What is the proper experimental unit for long-term rodent studies? An examination of the NTP benzyl acetate study

The National Toxicology Program (NTP) rat bioassay on benzyl acetate shows an apparent increase in acinar-cell adenomas of the pancreas in male rats [1]. The statistical significance of the apparent trend is examined using the animal, cage, or rack/shelf location as the statistical independent experimental (sampling) unit. Experimental, statistical, and empirical considerations indicate that, in this experiment, if there is a proper experimental unit, it is the shelf of animals on a rack rather than the individual animal or cage of animals. Using the shelf as the experimental unit, the apparent increase in acinar-cell adenomas is not statistically significant. There is strong evidence for pancreatic tumor rates to differ among shelves which implies that toxicologists should consider cage randomization.