NC3Rs crack-it solutions: Looking for project partner

Extrapolating in vitro to in vivo toxicity for predicting effects on growth in rats and mice: We are seeking a partner with expertise in mammalian cell culture to develop novel approaches forĀ in vitro-in vivo toxicity extrapolation to reduce the use of animals in mammalian chronic toxicity studies. Our expertise is in toxicokinetic-toxicodynamic modelling, ecotoxicity and environmental risk assessment. We have a BBSRC industrial CASE project starting in October 2016 to work on this topic, which includes access to data from existing toxicity studies with pesticides and expertise at our industrial partner. However we do not have the required expertise in cell culture assay development to generate the in vitro data to calibrate our toxicokinetic-toxicodynamic models. The ideal partner should (i) have facilities to carry out toxicity tests with pesticides, including analytical facilities, (ii) be willing to work collaboratively in protocol development, and (iii) maintain or regularly use a range of mammalian cells. More information on the NC3Rs website.

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Extrapolating in vitro to in vivo toxicity for predicting effects on growth in rats and mice
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Summer school - Dynamic Modelling of Toxic Effects

Date: 9-17 Aug 2016. Find more information here and here. Please get in touch if you are interested.

Toxicology across scales: Cell population growth in vitro predicts reduced fish growth

Rainbow trout gill cells. Phot credit: Vivian Lu Tan/Eawag
Rainbow trout gill cells. Phot credit: Vivian Lu Tan/Eawag

Environmental risk assessment of chemicals is essential but often relies on ethically controversial and expensive methods. We show that tests using cell cultures, combined with modeling of toxicological effects, can replace tests with juvenile fish. Hundreds of thousands of fish at this developmental stage are annually used to assess the influence of chemicals on growth. Juveniles are more sensitive than adult fish, and their growth can affect their chances to survive and reproduce. Thus, to reduce the number of fish used for such tests, we propose a method that can quantitatively predict chemical impact on fish growth based on in vitro data. Our model predicts reduced fish growth in two fish species in excellent agreement with measured in vivo data of two pesticides. This promising step toward alternatives to fish toxicity testing is simple, inexpensive, and fast and only requires in vitro data for model calibration. (Published in Science Advances, open access)

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Death Dilemma and Organism Recovery in Ecotoxicology

Why do some individuals survive after exposure to chemicals while others die? Either, the tolerance threshold is distributed among the individuals in a population, and its exceedance leads to certain death, or all individuals share the same threshold above which death occurs stochastically. The previously published General Unified Threshold model of Survival (GUTS) established a mathematical relationship between the two assumptions. According to this model stochastic death would result in systematically faster compensation and damage repair mechanisms than individual tolerance. Thus, we face a circular conclusion dilemma because inference about the death mechanism is inherently linked to the speed of damage recovery. We provide empirical evidence that the stochastic death model consistently infers much faster toxicodynamic recovery than the individual tolerance model. Survival data can be explained by either, slower damage recovery and a wider individual tolerance distribution, or faster damage recovery paired with a narrow tolerance distribution. The toxicodynamic model parameters exhibited meaningful patterns in chemical space, which is why we suggest toxicodynamic model parameters as novel phenotypic anchors for in vitro to in vivo toxicity extrapolation. GUTS appears to be a promising refinement of traditional survival curve analysis and dose response models. (Published in Environmental Science & Technology, open access)

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Death Dilemma and Organism Recovery in Ecotoxicology
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