Lower lowest observable adverse effect level

Thyroid effects were produced in rats in acute-duration studies at doses as low as 3 mg/kg/day (reduced serum levels of T4 hormone) but not at 1 mg/kg/day, in intermediate-duration studies at doses as low as 0.05 mg/kg/day (increased number and decreased size of follicles), and in chronic-duration studies at doses as low as 1.3 mg/kg/day. The no-observed-adverse-effect level (NOAEL) of 1 mg/kg/day is used herein as the basis for an acute-duration minimal risk level (MRL) for oral exposure. The acute-duration lowest-observed-adverse-effect level (LOAEL) for hepatic effects is identical to the LOAEL for acute thyroid toxicity, but is a less appropriate basis for the MRL because organ functional implications are not as clear. The intermediate-duration LOAELs for thyroid and hepatic effects are also comparable to each other, but neither of these LOAELs are suitable for an intermediate MRL because reproductive and developmental toxicity occurred at a lower dosage. The thyroid LOAEL for chronic-duration exposure is unsuitable for deriving a chronic MRL because decreased survival occurred at the same dose (lower doses were not tested), and thyroid, liver, and other effects occurred at lower doses in intermediate-duration studies. 

The traditional approach to development of an RfD and other pubhc-health-based risk guidance numbers is to select a critical study that is well conducted and provides the most sensitive, or lowest, no-observed-adverse-effect level (NOAEL), lowest-observed-adverse-effect level (LOAEL), or a lower 95% confidence limit on the benchmaik dose (BMDL). The relevance of the study exposure levels and pathways to the population of concern should also be considered. 

The recommended daily intake values as estimated by the United States Environmental Protection Agency (EPA) (4) and the Centers for Disease Control (CDC) (5,6) have been used for the present calculations. For the EPA the "Acceptable Daily Intake" (ADI) for 2,3,7,8-TCDD is 1 x 10" g/kg/day. This value is based on the lowest-observed-adverse-effect-level (LOAEL) of 1 X 10 g/kg/day for a reproductive effect in rats (7,8), a 10-fold uncertainty factor because a LOAEL is used as the basis of the calculation rather than a no-observed adverse effect level (NOAEL), and an additional uncertainty factor of 100 based on the existence of lifetime animal studies and lack of knowledge of the effects in man. (4). For a 10" (1/1,000,000) cancer risk, the EPA has estimated a 95% lower-limit criteria for a lifetime intake of... 

Taylor et al., 2002). Since the doses relate to the total fish and not to fish protein, the threshold doses given in milligrams of protein are even lower. Considering that fish have total protein contents of 15 to 25%, the lowest observed adverse effect level values published are estimated to range from approximately 1 to 100 mg protein (FDA, 2005). 

The BMD approach has been put forward as an alternative to the no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) approach for health effects because it provides a more quantitative alternative point of departure for the first step in the dose-response assessment (International Programme on Chemical Safety, in press). The BMD approach is based on a mathematical model being fitted to the experimental data within the observable range and estimates the dose that causes a low but measurable response (the benchmark response) typically chosen at a 5% or 10% incidence above the control. The BMD lower limit (BMDL) refers to the corresponding lower limit of a one-sided 95% confidence interval on the BMD. Using the lower bound takes into account the uncertainty inherent in a given study and assures (with 95% confidence) that the chosen benchmark response is not exceeded. 

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