Uncertainty Factor, oral reference dose derivation

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). 

The strychnine oral reference dose (RfD) of 0.0003 mg/kg/ day or 0.02 mg/day for a 70 kg person is derived from the Seidl and Zbinden (1982) short-term to subchronic study by applying an uncertainty factor of 10,000. This factor accounts for extrapolation from a less than chronic to a chronic exposure study, extrapolation from animals to humans, and differences in sensitivity among the human population. An additional factor of 10 is used because an LOAEL/FEL (2.5 mg/kg/day) was utilized in the estimation of the RfD instead of an NOAEL. The immediately dangerous to life and health (IDLH) dose for strychnine by NIOSH REE is 0.15 mg/m and the current OSHA PEL is 0.15mg/m. ... 

A 90 day rat oral gavage study resulted in depressed body and organ weights and depressed food consumption in high dose males (3600 mg kg day ). No effects were noted at 900 mg kg day Erom these results, the US Environmental Protection Agency derived an oral reference dose of 0.9 mg kg day for ethyl acetate (uncertainty factor = 1000). 

The no-effect level from the NTP study has been used to calculate a safe oral dose for xylene in humans of 2 mgkg day This is 10 times higher than the oral reference dose published by the US EPA on its IRIS database, 0.2 mg kg day based on the rat no-observed-adverse-effect level of 250 mg kg day adjusted for duration of exposure and then divided by an uncertainty factor of 1000. The inhalation reference concentration for xylene is currently 0.1 mg m, derived from a duration adjusted rat lowest-observed adverse-effect level of 39mgm divided by an uncertainty factor of 300. 

The initial process in the application of toxicity (dose-response) data in risk assessment is the extrapolation of findings to establish acceptable levels (AL) of human exposure. These levels may be reference values (inhalation reference concentrations, RfC or oral reference doses, RfD), minimal risk levels (MRL) values, occupational exposure limits, and so on. When the toxicity data are derived from animals, the lowest dose representing the NOAEL (preferably) or the LOAEL defines the point of departure (POD). In setting human RfD, RfC, or MRL values, the POD requires several extrapolations (see [13] and revisions). Extrapolations are often made for interspecies differences, intraspecies variability, duration of exposure, and effect level. Each area is generally addressed by applying a respective uncertainty factor having a default value of 10 their multiplicative value is called the composite uncertainty factor (UF). The UF is mathematically combined with the dose at the POD to determine the reference value ... 

An oral reference dose (RfD) of 0.1 mg/kg/day has been derived by EPA for carbon disulfide (IRIS 1995). The RfD is based on a NOAEL of 11 mg/kg/day carbon disulfide for fetal toxicity in rabbits following inhalation exposure (Hardin et al. 1981). An inhalation reference concentration (RfC) of 0.7 mg/m3 (0.2 ppm) was also derived for carbon disulfide (IRIS 1995). The RfC was based on a benchmark concentration (human-equivalent) of 19.7 mg/m3 (6.3 ppm) divided by an uncertainty factor of 30 (Johnson et al. 1983). 

EPA (IRIS 1996) has derived an oral reference dose (RfD) for tetrachloroethylene of 0.01 mg/kg/day with an uncertainty factor of 1,000, based on hepatotoxicity in mice (Buben and O Flaherty 1985). An inhalation reference concentration (RfC) for tetrachloroethylene has not been derived (IRIS 1996). 

The oral Reference Doses (RfDg) calculated in this report for chemical warfare agents, together with the Uncertainty and Modifying Factors used in their derivation, are listed in Table 38. Data were insufficient for deriving RfDeS for agents HT, T, and HN2. 

Development of subchronic RfDs parallels tlie development of chronic reference doses in concept the distinction is one of e.xposurc duration. Appropriate studies are evaluated and a subchronic NOAEL is identified. The RID is derived from the NOAEL by the application of the UFs and MF, as outlined above. When experimental data arc available only for shorter exposure durations than desired, an additional uncertainty factor is applied. This is similar to the application of the uncertainty factor for duration differences when a chronic RfD is estimated from subchronic animal data. On the other hand, if subchronic data are missing and a chronic oral RfD derived from chronic data exists, the chronic oral RfD is adopted as the subchronic oral RfD. In this instance, there is no application of an uncertainty factor to account for differences in exposure duration. 

The existing methods available for scientifically defensible risk characterization are not yet ideal since each step has an associated uncertainty resulting from data limitation and incomplete knowledge on exact mechanism of action of the toxic chemical on the human body. For noncancer end points, safety factors or uncertainty factors are applied since these effects are assumed to have a threshold below which no adverse effect is expected to be observed. US EPA has used the concept of a reference concentration (RfC) to estimate acceptable daily human exposure from HAPs. The RfC was adapted for inhalation studies based on a reference dose (RfD) method previously used for oral exposure assessment. The derivation of the RfC differs from that for the RfD in the use of dosimetric adjustment to extrapolate the exposure concentration for animals to a human equivalent concentration. Both are estimates, with uncertainty spaiming perhaps an order of magnitude, of a daily exposure to the human population, including sensitive subgroups, which would be without appreciable risk of deleterious effects over a lifetime. 

Chronic Reference Dose (RfD) RfD is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily oral exposure for a chronic duration (up to a lifetime) to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL, LOAEL, or benchmark dose, with uncertainty factors generally applied to reflect limitations of the data used. The RfD is generally used in EPA s noncancer health assessments. 

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