Toward risk assessment without animals: Development of Adverse Outcome Pathways for lung cancer

The risk for chemicals and other types of substances, including nanomaterials, to cause cancer is complex to assess and currently based mainly on animal experimentation, even though non-animal alternative methods exist.

Some of these cell-based methods and assays are accepted by regulatory instances for risk assessment, however, are mainly applied as weight of evidence information in addition to currently required animal data. In addition, novel high-throughput systems, capable of handling increasing numbers of samples in short time frames, require validation towards regulatory acceptance. The new Adverse Outcome Pathway (AOP) concept is expected to simplify and improve the integration of alternative methods towards becoming gold standard regulatory accepted methods for risk assessment. AOPs describe toxic mechanisms causally connected to human organ injury and disease. They provide a basis for development of mechanism-focused alternative methods predictive of the risk for toxicity. This project will develop AOPs for lung cancer, one of the most common and deadly forms of cancer associated with exposure to a wide range of inhalable substances. The project will apply toxicological big data derived from in vitro high-throughput testing and analyses of around 40 diverse nanomaterials. A novel bioinformatics pipeline will be utilized to integrate data and guide the development and refinement of AOPs for lung cancer. The overall aim will be to map assays, information and data in line with the AOP concept and thereby support further development and integration of AOP-aligned animal-free methods for cancer risk assessment of inhalable nanomaterials.

Populärvetenskaplig sammanfattning

Mot riskbedömning utan djurförsök: Utveckling av Adverse Outcome Pathways för lungcancer

Risken för kemikalier och andra typer av ämnen, t.ex. nanomaterial, att orsaka cancer är komplex att bedöma och grundar sig idag främst på djurexperiment, trots att det finns en rad djurfria cell-baserade test till förfogande. Vissa av dessa test accepteras av myndigheter för riskbedömning, men appliceras oftast enbart som stödinformation till djurexperiment. Det nya Adverse Outcome Pathway (AOP)-konceptet förväntas kunna förenkla och förbättra användningen av djurfria metoder i riskbedömning, genom dess starka fokus på toxiska mekanismer kausalt kopplade till organskador och sjukdomar. Detta projekt ämnar utveckla AOPs för lungcancer, en av de vanligaste och dödligaste formerna av cancer som idag orsakas av en lång rad inandningsbara ämnen. Projektet applicerar toxikologiska ’big data’ från ett fyrtiotal olika nanomaterial för att underlätta fortsatt utveckling och integrering av AOP-baserade djurfria metoder för cancerriskbedömning av inandningsbara nanomaterial.

Funding

Forska utan Djurförsök (Project No. N2020-0005)

Contact person

Penny Nymark

Assistant professor