ated with a hazard and is often expressed in terms such as cost. Not all harm is the same, and not all individuals would assess the same outcome as having equivalent harm.

Opposite harms are the benefits of the addition of substances. The ratio of costs to benefits is a critical unit in some safety assessment systems. Cost-benefit ratios may apply to individuals or groups. For example, an individual may benefit from a treatment but may experience side effects. Another example is the case of iron supplementation to reduce infant risk of anemia. Some or all of the infants within a group may benefit from receiving additional iron, while some may be harmed (e.g., experience constipation); on average, however, the population that benefits from iron fortification will be larger than the population that experiences harm.

Members of the general public, special interest advocates, lawmakers, scientists, leaders of government agencies, and industry representatives play significant roles in establishing safety guidelines. The public makes certain demands for lowering food safety risks (whether real or perceived risks as a result of misinformation) and expresses its concerns either through consumer organizations or through individual contact with appropriate government agencies. Consumer organizations may voice such concerns in a focused manner. Lawmakers weigh these concerns and, where appropriate, engage in debates that may result in new laws and regulations. In the process of establishing formal policy, other individuals and organizations often enter into the debate to influence the final statements of safety regulation. For example, scientists or professional organizations may contribute important information that derives from scientific studies, economists may provide information about the costs of implementing certain safety standards, and industry representatives may describe the impact of the regulation on manufacturers. Once laws are enacted, regulatory agencies are entrusted with the responsibility of developing, implementing, and enforcing regulations.


Among adults, guidance concerning the clinical relevance of differences in some physiological parameter (e.g., blood pressure) is derived from a body of accumulated evidence that provides a rationale for a clear definition of pathological state (e.g., hypertension). In testing an ingredient new to an infant formula, it is unlikely that investigators would detect any clear evidence of disease (which should have been ruled out by preclinical testing). Instead, more subtle differences in physiology or development may appear that lack sufficient evidence to inform clinical judgment. Investigators must determine whether a difference (e.g., level of growth) has an immediate health consequence for the infant and the level of difference that matters for the long term (e.g., a growth deficit associated with a particular ingredient rapidly disappears when other foods are added to the diet). In the absence of sufficient evidence for clinical judgment, investigators may be forced to utilize statistical or analytical approaches as the basis for making judgments about safety.

The process of establishing the safety of food products, especially infant formulas, is complex and requires empirical evidence from many disciplines. Each step in the process requires the application of the highest standards, whether using methods of bioassay, nutritional analysis, or basic chemistry. Eventually studies involving human subjects (particularly in the case of infants) must be conducted in order to demonstrate the product’s safety for the human consumer. Studies involving humans are almost always conducted as randomized clinical trials and standard methods of design and analysis are followed.

The most typical analytical approach to interpreting the data from scientific studies, including clinical trials, is the statistical significance test, also known as the null hypothesis significance test (NHST). This approach, which has recently come under much scrutiny and debate, formally

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