Deriving Oral Reference Doses

A Reference Dose (RfD) is an estimate (with an uncertainty spanning perhaps an order of magnitude or greater) of a daily exposure level for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects (USEPA 1989). Noncancer health risks at CERCLA (Comprehensive Environmental Response, Compensation, and Liability Act of 1980) Superfund sites are assessed by comparing potential levels of exposure for specific environmental pathways with reference doses indepen- 

EPA also allows for the use of subchronic and developmental RfDs in specific cases where exposures are less than chronic. Subchronic RfDs are to be used for characterizing potential noncarcinogenic effects associated with shortterm exposures lasting from 2 wk to 7 yr (USEPA 1989). Developmental RfDs are used to evaluate the potential effects on the developing fetus following a single exposure event. Subchronic RfDs accepted for use in the preparation of Superfund risk assessments are available in EPA s Health Effects Assessment Summary Table (HEAST USEPA 1996a). 

In cases in which potential exposures are less than 2 wk and exclude developmental effects, EPA allows for the use of the One-day and Ten-day Health Advisories issued by the EPA Office of Water (USEPA 1996b) as nonregulatory guidance values. The Health Advisories are derived in a manner similar to that used for Reference Doses. 

The NOAEL or LOAEL is then adjusted by the application of a set of Uncertainty Factors (UFs) and a Modifying Factor (MF), as shown in the following formula  

NOAEL = No-observed-adverse-effect level, expressed as mg chemical per kg body weight per day 

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Methods used to derive oral reference doses for chemical warfare agents follow standard EPA protocols (EPA, 1989 Dourson, 1994), employ appropriate toxicological data, and have undergone review for consistency by the NRC (Bakshi et al, 2000 Opresko et al, 1998, 2001), Because the EPA has nt)t officially verified the derived values for nerve agents, they are identified and referenced as estimated RfDs (RfD ). 

Several hundred semisynthetic derivatives have been prepared in an effort to obtain substances with better biological activities (for references see Ref.s)). Particularly positions 3 and 4 of the naphthoquinone ring system (numbering system as proposed by Prelog7 8) have been extensively substituted, since it has been shown that structural changes in these two positions do not critically affect the action of the substance on the target enzyme, the bacterial RNA polymerase (cf. Chapter 3.). They can, however, influence other parameters such as its ability to penetrate into cells, its pharmacokinetic properties and resorption, which are all important for clinical use as an antibiotic. Rifampicin (U.S. rifampin), which is a widely used orally active tuberculostatic agent, is a 3-(4-methyl piperazinyl)-iminomethyl derivative of rifamycin SV, synthesized via the 3-formyl derivative (Fig. 5)10 ... 

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