A study by Bradbury et al. [82] comparing the distribution of radio-iodinated serum albumin (RISA) in rabbits after intraparenchymal injection with that after intraventricular injection remains one of the most informative undertaken on the routes of elimination of large solutes. Their finding of RISA in the walls of arteries in the circle of Willis after intraparenchymal injection provides strong evidence that some of the albumin leaves the parenchyma along or within arterial walls and continues along them beyond the subarachnoid spaces. This evidence does not, however, indicate how large a fraction of the RISA takes this route. Bradbury et al. also observed that after intraparenchymal injection a smaller fraction of the amount injected passed through the cisterna magna and a larger fraction reached lymph than was evident after intraventricular injection. The RISA distribution following intraventricular injection can be interpreted as tracing the routes followed by CSF emerging from the ventricles. After mixing and passing through the cisterna magna, the CSF flows out of the brain by more than one route, some via the arachnoid villi leading to venous sinuses and some via the cribriform plate leading to the nasal mucosa. From the nasal mucosa large solutes including RISA pass into lymph. After intraventricular injection, the fraction of RISA reaching lymph is somewhat greater than half and represents that fraction of CSF from the ventricles that flows out via the cribriform plate [82]. After intraparenchymal injection, the fraction of RISA reaching lymph is substantially larger than that seen after intraventricular injection. This observation was interpreted by Bradbury et al. [82] as indicating that most of the RISA contained in ISF flowed out of the parenchyma into a portion of CSF that subsequently left the brain via the cribriform plate to the nasal mucosa rather than via the arachnoid villi. Weller, Carare and associates [95, 98, 107], who have used mice for their functional experiments, have since favoured the view that outflow of ISF from the parenchyma occurs via a route that does not entail mixing with any portion of the CSF. In their view ISF drains from the parenchyma along intramural periarterial pathways and exchange of large solutes is not possible between these pathways and CSF as the vessels pass through the subarachnoid spaces or basal cisternae.