Benchmark dose , defined

Benchmark Dose (BMD)—Usually defined as the lower confidence limit on the dose that produces a specified magnitude of changes in a specified adverse response. For example, a BMDio would be the dose at the 95% lower confidence limit on a 10% response, and the benchmark response (BMR) would be 10%. The BMD is determined by modeling the dose response curve in the region of the dose response relationship where biologically observable data are feasible. 

The concept of the Benchmark Dose (BMD), a benchmark is a point of reference for a measurement, in health risk assessment of chemicals was first mentioned by Crump (1984) as an alternative to the NOAEL and LOAEL for noncancer health effects in the derivation of the ADI/TDI these terms are addressed in detail in Chapter 5. The BMD approach provides a more quantitative alternative to the dose-response assessment than the NOAEL/LOAEL approach. The goal of the BMD approach is to define a starting point of depariure (POD) for the establishment of a tolerable exposure level (e.g., ADI/TDI) that is more independent of the study design. In this respect, the BMD approach is not... 

They suggested the effect parameter the Critical Effect Dose (CED, a benchmark dose. Section 4.2.5) derived from the dose-response data by regression analysis. This CED was defined as the dose at which the average animal shows the Critical Effect Size (CES) for a particular toxicological endpoint, below which there is no reason for concern. The distribution of the CED can probabilistically be combined with probabilistic distributions of assessment factors for deriving standards... 

A benchmark dose can be defined from a data set that does not include a NOAEL. 

The MOE is defined as a benchmark dose divided by the dose from exposure. As the dose from exposure becomes smaller, the MOE becomes larger and the likelihood of any adverse health effect as a result of the exposure becomes smaller or zero. The larger the MOE is, the more confidence that no adverse health effect will be observed as a result of the exposure. 

Often, estimates of exposure are compared directly with benchmark doses or concentrations (i.e. those that result in a critical effect of defined increase in incidence, such as 5% or 10%). Alternatively, they are compared with either a lowest-observed-adverse-effect level (LOAEL), the lowest concentration that leads to an adverse effect, or no-observed-adverse-effect level (NOAEL), the highest concentration that does not lead to an adverse effect, or their equivalents. This results in a margin of safety or margin of exposure . Alternatively, estimates of exposure are compared with tolerable or reference concentrations or doses, which are based on the division of benchmark doses and/or concentrations or the NOAELs or LOAELs by factors that account for uncertainties in the available data. 

CHARACTERIZING DOSE AND RISK IN A CUMULATIVE ASSESSMENT 277 CASE STUDY 280 Case Study Defining Risk 280 Case Study The Dose-Response Relationship 280 Case Study Using the Margin of Exposure to Characterize the Risk 281 Case Study Benchmark Doses 282 Case Study Margins of Exposure 284... 

One outcome of the dependence of the NOEL/ NOAEL on the statistical significance test is that it tends to penalize chemicals for which there is more or better data. To remedy this problem, the benchmark dose (BMD) concept was introduced as an alternative approach. The BMD depends on the specification of a low level effect that would typically be unobservable. The endpoint may be the specified percentage (5 or 10%) above background of a population for an endpoint deemed to be adverse. Since the endpoint is defined, determinations for different chemicals and different data sets tend to be more comparable. 

Benchmark-dose calculations for quantitative outcomes (e.g., birth weight or IQ) are more complicated than those for quantal responses, such as presence or absence of a defect. Although Crump (1984) discussed how to calculate a BMD for a quantitative outcome. Gay lor and Slikker (1992) were the first to develop the approach in any detail. Their first step is to fit a regression model characterizing the mean of the outcome of interest as a function of dose and assuming that the data are normally distributed. The next step is to specify a cutoff to define values... 

Even when such modeling decisions have been made, benchmark-dose calculations require specification of the cntoff point used to define an adverse effect (Pq) and the risk level (BMR) of the benchmark dose. Those are, in part, policy decisions. 

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. 

One approach to determining the critical dose of lead that affects postural balance in the occupational setting is the benchmark-dose method in which a concentration of lead results in an increased probability of an abnormal end point—a benchmark response—and thereby places exposed people at increased risk (Iwata et al. 2005). Iwata et al. (2005) defined their benchmark dose level as the 95% lower confidence hmit of the benchmark dose. In 121 lead-exposed workers who had a mean BLL of 40 pg/dL, almost all sway measures were significantly larger than those in controls. The mean benchmark dose level of the current BLL for postural sway was 14.3 pg/dL. 

Mathematical modelling of the dose-response relationship is an alternative approach to quantify the estimated response within the experimental range. This approach can be used to determine the BMD or benchmark concentration (BMC) for inhalation exposure, which can be used in place of the LOAEL or NOAEL (Crump, 1984). The BMD (used here for either BMD or BMC) is defined as the lower confidence limit on a dose that produces a particular level of response (e.g., 1%, 5%, 10%) and has several advantages over the LOAEL or NOAEL (Kimmel Gaylor, 1988 Kimmel, 1990 USEPA, 1995 IPCS, 1999). For example, (1) the BMD approach uses all of the data in fitting a model instead of only data indicating the LOAEL or NOAEL (2) by fitting all of the data, the BMD approach takes into account the slope of the dose-response curve (3) the BMD takes into account variability in the data and (4) the BMD is not limited to one experimental dose. Calculation and use of the BMD approach are described in a US EPA... 

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