BMDL lower confidence limit

When sufficient data are available, use of the benchmark dose (BMD) or benchmark concentration (BMC) approach is preferable to the traditional health-based guidance value approaches (IPCS, 1999a, 2005 USEPA, 2000 Sonich-Mullin et al 2001). The BMDL (or BMCL) is the lower confidence limit on a dose (the BMD) (or concentration, BMC) that produces a particular level of response or change from the control mean (e.g. 10% response rate for quantal responses one standard deviation from the control mean for a continuous response) and can be used in place of the NOAEL. The BMD/BMC approach provides several advantages for dose-response evaluation 1) the model fits all of the available data and takes into account the slope of the dose-response curve 2) it accounts for variability in the data and 3) the BMD/BMC is not limited to one experimental exposure level, and the model can extrapolate outside of the experimental range. 

The convention of using BMDL as the lower confidence limit follows the terminology proposed in the paper by Crump (1995) this has also been adopted for use in the EPA BMDS software, since it refers explicitly to the lower confidence lilnilyTighl National Academy of Sciences. All rights reserved. 

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. 

The current MeHg RfD is based on a BMD estimation. The selection of a particular BMD for the derivation of the RfD represents a critical decision, influenced by both scientific and policy considerations. The BMDL is defined as a lower confidence limit on the dose corresponding to a given increase in response (e.g., 1%, 5%, or 10%) over the background rate (Crump 1984), the benchmark response (BMR). It is intended to be applied as an alternative to the NOAEL to provide a point of departure for low-dose extrapolation. The BMD represents a refinement over the traditional NOAEL or LOAEL, since it is not constrained to be one of the observed or experimental doses, and uses the full-range of dose-response information inherent in the data. Various terms are used for BMD estimates. In this report, the term BMDL denotes the lower confidence limit on the dose corresponding to the BMR of interest, and BMD is used to denote the point estimate of the dose. 

Benchmark dose level (BMDL)or benchmark concentration level ( BMCL) is a statistical lower confidence limit on the dose or concentration at the BMD or BMC, respectively. Benchmark response (BMR) is an adverse effect, used to define a benchmark dose from which an RfD (or RfC) can be developed. The change in response rate over background of the BMR is usually in the range of 5 to 10%, which is the limit of responses typically observed in well-conducted animal experiments. 

Figure 24.3 shows how an effective dose that corresponds to a specific change of effect/response (e.g., 10%) over background and a 95% lower confidence bound on the dose is calculated. The latter is often referred to as the BMDL or LBMD, as opposed to the BMD, which does not have this confidence limited associated with it. 

The BMDL of 58 pph is calculated statistically and represents the lower 95% confidence limit on the dose (or hiomarker concentration) that is estimated to result in a 5% increase in the incidence of abnormal scores on the Boston Naming Test. 

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. 

Abbreviations BMDL, lower 95% confidence limit on the benchmark dose BMR, benchmark response WJ, Woodcock-Johnson Tests of Achievement CPT, Continuous Performance Test CVLT, California Verbal Learning Test TOLD, Test of Language Development WISC-R PIQ, Wechsler Intelligence Scale for Children-Revised performance IQ WISC-R FSIQ, Wechsler Intelligence Scale for Children-Revised Full-Scale IQ. 

BMDLs of BLL (lower 95% confidence limits of BMD) were estimated to be 12.1-17.3 (mean = 14.4) pg/dL for postural sway. All postural sway measmes except sagittal sway with eyes open were significantly larger in lead workers than controls (p< 0.001). 

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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