Monitoring

The first component of in-market surveillance, the monitoring component, involves procedures to detect adverse effects to infants after a formula has been put on the market. As discussed above, the probability that negative effects will emerge during in-market monitoring is likely to be quite small if the appropriate preclinical and clinical studies detected no negative effects associated with the introduction of a new ingredient to an existing formula. However the number of infants enrolled in clinical trials is small in relation to in-market use, and the trials may not detect a full range of variations. For this reason it is important to integrate in-market monitoring procedures into the evaluation process to judge the safety of new ingredients introduced into infant formulas.

Follow-up

The second component of in-market surveillance, the follow-up component, is one that is less often considered during clinical trials to assess the safety of new ingredients added to infant formulas. In contrast to in-market monitoring, which focuses on adverse effects occurring during the period of maximum formula usage, in-market follow-up concentrates on possible long-term adverse effects after the period of maximum formula usage. The length of a follow-up study will depend upon the nature of the ingredient, so the expert panel should define it on a case-by-case basis. As described later in this chapter, higher levels of assessments should be performed when the ingredient may affect slow-developing brain regions, hormone or neurotransmitter function, or behavior. In addition, follow-up during critical life transitions, such as entry into school or onset of puberty, should be emphasized.

Most clinical studies are confined to a short amount of time for the period of maximum exposure to the formulas, and they track adverse patterns only during the time of maximum exposure. However there is also the possibility that the new ingredient’s negative effects on the growth and development of children may have delayed onset and only appear later in life. Evidence from a number of sources supports the validity of this statement. First, there are both preclinical and clinical studies that document long-term cognitive and behavioral effects of early exposure to toxic substances (Galler and Tonkiss, 1998; Jacobson and Jacobson, 2000; Leech et al., 1999; Leviton et al., 1993; Richardson, 1998; Richardson et al., 1996; Romano and Harvey, 1998; Wasserman et al., 2000).

More critically, although the overall pattern of evidence is not totally consistent, there are a number of examples from both the clinical and preclinical research literature where negative effects of early exposure to toxic substances were not found upon initial testing, but did appear during follow-up assessment (Weiss, 1995; Winneke, 1990). Toxic substances that do not show their effects until well after the period of exposure to the substance have been labeled as chemical or neurobehavioral “time bombs” (Russell, 1990; Spencer, 1990). Delayed effects have been shown for prenatal or early postnatal exposure to drugs, alcohol (Griffith et al., 1994; Singer et al., 2002), and lead (Bellinger et al., 1991). Although not directly related to toxic exposure, epidemiological studies have also indicated that there may be delayed long-term adult biomedical consequences as a result of the quality of very early nutrition (Barker et al., 1993; Jackson, 2000) or of the level of morbidity in the first year of life (Bengtsson and Lindstrom, 2000).

There are a number of mechanisms through which a delayed impact of early exposure to toxic substances might occur. One involves cumulative effects. Biologically, cumulating intake of a low-level toxin can result in the gradual replacement of a specific neurotransmit-



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