Appropriateness of Uncertainty Factors

Reference Concentration (RfC)—An estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious noncancer health effects during a lifetime. The inhalation reference concentration is for continuous inhalation exposures and is appropriately expressed in units of mg/m3 or ppm. The RfC is operationally derived from the No-Observed-Adverse-Effect Level (NOAEL- from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfCs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfCs are not applicable to nonthreshold effects such as cancer. 

Information bearing on the toxicokinetics and toxicodynamics of the chemical under consideration, as well as structurally related analogues or chemicals that act by a similar mechanism of action, will be used to derive an appropriate interspecies uncertainty factor that may range from 10 to 3 or 1. In the absence of information on a subject or analogous chemical to set data-... 

Technically, the Submitter s recommendation was that the MRL should be based on the dermal, ocular, and nail effects observed in the rhesus monkeys of the Tryphonas study. The Submitter proposed using an uncertainty factor of 30 for an MRL based on that endpoint. However, the panelists comments focused on the use of uncertainty factors for the endpoint of immunological effects. In response to an earlier comment, the panelists agreed that basing the MRL on immunological effects was appropriate. 

Historically, risk assessment for noncancer endpoints has been based on the identification of a no observed adverse effect level (NOAEL) from a toxicity study with an animal model. The NOAEL is then divided by appropriate uncertainty factors to take potential inter- and intraspecies differences in response into account. However, this approach does not take into account the size of the toxicity study or the shape of the dose-response curve. The benchmark dose (BMD) approach has been suggested as an alternative to a NOAEL (Crump 1984). A BMD is a dose or concentration that produces a predetermined change (e.g., 10% or 1 standard deviation) in response rate of an adverse effect (called the benchmark response or BMR). A BMDL is the statistical lower confidence limit on the dose or concentration at the BMD. The BMD and BMDL are calculated using mathematical dose-response models, which make appropriate use of sample size and the shape of the dose-response curve (EPA 2009b, 2000a). The BMDL is like a NOAEL (i.e., as a point of departure) and is divided by an appropriate composite uncertainty factor to derive a reference value. 

Table 28 outlines the critical end-points for the organotin species and the estimated PNECs derived using appropriate uncertainty factors. For the purposes of comparability, all values have been converted to the chloride salt. 

Dibutyltin. A larger data set exists for dibutyltin, including both acute and long-term test results. The lowest concentration identified was a chronic NOEC of 0.015 mg/1 for Daphnia magna exposure to dibutyltin chloride. Long-term values were available across three trophic levels, and, therefore, an uncertainty factor of 10 was considered appropriate. 

The AEGL-1 values were based on concentrations at 0.5 ppm and 0.1 ppm, which were the thresholds for mild headaches in healthy individuals at exposure durations of 1 and 6 h, respectively (Stewart et al. 1974). This effect can be considered the threshold for mild discomfort (only one subject was affected at each exposure), which falls within the definition of an AEGL-1. The 0.5-ppm concentration was used to derive the 30-min and 1-h AEGL-1 values, and the 0.1-ppm concentration was used for the 4- and 8-h values. Because the time and concentration values were based on the most susceptible subject, these concentrations were adjusted by an uncertainty factor (UF) of 3 to account for potential differences in human sensitivity and scaled to the appropriate time periods using the C xt=k relationship. A UF of 3 was considered sufficient as no susceptible populations were identified (the headache effect is the same as that experienced by patients medicated with nitro... 

Several methods are available for developing OELs analogy, correlation, safety and uncertainty factors, and low-dose extrapolation (Table 14.5). The appropriate method must be selected on the basis of the appropriateness of the available data. For example, low-dose extrapolation may be appropriate only if sufficient pharmaco-... 

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. 

Although the measurement uncertainties limit the conclusions which can be drawn from these results, the data set proved useful for the determination of general Influences on rainwater composition In the Seattle area and for the demonstration of the application of these exploratory data analysis techniques. Current efforts to collect and analyze aerosol and rainwater samples over meteorologically appropriate time scales with precise analytical techniques are expected to provide better resolution of the factors controlling the composition of rainwater. 

WHO/IPCS (1994, 1999) stated that a minimum data set considered adequate for an assessment will vary according to the purpose of the assessment. The major deficiencies in a toxicity database, other than those related to the pivotal study, which increase the uncertainty of the extrapolation should be recognized by the use of an additional UF. Since the quality and/or completeness of different databases vary, the additional UF will also vary. For example, a value of 1 would be applied to a database that was considered complete for the evaluation of the compound under consideration, but a factor of 1-100 might be necessary for limited databases. If minor deficiencies in the data exist with respect to quality, quantity, or omission, then an extra factor of 3 or 5 would be appropriate. An extra factor of 10 would be appropriate where major deficiencies in the data exist, e.g., a lack of chronic toxicity studies and reproductive toxicity studies. It was pointed out that inadequacies of the pivotal study could also be considered as a subset of inadequacies of the database and that the total factor for limitations of the pivotal study plus adequacy of the overall database should not exceed 100 since such a database is generally not acceptable for development of a TDI. 

In conclusion, the uncertainty related to the confidence in the database should be taken into account by the use of an assessment factor. Since the quality, completeness, and/or consistency of different databases vary, the assessment factor will also vary and can only be assigned on the basis of expert judgment, preferably made transparent through the application of a set of criteria. In any case, the size of the factor should be considered in terms of other information in the database. The default value should be 1 in case of a high-confidence database, and a factor of 10 would be appropriate where major deficiencies in the data exist, e.g., a lack of chronic and reproductive toxicity studies when setting a tolerable intake. 

Often, the basis for safety factors is obscure and/or arbitrary. They are typically based on order of magnitude decisions, for example, determining a safe concentration and dividing it by 10. It may not be clear which sources of uncertainty they are intended to address. Even when they have been based on an explicit assessment of uncertainty, this probably will not have included more than a few sources of uncertainty. Therefore, it is not known whether the safety factors provide an appropriate level of protection against all the uncertainties affecting the assessment. 

When epidemiological data are available, the issues to be dealt with include selection of the appropriate study and control populations, evaluation of exposure levels and tissue doses, determination of the reliability of cancer ascertainment, allowance for the latent period and age distribution of cancers, control of biases and confounding factors, fitting of models to the data to characterize the dose-incidence relationship, and derivation of risk estimates with their associated ranges of uncertainty. 

The major components of uncertainty are combined according to the rules of propagation of uncertainty, often with the assumption of independence of effects, to give the combined uncertainty. If the measurement uncertainty is to be quoted as a confidence interval, for example, a 95% confidence interval, an appropriate coverage factor is chosen by which to multiply the combined uncertainty and thus yield the expanded uncertainty. The coverage factor should be justified, and any assumptions about degrees of freedom stated. 

The value of an ADI is entirely dependent on the quality of the experimental data and the judicious selection of the safety (uncertainty) factor, which is entirely judgmental. Among the factors influencing the quality of the experimental data, beyond the mechanics, are the selection of the appropriate animal model as the human surrogate, the... 

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