Benchmark dose approach

There are several problems associated with using the NOAEL approach to estimate RfDs and RfCs. The first obvious constraint is that the NOAEL must by definition be one of the experimental doses tested. Once this dose is identified, the rest of the dose-response curve is ignored. In some experimental designs where there is no identifiable NOAEL but LOAEL, the dose-response curve is again ignored, and the NOAEL is derived by application of uncertainty factors as described earlier. This NOAEL approach does not account for the variability in the estimate of the dose response, and furthermore experiments that test fewer animals result in larger NOAELs and thus larger RfDs and RfCs. 

An alternative approach known as the benchmark dose (BMD) approach has been developed and implemented by risk assessors as an alternative to the NOAEL approach to estimate RfDs and RfCs. This approach is not constrained by experimental design 

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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. 

EPA (1995a). U.S. Environmental Protection Agency. Use of the Benchmark Dose Approach in Health Risk Assessment, EPA/630/R-94/007 (National Technical Information Service, Springfield, Virginia). 

It should be emphasized that these methods will generally be considered for an acute lethal endpoint. Their use to set AEGL-1 and AEGL-2 values will be considered on a chemical-by-chemical basis. Different endpoints may require the use of different data sets in different or the same species, a different benchmark dose approach, or identification of a different response level. These factors wiU be considered for specific chemicals and toxicologic end-points. 

The standard approaches for using dose-response relationship information in the risk assessment process is the focus of ongoing efforts. Guidance provides for use of a point of departure when data are appropriate. The benchmark dose approach is commonly used. 

Over the past decade there has been a movement to harmonize cancer and noncancer risk assessment (Gaylor 1997 Bogdanffy et al. 2001) based on the premise that cancer and noncancer events share similar pharmacokinetic dependencies and overlapping MOAs and thus have similar dose-response relationships. The benchmark dose approach lends itself to the evaluation of both linear and nonlinear dose-response. In fact, one of the stated purposes of EPA s formalization of the benchmark dose process was to provide a standardized approach to chemical dose-response assessment, regardless of whether the chemical is a carcinogen. 

EFSA. 2009. Use of the benchmark dose approach in risk assessment. EFSA J. 1150 1-72. 

Piersma, A. H., Janer, G., Wolterink, G., Bessems, J. G., Hakkert, B. C., 8c Slob, W. (2008). Quantitative extrapolation of in vitro whole embryo culture embryotoxicity data to developmental toxicity in vivo using the benchmark dose approach. Toxicological Sciences, 101, 91. 

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... 

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). 

As an alternative to using the benchmark dose method, the more traditional approach of estimating threshold doses of substances that cause deterministic effects based on NOAELs could be used. In... 

In classifying waste, deterministic responses generally should be of concern only for hazardous chemicals (see Section 3.2.2.1). Therefore, the only important issue for risk assessment is the most appropriate approach to estimating thresholds for induction of responses in humans. The primary concern here is that consistent approaches should be used for all substances that induce deterministic effects. NCRP s recommendation that nominal thresholds in humans should be estimated using the benchmark dose method and a safety factor of 10 or 100, depending on whether the data were obtained in a study in humans or animals (see Section 6.1.2.1), is intended to provide consistency in estimating thresholds for all substances that cause deterministic effects. 

In many respects, the foundations and framework of the proposed risk-based hazardous waste classification system and the recommended approaches to implementation are intended to be neutral in regard to the degree of conservatism in protecting public health. With respect to calculations of risk or dose in the numerator of the risk index, important examples include (1) the recommendation that best estimates (MLEs) of probability coefficients for stochastic responses should be used for all substances that cause stochastic responses in classifying waste, rather than upper bounds (UCLs) as normally used in risk assessments for chemicals that induce stochastic effects, and (2) the recommended approach to estimating threshold doses of substances that induce deterministic effects in humans based on lower confidence limits of benchmark doses obtained from studies in humans or animals. Similarly, NCRP believes that the allowable (negligible or acceptable) risks or doses in the denominator of the risk index should be consistent with values used in health protection of the public in other routine exposure situations. NCRP does not believe that the allowable risks or doses assumed for purposes of waste classification should include margins of safety that are not applied in other situations. 

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. 

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... 

The effects of genotoxic compounds are considered non-threshold. Thus, risk assessment for a given exposure is usually performed by a linear or sub-linear extrapolation from the high dose effects observed in animals to the lower human exposure. Since the outcome of the extrapolation depends on the model applied and extrapolation over different orders of magnitude is error prone, the European Food and Safety Authority (EFSA 2005) recommended to avoid this extrapolation and proposed the MOE approach. This approach uses the benchmark dose, or the T25 calculated from a carcinogenicity study and compares this with human exposure. A MOE of 10,000 and more is considered to be of minor concern. The advantage is that neither a debatable extrapolation from high to low doses needs to be performed nor are hypothetical cancer cases calculated. For details of the different approaches see, SCHER, SCCP, SCENIHR (2008). 

THIS CHAPTER contains a brief description of the methods used by toxicologists at Oak Ridge National Laboratory (ORNL) to derive the U.S. Army s interim reference doses (RfDs) for GA, GB, GD, VX, sulfur mustard, and lewisite. Those methods were based on the procedures outlined by the U.S. Enviromnental Protection Agency for Superfund risk assessment guidelines (EPA 1989) and for reference concentrations (EPA 1994). An alternative method, the benchmark-dose (BD) approach (Crump 1984) is also described. Because uncertainty factors are integral to both approaches, further consideration is also given to the statistical distribution and confidence associated with them. 

Two examples of alternative approaches to cancer risk assessment would be estimations based on threshold-response (EPA, 2005a) and benchmark dose modeling (EPA, 1995, 2000). As a practical matter, if the proposed basis of safety relies on a threshold or mode-of-action characterization to dismiss or mitigate animal tumor data, PDA would reconunend that the safety narrative clearly discuss the scientific rationale and present all relevant data for consideration. In the absence of adequate evidence to the contrary, PDA presumes that certain assumptions are appropriately protective of safety, namely that (i) the induction of tumors in animals is relevant to human... 

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