Use of Toxicological Data in Evaluating Chemical Safety Gloria Rachamin PhD

6 Derivation of Exposure Limits

Traditionally, two different approaches have been used by regulatory agencies to derive exposure limits for substances that produce threshold and nonthreshold effects (19). The safety/uncertainty factor method has been used for threshold (noncancer) end points. For a cancer end point, the general approach has been to use a low-dose extrapolation risk model. Recently, a unified approach for threshold and nonthreshold effects has been proposed for deriving exposure limits by using the benchmark dose and uncertainty factors (57). The three approaches are described here. 6.1 The Safety/Uncertainty Factor Approach for Threshold Effects

The traditional safety/uncertainty factor approach of dividing the no-observed-adverse-effect level (NOAEL) of the critical effect by a safety factor has been widely used to derive "safe" exposure limits for chemicals that produce threshold effects (52). The ACGIH has used this approach for both threshold and nonthreshold effects in developing TLVs (58).

Historically, a safety factor of 100 has been applied to the NOAEL to account for all uncertainties, including interindividual and interspecies variation. Over the years, it became customary to divide this factor into two factors of 10 to account for interspecies and intraspecies variability, respectively (6).

Although the terms safety factor and uncertainty factor have the same meaning, the USEPA (13) recommended using the term uncertainty because "safety factor" may be inadvertently interpreted as absolute safety. It has further endorsed the use of uncertainty and modifying factors when deriving the oral reference (RfD) (13) and the reference inhalation concentration (RfC, USEPA 1994) for

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noncancer effects. The RfC (expressed in mg/m ) is defined as "an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous exposure to the human population (including sensitive subgroups) that is likely to be without appreciable risk of deleterious effects during a lifetime" (14). The same general principles apply to the derivation of the inhalation reference concentration and the oral reference dose (13, 14), but the RfC methodology has been expanded to account for the dynamics of the respiratory system as the route of entry. In the RfC method, the NOAEL from animal studies is converted to a refined dosimetric adjustment referred to as human equivalent concentration (HEC). The dose is also defined as the agent mass deposited per unit tissue volume delivered to specific target sites in the respiratory tract or made available to uptake and metabolic processes for systemic distribution. This methodology further distinguishes between gases or particulates and the type of effect the substance exerts, pulmonary or extra pulmonary.

The RfC is derived from the NOAEL (or the LOAEL, if the NOAEL is not available) as follows

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