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Dogs play an important role in toxicology because of their importance as a large animal, pre-clinical model for evaluating potential toxicity in human drug development including the effects of investigational drugs on the immune system. The purpose of this paper is to review the development of the canine immune system during the fetal, neonatal and postnatal periods and to compare it with that of the human immune system. Unlike rodents, the development of the canine immune system shares many similarities to that of the human. In both dogs and humans, the immune system, including the mucosal immune system, is fully developed before birth although the maturity of the immune response may continue into the postnatal period. [ABSTRACT FROM AUTHOR]

The benefits and costs are discussed for the possibility of using pups generated in breeding studies for additional assessments, such as evaluating immunotoxicity. Such an approach is logistically challenging, but not overwhelming. [ABSTRACT FROM AUTHOR]

Acrylamide (AA) is a food contaminant present in a wide range of frequently consumed foods, which makes human exposure to this toxicant unfortunately unavoidable. However, efforts to reduce the formation of AA in food have resulted in some success. This review aims to summarize the occurrence of AA and the potential mitigation strategies of its formation in foods. Formation of AA in foods is mainly linked to Maillard reaction, which is the first feasible route that can be manipulated to reduce AA formation. Furthermore, manipulating processing conditions such as time and temperature of the heating process, and including certain preheating treatments such as soaking and blanching, can further reduce AA formation. Due to the high exposure to AA, recognition of its toxic effect is necessary, especially in developing countries where awareness about AA health risks is still very low. Therefore, this review also focuses on the different toxic effects of AA exposure, including neurotoxicity, genotoxicity, carcinogenicity, reproductive toxicity, hepatotoxicity, and immunotoxicity. [ABSTRACT FROM AUTHOR]

Perfluorinated alkyl substances have been in use for over sixty years. These highly stable substances were at first thought to be virtually inert and of low toxicity. Toxicity information slowly emerged on perfluorooctanoic acid and perfluorooctane sulfonate. More than thirty years ago, early studies reported immunotoxicity and carcinogenicity effects. The substances were discovered in blood samples from exposed workers, then in the general population and in community water supplies near U.S. manufacturing plants. Only recently has research publication on perfluorooctanoic acid and perfluorooctane sulfonate intensified. While the toxicology database is still far from complete, carcinogenicity and immunotoxicity now appear to be relevant risks at prevalent exposure levels. Existing drinking water limits are based on less complete evidence that was available before 2008 and may be more than 100-fold too high. As risk evaluations assume that untested effects do not require regulatory attention, the greatly underestimated health risks from perfluorooctanoic acid and perfluorooctane sulfonate illustrate the public health implications of assuming the safety of incompletely tested industrial chemicals. [ABSTRACT FROM AUTHOR]

The immune system has been recognized for decades as a potential “target organ” of toxicity. Immune system activation can result in cytokine release resulting in severe systemic toxicity. Immunosuppression can result in impaired host defense and an increase in opportunistic infection, reemergence of latent infection, poor responses to vaccination, or increased risk of certain cancers. Several regulatory documents have addressed various aspects of immunotoxicity assessments. Nonhuman primates (NHPs) and in particular macaques are often the only relevant species for biotechnology-derived investigational new drugs based on cross-reactivity with human and NHP targets. This article reviews the challenges and opportunities associated with monitoring immune function in NHPs in the context of regulatory expectations. The article emphasizes how a comprehensive assessment of immunotoxicity remains a challenge due to interanimal variability associated with certain parameters (e.g., T-dependent antibody response)and it identifies gaps, such as the stage of development of certain assays (e.g., cytotoxic T-cell function). Despite these challenges, a thorough assessment of target biology-driven theoretical risks, in combination with proper integration of all information from the standard toxicology studies, and the refinement of certain assays should enable proper risk assessment. To this effect, emphasis should be placed on leveraging predictive in vitro assays using human cells. [ABSTRACT FROM AUTHOR]

The immune system functions primarily as a defense mechanism to provide protective immunity against microbial pathogens and cancer. The resulting protective responses occur through the complex interaction of tissues, cells, proteins, and molecular pathways that act in concert with other systems (e.g., nervous and endocrine) to provide the host with immunologic responses that cause pathologic processes seen primarily as inflammatory reactions. The pathologic responses can be attributed to either normal responses to infectious organisms and cancer cells, misdirected responses as in the case of hypersensitivity or autoimmune diseases, or deficient responses attributable to deficiencies or defects in components of the immune system. Pathologists need to have a basic understanding of the immune system to not only interpret findings as to their likely pathogenesis, but also to predict when the immune system may be a potential target. This review will be limited to a general overview of the basic immunologic responses and primary components involved. [ABSTRACT FROM PUBLISHER]

Characteristic susceptibility to environmental and pharmaceutical exposure may occur during periods in life of marked histophysiological changes of the immune system. Perinatal development is such a period; pregnancy followed by lactation is potentially another one. Here, we explored the influence of pregnancy and lactation on the model immunotoxic compound di-n-octyltin dichloride (DOTC) in rats using clinical and histopathological parameters. Female rats were exposed to 0, 3, 10, or 30 mg DOTC/kg feed during pregnancy and up to 20 (at weaning) or 56 days after delivery. Age-matched nonmated females were exposed during the same time periods. DOTC at the level of 10 and 30 mg/kg decreased thymus weight and affected thymus morphology in the lactating rats. In addition, DOTC decreased the numbers of neutrophils in the lactating rats. These effects were no longer apparent at day 56 despite continuous exposure to DOTC. This explorative study indicates that the innate and adaptive immune system may be especially sensitive to immunotoxicants during pregnancy and lactation. [ABSTRACT FROM PUBLISHER]

Perfluorinated compounds (PFCs) are environmentally widespread, persistent, and bioaccumulative chemicals with multiple toxicities reported in experimental models and wildlife, including immunomodulation. The two most commonly detected compounds, which also generally occur in the highest concentrations in environmentally exposed organisms, are perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). PFOA and PFOS have been reported to alter inflammatory responses, production of cytokines, and adaptive and innate immune responses in rodent models, avian models, reptilian models, and mammalian and nonmammalian wildlife. Mounting evidence suggests that immune effects in laboratory animal models occur at serum concentrations below, within the reported range, or just above those reported for highly exposed humans and wildlife. Thus, the risk of immune effects for humans and wildlife exposed to PFCs cannot be discounted, especially when bioaccumulation and exposure to multiple PFCs are considered. This review contains brief descriptions of current and recently published work exploring immunomodulation by PFOA, PFOS, and other PFCs in rodent models, alternative laboratory models, and wildlife. [ABSTRACT FROM PUBLISHER]

Developmental immunotoxicity (DIT) testing is centered around the concern that exposure to immunotoxicants early in development may result in enhanced susceptibility of, or unique or more persistent effects on, the immune system, in comparison to adult exposure. Developmental immunotoxicity has been the focus of numerous workshops and reviews for at least fifteen years. Most of these earlier activities have focused on both environmental chemicals and pharmaceuticals and have concluded that the best approach to DIT is to address the possible impacts of exposure during all of the critical windows of development. This article will emphasize the critical role played by exposure during the juvenile stage of development. This article will also highlight several key issues that distinguish DIT testing of pharmaceuticals. Representatives from the pharmaceutical, biotechnology, academic, and regulatory sectors (both FDA and EMA) were brought together during a two-day workshop in May 2010 to consider the current state of the science of DIT as it pertains to the testing of pharmaceuticals. It is important to emphasize at the onset that there are currently no regulatory guidelines for either drugs or nondrug chemicals specifically focused on assessment of DIT, although some general guidelines are included in both developmental and reproductive toxicity and general immunotoxicology guidance documents. [ABSTRACT FROM PUBLISHER]

Current immunotoxicity testing guidance for drugs, high production–volume chemicals, and pesticides specifies the use of animal models to assess potential biomarkers of immune system effects (e.g., lymphoid organ and bone marrow indices, histopathology) or actual measures of immune function (e.g., responses to challenge with antigens or pathogens). These assays are resource intensive and often require special training or experience to ensure reliable results. Alternative in vitro assays to detect immunosuppression and allergic hypersensitivity have the potential to reduce animal use and testing costs and increase immunotoxicity screening and prioritization efforts. Alternative models to detect immunosuppression tend to address broad modes of action because suppression may be caused by a wide variety of events; current in vitro models access the supply of innate and adaptive immune system cells as well as cellular markers associated with function, including gene expression, protein synthesis, and proliferation. Events leading to the induction of allergic hypersensitivity, particularly contact hypersensitivity, are more restricted, and alternative methods currently exploit chemical properties and activation of defined cell populations to detect and estimate the potency of skin sensitizers. [ABSTRACT FROM PUBLISHER]

Enhanced histopathology (EH) of the immune system is a tool that the pathologist can use to assist in the detection of lymphoid organ lesions when evaluating a suspected immunomodulatory test article within a subchronic study or as a component of a more comprehensive, tiered approach to immunotoxicity testing. There are three primary points to consider when performing EH: (1) each lymphoid organ has separate compartments that support specific immune functions; (2) these compartments should be evaluated individually; and (3) semiquantitative descriptive rather than interpretive terminology should be used to characterize any changes. Enhanced histopathology is a screening tool that should be used in conjunction with study data including clinical signs, gross changes, body weight, spleen and thymus weights, other organ or tissue changes, and clinical pathology. Points to consider include appropriate tissue collection, sectioning, and staining; lesion grading; and diligent comparison with concurrent controls. The value of EH of lymphoid organs is to aid in the identification of target cell type, changes in cell production and cell death, changes in cellular trafficking and recirculation, and determination of mechanism of action. [ABSTRACT FROM PUBLISHER]

As the molecular pathobiology of immunologically based diseases, such as rheumatoid arthritis, has become clearer, pharmaceutical researchers have responded with highly efficacious and selective biological compounds. In contrast to older, nonspecific small-molecule therapeutics, the exquisite species sensitivity of monoclonal antibodies has introduced new challenges to preclinical safety studies. Repeated exposure of animals to biopharmaceutical compounds tends to be restricted in the species in which these compounds have pharmacological action, and it tends to stimulate antidrug immune responses with acceleration of clearance, thereby limiting the duration of repeat-dose studies and potentially resulting in hypersensitivity reactions. Thus, the safety testing of biopharmaceutical compounds has necessitated the use of relatively short-term studies in rodents, whereas nonhuman primates have become the primary tool for large-animal, repeat-dose studies. However, as the number of highly targeted and efficacious small-molecule immunomodulators rapidly increases, these molecules will be developed in a manner similar to that of other small molecules with regard to safety assessment. Because such approaches inherently push drug levels to achieve maximally tolerated doses, the pharmacologic specificity of these new small-molecule drugs may be lost as they affect additional receptors and pathways. Therefore, toxicologic pathologists must refamiliarize themselves with the consequences of profound immunosuppression in species other than nonhuman primates. The interrelationships of cytokine signaling and receptor biology are complex, highly integrated, and at times paradoxical, and the loss of specificity at high doses may result in unforeseen consequences caused by the impact on complex down-stream pathways that culminate in exaggerated and adverse responses. The species specificity of such responses may not be inherently familiar or anticipated. [ABSTRACT FROM PUBLISHER]

Chronic jet fuel exposure could be detrimental to the health and well-being of exposed personnel, adversely affect their work performance and predispose these individuals to increased incidences of infectious disease, cancer and autoimmune disorders. Short-term (7 day) JP-8 jet fuel exposure has been shown to cause lung injury and immune dysfunction. Physiological alterations can be influenced not only by jet fuel exposure concentration (absolute amount), but also are dependent on the type of exposure (aerosol versus vapor) and the composition of the jet fuel (hydrocarbon composition). In the current study, these variables were examined with relation to effects of jet fuel exposure on immune function. It was discovered that real-time, in-line monitoring of jet fuel exposure resulted in aerosol exposure concentrations that were approximately one-eighth the concentration of previously reported exposure systems. Further, the effects of a synthetic jet fuel designed to eliminate polycyclic aromatic hydrocarbons were also examined. Both of these changes in exposure reduced but did not eliminate the deleterious effects on the immune system of exposed mice. [ABSTRACT FROM AUTHOR]

Paraquat (PQ) can cause acute lung injury in humans and experimental animals. However, the role of growth factors in the progression of injury has not been clearly established. We developed an animal model of PQ-induced lung injury using Wistar rats. One milliliter of PQ solution (30, 60, and 120 mg/kg) was applied through the lavage, while the same amount of vehicle was applied to control rats. Based on histopathology, the lungs of some animals exposed to PQ showed acute fulmination, resulting in death, while others showed a more protracted injury, resulting in typical pulmonary fibrosis at 21 days. Using this PQ-poisoned rat model, we examined the intrapulmonary gene expression and circulatory level of cytokines and growth factors at 8 hours, 24 hours, 3 days, 7 days, 14 days, and 21 days after PQ administration. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated that the gene expression levels of interleukin-1 beta and interleukin-6 were significantly increased at 21 days after PQ challenge compared with the controls. The mRNA expression of tumor necrosis factor-alpha was also significantly increased except on days 14 and 21 after PQ treatment. Moreover, PQ-treated rats showed enhanced gene expression of growth factors such as platelet-derived growth factor-A and insulin-like growth factor-1 at 21 days and transforming growth factor-beta 1 at 14 days. ELISA results showed the circulatory level of cytokines and growth factors coincided with intrapulmonary gene expression. The synergistic effects of these molecules are presumed to cause pulmonary damage due to PQ challenge and may become targets of treatment. [ABSTRACT FROM PUBLISHER]

Immunotoxicology has developed into an integral regulatory requirement of the toxicological assessment of xenobiotics. Histopathological assessment of lymphoid tissues can provide genuine insight into perturbations of lymphoid cell populations. To facilitate retrospective examination of lymphoid organs should concerns over immunotoxicity be raised, we have endeavored to develop a panel of immunohistochemical techniques to demonstrate T-cells and T-cell subsets in formalin-fixed, paraffin-embedded rat lymphoid tissues. We were successful in developing methods for CD3 and CD8 but failed to arrive at a satisfactory technique for the direct demonstration of CD4 in these tissues. Taking the assumption that the majority of mature T-cells are either CD4+ or CD8+, we have combined our methods for CD3 and CD8 in a novel dual-labeling IHC method to simultaneously demonstrate CD3, CD8, and, by implication, CD4 in rat spleen, thymus, lymph node, and Peyer's patch. [ABSTRACT FROM AUTHOR]

The responses to insults including chemical toxins, irradiation and infectious agents involve morphologic, biochemical and molecular changes in the immune system. The changes in specific tissues and cells often can be detected by histopathology and its associated field of immunohistochemisty (IHC). Cells normally express specific proteins (antigens) that can be detected by IHC. When responses to xenobiotics occur, cells often up or down regulate proteins. The art of IHC requires specialized procedures for detection of antigens. Fixation, tissue processing, immunoreactions and antigen retrieval methods are important elements of IHC. We review the antibodies, their sources, use of frozen or fixed paraffin-embedded tissues and specific IHC methods including antigen retrieval and illustrate how they can be effectively used to characterize the immunotoxicologic effects of agents. [ABSTRACT FROM AUTHOR]

Lymph nodes function as filters of tissues and tissue fluids and are sites of origin and production of lymphocytes for normal physiological functions. As part of this normal function, they react to both endogenous and exogenous substances with a variety of specific morphological and functional responses. Lesions can be both proliferative and nonproliferative, and can be treatment-related or not. The histological evaluation of lymph nodes is necessary in order to understand the immunotoxic effects of chemicals with the resulting data providing an important component of human risk assessment. It is the challenge of the toxicologic pathologist to interpret the pathology data within the complete clinical evaluation of the entire animal. Daily insults, ageing and toxins can alter the normal histology and primary function of lymph nodes. Therefore it is important to distinguish and differentiate lesions that occur naturally during normal development and ageing from those that are induced by xenobiotics. To achieve this goal, comparison with strain- age- and sex-matched controls is crucial. [ABSTRACT FROM AUTHOR]

The thymus is a primary lymphoid organ that manifests dynamic physiological changes as animals age in addition to being exquisitely sensitive to stress and toxic insult. It is typically the first lymphoid tissue to respond to immunotoxic xenobiotics, with the first change being loss of cortical lymphocytes by apoptosis. This is followed by removal of the apoptotic cellular debris and, in the absence of recovery, may lead to loss of the cortico-medullary demarcation and organ atrophy. Nonneoplastic proliferative changes include focal lymphoid hyperplasia and proliferation of medullary epithelial cells, often with formation of ribbons, cords, or tubules. Thymomas are relatively rare tumors that exhibit a wide spectrum of morphologic types but do not metastasize. Thymic lymphomas are common in some mouse strains and can become leukemic with hematogenous spread throughout the body. [ABSTRACT FROM AUTHOR]

The thymus is a primary or central lymphoid organ in which T lymphocytes undergo diffentiation and maturation autonomously within the cortex, without the need for antigenic stimulation, and it is essential for the normal development and function of the immune system. The thymus has been shown to be a sensitive target organ following exposure to immunotoxicants and endogenous corticosteroids, and a decrease in size or weight is often one of the first noted measures of compound-induced effects with cortical lymphocytes (thymocytes) being especially susceptible. Therefore, changes in thymus histopathology and architecture are considered to be of particular relevance for immunotoxicity screening. The separate compartments in each lymphoid organ should be evaluated separately and descriptive rather than interpretive terminology should be used to characterize changes within those compartments (Haley et al., 2005). Therefore, enhanced histopathological evaluation of the thymus involves the determination of the size and cellularity of the cortex and medulla, which should be noted separately. Other changes to evaluate include, but are not limited to, increased lymphocyte apoptosis, lymphocyte necrosis, cortex:medulla ratio and an increase or decrease in the epithelial component of the thymus. [ABSTRACT FROM AUTHOR]

Routine histopathology of lymphoid organs is the cornerstone in the identification of immunotoxic and immunomodulatory compounds. Enhanced histopathology is a systematic approach that can be used to further characterize, both qualitatively and semi-quantitatively, the immunomodulatory effects that may occur within both primary and secondary lymphoid organs. The lymph nodes are the major route of entry for antigens and pathogens, via the afferent lymph flow, and they can be sensitive indicators of compounds with regional or systemic immunomodulatory/toxic effects and should therefore be included in the battery of lymphoid organs to evaluate for enhanced histopathology. As with all lymphoid organs, the separate compartments should be evaluated independently and descriptive rather than interpretive terminology should be used to characterize changes within those compartments. This data, in conjunction with gross findings, clinical pathology and changes in organ weight (i.e., thymus), will enable the pathologist to determine if a significant effect on the immune system is present. Moreover, this data may enable the pathologist to determine the critical site or compartment in the targeted tissue, provide some indication of target cell population (B or T cell) and characterize a dose-response relationship. [ABSTRACT FROM AUTHOR]

This article provides a brief history of the development of the field of immunotoxicology from one individual perspective and separates the discussion into five phases: the methods development and validation phase; the compound testing phase; the many meetings and organization of the specialty section phase; the mechanistic studies phase; and the guidelines phase. During the discussion of each phase, major highlights, accomplishments, contributors and key references are provided. The immunotoxicology guidelines for the testing of pharmaceutical chemical entities across the three major geographic axes are also presented and compared, along with some of the concerns raised by industry with these guidelines. The mandatory requirement of functional tests represents the major concern and difference between the Committee of Proprietary Medicinal Products (CPMP) and the new Food and Drug Administration (FDA) guidance. The scientific basis for the recommendation of the functional tests proposed in the guidance documents based on National Institute of Environmental Health and Safety/National Toxicology Program (NIEHS/NTP)-sponsored studies is described. Experience at Sanofi-Synthelabo, with the testing of 29 new chemical drug entities developed across a broad range of therapeutic classes using this testing paradigm and functional tests to define their immunotoxic potential, yielded a low number of compounds (6.8%) that produced any abnormal reaction. The two positive compounds might have been anticipated based on their pharmacology. [ABSTRACT FROM PUBLISHER]

Exposure to natural environmental products, biopharmaceuticals, or investigational adjuvants has the potential to negatively impact the immune system, resulting in either up- or downregulation of immune function (immunomodulation). Many current protocols for primate toxicologic testing call for the evaluation of changes in immune cell number (peripheral blood or tissue), alterations in the weights of immune system organs (lymph nodes, spleen, thymus), and/or increases in the overall incidence of infections or neoplasms; these data are relied upon to suggest altered immune function. However, these are informative only when clear differences in frequency and/or severity of effects can be distinguished across control and dosed groups. In the absence of such distinct morphologic or clinical pathologic changes, the identification of potential immunomodulatory effects can present a much greater challenge. Additional evaluations may be needed to detect altered immune system integrity; these are based on in vivo assessments in primates of cellular or humoral responsiveness. Immunomodulatory effects can be characterized by in vitro or in vivo immune function tests; these tests require prestudy planning to integrate assessments into ongoing toxicology programs. These methods also involve specialized training and equipment, particularly if the intent is to evaluate parameters in a GLP laboratory setting. In primate toxicology, the added costs required to perform a complete functional analysis of the immune system can be substantial, but may be warranted depending on the clinical development plans. Two analytical methods that are easily incorporated into the standard toxicology profile in primates are flow cytometry and immunohistochemistry. Flow cytometry (FC) is used to assess... [ABSTRACT FROM AUTHOR]

Procedures to reveal 'immunotoxic' potentials of chemicals in animal experiments (mostly in rodents) have been recommended, but the selection of test systems is rather arbitrary. The predictive power of extrapolations to the possible situation in humans is unknown because human studies to confirm or to reject clues from animal data are largely lacking. End points selected in animal studies and those expected to be relevant in humans are not identical. Results of animal experiments are based on doses, generally ignoring the important species differences in pharmacokinetics. This unfavorable situation is especially pronounced when attempting to evaluate 'environmental chemicals'. Because much more information is available on many medicinal drugs, exposures can be defined and pharmacokinetic data are available or obtainable. The situation is even more complicated when attempting to assess possible adverse effects on the developing immune system: in addition to the problems mentioned, numerous different developmental periods with varying susceptibilities must be considered, and species differences in the immune response are superimposed with large differences in pre-, early post-, and later postnatal development. Simultaneously, the kinetic variables are continuously changing with time (with additional variability among species). Different results, even between rats and mice, are bound to occur. Extrapolation to the situation possibly relevant for human exposure will be almost impossible, especially from rodent data. The majority of such effects induced peri- or early post-natally may be expected to be reversible. It must also be assessed whether qualitatively different adverse effects are likely to be induced during 'development', which cannot be revealed (accepting quantitative differences) by more easily performed tests on the adult organism. Considering the intrinsic difficulties, the most promising approach would be to directly obtain data from human trials.... [ABSTRACT FROM AUTHOR]

Macaques are well suited for preclinical testing of biopharmaceutics due to reproductive and developmental similarities with humans. In order to characterize ontogeny of the immune system in this model, we studied lymphocyte and antigen-presenting cell populations in developing lymphoid tissues of rhesus macaque fetuses during the second and third trimesters [gestation days (GD) 75-145, term 165 days]. Systemic lymphoid tissues (thymus, spleen and lymph nodes, and intestinal tissue) were examined for morphology and cell surface markers by immunohistochemistry. Lymphocytes were further characterized by flow cytometry for differentiation markers. Splenic tissue from early second trimester fetuses was populated mainly by CD20[sup +] B cells while the thymus contained large numbers of CD3[sup +] T cells. In the late second trimester (day 80), approximately equal populations of B and T cells were present in both tissues and numerous dendritic cells (p55[sup +]) were present in the intestinal lamina propria. By the second trimester, the rhesus macaque fetal lymphoid system is well developed. Analysis of lymphoid organs from retinoic acidtreated fetuses indicated that the T-cell (thymus)-dependent compartment of the spleen white pulp in specimens with thymic aplasia showed a reduction in size and proportion of CD3[sup +] T cells compared to controls. Our findings indicate that RA-induced thymic defects result in disrupted development of the splenic T-cell-dependent compartment. [ABSTRACT FROM AUTHOR]

Evidence is presented to demonstrate that the rat is a sensitive rodent species for developmental immunotoxicity testing of chemicals. A battery of immune function assays was performed in adult rats, which were exposed perinatally (i.e., during gestational, lactational, and]or juvenile development) to three different classes of environmental chemicals. The chemicals employed were the following: the organotins di-n-octyltindichloride (DOTC) and tributyltin oxide (TBTO); the polyhalogenated aromatic hydrocarbon 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); and the organochlorine pesticides methoxychlor (MXC) and heptachlor (HEP). Suppression of immune function was observed in adult rats exposed to each of these chemicals during immune system development. The duration of immune function suppression in the rats so exposed ranged from three weeks (i.e., DOTC and MXC) to 19 months (i.e., TCDD) after the last exposure to the chemical. [ABSTRACT FROM AUTHOR]

While the history of immunotoxicology research involving experimental animals of immature ages dates back over several decades, there exist remarkably little data, to date, directly comparing the impact of developmental status on immunotoxicological risk. Given the size of the nonadult human population and the potential for differential vulnerability among the various ages, this represents a serious gap of knowledge in efforts to minimize environmentally linked health risks. This article frames the issues surrounding developmental immunotoxicological evaluations. In particular, the issues introduced include those of potential animal models, strain/genotype selection, gender, age of exposure, and age of assessment. Recent research results involving early exposure to lead (Pb) and other chemicals are discussed to highlight the nature of the decisions that are available and the potential cost-benefit associated with various approaches to evaluation. [ABSTRACT FROM AUTHOR]

A workshop entitled 'Developmental Immunotoxicology and Risk Assessment' was held on 12-13 June 2001, in Washington, DC. The workshop was organized jointly by the Immunotoxicology Technical Committee (ITC) of the International Life Sciences Institute's" (ILSI) Health and Environmental Sciences Institute (HESI) with input from the U.S. Environmental Protection Agency (EPA). Growing public concern that early exposure of the developing immune system to immunotoxic compounds may cause significant or persistent postnatal immunosuppression prompted the workshop. The main goal of the workshop was to examine scientific questions that underlie developmental immunotoxicity tests and the interpretation of the results as they relate to human risk assessment. A second goal was to provide a framework, based on current scientific knowledge, for the development of meaningful testing guidelines. The workshop focused on a series of questions that included how to address critical windows of exposure, how to develop and apply more predictive endpoints, does early chemical exposure cause transient or permanent effects on the immune system, as well as other related questions. On the first day, experts were invited to give scientific presentations relating to comparative developmental immunology, models of immunosuppression, and the regulatory aspects of developmental immunotoxicology. The second day was devoted to a panel discussion that included all the speakers as well as meeting participants, which attempted to answer each of the specific questions raised at the workshop. In general, it was acknowledged that there are a variety of techniques available for assessing immunosuppression in adult animal models, but there is uncertainty about how to apply these to a developing animal, especially if the goal is to have some standard procedure that can be applied for regulatory risk assessment. It was pointed out that although we know a lot about the developing immune system of... [ABSTRACT FROM AUTHOR]

Cyclophosphamide (CP) is one of the most popular alkylating anticancer drugs in spite of its toxic side effects including immunotoxicity, hematotoxicity, mutagenicity and a host of others. The present study was undertaken to assess the protective effects of total aqueous extract of a medicinal plant, Indian gooseberry (Emblica officinalis Gaertn.) in mice treated with CP. These protective effects were studied on immunological parameters and kidney and liver antioxidants. Plant extract treatment at a dose of 100 mg/kg body weight per os (p.o.) for 10 days resulted in the modulation of these parameters in normal as well as CP (50 mg/kg)-treated animals. Plant extract in particular was very effective in reducing CP-induced suppression of humoral immunity. Plant extract treatment in normal animals modulated certain antioxidants of kidney and liver. In CP-exposed animals, plant pretreatment provided protection to antioxidants of kidney. Not only were the reduced glutathione levels significantly (p<0.001) increased but plant extract treatment resulted in restoration of antioxidant enzymes in CP-treated animals. It is suggested that E. officinalis or its medicinal preparations may prove to be useful as a component of combination therapy in cancer patients under CP treatment regimen. Human & Experimental Toxicology (2001) 20, 643–650. [ABSTRACT FROM AUTHOR]

Effects on immune parameters following topical exposure to 2-butoxyethanol (BE) in mice are reported in the present study. The objective was to determine whether subacute topical exposure to BE can modulate functional immune responses and/or nonspecific immune parameters such as lymphoid organ weight and cellularity. Female BALB/c mice were topically exposed to vehicle or BE at concentrations of 100, 500, 1000, and 1500 mg BE/kg/day for 4 consecutive days. Assessment of immune parameters began 24 hours after the final dose. No effects were observed at any of the BE concentrations on thymus cellularity or thymus to body weight ratio. A significant increase in spleen cellularity and spleen to body weight ratio was observed at 1500 mg BE/kg/day. Topical BE exposure significantly reduced the splenic T cell proliferative response to con-canavalin A (Con A) and the mixed lymphocyte response (MLR) to allogeneic antigen. No significant effect was observed in the splenic B cell proliferative response to lipopolysaccharide (LPS), nor was there an effect on the in vitro primary antibody response to sheep red blood cells (SRBCs). No significant alteration occurred in either splenocyte cytotoxic T lymphocyte (CTL) activity or natural killer (NK) cell activity following topical BE exposure. This study suggests that topical exposure to BE may suppress some aspects of T cell immunity but does not affect B cell immunity. [ABSTRACT FROM PUBLISHER]

The article presents a systematic approach to Enhanced Histopathology which involves the subjective and semi-quantitative histological evaluation of various lymphoid tissues to identify specific cellular and architectural changes. Enhanced histopathology can assist pathologists to identify immunomodulatory drugs and chemicals. The article finally concludes that standard operating procedures in the laboratories should be established and appropriate guidelines should be followed.