Formation of Structural Categories to Allow for Read‐Across for Teratogenicity
Steven J. Enoch, M Cronin, Judith Clare Madden, Mark Hewitt · QSAR & Combinatorial Science · 2009
Abstract Reproductive toxicity is a key endpoint under REACH as it is costly, both financially and in the numbers of animal used. These factors make the development of alternative methods for the identification and assessment of chemicals potentially able to cause reproductive toxicity very important. Category formation and read‐across have been suggested to be powerful methods that can utilize existing toxicological data in a transparent and interpretable manner, allowing chemical risk assessments to be carried out with minimal animal usage. Category formation relies on chemical similarity and the ability to select chemicals that act via a single mechanism of toxic action. This study therefore has investigated the use of 2D similarity indices available within the freely downloadable Toxmatch software to form mechanistically transparent categories for 57 query chemicals from a database of 233 chemicals for which teratogenicity (an important endpoint within reproductive toxicity) had been previously assessed. The hypothesis being that chemicals selected as being similar should act via a single mechanism of action, even if that mechanism is unknown. Read‐across predictions were then performed for the query chemicals for which a category could be formed. The results showed that mechanistic categories could be formed for 17 of the 57 query chemicals, within these categories read across predictions enabled the teratogenicity of the query chemicals to be correctly predicted. It was concluded that 2D similarity methods offer a useful method for building chemical categories for teratogenicity in which a‐priori mechanistic knowledge is limited.