Lowest-observed-adverse-effect level LOAEL benchmark

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. 

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. 

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... 

The standard benchmarks typically used in toxicology studies including the no-observed-effect level (NOEL), no-observed-adverse-effect level (NOAEL), and lowest-observed-adverse-effect level (LOAEL) are usually not applicable with cytotoxic oncology molecules.5859 Rather, benchmarking in rat and dog studies with oncology therapeutics includes the dose that results in 10 percent mortality over the duration of the study (STD10) in rats, and the highest... 

Until recently, safe doses for noncancer effects have been derived directly from toxicology study doses such as no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs). The NO-AEL represents the highest experimental dose for which no adverse health effects are observed, while the LOAEL represents the lowest dose for which the adverse health effect is observed. Dividing the study NOAEL or LOAEL by a series of uncertainty factors yields a dose that is generally considered safe. A recent alternative to using the NOAEL or LOAEL in this calculation is the use of a benchmark dose (BMD) to serve as the starting point for deriving safe doses. 

Chronic Reference Concentration (RFC) RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a continuous inhalation exposure for a chronic duration (up to a lifetime) to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. It can be derived from a NOAEL, lowest observed adverse effect level (LOAEL), or benchmark concentration, with uncertainty factors generally applied to reflect limitations of the data used. 

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. 

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). 

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