A path forward for improved noncancer assessment: the truly adverse dose (the TAD)

Conventional noncancer assessment involves the computation of hazard quotients (HQ), simple ratios of an individual’s or a population’s estimated chemical intake, and a reference dose (the RfD) that is held to reflect a safe level of exposure. HQs > 1, indicating RfD exceedance, have considerable uncertainty for two reasons. It is not known that the critical effect of the animal study that supports the RfD is adverse (i.e., harmful), and it is unclear at what dose higher than an RfD, truly health compromising effects are triggered. Through methodically reviewing critical studies of the U.S. EPA’s IRIS database, we investigated the efficacy of the present assessment scheme with its considerable emphasis on RfD development. Aside from noted inconsistencies in reporting, and a substantial percentage of oral noncarcinogens having a less than ideal toxicological review source, our analysis found numerous instances of absent toxicological information to fuel HQ computation, with this largely a function of the dated nature of the supporting studies. In light of our analysis, we propose a recommended replacement scheme for noncancer assessment. In place of estimating the degree to which RfDs are exceeded, we recommend determining whether Truly Adverse Doses (TADs), to be newly developed, are approached.