ABSTRACT
Regulatory toxicology is that area of toxicology directed at protecting public health by regulating exposure to potentially harmful materials. Historically, regulatory toxicology has developed in a manner that has re¦ected humankind’s
ability to relate exposure to certain agents to adverse health effects. Thus, because effects were observable and could be easily associated with exposure, early regulatory attention generally focused on preventing the acute effects of chemical agents. Food and drugs were the focus of early regulation
Background ................................................................................................................................................................................. 35 Current Regulatory Framework .................................................................................................................................................. 37 Risk Assessment Paradigm ......................................................................................................................................................... 41 Toxicology Information Used in the Regulatory Process ........................................................................................................... 45 Evaluation of Carcinogens .......................................................................................................................................................... 48
Background ............................................................................................................................................................................ 48 Mechanisms of Carcinogenesis .............................................................................................................................................. 48 Hazard Identi•cation .............................................................................................................................................................. 49
Animal Studies .................................................................................................................................................................. 49 Approaches to Interpretation of Carcinogenicity Findings ............................................................................................... 51
Dose-Response Assessment................................................................................................................................................... 57 Low-Dose Extrapolation ................................................................................................................................................... 58
Evaluation of Noncancer Effects ................................................................................................................................................ 59 Acceptable Exposure Level .................................................................................................................................................... 59
Identifying a Point of Departure ........................................................................................................................................ 60 Selecting Uncertainty Factors ........................................................................................................................................... 62
Alternative Approaches to the Risk Reference Dose ............................................................................................................. 66 Incorporating Information on Severity of Effect .................................................................................................................... 66
Physiologically Based Pharmacokinetic Models ........................................................................................................................ 67 Role of High-Risk Groups .......................................................................................................................................................... 72
Consideration of Speci•c High-Risk Groups ......................................................................................................................... 72 Regulatory Implications ......................................................................................................................................................... 73
Nitrates in Drinking Water ................................................................................................................................................ 74 Cadmium ........................................................................................................................................................................... 74
Susceptible Groups and Early-Life-Stage Exposure to Carcinogens ..................................................................................... 75 Implications of Chemical Interactions for the Regulatory Process............................................................................................. 75
Implications of Chemical Interactions ................................................................................................................................... 77 Approaches Used by Regulatory Agencies to Assess Interactions ........................................................................................ 77
Hazard Index Approach ..................................................................................................................................................... 77 Toxicity Equivalency Factor Approach ............................................................................................................................. 78 Cumulative Risk Assessment ............................................................................................................................................ 78 Complex Mixture Approach .............................................................................................................................................. 78
Conclusions ............................................................................................................................................................................ 79 Conclusions ................................................................................................................................................................................. 79 Questions ..................................................................................................................................................................................... 80 Acknowledgments ....................................................................................................................................................................... 80 Keywords .................................................................................................................................................................................... 80 References ................................................................................................................................................................................... 80
effects with exposure to materials in the diet or medications. Hutt1 notes that adulteration of the food supply was a serious problem in the ancient world, and he quotes Pliny the Elder, writing in the •rst century AD, as saying, “So many poisons are employed to force wine to suit our taste – and we are surprised that it is not wholesome!”
