dependent on chemical classes (13). Extreme events, such as increased intensities of drought and floods, will further exacerbate these interactive effects. Global climate change associated stressors are known to affect the toxicokinetics and toxicodynamics of pesticides. Temperature changes alter chemical uptake, metabolism, and excretion, altering bioaccumulation and 190 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

availability at a given molecular target (17). Additionally, studies demonstrate that temperature can alter the mechanistic toxicity of pesticides, generally resulting in increased toxicity with increasing temperature (18, 19). Alternatively, pyrethroid pesticides are known to be more toxic at lower temperatures but cause greater endocrine disruption at higher temperatures (20–23). A study testing the survival of the amphipod Hyalella azteca exposed to pyrethroids including bifenthrin at different temperatures revealed that toxicity of pyrethroid pesticides doubled at 18 °C and even tripled at 13 °C, relative to the standard toxicity test guideline conditions of 23 °C (21, 24, 25). Change in temperature can affect metabolic function and toxicokinetic rates in organisms, which was reported for pyrethroid toxicity at lower temperatures (26). Salinity differences can also affect the bioavailability of pesticides, where their lower water solubility at higher salinities likely leads to elevated sediment concentrations, increasing bioconcentration in benthic macroinvertebrates (27, 28). For example, the solubility of the phenylpyrazole insecticide Fipronil (and its degradation products) decreases considerably with increased salinity, making it more bioavailable to benthic invertebrate populations (29). Salinity changes can, in addition, influence sensitivity to contaminant exposure (12, 30). Salinity enhances the toxicity of several agricultural pesticides (31), and prior exposure to pesticides can affect the potential for acclimation to salt water in anadromous fish species during outmigration (32), highlighting carryover effects, which are not generally evaluated in toxicological assessments. The combined environmental variable will create additional complexity such as that seen in Hasenbein et al. (33), where the highest mortality was observed for H. azteca exposed to 1 ng/L bifenthrin at the lowest tested temperature (12 °C) and the highest salinity level of 8 ppt. The combination of an increase in toxicity at low temperature with increasing salinity likely reduced the organisms’ capability to contend with these picomolar exposure concentrations. This suggests that bifenthrin is more toxic at higher salinity (18); perhaps resulting from increased bioavailability at higher salinities (34), or that increases in salinity can impact ionic regulation, therefore increasing organismal sensitivity to contaminant exposure (12, 30)— or both. Changes in other physicochemical parameters have also been shown to alter toxicity. Synergistic effects of low dissolved oxygen and pesticide exposure in Daphnia manga neonates resulted in reduced juvenile growth rate, mature size, clutch size, neonate body size, and neonatal neckteeth development (35). Similarly, it has long been known that pH alters the bioavailability and uptake of pesticides (36). Altered environments are, more often than not, likely to result in habitat compression. In fact, climate change models, when integrated with ecophysiological metrics, are indicative of habitat compression (10, 37). Contaminants have been shown to act synergistically with multiple environmental factors and are likely to exacerbate GCC effects; as such, they will lead to further habitat compression (Figure 1). Standard regulatory ecotoxicology, however, does not take an organism’s fundamental niche nor the potential habitat compression into account, and rather evaluates the impact of pesticides upon organisms maintained under optimal conditions, with little consideration for the range of environmental conditions they inhabit. Essentially, standard toxicology 191 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

tests data utilized for regulation are obtained from evaluations conducted at the dashed line displayed in Figure 1A. This is a legacy of environmental toxicology, where single organisms (i.e., humans) are the end focus of such assessments. This regulatory approach, though somewhat informative, has been repeatedly shown to underestimate ecological risk, as the effects of multiple stressors are known to differ from those predicted based on the sum of individual stressors (33, 38–40); thus, they cannot be considered ecologically relevant.

Figure 1. Pesticide-driven habitat compression: Standard regulatory toxicology approaches assume no habitat compression and only evaluate potential. Current standards for a reduction in performance at a species’ optimal temperature (A: performance is reduced within the organisms’ optimal environmental condition—dashed line). Within an ecological context, however, the reality is that a species’ environmental tolerance may be compromised; thus, their habitat is compressed (B). Dependent on contaminant classes responsible, this habitat compression can take several forms, shifting toward lower temperatures when pesticides are more toxic at warmer temperatures (C: e.g., organophosphate pesticides) or toward warmer temperatures when pesticides are more toxic at lower temperatures (D: e.g., pyrethroid pesticides). Habitat compression is indicated by the yellow arrows. While temperature has been used in this example, habitat compression and organismal responses are directly applicable to pesticide interactions with all GCC stressors. Stress due to GCC may reduce the potential for resistance to, and recovery from, toxicant exposure (41). The presented examples highlight the need for ecologically and environmentally relevant exposures that integrate multiple stressors to gain essential evidence for the significant effects caused by alterations of GCC stressors and pesticides. The aims of this chapter are to highlight existing toxicological approaches and approaches commonly used in other research fields, 192 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

which could be utilized in standard ecotoxicological testing to determine pesticide impacts in the light of GCC.

Considerations for Climate Change in Ecotoxicological Approaches Pesticide evaluation, registration, and monitoring need to measure the same standard endpoints in order to establish values for management practices. Evaluation is traditionally based on acute toxicity (survival/mortality), growth, or reproduction rates for fish and invertebrates, and inhibitory concentration (IC50) for vascular plants and algae (Code of Federal Regulations - 40CFR Part 158: Subpart G 158.630 and 158.660). Median lethal or effect concentrations (LC50s, EC50s) have thus been the foundation of pesticide toxicology for decades. However, pesticide exposure in the environment likely presents sublethal and intermittent impacts on exposed species, such that the relevance of LC50 type metrics is limited and not cost- or time effective. Molecular and cellular studies as well as high-throughput screening can determine which chemicals, or chemical classes, can help identify risk based on the chemical mechanism of toxicity and help highlight chemicals that need longer-term assessments. However, such approaches need to be grounded in systemic biological endpoints in order to fully understand the consequences of pesticide exposure. Standard Approaches to Regulating Pesticide Registration and Use The European regulatory framework for chemicals (REACH) stipulates that standardized ecotoxicological hazard assessments should be conducted using organisms from different trophic levels (primary producers, primary and secondary consumers) (42). Similar approaches are established through the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), managed through the U.S. Environmental Protection Agency (US EPA), where for aquatic environments, hazard assessment is completed using a freshwater fish and a model invertebrate species (43) and algae (e.g., Selenastrum capricornutum; (44)). According to the Organization for Economic Co-operation and Development (OECD) (45), internationally-agreed testing assessment can be divided into three stages: 1.

Preliminary effects assessment (Tier 1). Only short-term toxicity data are available, such as quantitative structure-activity relationship (QSAR) estimates or median lethal/effect concentration (LC50 or EC50) values derived from laboratory exposures. In QSAR modeling, chemical effects are predicted based on supposed relationships between physicochemical properties or theoretical molecular descriptors of chemicals (46). An LC50 is the estimated concentration of the test material that will kill or immobilize 50% of the test organisms in a predetermined period of time. Similarly, median effect concentrations (EC50) can be calculated for any specified effect. 193

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2.

3.

Refined or intermediate effects assessment (Tier 2). This can take place if few or no observed effect concentrations (NOECs) from chronic tests are available. A NOEC is the highest test concentration below which no adverse effect occurs (47). Comprehensive effects assessment (Tier 3). Field studies and multispecies toxicity studies (or many chronic test results) are taken into account (45).

The large number of existing chemicals does not allow an in-depth risk assessment at the level of disturbance of an ecosystem. Thus, the generic risk assessment scheme has been developed into a system in which the information gained from each tier for multiple trophic levels (e.g., algae, daphnia, fish) in conjunction with an assessment factor (in the range of 1–1000) can be used to calculate the predicted no effect concentration (PNEC). The PNEC represents an estimate of the putative effects that each contaminant may have in specific ecosystem situations (48, 49). The calculation of the predicted environmental concentration (PEC) gives an estimate of the level of exposure for a given scenario and is thus essential for an initial indication of negative impact (50). The quotient of the PEC of a chemical and its toxic potential is given by the PNEC value, which results in a PEC/PNEC ratio (the Risk Quotient, RQ), widely used as a standardized measure of risk in environmental risk assessment (51). Other approaches based on species sensitivity distributions (SSDs) or detailed toxicokinetic and/or dynamic modeling can be used in situations where a considerable amount of ecotoxicological information is available for every single component in the mixture (52, 53). SSDs quantify the fraction of species that are potentially affected in contaminated environmental habitats using sensitivity data of several test species (54–56). However, REACH and FIFRA request limited datasets, which are considered to be insufficient for the estimation of SSDs or more elaborate modeling approaches (48). Approaches Aimed at Evaluating Sublethal Impacts of Pesticides Impacts on Populations and Communities Aquatic systems commonly face complex mixtures of pesticides, which can have unanticipated consequences leading to indirect effects at the community level and altered abiotic variables. This can result in reduced ecological fitness and consequently reduced survival of individual non-target species at different trophic levels through sublethal physiological, behavioral, or immunological effects, potentially leading to changes in structure and function of non-target populations and affecting food web and ecosystem dynamics (57). Sublethal impacts of pesticides, such as growth inhibition or swimming impairments, have been shown to lead to failure to reach maturity and reproduce (58). Consequently, a population exposed to pesticides could become even more sensitive to climate change stressors, depending on the duration and intensity of exposure. Recovery of affected populations following pesticide exposure is governed by many factors, such as the persistence and type of the compound, time of year 194 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

when the exposure occurred, distance to unexposed habitat with recolonization sources, and species traits related to life history and dispersal (41). The combination of factors such as temperature-induced effects (59) and interspecific interactions such as predation (60) or competition (61) could lead to a magnified impact on those populations and thus the entire food web (62). This highlights the difficulty of making assumptions on how GCC stressors may interact with pesticides on the population and community level, and these factors need to be accounted for when extrapolating stressor effects from the individual level to the population or community level (41, 63). The number of studies that address the combined impacts of climate and pesticide effects on species interactions and community-level endpoints are scarce (see review, (41)). However, a combination of factorial studies with the use of mechanistic community models is suggested (64).

Whole Organism Impacts Sublethal endpoints represent sensitive and ecologically significant approaches to understanding sensitive organism-level responses to chemical stressors. As sublethal effects may magnify and manifest in the population and thus in the food web, sublethal endpoints provide population relevant information for ecological risk assessment. Sublethal endpoints are of increasing importance, especially in waters where contaminant concentrations are detected at low levels, where chronic exposures are expected, or where developmental or seasonal carryover effects would have detrimental impacts on populations (43, 65). Many contaminants have been shown to cause long-term health effects or reproductive impairment, which are often not detectable using traditional toxicity testing methods (e.g., (22, 66, 67)). Neurotoxic pesticides present in aquatic systems may affect motility at sublethal exposure levels (66, 68, 69), suggesting motility to be a highly environmentally relevant endpoint, particularly since motility in itself can be used to determine multiple endpoints of interest, such as velocity, twitching, seizures, and avoidance responses to olfactory cues. It is especially useful for estimating effects on an individual level in fish (70–76) and has also been applied in experiments involving aquatic invertebrates (33, 77–81). The assessment of swimming performance incorporates biochemical and physiological responses and directly evaluates the effect of neurotoxic contaminants on nerve cell transmissions and resulting muscle activity (68, 73). Inability to swim normally will therefore negatively affect individual fitness and survival, with potential consequences at the population level (71, 74). Hasenbein et al. (81) determined significant effects on motility of Chironomus dilutus in 10-day exposures to two pyrethroids, lambda-cyhalothrin and permethrin, and the organophosphate chlorpyrifos at exposures within the range of reported environmental concentrations (5.50 ng/L lambda-cyhalothrin, 24.23 ng/L permethrin, 90.92 ng/L chlorpyrifos) (82–85) that exceeded NOEC and EC50s determined for growth and immobility in this study (85–88). Other sublethal behavioral effects observed include case abandonment in the caddisfly Brachycentrus americanus when exposed to esfenvalerate (type 195 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

II pyrethroid), which is associated with energetically costly activities such as case rebuilding (89) and subsequent impacts on caddisfly growth (90). These behavioral impacts negatively affect individual fitness and survival, with potential consequences at the population level (71, 74).

Figure 2. Application of chlorpyrifos-containing products compared to natural patterns in acetylcholine esterase activity in striped bass (Morone saxatilus) young of the year. (A) Summed monthly application of pest management products containing chlorpyrifos (i.e., formulation) compared to pounds of the chemical applied in California’s Napa, Sacramento, San Joaquin, and Yolo counties in 2016. (B) Monthly average acetylcholine esterase activity (bars) in young of the year striped bass collected at various sites in the Sacramento–San Joaquin Delta compared to surrounding water temperatures (line). Data collected from the California Department of Pesticide Regulation Pesticide Information Portal for the 2016 annual data (https://calpip.cdpr.ca.gov/main.cfm; accessed July 2018) or estimated from Durieux et al. (110) from fish collected in 2007.

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The impact of chemicals on behavior incorporates an organism’s biochemical and physiological responses to chemical exposure and can be directly related to a contaminant’s mechanism of action (68, 73). For example, the behavioral impacts of organophosphate pesticides (OPs) have been linked to disruption at the acetyl cholinesterase enzyme (AChE), and this includes OP-induced changes to swimming performance (91, 92). The acetyl cholinesterase enzyme is responsible for the removal of the neurotransmitter acetylcholine (ACh) from terminal synapses and is responsible for tightly controlled neuronal and neuromuscular transmission. Organophosphate and carbamate insecticides inhibit AChE in both vertebrate and invertebrate organisms (93–96), leading to a buildup of ACh at the synapse and observed neurotoxicity (97). As such, altered AChE activity is a well-established biomarker used to demonstrate OP and carbamate pesticide exposure (see review by Key and Fulton, (98)), including organisms collected in OP-contaminated aquatic environments (see references in Fulton and Key, (99)). Altered AChE activity, or expression, is also suggested as a general stress marker for pyrethroid pesticides (100, 101), metals (102), and general mixture exposures (103). An example of sublethal organismal impact, in relation to a chemical’s mechanism of action, includes pyrethroid pesticide activity toward voltage-gated sodium channels (VGSC) responsible for controlled cellular depolarization in neuronal signaling and striated muscle cell contraction. Pyrethroids alter the activation and inactivation state of VGSC, resulting in prolonged open periods of individual channels leading to neuronal hyperactivity and organismal paralysis or erratic movements, depending on exposure concentration. Pyrethroids can also affect VGSC in cardiac tissue, where Haverinen and Vornanen (104) demonstrate that the Type II pyrethroid deltamethrin reduces sodium currents in carp sinoatrial cells, leading to reduced atrial force and contractions, common signs of cardiac arrhythmia (104). Furthermore, while a common biomarker for VGSC disruption is not currently available, signs of pyrethroid-induced impacts in aquatic environments include developed resistant to pyrethroid toxicity caused by mutations in VGSC channels (H. azteca (105)). Sublethal, biochemical, and molecular biomarker studies have been useful in defining impacts in laboratory and field settings and define important key events leading to pesticide-induced changes in organismal health. However, there is a great need for research that addresses whether altered function or expression is affected by other environmental factors in combination with pollutant stress. Studies have shown, for example, that the activity of AChE and enzymes related to altered oxidative stress and pollutant metabolism is sensitive to variable environmental parameters (106–108) and displays variability in organisms collected in the field during different times of the year (109). But this sensitivity or variability seems to vary across taxa where work collected to date shows that fish species and marine bivalves often display the highest AChE activity during the warmest time of the year (Figure 2) (109, 110); however, AChE activity in Chironomus species acts as a robust biomarker for OP exposure regardless of changing temperature (108, 111). Few molecular pathways have the depth of available data, with the exception of perhaps cytochrome P450 (e.g., EROD activity), needed to evaluate sensitivity to pesticides in light of GCC. This is especially true for newer pesticides such as pyrethroids that target VGSC (112) 197 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

and endocrine pathways (22), or ryanoid insecticides, known to target ryanodine sensitive Ca2+ channels (113). These targets are sensitive to environmental parameters, especially temperature or temperature acclimation (114–116) such that pollutants and GCC would likely lead to compounding impacts on the neuronal, neuromuscular, and endocrine health of organisms. Once such data are available, they might help guide pesticide use practices such as application time or location. One example is the use of AChE active pesticides during periods of the year when species might be the most sensitive due to seasonally induced or temperature-induced increases in AChE activity (Figure 2). Finally, environmental parameters or other stressors (e.g., disease or handling) can also influence the expression of specific isoenzymes as a form of compensation. AChE isoenzymes vary in trout acclimated to warm and cold temperatures (117), and similar results have been demonstrated for numerous other molecular pathways (118, 119) with changing environments. There are few studies; however, that address variable isoenzyme sensitivity to pollutants, confounding conclusions about biomarker use in populations.

Evaluating Sublethal Effects with ’omic Technologies Research utilizing ’omics (genomics, proteomics, and metabolomics) approaches has received growing attention over the past decade, as it provides a means of characterizing the subcellular biological processes underlying higher-order responses to contaminants and other stressors (120, 121). These approaches have the ability to determine molecular pathways associated with exposure as well as to provide for mechanistic evaluations of the biochemical status of organisms in response to pesticides. ’Omic techniques have been proven to be very powerful in assessing the effects of climate alterations to fully understand the biological consequences of GCC and its long-term effects on biodiversity (33, 120, 122, 123). Responses at these lower levels of biological organization (molecular and cellular responses) occur rapidly and are generally stressor specific. Transcriptomic and proteomic approaches can be used in hypothesis-driven research, as well as in discovery research, toward identifying a pathway-specific response and functional biochemical alterations that can be further developed as molecular and biochemical biomarkers of effect and rapid assessment of physiological condition (32). These tools can provide early signs of toxicological effects on individuals and populations. RNA-sequencing technology, for example, has become increasingly powerful in the study of non-model species (122, 124) and in particular for species of conservation concern (120). Transcriptome-wide screening approaches allow for valuable insight into the complex responses to GCC stressors, distinguishing between specific responses to changes in temperature (e.g., heat shock proteins), salinity (e.g., ion regulation transporter), and pollutants (e.g., oxidative stress and neurological system processes), and respective interactions. Ideally, these responses can be matched with whole-organism and population-level responses to support long-term predictions of GCC impacts on aquatic organisms. 198 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

In Vitro Screens for Chemical Prioritization Receptor-, protein-, or cellular-based assays have long been utilized for the identification of the chemical mechanism of action and allow for the definition of chemical affinity (Kd) and effective or inhibitory concentrations compared to the elicited maximum response (e.g., EC50 or IC50). Such approaches are now widely used in both human and ecology centric toxicology studies, and due to current technological advances, they have been developed as assays capable of screening a large number of chemicals in one setting. The best examples are those assays that form the core of the Toxicology in the 21st Century (Tox21) program (125, 126) supported by the US EPA, the NIH National Toxicology Program, and the U.S. Food and Drug Administration. Since its inception in 2007, the Tox21 program has screened over 10,000 chemicals in over 700 bioassays, leading to a great understanding of the potential risks of current use chemicals. These in vitro assays often lack a realistic picture of chemical adsorption, distribution, metabolism, and elimination (ADME) characteristics important for understanding in vivo impacts. To combat such shortcomings, recent additions have included rapid assessments of zebrafish (Danio rerio) mortality, hatching success, and teratology to screen chemical libraries involved in the Tox21 program (i.e., US EPA ToxCast Libraries) (127, 128). This inclusion seems promising as chemicals flagged for additional testing by the Tox21 screening process often correlate with impacts seen in zebrafish (129). Some work also suggests that additional in vitro cellular models may help predict bioavailability, metabolism, and clearance, but these models often lack validation or are not currently accepted by regulatory agencies (130). The Tox21 approach will help prioritize chemicals for further testing but may not describe comparative sensitivity, even though studies by Dreier and colleagues (131) have shown that Tox21 assay screening results for endocrine disrupting chemicals may predict impacts seen in non-target species.

In Silico Meta-Analysis The rapid growth of high-throughput and ’omics technology and application in toxicology has resulted in vast datasets being submitted to publicly available repositories worldwide. The ability to leverage these databases has infinite potential toward utilizing data-driven toxicity evaluations (120, 132–134). This meta-analysis approach extrapolates responses across multiple endpoints, species, and chemical groups and rapidly evaluates existing toxicological data on chemicals with the following outcomes: (1) effective confirmation and validation with reduced need for further testing, (2) rapid identification of chemicals for which further information is required, and (3) development of tools (e.g., biomarkers) or functional approaches with which to gain specific information. Wang et al. (132) demonstrate how this data-driven in-silico approach, known as connectivity mapping (Cmap), originally proposed for biomedical research (135), can effectively be used without the need for time-consuming processes of development and validation. Cmap determined similarities in the underlying mechanisms of action of chemicals; connecting chemicals and 199 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

disease-based transcriptomic profiles and software packages have been developed for this purpose (136). Wang et al. (132) evaluated over 3500 zebrafish (D. rerio) and fathead minnow (Pimephales promelas) transcriptomic datasets by which stressor-specific effect signatures were identified, aiding the development of biomarkers focused on contaminants of concern. Hypothesis about the Mechanisms of Action of These Contaminants Meta-analytical approaches at the ’omics level should further incorporate the multitude of published effect-based data obtained at multiple levels of biological organization (tissue, organ, whole organism, population, and communities) to further confirm or develop adverse outcomes with ecological significance. Analyses that focus on multiple species of ecological relevance could provide an indication of risks across trophic and ecosystem linkages (133). Furthermore, there is a growing number of GCC-related research for which there is an abundance of transcriptomic data (e.g., thermal stress (122) and salinity stress (123), pathogens and disease (137, 138), dissolved oxygen (139), and pH (140)). These and other datasets could be used to integrate and differentiate between responses to environmental stressors, contaminant stress, and respective interactions.

Interdisciplinary Approaches: Conservation Physiology and Toxicology Organisms are adapted genetically to a specific range of environmental conditions. Aquatic organisms inhabit a limited range that is determined by physicochemical parameters such as temperature, salinity, pH, and dissolved oxygen. This adaptation is a result of optimized structural and kinetic coordination of molecular, cellular, and systemic processes. Environmental factors that impact organismal performance therefore limit their geographical distribution (141). Global climate change has in fact been associated with poleward shifts in species distribution, population collapses and local extinctions, changes in the seasonal timing of biological events, and changes in community composition (142). Conservation biology has played a key role in understanding the influence of GCC on aquatic systems. Conservation physiology is defined by Cooke et al. (143) as: “An integrative scientific discipline applying physiological concepts, tools, and knowledge to characterizing biological diversity and its ecological implications; understanding and predicting how organisms, populations, and ecosystems respond to environmental change and stressors; and solving conservation problems across the broad range of taxa (i.e. including microbes, plants, and animals).” Conservation physiologists focus on “strategies to rebuild populations, restore ecosystems, inform conservation policy, generate decision-support tools, and manage natural resources.” Although this definition encompasses the evaluation of contaminants among environmental change stressors, the field of conservation physiology does not readily incorporate the synergistic impact that contaminants may pose on species of concern. However, 200 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

GCC-associated stressors are major areas of overlap between conservation biologists and ecotoxicologists (144), with many of the approaches utilized in conservation physiology being readily applicable to determine changes in sensitivity to contaminant exposure and provide a particularly strong means of evaluating sublethal toxicity. Physiology metrics have proven effective in explaining life-history strategies and predicting resilience to climate change (145), for example, by examining the physiological capacity toward determining maximum and minimum tolerance ranges. A stronger ecotoxicological risk assessment can thus be constructed through addressing specific endpoints known to be affected by GCC-related stressors, upon which toxicological assessments can be determined, for example, by conducting toxicological studies that incorporate tolerance ranges applicable to the model species being used. GCC variables in the context of toxicology have only recently received focus, and this is especially true for cellular-based assays aimed at addressing the combined effects on particular mechanisms or modes of toxicity. For example, rainbow trout hepatocytes have long been a model in toxicology (146, 147), but only recent studies have begun addressing effects of environmental parameters alone or in concert with a chemical. Work has demonstrated that environmentally relevant temperature stress alone alters mitochondrial function in rainbow trout hepatocytes and exacerbates cadmium toxicity (148). Interestingly, trout preacclimation to suboptimal warm temperatures, rather than acute temperature stress in vitro, also displayed a modest increase in hepatocyte sensitivity to cadmium (149). The combined impacts described by Olsvik et al. (149) were not evident with the simple cytotoxicity assay but rather were highlighted by the altered expression of genes related to oxidative stress, demonstrating the need to integrate multiple endpoints in GCC and toxicity assessments. Although information on combined impacts is limited, in general, future studies should include integrative assessments in both model and non-model species, as temperature stress and temperature acclimation will likely have diverse impacts on the physiology, or underlying biochemical function or molecular signaling, of phylogenetic distinct organisms, and these impacts may be related to habitat choice (114, 150–152). Thus, a comprehensive ecotoxicological assessment can be only achieved through the integration of systems biology approaches to investigate complex organismal and ecosystem interactions intent on modeling and discovering emergent properties of the system (153). Advances in the development of adverse outcome pathway assessments (154) are needed, as well as the incorporation of carryover effects across life history strategies, developmental stages, and physiological states across seasons, all of which influence long-term population dynamics (155).

Conclusions Global climate change models predict that a longer growing season (spring-summer) will result from milder temperatures, which will likely result in a shift to earlier pesticide application in some geographical areas. Similarly, fall pesticide applications can be expected to be delayed, resulting in increased and 201 Goh et al.; Pesticides in Surface Water: Monitoring, Modeling, Risk Assessment, and Management ACS Symposium Series; American Chemical Society: Washington, DC, 2019.

repeated application pesticide use. Furthermore, with predictions of more intense fall and winter precipitations (extreme events), more frequent freeze/thaw events are likely to increase the risk of leaching and surface runoff, highlighting the need for new and extensive data on the risk of pesticide exposure during the winter season, particularly in cold climate regions. Future efforts on mitigation strategies can be improved by enhancing awareness of altered threats of pesticide mixtures under predicted climate change conditions. As such, environmental monitoring of pesticides will continue to be important and may need to be intensified. Ecotoxicology has and always will be a truly interdisciplinary field. This field is constantly evolving and hungry for new tools and approaches to rapidly and thoroughly evaluate the impact of an ever-changing number of contaminants on complex ecosystems. On the other hand, pesticide regulation continues to be extremely limited in the number of endpoints used (growth, survival, reproduction) and is also heavily limited by a number of species used to evaluate toxicity. It is clear that a handful of model species do not even begin to represent communities and ecosystems being evaluated. Sensitivity differences between taxa are broad, and we cannot expect toxicity as assessed by using one species to predict impacts on other species, even when those species are members of the same family (156). In-silico-based evaluations may likely be the broadest of approaches to address needed changes in ecotoxicological focus in light of GCC. Data from continuously generated toxicological evaluations across multiple species under different climatic conditions, which include higher level endpoint data such as behavior and reproduction, need to be expanded upon and submitted to online repositories. Databases need to continue to further expand and new bioinformatic algorithms need to be developed to gather this information from the vast number of peer-reviewed sources available. For this to occur, researchers, regulators, environmental managers, and stakeholders need to become more integrated and share co-equal goals.

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