Pulmonary toxicity – a challenge for drug and chemical development
Despite the common assumption that adverse drug reactions only affect the kidney and liver, more than 600 medications inducing lung toxicity have been reported.1 Lungs are susceptible to toxicity due to their large surface area and metabolism of certain substances2, such as antibiotics and anti-inflammatories, and specialist drugs targeting the cardiovascular system and tumours. This has resulted in 4-10% of patients developing pulmonary toxicity.3
“There are more than 600 medications known to induce pulmonary toxicity” (1)
Newcells Biotech is developing a functional lung 3–D model derived from human induced pluripotent stem cells (hiPSC). The structure of the in vitro model mimics the in vivo airways of the lung by presenting tight epithelial junctions and a structured pseudostratified epithelium of functional basal cells, goblet cells, club cells and beating ciliated cells with a mucus layer on the apical side visible by brightfield microscopy. This model is the first functional air-liquid interface iPSC-derived lung airway model, overcoming the drawbacks of previous in vitro models, which contained limited cell types and functionality. The model has been validated against environmental pollutants in collaboration with Public Health England; for more detail about this see our previous blog.
Due to the rapid increase of new chemicals released into the market (approximately 3,000 annually)4, the Registration, Evaluation, Authorization and restriction of Chemicals (REACH) reported that 90,000 vertebrate animals are employed annually in toxicity testing in Europe alone.5 While most toxicology studies are performed by exposing animals to high-dose concentrations and tracking toxic responses to substances, in many cases, these animal studies don’t effectively replicate reactions in humans.2,6 This is either due to interspecies differences metabolising the substance or inability to test multiple drug-to-drug interactions due to high–cost and animal availability. 6 These disparities increase the possibility of adverse reactions in humans and this is why environmental and toxicological organisations are seeking to employ human cell models to minimise the potential morbidity and mortality from pulmonary disease with novel approaches to toxicity screening.2,6
Newcells’ lung 3-D in vitro model is being designed to increase the available testing capacity of ethical and cost-effective replacements for ineffective animal models and to aid industry in more extensively testing for pulmonary toxicity.
- Drug-Induced Pulmonary Toxicity: Practice Essentials, Background, Pathophysiology [Internet]. [cited 2020 Feb 6]. Available from: https://emedicine.medscape.com/article/1343451-overview
- Schwaiblmair M, Behr W, Haeckel T, Märkl B, Foerg W, Berghaus T. Drug Induced Interstitial Lung Disease. Vol. 6, The Open Respiratory Medicine Journal. 2012.
- Ellis SJ, Cleverley JR, Müller NL. Drug-Induced Lung Disease. Am J Roentgenol [Internet]. 2000 Oct [cited 2020 Feb 6];175(4):1019–24. Available from: http://www.ajronline.org/doi/10.2214/ajr.175.4.1751019
- Bengtsson BMI. Global Trends – Threats or Challenges to Future Food Security and Food Safety. In: Agricultural Research at the Crossroads [Internet]. CRC Press; 2018 [cited 2020 Feb 7]. p. 97. Available from: https://books.google.co.uk/books?id=gJWwDwAAQBAJ&printsec=frontcover#v=onepage&q&f=false
- Rovida C, Hartung T. Re-evaluation of animal numbers and costs for in vivo tests to accomplish REACH legislation requirements for chemicals – A report by the transatlantic think tank for toxicology (t4). ALTEX. 2009;26(3):187–208.
- Krewski D, Acosta D, Andersen M, Anderson H, Bailar JC, Boekelheide K, et al. Toxicity testing in the 21st century: A vision and a strategy. Vol. 13, Journal of Toxicology and Environmental Health – Part B: Critical Reviews. 2010. p. 51–138.