Assessment factors for extrapolation from short-time to chronic exposure--are the REACH guidelines adequate?

Due to the relative scarcity of long-term toxicity data, assessment factors for extrapolation from relatively short to chronic exposures have an important role in the risk assessment of chemicals. A recent REACH guidance document includes recommended default assessment factors that cover subacute-subchronic, subchronic-chronic, and subacute-chronic extrapolations. The recommended assessment factors are smaller than in most previous proposals, since they are calibrated to achieve central estimates (50th percentile of the target distribution) rather than a higher percentile such as the 95th, as has been more common. These assessment factors are nevertheless presented as representing a "widely agreed level of conservatism", a statement that may lead to misunderstandings of what is achieved by using them in a risk assessment. Assessment factors have been based on evidence from animal studies with different designs, in particular with focus on different endpoints. Our re-analysis of experimental data shows that using mortality as an endpoint leads to smaller assessment factors than if the factors are derived from corresponding ratios for non-lethal toxicity.