Benchmark dose

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. 

Benchmark Dose Model—A statistical dose-response model applied to either experimental toxicological or epidemiological data to calculate a BMD. 

Barnes, D.G. et al.. Benchmark dose workshop criteria for use of a benchmark dose to estimate a reference dose, Regul. Toxicol Pharmacol, 21, 296, 1995. 

Fowles, J.R., G.V.Alexeeff, and D.Dodge. 1999. The use of benchmark dose methodology with acute inhalation lethality data. Regul. Toxicol. Pharmacol. 29 262-278. 

Belt-conveyor scales, 26 244—245 Belt filter press, 25 913 Belt saponification, in vinyl alcohol polymerization, 25 609-610 Benard instability, 11 764 Benazepril hydrochloride, molecular formula and structure, 5 149t Benchmark dose and margin-of-exposure method, 25 244... 

For all toxic effects other than carcinogenicity, a threshold in the dose-response curve is assumed. The lowest NOAEL from all available studies is assumed to be the approximate threshold for the groups of subjects (humans or animals) in which toxicity data were collected. Alternatively, a benchmark dose (BMD) may be estimated from the observed dose-response curve, and used as the point-of-departure for risk assessment (see below and Box). 

In recent years a new procedure has been adopted by the EPA for dealing with responses in the range of what we have been calling the NOAEL. The procedure is called benchmark dosing, and the benchmark dose has now replaced the NOAEL in these types of evaluation. We shall continue to use the NOAEL in our discussions, but the relationship between a NOAEL and a benchmark doses is explained in the Box, and in the section to come on carcinogens. 

Figure 8.1 Dose-response curves for carcinogens and illustration of low-dose extrapolation using linear, no-threshold model. Benchmark dose (BMD) is also illustrated.

Daily Intake (ADI/TDI), or Reference Dose (RfD) these terms are addressed in detail in Chapter 5. As an alternative to the traditional NOAEL approach, the Benchmark Dose (BMD) (a model-derived estimate or its lower conhdence limit of a particular incidence level, see Section 4.2.5) for the critical effect has been proposed for use in the quantitative assessment of the dose-response. 

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... 

FIGURE 4.8 Benchmark Dose modehng illustrating the Benchmark Dose (BMD), the henchmark response (BMR), and the Benchmark Dose Lower Limit (BMDL). 

Barlow, S. 2005. Threshold of Toxicological Concern (TTC). A tool for assessing substances of unknown toxicity present at low levels in the diet. ILSI Europe Concise Monograph Series. Europe, Bmssels, Belgium ILSI. http //europe.ilsi.org/publications/Monographs/ThreshoIdToxicoIogicaIConcem.htm Barnes, D., G. Daston, J. Evans, et al. 1995. Benchmark dose workshop Criteria for use of a benchmark dose to estimate a reference dose. Regul. Toxicol. Pharmacol. 21 296-306. 

Falk Filipsson, A., S. Sand, J. Nilsson, and K. Victorin. 2003. The benchmark dose method - Review of available models, and recommendations for application in health risk assessment. Crit. Rev. Toxicol. 33 505-542. 

Gephart, L.A., W.F. Salminen, M.J. NicoUch, and M. Pelekis. 2001. Evaluation of subchronic toxicity data using the benchmark dose approach. Regul. Toxicol. Pharmacol. 33 37-59. 

US-EPA. 1995. The use of the benchmark dose approach in health risk assessment. US Environmental Protection Agency (EPA), Office of Research and Development, Doc. EPA/630/R-94/007, Washington, DC. 

In the hazard assessment process, described in detail in Chapter 4, all effects observed are evaluated in terms of the type and severity (adverse or non-adverse), their dose-response relationship, and the relevance for humans of the effects observed in experimental animals. For threshold effects, a No- or a Lowest-Observed-Adverse-Effect Level (N/LOAEL), or alternatively a Benchmark Dose (BMD), is derived for every single effect in all the available smdies provided that data are sufficient for such an evaluation. In the last step of the hazard assessment for threshold effects, all this information is assessed in total in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). 

BMDL5 5% lower confidence limit of the benchmark dose. 

Gaylor et al. (1999) have proposed a total default UF in the order of 10,000 for severe, irreversible adverse health effects when establishing human exposure guidelines based on a benchmark dose (BMDLjo) derived from animal data. For reversible biological effects, a smaller default UF in the order of 1000 may be employed. 

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... 

Gaylor, D.W., R.L. Kodell, J.J. Chen, and D. Krewski. 1999. A unified approach to risk assessment for cancer and noncancer endpoints based on benchmark doses and uncertainty/safety factors. Regul. Toxicol. Pharmacol. 29 151-157. 

Similarly, in order to avoid any quantitative estimate, an MOE approach has been recommended by, e.g., JECFA (the Joint FAO/WHO Expert Committee on Food Additives) and EFSA (the European Food Safety Authority) in the assessment of compounds that are both genotoxic and carcinogenic by using a benchmark dose (BMD) approach to estimate the BMDLio (benchmark dose lower limit) representing the lower bound of a 95% confidence interval on the BMD corresponding to a 10% tumor incidence (see Section 6.4). 

The most frequently used POD for threshold effects (Section 4.2) is the NOAEL (Section 4.2.4). This NOAEL is generally obtained from studies in experimental animals. If reliable human data are available to derive the NOAEL, this value is preferable to the NOAEL from experimental animals. Where a NOAEL cannot be derived, a LOAEL, if available, can be used. An alternative POD to the NOAEL/LOAEL is the benchmark dose (BMD) (Section 4.2.5). The tolerable intake can also, in some cases, form the basis as the POD. In this chapter, the POD will be denoted as a derived no-effect level (DNEL) in order to provide a general term for the various types of PODs that can form the basis for the risk characterization. 

Guidance values are developed from a standard such as, e.g., an Acceptable/Tolerable Daily Intake (ADI/TDI), and Reference Dose/Concentration (RfD/RfC). For threshold effects, the standard is derived by dividing the No-Observed-Adverse-Effect Level (NOAEL) or Lowest-Observed-Adverse-Effect Level (LOAEL), or alternatively a Benchmark Dose (BMD) for the critical effect (s) by an overall assessment factor, described in detail in Chapter 5. For non-threshold effects, the standard is derived by a quantitative assessment, described in detail in Chapter 6. 

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