Dose response assessment supporting data

Dose-response assessment today is generally performed in two steps (1) assessment of observed data to derive a dose descriptor as a point of departure and (2) extrapolation to lower dose levels for the mmor type under consideration. The extrapolation is based on extension of a biologically based model (see Section 6.2.1) if supported by substantial data. Otherwise, default approaches that are consistent with current understanding of mode of action of the agent can be applied, including approaches that assume linearity or nonlinearity of the dose-response relationship, or both. The default approach is to extend a straight line to the human exposure doses. 

IRIS contains data from EPA in support of human health risk assessment, focusing on hazard identification and dose-response assessment for specific chemicals. 

The science supporting the use of UFs has evolved considerably over the past years. Increased knowledge of inter- and intraspecies sensitivity, mechanism of action, and detailed evaluation of databases has led to improvements that allow for the incorporation of more scientific data into the dose-response assessment of noncancer toxicity, and permit the use of factors other than the standard default values. 

IRIS is a toxicology data file that contains data in support of human health risk assessment. It is compiled by the US EPA and contains over 500 chemical records. IRIS data, focusing on hazard identification and dose-response assessment, are reviewed by work groups of EPA scientists and represents EPA consensus. Among the key data provided in IRIS are EPA carcinogen classifications, unit risks, slope factors, oral reference doses, and inhalation reference concentrations. 

Historical control data is an essential component of the study directors toolbox for interpreting reproductive and developmental toxicity data. Scientific judgment and expertise should be used to determine if historical control data is needed for interpretation of study data, which historical control data is appropriate, and how it should be used to support interpretation of a finding. This tool can be a valuable addition to a comprehensive assessment of the study data, which includes determining whether a dose-response is present and whether any statistically significant findings occurred. Sound data interpretation requires that the litter, not the fetus or pup, be used as the experimental unit in developmental and reproductive toxicity studies. For continuous data (e.g., fetal weight). 

In characterizing the database, a number of assumptions are applied when data are not available or are incomplete (USEPA, 1991 IPCS, 2005 Kimmel et al., 2006). These include uncertainties about toxicokinetics, mechanism of action, low-dose-response relationships, and human exposure patterns. Each of these assumptions is supported to some extent by the scientific literature. The following assumptions are generally accepted in risk assessment strategies ... 

Identifying dose-response relationships is an important component of any risk assessment. This process establishes the exposure levels that produce effects, as well as those that produce no effects. As noted in Box 2, it is important to characterize what data were used, what model was employed to develop the dose-response curve(s), and whether chemical-specific information is available to support the observed dose-response relationship. While the risk assessment paradigm shown in Figure 21 separates hazard... 

Subsequent doses Increase the dose in a stepwise fashion to 2, 5, or 10 mg daily to achieve desired improvement of symptoms or flow rates. Doses of 10 mg once daily are generally required for clinical response therefore, treatment with 10 mg for a minimum of 4 to 6 weeks may be required to assess whether a beneficial response has been achieved. There is insufficient data to support the use of doses greater than 20 mg in patients who do not respond. 

The first tolerability studies in early clinical development always provide pharmacokinetic (PK) data over a considerable dose range. Especially the explorative first-in-man study with escalating single doses, or an explorative proof of principle study with escalating multiple doses provides a valuable basis for an exploratory assessment of dose linearity/ proportionality of drugs in humans. In addition such an assessment can directly help within the same study to optimize the dose selection and dose progression. Already in this early phase of the development, these data are going to support exposure-response relationships, and thus a potential submission (US FDA 2003, ICH E4 1994). 

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