Benchmark Dose Method

3 Benchmark dose method. In recent years, confidence in the ability of statistical curve-fitting models to accurately predict cancer incidence in humans based exclusively on data obtained from animal studies has lessened (Crump, 1996). The reasons are manifold and include that (1) the pharmacokinetic behavior of chemicals in humans is often different than in animals, (2) the study animals 

The benchmark dose method is particularly useful when the mode of action of a chemical that causes stochastic effects is thought to be nonlinear. In these circumstances, the response is assumed to decrease more rapidly than linearly with decreasing dose. Alternatively, the mode of action may theoretically have a threshold for example, the carcinogenicity of a substance may be a secondary effect of its toxicity or of an induced physiological change that is itself a threshold phenomenon. 

The benchmark dose method and MOE analyses are essentially the same for substances that cause stochastic or deterministic effects. For both types of substances, the point of departure in the dose-response curves for purposes of protecting human health is a dose at which some response is expected, either LED10 or some other human equivalent dose or concentration as the data support. For stochastic responses (e.g., cancers), the point of departure when animal data are used is a human equivalent dose or concentration 

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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. 

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. 

In traditional toxicological methods of determining virtually safe doses of hazardous chemicals, nominal thresholds for deterministic responses in humans are estimated based on a NOAEL obtained in human or animal studies. In most high-quality studies, NOAEL is approximately the same as the lower confidence limit of the benchmark dose that corresponds to a 10 percent increase in the number of responses. Thus, as an alternative to the benchmark dose method, the nominal threshold in humans could be set at a factor of 10 or 100 lower than NOAEL obtained in a high-quality human or animal study. However, the benchmark dose method preferred by NCRP... 

Fig. 3.6. Illustration of use of benchmark dose method to estimate nominal thresholds for deterministic effects in humans. The benchmark dose (EDio) and LEDi0 are central estimate and lower confidence limit of dose corresponding to 10 percent increase in response, respectively, obtained from statistical fit of dose-response model to dose-response data. The nominal threshold in humans could be set at a factor of 10 or 100 below LED10, depending on whether the data are obtained in humans or animals (see text for description of projected linear dose below point of departure).

The benchmark dose method was developed to overcome difficulties with determining NOAEL based on dose-response data. The potential advantages of the method include the following (Crump, 1984 1995) ... 

The benchmark dose method makes use of all the dose-response data by fitting a dose-response model to the data, whereas the determination of a NOAEL generally involves a comparison of responses at discrete and well separated doses with responses in control subjects. 

A NOAEL is constrained to be one of the administered doses, but this is not the case with the benchmark dose method. 

The determination of a NOAEL generally involves dose data that are categorized into distinct groups, but this categorization is arbitrary in some studies. Grouping of data into distinct dose categories is not required in the benchmark dose method. 

The benchmark dose method can also be applied to chemicals that cause stochastic effects (Section 3.2.1.3.3). This is indicated by the projected linear response at doses below LEDi0 in Figure 3.6. 

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. 

For most chemicals that induce deterministic effects, the nominal threshold in humans or animals has been estimated based on NOAELs or LOAELs. However, the benchmark dose method should provide more reliable estimates of thresholds (see Section 3.2.1.2.7). Therefore, whenever the nominal threshold in humans for an important chemical in waste that induces deterministic effects has been estimated based on NOAELs or LOAELs, NCRP believes that the data should be re-evaluated using the benchmark dose method to promote greater consistency in classifying waste. As in the case of chemicals that induce stochastic effects discussed in the previous section, NCRP believes that uncertainties in the data beyond those incorporated in the benchmark dose method should be taken into account, if need be, in setting allowable exposures, rather than in an estimate of the nominal threshold. 

Malsch PA, Proctor DM, Finley BL. 1994. Estimation of chromium inhalation reference concentration using the benchmark dose method a case study. Regul Toxicol Pharmacol 20 58-82. 

Scott PK, Proctor DM. 1997. Evaluation of 10% minimum elicitation threshold for Cr(VI)-induced allergic contact dermititis using benchmark dose methods. J Soil Contam 6(6) 707-731. 

The results of the subcommittee s evaluations are presented in Chapters 2 through 9. Chapter 2 reviews the method used by the Army to derive RfDs, and also inclndes a discussion of the benchmark dose method as a point of departure for calculating RfDs. Chapters 3 throngh 6 evaluate the RfDs for the nerve agents GA, GB, GD, and VX. Chapter 7 evalnates the RfD and slope factor for sulfnr mustard, and Chapter 8 provides an evaluation of the RfD for lewisite. Research recommendations are presented at the end of Chapters 3-8 for each of the specific chemical-warfare agents. 

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. 

In the draft ruling, the U.S. EPA summcirized the toxicity information on isopropyl-bromide and another similcu ly structured chemical, the pesticide dibromochloro-propane (DBCP), and used the greater toxicity of these chemiccds as one means to support the need for an uncertcunty factor to lower the value obtcuned for nPB using the benchmark dose method. 

Stelljes, M. E., and R. R. Wood. 2004. Development of an Occupational Exposure Level for n-Propylbromide Using Benchmark Dose Methods. / egu/atory Toxicology and Pharmacology 40 136-50. 

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