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Air pollution is a diverse and dynamic mixture of gaseous and particulate matter, limiting our understanding of associated adverse health outcomes. The biological effects of two simulated smog atmospheres (SA) with different compositions but similar air quality health indexes were compared in a non-obese diabetic rat model (Goto-Kakizaki, GK) and three mouse immune models (house dust mite (HDM) allergy, antibody response to heat-killed pneumococcus, and resistance to influenza A infection). In GK rats, both SA-PM (high particulate matter) and SA-O(3) (high ozone) decreased cholesterol levels immediately after a 4-hour exposure, whereas only SA-O(3) increased airflow limitation. Airway responsiveness to methacholine was increased in HDM-allergic mice compared with non-allergic mice, but exposure to SA-PM or SA-O(3) did not significantly alter responsiveness. Exposure to SA-PM did not affect the IgM response to pneumococcus, and SA-O(3) did not affect virus titers, although inflammatory cytokine levels were decreased in mice infected at the end of a 7-day exposure. Collectively, acute SA exposures produced limited health effects in animal models of metabolic and immune diseases. Effects of SA-O(3) tended to be greater than those of SA-PM, suggesting that gas-phase components in photochemically-derived multipollutant mixtures may be of greater concern than secondary organic aerosol PM.

The discipline of immunotoxicology had its origins in the early 1970s, following the recognition of altered immune function and increased sensitivity to infections and cancers after exposure to environmental chemicals and therapeutic drugs. Reduced resistance to infectious disease was a well-documented consequence of primary and acquired immunodeficiencies, but a novel finding following xenobiotic exposure. The awareness of the consequences of altered immune function was likely heightened by the HIV epidemic, leading some to inappropriately characterize xenobiotic-induced immunosuppression as “chemical AIDS”, although it is now clear that mild to moderate suppression is the most likely outcome of inadvertent exposure. The human health implications of studies in which chemical exposure reduced resistance to infection, drove an early focus on immunosuppression within the toxicology community. Allergic hypersensitivity was well known to clinicians and symptoms were readily apparent, and therefore was not the initial focus of the developing toxicology subspecialty of immunotoxicology. The first review in the field of immunotoxicology was published by Vos in 1977, and, as research expanded during the years that followed, many of the assays, methodologies and approaches that are currently used to identify potential immunotoxicants were developed. Over the years, advances in our understanding of basic immunology have made it clear that allergy, immunosuppression and, in some cases, autoimmunity, are a matter of polarization of the immune response by immunotoxicants, rather than independent outcomes of chemical exposure.

The goal of immunotoxicity testing is to obtain data useful for immunotoxicity safety assessment. Guidance in the performance of immunotoxicity safety evaluations is provided in documents from the US EPA for chemicals and the ICH S8 document for pharmaceuticals. The ICH S8 document outlines a tiered approach that includes (1) standard toxicity studies with associated hematology, immune system organ weights, and histopathology data; (2) functional assays, such as cytotoxic T lymphocyte (CTL) assays, natural killer (NK) cell assays, respiratory burst, phagocytosis, and T-cell-dependent antibody response (TDAR) assays; and (3) host resistance assays. Host resistance assays are considered the gold standard in immunotoxicity testing and provide a critical overview of the extent to which innate, adaptive, and homeostatic regulatory immune functions are integrated to protect the host. Both comprehensive and targeted host resistance assays are available, each with distinct advantages. This chapter serves to provide a general overview of the various assays that may be used, as well as a summary of procedures.

The goal of immunotoxicity testing is to obtain data useful for immunotoxicity safety assessment. Guidance in the performance of immunotoxicity safety evaluations is provided in documents from the US EPA for chemicals and the ICH S8 document for pharmaceuticals. The ICH S8 document outlines a tiered approach that includes (1) standard toxicity studies with associated hematology, immune system organ weights, and histopathology data; (2) functional assays, such as cytotoxic T lymphocyte (CTL) assays, natural killer (NK) cell assays, respiratory burst, phagocytosis, and T-cell-dependent antibody response (TDAR) assays; and (3) host resistance assays. Host resistance assays are considered the gold standard in immunotoxicity testing and provide a critical overview of the extent to which innate, adaptive, and homeostatic regulatory immune functions are integrated to protect the host. Both comprehensive and targeted host resistance assays are available, each with distinct advantages. This chapter serves to provide a general overview of the various assays that may be used, as well as a summary of procedures.

T-cell-dependent antibody responses (TDAR) are suppressed in female C57BL/6N mice exposed to ≥3.75 mg/kg of perfluorooctanoic acid (PFOA) for 15 days. To determine if suppression of humoral immunity by PFOA is peroxisome proliferator activated receptor alpha (PPARα)-dependent and if suppression is associated with specific targeting of T- or B-cells, three separate experiments were conducted: (1) female PPARα constitutive knockout (PPARα KO; B6.129S4-Ppar(tm1Gonz)N12) and wild-type controls (WT; C57BL/6-Tac) exposed to 0, 7.5, or 30 mg PFOA/kg for 15 days were immunized on Day 11 with a T-cell-dependent antigen and sera then collected for measures of antigen-specific IgM titers (TDAR) 5 days later; (2) female C57BL/6N WT mice exposed to 0, 0.94, 1.88, 3.75, or 7.5 mg PFOA/kg for 15 days were immunized with a T-cell-independent antigen on Day 11 and sera were then collected for analyses of antigen-specific IgM titers (TIAR) 7 days later; and (3) splenic lymphocyte phenotypes were assessed in unimmunized female C57BL/6N WT mice exposed to 0, 3.75, or 7.5 mg PFOA/kg for 10 days to investigate effects of PFOA in the absence of specific immunization. Separate groups of mice were immunized with a T-cell-dependent antigen after 11 days of exposure and splenic lymphocyte sub-populations were assessed after 13 or 15 days of exposure to assess numbers of stimulated cells. The results indicated that exposure to ≥1.88 mg PFOA/kg suppressed the TIAR; exposure to 30 mg PFOA/kg suppressed the TDAR in both PPARα KO and WT mice. The percentage of splenic B-cells was unchanged. Results obtained in the PPARα KO mice indicated that PPARα suppression of TDAR was independent of PPARα involvement. Suppression of the TIAR and the TDAR with minimal lymphocyte sub-population effects suggested that effects on humoral immunity are likely mediated by disruption of B-cell/plasma cell function.

This overview is an update of the unit originally published in 2004. While the basic tenets of immunotoxicity have not changed in the past 10 years, several publications have explored the application of immunotoxicological data to the risk assessment process. Therefore, the goal of this unit is still to highlight relationships between xenobiotic-induced immunosuppression and risk of clinical diseases progression. In immunotoxicology, this may require development of models to equate moderate changes in markers of immune functions to potential changes in incidence or severity of infectious diseases. For most xenobiotics, exposure levels and disease incidence data are rarely available, and safe exposure levels must be estimated based on observations from experimental models or human biomarker studies. Thus, it is important to establish a scientifically sound framework that allows accurate and quantitative interpretation of experimental or biomarker data in the risk assessment process.

Dibromoacetic acid (DBA) is a disinfection by-product commonly found in drinking water as a result of chlorination/ ozonation processes. The Environmental Protection Agency estimates that more than 200 million people consume disinfected water in the United States. This study was conducted to evaluate the potential immunotoxicological effects of DBA exposure when administered for 28 days via drinking water to B₆C₃F₁ mice, at concentrations of 125, 500, and 1000 mg/L. Multiple endpoints were evaluated to assess innate, humoral, and cell-mediated immune components, as well as host resistance. Standard toxicological parameters were unaffected, with the exception of a dose-responsive increase in liver weight and a decrease in thymus weight at the two highest exposure levels. Splenocyte differentials were affected, although the effects were not dose-responsive. Exposure to DBA did not significantly affect humoral immunity (immunoglobulin M [IgM] plaque assay and serum IgM anti-sheep erythrocyte titers) or cell-mediated immunity (mixed-leukocyte response). No effects were observed on innate immune function in either interferon-γ-induced in vitro macrophage cytotoxic activity or basal natural killer (NK)-cell activity. Augmented NK-cell activity (following exposure to polyinosinic-polycytidylic acid) was decreased at the low dose, however the effect was not dose-responsive. Finally, DBA exposure had no effect on resistance to infection with either Streptococcus pneumoniae or Plasmodium yoelii, or challenge with B16F10 melanoma cells. With the exception of changes in thymus weight, these results indicate that DBA exposure resulted in no immunotoxic effects at concentrations much larger than those considered acceptable in human drinking water.

We report a new measurement of the decay Ω − → Ξ − π + π − with 76 events and a first observation of the decay Ω ¯ + → Ξ ¯ + π + π − with 24 events, yielding a combined branching ratio ( 3.74 − 0.56 + 0.67 ) × 10 − 4 . This represents a factor 25 increase in statistics over the best previous measurement. No evidence is seen for CP violation, with B ( Ω − → Ξ − π + π − ) = 4.04 − 0.71 + 0.83 × 10 − 4 and B ( Ω ¯ + → Ξ ¯ + π + π − ) = 3.15 − 0.89 + 1.12 × 10 − 4 . Contrary to theoretical expectation, we see little evidence for the decays Ω − → Ξ 1530 ∗ 0 π − and Ω ¯ + → Ξ ¯ 1530 ∗ 0 π + and place a 90% C.L. upper limit on the combined branching ratio B ( Ω − ( Ω ¯ + ) → Ξ 1530 ∗ 0 ( Ξ ¯ 1530 ∗ 0 ) π ∓ ) 7.0 × 10 − 5 .

Assessing the risk profiles of potentially sensitive populations requires a "tool chest" of methodological approaches to adequately characterize and evaluate these populations. At present, there is an extensive body of literature on methodologies that apply to the evaluation of the pediatric population. The Health and Environmental Sciences Institute Subcommittee on Risk Assessment of Sensitive Populations evaluated key references in the area of pediatric risk to identify a spectrum of methodological approaches. These approaches are considered in this article for their potential to be extrapolated for the identification and assessment of other sensitive populations. Recommendations as to future research needs and/or alternate methodological considerations are also made.

One hundred young redfish (Sciaenopsocellata) were caught by hook and line fishing and stocked in two 0.1 ha ponds. The ponds, located near Baytown, Texas on the Galveston Bay complex, received heated discharge water from the Cedar Bayou Generating Station of the Houston Lighting and Power Company. Once established in the ponds, the fish were taught to eat Purina trout chow pellets. The ponds were drained periodically and redfish were counted, weighed, and measured. Eighty-three fish were alive at the end of the study. Mean daily weight and length gain in the two ponds were 3.15 g and 2.69 g and 0.76 mm and 0.85 mm, respectively. Food conversion values ranged from 2.70 to 6.61. Mean KSL values ranged from 1.67 to 1.94.

BACKGROUND: Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links, between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an "adverse effect" in the context of hazard identification and risk assessment. OBJECTIVES: Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (Upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. DISCUSSION: Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may, be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. CONCLUSIONS: For certain classes of early perturbations, Sufficient information oil the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will Support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population

Natural killer (NK) cells are a subset of lymphocytes capable of killing tumor cells, virally infected cells and antibody-coated cells. Dibutyltin (DBT) dichloride is an organotin used as a stabilizer in polyvinylchloride (PVC) plastics and as a deworming product in poultry. DBT may leach from PVC water supply pipes and therefore poses a potential risk to human health. We previously reported diminished NK cells lysis of tumor cells following exposure to DBT in serum-free cell culture medium. However, under in vivo conditions, circulating cells will be exposed to DBT in the presence of 100% plasma; thus we investigated whether serum supplementation and incubation time modulates DBT effects on NK cell killing and the accumulation of DBT in freshly isolated NK cells, to determine whether a serum-free model accurately predicts possible effects of DBT on human NK cells under in vivo conditions. Lytic function was decreased by approximately 35% at an intracellular DBT (DBTi) concentration of 200 microM and nearly complete loss of lytic function was observed at DBTi above 300 microM for one h. However, an intracellular concentration of 50 microM DBT, achieved over 24 h of exposure in 50% serum, reduced lytic function by 50%. Thus, conditions that reflect prolonged contact with circulating DBT, in the presence of serum, suggest that NK cell activity is decreased at lower DBTi. These data indicate that the model is useful in predicting potential human effects of relatively low DBTi concentrations.

Organotins are used commercially as pesticides, antifouling agents and stabilizers for polyvinyl chloride (PVC) pipe. Mono- and di-substituted butyltins, used in PVC pipe production, are of concern to the US EPA because they leach from supply pipes into drinking water and are reported multisystem toxicants. We assessed several immune functions in Sprague-Dawley rats after adult or developmental dimethyltin dichloride (DMTC) exposure because various organotins have been reported to be immunotoxic. Adult male and female rats were given drinking water containing 0, 20 or 40 mg DMTC/L (0, 1.7, or 3.4 mg DMTC/kg body weight [BW]) for 28 days. Pregnant females were given the same DMTC drinking water concentrations for a total of 37 days, from gestational day (GD) six through weaning of pups (0, 2.4, or 4.6 mg DMTC/kg BW during gestational exposure; 0, 3.6, or 6.9 mg DMTC/kg BW during postnatal exposure). On postnatal day (PND) two, litters were sexed, weighed, and culled to four males and four females per dam. Delayed-type hypersensitivity (DTH), antibody synthesis, and natural killer (NK) cell activity were evaluated in adults (N=8/sex/group) and in immunologically mature offspring (N=6/sex/group). Although water consumption was decreased in all of the DMTC dose groups, the immune functions evaluated were not affected. Our data suggest that these immune functions are not sensitive to the levels of DMTC anticipated to occur in drinking water delivered via PVC pipe as the concentrations we used were several orders of magnitude higher than those expected to leach from PVC pipes.

Greater susceptibility to infection is a hallmark of compromised immune function in humans and animals, and is often considered the benchmark against which the predictive value of immune function tests are compared. The focus of this paper is resistance to infection with the parasitic nematode Trichinella spiralis as a model of host resistance. Topics include overviews of parasite biology, host immune responses that limit infection and methods used to evaluate the host response to infection. Detailed protocols are provided for adult and larval parasite counts, female parasite fecundity, parasite antigen-driven lymphocyte proliferation and antibody responses to infection.

Evaluation of xenobiotic-induced changes in gene expression as a method to identify and classify potential toxicants is being pursued by industry and regulatory agencies worldwide. A workshop was held at the Research Triangle Park campus of the Environmental Protection Agency to discuss the current state-of-the-science of "immunotoxicogenomics" and to explore the potential role of genomics techniques for immunotoxicity testing. The genesis of the workshop was the current lack of widely accepted triggering criteria for Tier 1 immunotoxicity testing in the context of routine toxicity testing data, the realization that traditional screening methods would require an inordinate number of animals and are inadequate to handle the number of chemicals that may need to be screened (e.g., high production volume compounds) and the absence of an organized effort to address the state-of-the-science of toxicogenomics in the identification of immunotoxic compounds. The major focus of the meeting was on the theoretical and practical utility of genomics techniques to (1) replace or supplement current immunotoxicity screening procedures, (2) provide insight into potential modes or mechanisms of action, and (3) provide data suitable for immunotoxicity hazard identification or risk assessment. The latter goal is of considerable interest to a variety of stakeholders as a means to reduce animal use and to decrease the cost of conducting and interpreting standard toxicity tests. A number of data gaps were identified that included a lack of dose response and kinetic data for known immunotoxic compounds and a general lack of data correlating genomic alterations to functional changes observed in vivo. Participants concluded that a genomics approach to screen chemicals for immunotoxic potential or to generate data useful to risk assessors holds promise but that routine use of these methods is years in the future. However, recent progress in molecular immunology has made mode and mechanism of action studies much more practical. Furthermore, a variety of published immunotoxicity studies suggest that microarray analysis is already a practical means to explore pathway-level changes that lead to altered immune function. To help move the science of immunotoxicogenomics forward, a partnership of industry, academia, and government was suggested to address data gaps, validation, quality assurance, and protocol development.

The Near Detector for the MINOS Experiment at Fermilab is composed of alternating planes of scintillator strips and steel plates, and is read out with 64-channel, multi-anode photomultiplier tubes. The instrumentation uses a custom integrated circuit designed at Fermilab for the front end analog processing, called the QIE. The system can measure single photoelectrons to high precision with a dynamic range of 16 bits. The electronics operates in two modes. It records all events that occur during the 10 /spl mu/s "fast spill" of the beam from the Fermilab Main Injector at a rate of 53 MHz, using a gate from the beamline controls to force data acquisition. The system can also acquire data from cosmic rays that pass through the detector for calibration. In this case, dynode signals from the photomultipliers are used as the trigger, causing digitization and readout of the associated channels. Zero suppression and normalization are done in the front end electronics. The system is "triggerless" in that there is no global hardware trigger. Instead, each event is tagged with a "timestamp", which is used in postprocessing to reconstruct events and discard noise hits. The system of 10,000 channels is now built and installed, and operational at Fermilab. The components of the system are described and preliminary system performance is reported.

It is well established that human diseases associated with abnormal immune function, including some common infectious diseases and asthma, are considerably more prevalent at younger ages. The immune system continues to mature after birth, and functional immaturity accounts for much of the increased susceptibility in the young. Although not established absolutely, it is generally believed that development constitutes a period of increased immune system susceptibility to xenobiotics, since adverse effects may occur at lower doses and/or immunomodulation may be more persistent, thus increasing the relative risk of xenobiotic exposure to the immunologically immature organism. Data from published reports were compared to determine whether age and developmental stage at exposure influence the immunotoxic effects of diethylstilbestrol (DES), diazepam (DZP), lead (Pb), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and tributyltin oxide (TBTO). These compounds were chosen for comparison based on the fact that each h...

Recent advances in genomics-based identification of gene families and gene polymorphisms associated with immune system dysfunction have answered basic questions in immunology and have begun to move forward our understanding of immune-related disease processes. In toxicology, "omic" technologies have the potential to replace or supplement current immunotoxicological screening procedures, to provide insight into potential mode or mechanisms of action, and to provide data suitable for risk assessment. The application of omic technologies to the study of the immune system also has great potential to appreciably impact the diagnosis and treatment of immune-related diseases. This review focuses on the use of omic technologies in immunopharmacology and immunotoxicology, specifically considering the potential for these technologies to impact chemical hazard identification, risk characterization and risk assessment, and the development and application of novel therapeutics. The state of the science of omics technologies and the immune system is addressed in terms of a continuum of understanding of how omics technologies can and cannot yet be applied in the various aspects of immunopharmacology and immunotoxicology. Additionally, information gaps are identified that, once addressed, will move each area further down the continuum of understanding.

The primary alternative to petroleum-based fuels is ethanol, which may be blended with gasoline in the United States at concentrations up to 15% for most automobiles. Efforts to increase the amount of ethanol in gasoline have prompted concerns about the potential toxicity of inhaled ethanol vapors from these fuels. The well-known sensitivity of the developing nervous and immune systems to ingested ethanol and the lack of information about the neurodevelopmental toxicity of ethanol-blended fuels prompted the present work. Pregnant Long-Evans rats were exposed for 6.5h/day on days 9-20 of gestation to clean air or vapors of gasoline containing no ethanol (E0) or gasoline blended with 15% ethanol (E15) or 85% ethanol (E85) at nominal concentrations of 3000, 6000, or 9000 ppm. Estimated maternal peak blood ethanol concentrations were less than 5mg/dL for all exposures. No overt toxicity in the dams was observed, although pregnant dams exposed to 9000 ppm of E0 or E85 gained more weight per gram of food consumed during the 12 days of exposure than did controls. Fuel vapors did not affect litter size or weight, or postnatal weight gain in the offspring. Tests of motor activity and a functional observational battery (FOB) administered to the offspring between post-natal day (PND) 27-29 and PND 56-63 revealed an increase in vertical activity counts in the 3000- and 9000-ppm groups in the E85 experiment on PND 63 and a few small changes in sensorimotor responses in the FOB that were not monotonically related to exposure concentration in any experiment. Neither cell-mediated nor humoral immunity were affected in a concentration-related manner by exposure to any of the vapors in 6-week-old male or female offspring. Systematic concentration-related differences in systolic blood pressure were not observed in rats tested at 3 and 6 months of age in any experiment. No systematic differences were observed in serum glucose or glycated hemoglobin A1c (a marker of long-term glucose homeostasis). These observations suggest a LOEL of 3000 ppm of E85 for vertical activity, LOELs of 9000 ppm of E0 and E85 for maternal food consumption, and NOELs of 9000 ppm for the other endpoints reported here. The ethanol content of the vapors did not consistently alter the pattern of behavioral, immunological, or physiological responses to the fuel vapors. The concentrations of the vapors used here exceed by 4-6 orders of magnitude typical exposure levels encountered by the public.

The α decay parameter in the process Ω − → Λ K − has been measured from a sample of 4.50 million unpolarized Ω − decays recorded by the HyperCP (E871) experiment at Fermilab and found to be [ 1.78 ± 0.19 ( stat ) ± 0.16 ( syst ) ] × 10 −2 . This is the first unambiguous evidence for a nonzero α decay parameter, and hence parity violation, in the Ω − → Λ K − decay.

The HyperCP experiment (Fermilab E871) was designed to search for rare phenomena in the decays of charged strange particles, in particular CP violation in $\Xi$ and $\Lambda$ hyperon decays with a sensitivity of $10^{-4}$. Intense charged secondary beams were produced by 800 GeV/c protons and momentum-selected by a magnetic channel. Decay products were detected in a large-acceptance, high-rate magnetic spectrometer using multiwire proportional chambers, trigger hodoscopes, a hadronic calorimeter, and a muon-detection system. Nearly identical acceptances and efficiencies for hyperons and antihyperons decaying within an evacuated volume were achieved by reversing the polarities of the channel and spectrometer magnets. A high-rate data-acquisition system enabled 231 billion events to be recorded in twelve months of data-taking., Comment: 107 pages, 45 Postscript figures, 14 tables, Elsevier LaTeX, submitted to Nucl. Instrum. Meth. A

Organotins are used commercially as agricultural pesticides, antifouling agents, and stabilizers for polyvinyl chloride (PVC) pipe. Mono- and di-substituted methyl and butyltins, used in PVC pipe production, are of concern as they leach from supply pipes into drinking water and have been reported to cause multisystem toxicity, including immunotoxicity. As part of an ongoing study to evaluate immunotoxic effects of organotins, we assessed immune function in adult Sprague-Dawley (CD) rats after exposure to dibutyltin dichloride (DBTC). Individually-housed adult male and female CD rats were given drinking water containing 0, 10, or 25 mg DBTC/L (final concentration) in 0.5% Alkamuls for 28 days. Water bottles were changed and water consumption was monitored twice weekly and body weights (BW) were recorded weekly. Delayed-type hypersensitivity (DTH), primary and secondary antibody responses to sheep red blood cells, and natural killer (NK) cell activity were evaluated in separate groups of treated and control animals on day 29 of exposure. Water consumption was significantly decreased in both sexes at 25 mg DBTC/L. BW, immune organ weights, the DTH response, and NK cell activity did not vary by dose. Different results for antibody responses in male rats were obtained in two experimental replicates. In the first replicate, IgG was elevated at the highest dose whereas in the second replicate, IgM was suppressed. However, as these effects occurred at the high dose of 25 mg DBTC/L, which is a concentration a million times higher than levels of DBTC reported in drinking water, our data suggest that DBTC is unlikely to cause immunotoxicity at concentrations found in drinking water supplies.

A number of regulatory agencies in western Europe, Japan and the United States now include guidelines for evaluating the potential immunotoxicity of chemicals, including drugs, as part of routine toxicity testing. Most testing guidelines recommend observational or functional assays that, based on studies in laboratory animals, are able to detect changes in immune function that are associated with increased susceptibility to infectious or neoplastic cell challenge. To appreciate how well observational and functional endpoints are likely to predict an increased risk of infection in humans, it is important to establish correlations between alterations in human immune function and an increased risk of disease. This review will address the clinical evidence for increased risk of disease in humans with mild to moderate levels of immunosuppression using examples from the literature, discuss specific immune system defects associated with increased rates of infection, and examine factors that impact the interpretation of clinical data. The most comprehensive data bases that address these relationships, those derived from patients with primary immunodeficiency and AIDS, are not discussed in this review. These are extreme examples of immunodeficiency and neither the specific clinical diseases that result, nor eventual outcomes, have much in common with that which occurs in individual with chronic mild-to-moderate immunosuppression.

Each year, 75 million pounds of the broadleaf herbicide atrazine (ATR) are applied to crops in the United States. Despite limited solubility, ATR is common in ground and surface water, making it of regulatory concern. ATR suppresses the immunomodulatory hormones prolactin (PRL) and the thyroid hormones (THs), with developmental exposure to ATR permanently disrupting PRL regulation. We hypothesized that ATR may cause developmental immunotoxicity through its disruption of PRL or THs. To test this hypothesis, pregnant Sprague-Dawley (SD) rats were exposed to 35-mg ATR/kg/d from gestational day (GD) 10 through postnatal day (PND) 23. Separate groups were exposed to bromocryptine (BCR) at 0.2 mg/kg/2x/day to induce hypoprolactinemia or to propylthiouracil (PTU) at 2 mg/kg/day to induce hypothyroidism. After the offspring reached immunologic maturity (at least 7 weeks old), the following immune functions were evaluated: natural killer (NK) cell function; delayed-type hypersensitivity (DTH) responses; phagocytic activity of peritoneal macrophages; and antibody response to sheep erythrocytes (SRBC). ATR decreased the primary antibody and DTH responses in male offspring only. Neither PTU nor BCR caused immunosuppression in any measured variable, although PTU increased phagocytosis by peritoneal macrophages. These results demonstrate that developmental exposure to ATR produced gender-specific changes in immune function in adult rats and suggest that immune changes associated with ATR are not mediated through the suppression of PRL or THs.

Direct CP violation in nonleptonic hyperon decays can be established by comparing the decays of hyperons and anti-hyperons. For Ξ decay to Λπ followed by Λ to pπ, the proton distribution in the rest frame of Lambda is governed by the product of the decay parameters αΞαΛ. The asymmetry ΛΞΛ, proportional to the difference of αΞαΛ of the hyperon and anti-hyperon decays, vanishes if CP is conserved. We report on an analysis of a fraction of 1997 and 1999 data collected by the HyperCP (E871) collaboration during the fixed-target runs at Fermilab. The preliminary measurement of the assymmetry is AΞΛ = [−7±12(stat)±6.2(sys)] × 10−4, an order of magnitude better than the present limit.

FNAL E871 (HyperCP) collected over 38 terabytes of data during the 1997 fixed-target run at Fermilab. The data-acquisition (DAQ) system wrote data to tape with a typical rate of 13 MB/s. A second data collection period in 1999 allowed for the collection of a further 82 terabytes of data. However, changes in the spill structure and an increase in primary beam intensity necessitated an upgrade of the 1997 DAQ system. The 1999 run of HyperCP featured a DAQ system which recorded data on 20,421 8 mm tapes at a sustainable rate of 27 MB/s. The rationale and methods for this upgrade are detailed within.

At present, several animal-based assays are used to assess immunotoxic effects such as immunosuppression and sensitization. Growing societal and ethical concerns, European legislation, and current research demands by industry are driving animal-based toxicity testing towards new animal-free testing strategies. There is a growing belief that non-animal approaches can assure human safety, provided that biological markers are available to identify the immunotoxic potentials of new chemicals to which humans are exposed. The understanding that the immune system can be the target of many chemicals, resulting in a range of adverse effects on the host’s health, has raised serious concerns from the public and within the regulatory agencies. Hypersensitivity and immunosuppression are considered the primary focus for developing in vitro methods in immunotoxicology. However, in vitro assays to detect immunostimulation and autoimmunity are also needed. Reviews of the state of the art in the field of in vitro immunotoxicity reveal a limited number of cell-based immunotoxicity assays for predicting the toxicity of xenobiotics toward the immune system. The objective of this chapter is to review the progress that has been made in understanding mechanisms and key adverse outcome pathways and their components that are involved in responses to toxicant exposure, and application of this understanding to test development and hazard prediction of xenobiotics.

The Fermilab HyperCP experiment has accumulated the world's largest sample of Ξ− and Ξ + hyperon decays within two running periods in 1997 and 1999. The primary goal of the experiment is to search for direct CP violation in the decay sequences Ξ− → Λ π− → p π− π− and Ξ + → Λ π+ → p π+ π+. A violation of CP would manifest itself as a difference between the angular distribution of the proton and the antiproton in the Λ and Λ helicity frame. The amount of data is enough to reach a statistical sensitivity of 1.4 × 10−4 in the CP violating asymmetry A ΞΛ = (αΞ αΛ − α Ξ α Λ )/(αΞ αΛ + α Ξ α Λ ). We present an analysis method used to take into account the slight differences in the production of the Ξ− and Ξ + samples. A preliminary results on A ΞΛ at the level of a few 10−3 and based on a few percent of the 1997 data will be presented.

Bromate is one of the water disinfection by-products (DBPs) produced during the process of ozonation. The purpose of this study was to evaluate the immunotoxic potential of sodium bromate (SB) in female B6C3F1 mice. SB was administered in the drinking water for 28 days at doses of 80-800 mg/l. There was no difference in drinking water consumption between the animals exposed to SB and the tap water controls. Exposure to SB did not produce any signs of overt toxicity. Furthermore, no significant differences were observed in body weight, body weight gain, or the weights of thymus, liver, kidneys or lungs. No gross pathological lesions were observed in SB-treated animals. However, animals exposed to SB had a significant increase in absolute (28%) and relative (26%) spleen weights. The erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), platelet count, total leukocyte count, and counts of differential leukocytes were unaffected by SB. A dose-related increase in reticulocytes was observed following exposure to SB with the greatest increase (78%) observed at the highest dose level. Overall, there were no changes in the absolute number of total T cells, CD4+CD8- T cells, CD4-CD8+ T cells, natural killer (NK) cells and macrophages. Exposure to SB did not affect the percentage of B cells, although a slight increase in absolute number of B cells at the dose of 600 mg/l was observed. There was no alteration in IgM antibody-forming cell (AFC) response, mixed leukocyte reaction (MLR) and NK cell activity after exposure to SB. When the activity of peritoneal macrophages, unstimulated or stimulated with IFN-gamma and LPS, was evaluated using the cytotoxic/cytostatic assay of B16F10 tumor cells, the suppressive effect of macrophages on the proliferation of B16F10 tumor cells was decreased after exposure to SB. In conclusion, SB, when administered in the drinking water at doses from 80 mg/l to 800 mg/l, produced minimal toxicological and immunotoxic effects in female B6C3F1 mice.

The data acquisition system of the HyperCP experiment at Fermilab recorded about 50 TB of data on 12 000 tapes in 1997. The system recorded data at a sustained throughput of 12 MB/s typically and was capable of a maximum rate of 16 MB/s. The front-end electronics systems read 20 000 channels and achieved a typical readout dead time of about 3 μs per event, allowing operation at a trigger rate of 75 kHz with less than 30% dead time.

A sensitive search for direct CP violation in Ξ− (Ξ+) and Λ (Λ) decays is underway at FNAL. Experiment E871 (HyperCP) intends to perform a precision measurement of the angular distribution of protons (anti-protons) with respect to the helicity axis in the rest frame of the Λ (Λ). The slopes of these distributions give the decay parameters αΞαΛ and αΞαΛ. An asymmetry parameter A in terms of these decay parameters has been defined for which a non-zero value would be unambiguous evidence for direct CP violation. Theoretical predictions for A range from no asymmetry up to ∼ 10−3. HyperCP expects to measure A with an uncertainty of ∼ 2 × 10−4.

Recent epidemiological studies have reported associations between the consumption of chlorinated drinking water and various types of human cancer; in addition, exposure to chlorine (Cl-) in drinking water has been reported to suppress certain immune functions in laboratory animals. The current studies were conducted to extend our knowledge of the effects of drinking water exposure to Cl-. Female C57BL/6 mice were administered hyperchlorinated drinking water (7.5, 15, or 30 ppm Cl-) for 2 weeks prior to sacrifice for evaluation of spleen and thymus weights, the plaque-forming cell (PFC) response, hemagglutination (HA) titer, and lymphocyte proliferation (LP). Significant reductions in organ weights and immune response were observed in the positive control groups (i.e. dexamethasone- or cyclophosphamide-exposed mice). No consistent differences were observed between the Cl--exposed animals and vehicle control mice for the evaluated parameters. Thus, under the conditions of these experiments, 2 weeks of exposure to hyperchlorinated drinking water had no apparent adverse effects on immune function.

The potential for chemicals to adversely affect human immunologic health has traditionally been evaluated in rodents, under laboratory conditions. These laboratory studies have generated valuable hazard identification and immunotoxicologic mechanism data; however, genetically diverse populations exposed in the wild may better reflect both human exposure conditions and may provide insight into potential immunotoxic effects in humans. In addition, comparative studies of species occupying reference and impacted sites provide important information on the effects of environmental pollution on the immunologic health of wildlife populations. In this symposium overview, Peter Hodson describes physiological changes in fish collected above or below the outflows of paper mills discharging effluent from the bleaching process (BKME). Effects attributable to BKME were identified, as were physiological changes attributable to other environmental factors. In this context, he discussed the problems of identifying true cause and effect relationships in field studies. Mohamed Faisal described changes in immune function of fish collected from areas with high levels of polyaromatic hydrocarbon contamination. His studies identified a contaminant-related decreases in the ability of anterior kidney leukocytes to bind to and kill tumor cell line targets, as well as changes in lymphocyte proliferation in response to mitogens. Altered proliferative responses of fish from the contaminated site were partially reversed by maintaining fish in water from the reference site. Peter Ross described studies in which harbor seals were fed herring obtained from relatively clean (Atlantic Ocean) and contaminated (Baltic Sea) waters. Decreased natural killer cell activity and lymphoproliferative responses to T and B cell mitogens, as well as depressed antibody and delayed hypersensitivity responses to injected antigens, were identified in seals fed contaminated herring. In laboratory studies, it was determined that rats fed freeze-dried Baltic Sea herring had higher virus titers after challenge with rat cytomegalovirus (RCMV) than rats fed Atlantic Ocean herring; perinatal exposure of rats to oil extracted from Baltic herring also reduced the response to challenge with RCMV. Keith Grassman reported an association between exposure to polyhalogenated aryl hydrocarbons and decreased T cell immunity in the offspring of fish-eating birds (herring gulls and Capsian terns) at highly contaminated sites in the Great Lakes. The greatest suppression of skin test responses to phytohemagglutinin injection (an indicator of T cell immunity) was consistently found at sites with the highest contaminant concentrations. Judith Zelikoff addressed the applicability of immunotoxicity studies developed in laboratory-reared fish for detecting altered immune function in wild populations. She presented data from studies done in her laboratory with environmentally relevant concentrations of metals as examples. Although the necessity of proceeding with caution when extrapolating across species was emphasized, she concluded that published data, and results presented by the other Symposium participants, demonstrate that assays similar to those developed for use in laboratory rodents may be useful for detecting immune system defects in wildlife species directly exposed to toxicants present in the environment.

Perfluorinated compounds (PFCs) have been recognized as an important class of environmental contaminants commonly detected in blood samples of both wildlife and humans. These compounds have been in use for more than 60 years as surface treatment chemicals, polymerization aids, and surfactants. They possess a strong carbon-fluorine bond, which leads to their environmental persistence. There is evidence from both epidemiology and laboratory studies that PFCs may be immunotoxic, affecting both cell-mediated and humoral immunity. Reported effects of PFCs include decreased spleen and thymus weights and cellularity, reduced specific antibody production, reduced survival after influenza infection, and altered cytokine production. Immunosuppression is a critical effect associated with exposure to PFCs, as it has been reported to reduce antibody responses to vaccination in children. Mounting evidence suggests that immunotoxicity in experimental animals can occur at serum concentrations below, within, or just above the reported range for highly exposed humans and wildlife. Considering bioaccumulation and exposure to multiple PFCs, the risk of immunotoxicity for humans and wildlife cannot be discounted. This review will discuss current and recently published work exploring the immunomodulatory effects of PFCs in experimental animals and humans.

Using a silicon-microstrip detector array to identify secondary vertices, we have observed {ital b}{r_arrow}{ital J}/{psi}{r_arrow}{mu}{sup +}{mu}{sup {minus}} decays in 800 GeV/{ital c} proton-gold interactions. The doubly differential cross section for {ital J}/{psi} mesons originating from {ital b}-quark decays, assuming linear dependence on nucleon number, is {ital d}{sup 2}{sigma}/{ital dx}{sub {ital Fdp}}{sup 2}{sub {ital T}}=107{plus_minus}28{plus_minus}19/nucleon at {ital x}{sub {ital F}}=0.05 and {ital p}{sub {ital T}}=1GeV/{ital c}. This measurement is compared to next-to-leading-order QCD predictions. The integrated {ital b}-quark production cross section, obtained by extrapolation over all {ital x}{sub {ital F}} and {ital p}{sub {ital T}}, is {sigma}({ital pN}{r_arrow}{ital bb}{ovr bar}+{ital X})=5.7{plus_minus}1.5{plus_minus}1.3 nb/nucleon.

We have previously shown decreased resistance to Trichinella spiralis (Ts) infection and reduced parasite antigen-specific responses in B6C3F1 mice exposed to TCDD before infection. The current study was done to characterize the effects of preinfection administration of 1, 10, or 30 micrograms TCDD/kg on host resistance of female F344 rats to Ts infection and to examine parasite antigen-specific responses in the spleen and mesenteric lymph nodes of infected animals. TCDD exposure did not affect adult parasite elimination from the small intestine or the numbers of encysted larvae in the muscle, although host control of newborn larvae production in female parasites isolated from the highest dose group was compromised. Proliferative responses of lymphocytes cultured with parasite antigen were enhanced in groups of rats exposed to 30 micrograms TCDD/kg. These results, which are in marked contrast to the effects obtained in B6C3F1 mice, demonstrate a clear species difference in the effects of TCDD on immune function in rodents and underscore the need to determine which species more closely reflects the potential outcome of human exposure to TCDD.

Immunotoxicology is the study of undesired modulation of the immune system by extrinsic factors. Toxicological assessments have demonstrated that the immune system is a target following exposure to a diverse group of xenobiotics including ultraviolet radiation, chemical pollutants, therapeutics, and recreational drugs. There is a well-established cause and effect relationship between suppression of the immune response and reduced resistance to infections and certain types of neoplasia. In humans, mild-to-moderate suppression of the immune response is linked to reduced resistance to common community-acquired infections, whereas opportunistic infections, which are very rare in the general population, are common in individuals with severe suppression. Xenobiotic exposure may also result in unintended stimulation of immune function. Although a cause and effect relationship between unintended stimulation of the immune response and adverse consequences has yet to be established, evidence does suggest that hypersensitivity, autoimmunity, and pathological inflammation may be exacerbated in susceptible populations exposed to certain xenobiotics. Xenobiotics can act as allergens and elicit hypersensitivity responses, or they can modulate hypersensitivity responses to other allergens such as pollen or dust mite by acting as adjuvants, enhancing the development or expression of hypersensitivity. Allergic contact dermatitis, allergic rhinitis, and asthma are the most commonly encountered types of hypersensitivity reactions resulting from chemical exposure. The immunologic effectors and mechanisms involved in autoimmune reactions are the same as those associated with responses to foreign antigens; however, the reactions are directed against the host's own cells. Thus, chemicals that induce immune suppression, nonspecific immunostimulation, or hypersensitivity may also impact autoimmunity. Risk assessment for immunotoxicity should be performed using the same approaches and principles for other noncancer effects. However, since xenobiotics may have effects on more than one aspect of immune function, immunotoxicity data should be evaluated separately for evidence of suppression, stimulation, hypersensitivity, and autoimmunity.

Epidemiological data suggest that occupational exposure to the amphibole-containing vermiculite in Libby, MT, was associated with increased risk for developing autoimmune diseases and had an odds ratio of 3.23 for developing rheumatoid arthritis (RA). The collagen-induced arthritis (CIA) and the peptidoglycan-polysaccharide (PG-PS) models of RA were employed to determine whether exposure to Libby amphibole (LA) induced a more rapid onset, increased expression, or prolonged course of RA. Female Lewis rats were intratracheally instilled with total doses of 0.15, 0.5, 1.5, or 5 mg LA or 0.5 or 1.5 mg amosite asbestos, and arthritis was induced with either the PG-PS or CIA model. Neither LA nor amosite exposure affected the disease course in the CIA model, or the production of rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies. LA exposure reduced swelling in the PG-PS model and decreased anti-PG-PS and total immunoglobulin M (IgM) antibody titers. Both amosite and LA exposure increased the number of rats with circulating anti-nuclear antibodies (ANA), the majority of which presented a speckled staining pattern. However, this ANA enhancement was not dose responsive. These results failed to show a positive correlation between LA exposure and RA disease in two animal models, although upregulated ANA suggest an altered immunological profile consistent with other systemic autoimmune diseases.

Specific environmental factors including chemicals, drugs, microbes, and both physical and psychological factors can affect the immune system producing dysfunction and, ultimately, an increased risk of chronic disease. Several different types of immune alterations can result from environmentally induced immunotoxicity and these connect immune insult to chronic disease. We illustrate how many immune-based chronic diseases arising in nonlymphoid tissues may be categorized based on the target tissue (e.g., skin, lung) rather than on the probable cause: a dysfunctional immune system. Finally, we discuss various factors that affect: (1) susceptibility to immunotoxicity and (2) the specific spectrum of disease outcomes following exposure.

As described in prior chapters of this book, chronic diseases connected to immune and inflammatory dysfunction are often categorized based on the affected tissues and, as a result, can be overlooked as being immune-mediated diseases. These diseases are numerous in nature, costly to individuals, families and nations, and pervasive. They represent an emerging global health threat where effective strategies capable of reducing disease prevalence have been slow to emerge. This concluding chapter includes information on four additional immune/inflammatory-based diseases or conditions: psoriasis, autoimmune thyroiditis, frailty, and an isolation-withdrawal state. It also provides an overview of plans for reducing the risk of immune-based chronic disease and emphasizes the importance of acting early in life and using safety data that are directly relevant to priority chronic diseases. The risk-reduction strategy combines four key components: widespread outcome-based safety testing that precedes human exposure, whole-life-considered therapeutic interventions, strategic research, and effective public health policies.

Immunotoxicology is the study of undesired modulation of the immune system by extrinsic factors. Toxicological assessments have demonstrated that the immune system is a target following exposure to a diverse group of xenobiotics including ultraviolet radiation, chemical pollutants, therapeutics, and recreational drugs. There is a well-established cause and effect relationship between suppression of the immune response and reduced resistance to infections and certain types of neoplasia. In humans, mild-to-moderate suppression of the immune response is linked to reduced resistance to common community-acquired infections, whereas opportunistic infections, which are very rare in the general population, are common in individuals with severe suppression. Xenobiotic exposure may also result in unintended stimulation of immune function. Although a cause and effect relationship between unintended stimulation of the immune response and adverse consequences has yet to be established, evidence does suggest that hypersensitivity, autoimmunity, and pathological inflammation may be exacerbated in susceptible populations exposed to certain xenobiotics. Xenobiotics can act as allergens and elicit hypersensitivity responses, or they can modulate hypersensitivity responses to other allergens such as pollen or dust mite by acting as adjuvants, enhancing the development or expression of hypersensitivity. Allergic contact dermatitis, allergic rhinitis, and asthma are the most commonly encountered types of hypersensitivity reactions resulting from chemical exposure. The immunologic effectors and mechanisms involved in autoimmune reactions are the same as those associated with responses to foreign antigens; however, the reactions are directed against the host’s own cells. Thus, chemicals that induce immune suppression, nonspecific immunostimulation, or hypersensitivity may also impact autoimmunity. Risk assessment for immunotoxicity should be performed using the same approaches and principles for other noncancer effects. However, since xenobiotics may have effects on more than one aspect of immune function, immunotoxicity data should be evaluated separately for evidence of suppression, stimulation, hypersensitivity, and autoimmunity.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been reported to decrease host resistance to a variety of infectious agents when exposure occurs prior to infection. Resistance to viral infection has been observed at doses as low as 0.1 microgram TCDD/kg body wt, well below the thymolytic dose in mice. In the present study, female B6C3F1 mice were exposed to a single intraperitoneal injection of 0, 0.1, 1.0, 10.0, or 30.0 micrograms TCDD/kg 7 days prior to infection to determine the effects of TCDD exposure on resistance to the nematode parasite Trichinella spiralis. Exposure to 10 or 30 micrograms TCDD/kg delayed adult parasite elimination from the small intestine. Significantly more larvae were released by female parasites and greater numbers of encysted larvae were recovered from the muscle of mice exposed to TCDD. Proliferative responses of splenocytes and mesenteric lymph node cells stimulated with T. spiralis antigen were significantly suppressed at exposure levels of TCDDor = 1.0 microgram/kg 7 days after infection and in splenocytes only at 14 days after infection, demonstrating the greater sensitivity of proliferative responses to TCDD exposure than actual host resistance to Ts infection. Suppressed proliferation was observed at doses which produced TCDD concentrationsor = 0.2 pmol/g of lymphoid tissue on Day 7 of infection. In addition, it was determined that infected mice had higher TCDD levels than noninfected mice given the same dose. These results suggest an interaction between TCDD exposure and infection, i.e., that exposure to TCDD altered the host response to infection, while infection delayed elimination of TCDD from the host.

The differential cross sections do/dxF for J/G produced inclusively in 800 GeV/c p-Cn and pBe collisions have been measured in the kinematic range 0.30 5 IF < 0.95 through the decay mode J/G + p+p-. They are compared with the predictions of the semilocal duality model for several sets of parton density functions. No evidence for a suggested intrinsic charm contribution to the cross section is observed. The ratio of the differential cross sections for Cu and Be targets confirms the suppression of J/$ production in heavy nuclei at large ZF.

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.

Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm.