Reference dose

A reference dose is the United States Environmental Protection Agency's maximum acceptable oral dose of a toxic substance. Reference doses are most commonly determined for pesticides. The EPA defines an oral reference dose (abbreviated RfD) as:n 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. A reference dose is the United States Environmental Protection Agency's maximum acceptable oral dose of a toxic substance. Reference doses are most commonly determined for pesticides. The EPA defines an oral reference dose (abbreviated RfD) as: Unlike National Ambient Air Quality Standards, RfDs are not enforceable standards. Instead, the EPA uses RfDs as risk assessment benchmarks and tries to set other regulations so that people are not exposed to chemicals in amounts that exceed RfDs. According to the EPA, 'n aggregate daily exposure to a at or below the RfD (expressed as 100 percent or less of the RfD) is generally considered acceptable by EPA.' 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. The EPA then looked at dietary exposure to endosulfan, and found that for the most exposed 0.1% of children age 1–6, their daily consumption of the endosulfan exceeded this RfD. 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. Reference doses are chemical-specific, i.e. the EPA determines a unique reference dose for every substance it evaluates. Often separate acute and chronic RfDs are determined for the same substance. Reference doses are specific to dietary exposure. When assessing inhalation exposure, EPA uses 'reference concentrations' (RfCs), instead of RfDs. Note that RfDs apply only to non-cancer effects. When evaluating carcinogenic effects, the EPA uses the Q1* method. RfDs are usually derived from animal studies. Animals (typically rats) are dosed with varying amounts of the substance in question, and the largest dose at which no effects are observed is identified. This dose level is called the 'No observable effect level,' or NOEL. To account for the fact that humans may be more or less sensitive than the test animal, a 10-fold uncertainty factor is usually applied to the NOEL. This uncertainty factor is called the 'interspecies uncertainty factor' or UFinter. An additional 10-fold uncertainty factor, the 'intraspecies uncertainty factor' or UFintra, is usually applied to account for the fact that some humans may be substantially more sensitive to the effects of substances than others. Additional uncertainty factors may also be applied. In general: Frequently, a 'no-observed-adverse-effect level' or NOAEL is used in place of a NOEL. If adverse effects are observed at all dose levels tested, then the smallest dose tested, the 'lowest-observed-adverse-effect level' or LOAEL, is used to calculate the RfD. An additional uncertainty factor usually applied in these cases, since the NOAEL, by definition, would be lower than the LOAEL had it been observed. If studies using human subjects are used to determine a RfD, then the interspecies uncertainty factor can be reduced to 1, but generally the 10-fold intraspecies uncertainty factor is retained. Such studies are rare. As an example, consider the following determination of the RfD for the insecticide chlorpyrifos, adapted from the EPA's Interim Reregistration Eligibility Decision for chlorpyrifos. 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. Cholinesterase inhibition was observed at all dose levels tested, the lowest of which was 1.5 mg/kg. This level was thus identified at the lowest observed adverse effect level (LOAEL). A NOAEL of 0.5 mg/kg was estimated by dividing the LOAEL by a three-fold uncertainty factor. The NOAEL was then divided by the standard 10-fold inter- and 10-fold intraspecies uncertainty factors to arrive at the RfD of 0.005 mg/kg/day. 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. A RfD that has been divided by an additional uncertainty factor that only applies to certain populations is called a 'population adjusted dose' or PAD. For chlorpyrifos, the acute PAD (or 'aPAD') is thus 5×10−4 mg/kg/day, and it applies to infants, children, and women who are breast feeding. 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. As with the acute RfD, the chronic RfD of 3×10−4 mg/kg/day was determined by dividing this NOAEL by the inter- and intraspecies uncertainty factors. 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. Like the aPAD, this cPAD applies to infants, children, and breast feeding women. 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 (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. 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.