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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.

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.

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.

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 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.

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.

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.

Charged-particle tracking in the international Muon Ionisation Cooling Experiment (MICE) will be performed using two solenoidal spectrometers, each instrumented with a tracking detector based on 350 {\mu}m diameter scintillating fibres. The design and construction of the trackers is described along with the quality-assurance procedures, photon-detection system, readout electronics, reconstruction and simulation software and the data-acquisition system. Finally, the performance of the MICE tracker, determined using cosmic rays, is presented., Comment: 43 pages, 38 figures

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.

The T-cell-dependent antibody response is suppressed in mice exposed to 3.75, 7.5, 15, and 30 mg PFOA (perfluorooctanoic acid)/kg body weight (bw). Reduced bw accompanied immunosuppression at 15 and 30 mg/kg. We investigated the hypothesis that the observed immunosuppression is secondary to elevated serum corticosterone levels by assessing immune function in adrenalectomized (adx) or sham-operated C57BL/6N female mice exposed to 0, 7.5, or 15 mg PFOA/kg bw in drinking water for 10 days. Bw, primary antibody responses to a T-dependent antigen, clinical serum chemistries related to liver health, and serum corticosterone levels were evaluated. Exposure to 15 mg/kg decreased bw by approximately 10% after 8 days of dosing and until 2 days postdosing in both adx and sham animals; bw of adx animals were still reduced 5 days postdosing. IgM antibody titers were statistically reduced by 15% in sham animals and 18% in adx animals exposed to 15 mg/kg and by 11.8% in adx animals exposed to 7.5 mg/kg. Corticosterone concentrations were elevated by 157% in dosed sham animals relative to control animals and were reduced by 27% in dosed adx animals relative to control animals (neither changes were statistically significant). Clinical serum chemistries related to liver health were not statistically altered by either dose or adrenalectomy. The failure of adrenalectomy to protect mice from the immunosuppressive effects of PFOA indicates that suppression of antibody synthesis is not the result of liver toxicity or stress-related corticosterone production.

The Main Injector Neutrino Oscillation Search (MINOS) experiment uses an accelerator-produced neutrino beam to perform precision measurements of the neutrino oscillation parameters in the "atmospheric neutrino" sector associated with muon neutrino disappearance. This long-baseline experiment measures neutrino interactions in Fermilab's NuMI neutrino beam with a near detector at Fermilab and again 735 km downstream with a far detector in the Soudan Underground Laboratory in northern Minnesota. The two detectors are magnetized steel-scintillator tracking calorimeters. They are designed to be as similar as possible in order to ensure that differences in detector response have minimal impact on the comparisons of event rates, energy spectra and topologies that are essential to MINOS measurements of oscillation parameters. The design, construction, calibration and performance of the far and near detectors are described in this paper., Comment: Revised according to referee's comments. 91 pages, 43 figures, submitted to NIM. arXiv figures are greatly compressed, please see NIM itself or the Fermilab library server for full resolution figures

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 United States EPA, they leach from supply pipes into drinking water and are reported multisystem toxicants. We assessed immune function in Sprague-Dawley rats after developmental dibutyltin dichloride (DBTC) exposure. Pregnant rats were given drinking water containing 0, 10, or 25 mg/L of DBTC (final concentration) in 0.5% Alkamuls from gestational Day (GD) 6 through weaning of pups (37 days total). Approximate doses to dams: 1 and 2.5 mg DBTC/kg body weight (BW) during gestation, or 2.0 and 4.4 mg DBTC/kg BW while nursing. Litters were sexed, weighed, and culled to 4 males and 4 females per dam on postnatal Day (PND) 2. Beginning on PND3, litters of half of the dams per dose were gavaged with 0, 1.0, or 2.5 mg DBTC/kg BW 3X/week for 10 doses (maternal + direct treatment); remaining litters were exposed indirectly via lactation (maternal treatment). BW of litters exposed to 2.5 mg DBTC/kg BW was 10-20% lower (por = 0.05) relative to other groups from PND14 (males) or PND17 (females) through PND37. Delayed-type hypersensitivity (DTH), antibody synthesis, and natural killer (NK) cell activity were evaluated in immunologically mature offspring (N = 6/sex/group). DTH responses and antibody synthesis did not differ by dose, sex, or exposure. NK cell activity in the 10 mg DBTC/L maternal only group was greater in male offspring than in female. In female offspring from the maternal + direct group, cytotoxicity increased by dose at the 25:1 effector:target cell ratio. Our data suggest that developmental immunotoxicity from DBTC-tainted drinking water is unlikely as the concentrations we used were several orders of magnitude higher than concentrations expected to leach from PVC pipes.

Organotin compounds used in polyvinyl chloride (PVC) pipe production are of concern to the U.S. Environmental Protection Agency (EPA) because they leach from supply pipes into drinking water and are reported multisystem toxicants. Immune function was assessed in male Sprague-Dawley rats exposed to the mixture of organotins used in PVC pipe production. Although several of these organotins are reported immunotoxicants, their immunotoxicity as a mixture when given by drinking water has not been evaluated. Adult male rats were given drinking water for 28 d containing a mixture of dibutyltin dichloride (DBTC), dimethyltin dichloride (DMTC), monobutyltin trichloride (MBT), and monomethyltin trichloride (MMT) in a 2:2:1:1 ratio, respectively, at 3 different concentrations (5:5:2.5:2.5, 10:10:5:5, or 20:20:10:10 mg organotin/L), MMT alone (20 or 40 mg MMT/L), or plain water as a control. Delayed-type hypersensitivity, antibody synthesis, and natural killer cell cytotoxicity were evaluated in separate endpoint groups (n = 8/dose; 24/endpoint) immediately after exposure ended. The evaluated immune functions were not affected by the mixture or by MMT alone. Our data suggest that immunotoxicity is unlikely to result from the concentration of organotins present in drinking water delivered via PVC pipes, as the concentrations used were several orders of magnitude higher than those expected to leach from PVC pipes.

Background Perfluorooctanoic acid (PFOA), an environmentally persistent compound of regulatory concern, has been reported to reduce antibody responses in mice at a single dose. Objective The aim of this study was to evaluate PFOA effects on humoral and cellular immunity using standard assays for assessing immune function, and to derive dose–response data. Methods C57BL/6J mice received 0 or 30 mg PFOA/kg/day for 10 days; half of the exposed groups were switched to vehicle and half continued on PFOA for five days. C57BL/6N mice received 0–30 mg/kg/day of PFOA in drinking water for 15 days. Mice were immunized with sheep red blood cells or sensitized to bovine serum albumin in Freund’s complete adjuvant on day 10 of exposure; immune responses were determined 1 day post-exposure. Results We found that 30 mg PFOA/kg/day given for 10 or 15 days reduced IgM synthesis; serum collected 1 day postexposure contained 8.4 × 104 or 2.7 × 105 ng PFOA/mL, respectively. IgM synthesis was suppressed at exposures ≥ 3.75 mg PFOA/kg/day in a dose-dependent manner, and IgG titers were elevated at 3.75 and 7.5 mg PFOA/kg/day. Serum PFOA at 3.75 mg/kg/day was 7.4 × 104 ng/mL 1 day postexposure, or 150-fold greater than the levels reported in individuals living near a PFOA production site. Using a second-degree polynomial model, we calculated a benchmark dose of 3 mg/kg/day, with a lower bound (95% confidence limit) of 1.75 mg/kg/day. Cell-mediated function was not affected. Conclusions IgM antibodies were suppressed after PFOA exposure. The margin of exposure for reduced IgM antibody synthesis was approximately 150 for highly exposed human populations.

The asymmetry in the {bar p} angular distribution in the sequential decay {bar {Omega}}{sup +} {yields} {bar {Lambda}}K{sup +} {yields} {bar p}{pi}{sup +}K{sup +} has been measured to be {bar {alpha}}{sub {Omega}}{bar {alpha}}{sub {Lambda}} = [+1.16{+-}0.18(stat){+-}0.17(syst)]x10{sup -2} using 1.89x10{sup 6} unpolarized {bar {Omega}}{sup +} decays recorded by the Hyper CP (E871) experiment at Fermilab. Using the known value of {alpha}{sub {Lambda}}, and assuming that {bar {alpha}}{sub {Lambda}} = -{alpha}{sub {Lambda}}, {bar {alpha}}{sub {Omega}} = [-1.81{+-}0.28(stat){+-}0.26(syst)]x10{sup -2}. A comparison between this measurement of {bar {alpha}}{sub {Omega}}{bar {alpha}}{sub {Lambda}} and recent measurements of {alpha}{sub {Omega}}{alpha}{sub {Lambda}} made by HyperCP shows no evidence of a violation of CP symmetry.

The complete 5.4 kton MINOS far detector has been taking data since the beginning of August 2003 at a depth of 2070 meters water-equivalent in the Soudan mine, Minnesota. This paper presents the first MINOS observations of muon neutrino and muon anti-neutrino charged-current atmospheric neutrino interactions based on an exposure of 418 days. The ratio of upward to downward-going events in the data is compared to the Monte Carlo expectation in the absence of neutrino oscillations giving: R_data(up/down)/R_MC(up/down) = 0.62^{+0.19}_{-0.14} (stat.) +- 0.02 (sys.). An extended maximum likelihood analysis of the observed L/E distributions excludes the null hypothesis of no neutrino oscillations at the 98 % confidence level. Using the curvature of the observed muons in the 1.3 T MINOS magnetic field muon neutrino and muon anti-neutrino interactions are separated. The ratio of muon neutrino to muon anti-neutrino events in the data is compared to the Monte Carlo expectation assuming neutrinos and anti-neutrinos oscillate in same manner giving: R_data(numubar/numu)/R_MC(numubar/numu) = 0.96^{+0.38}_{-0.27} (stat.) +- 0.15 (sys.), where the errors are the statistical and systematic uncertainties. Although the statistics are limited, this is the first direct observation of atmospheric neutrino interactions separately for muon neutrinos and muon anti-neutrinos.

This letter reports results from the MINOS experiment based on its initial exposure to neutrinos from the Fermilab NuMI beam. The rate and energy spectra of charged current muon neutrino interactions are compared in two detectors located along the beam axis at distances of 1 km and 735 km. With 1.27 x 10^{20} 120 GeV protons incident on the NuMI target, 215 events with energies below 30 GeV are observed at the Far Detector, compared to an expectation of 336 \pm 14.4 events. The data are consistent with muon neutrino disappearance via oscillation with |\Delta m^2_{23}| = 2.74^{+0.44}_{-0.26} x 10^{-3} eV^2/c^4 and sin^2(2\theta_{23}) > 0.87 (at 60% C.L.)., Comment: To be submitted to PRL. 6 pages, 4 figures

We have measured the $\ensuremath{\alpha}$ parameter of the ${\ensuremath{\Omega}}^{\ensuremath{-}}\ensuremath{\rightarrow}\ensuremath{\Lambda}{K}^{\ensuremath{-}}$ decay using data collected with the HyperCP spectrometer during the 1997 fixed-target run at Fermilab. Analyzing a sample of $0.96\ifmmode\times\else\texttimes\fi{}{10}^{6}$ ${\ensuremath{\Omega}}^{\ensuremath{-}}\ensuremath{\rightarrow}\ensuremath{\Lambda}{K}^{\ensuremath{-}}$, $\ensuremath{\Lambda}\ensuremath{\rightarrow}p{\ensuremath{\pi}}^{\ensuremath{-}}$ decays, we obtain ${\ensuremath{\alpha}}_{\ensuremath{\Omega}}{\ensuremath{\alpha}}_{\ensuremath{\Lambda}}=[1.33\ifmmode\pm\else\textpm\fi{}0.33(\mathrm{s}\mathrm{t}\mathrm{a}\mathrm{t})\ifmmode\pm\else\textpm\fi{}0.52(\mathrm{s}\mathrm{y}\mathrm{s}\mathrm{t})]\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}2}$. With the accepted value of ${\ensuremath{\alpha}}_{\ensuremath{\Lambda}}$, ${\ensuremath{\alpha}}_{\ensuremath{\Omega}}$ is found to be $[2.07\ifmmode\pm\else\textpm\fi{}0.51(\mathrm{s}\mathrm{t}\mathrm{a}\mathrm{t})\ifmmode\pm\else\textpm\fi{}0.81(\mathrm{s}\mathrm{y}\mathrm{s}\mathrm{t})]\ifmmode\times\else\texttimes\fi{}{10}^{\ensuremath{-}2}$.

The novel sources of CP violation observed in charged χ and λ hyperon decays were investigated. A comparison of the p and p angular distributions in the hyperon decays was made using a subset of the data from the HyperCP experiment (E871) at Fermilab. A possible source of bias was found to be a momentum-dependent differential loss of events due to interactions of the χ- and χ+ decay products. The obtained result was observed to be stable with respect to time, χ momentum, and secondary-beam intensity, The results show that differences between the χ- and χ+ production angles could cause a bias due to production polarization differences.

We have searched for Theta+(1.54) -> K0,p decays using data from the 1999 run of the HyperCP experiment at Fermilab. We see no evidence for a narrow peak in the K0,p mass distribution near 1.54 GeV/c among 106,000 K0,p candidates, and obtain an upper limit for the fraction of Theta+(1.54) to K0,p candidates of

The HyperCP experiment (E871) at Fermilab has collected the largest sample of hyperon decays in the world. With a data set of over a million Ω− → ΛΚ− decays we have measured the product of αΩαΛ from which we have extracted αΩ. This preliminary result indicates that αΩ is small, but non‐zero. Prospects for a test of CP symmetry by comparing the α parameters in Ω− and Ω+ decays will be discussed.

Increased mortality following influenza A infection was reported in B6C3F1 mice exposed to a low (0.01 micro g/kg) dose of dioxin. However, mortality was not associated with increased viral load and antibody titers to the virus were not decreased at doses of TCDD < or = 10 micro g/kg, suggesting that viral overgrowth, secondary to immunosuppression, was not the proximate cause of death. We tested the hypothesis that mitochondrial toxicity and dysfunction, similar to Reye's syndrome (RS) in humans, is responsible for increased mortality in dioxin-exposed, infected B6C3F1 female mice, based on similarities in the biochemical and immunological events that occur in RS and in TCDD-exposed animals. Endpoints were also included to test the hypothesis that increased pulmonary inflammation following dioxin exposure, in the absence of mitochondrial toxicity, was associated with increased mortality. Dose-related effects of TCDD alone, infection with influenza A alone, and combined TCDD exposure/influenza infection were evaluated. Mice were given a single ip injection of 0, 0.001, 0.01, 0.1, or 1.0 micro g TCDD/kg, 7 days before infection by intranasal instillation of an estimated LD(10-20) of influenza A Hong Kong/8/68 (H3N2) and were terminated 1, 7, and 10 days after infection. Serum, bronchoalveolar lavage fluid (BALF), and lung tissue were collected for various measurements, including clinical chemistries, cell counts, cytokine analysis, and viral titers. Exposure to < or = 1.0 micro g TCDD/kg did not increase mortality; virus titers were similar at all doses of TCDD and there was no dioxin-related effect on serum NH(3) or glucose concentrations, two prominent indicators of the altered mitochondrial oxidative metabolism typically observed in RS. A study was therefore conducted over a wider range of TCDD doses. A single injection of 0, 0.025, 0.5, or 10 micro g TCDD/kg preceded infection by 7 days; subgroups of noninfected control and highest dose group (10 micro g TCDD/kg) mice were also evaluated for biochemical and immunological endpoints on the equivalent of infection day 4 to provide baseline data. Five days after infection the same endpoints described above were evaluated. The 10 micro g TCDD/kg dose increased mortality, but once again did not increase virus titer; as in previous experiments, serum biochemistry endpoints did not support mitochondrial dysfunction. These results suggest that RS is an unlikely explanation for increased influenza mortality in TCDD-exposed mice. Rather, constituents in BALF implicate increased pulmonary inflammation as the mode of TCDD action.

Using data collected with the HyperCP (E871) spectrometer during the 1997 fixed-target run at Fermilab, we report the first observation of the decay K--->pi(-)mu(+)mu(-) and new measurements of the branching ratios for K+/--->pi(+/-)mu(+)mu(-). By combining the branching ratios for the decays K+-->pi(+)mu(+)mu(-) and K--->pi(-)mu(+)mu(-), we measure Gamma(K+/--->pi(+/-)mu(+)mu(-))/Gamma(K+/--->all) = (9.8+/-1.0+/-0.5)x10(-8). The CP asymmetry between the rates of the two decay modes is [Gamma(K+-->pi(+)mu(+)mu(-))-Gamma(K--->pi(-)mu(+)mu(-))]/[Gamma(K+-->pi(+)mu(+)mu(-))+Gamma(K--->pi(-)mu(+)mu(-))] = -0.02+/-0.11+/-0.04.

The primary purpose of the HyperCP experiment at Fermilab is to test CP in hyperon decays by comparing the decay distributions for Ⅺ− (“cascade”) decays in the decay sequence: Ⅺ− → π− + Λ0, Λ0 → π− + p, with those for the antiparticle Ⅺ+. In addition, we can test CP in charged kaon decays by comparing the slopes of the Dalitz plot for Κ+ and Κ− decays. We are also looking at rare decay modes of charged kaons and hyperons, particularly those involving muons. In two runs in 1997 and 1999, we collected approx. 500 millon charged kaon decays, 2.5 billion Ⅺ− and Ⅺ+ decays, and 19 million Ω− and Ω+ decays. This is the largest sample of fully reconstructed particle decays ever collected.

Although reductionist experimental designs are excellent for identifying cells, molecules, or functions involved in resistance to particular microbes or cancer cells, they do not provide an integrated, quantitative view of immune function. In the present study, mice were treated with either dexamethasone (DEX) or cyclosporin A (CyA), and immune function and host resistance were evaluated. Multivariate statistical methods were used to describe the relative importance of a broad range of immunological parameters for host resistance in mice treated with various dosages of DEX. Multiple regression and logistic regression analysis indicated that changes in 24 immunological parameters explained a substantial portion of the changes in resistance to B16F10 tumor cells or streptococcus group B. However, at least 40% of the change in host resistance remained unexplained. DEX at all dosages substantially suppressed numerous relevant immunological parameters, but significantly decreased resistance to Listeria monocytogenes only at the highest dosage. In contrast, CyA substantially decreased resistance to L. monocytogenes at dosages that caused relatively minor suppression of just a few immunological parameters (unfortunately, CyA data and host resistance data for L. monocytogenes were not suitable for multivariate analysis). These results illustrate that mathematical models can be used to explain changes in host resistance on the basis of changes in immune parameters, and that moderate changes in relevant immunological parameters may not produce the types of changes in host resistance expected on the basis of results from reductionist experimental designs.

Exposure to various xenobiotics, including oxidant gases, diesel exhaust, and certain pesticides, has been reported to exacerbate pulmonary allergic hypersensitivity responses. Increased lymphocyte proliferative responses to parasite antigens or increased antibody responses to sheep erythrocyte have also been reported in rats exposed to TCDD before infection or immunization. As a result, these studies were conducted to test the hypothesis that TCDD exposure exacerbates the allergic response to house dust mite antigen. Brown Norway rats were injected, ip, with 0, 1, 10, or 30 microg TCDD/kg 7 days before intratracheal (it) sensitization to semipurified house dust mite allergen (HDM). Fourteen days later, rats were challenged with HDM and immediate bronchospasm was measured. At this time point, plus 2 and 7 days later, inflammatory cells in bronchoalveolar lavage fluid (BALF), HDM-specific IgE levels in serum, and HDM-driven cell proliferation in bronchial lymph nodes and spleen were evaluated. TCDD exposure decreased both immediate bronchoconstriction and specific IgE synthesis after the HDM challenge; 7 days later, HDM-specific IgE responses remained suppressed. Total serum IgE levels were similar in all groups. HDM challenge alone significantly increased cellular and biochemical indicators of lung injury, both of which were suppressed by TCDD exposure. The proliferative response of lymph node cells, but not of spleen cells, to HDM was also suppressed at the highest TCDD dose, although the splenic response to Concanavalin A was elevated. It appears that early events in the response to HDM are affected by TCDD exposure, since message for IL5 was dramatically reduced 2 days after sensitization, but not after challenge. We therefore conclude that TCDD exposure suppressed, rather than enhanced the development of allergic immune responses and the expression of immune-mediated lung disease.

In immunotoxicology, the critical functions of the immune system (host resistance to infection and neoplasia) cannot be measured directly in humans. It is theoretically possible to predict changes in host resistance based on changes in immunological functions known to mediate host resistance. However, quantitative predictive models of this type have not yet been achieved in humans or in animal models. Multivariate statistical methods were developed for analysis and modeling of the effects of several explanatory variables on a dependent variable, and they seem well suited for attempts to predict host resistance changes caused by changes in immunological parameters. However, these methods were developed with the assumption that all variables can be measured for each experimental subject. For a number of reasons, this generally cannot be done in comprehensive immunotoxicology evaluations. In the present study, the suitability of multivariate methods for analysis of variables measured in different experiments was examined, using a limited data set consisting of immunological parameters that could all be measured for each mouse. Analysis was done on the original data set and test data sets produced by randomizing data within dosage groups. This was done to simulate the random pairing of data that would occur if measurements were obtained from different sets of mice in different experiments. Statistical theory indicates that randomization will disrupt the correlation matrices that are central in multivariate analyses. However, the present results demonstrate empirically that for at least one immunotoxicant (dexamethasone), remarkably similar multivariate models were obtained for the original and 109 randomized data sets. In contrast, the randomized data sets produced substantially different multivariate models when data obtained with a different immunotoxicant (cyclosporin A) were analyzed. The major difference between the two data sets was that dexamethasone strongly and dose-responsively suppressed many more parameters than did cyclosporin A. Additional work is needed to determine whether there are consistent criteria that could be used to identify immunotoxicology data sets, which would be amenable to multivariate analysis.

Results of a search for the three neutral charm decays, D0 -> mu e, D0 -> mu mu, and D0 -> e e, are presented. This study was based on data collected in Experiment 789 at the Fermi National Accelerator Laboratory using 800 GeV/c proton-Au and proton-Be interactions. No evidence is found for any of the decays. Upper limits on the branching ratios, at the 90% confidence level, are obtained., 28 pages, 18 figures. Submitted to Physical Review D

Fermilab experiment 871, HyperCP, is a search for direct CP violation in Ⅺ and Λ hyperon decays. A non-zero value in the asymmetry parameter A, defined in terms of the decay parameter products αⅪαΛ and αⅪαΛ, would be unambiguous evidence for direct CP violation. The first data-taking run finished at the end of 1997 and accumulated over one billion Ⅺ− and Ⅺ+ decays. A sensitivity in A of ≈10−4 is expected. A review of CP violation in hyperon decays is given, the HyperCP detector is described, and the status of the data analysis is discussed.

Fermilab experiment 789 studies low‐multiplicity decays of neutral D and B mesons in a high‐rate fixed‐target environment. Preliminary results from the 1991 run are presented.

been as large as some that we have observed at D-3 (also see Fitzgerald, 1982). In seven visits to D-3, 5 (6.2%) LAR-A(2n) x C. gularis, 61 (76.2%) LAR-A(2n), and 14 (17.5%) C. gularis have been collected. These data indicate that, although hybridization between these forms is relatively common, a large-scale breakdown of reproductive isolation between LAR-A(2n) and C. gularis is not occurring at the site. We are grateful to the J. William Fulbright College of Arts and Sciences for providing a research incentive grant in 1986 and to the Department of Zoology for providing financial support in 1988 and 1989. Field research in Texas was conducted under authority of Texas Parks and Wildlife permit no. 61.

Benzene is widely used by chemical industries and exposure to benzene has been shown experimentally to be immunotoxic in adult animals. This study addressed whether exposure of fetuses in utero to benzene compromises the development of fetal B lymphopoiesis and whether B-lymphocyte development recovers postnatally. Pregnant BALB/C dams were given intraperitoneal injections of benzene (100 mg/kg, twice daily) from day 12.5 of gestation through day 19.5 of gestation. Phenotypic analysis revealed that fetal liver cell suspensions from embryos exposed in utero contained fewer pre-B cells and B cells than corresponding controls. Fetal liver cell cultures established from these embryos also produced fewer B cells. In contrast, levels of pre-B cells were elevated in the livers of 8-day-old neonates that had been exposed to benzene in utero. Moreover, responsiveness to the B-cell mitogen, LPS, was significantly decreased in spleen cell cultures derived from these neonates. These results indicate that in utero exposure to high concentrations of benzene alters fetal B lymphopoiesis and may compromise immune responsiveness postnatally.

A single intramuscular injection of nickel chloride (18.3 mg/kg) caused a significant reduction in murine splenic natural killer (NK) cell activity. This reduction in NK activity was not associated with a significant reduction in spleen cellularity nor in the production of suppressor cells. In a 4-hr 51Cr-release assay, NK cell activity was suppressed in both CBA/J and C57BL/6J mice. Administration of the nickel dose (i.e., 18.3 mg/kg total) over a 2-week period also caused a significant reduction in NK cell activity. In an in vivo NK assay, the clearance of [125I]iododeoxyuridine-labeled YAC-1 tumor cells from the lungs of nickel-treated mice was significantly reduced compared with saline injected controls. Another in vivo correlate of nickel-induced NK suppression was observed in mice injected with the B16-F10 melanoma. Mice given a single intramuscular injection of NiCl2 (18.3 mg/kg) developed significantly greater numbers of lung tumors than saline controls. The results indicate that NiCl2 is a potent suppressor of NK cell activity.

The purpose of this discussion is (a) to develop a method by which test track data can be related directly to any railroad’s rock and roll problem, and (b) to provide a means for objectively evaluating the railroad’s requirements for rock and roll control devices.