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Benchmark Dose Tools

Multitumor (MS_Combo) - Synopsis and Model Documentation

The MS_Combo program models several dichotomous (e.g., cancer) endpoints  the user wishes to consider together. It addresses the question that might be asked in a regulatory context, “What doseHelpdoseThe amount of a substance available for interactions with metabolic processes or biologically significant receptors after crossing the outer boundary of an organism. The POTENTIAL DOSE is the amount ingested, inhaled, or applied to the skin. The APPLIED DOSE is the amount presented to an absorption barrier and available for absorption (although not necessarily having yet crossed the outer boundary of the organism). The ABSORBED DOSE is the amount crossing a specific absorption barrier (e.g. the exchange boundaries of the skin, lung, and digestive tract) through uptake processes. INTERNAL DOSE is a more general term denoting the amount absorbed without respect to specific absorption barriers or exchange boundaries. The amount of the chemical available for interaction by any particular organ or cell is termed the DELIVERED or BIOLOGICALLY EFFECTIVE DOSE for that organ or cell. level corresponds to a risk level of interest, where the risk in question is that of getting one or more of the endpoints under consideration?”  

The National Research Council (1994) Exitconcluded that an approach based on counts of animals with one or more of the endpoints (e.g., counts of "tumor-bearing animals") would tend to underestimate overall risk when tumors occur independently across sites. In addition, application of a single dose-responseHelpresponseThe biological result of an exposure or dose. Biological responses can be quantified in several ways. Some examples of the type of response data that can be used in a BMD dose-response analysis are dichotomous data (quantal data), nested data, continuous data, and categorical data. model to pooled endpoint incidences does not reflect possible differences in dose-response relationships across endpoints.

The MS_Combo program fits multistage models to two or more endpoints separately from one another.  Given those fits, MS_Combo estimates a benchmark doseHelpbenchmark doseAn exposure due to a dose of a substance associated with a specified low incidence of risk, generally in the range of 1% to 10%, of a health effect; or the dose associated with a specified measure or change of a biological effect. (BMD) for the risk level specified by the user, as well as bounds on that BMD: BMDL (lower) and BMDU (upper).  The assumption is that the endpoints are independent of one another (conditional on the dose level).

Previously, a user could manually estimate the BMD for multiple endpoints (using separate multistage model runs), but could not estimate the bounds.  MS_Combo automates the computation of the BMD and uses the profile likelihood method to find the bounds for the combination of the endpoints. 

Review the Multitumor model technical background document for more on the assumptions and application of the BMDS MS_Combo program.


National Research Council. (1994). Science and judgment in risk assessment. National Academies Press.

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