In silico toxicokinetics - modelling bioaccumulation
To better predict a compound’s bioaccumulation potential in “air breathing terrestrial mammals (humans, rodents, dogs, horses, monkeys, …)”, ECHA (EU) initiated and has led a project fall 2015 – spring 2019 in which elimination half-lives (t1/2) were collected mainly for numerous pesticides from various in vivo toxicokinetic studies. The basis for the TK studies were often OECD 417, a guideline for the conduct of a study in rats with quite some flexibility in study design depending on the characteristics of the compound. The elimination t1/2 were entered into an Excel format database which presently (May 2019) consists of nearly 2,900 elimination t1/2 data points mainly for plasma, but also for various organs ( ~ 1,300 compounds). Data are mainly for rats, but also other species including humans are sometimes available. The Excel sheet also contains information regarding various physical parameters (Mw, log Pow, log Poa, solubility, pKa, functional groups, etc.), smiles codes and CAS nrs. Also study details regarding animal strain, ages of animals, single or repeated administration, doses, etc is included.
This MSc student project (9-12 months) aims at:
-further developing the database with collection of elimination t1/2 particularly for brain and fat tissues from the open scientific literature. The library at NIPH can assist with literature database searches. Study information, elimination t1/2, and physical parameters (available at PubChem or elsewhere) is to be entered into the database.
-towards the latter part of the project it should be investigated if compounds having long elimination t1/2 have some common chemical structural or physical features by performing computer-based quantitative structure-activity relationship (QSAR) analyses. QSAR can predict toxicokinetics (bioaccumulation) parameters for a compound with unknown distribution profile/half-lives. Thus, a successful project can minimize the number of future animal studies needed.
The candidate should be interested in computer-based work, learning how toxicokinetic studies are performed, and learning QSAR. During the project there will be potential for visits for training in QSAR This type of work is highly relevant for students who are interested in becoming a regulatory toxicologist.