FDA then reviews the available toxicology studies. It has developed guidelines (Toxicological Principles for the Safety of Food Ingredients, commonly known as The Redbook [FDA/CFSAN, 2001]) for food additive petitioners to use when assembling the required data in support of their petitioned use. The Redbook outlines the types of toxicological testing FDA normally expects to be provided in support of the food additive’s safety, based initially on the additive’s chemical structure and probable human exposure (The Redbook provides guidance and is not a requirement). Using this information, FDA assigns additives to initial “concern levels” (or “minimum testing levels”) of I, II, or III. In its data review, FDA applies toxicological decision elements to further refine the scope of needed toxicological data.
From the animal studies FDA determines the highest level of intake associated with no adverse toxicological effects in the most sensitive, longest duration, most relevant animal study. This “highest no-effect level” is then divided by an “uncertainty factor” (or “safety factor”), often a factor of 100, to account for both intra- and interspecies variability. The resulting value is the acceptable daily intake (ADI) for the additive. The ADI is compared to the EDI to determine whether the proposed use of the additive is consistent with a reasonable certainty of no harm.
For some substances, the traditional risk assessment approach is not applicable. For example, an additive may be so toxicologically inactive that not enough of the additive can be orally ingested by the test animals to elicit a toxic response without perturbing normal nutrition. In such cases it is difficult to determine an ADI. FDA may then employ other types of decision elements. In these cases increased emphasis may be placed on, for example, chemical identity information and structure-activity relationships; data on absorption, distribution, metabolism, and excretion; and human tolerance studies (to look at physiological and nutritional responses).
Once all the information has been evaluated, FDA concludes whether the proposed use of a food additive is consistent with a reasonable certainty of no harm and can be safely marketed. After a new food additive is on the market, FDA may monitor the substance for safety through examination of available clinical studies and postmarket surveillance (Personal communication, A.Rulis, FDA, January 25, 2002).
Based on the 1958 FAA to the Federal Food, Drug, and Cosmetic Act, FDA developed specific processes to determine whether substances used in foods were safe for their intended use (see previous section). Food additives, as defined in the amendment, are subject to premarket approval by FDA unless they are GRAS or fall within another statutory exception (21 USC321(s)). Requirements for premarket approval are discussed in the previous section.
For about a dozen years after the passage of the FAA, FDA assumed a lenient approach to dealing with the GRAS exception. In the early 1970s however, in response to public concern about the apparent carcinogenicity of cyclamate, which FDA had listed as GRAS, FDA adopted a more rigorous approach (Degnan, 2000). In 1972 FDA contracted with the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology for assistance with a comprehensive review of GRAS substances. LSRO established a Select Committee on GRAS Substances that examined monographs on each substance that provided all known data on physical and chemical properties of the substance, human exposure data, animal and human toxicity data, and reports of special studies on mutagenicity, carcinogenicity, and teratogenicity of the substances. The Select Committee reached one of five conclusions on each GRAS substance reviewed: (1) continue as GRAS, (2) continue as GRAS with limitations, (3) uncertainties exist—issue interim food additive order requiring further testing, but continue as