Evaluation of the immunotoxicity of low level PCB exposure in the rat

Weanling male Fischer 344 rats were exposed daily by gastric intubation for up to 15 weeks to the polychlorinated biphenyl (PCB) Aroclor 1254 at 0.1, 1, 10, or 25 mg/kg body weight. At 5, 10 and 15 weeks groups of rats were killed and immune functions were evaluated. The immune parameters examined included the following: body and lymphoid organ weights, mitogen-stimulated lymphoproliferative (LP) responses, natural killer (NK) cell activity, mixed lymphocyte reaction (MLR), and cytotoxic T lymphocyte (CTL) response. After 15 weeks of dosing body weights were reduced in rats receiving 25 mg/kg PCB while thymus weights were decreased in rats receiving 10 and 25 mg/kg. NK cell activity was reduced in rats dosed for 15 weeks at 10 and 25 mg/kg. The LP response to phytohemagglutinin was enhanced in rats dosed for 15 weeks at 25 mg/kg PCB. Exposure of rats to PCB did not affect the MLR or CTL responses. Other groups of rats were exposed to cyclophosphamide (CY) and served as positive controls for the immune assays employed. CY induced alterations in all of the immune parameters measured, indicating that this is an appropriate battery of immune function tests which is capable of detecting immune alterations in the rat. Alterations in immune function induced by daily gastric intubation with PCB were accompanied by reductions in body weight and/or hepatomegaly. These results suggest that the observed immune alterations may be related to the overt toxicity of this PCB in the rat.     

Foetal Uptake of Coplanar Polychlorinated Biphenyl (PCB) Congeners in Mice

Abstract: Earlier studies (Darnerud et al. 1986) have shown that the Ah-receptor binding polychlorinated biphenyl (PCB) congener 3,3′,4,4′-tetrachlorobiphenyl (IUPAC number CB-77) accumulated as hydroxy and methylsulphone metabolites in late gestational mice foetuses. In the present paper the foetal accumulation potential in mice of other dioxin-like PCB congeners was studied: 3,3′,4,4′,5-pentachlorobiphenyl, 3,3′,4,4′,5,5′-hexachlorobiphenyl and 2,3,3′,4,4′-pentachlorobiphenyl (IUPAC numbers CB-126, CB-169, CB-105, to some extent dioxin-like) were compared to results of CB-77 (all congeners ^l4C-labelled and in equimolar doses (2.0 umol/kg body wt.)). CB-77 resulted in the comparatively strongest foetal ^l4C-accumulation, when measured in plasma or whole body homogenate four days after administration (day 17 of pregnancy); the plasma ¹⁴C-values (calculated as pmol/g wet wt.) were 760, 130, 60 and 40 for CB-77, -126, 105 and -169, respectively, and the CB-77 derived radioactivity in the foetal compartment was 3.6% of administered dose (i.e. a considerable portion of the remaining maternal body radioactivity). Thin-layer chromatography (TLC) results, suggesting extensive CB-77 metabolism and foetal metabolite uptake, support earlier findings. The effects of CB-77 and CB-169 on foetal 7-ethoxyresorufin-O-deethylase (EROD) activities (day 17 of gestation; two days after 5 mg/kg body wt. dose (14.0-17.0 Umol/kg body wt.)) was about 20 times lower than of CB-126. In the dam, high radioactivity levels were observed in the liver and fat (highest concentrations found in CB-126 and CB-105, respectively). Strain comparison - foetal ^l4C-uptake (four days after administration of CB-77) in C57BL mice was almost five times higher than in NMRI - may be correlated to earlier observed differences in EROD activities between these strains. The present results indicate that congener and strain differences exist regarding both foetal and maternal distribution patterns of coplanar PCB congeners and point out the difference in foetal disposition between CB-77 and the other studied congeners.     

Milk Transfer and Neonatal Uptake of Coplanar Polychlorinated Biphenyl (PCB) Congeners in Mice

Abstract: The selective accumulation of 3,3′,4,4′-tetrachlorobiphenyl metabolites in late gestational foetal blood and soft tissues in mice as a result of administration of different coplanar polychlorinated biphenyl (PCB) congeners, is reported elsewhere. The situation in the nursing neonate after maternal exposure to the same congeners is now studied: The ¹⁴C-labelled congeners 3,V,4,4′-telrachlorobiphenyl (IUPAC number CB-77), 3 ,3′,4,4′,5-pentachlorobipheny] (IUPAC number CB-126), 3 ,3′,4,4′,5,5′-hexachlorobiphenyl (IUPAC number CB-169) (all three non-ortho congeners) and 2,3,3′,4,4′-pentachlorobiphenyl (IUPAC number CB-105) (mano-ortho congener) were injected intravenously in lactating mice at day 11 post partum. One day and four days later, milk and neonatal/maternal tissues and plasma radioactivity was monitored by liquid scintillation counting (dose: 2.0 μmol (20-50 μCi)/kg body weight). In milk, CB-126, -169 and -105 showed higher levels (1450-2520 pmol/ml; one day after administration) than did CB-77 (580 pmol/ml), and in neonates, the relative whole-body levels of radioactivity (CB-169 and -105 highest) were related to the levels seen in milk (probably the consequences of their metabolic persistence). The comparably high ¹⁴C-concentration found in neonatal liver (about 15,000 pmol/kg) after CB-126 administration and in plasma (880 pmol/ml) after CB-77 administration could be explained by binding to specific proteins. In general, neonatal mice had two to seven times higher plasma levels than those of their mothers. These results indicate that CB-126, -169 and -105 are transferred via milk to neonates in considerable quantity and are deposited mainly in neonatal liver, whereas CB-77 is transferred in a comparably lower amount and accumulated in neonatal plasma. The lower ^l4C-levels in the NMRI mothers and offspring (about half of C57BL values in maternal and neonatal plasma), could possibly be explained by a differentiated metabolism of CB-77 in these two strains.     

Contrasting effects of coplanar versus non-coplanar PCB congeners on immunomodulation and CYP1A levels (determined using an adapted ELISA method) in the common sea star Asterias rubens L

Biological effects of two structurally contrasting PCB congeners (coplanar 77 and non coplanar 153) were investigated by measuring the induction of CYP1A immunopositive protein (CYP1A IPP) in the pyloric caeca and the production of reactive oxygen species (ROS) by amoebocytes in the common sea star Asterias rubens. CYP1A IPP was quantified using a specially designed ELISA which uses competitive binding between sea stars and trout CYP1A IPPs. Only the coplanar congener had a significant effect on the two considered biological responses. Intensity of the effects was dose-dependent. However, the highest dose of PCB 77 induced a dramatic decrease of ROS production. It is concluded that coplanar PCBs straightforwardly affect key biological processes such as the immune system and mixed-function oxidase (MFO) system.     

Coplanar PCB congeners increase uterine weight and frontal cortical dopamine in the developing rat: implications for developmental neurotoxicity.

We show that developmental exposure of the laboratory rat to the coplanar polychlorinated biphenyl (PCB) congener 3,4,3',4'-tetrachlorobiphenyl (TCB) and the structurally similar congener 3,4,5,3',4'-pentachlorobiphenyl (PtCB) elevates dopamine (DA) concentrations in the prefrontal cortex (PFC). To determine whether these coplanar congeners are estrogenic, and may thus contribute to the elevations in PFC DA, we measured uterine wet weight (UWW) in prepubertal rats exposed to TCB or PtCB. For comparison, additional animals were exposed to either the ortho-substituted congener 2,4,2',4'-tetrachlorobiphenyl (o-TCB) or 3,4,5,3',4',5'-hexachlorobiphenyl (HCB), a coplanar congener highly resistant to metabolism. Both TCB and PtCB increased UWW, but this effect was blocked after exposure to the anti-estrogen ICI 182,780. Neither o-TCB nor HCB altered UWW. These results demonstrate that certain coplanar PCB congeners and/or their metabolites, are estrogenic, and suggest that exposure during critical periods of neuronal development may increase central DA concentrations, and by inference, alter behavior.     

纳米药物免疫毒性研究进展

纳米药物由于粒径小等特性,极易进入体内,并透过多种生理屏障与免疫细胞或细胞表面蛋白相互作用,发生特异性反应,诱发免疫应答,增强或降低机体的免疫功能。此外,免疫系统自身的复杂性和纳米药物类型多样性增加了研究纳米药物免疫毒性的难度。纳米药物对机体可能具有免疫抑制或免疫刺激包括抗原性、佐剂特性和炎症反应等免疫学特性,不同的纳米药物也已发现可以诱导机体产生不同程度的免疫反应。本文就纳米药物的免疫学特性、免疫系统与纳米药物的相互作用以及不同纳米药物免疫毒性研究方法进行综述。     

Role of metabolism in parathion-induced hepatotoxicity and immunotoxicity

The objective of this study was to investigate whether metabolic activation of parathion by cytochrome P-450s (CYPs) was responsible for pesticide-induced hepatotoxicity and immunotoxicity. Initially, to investigate parathion metabolism in vitro, the production of paraoxon and p-nitrophenol, major metabolites of parathion, was determined by high-performance liquid chromatography (HPLC). Subsequently, metabolic fate and CYP enzymes involved in the metabolism of parathion were partially monitored in rat liver microsomes in the presence of the NADPH-generating system. Among others, phenobarbital (PB)-induced microsomes produced the metabolites paraoxon and p-nitrophenol to the greatest extent, indicating the involvement of CYP 2B in parathion metabolism. When female BALB/c mice were treated orally with 1, 4, or 16 mg/kg of parathion in corn oil once, parathion suppressed the antibody response to sheep red blood cells. To further investigate a possible role of metabolic activation by CYP enzymes in parathion-induced toxicity, female BALB/c mice were pretreated intraperitoneally with 40 mg/kg PB for 3 d, followed by a single oral treatment with 16 mg/kg parathion. PB pretreatment produced a decrease in hepatic glutathione content and increases in hepatotoxic paramenters in parathion-treated mice with no changes in the antibody response. In addition, greater p-nitrophenol amounts were produced when mice were pretreated with PB, compared to treatment with parathion alone. These results indicate that parathion-induced hepatotoxicity might be differentiated from immunotoxicity in mice.     

Developmental immunotoxicity of atrazine in rodents

There is a substantial literature reporting that the developing immune system is more sensitive to toxic insult and that the measurable phenotype resulting from prenatal/neonatal exposure often differs from that seen in adult exposure models (reviewed in Holladay and Steven, and Smialowicz et al.). Atrazine is a common herbicidal contaminant of groundwater in agricultural areas in the USA. The potential immunotoxicity of atrazine has been extensively studied using adult-exposure models; however, few studies have explored its immunotoxicity in a prenatal and/or lactational exposure model. Prenatal/lactational atrazine exposure affects the function of young adult rodent immune systems in both sex- and age-dependant manners. In our studies, the humoural and cell-mediated immune responses of offspring from atrazine-exposed dams were assessed at two ages, 3 and 6 months of age to test the hypothesis that prenatal/lactational atrazine exposure would cause greater health complications as the mice aged. Male offspring showed a significant immunopotentiation at three moa that was not apparent at 6 months. Three-month-old female offspring showed no significant difference in immune response from controls. However, at 6 months, female litter mates showed a significant depression in their immune function. These results indicate a decreasing trend in immune capacity. Rooney et al. showed a significant depression of the immune function of young male rat exposure prenatally and lactationally to atrazine. These results demonstrate a sex- and age-dependant effect of prenatal exposure to atrazine on the immune system of the adult offspring using two rodent strains.     

Role of corticosteroids in cadmium induced immunotoxicity

Cadmium chloride at doses of 30, 100 and 300 ppm was orally fed to swiss albino mice for 35 days and the humoral and cell mediated immunity was studied by measuring the haemagglutination titre and delayed type hypersensitivity response respectively. Further, the blood corticosteroid level was determined in all the groups. Cadmium at doses of 100 and 300 ppm was found to significantly (p < 0.05) suppress both humoral and cellular immunity with simultaneous increase in the level of blood corticosterone and aldosterone. In order to assess whether the suppression of immune response in cadmium exposed mice is mediated by corticosteroids, aminoglutethemide, an adrenal blocker was administered to mice along with cadmium and the immune response was studied. Aminoglutethemide when administered alone caused significant (p < 0.05) stimulation of immunoglobulin level and delayed type hypersensitivity response as compared to cadmium (300 ppm) fed mice. When co-administered with cadmium, the cadmium induced immunosuppression was reversed back to normal. The results of this study indicate the involvement of adrenal hormones in cadmium induced immunosuppression suggesting that cadmium activates the corticosteroid associated immunoregulatory circuit.     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官，无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟，这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时，胸腺是敏感的靶器官，胸腺的大小或重量出现明显的降低，这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此，胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联，对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官，无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟，这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时，胸腺是敏感的靶器官，胸腺的大小或重量出现明显的降低，这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此，胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联，对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官,无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟,这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时,胸腺是敏感的靶器官,胸腺的大小或重量出现明显的降低,这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此,胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联,对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

胸腺在免疫毒性病理学评价中的作用和意义

胸腺是中枢性淋巴器官，无须抗原的刺激T淋巴细胞在皮质自主地进行分化和成熟，这是免疫系统正常功能发育的重要组成部分。当暴露于免疫毒性物质和内源性糖皮质激素时，胸腺是敏感的靶器官，胸腺的大小或重量出现明显的降低，这往往是化合物或药物导致的敏感的皮质胸腺细胞改变最初观测到的指标。因此，胸腺组织病理学和重量的改变与免疫毒性的筛选具有特定的关联，对胸腺的病理学评价在免疫毒性研究中具有重要作用和意义。文中从胸腺生理和毒性病理学的角度对其作用和研究意义进行综述。     

Developmental windows of differential lead-induced immunotoxicity in chickens

The developing immune system of rodents has been shown to exhibit increased sensitivity to lead-induced immunotoxicity compared with that of adults. However, little is known about potential windows of increased vulnerability during discrete periods of embryonic development. To investigate differential embryonic sensitivity to lead-induced immunotoxicity, sublethal doses of lead ranging from 5 to 400 microg/egg were introduced into fertilized Cornell K Strain White Leghorn chicken eggs via the air sac at one of four different stages of embryonic development (5, 7, 9, and 12 days of incubation, designated as E5, E7, E9, and E12, respectively). Lead levels of blood and bone were determined at hatching and lead-induced immunotoxicity was evaluated in 5-6 week old young chickens using a delayed-type hypersensitivity (DTH) reaction against bovine serum albumin (BSA), macrophage production of nitric oxide, and interferon-gamma (IFN-gamma) production by splenic lymphocytes as immune indicators. Splenic lymphocyte production of IFN-gamma was significantly suppressed (measured for E7 and E9 exposures only, P<0.05) among lead treated groups when compared with controls. Macrophage production of nitric oxide (measured as nitrite production) was significantly depressed (P<0.05) following E5, E7, and E9 lead exposures but not following E12 lead exposure. In contrast with this pattern, DTH function was unaltered following the E5, E7, and E9 exposures, but was significantly depressed (P<0.05) after E12 exposure to lead. Since the same lead dose (200 microg/egg) given at E9 and E12 produced the same blood and bone lead levels and resulted in a different outcome regarding DTH function, the capacity of lead to influence DTH function appeared to emerge between days 9 and 12 of in ovo development. Based on these results, it is hypothesized that lead exposure during different windows of embryonic development is likely to result in different immunotoxic outcomes in the juvenile.     

Nanosafety studies of nanomaterials about biodistribution and immunotoxicity

A diverse array of nanomaterials such as nanosilicas and carbon nanotubes are in widespread use due to the development of nanotechnology. Nanomaterials are already being applied in universal fields such as electronics, sunscreens, cosmetics, and medicine, because they have unique physicochemical properties such as high conductivity, strength, durability, and chemical reactivity. The advent of nanomaterials has also provided extraordinary opportunities for biomedical applications. However, the increasing use of nanomaterials has raised public concern about their potential risks to human health. In particular, recent reports have indicated that carbon nanotubes induced exaggerated inflammation and mesothelioma-like lesions in mice. However, few studies have examined the immunotoxicity of nanomaterials and it is essential to progress studies on the immunotoxicity of nanomaterials to ensure their safety. In this regard, we have attempted to elucidate the pharmacodynamics and immunotoxicity of nanomaterials, in order to develop novel safe nanomaterials and to establish scientifically based regulations. In this review, we would like to introduce our data on the immunotoxicity of nanosilicas, especially the relationship between physical properties (primary grain size, configuration and surface charge), pharmacodynamics of these materials, and their immunotoxicity. We consider that our study will improve the quality of human life by safely using nanomaterials, which can benefit society in general.     

Induction of immunotoxicity in mice by polyhalogenated biphenyls

Acute administration of Aroclor-1254 (500 mg/ kg) or 3,4,5,3,4,5-hexabromobiphenyl (HBB) (2–6 mg/ kg) IP, profoundly inhibited the plaque forming response to subsequent challenge with sheep erythrocytes in Ah locus positive (C57B1/6N or B6C3F1N) mice. These studies showed: 1) the immunotoxicity results paralleled enzyme induction results insofar as HBB was approximately 100 times more potent than Aroclor 1254; (2) neither Aroclor nor HBB treatment caused significant induction in the Ah locus negative DBA/2N mice; 3) when B6C3F1 mice were challenged with sheep red blood cells (SRBC) 6 or 16 weeks post Aroclor 1254 treatment, substantial recovery of a PFC response was observed; 4) when these compounds were administered to older (76-week-old) (B6C3F1 mice, severe depression of a PFC response was observed. In contrast to its profound depression of a PFC response, Aroclor-1254 (up to 1250 mg/kg) caused slight increases in lymphocyte proliferation induced by either T or B cell mitogens. A single 500 mg/kg dose of Aroclor-1254 also suppressed the ability of recipient B6C3F1 animals to reject a challenge with either the syngenic fibrosarcoma (PYB6) or the gram negative pathogen (Listeria monocytogenes).     

Subchronic immunotoxicity and screening of reproductive toxicity and developmental immunotoxicity following single instillation of HIPCO-single-walled carbon nanotubes: purity-based comparison

Impurity has been suggested as an important factor determining toxicity following exposure to single-walled carbon nanotubes (SWCNTs). In this study, we first compared immunotoxicity based on iron content on day 90 after a single intratracheal instillation of SWCNTs in male and female mice. The inflammatory responses were generally stronger in mice exposed to acid-purified (P)-SWCNTs compared to raw (R)-SWCNTs. In addition, both R- and P-SWCNTs induced Th1-polarized immune responses with apoptotic death of BAL cells and systemically impaired the function of antigen-presenting cells (APC). We also screened reproductive and developmental toxicity by cohabitating male and female mice on day 14 after instillation. Interestingly, the pregnancy rate rapidly decreased following exposure to both types of SWCNTs, especially R-SWCNTs. In addition, we investigated developmental immunotoxicity of the offspring on day 28 after exposure to both types of SWCNTs. Their hematological changes were clearer relative to those of the parents and a significant decrease in the alkaline phosphatase and potassium levels was observed in mice of both sexes exposed to the higher dose of R- and P-SWCNTs. In conclusion, we suggest that SWCNTs may induce Th1-polarized immune responses accompanied by suppression of APC function on day 90 after a single instillation without significant iron content dependance. In addition, the consecutive exposure of SWCNTs to the subsequent generation may exacerbate metabolic and hematological disturbance. Furthermore, our results underscore the need to clarify the reproductive and developmental health effects of SWCNTs.     

Effect of ketamine on cocaine-induced immunotoxicity in rats

The abuse of cocaine (COC) with ketamine (KET) is currently popular among young drug abusers and has been associated with increased risk of human immunodeficiency virus (HIV) infection. The effect of subacute exposure to COC and KET alone and in combination on the immune system was assessed in adult male Sprague-Dawley (SD) rats. To simulate the route and mode of human exposure, rats were treated with COC alone (5 mg/kg, i.v.), KET alone (100 mg/kg, p.o.) or KET followed immediately by COC (same doses and routes of administration) once-a-day for 7 consecutive days. Rats were sacrificed 30 minutes following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, whereas immunoglobulin M (IgM) antibody response to sheep erythrocytes (SRBCs) was increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin-10 (IL-10) concentration; however, it did not affect serum interferon gamma (INF-gamma) concentration. Spleen histology showed hyperplasia of white pulp whereas thymus gland demonstrated mild cortical degeneration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when coadministered with COC, significant reduction of bodyweight, spleen/bodyweight, and thymus/bodyweight ratios with degeneration of splenic white pulp and thymic cortex occurred. Moreover, the primary immunoglobulin response to SRBC and serum IL-10 concentration were decreased without significant change in serum IFN-gamma or circulating leukocytic counts. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. On the other hand, a significant increase in plasma and tissue concentrations of norcocaine (NC) resulted following KET and COC administration in combination. Daily SKF-525A pretreatment at a dose of 30 mg/kg, i.p., for 7 days 1 hour prior to KET and COC in combination effectively reversed the effects of this combination on body weight, organ/bodyweight ratios, histopathology, and serum IgM and IL-10 concentrations without affecting leukocytic counts. On the other hand, SKF-525A pretreatment did not change the immunomodulatory effects of COC compared to non-pretreated animals. The results suggest that COC-induced immunomodulation most likely occurred through neuroendocrinal mechanisms. On the other hand, enhanced oxidative metabolism of COC in the presence of KET-induced immunosuppression.     

Different effects of PCB101, PCB118, PCB138 and PCB153 alone or mixed in MCF-7 breast cancer cells

Polychlorinated biphenyls (PCBs) are ubiquitous, persistent environmental contaminants that can be a potential health hazard. In the present study we analyzed the potential estrogenic effect in MCF-7 cells of four biologically relevant PCB congeners, alone or in mixtures, present in dairy products, vegetable oil and fish: PCB101, PCB118, PCB138 and PCB153. The mixture of four PCB was tested at seven different concentrations. We investigated the ability of these PCBs, alone or mixed, to induce cell proliferation, and the level of estrogen-regulated protein pS2, in human MCF-7 breast cancer cells. PCB153 (35 microM) stimulated cell proliferation from 48 h up to day 6, PCB118 (40 microM) only at 48 h, but PCB101 (45 microM) and PCB138 (15 microM) applied to the cells for 6 days had no effect. In contrast, the various concentrations of mixtures significantly reduced cell proliferation at different times. No change in pS2 levels was seen after treatment with the PCBs alone or mixed. In exploring the mechanism of these events, we found that PCB153 induced mitogen-activated protein kinase (MAPK) ERK1/2 at 4, 8 and 12 h, while the antiproliferative effect seemed to be related to an apoptotic action beginning at 12 h and ending at 48 h. These findings indicate that these PCBs alone or mixed have no estrogenic effect in MCF-7 cells, although PCB153 induce an ERK1/2-mediated mitogenic effect. On the contrary the mixture of PCBs induces an antiproliferative effect, ascribable to an apoptotic action.     

Evaluation of the potential immunotoxicity of bromodichloromethane in rats and mice

In the past two decades, concern has been expressed over the potential carcinogenicity of disinfection by-products (DBPs) found in chlorinated drinking water. More recently, research efforts have expanded to include noncancer endpoints as well. The objective of the present studies was to evaluate the potential of bromodichloromethane (BDCM), one of the most prevalent DBPs, to adversely affect immune function in mice and rats following drinking water or gavage exposure. Antigen-specific immunity was assessed as the antibody response to sheep erythrocytes; responses to T- and B-cell mitogens were evaluated as a non-antigen-specific measure of the proliferative potential of splenic and mesenteric lymph node lymphocytes. In consideration of an exposure route relevant to humans, C57BL/6 mice received 0.05, 0.25, or 0.5 g BDCM/L and F344 rats received 0.07 or 0.7 g BDCM/L via drinking water. In order to evaluate the effects of higher doses, animals were administered 50, 125, or 250 mg BDCM/kg/d (mice) or 75, 150, or 300 mg BDCM/kg/d (rats) via gavage. Under the conditions of these studies, no significant adverse effects on immune function were observed in mice. Despite some changes that were observed in non-antigen-specific immunity in rats, these experiments suggest that the immune system is not a sensitive target organ for BDCM toxicity.