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2 Defining Safety for Infants ABSTRACT “Safety” refers to a reasonable certainty of no harm and is described by noting a range along a continuum, rather than as an absolute point or value (Food Addi- tives Amendment, P.L. 85-929 of the Federal Food, Drug and Cosmetic [FD&C] Act, 21 U.S.C. §301). The relationship between biology and safety is mediated through the concepts of harm, benefit, and risk. Manufacturers may propose the addition of a new ingredient to infant formulas by demonstrating the safety, not the efficacy (the capacity to produce an intended effect under the realistic situation of product use), of the proposed ingredient. Foods are generally considered to be inherently efficacious (with inherent sensory proper- ties and nutrition) and, thus, efficacy is not a consideration in their safety assess- ment. In the case of infant formulas, this assumption is modified to some degree because it has been proposed that the products must be capable of sustaining physi- cal growth for a specified period of time. Currently, however, manufacturers are not required to demonstrate the benefits of an individual ingredient in the product. In- fancy is a uniquely vulnerable period that complicates the interpretation of safety guidelines. Not all organ systems are fully mature at birth, and as they undergo further development they are highly susceptible to nutritional inputs, illnesses, care practices, and other environmental inputs. Early infancy represents a period of growth and development when a successful outcome depends on the timely emer- gence of critical structures and developmental processes. The gastrointestinal, renal, and immune systems, as well as brain and neurological functions, could be affected by exposure to potentially harmful substances contained in infant formulas. Optimi- zation of nutrition and minimization of exposure to potentially harmful substances in the food supply is of heightened importance during infancy. The committee con- cluded that there are six issues that must be considered as important safety issues when regulating infant formulas: (1) infant formulas are the sole or predominant source of nutrition for many infants, (2) formulas are fed during a sensitive period of 29

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30 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS development and may therefore have short- and long-term consequences for infant health, (3) animals may not be the most appropriate model on which to base deci- sions of safety, (4) “one size fits all” food safety models may not work for all new additions to formulas, (5) infant formulas could be considered as more than just food, and (6) potential benefits, along with safety, should be considered when add- ing a new ingredient to formulas. INTRODUCTION A discussion on guidelines to ensure the safety of ingredients new to infant formulas requires a broad understanding of the concepts and models of safety regulations and an in- depth review of infancy as a unique period that requires unique safety measures. This chapter describes fundamental concepts of safety regulations, statistical considerations in assessing food safety, models of safety assessment (including the Novel Foods model of Health Canada), and special considerations for ensuring the safety of infants and regulating infant formulas. U.S. REGULATORY AGENCIES Several federal, state, and local agencies monitor the safety and quality of substances that are ingested and inhaled by the general public. Each agency operates within its own domain using its own set of rules and procedures, but the agencies work collaboratively on some issues to ensure the safety and quality of food, water, and air. The Food and Drug Administration (FDA) has the primary responsibility for regulating ingredients new to infant formulas and other agencies serve in peripheral roles. FUNDAMENTAL CONCEPTS OF SAFETY REGULATIONS The terms safety, hazard, risk, harm, and benefit are central to the full understanding of safety assessment. Safety refers to a reasonable certainty of no harm (21 U.S.C §348) (e.g., for food ingredients in the U.S. regulatory system) or, in some systems (e.g., for pharmaceu- tical drugs in the U.S. regulatory system), a reasonable balance between costs (harm) and benefits. Safety is an intellectual concept; it is not an inherent biological property of a substance. Safety is described by noting a range along a continuum, not an absolute point or value. The relationship between biology and safety is mediated through concepts of harm, benefit, and risk. As such, the concept of safety and its assessment is influenced by many different organizations, individuals, and intellectual disciplines. A hazard generally refers to some substance or combination of substances (organic or inorganic, or in some cases psychological) that may, under some circumstances or for some individuals, produce undesired health-related outcomes. Nearly any substance can have the potential to produce an undesired health outcome to some individual under some circumstance. Exposure to a hazard, however, does not guarantee that an undesired outcome will occur. The likelihood that such an outcome will occur given exposure to a hazard is what is referred to as the risk of that hazard. The risk of a hazard is not a general (main effect) property of the substance, but rather it is an interaction between the nature of the hazard, the circumstances of the exposure (e.g., the magnitude, the timing, and the specific features of the individual, such as health status, age, and susceptibility), and other such conditions that moderate the actual health impact of the hazard. Harm refers to the nature of the undesired outcome (usually a health outcome) associ-

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31 DEFINING SAFETY FOR INFANTS 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 popula- tion 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 con- sumer 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 regula- tion on manufacturers. Once laws are enacted, regulatory agencies are entrusted with the responsibility of developing, implementing, and enforcing regulations. STATISTICAL CONSIDERATIONS IN FOOD SAFETY DETERMINATION Among adults, guidance concerning the clinical relevance of differences in some physi- ological 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 suffi- cient evidence to inform clinical judgment. Investigators must determine whether a differ- ence (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, nutri- tional 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, includ- ing 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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32 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS applies a set of principles for establishing a “rule of evidence” in scientific inquiry. In the simplest terms, NHST provides a set of rules for decision making under uncertainty. First, a set of two mutually exclusive alternative conditions is specified. For example, the addition of substance X to an infant formula either: (a) hinders the ability of the infant to maintain proper physical growth, or (b) it does not hinder proper physical growth. Second, a set of risk probabilities are specified (the “alpha level” of the test and the “power” of the test), which allows the researcher to control the probabilities of drawing an incorrect infer- ence. Third, a set of assumptions is specified that, taken together with the null and alterna- tive hypotheses, allow the complete specification of the behavior of some statistical index. From this model one can specify a set of decision rules to draw some conclusions based on the empirical results of the experiment. The result of such a statistical test procedure does not establish with certainty the “true state of nature,” but rather it expresses a degree of confidence that one of the two states is not likely to occur. The randomized clinical trial and associated NHST are the mainstays of certain safety and efficacy approaches, such as the FDA drug trials described later, but they have certain potential limitations in their applica- tion to the safety of ingredients new to infant formulas. The first limitation is that NHST lacks a certain degree of direct applicability. The basic concept underlying the safety of an ingredient added to infant formulas is the “reasonable certainty of no harm” concept without a requirement for the demonstration of benefit. NHST, however, is generally formulated to demonstrate the superiority of one condition versus an- other. The fundamental idea in the formulation of reasonable certainty of no harm is one of equivalence, not of difference. While one can manipulate the null and alternative hypothesis in this circumstance (e.g., to make the “no difference” condition the alternative hypothesis), the resulting formulation is awkward and shifts the probabilistic control of the important error rate to that of power rather than to the more direct alpha level of the resulting test. Due to its highly unusual nature, it is likely that this test’s results will not be properly understood and interpreted. The second limitation is that NHST is concerned with demonstrating a difference rather than with the size or importance of the difference. In a number of scientific disciplines, most notably psychology, there has been a shift in emphasis from statistical significance to clinical significance. When formulated as clinical significance, the question becomes whether the difference that is detected by NHST is one that has any practical health consequences from the perspective of the individual receiving the treatment. Thus it is recognized that while a very small (potentially clinically inconsequential) difference can be detected by NHST (par- ticularly in very large samples), the most important question is to determine whether the difference has any health implications. In order to address these different questions, a number of approaches to testing have been adopted that include the following features: • a greater focus on effect size estimates, • the use of confidence intervals as the primary way of reporting the results of experi- ments, and • the use of alternative statistical tests that are not based on the sample mean as the primary way of characterizing populations. One approach to determine clinical significance is the use of dominance statistics (Cliff, 1993). In this approach it is asked, in a probabilistic manner, how likely is it that an individual chosen at random from the group receiving treatment A will score better than an individual chosen at random from the group receiving treatment B. Using the dominance

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33 DEFINING SAFETY FOR INFANTS statistic approach, the question of weight maintenance might be approached as determining the probability that an infant drawn at random from a group consuming the new formula would weigh less than an infant drawn at random from a group fed the existing formula. If this probability were not too extreme, it might argue for the safety of the new addition relative to that of a formula without that addition. An alternative approach to NHST may also be considered. For example, Seaman and Serlin (1998) developed methodologies that allow the direct demonstration of equivalence (as opposed to the subtly different approach of NHST that is oriented to showing differ- ences). Such approaches may be applied to establish rules to determine the safety of ingredi- ents new to infant formulas. In assessing the safety of ingredients new to infant formulas, investigators must consider whether the NHST approach is the most appropriate method to analyze empirical data or whether an approach that more directly assesses effect sizes, clinical significance, domi- nance, or equivalency is preferred. Of particular importance in the selection of a proper analytical technique is the question of whether any decrease in infant growth rate can be tolerated. If slower growth rates or other minor differences in physiology or function cannot be tolerated, then investigators may wish to demonstrate equivalency, rather than merely detect differences. In addition, the error rate that one is willing to tolerate must be carefully considered rather than routinely adopting the traditional 0.05 alpha level. It is the alpha level that indicates the “societal” values for the acceptance of risk and harm. MODELS OF SAFETY ASSESSMENT Virtually all other models used to assure the safety of ingested or inhaled substances are variations of the food and drug safety models (described below): the nutrients model based on dose-response relationships; the in-market monitoring and surveillance model; the novel foods and food additives models, based on a reasonable certainty of no harm; and the drug model, based on risk-benefits assessments. Food Models Nutrients Model The Dietary Reference Intakes (DRIs) are a set of quantitative reference values for nutrient intake to be used for planning and assessing diets, and they are based on risk assessments. One of the DRIs, the Tolerable Upper Intake Level (UL), uses risk assessment approaches. The UL uses a substantially different approach from the one used for food additives in that it does not address any particular food product or ingredient, yet it provides useful information on the magnitude of intake of nutrients for individuals as a function of age, gender, pregnancy and lactation status, and other such factors. At the heart of the DRI methodology is a dose-response relationship (e.g., the examination of a targeted health outcome as a function of the intake of the nutrient in question). The UL is the level of intake at which one would expect virtually no risk of an adverse health outcome for almost all healthy individuals in the population. There would be an increased risk of an adverse health outcome if more than the UL were consumed. The actual risk assessment methodology of the DRI approach is quite complex; it is described in Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients (IOM, 1998) and in each of the nutrient-specific DRI reports, most recently in Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate (IOM, 2004).

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34 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS In-Market Monitoring and Surveillance A different approach to ensuring food safety is in-market monitoring and surveillance. For instance, once an infant formula is released for general consumption, FDA requires that the manufacturer maintain and analyze records of consumer complaints. Further, the manu- facturer is required to report to FDA cases where the evidence suggests a reasonable possibil- ity of a link between consumption of the formula and an infant illness, death, or a reduction in intake of required nutrients. This is currently a passive system that merely requires that a caregiver report a suspected case, but it is one more mechanism by which the safety of infant formulas can be monitored. Details of in-market monitoring and surveillance are discussed in Chapter 7. Novel Foods Model In 1994 Health Canada issued the Guidelines for the Safety Assessment of Novel Foods (Health Canada, 1994) to assist in the design of premarket notifications for novel foods. The manufacturer must submit a request to Health Canada 45 days prior to the sale or advertis- ing for sale of any novel food under specific requirements laid out in Division 28 of the Food and Drug Regulations (Canada, 2001). Where it is determined that data of a scientific nature are required to support the safety of the product, a safety assessment may include an evaluation of microbiological, molecular, chemical, nutritional, and toxicological endpoints in preclinical and clinical studies. Specifically, the assessment may evaluate the process used to develop the novel food (molecular, chemical, and microbiological), the comparison of the characteristics of the novel food with that of its traditional counterpart (nutritional and toxicological), safety issues related to a source with no history of use in the food supply (nutritional and toxicological), and the potential allergenicity from proteins introduced into the food (nutritional). Health Canada may request additional information to assess the safety of the novel food and, if satisfied, will notify the manufacturer that the information is sufficient and the product is safe for consumption. Food Ingredients Model The food safety evaluation of food ingredients and associated regulations in the United States is based on “reasonable certainty of no harm.” Sections 201(s), 201(z), 409, and 412 of the FD&C Act and FDA’s Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, also known as the Redbook1 (OFAS, 2001, 2003), are the regulations and guidelines that are used to assess the safety of food ingredients and infant formulas. Regulatory oversight of the addition of new ingredients to infant formulas is governed largely by two processes: the Food Additive Petition and the Generally Recognized as Safe (GRAS) Notification. It is important to note that these procedures are to ensure the safety (a reasonable certainty of no harm)—not the benefits—of the proposed ingredient. A food additive is any product added to a food that is not generally recognized as safe by qualified experts (see Box 4-1 in Chapter 4 for the complete definition). The food additive petition 1This FDA document should not be confused with the American Academy of Pediatrics’ Red Book of childhood infectious diseases.

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35 DEFINING SAFETY FOR INFANTS process requires that the manufacturer file a petition with FDA that provides all available data on the safety of the product and proposes the conditions under which such an additive may be safely used. FDA may issue a safety declaration upon review of the petition. In this case it is FDA that makes the affirmative declaration of the safety of the additive in the context of its proposed use. By contrast, the GRAS Notification process requires that the manufacturer make the initial declaration of the safety of the product based on consensus by qualified experts. FDA then reviews the notification and, if all of its questions are satisfactorily answered, the agency issues a letter of no objection. Because this process has become the primary route of introduction of new ingredients to infant formulas, the GRAS Notification process is re- viewed in greater detail in Chapter 4. Infant formulas are the sole source of nutrition for many infants and, therefore, one step is required for the approval of modifications to formulas that is not required for other foods. Manufacturers seeking to market a new infant formula need to comply with regulations under Section 412 of the FD&C Act. New regulations under that section of the FD&C Act have been proposed that would require manufacturers to demonstrate that the formula containing the new ingredient in the matrix in which the product is delivered is capable of sustaining physical growth and development over 120 days, the period when the formula is likely to be the sole source of infant nutrition. In 1982 FDA issued, and later updated, the Redbook (OFAS, 2001, 2003).2 These guidance documents were prepared to assist in the design of protocols for animal studies conducted to test the safety of food ingredients and include detailed guidelines for testing the effects of food ingredients on mothers and their developing fetuses. However, due to the special conditions surrounding infancy described below, special considerations need to be taken into account when applying the Redbook in the case of infant formulas. As mentioned previously, since virtually all models of safety determination are based on empirical evidence, only minor variations of the basic models seen in the FDA food safety determination system are possible. These differences are based more upon emphasis and implementation than on any profound differences in methodology. One major exception to this uniformity is the food safety model based upon the “reasonable certainty of no harm” concept. As opposed to other models where benefits from the addition of the new ingredient need to be demonstrated, in that model safety is seen as no harm and no proof of beneficial effects is needed. As discussed further in Chapter 4, the committee believes that for infant formulas, the concepts of efficacy (benefit) and safety are not always mutually exclusive because of the uniqueness of the infant population and, therefore, potential benefit should be considered when allowing new ingredients to be added to infant formulas. Drug Safety Model Structurally the FDA drug approval process closely resembles the food additive model of food safety. A manufacturer that wishes to market a new drug submits a petition to FDA, 2The original Redbook (Redbook I) was published in 1982, revised in 1993, and updated in 2001 (draft Redbook II). In 2000, FDA released a revised version of the publication as Redbook 2000: Toxicological Prin- ciples for the Safety Assessment of Food Ingredients. However, some chapters in Redbook 2000 have not yet been revised, so both the draft Redbook II and Redbook 2000 are used as guidance documents when conducting animal studies. Appendix C lists the contents of the draft Redbook II and Redbook 2000 and indicates which chapters in Redbook 2000 have been updated.

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36 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS along with a specified set of empirical evidence concerning the product. FDA (with advice from an established panel of experts) evaluates the evidence and, if satisfied that the drug meets its regulatory criteria, approves the drug for commercial use. In the drug approval process, however, the evidentiary basis for the decision is quite different from that employed in the food additive model where evidence of benefit is not necessary. First, the applicant must offer evidence through one or more clinical trials of the efficacy of the drug. That is, there must be clear and cogent evidence that the drug does what it claims to do. In addition, it must be shown to have the same effect as the current standard treatment of the condition being studied. Second, side effects (e.g., adverse reactions) of the drug must be carefully studied and reported. The criterion for approval of the applicant product is then based upon an assessment of the benefit:risk ratio. Other Safety Models As noted above, virtually all other models used to assure the safety of substances ingested or inhaled are variations of the food and drug safety models. Given the number of regulated substances (e.g., air, water, lead) and the number of agencies charged with regulat- ing them at the federal, state, and local level, it is not surprising that numerous variations in safety determination practices exist. Most of these differences, however, are at the technical level rather than at the conceptual level (e.g., setting the standard for lead is conceptually very much like the establishment of upper boundaries in the DRI process). SPECIAL CONSIDERATIONS FOR INFANT FORMULAS Infancy as a Vulnerable Period Dealing with infancy makes interpretation of safety guidelines particularly difficult. Infancy is a period of very rapid development, and change is the rule rather than the exception. Infants are nonverbal and cannot report their own experiences, and parents may not be able to accurately interpret the signals that infants provide. It is reasonable to expect that any harmful effects from an ingredient might be subtle. Throughout this report, the committee describes the period of infancy as so special and the consequences of any harm so great that the public should be unwilling to tolerate any harm due to the addition of an ingredient new to infant formulas, even if there are benefits to most who would be exposed to the new ingredient. At birth, infants make a dramatic transition from a highly controlled prenatal environ- ment where oxygen and nutrients are delivered directly from the mother to infant via the blood supply, to one that involves enteral feeding and thus requires an efficient gastrointes- tinal system and coordination of a wide range of functions. Not all organ systems are fully mature at birth, and as they undergo further development, they are highly susceptible to environmental inputs. Early infancy represents a period of growth and development when a successful outcome depends on the timely emergence of critical structures and developmen- tal processes. At the same time, infancy is a period of heightened vulnerability to nutritional inputs, illnesses, care practices, and other environmental influences. Depending on the tis- sues involved and the timing and severity of insults, effects may be irreversible or the ability to compensate for differences may be limited. Furthermore, infants have a higher food consumption rate than adults when expressed on a per kilogram body-weight basis, and they typically rely on a sole nutrient source (human milk or milk substitutes) in the early months of life. Thus optimization of nutrition and minimization of exposure to potentially harmful

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37 DEFINING SAFETY FOR INFANTS substances in the food supply is of heightened importance during infancy. Examples of the various systems that could be affected by exposure to potentially harmful substances con- tained in infant formulas are described below. Gastrointestinal and Renal Function With the exception of exocrine pancreatic function and bile acid metabolism, the gas- trointestinal tract is anatomically and functionally fully developed in infants born at term, and dietary contents do not influence their development. Trophic factors can be found in human milk and in the gastrointestinal tract, but their function is unclear. As these factors are more fully identified and their structure, composition, and physiological effects under- stood, it is possible that one or several may have effects on infant organ systems. Similar to the gastrointestinal tract, development of renal function is not influenced by dietary content. Glomular filtration does not approximate adult values until about 3 years of age, and tubular reabsorption and urine acidification reach normal values at several months of age. However both are sufficient for healthy term infants, but contribute to fluid and electrolyte abnormalities in infants who are ill and in those who are fed an inappropriate diet. Immune Function The infant immune system is not fully mature at birth; it has deficits in the ability to prevent invasion of pathogens and to respond to antigens. Of particular concern in the context of ingredients new to infant formulas is the increased permeability of the gut mucosal barrier in the presence of inflammation or infection or if the integrity of the epithelial cell layer is disrupted. The increased permeability allows macromolecules to be absorbed, which stimulates allergic responses to food proteins. Brain and Behavior There is rapid development of both brain and behavior during the first year of life. Both subcortical and cortical central nervous system (CNS) structures mature and allow the appearance of critical developmental functions, such as visually guided reaching, face recog- nition and orientation toward faces, explicit and working memory, focused attention, and inhibitory control (Johnson, 2001; Nelson, 1995). The quality of the young infant’s nutri- tional intake can be an important influence on CNS development and function (Rao and Georgieff, 2000; Wauben and Wainwright, 1999). For example, iron deficiency anemia in the first year interferes with the development of functional CNS processes, such as alteration in the number of dopamine receptors or degree of myelination (Lozoff et al., 1998; Wauben and Wainwright, 1999). These functional changes in turn can have long-term cognitive and behavioral consequences that cannot be compensated for by subsequent nutritional inter- ventions (Lozoff et al., 1998). A similar process is also seen with regard to behavioral development. The infant’s increasing behavioral competencies and patterns of social-emotional functioning during the first year can impact upon critical developmental mediators, such as patterns of parent-child relations, stress reactivity, initiation of self-regulation skills, and extent of infant interactions with the larger environment (Gunnar, 2000; Ruff and Rothbart, 1996). Interference with the development of these critical mediators also can have long-term consequences for later functional competence (Wachs, 2000). Since a large proportion of the infant’s nutrition

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38 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS during the first year may be supplied by formulas, changes to formulas that impact upon normally occurring brain and behavioral developmental patterns can have potential long- term consequences. Important Safety Considerations Most of the principles that govern the safety of ingredients new to infant formulas derive from the same principles that govern food safety for older children and adults. The commit- tee concluded that the six issues described below and summarized in Box 2-1 must be considered as important safety issues when regulating infant formulas. 1. Infant formulas are the sole or predominant source of nutrition for many infants. Even for infants for whom formulas are a supplement to human milk, formulas can consti- tute a major source of nutrition. For infants, formulas represent a much larger percentage of the total nutritional intake than is any single substance for the older child, adolescent, or adult. Given the extremely high dependence on this one source of dietary input, safety rules based upon models deemed appropriate for persons with a wide range of dietary inputs may be inappropriate. 2. Formulas are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. The first 12 to 18 months of life is a period of extremely rapid growth and development for the human infant that is only begin- ning to be understood. The brain and neural system change dramatically during this period, as do other organ, cognitive, and social-emotional systems. These changes are thought to have long-range implications for the human—not all of which are expressed directly during infancy. The current safety models for infant formulas only look at relatively short-term outcomes and are narrowly limited to the maintenance of physical growth. 3. Animals may not be the most appropriate model on which to base decisions of safety. In the case of infants, limitations of using experimental animals as models are due not only to species differences, as in the case of adults, but also to developmental differences in animals versus infants. The differences in growth rates and the resulting differences in biological effects of ingredients could therefore accentuate the concerns that already exist when using animal models. Given these differences, animal models may not uncover possible threats to the long-term well-being of infants due to the addition of new ingredients; this issue is of critical significance if the models used are developmentally inappropriate. 4. “One size fits all” food safety models may not work for all new additions to formu- BOX 2-1 Important Safety Considerations When Regulating Infant Formulas 1. Infant formulas are the sole or predominant source of nutrition for many infants. 2. Formulas are fed during a sensitive period of development and may therefore have short- and long-term consequences for infant health. 3. Animals may not be the most appropriate model on which to base decisions of safety. 4. “One size fits all” food safety models may not work for all new additions to formulas. 5. Infant formulas could be considered as more than just food. 6. Potential benefits, along with safety, should be considered when adding a new ingredient to formulas.

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39 DEFINING SAFETY FOR INFANTS las. The basic models of food safety are based upon the assumption that nearly all individu- als function basically in similar ways with regard to the safety of substances in their diet (although there are gross subtypes with different dietary needs, such as premature infants and infants with food allergies). However it may be speculated that there are more subtle underlying subgroups (e.g., genetic subtypes) for which new substances may or may not have the same safety characteristics as they would for individuals not in those subgroups. In clinical trials the minimum sample size required to detect systematic group differences in response to a new ingredient is likely to be entirely inadequate for subgroup analyses. 5. Infant formulas could be considered as more than just food. The rules governing the safety of infant formulas are regulated under the logic of infant formulas being a “food product,” and there is no doubt that the primary purpose of infant formulas is nutrition. However infant formulas can also be seen as a potential delivery system for non-nutritional agents. This potential as a delivery system should cause one to consider the question of what are the appropriate (both legal and ethical) boundaries for additions to infant formulas. Consideration must be given to constructs that will appropriately set the limits and provide the definitions for an addition being “nutritional.” The presence of the substance in human milk may not be a sufficient definition of a nutritional substance, and other factors, such as whether the substance is produced from genetically modified sources, need to be considered. In addition, the regulatory steps to follow to ensure the safety of a substance whose purpose is non-nutritional (e.g., a substance whose purpose is to reduce infant discomfort) need to be determined. 6. Potential benefits, along with safety, should be considered when adding a new ingre- dient to formulas. Food products are generally considered to be inherently beneficial or efficacious (with inherent sensory properties and nutrition) and thus efficacy (i.e., health benefits) has not been a consideration in the safety assessment of foods. In the case of infant formulas, this starting assumption may be modified through the additional requirement in proposed regulations (FDA, 1996) that the product be capable of sustaining physical growth for a specified period of time, that is, it is already required that the final formulated product be demonstrated to be efficacious from the point of view of physical development. (This proposed requirement, however, is usually stated as a safety criterion rather than as an efficacy criterion, that is, a lack of efficacy would be a risk to the organism and therefore a safety concern.) Other than this proposed requirement for sustaining physical growth, however, the manufacturer would not need to demonstrate the benefits of any proposed new ingredient to infant formulas. Given the special circumstances of the use of infant formulas and the fact that is it virtually impossible to understand the long-term outcomes of adding any given ingredient (the clinical trials are, of necessity, of relatively short duration), prudence would seem to dictate that an ingredient not be added to an infant formula unless it can be shown that some benefit is accrued to the infant through its addition. Since the committee was not charged with addressing efficacy, it recommends that consideration be given to convening a group of experts to explore if benefit could be an appropriate requirement for adding a new ingredient to infant formulas. SUMMARY Infancy is a uniquely vulnerable period that complicates the interpretation of safety guidelines. Manufacturers may propose the addition of a new ingredient to infant formulas by demonstrating the safety of the proposed ingredient. They are not required to demon- strate the benefit of an individual ingredient in the product. Although the committee believes

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40 INFANT FORMULA: EVALUATING THE SAFETY OF NEW INGREDIENTS that, in the case of infant formulas, efficacy is an important consideration, the committee did not discuss this issue because it was beyond its charge. The six safety considerations discussed in this chapter are important when developing safety guidelines for adding ingredients new to infant formulas. In making recommendations in the chapters that follow, the committee considers these six special issues that set infant nutrition apart from that of toddlers, children, and adults. REFERENCES Canada. 2001. Departmental Consolidation of the Food and Drugs Act and the Food and Drug Regulations. Ottawa: Minister of Public Works and Government Services Canada. Cliff N. 1993. Dominance statistics: Ordinal analyses to answer ordinal questions. Psychol Bull 114:494–509. FDA (Food and Drug Administration). 1996. Current good manufacturing practice, quality control procedures, quality factors, notification requirements, and records and reports, for the production of infant formula. Proposed rule. Fed Regist 61:36153–36219. Gunnar MR. 2000. Early adversity and the development of stress reactivity and regulation. In: Nelson CA, ed. The Effects of Early Adversity on Neurobehavioral Development. The Minnesota Symposia on Child Psychology. Vol. 31. Mahwah, NJ: Lawrence Erlbaum Associates. Pp. 163–200. Health Canada. 1994. Guidelines for the Safety Assessment of Novel Foods. Ottawa: Food Directorate, Health Protection Branch, Health Canada. IOM (Institute of Medicine). 1998. Dietary Reference Intakes: A Risk Assessment Model for Establishing Upper Intake Levels for Nutrients. Washington, DC: National Academy Press. IOM. 2004. Dietary Reference Intakes for Water, Potassium, Sodium, Chloride, and Sulfate. Washington, DC: The National Academies Press. Johnson MH. 2001. Functional brain development in humans. Nat Rev Neurosci 2:475–483. Lozoff B, Klein NK, Nelson EC, McClish DK, Manuel M, Chacon ME. 1998. Behavior of infants with iron- deficiency anemia. Child Dev 69:24–36. Nelson CA. 1995. The ontogeny of human memory: A cognitive neuroscience perspective. Dev Psychol 31:723– 738. OFAS (Office of Food Additive Safety). 2001. Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food. Redbook II-Draft. Washington, DC: OFAS, Center for Food Safety and Applied Nutrition, Food and Drug Administration. OFAS. 2003. Redbook 2000. Toxicological Principles for the Safety of Food Ingredients. Online. Center for Food Safety and Applied Nutrition, Food and Drug Administration. Available at http://www.cfsan.fda.gov/ ~redbook/red-toca.html. Accessed November 19, 2003. Rao R, Georgieff MK. 2000. Early nutrition and brain development. In: Nelson C, ed. The Minnesota Symposia on Child Psychology. The Effects of Adversity on Neurobehavioral Development. Vol. 31. Mahway, NJ: Lawrence Erlbaum Associates. Pp. 1–30. Ruff HA, Rothbart MK. 1996. Attention in Early Development. Themes and Variations. New York: Oxford University Press. Seaman MA, Serlin RC. 1998. Equivalence confidence intervals for two-group comparisons of means. Psychol Methods 3:403–411. Wachs TD. 2000. Necessary but Not Sufficient. The Respective Roles of Single and Multiple Influences on Individual Development. Washington, DC: American Psychological Association. Wauben IP, Wainwright PE. 1999. The influence of neonatal nutrition on behavioral development: A critical appraisal. Nutr Rev 57:35–44.