Reference Dose - Consensus

Consensus

Because the RfD assumes "a dose below which no adverse noncarcinogenic health effects should result from a lifetime of exposure", the critical step in all chemical risk and regulatory threshold calculations is dependent upon a properly derived dose at which no observed adverse effects (NOEAL) were seen which is then divided by an uncertainty factor that considers inadequacies of the study, animal-to-human extrapolation, sensitive sub-populations, and inadequacies of the database. The RfD that is derived is not always agreed upon. Some may believe it to be overly protective while others may contend that it is not adequately protective of human health.

For example, the EPA completed its draft toxicological review of perchlorate in 2002 and proposed an RfD of 0.00003 milligrams per kilogram per day (mg/kg/day) based primarily on studies that identified neurodevelopmental deficits in rat pups. These deficits were linked to maternal exposure to perchlorate. Subsequently, the National Academy of Science (NAS) reviewed the health implications of perchlorate, and in 2005 proposed an alternative reference dose of 0.0007 mg/kg/day based primarily on a 2002 study by Greer et al. During that study, 37 human subjects were split into four exposure groups exposed to 0.007 (7 subjects), 0.02 (10 subjects), 0.1 (10 subjects), and 0.5 (10 subjects) mg/kg/day. Significant decreases in iodide uptake were found in the three highest exposure groups. Iodide uptake was not significantly reduced in the lowest exposed group, but four of the seven subjects in this group experienced inhibited iodide uptake. The RfD proposed by NAS was accepted by EPA and added to its integrated risk information system (IRIS) in 2005.

Ginsberg and Rice, in a commentary submitted to the journal Environmental Health Perspectives (EHP), argued that the 2005 NAS RfD was not protective of human health based on the following:

1. The NAS report described the level of lowest exposure from Greer et al as a NOEL. However, there was actually an effect at that level although not statistically significant largely due to small size of study population (four of seven subjects showed a slight decrease in iodide uptake).
2. Reduced iodide uptake was not considered to be an adverse effect. However, it is a precursor to an adverse effect (hypothyroidism). Therefore, additional safety factors, they argued, are necessary when extrapolating from the point of departure to the RfD.
3. Consideration of data uncertainty was insufficient because the Greer, et al. study reflected only a 14-day exposure to healthy adults and no additional safety factors were considered to protect sensitive subpopulations. For example, the potential for greater toxicity to breastfeeding newborns was not considered.

Although there has generally been consensus with the Greer et al study, there is not consensus with regard to developing a perchlorate RfD. One of the key differences results from how the point of departure is viewed (i.e., NOEL or LOAEL), or whether a benchmark dose should be used to derive the RfD. Defining the point of departure as a NOEL or LOAEL has implications when it comes to applying appropriate safety factors to the point of departure to derive the RfD.