Postnatal Hepatobiliary and Gastrointestinal Systems Development and Impact on ADME.

Toxicity can result from variable target organ sensitivity and exposure based on postnatal development. Changes in the gastrointestinal tract (GIT) in neonates are driven by initial enteral feedings. These are important for nutrient uptake as well as drug disposition and include motility, expansion of enzyme and transporter function, permeability, intestinal microbiome, and species-specific maturation. Some aspects of GIT function do not mature until driven by increased dietary complexity. As with the GIT, postnatal hepatic maturation in the rat includes a variety of anatomic and functional changes that include refinements in the activities or expression of drug transporters and drug-metabolizing enzymes. These changes may impact rodent pharmacokinetics, nonclinical toxicity profiles, and estimation of safe pediatric doses. Pilot or dose range finding studies can help characterize and mitigate toxicity related to drug disposition, especially in juvenile rodents. Interpretation of developmental toxicity requires knowledge of developing systems in humans and nonclinical models.

Exploring the use of current immunological assays for the developmental immunotoxicity assessment of food contact materials.

The mammalian immune system is a highly complex, interactive network of cells that facilitates innate and adaptive immune responses. The neonatal immune system may be more susceptible to chemical perturbations than that of the adult. The effects of immunotoxicants during development may not be fully detected in toxicity studies performed on adult animals. Studies characterizing the ontogeny of the immune system in developing animals have shown that there are different critical windows of susceptibility to immunotoxicants. Developmental differences are evident among species compared to humans. Functional immune assays, such as the T-cell antibody dependent response assay, in rat models have been validated for use in the assessment of immunotoxicity with other assays. Recently, published studies have explored the feasibility of using additional techniques, such as in vitro studies using human whole blood cells or cell lines, mostly lacking either sensitivity or proper validation for regulatory purposes. However, some techniques may be developed further to enable translation of animal toxicity findings to human risk assessment of potential immunotoxicants. This paper summarizes the information on the developing immune system in humans versus rats and how the currently available assays might be used to contribute to the safety assessment of food contact substances.

Physiology of the Neonatal Gastrointestinal System Relevant to the Disposition of Orally Administered Medications.

A thorough knowledge of the newborn (age, birth to 1 month postpartum) infant's gastrointestinal tract (GIT) is critical to the evaluation of the absorption, distribution, metabolism, and excretion (ADME) of orally administered drugs in this population. Developmental changes in the GIT during the newborn period are important for nutrient uptake as well as the disposition of orally administered medications. Some aspects of gastrointestinal function do not mature until driven by increased dietary complexity and nutritional demands later in the postnatal period. The functionalities present at birth, and subsequent maturation, can also impact the ADME parameters of orally administered compounds. This review will examine some specific contributors to the ADME processes in human neonates, as well as what is currently understood about the drivers for their maturation. Key species differences will be highlighted, with a focus on laboratory animals used in juvenile toxicity studies. Because of the gaps and inconsistencies in our knowledge, we will also highlight areas where additional study is warranted to better inform the appropriate use of medicines specifically intended for neonates.

Safety assessment for octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)-propionate (CAS Reg. No. 2082-79-3) from use in food contact applications.

Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (CAS Reg. No. 2082-79-3), currently marketed as Irganox 1076 (I-76), is a sterically hindered phenolic antioxidant used in a variety of organic substrates, including those used in the manufacture of food contact articles. In 2012, the US Food and Drug Administration (USFDA), Office of Food Additive Safety (OFAS), initiated a post-market re-evaluation of the food contact applications of I-76. This project aimed to ensure that current dietary exposures from the use of I-76 in food contact articles are accurately captured and the safety assessment considered all relevant and available toxicological information. To accomplish these aims, the USFDA reviewed the available toxicological studies and chemistry information on food contact applications of I-76. Based on this in-depth analysis, a NOAEL of 64 mg/kg-bw/d (female rats) from a chronic rat study and a cumulative estimated dietary intake (CEDI) of 4.5 mg/p/d, was used to calculate a margin of exposure (MOE) of ∼850. We concluded that the previous and current exposure levels provide an adequate margin of safety (MOS) and remain protective of human health for the regulated uses.

Ten-year retrospective assessment of the performance of the Food Contact Notification (FCN) programme.

The Food Contact Notification (FCN) programme was authorised by the US Food and Drug Administration (USFDA) Modernization Act of 1997. Manufacturers may file FCNs for food contact substances (FCSs) not already authorised or pre-sanctioned by the USFDA by demonstrating a reasonable certainty of no harm for their intended uses. The Division of Food Contact Notifications (DFCN) 10-year Retrospective Assessment Group was formed to collect and develop metrics associated with the first decade of the FCN Programme and determine the extent selected aspects of the review process contributed to the effective FCN. Comparative analysis of 924 FCNs revealed that 76% become effective, 23% were withdrawn and 1% received a not accepted status. The focus of the Group was to identify factors impacting the likelihood of an FCN becoming effective.

Infant toxicology: state of the science and considerations in evaluation of safety.

Differences in the physiology and biological susceptibilities of adults and infants have led to growing interest in safety evaluation methods for exposures from infant formula packaging. In addition to potential physiological differences, infants aged 0-6 months may consume a sole source of food, infant formula or breast milk, and consume higher amounts of food relative to body weight compared to adults. While the duration of the exposure is short compared to the expected lifespan of the individual, it occurs during a period of important developmental processes. The purpose of this document is to (1) review key biological and exposure elements that may impact the evaluation of safety for food contact products intended for use by infants, (2) summarize the current reproductive and developmental toxicity testing protocols available, and (3) identify potential data gaps concerning this period of development.