Modelling the effects of dietary toxicity on the growth of rodents: applications in chemical risk assessment

Before being approved for use, pesticides undergo ecological risk assessment (ERA) to identify any adverse effects they may have on non-target species. For terrestrial mammals, dietary toxicity studies on laboratory animals, lasting up to two years, are used to assess chronic toxicity. However, such studies are limited in their ability to assess ecological risk, as constant dietary exposure to pesticides over long periods is an unrealistic scenario in the field. In silico models have long been suggested as a way of addressing the limitations of laboratory testing, by simulating the processes underlying toxicity. Toxicokinetic-toxicodynamic (TK-TD) models simulate both the uptake of a chemical into an animal’s body, and the resulting stress on biological processes which leads to observed effects. This thesis comprises a series of studies in which TK-TD models were developed to simulate the effects of dietary toxicity on the growth of rodents, and applications for ERA and the reduction of animal testing were explored. Unpublished raw data from regulatory toxicokinetics and toxicity studies on several pesticides were provided by Syngenta. First, a protocol for TK-TD modelling with regulatory datasets was developed. This produced TK-TD models that successfully predicted the growth rate of laboratory rats exposed to various pesticides and dietary dose levels. These TK-TD models were then used to facilitate comparisons between in vitro and in vivo toxicity data. While no predictive relationships were identified, this study demonstrated how in vitro and in silico methods may be combined to obviate the need for animal testing in future. Finally, a new method for converting observed feeding data into growth model inputs was developed, improving model accuracy and realism. This enhances the ability of models to separate the effects of toxicity and feeding avoidance on body weight, a valuable insight for assessing ecological risk.