Predictive models in ecotoxicology: Bridging the gap between scientific progress and regulatory applicability-Remarks and research needs.

This paper concludes a special series of 7 articles (4 on toxicokinetic-toxicodynamic [TK-TD] models and 3 on quantitative structure-activity relationship [QSAR] models) published in previous issues of Integrated Environmental Assessment and Management (IEAM). The present paper summarizes the special series articles and highlights their contribution to the topic of increasing the regulatory applicability of effect models. For both TK-TD and QSAR approaches, we then describe the main research needs. The use of TK-TD models for describing sublethal effects must be better developed, particularly through the improvement of the dynamic energy budget (DEBtox) approach. The potential of TK-TD models for moving from lower (molecular) to higher (population) hierarchical levels is highlighted as a promising research line. Some relevant issues to improve the acceptance of QSAR models at the regulatory level are also described, such as increased transparency of the performance assessment and of the modeling algorithms, model documentation, relevance of the chosen target for regulatory needs, and improved mechanistic interpretability. Integr Environ Assess Manag 2019;00:000-000. © 2019 SETAC.

Predictive Models in Ecotoxicology: Bridging the Gap Between Scientific Progress and Regulatory Applicability.

This special series is the outcome of the session "Predictive models in ecotoxicology: Bridging the gap between scientific progress and regulatory applicability," held at the 27th SETAC Europe annual meeting (Brussels, May 2017). In this foreword the rationale behind the special series, the reasons for proposing it, and its objectives are described briefly. Integr Environ Assess Manag 2018;14:601-603. © 2018 SETAC.

Investigating apical adverse effects of four endocrine active substances in the freshwater gastropod Lymnaea stagnalis.

The hermaphroditic gastropod Lymnaea stagnalis is proposed as a candidate species for the development of OECD guidelines for testing of the reprotoxicity of chemicals, including endocrine active substances (EASs). Up to now, only a few putative EASs have been tested for their reproductive toxicity in this species. In this study, we investigate the effects of four EASs with different affinities to the vertebrate estrogen and androgen receptors (chlordecone as an estrogen; cyproterone acetate, fenitrothion and vinclozolin as anti-androgens) on the reproduction of L. stagnalis in a 21-day semi-static test. Testosterone and 17α-ethinylestradiol (EE2) were used as the reference compounds. The tested EASs had no significant effect on growth and survival at the tested concentration ranges (ng to µg/L). Classical reproduction endpoints (i.e., oviposition and fecundity) were not responsive to the tested chemicals, except for chlordecone and 17α-ethinylestradiol, which hampered reproduction from 19.6 µg/L and 17.6 µg/L, respectively. The frequency of polyembryonic eggs, used as an additional endpoint, demonstrated the effects of all compounds except EE2. The molecular pathways, which are involved in such reproduction impairments, remain unknown. Our results suggest that egg quality is a more sensitive endpoint as compared to other reproductive endpoints commonly assessed in mollusk toxicity tests.

Considerations for test design to accommodate energy-budget models in ecotoxicology: a case study for acetone in the pond snail Lymnaea stagnalis.

Toxicokinetic-toxicodynamic (TKTD) modeling offers many advantages in the analysis of ecotoxicity test data. Calibration of TKTD models, however, places different demands on test design compared with classical concentration-response approaches. In the present study, useful complementary information is provided regarding test design for TKTD modeling. A case study is presented for the pond snail Lymnaea stagnalis exposed to the narcotic compound acetone, in which the data on all endpoints were analyzed together using a relatively simple TKTD model called DEBkiss. Furthermore, the influence of the data used for calibration on accuracy and precision of model parameters is discussed. The DEBkiss model described toxic effects on survival, growth, and reproduction over time well, within a single integrated analysis. Regarding the parameter estimates (e.g., no-effect concentration), precision rather than accuracy was affected depending on which data set was used for model calibration. In addition, the present study shows that the intrinsic sensitivity of snails to acetone stays the same across different life stages, including the embryonic stage. In fact, the data on egg development allowed for selection of a unique metabolic mode of action for the toxicant. Practical and theoretical considerations for test design to accommodate TKTD modeling are discussed in the hope that this information will aid other researchers to make the best possible use of their test animals.

Modeling the contribution of toxicokinetic and toxicodynamic processes to the recovery of Gammarus pulex populations after exposure to pesticides.

Because aquatic macroinvertebrates may be exposed regularly to pesticides in edge-of-the-field water bodies, an accurate assessment of potential adverse effects and subsequent population recovery is essential. Standard effect risk assessment tools are not able to fully address the complexities arising from multiple exposure patterns, nor can they properly address the population recovery process. In the present study, we developed an individual-based model of the freshwater amphipod Gammarus pulex to evaluate the consequences of exposure to 4 compounds with different modes of action on individual survival and population recovery. Effects on survival were calculated using concentration-effect relationships and the threshold damage model (TDM), which accounts for detailed processes of toxicokinetics and toxicodynamics. Delayed effects as calculated by the TDM had a significant impact on individual survival and population recovery. We also evaluated the standard assessment of effects after short-term exposures using the 96-h concentration-effect model and the TDM, which was conservative for very short-term exposure. An integration of a TKTD submodel with a population model can be used to explore the ecological relevance of ecotoxicity endpoints in different exposure environments.

Reproductive impacts of tributyltin (TBT) and triphenyltin (TPT) in the hermaphroditic freshwater gastropod Lymnaea stagnalis.

Tributyltin (TBT) and triphenyltin (TPT) are emblematic endocrine disruptors, which have been mostly studied in gonochoric prosobranchs. Although both compounds can simultaneously occur in the environment, they have mainly been tested separately for their effects on snail reproduction. Because large discrepancies in experimental conditions occurred in these tests, the present study aimed to compare the relative toxicity of TBT and TPT under similar laboratory conditions in the range of 0 ng Sn/L to 600 ng Sn/L. Tests were performed on the simultaneous hermaphrodite Lymnaea stagnalis, a freshwater snail in which effects of TPT were unknown. Survival, shell length, and reproduction were monitored in a 21-d semistatic test. Frequency of abnormal eggs was assessed as an additional endpoint. Triphenyltin hampered survival while TBT did not. Major effects on shell solidity and reproduction were observed for both compounds, reproductive outputs being more severely hampered by TBT than by TPT. Considering the frequency of abnormal eggs allowed increasing test sensitivity, because snail responses to TBT could be detected at concentrations as low as 19 ng Sn/L. However, the putative mode of action of the 2 compounds could not be deduced from the structure of the molecules or from the response of apical endpoints. Sensitivity of L. stagnalis to TBT and TPT was compared with the sensitivity of prosobranch mollusks with different habitats and different reproductive strategies.

Hormesis on life-history traits: is there such thing as a free lunch?

The term "hormesis" is used to describe dose-response relationships where the response is reversed between low and high doses of a stressor (generally, stimulation at low doses and inhibition at high ones). A mechanistic explanation is needed to interpret the relevance of such responses, but there does not appear to be a single universal mechanism underlying hormesis. When the endpoint is a life-history trait such as growth or reproduction, a stimulation of the response comes with costs in terms of resources. Organisms have to obey the conservation laws for mass and energy; there is no such thing as a free lunch. Based on the principles of Dynamic Energy Budget theory, we introduce three categories of explanations for hormesis that obey the conservation laws: acquisition (i.e., increasing the input of energy into the individual), allocation (i.e., rearranging the energy flows over various traits) and medication (e.g., the stressor is an essential element or acts as a cure for a disease or infection). In this discussion paper, we illustrate these explanations with cases where they might apply, and elaborate on the potential consequences for field populations.