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Safe" doses estimated with standard methods by agencies around the world, whether ADIs, ECNCs, MRLs, TDCs, TCs, TIs, RfCs, or RfDs, should be considered as accurate-but imprecise-estimations of doses or concentrations believed to be without risk to populations of humans (including sensitive subgroups). Restated, these "safe" doses are thought to be below population thresholds for adverse effect, but the degree to which they underestimate the population threshold is generally not known. Part of this imprecision comes from the use of 10-fold default uncertainty factors. We show research and case studies drawn from a large sample of U.S. EPA and Health Canada risk values where uncertainty factors other than a default value of 10-fold were used in the estimation of a RfD, RfC, TDI or TC. Percentages for the use of these "dataderived" factors vary between 3.6% and 47%. In five case studies, we explicitly review the types of data that have been used to support a change in the default value, why the data support a different UF, and what assumptions have been satisfied, replaced, or how the uncertainty was reduced.

Physiologically based pharmacokinetic (PBPK) models have been developed describing the disposition kinetics of nicotine and its major metabolite, cotinine, in man. Separate 9-compartment, flow-limited PBPK models were initially created for nicotine and cotinine. The physiological basis for compartment designation and parameter selection has been provided; chemical-specific tissue-to-blood partition coefficients and elimination rates were derived from published human and animal data. The individual models were tested through simulations of published studies of nicotine and cotinine infusions in man using similar dosing protocols to those reported. Each model adequately predicted the time course of nicotine or cotinine concentrations in the blood and urine following the administration of nicotine or cotinine. These individual models were then linked through the liver compartments to form a nicotine-cotinine model capable of predicting the metabolic production and disposition of cotinine from administered nicotine. The potential for integrating this functional PBPK model with an appropriate pharmacodynamic model for the characterization of nicotine's physiological effects is discussed.

The willingness of the agencies involved in the regulation of pharmaceuticals to accept data from newly proposed models for carcinogenicity testing (eg, transgenic animals, neonatal rodent models, initiation-promotion models) has stimulated international interest in gaining experience and a greater understanding of the strengths and limitations of the speci c models. Over a 4-year period, the International Life Sciences Institute (ILSI) Health and Environmental Science Institute (HESI) has coordinated a large-scale collaborative research program to help to better characterize the responsiveness of several models proposed for use in carcinogenicity assessment. The overall objective of this partnership among industry, government, and academic scientists was to evaluate the ability of these new models to provide useful information for human cancer risk assessment. This research program re ected a commitment of nearly US$35 million by over 50 industrial, government, and academic laboratories from the United States, Europe, and Japan. Evaluation of the models required the development of standardized protocols to allow reproducibility and comparability of data obtained across multiple laboratories. Test compounds were selected on the basis of mechanistically meaningful carcinogenic activity or noncarcinogenicity in the rodent bioassay as well as humans. Criteria were established for dose selection, pathology review, quality control, and for evaluation of study outcome. The database from these studies represents an important contribution to the future application of new models for human cancer risk assessment. Beyond the data, the collaborative process by which the models were evaluated may also represent a prototype for assessing new methods in the future.

Advances in genetic engineering have created opportunities for improved understanding of the molecular basis of carcinogenesis. Through selective introduction, activation, and inactivation of specific genes, investigators can produce mice of unique genotypes and phenotypes that afford insights into the events and mechanisms responsible for tumor formation. It has been suggested that such animals might be used for routine testing of chemicals to determine their carcinogenic potential because the animals may be mechanistically relevant for understanding and predicting the human response to exposure to the chemical being tested. Before transgenic and knockout mice can be used as an adjunct or alternative to the conventional 2-year rodent bioassay, information related to the animal line to be used, study design, and data analysis and interpretation must be carefully considered. Here, we identify and review such information relative to Tg.AC and rasH2 transgenic mice and p53 +/-and XPA -/-knockout mice, all of which have been proposed for use in chemical carcinogenicity testing. In addition, the implications of findings of tumors in transgenic and knockout animals when exposed to chemicals is discussed in the context of human health risk assessment.

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The current approach for carcinogenicity testing usually incorporates a genetic toxicity screen, 14-and 90-day subchronic toxicity studies in rats and mice, toxicokinetic and disposition studies, and 2-yr chronic bioassays in rats and mice. The 2-yr bioassays are both time and resource intensive, and questions have been raised regarding the relevance of some of the carcinogenic responses in rodents for human risk assessment. At the 1996 meeting of the International Conference on Harmonization (ICH) Expert Working Group on Safety, the international pharmaceutical and regulatory communities acknowledged the limited utility of certain aspects of conventional rodent studies and proposed a new scheme for carcinogenicity testing for pharmaceuticals (Fed. Reg. 61: 43298-43300). The proposed strategy incorporates a conventional bioassay in a single rodent species and the option to conduct a short-or medium-term in vivo assay with a tumor end point in place of the second species bioassay. The available alternative models include initiation-promotion assays, newborn rodent assays, and several transgenic mouse assays that have recently been developed. The willingness of the regulatory authorities to accept data from these new experimental approaches as part of the safety assessment process for pharmaceuticals has stimulated international interest in gaining experience and a greater understanding of the strengths and limitations of the specific models. These new methods have not been fully characterized, and the scientific community is considering their most appropriate application(s).The Alternatives to Carcinogenicity Testing Technical Committee was formed under the auspices of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute to assist in the further evaluation of these new experimental approaches for carcinogenicity testing. Through the efforts of this committee, which is composed of interested scientists from industry, government, and academia, an international collaborative research program was established. The goals of this research program, currently being conducted in more than 45 laboratories in the United States, Europe, and Japan, are: to expand the data base on several of these new test methods; to enhance the understanding of the specific responses of each model to compounds representing a range of chemical and pharmaceuticalltherapeutic classes, including various modes of toxic and carcinogenic action; to evaluate potential criteria that should be considered in the selection of one model over another for a particular