unknown origin) and so lead to better measures of attributable risks. Biologically based mathematical models will continue to evolve in concert with advances in biology and medicine.
CONCLUSIONS AND RECOMMENDATIONS
Mechanistic understanding of toxicity has strong implications for improvement in the development of low dose extrapolation for the regulation of chemical substances. Currently, low dose extrapolation uses a multistage model with data developed from human occupational exposures or from whole animal bioassays (Anderson et al., 1983). The newer two-stage model examined in this report attempts to use data related more to mechanisms of toxicity. Its potential utility (and the gathering of the data needed to use it) derives from the recent rapid development of biologic investigative techniques.
Understanding of and data on cell birth and death are required for the development and use of the two-stage model, but they do not exist for most chemicals. A better mechanistic understanding must be developed, if modeling efforts are to take advantage of cell birth and death data. If the mechanism of a toxic effect is not understood, inappropriate dose-response data are likely to be used in the extrapolation process, which could then produce an incorrect result. The committee recommends that when critical assumptions about mechanisms of toxicity are made, they must be clearly stated.
The two-stage model can be used as a basis for decision-making, if there is sufficient mechanistic understanding and if a sufficient data base is available. The committee recognizes that regulators face the question of how to determine when such understanding, data, and models are sufficient and appropriate; no hard and fast rules can be given. Complicating the issue is that there is a continuum in the extent of mechanistic understanding and data on any chemical. The risk management context need also be considered.
Scientific work on the two-stage model of carcinogenesis has proceeded sufficiently for it to be clear that its further development should be strongly encouraged. Regulatory agencies might review decisions and standards on materials with economic or public health importance to see whether enough data are available or can be rapidly collected to permit
application of the two-stage model for additional perspective. The judgment of scientists as to whether sufficient data are available or could be collected might be helpful to regulatory agencies before they decide to apply this newer model in risk assessment. Experience in conducting such reviews will probably lead to a set of criteria for determining when the two-stage model should be used. The proposed reviews should be conducted on only a narrowly limited number of materials. And they must not be allowed to substitute for or interfere with the prompt regulation of or setting of standards for materials currently or soon to be under examination.
The committee recommends exploratory applications of the two-stage model along with its testing and validation. A first stage in the testing requires mechanistic understanding and the gathering of sufficient data to permit its use. Comparative information on humans must be developed as a part of the validation process. The committee also recommends that statistical confidence-interval methods, sensitivity analyses and related quantitative methods as appropriate be applied to determine the extent that the data are consistent with other mathematical representations and ranges of risk. Although the committee recognizes that the simulation approach to model fitting can have very important uses, particularly for exploratory data analysis and when no closed-form solution of the two-stage model is available, the committee recommends that whenever the model is applied in formal risk assessment, formal statistical methods (e.g., maximum likelihood) should be employed.