Developmental immunotoxicity testing is expected to provide hazard and dose response information that can be utilized in formulating risk assessment decisions for any chemical. Adverse outcomes identified through developmental immunotoxicity testing, and their associated NOAELs or LOAELs, are considered appropriate for use in establishing endpoints and doses for risk assessment, particularly for any population group that includes fetuses, infants, or children. It is important to compare information on the immune response of adult animals with that of the immature individual, as obtained through developmental immunotoxicity testing. When the database contains evidence for concern regarding toxicity to adult immune system structure or function, and no data are available that assess developmental immuno-toxic potential, the resulting uncertainties should be accounted for in the risk assessment. A database uncertainty factor applied to RfD/RfC derivation can be used to address this deficiency. The need for and the magnitude of such an uncertainty factor should be based upon an assessment of the chemical database, considering the weight-of-the-evidence that was used in arriving at the conclusion that a developmental immunotoxicity study would be required.
As mentioned earlier, the EPA has recently released a review of the RfD and RfC processes (USEPA 2002b) that calls for setting reference values not only for chronic exposure, but also for less-than-lifetime durations of exposure. These include acute (<24 hours), short-term (up to 30 days), and longer-term (up to 10% of the lifespan) exposures. The review also calls for a life-stage approach to the assessment of data, and particularly to the identification of potential data gaps that should be considered in applying uncertainty factors. Developmental immunotoxicity is one of many developmental endpoints that would be considered in setting reference values for various durations of exposure. In this process, various endpoints considered relevant and having sufficient data are carried through the process of sample reference value derivation. Then a final reference value is derived for each duration of exposure, based on a weight of evidence characterization of the database available, the degree of uncertainty in the database as a whole, and those endpoints and sample reference values considered to be protective of the exposed population including susceptible subgroups. Latent effects are important to consider in the derivation of these less-than-lifetime values, as the definition of these reference values includes the concept that they are to be protective of effects that may occur over a lifetime. Although these approaches have yet to be implemented, some offices within EPA have been setting various duration reference values for a number of years, e.g., the Office of Pesticide Programs (OPP) has established acute and chronic reference doses for pesticides since 1998, and the Office of Water (OW) has set acute, short-term, longer-term, and chronic health advisories for water contaminants for a number of years. EPA's Integrated Risk Information System (IRIS) program is implementing a pilot effort to evaluate the practicability of setting various duration reference values for inclusion in the IRIS database.
Once reference values have been derived, this information is integrated with the exposure assessment to characterize the overall risk. Risk characterization summarizes all of the information that has been evaluated, and develops an estimate of risk or a comparison of the toxicity data with estimated human exposure. This ratio of the NOAEL, LOAEL, or BMDL to the human exposure estimate is called the Margin of Exposure (MOE). Consideration of whether the size of the MOE is adequate is a risk management decision that includes economic, social, political and other regulatory factors, but the same issues that go into determining the size of the uncertainty factors applied in the reference value process should be considered in judging the adequacy of the MOE. A detailed description of the considerations in risk characterization can be found in the Handbook on Risk Characterization (USEPA 2000).
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