Reference dose uncertainty factor

Toxic Hazards. Either information on the carcinogenic potency of a chemical (Slope Factor, Weight-of-Evidence Class designation), estimates of non-carcinogenic toxic potential (Reference Dose, Uncertainty and Modifying Factors, and Statement of Confidence), or both, can be reported for several hundred chemicals. Values for both inhalation and oral exposure are available. If the desired toxicity value for a chemical has not yet been included in IRIS, an alternative database extracted from the Health Effects Assessment Summary Tables (HEAST) is automatically searched. 

This large volume indicates that there is cither no health problem or there is considerable uncertainty (i.e., the product of the uncertainty factors is large) in estimating a reference dose for atrazine. 

There are several limitations to tliis approach that must be acknowledged. As mentioned earlier, tlie level of concern does not increase linearly as the reference dose is approached or exceeded because the RfDs do not luive equal accuracy or precision and are not based on the same severity of effects. Moreover, luizm-d quotients are combined for substances with RfDs based on critical effects of vaiy ing toxicological significance. Also, it will often be the case that RfDs of varying levels of confidence Uiat include different uncertainty adjustments and modifying factors will be combined (c.g., extrapolation from animals to hmnans, from LOAELs to NOAELs, or from one exposure duration to anoUier). 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the no-observed-adverse-efifect level (NOAEL-from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. 

The Environmental Protection Agency derived a reference dose (RfD) of 0.08 mg/kg/day based on the same NOAEL from the Hart (1980) study. The RfD, however, utilized an additional uncertainty factor of 10 to extrapolate to chronic exposure. 

EPA has derived both an oral reference dose (RfD) and an inhalation reference concentration (RfC) for chronic exposure to hydrogen sulfide. The RfD of 0.003 mg/kg/day is based on the NOAEL of 3.1 mg/kg/day for gastrointestinal disturbance in pigs in a study by Wetterau et al. (1964) (IRIS 1998). The NOAEL value of 3.1 mg/kg/day was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation (10), sensitive individuals (10), and subchronic exposure (10) (IRIS 1998). 

PEL Pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE SIC SIR SMR STEL STORET TLV TSCA TRI TRS TWA u.s. UF yr WHO wk permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification Standardized incidence ratio standard mortality ratio short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory total reduced sulfur time-weighted average United States uncertainty factor year World Health Organization week... 

Uncertainty Factor (UF)—A factor used in operationally deriving the Minimal Risk Level (MRL) or Reference Dose (RfD) or Reference Concentration (RfC) from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the... 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

An estimate for the lowest level of toxicological concern for human exposure to a chemical is developed by dividing the appropriate NOAEL by the uncertainty factor. Historically, this estimate has been termed the acceptable daily intake (or ADI) although it has been replaced by what EPA calls the reference dose (or RfD). Both ADIs and RfDs are expressed in terms of the amount of chemical exposure per amount of body weight per day. 

In 1988, the US-EPA adopted the ADI approach in its regulatory measures against environmental pollution with a number of modifications (US-EPA 1988, 1993). Instead of the terms ADI and safety factor, the terms Reference Dose (RfD) and uncertainty factor (UF), respectively, were selected. The RfD is derived from the NOAEL by dividing by the overall UF. The overall UF originally suggested and reconfirmed in 2002 (US-EPA 2002) generally consists of a 10-fold factor for each of the following ... 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

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