It is an estimate, with uncertainty spanning perhaps an order of magnitude, of a daily oral exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime.
For example, the EPA set an acute RfD for children of 0.0015 mg/kg/day for the organochlorine insecticide endosulfan, based on neurological effects observed in test animals.
To remedy this, the EPA revoked the use of endosulfan on the crops that contributed the most to exposure of children: certain beans, peas, spinach, and grapes.
[4] The EPA determined the acute RfD to be 0.005 mg/kg/day based on a study in which male rats were administered a one-time dose of chlorpyrifos and blood cholinesterase activity was monitored.
Other studies showed that fetuses and children are even more sensitive to chlorpyrifos than adults, so the EPA applies an additional ten-fold uncertainty factor to protect that subpopulation.
The EPA also determined a chronic RfD for chlorpyrifos exposure based on studies in which animals were administered low doses of the pesticide for two years.
Cholinesterase inhibition was observed at all dose levels tested, and a NOAEL of 0.03 mg/kg/day estimated by dividing a LOAEL of 0.3 mg/kg/day by an uncertainty factor of 10.
The chronic PAD ("cPAD") of 3×10−5 mg/kg/day was determined by applying an additional 10-fold uncertainty factor to account for the increased susceptibility of infants and children.
Because the RfD assumes "a dose below which no adverse noncarcinogenic health effects should result from a lifetime of exposure",[5] the critical step in all chemical risk and regulatory threshold calculations is dependent upon a properly derived dose at which no observed adverse effects (NOAEL) 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.
For example, in 2002 the EPA completed its draft toxicological review of perchlorate 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.
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.