Some Comments on the Selection of Human Intraspecies Uncertainty Factors

ABSTRACT

The Reference Dose (RfD) is used in the risk assessment of non-carcinogenic chemicals. It is derived by dividing a point of departure by the product of the uncertainty (UFs) and modifying factors (MFs). Separate UFs are used for different variables, e.g., intraspecies variation and, in general, each UF is an order of magnitude (10-fold). On the other hand, the MF is usually based on some known variable such as differences in absorption of a chemical from food and water and its default value is one. The USEPA's Integrated Risk Information System (IRIS) has 14 chemicals that have RfDs based on human studies. We examined those IRIS files to determine the rationale for setting human intraspecies uncertainty factors (UF_H). The first consideration was that the chemical had an adequate peer-reviewed human database. Without such, it would not be possible to derive an RfD based on human data. Ten of the 14 chemicals had an UF_H of 1 or 3; four of these were essential trace elements (ETEs). The rationales for using less than a 10-fold UF_H for the ETEs included; 1) nutritional data, 2) large human exposure groups, 3) minimal effect levels and/or 4) several studies with similar effect levels. For the other compounds, reasons included; 1) large human exposure groups, 2) a critical effect that was not adverse (cosmetic), 3) the most sensitive population was exposed, 4) the compound was on the FDA's “generally regarded as safe” (GRAS) list, 5) database uncertainties and 6) less-than-lifetime exposure adjusted for 70 years exposure. It is important to understand the reasons for selecting a UF_H of 1, or 3 as they will apply to future chemicals considered by the USEPA and other agencies.

Keywords:

• reference dose
• human uncertainty factor
• essential trace elements
• arsenic
• benzoic acid
• fluoride
• manganese
• molybdenum
• nitrate
• nitrite
• selenium
• silver and zinc.

The opinions in this manuscript are those of the authors and do not necessarily represent the opinions and/or policies of the U.S. Environmental Protection Agency.

Notes

¹ In addition, the USEPA is using the Benchmark Dose (BMD), when possible, as a point of departure to derive RfDs. A BMD₀₅ would be an effective dose for 5% of the study population. The BMDL, the 95% lower confidence level for the BMD, is then divided by the UF x MF, depending upon the chemical's database, to derive the RfD.

∗An UF is usually 1, 3 or 10 under normal circumstances. In establishing the UF or MF, it is recognized that professional scientific judgment must be used.

∗At the time of its RfD derivation, F was considered to be a beneficial element and not an essential trace element by the National Research Council (NRC 1989).

∗MF of 10 for greater potency of nitrite in inducing methemoglobinemia.

∗Abbreviations: ETEs, Essential trace elements; GRAS, Generally regarded as safe.