A Practical Approach, Second Edition=Ronald D. Ho.pdf

880 DEVELOPMENTAL REPRODUCTIVE TOXICOLOGY: A PRACTICAL APPROACH, SECOND EDITIONexplained in the general safety clause for food additives, FDA regulations define “safety” as areasonable certainty in the minds of competent scientists that the substance is not harmful underthe intended conditions of use. It does not require proof beyond any possible doubt that no harmwill result under any conceivable circumstance. This concept of safety requires the considerationof available data on the additive in question, as well as additional relevant information including:(1) the probable consumption of the additive, (2) the cumulative effect of such additive in the dietof humans or animals, and (3) safety factors that qualified experts consider appropriate.1. Guidance for Food AdditivesThe act requires that chemicals added to food be tested and/or evaluated for safety. This is a generalrequirement for food additives and color additives. Safety evaluation usually involves toxicologytesting by a battery of studies in animals. Protocols for safety testing reflect the increased sophisticationof the science of toxicology as well as an increased concern about food safety. 1 Despitethe increased sophistication of knowledge and techniques, the four principles of toxicity testing forthe evaluation of food additives published by the National Research Council (NRC) 2 remainessentially the same. These principles are:• Animal test endpoints are appropriate for identifying human risk.• Extrapolation of safety information from animal test data to humans requires an understanding ofspecies differences in metabolism and disposition, sensitivity of target tissue, and rates of injuryand repair.• The principle of dose response relationship, that intensity, time of onset, and duration of biologicaleffects are related to dose, is central to toxicological evaluation. Generally, the greater the dose,the greater the likelihood of observing a toxic effect.• The potential exposure from the intended use must be assessed in the evaluation of the safety offood additives.Shortly after the NRC publication, the FDA issued Toxicological Principles for the Assessmentof Direct Food Additives and Color Additives Used in Food. 3 The publication was intended to serveseveral purposes: to assess a substance’s potential for causing toxicity, to determine if safe conditionsof use can be established for food additives, and to provide testing guidance, including a prioritybasedranking scheme for food additives that ranks compounds according to their level of healthconcern (based on the extent of human exposure and the compound’s known or presumed toxicologicaleffects). The 1982 guidelines provided general toxicity guidelines and promulgated individualtests to be used for determining a compound’s potential for causing specific types of toxicity,such as reproductive and teratological effects. Tests for reproductive and teratological effects hadbeen available before this time, but this was the first time they were issued together with other testsas part of a set of guidelines. Further expansion and refinement of the tests was done in the 1993Draft Redbook II. 4 As the individual guidelines are reviewed and updated, they are made availableonline on FDA’s Web site. 5 The testing guidelines for female reproduction and teratology studiesare posted online (http://www.cfsan.fda.gov/~redbook/redivc9a.html for reproduction studies andhttp://www.cfsan.fda.gov/~redbook/redivc9a.html for developmental toxicity studies) and arereadily available, so they will not be repeated here.2. Estimating Exposure to a Direct Food AdditiveSection 409 of the act describes the statutory requirements that are required to establish safety ofa food additive. The chemical and technological data encompass four general areas of information:(1) identity of the additive, (2) proposed use of the additive, (3) intended technical effect of theadditive, and (4) a method of analysis for the additive in food. Section 409 also requires thatprobable consumption of an additive and of any substance formed in or on food because of its use© 2006 by Taylor & Francis Group, LLC