Benchmark dose level

EPA report to Congress states that a number of additional studies of human populations generally support the dose range of the benchmark dose level for perinatal effects. The agency is awaiting the results of this NRC report before updating its RfD based on more recent data. 

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. 

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... 

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. 

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). 

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. 

The DNEL derivation starts with the determination of the appropriate dose descriptor. The most common dose descriptor for teratogenic effects is the NOAEL. But when a NOAEL cannot be identified, the lowest observed adverse effect level (LOAEL) or a calculated benchmark-dose value (BMD ) may serve as a basis for the DNEL derivation. If several toxicity studies are available addressing teratogenicity, usually the lowest dose descriptor is chosen. 

For noncarcinogenic hazardous chemicals, NCRP believes that the threshold for deterministic effects in humans should be estimated using EPA s benchmark dose method, which is increasingly being used to establish allowable doses of noncarcinogens. A benchmark dose is a dose that corresponds to a specified level of effects in a study population (e.g., an increase in the number of effects of 10 percent) it is estimated by statistical fitting of a dose-response model to the dose-response data. A lower confidence limit of the benchmark dose (e.g., the lower 95 percent confidence limit of the dose that corresponds to a 10 percent increase in number of effects) then is used as a point of departure in establishing allowable doses. 

Although dose-response assessments for deterministic and stochastic effects are discussed separately in this Report, it should be appreciated that many of the concepts discussed in Section 3.2.1.2 for substances that cause deterministic effects apply to substances that cause stochastic effects as well. The processes of hazard identification, including identification of the critical response, and development of data on dose-response based on studies in humans or animals are common to both types of substances. Based on the dose-response data, a NOAEL or a LOAEL can be established based on the limited ability of any study to detect statistically significant increases in responses in exposed populations compared with controls, even though the dose-response relationship is assumed not to have a threshold. Because of the assumed form of the dose-response relationship, however, NOAEL or LOAEL is not normally used as a point of departure to establish safe levels of exposure to substances causing stochastic effects. This is in contrast to the common practice for substances causing deterministic effects of establishing safe levels of exposure, such as RfDs, based on NOAEL or LOAEL (or the benchmark dose) and the use of safety and uncertainty factors. 

Traditionally, the benchmark dose for noncancer endpoints has been the no observed effect level (NOEL), or the lowest observed effect level (LOEL) when the NOEL is not quantifiable. The NOEL is the highest dose of a substance for which there are neither statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control. Because the NOEL is limited to one of... 

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. 

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. 

Division of benchmark doses and/or effect levels by default uncertainty factors represents the lower end of a continuum of increasingly data-informed approaches to estimation of hazard. For example, where additional adequate quantitative data on interspecies differences or human variability in either toxicokinetics or toxicodynamics (mode of action) are available, chemical-specific adjustment factors provide for their incorporation to replace appropriately weighted components of default uncertainty factors. This requires subdivision of default... 

Allen BC, Kavlock RJ, Kimmel CA, Faustman EM. 1994. Dose-response assessment for developmental toxicity II. Comparison of generic benchmark dose estimates with no observed adverse effect levels. Fund Appl Toxicol 23 487 195. 

Once an assessment has determined that the data indicate human risk potential for reproductive and developmental toxicity, the next step is to perform a quantitative evaluation. Dose-response data from human and experimental animal reproductive and developmental toxicity studies are reviewed to identify a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL), and/or to derive a benchmark dose (BMD). Duration adjustments of the NOAEL, LOAEL, or BMD are often made, particularly for inhalation exposures when extrapolating to different exposure scenarios. Such adjustments have not been routinely applied to developmental toxicity data. The subcommittee recommends that duration adjustments be considered for both reproductive and developmental toxicity... 

Benchmark dose (BMD). The BMD is used as an alternative to the NOAEL for reference dose calculations. The dose response is modeled and the lower confidence bound for a dose at a specified response level is calculated. For a further description, see the section on BMD calculation. 

The cumulative assessment for endpoint (1) combines only those chemicals and routes that are associated with endpoint (1) via a common mechanism and incorporates only those No Observed Adverse Effect Levels (NOAELs), benchmark doses, uncertainty factors, etc. associated with endpoint (1). A similar cumulative assessment would be carried out for endpoint (2). Guidance on aggregate exposure and cumulative risk assessment has been recently published (USEPA, 2003). 

Benchmark dose (BMD) One of a number of possible specified dose values which is used as a reference point. For example, a No Observed Adverse Effect Level (NOAEL) and an effective dose (e.g. EDio) are both benchmark doses (Sielken, Ch. 8). 

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