HARMONIZATION - DEVELOPING CONSISTENT GUIDELINES FOR APPLYING MODE OFACTION AND DOSIMETRY INFORMATION TO CANCER AND NONCANCER RISK ASSESSMENT

The 1983 book, Risk Assessment in the Fecal Government: Managing the P rocess, recommended developing consistent inference guidelines for can cer risk assessment. Ever the last 15 years, extensive guidance have b een provided for hazard assessment for cancer and other endpoints. How ever, as noted in several recent reports, much less progress has occur red in developing consistent guidelines for quantitative dose response assessment methodologies. This paper proposes an approach for dose re sponse assessment guided by consideration of mode of action (pharmacod ynamics) and tissue dosimetry (pharmacokinetics). As articulated here, this systematic process involves eight steps in which available infor mation is integrated, leading first to quantitative analyses of dose r esponse behaviors in the test species followed by quantitative analyse s of relevant human exposures. The process should be equally appropria te for both cancer and noncancer endpoints. The eight steps describe t he necessary procedures for incorporating mechanistic data and provide multiple options based upon the mode of action by which the chemical causes the toxicity. Given the range of issues involved in developing such a procedure, we have simply sketched the process, focusing on maj or approaches for using toxicological data and on major options; many details remain to be filled in. However, consistent with the revised c arcinogen risk assessment guidance (USEPA, 1996c), we propose a proces s that would ultimately utilize bioiogically based or chemical specifi c pharmacokinetic and pharmacodynamic models as the backbone of these analyses. In the nearer term, these approaches will be combined with a nalysis of data using more empirical models including options intended for use in the absence of detailed information. A major emphasis in d eveloping any harmonized process is distinguishing policy decisions fr om those decisions that are affected by the quality and quantity of to xicological data. Identification of data limitations also identifies a reas where further study should reduce uncertainty in the final risk e valuations. A flexible dose response assessment procedure is needed to insure that sound toxicological study results are appropriately used to influence risk management decision-making and to encourage the cond uct of toxicological studies oriented toward application for dose resp onse assessments.