The use of carbon monoxide (CO) in the packaging of meat and fish has generated considerable debate. Carbon monoxide, in combination with nitrogen and carbon dioxide, is used in a packaging process for fresh meat called Modified Atmosphere Packaging (MAP). In the MAP process, the meat is placed in a container with an "impermeable film similar to a vacuum package but ... the air [is evacuated] from the package and replac[ed] ... with a specified mixture of gases that provides for better control of product properties." The presence of CO results in the meat turning a bright red color that lasts longer than the color in untreated meat. Additionally, fish treated with CO (for example, as part of a gas mixture called "tasteless smoke") gain a fresher appearance and a red tint. Conflicting studies have shown that consumers rely primarily on the appearance, including the red color of meat or fish, when choosing which package to purchase, and alternatively, that consumers rely mostly on "sell by" dates. The meat industry, consumer groups, scientists, and policy makers disagree as to whether the use of CO in meat and fish packaging should be regulated by the Food and Drug Administration (FDA) and the United States Department of Agriculture (USDA), through labeling or otherwise, and whether CO should be a substance Generally Recognized As Safe (GRAS) under current and proposed FDA rules. The meat industry, some scientists, and other supporters argue that MAP reduces shrinkage of the meat, allows for a longer shelf life, "keep[s] meat fresh, protect[s] meat, [and] prevent[s] cross-contamination" because MAP packages are tamper resistant and leak-proof. One scientist believes that MAP offers "better flavor, greater tenderness, and suppression of bacterial growth." Supporters of MAP also assert that such products are more sustainable, less wasteful, and more flexible in terms of distribution because more packages can be transported per truck. Additionally, they note that consumers prefer the bright red color of meat achieved in MAP. Finally, MAP system supporters dispute the scientific basis for claims that the use of carbon monoxide is misleading or dangerous and declare the consumers use "sell by" dates when determining the freshness of many products. Opponents allege that the use of CO misleads consumers into thinking meat and fish are fresher than they are; that certain populations, such as those with a reduced sense of smell, will be at increased risk if they consume spoiled meat or fish that still appears fresh due to the use of CO; that consumers may eat undercooked meat because meat packed in MAP systems may brown faster when cooked than untreated meat; that "sell by" dates are not adequate to assist consumers in determining freshness; that consumers will be exposed to CO; that such MAP products are misbranded and adulterated under the Federal Food, Drug, and Cosmetic Act; and that the FDA is violating its own regulations on CO. Another concern of consumer groups and some scientists is that CO provides a cover for spoiled or "temperature abused" meat and fish, meaning that the use of CO conceals visual cues of decomposition caused in part by exposure to changes in temperature or storage or transport at improper temperatures. Fish, such as tuna, may develop toxic levels of scombrotoxin (histamine) through time and/or temperature abuse, which can make consumers ill. Opponents of the use of CO on meat and fish note that the European Union, Canada, Singapore, and Japan have prohibited or decided not to recognize or approve CO for use in fresh meat or fresh fish packaging. Additionally, certain grocery store chainsâincluding Giant, Safeway, Kroeger, and Publixâeither do not sell or have announced that they will no longer sell MAP products. Others have taken different steps. At a March hearing, a Target Corporation executive testified that its primary meat supplier had received approval from FSIS to add a label to its packaging that would state: "Color is not an accurate indicator of freshness. Refer to Use or Freeze By [date]." Both the FDA and USDA play a role in food safety and the types of substances that can be added to food. This section will focus on the FDA's regulation of food additives and GRAS substances, which the agency is responsible for under the Federal Food, Drug, and Cosmetic Act (FFDCA) and parts of Title 21, Code of Federal Regulations. FFDCA Â§ 201(s) defines a food additive as: any substance the intended use of which results or may reasonably be expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of any food (including any substance intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food; and including any source of radiation intended for such use).... The latter half of the above definition includes "food contact substances," which the FFDCA defines as "any substance intended for use as a component of materials used in manufacturing, packing, packaging, transporting, or holding food if such use is not intended to have any technical effect in such food." The definition of food additive excludes certain classes of substances: (1)Â pesticide chemical residues in or on a raw agricultural commodity or processed food, (2) pesticide chemicals, (3) color additives, (4) substances used in accordance with their sanction or approval under FDA and USDA laws prior to 1958, (5) new animal drugs, (6) dietary ingredients in dietary supplements, and (7) substances GRAS under the conditions of the substances' intended use. These seven categories of substances are exemptions to FFDCA Â§ 201(s) and do not have to obtain FDA approval as food additives before they can enter the market. If a food additive does not meet one of the exemptions under the FFDCA, a rule must be in place that details the circumstances under which the food additive can be safely used. GRAS substances must be "generally recognized, among experts qualified by scientific training and experience to evaluate [their] safety." FDA regulations recognize the difficulty of establishing the harmlessness of a substance and therefore define safety as "a reasonable certainty in the minds of competent scientists that the substance is not harmful under the intended conditions of use." The person seeking GRAS status for a substance has the burden of proving the substance is GRAS under conditions of the substances' use. A determination that a substance has GRAS status is not limited to FDA scientists. Experts may base their view of a general recognition of safety on either (1) scientific procedures or (2) common use of a substance in food prior to January 1, 1958. The first type of GRAS substances is those that have "been adequately shown through scientific procedures ... to be safe under the conditions of [their] intended use." Scientific procedures include published and unpublished human, animal, analytical, and other scientific studies that are "appropriate to establish the safety of a substance." A GRAS determination based on scientific procedures "require[s] the same quantity and quality of scientific evidence as is required to obtain approval of a food additive regulation for the ingredient." The GRAS determination must "ordinarily" be based on published studies, but can be corroborated by unpublished studies and other information. FDA regulations do not require a unanimous opinion from the scientific community that a substance is GRAS under the conditions of its intended use; rather, the person seeking GRAS status "must show that there is a consensus of expert opinion regarding the safety of the use of the substance." However, "a severe conflict among experts regarding the safety of the use of a substance, precludes a finding" that a substance is GRAS. The second type of GRAS substances is those that were "used in food prior to January 1, 1958, [and shown] through either scientific procedures or experience based on common use in food[] to be safe under the conditions of [their] intended use." FDA regulations define the phrase "common use in food" as "a substantial history of consumption of a substance for food use by a significant number of consumers." In this instance, a GRAS determination ordinarily turns on "generally available data and information." These substances are known as prior-sanctioned substances. They can include substances used in food where the use prior to January 1, 1958, "occurred exclusively or primarily outside of the United States if the information about the experience establishes that the use of the substance is safe." Published information regarding substances used outside the United States must be corroborated. The FDA lists some GRAS substances in 21 C.F.R. Part 182. However, this list of GRAS substances is not exhaustive as "[i]t is impracticable to list all substances that are [GRAS] for their intended use." The list of GRAS substances in 21 C.F.R. Part 182 includes spices, essential oils, natural extracts, synthetic flavoring substances, substances that migrate from dry food packaging and paper products, multipurpose substances, anticaking agents, chemical preservatives, emulsifying agents, stabilizers, sequestrants, and nutrients. The FDA Commissioner can affirm the GRAS status of a substance based on a petition from a manufacturer or others or on his or her own initiative. Substances affirmed as GRAS, listed in 21 C.F.R. Part 184, differ from the GRAS substances listed in Part 182 because their GRAS status has been sustained through a notice-and-comment rulemaking. The concept of affirming the GRAS status of substances began in 1969, when questions arose about whether cyclamate salts, a substance that had been considered GRAS, were safe because "they were implicated in the formation of bladder tumors in rats."