TWAc-Check: A New Approach to Determine the Appropriate Use of Time-Weighted Average Concentration in Aquatic Risk Assessment.

In pesticide risk assessment, regulatory acceptable concentrations for surface water bodies (RACsw,ch) are used that are derived from standard studies with continuous exposure of organisms to a test compound for days or months. These RACsw,ch are compared with the maximum tested concentration of more realistic exposure scenarios. However, the actual exposure duration could be notably shorter (e.g., hours) than the standard study, which intentionally leads to an overly conservative Tier 1 risk assessment. This discrepancy can be addressed in a risk assessment using the time-weighted average concentration (TWAc). In Europe, the applicability of TWAc for a particular risk assessment is evaluated using a complex decision scheme, which has been controversial; thus we propose an alternative approach: We used TWAc-check (which is based on the idea that the TWAc concept is just a model for aquatic risk assessment) to test whether the use of a TWAc is appropriate for such assessment. The TWAc-check method works by using predicted-measured diagrams to test how well the TWAc model predicts experimental data from peak exposure experiments. Overestimated effects are accepted because the conservatism of the TWAc model is prioritized over the goodness of fit. We illustrate the applicability of TWAc-check by applying it to various data sets for different species and substances. We demonstrate that the applicability is case dependent. Specifically, TWAc-check correctly identifies that the use of TWAc is not appropriate for early onset of effects or delayed effects. The proposed concept shows that the time window is a decisive factor as to whether or not the model is acceptable and that this concept can be used as a potential refinement option prior to the use of toxicokinetic-toxicodynamic models. Environ Toxicol Chem 2022;41:1778-1787. © 2022 Bayer AG. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Short-term to long-term extrapolation of lethal effects of an herbicide on the marine mysid shrimp Americamysis Bahia by use of the General Unified Threshold Model of Survival (GUTS).

Risk assessments for plant protection products and their active ingredients that are based on standard laboratory tests performed under constant exposure conditions may result in an overestimation of risks because exposure in the environment is often characterized by a few short peaks. Here, the General Unified Threshold Model of Survival (GUTS) was used to conduct a refined risk assessment for the herbicide tembotrione and its effects on the marine invertebrate Americamysis bahia, for which the standard chronic effect assessment failed. The GUTS model was first calibrated with time-to-effect and concentration-response data from 2 independent acute experiments with A. bahia. Model parameters for both toxicodynamic assumptions of stochastic death (SD) and individual tolerance (IT) were estimated with the reduced GUTS model (GUTS-RED) using the scaled internal concentration as a dose metric. Both the calibrated GUTS-RED-SD and GUTS-RED-IT models described survival dynamics well. Model validation using datasets of 2 independent chronic tests yielded robust predictions of long-term toxicity of tembotrione on A. bahia, with GUTS-RED-IT being more reliable than GUTS-RED-SD. The validated model was subsequently used to predict survival from time-variable exposure profiles, as derived from the FOrum for Co-ordination of pesticide fate models and their USe (FOCUS). Because ecotoxicological independence of peaks had not been empirically verified, the link between exposure and effects was assessed with complete exposure profiles. Effect thresholds resulting from different peak exposure concentrations and durations were determined with GUTS and directly compared with the exposure concentrations from the FOCUS surface water scenarios. The derived values were higher than the predicted FOCUS critical concentrations. Additionally, comparing the areas under the curve (AUCs) derived with GUTS for multiple peak exposure profiles to those from FOCUS revealed significant additional safety margins, demonstrating that only unrealistically high exposure concentrations would produce significant effects. In conclusion, no unacceptable effects of tembotrione on aquatic invertebrates under realistic environmental exposure conditions are expected. Integr Environ Assess Manag 2019;15:29-39. © 2018 SETAC.

Modelling survival: exposure pattern, species sensitivity and uncertainty.

The General Unified Threshold model for Survival (GUTS) integrates previously published toxicokinetic-toxicodynamic models and estimates survival with explicitly defined assumptions. Importantly, GUTS accounts for time-variable exposure to the stressor. We performed three studies to test the ability of GUTS to predict survival of aquatic organisms across different pesticide exposure patterns, time scales and species. Firstly, using synthetic data, we identified experimental data requirements which allow for the estimation of all parameters of the GUTS proper model. Secondly, we assessed how well GUTS, calibrated with short-term survival data of Gammarus pulex exposed to four pesticides, can forecast effects of longer-term pulsed exposures. Thirdly, we tested the ability of GUTS to estimate 14-day median effect concentrations of malathion for a range of species and use these estimates to build species sensitivity distributions for different exposure patterns. We find that GUTS adequately predicts survival across exposure patterns that vary over time. When toxicity is assessed for time-variable concentrations species may differ in their responses depending on the exposure profile. This can result in different species sensitivity rankings and safe levels. The interplay of exposure pattern and species sensitivity deserves systematic investigation in order to better understand how organisms respond to stress, including humans.

Demographic Toxicokinetic-Toxicodynamic Modeling of Lethal Effects.

The aquatic effect assessment of chemicals is largely based on standardized measures of toxicity determined in short-term laboratory tests which are designed to reduce variability. For this purpose, uniform individuals of a species are kept under environmental and chemical exposure conditions which are as constant as possible. In nature, exposure often appears to be pulsed, effects might last longer than a few days, sensitivity might vary among different sized organisms and populations are usually size or age structured and are subject to demographic processes. To overcome this discrepancy, we tested toxicokinetic-toxicodynamic models of different complexities, including body size scaling approaches, for their ability to represent lethal effects observed for Daphnia magna exposed to triphenyltin. The consequences of the different toxicokinetic and toxicodynamic assumptions for population level responses to pulsed exposure are tested by means of an individual based model and are evaluated by confronting model predictions with population data for various pulsed exposure scenarios. We provide an example where increased model complexity reduces the uncertainty in model outputs. Furthermore, our results emphasize the importance of considering population demography in toxicokinetics and toxicodynamics for understanding and predicting potential chemical impacts at higher levels of biological organization.

Modelling the impact of the environmental scenario on population recovery from chemical stress exposure: a case study using Daphnia magna.

Recovery of organisms is an important attribute for evaluating the acceptability of chemicals' effects in ecological risk assessment in Europe. Recovery in the field does not depend on the chemical's properties and type of exposure only, but it is strongly linked to important environmental variables and biological interactions as well. Yet, these remain only marginally considered in the European risk assessment of chemicals. Here, we use individual-based modelling to investigate how the environmental scenario affects Daphnia magna population recovery from chemical exposure. Simulation experiments were performed for chemicals with lethality levels ranging from 40% to 90% at different food and temperature conditions. The same toxicity levels were then tested in combination with biological interactions including predation or competition. Results show that for the same chemical effect strength, populations often exhibited different recovery times in a different environmental context. The interactions between the chemical and the environmental variables were the strongest determinants of population recovery. Most important, biotic interactions even induced opposite effects on recovery at low and at high mortality levels. Results of this study infer that no specific role can be attributed to any abiotic or biotic variable in isolation. We conclude that unless the complex interactive mechanisms between the different factors constituting the full environmental scenario are taken into account in risk assessment, we cannot achieve a complete understanding of recovery processes from chemical effects.

Predicting the sensitivity of populations from individual exposure to chemicals: the role of ecological interactions.

Population responses to chemical stress exposure are influenced by nonchemical, environmental processes such as species interactions. A realistic quantification of chemical toxicity to populations calls for the use of methodologies that integrate these multiple stress effects. The authors used an individual-based model for Daphnia magna as a virtual laboratory to determine the influence of ecological interactions on population sensitivity to chemicals with different modes of action on individuals. In the model, hypothetical chemical toxicity targeted different vital individual-level processes: reproduction, survival, feeding rate, or somatic growth rate. As for species interactions, predatory and competition effects on daphnid populations were implemented following a worst-case approach. The population abundance was simulated at different food levels and exposure scenarios, assuming exposure to chemical stress solely or in combination with either competition or predation. The chemical always targeted one vital endpoint. Equal toxicity-inhibition levels differently affected the population abundance with and without species interactions. In addition, population responses to chemicals were highly sensitive to the environmental stressor (predator or competitor) and to the food level. Results show that population resilience cannot be attributed to chemical stress only. Accounting for the relevant ecological interactions would reduce uncertainties when extrapolating effects of chemicals from individuals to the population level. Validated population models should be used for a more realistic risk assessment of chemicals.

Promoting effects on reproduction increase population vulnerability of Daphnia magna.

Environmental risk assessment of chemicals is based on single species tests at the individual level with single compounds. However, the protection goal is the sustainability of a population, which faces several natural stressors and mixtures of chemicals in the environment. Therefore, experiments were undertaken to quantify the combined effects of chemicals with different modes of action on Daphnia magna populations. Populations continuously exposed to dispersogen A and at abundance equilibrium were treated with a 2-d pulse of p353-nonylphenol. In previous studies, dispersogen A was shown to act as a natural info-chemical, promoting the reproduction of daphnids (higher offspring quantity) coupled with reduced offspring fitness, whereas nonylphenol in pulsed-exposure caused size-selective mortality. Dispersogen A caused accelerated population growth to maximum abundance, shifted the population structure towards smaller individuals, and increased the population sensitivity to nonylphenol. The authors showed that a positive effect observed at the individual level can be transposed to a negative effect when monitored at the population level. So far, positive effects are not addressed in environmental risk assessment, and even in higher-tier testing, population structure is not quantified. Both factors indicate a potential mismatch between protection aim and risk assessment practice.