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From page 70... ... The committee recommends implementing a flexible, two-level assessment approach to help guide the expert panel's decisions on the appropriate preclinical studies (including preanimal tests; absorption, distribution, metabolism, and excretion studies; toxicity studies; and neurological studies) to assess the safety of ingredients new to infant formulas. Read the entire page →
From page 71... ... INTRODUCTION This chapter describes the importance and the unique aspects of conducting preclinical studies to assess the safety of infant formulas. Current regulatory guidelines for preclinical studies are described, and a two-level assessment process is proposed. Read the entire page →
From page 72... ... In other words, the general approach is to deal with the targeted ingredient, as well as the nontargeted compounds, such as metabolites of the targeted ingredient, the vehicle required for delivery of the targeted ingredients, and impurities introduced in the manufacturing process. CURRENT REGULATORY GUIDELINES FOR PRECLINICAL STUDIES In considering how to construct guidelines for preclinical studies of ingredients new to infant formulas, the committee drew on existing guidelines for the testing of food ingredients and infant formulas. Read the entire page →
From page 73... ... Health Canada refers manufacturers to internationally accepted guidelines for preclinical testing or asks to be consulted because decisions are made on a case-by-case basis. OVERVIEW OF RECOMMENDED LEVELS OF ASSESSMENT RECOMMENDATION: A hierarchy of two levels of preclinical assessment, using tech niques from cellular-molecular studies through whole-animal studies, should be imple mented to assess the safety of ingredients new to infant formulas on developing organ systems: � Level 1 assessments. Read the entire page →
From page 74... ... Organ level studies - Gastrointestinal tract No - Hepatic - Renal - Hematology - Immune - Endocrine - Neurologic 5 Any positive test for toxicity or concern for Yes safety? No 6 10 7 DISCONTINUE Neurological Safety Assessment DISCONTINUE PROCESS (See Figure 5-2) Read the entire page →
From page 75... ... No 4 Any evidence of adverse effect/event or concern Yes for safety? No 9 6 5 Continue to clinical Re-evaluate results before DISCONTINUE studies considering clinical trials PROCESS FIGURE 5-2 Proposed levels of preclinical assessment algorithm. Read the entire page →
From page 76... ... The production of metabolites can also be followed upon adding TABLE 5-1 Examples of Potential in vitro Tests to Assess Genetic Toxicity Test Name Function of Test Reference Ames test Microsome reverse mutation Aeschbacher et al., 1983 Mouse lymphoma Genetic forward mutations McGregor et al., 1987, 1988a, thymidine kinase gene 1988b; Myhr and Caspary, mutation assay 1988; Myhr et al., 1990 Mammalian erythrocyte Micronuclei deletions, chromosomal Schlegel and MacGregor, 1982; micronucleus test aberrations Schlegel et al., 1986 Polymerase chain reaction Changes in gene expression and Innis, 1990 deoxyribonucleic (DNA) sequence, polymorphisms, point mutations DNA microarraya Identifies genes that are up or down Cohen et al., 2002; Daniel, 2002; regulated DeRisi and Iyer, 1999; Guengerich, 2001; Lee et al., 2000; Moreno-Aliaga et al., 2001; Perou et al., 1999; Wang, 2000; Williams, 1999 Proteonomicsa Identifies proteins that are altered Anderson and Anderson, 1998; after exposure to the ingredient Bogyo and Hurley, 2003; Govorun and Archakov, 2002; Hochstrasser, 1998; Jungblut et al., 1999; MacBeath, 2002 Bioinformaticsa ? Read the entire page →
From page 77... ... and should be consulted. CONDUCTING ANIMAL TOXICITY STUDIES Several toxicity studies must be performed in animals to ensure the safety of ingredients new to infant formulas (see Figure 5-1, Box 4) Read the entire page →
From page 78... ... The nonhuman primate and the piglet are more amenable for these types of studies because they readily accept infant formulas as a nutrient source. The advantages and disadvantages of using each of these animal models is discussed below and summarized in Table 5-12. Read the entire page →
From page 79... ... . These studies generally show that infant formulas enriched with LC-PUFAs and fed to neonatal pigs result in increased incorporation of these fatty acids into neuronal membranes and myelin. Read the entire page →
From page 80... ... . For example, the GRAS Notification by Martek for the addition of LC-PUFAs to infant formulas lists multiple toxicity protocols involving rats (Hahn, 2000) Read the entire page →
From page 81... ... The committee proposes the addition of developmental toxicity studies to the assessment of ingredients new to infant formulas in addition to the recommended guidance in the Redbook. Read the entire page →
From page 82... ... In the evaluation of ingredients new to infant formulas, the latter consideration is less relevant since pregnant mothers do not consume these ingredients. The main manifestations of an effect on the developing organism are death, structural abnormality, altered or retarded growth, and functional deficiency. Read the entire page →
From page 83... ... Organ-Level Studies Examination of organs from the selected animal models can reveal important information concerning the effects of ingredients at the organ level. Different compounds will have different effects on the different organs and, as discussed earlier in this chapter, the general approach to evaluate the effect of new compounds added to infant formulas, as well as other material, should therefore be driven by the class of the functional substance and by the full characterization of the ingredient. Read the entire page →
From page 84... ... Renal Function The kidney is the major excretory organ and also serves a role in blood pressure homeostasis. Ingredients new to infant formulas or their metabolites may be excreted by the kidney and may potentially damage the glomerular or reno-vascular function of the organ. Read the entire page →
From page 85... ... aALAT = alanine amino transferase, ASAT = aspartate amino transferase, LDH = lactate dehydrogenase, LDL = low-density lipoprotein, VLDL = very low-density lipoprotein, HDL = high-density lipoprotein. Hematological Function Ingredients new to infant formulas or their metabolites may have profound effects on the bone marrow. Read the entire page →
From page 86... ... . Because the immune system of the infant is essentially complete, animal models that predict adult allergic responses can also serve as models for infants. Read the entire page →
From page 87... ... CONDUCTING NEUROLOGICAL TESTS Background As explained in detail in Chapter 6, there are important reasons to include neurological tests in safety assessments of new ingredients for infant formulas, including the sensitivity of Read the entire page →
From page 88... ... growth and development to toxic substances and the long-term predictive value of behavioral measures. Therefore the scope of work defined for this project placed special emphasis on the potential effects of ingredients to be added to infant formulas on the rapidly developing infant brain. Read the entire page →
From page 89... ... Protein, energy, iron, zinc, selenium, iodine, folate, vitamin A, choline, and LC-PUFAs are nutritional components that influence early brain development with measurable clinical effects in humans and animal models (Georgieff and Rao, 2001) Read the entire page →
From page 90... ... Preclinical studies should assess the neurological safety of the nutrients by measuring the physiological and pharmacological levels of the nutrients. The goal is to match structural and biochemical alterations to changes in function (e.g., behavior) Read the entire page →
From page 91... ... . The following sections describe various techniques for using preclinical studies to assess the effect of ingredients new to infant formulas on the developing brain. Read the entire page →
From page 92... ... MRI can be used in the developing human and all typical animal models to assess nutrient effects on total brain volume, regional volumes, myelination, and the visualization of some nutrients (for review, see Casey et al., 2001) Read the entire page →
From page 93... ... However many compounds being considered for addition to infant formulas (e.g., choline) are likely to have a significant impact on these systems and will require this type of assessment. Read the entire page →
From page 94... ... SUMMARY Preclinical studies are a vital first step to assess the safety and quality of ingredients new to infant formulas. Regulatory guidelines for preclinical studies must be based on considerations of the diversity of the potential new ingredients and the ingredients' source and matrix. Read the entire page →
From page 95... ... 1992. Human milk and formula fatty acids. Read the entire page →
From page 96... ... 1988b. Responses of the L5178Y tk+/tk� mouse lymphoma cell forward mutation assay to coded chemicals. Read the entire page →
From page 97... ... 2001. Effects of delta5 polyunsaturated fatty acids of maritime pine (Pinus pinaster) Read the entire page →

From page 70...

... The committee recommends implementing a flexible, two-level assessment approach to help guide the expert panel's decisions on the appropriate preclinical studies (including preanimal tests; absorption, distribution, metabolism, and excretion studies; toxicity studies; and neurological studies) to assess the safety of ingredients new to infant formulas.