Modelling chronic toxicity in terrestrial mammals
Lead Research Organisation:
University of York
Department Name: Environment
Abstract
Small mammals (e.g. field voles, wood mice) contribute to ecosystem services both in their own right and as prey for iconic predators such as birds of prey. In order to maintain food security while preserving ecosystem services it is important to understand the mechanisms of how different pesticide exposure patterns lead to ecotoxicological effects under field conditions.
The aim of this project is to develop a toxicokinetic-toxicodynamic (TKTD) model to better understand, simulate and predict toxic effects of pesticides on wildlife, specifically effects on growth of small mammals. Existing laboratory toxicity studies with rats and mice will be used to develop and calibrate the model. The model aims to achieve two objectives: A. In-vitro to in-vivo toxicity extrapolation for effects on growth B. Assess the effects of different exposure patterns in the field for risk assessment.
The aim of this project is to develop a toxicokinetic-toxicodynamic (TKTD) model to better understand, simulate and predict toxic effects of pesticides on wildlife, specifically effects on growth of small mammals. Existing laboratory toxicity studies with rats and mice will be used to develop and calibrate the model. The model aims to achieve two objectives: A. In-vitro to in-vivo toxicity extrapolation for effects on growth B. Assess the effects of different exposure patterns in the field for risk assessment.
People |
ORCID iD |
| Roman Ashauer (Primary Supervisor) | |
| Thomas Martin (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/P504944/1 | 01/12/2016 | 30/05/2021 | |||
| 1843850 | Studentship | BB/P504944/1 | 01/12/2016 | 31/05/2021 | Thomas Martin |
| Description | The research has demonstrated that toxicokinetic-toxicodynamic models based on the dynamic energy budget (DEBtox) can accurately predict toxic effects on growth rate of rats due to dietary pesticide exposure. The use of these methods has previously focused on invertebrates and aquatic vertebrates. As dietary intake is the primary exposure route of terrestrial mammals to pesticides, a framework has been developed so that data from dietary toxicity studies can be used to construct detailed model inputs. Toxicokinetic modelling predicts the internal pesticide concentration resulting from dietary intake while the toxicodynamic model links internal concentration to stress on growth, modelled using a simple model based on the dynamic energy budget (DEB) theory (DEBkiss). The calibrated models can be used to predict the internal exposure profile and effects on growth in novel scenarios. The model will be used later in the project to predict internal exposure profile and effects in realistic exposure scenarios for terrestrial mammals in the field. The model can also predict the effects of truly constant exposure , as opposed to dietary exposure which varies with feeding rate. These predictions are valuable for in vitro - in vivo extrapolation, work is currently underway to test the ability of in vitro assays to predict toxic effects on growth in vivo using model predictions. Separate model inputs for feeding rate and pesticide intake are generated from the data which allows the models to gain additional insight into data sets. In studies of dietary toxicity, feeding rate and pesticide intake are inextricably linked and any observed reduction in growth (relative to controls) may result from a combination of reduced feeding and toxic action. Statistical analysis can determine whether average feeding rate was significantly different between treatments, and so whether it likely impacted upon growth rate but this does not capture temporal variation in feeding rate and provides no information as to its relative effect. This temporal variation is included in our model predictions. By separating the effects of feeding rate from the effects on growth rate, the models can indicate the degree to which feeding rate or toxic action affected growth over time. We have also shown that unlike for fish, TK-TD models are not yet able to accurately extrapolate growth effects in mammals from in vitro data. Several possible reasons for this were identified such as low in vitro sensitivity or complex metabolic pathways. Perhaps most crucial though, is that model requirements differ between in vitro and in vivo scenarios. To predict effects in vivo only requires that the internal concentration of the test compound is predicted to within a given proportion (i.e. the predicted value is always the actual concentration multiplied by X) however to compare in vitro and in vivo effects the actual concentration must be known in both cases. In principle, TK-TD models could be highly valuable as a means of comparing in vivo (fluctuating exposure) with in vitro (constant exposure) and testing methods of extrapolation between the two levels. However, we found the proposed methods were not yet suitable for this purpose. |
| Exploitation Route | We have worked with a simplified DEB model and focused on one endpoint, growth. The DEB model framework can also consider reserve dynamics and reproductive output which could be explored by others. We have also identified the need for greater information on on recovery, it is important to know the age at which growth ceases and the potential for recovery beyond this age in the species of interest. Such information would enable long term predictions of the effects of dietary toxicant exposure on growth. We also showed that unlike for fish, TK-TD models are not yet able to accurately extrapolate growth effects in mammals from in vitro data. Future work should focus on improving accuracy and validation of in vivo TK models so that they can facilitate comparisons of effects observed in vitro and in vivo. This may require in vivo data collection to assess whether gavage dosing (currently used in toxicokinetics testing) is suitable for predicting kinetics under dietary dosing (used in longer term toxicity testing). |
| Sectors | Agriculture, Food and Drink,Chemicals,Environment |
| Title | Toxicokinetic-toxicodynamic model for predicting the effects of dietary toxicity on growth in rats |
| Description | The model is made up of three components: 1. A toxicokinetic model which predicts a measure of internal toxicant concentration based on dietary intake. 2. The DEBkiss growth model (a simplified version of the Dynamic Energy Budget (DEB) model) which predicts the animal growth rate using feeding rate as an input. 3. The DEBtox toxicodynamic model which links internal toxicant concentration to 'stress' on growth parameters. We have developed a framework for using the results of dietary toxicity studies to generate model inputs (toxicant intake and feeding rate over time), parameterise and calibrate models (by fitting to measured body mass over time). |
| Type Of Material | Model of mechanisms or symptoms - mammalian in vivo |
| Year Produced | 2019 |
| Provided To Others? | No |
| Impact | This tool can be used to predict effects in novel scenarios and can provide additional insight into toxicological data sets by providing information regarding the relative impacts of feeding rate and toxic action on growth rate. |