Introduction

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It is well established that diseases associated with abnormal immune function, including asthma and common infectious diseases, are considerably more prevalent in the very young when compared to the adult population. A number of factors are thought to account for these differences. The most obvious are age-related differences in the integrity of the host's anatomical and functional barrier and general immuno-competency. During the last decade, however, experimental and clinical studies have also suggested that exogenous factors can influence immune-mediated diseases in the young. These factors include, among others, obesity, nutrition and, as will be the focus of the following chapters, certain therapeutic and environmental exposures. The latter is supported, in part, by the alarming observation that the number of children who develop allergic asthma has increased markedly over the past four decades, particularly in urban areas (e.g., Timonen and Pekkanen 1997; Akinbami and Schoendorf 2002; Thurston et al. 1997; Smyth 2002). This is further supported by a plethora of laboratory studies conducted in rodents, guinea pigs, and nonhuman primates which demonstrate that, while not a causative agent for asthma, air pollutants, such as ozone and diesel exhaust, exacerbate asthma to common protein allergens such as house dust mites (i.e., shift the dose response curve to the left) (e.g., Schelegle et al. 2003). Interestingly, it has been found that children living in rural environments (i.e., farming communities) are less likely to develop allergic asthma (Ehrenstein et al. 2000). This is thought due to high levels of endotoxin in their environment, which skew Th1:Th2 cells toward a predominant Th1 phenotype. Less studied from a clinical perspective, but equally alarming, are results from studies demonstrating increases in infectious disease in children following perinatal exposure to certain therapeutic or environmental agents. An important study in this area was conducted by Weisglas-Kuperus et al. (2000), who demonstrated that exposure to levels of halogenated aromatic hydrocarbons normally found in highly industrialized countries are associated with increases in childhood infections and lower vaccination responses. Clinical undertakings in this area are rare but, as detailed in many of the following chapters, are supported by extensive laboratory studies.

While these studies have drawn some concern, it was not until the landmark report prepared in 1993 by the National Research Council entitled "Pesticides in the Diets of Infants and Children" (NRC 1993) that the regulatory agencies expressed interest regarding children's health protection from agents that may potentially damage the immune system. The scientific basis for this concern stems not only from likely pharmacokinetic differences between the adult and neonate, which would not be unique for immunotoxicity, but also from the fact that the developing immune system, which can be thought of as beginning at conception and completed at puberty, differs inherently from the adult system in its biological and physiological responses to injury. Thus, it has been suggested that the developing immune system, by its nature, may be more sensitive to injury or the toxic effects may be more persistent when compared to adult exposure. Clinical effects may also be expressed immediately or later in life and be manifested as either increased infectious or neoplastic diseases resulting from immunosuppression or increased incidences/severity of allergic or autoimmune disease resulting from immune dysregulation. The specific type(s) of immunotoxicity that might ensue would not only be dependent upon the toxicokinetic properties of the particular agent but also the time of exposure, referred to as critical windows of development. The NRC report discussed the potential unique vulnerability of children to pesticides and argued for a more thorough assessment of children's health in risk assessment. This report was followed in 1996 by the Food Quality Protection Act (FQPA), which required EPA and other regulatory agencies that deal with pesticides to specifically consider children's health risks. Amendments to the Safe Drinking Water Act (SDWA) in the same year (1996) also emphasized children's health in setting health advisories for drinking water.

Following publication of the NRC report and passage of the FQPA, more attention was focused on the development, characterization, and standardization of methods for developmental neurotoxicity and reproductive toxicity assessment (e.g., Garman et al. 1993; Levine and Butcher 1990), while at least initially, assessment of the developing immune system was not addressed. This was not due to any notion that the developing immune system is any more or less vulnerable than other developing organ systems to toxic injury, but rather reflects the fact that immunotoxicity assessment, in general, represents a relatively new effort in toxicology and efforts in this area have traditionally followed behind those in other areas. During the last 5 years, a number of workshops have been held where experts have convened to present their research on the role of environmental factors in childhood asthma. These conferences have been useful as they have allowed identification of additional research needs and have been instrumental in spurring interest in the area. Regarding immunosuppression, a workshop was convened by ILSI/HESI in June 2001, which not only provided an opportunity for experts to present their findings but also allowed discussions to address specific questions that relate to developmental immunotoxicity tests and their interpretation for risk assessment (Sandler, 2002). This workshop was followed by a "consensus" workshop sponsored by NIEHS/NIH and NIOSH/CDC on the most appropriate screening tests to evaluate developmental immunotoxicity (Luster et al. 2003). ILSI/HESI has recently held a panel discussion that discussed additional methodological details for conducting developmental immunotoxicology screening tests (Holsapple 2003; Holsapple, in preparation). This information should be useful to investigators in the area of developmental immunotoxicology.

The current volume represents the first textbook dealing exclusively with developmental immunotoxicology. It begins with overviews of immune system development in experimental animal models and human, areas that have been the focus of immunological research for a number of decades as well as the complex issues dealing with the evolution of developmental immunology and risk assessment. This is followed by sections describing different animal models used to study developmental immunotoxicity and examples of specific developmental immunotoxic agents, including therapeutics. Although the volume is focused on immunosuppression, chapters have been included describing the consequences of immune dysregulation (i.e., autoimmune and allergic diseases) following developmental exposures. The text concludes with several chapters that describe the role of neuroimmune interactions as it relates to developmental immunotoxicology.

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