ToxSci Advance Access originally published online on September 17, 2007
Toxicological Sciences 2007 100(2):328-332; doi:10.1093/toxsci/kfm244
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published by Oxford University Press 2007.
Immunotoxicity—The Risk is Real
U.S. Environmental Protection Agency, Office of Research and Development, National Health and Environmental Effects Research Laboratory, MD B143-01, Research Triangle Park, North Carolina 27711
1 For correspondence via fax: (919) 541-0026. E-mail: selgrade.maryjane{at}epa.gov.
Received July 5, 2007; accepted September 11, 2007
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONIMMUNE SUPPRESSION ASSOCIATED...IMPLICATIONS FOR RISK OF...CONCLUSIONSREFERENCES |
|---|
Several papers published over the last year represent significant progress in closing the gap between rodent immunotoxicity data and human risk and indicate that, at least for the developing immune system, the concern raised by rodent data is justified. The studies reviewed here show that suppression of immune responses in rodents is predictive of suppression of immune responses in humans and that there is a relationship between immune suppression following developmental exposure to the toxicants and enhanced risk of infectious or neoplastic disease in humans. The three cases highlighted here are remarkable in that they all deal with real-world environmental exposures that represent different media—air (cigarette smoke), water (arsenic), and food (polychlorinated biphenyls [PCBs])—and constitute very real risks. Moreover, the arsenic and PCB studies actually demonstrate a quantitative relationship between human exposure and immune suppression. There is evidence that in utero exposure to cigarette smoke and arsenic but not PCBs is associated with increased risk of allergic disease as well. There is clearly potential for designing studies that could address both issues.
Key Words: immunotoxicity; allergy; cigarette smoke; arsenic; polychlorinated bipenyls.
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONIMMUNE SUPPRESSION ASSOCIATED...IMPLICATIONS FOR RISK OF...CONCLUSIONSREFERENCES |
|---|
A major limitation of immunotoxicity risk assessment has been the lack of human data (Descotes, 2006
). This is at least true for assessment of immunosuppression, which is often restricted to animal models and assays to predict unexpected immunosuppression. Despite rigorous efforts to standardize and identify the most predictive assays for immunotoxicity (Luster et al., 1988, 1992) and relate these assays to enhanced susceptibility to infectious agents or tumorigenic cells in rodents (Luster et al., 1993), along with extensive data showing that a number of chemicals are immunotoxic in rodent tests (Selgrade, 2004), some doubts persist concerning the need to conduct functional immunotoxicity tests (Gore, 2006). Also, risk assessors remain uncertain about the use of these rodent data for predicting human risk. Recently, concern over immunotoxicity has been heightened by the realization that the developing immune system may be more sensitive than the adult immune system, at least in response to some well-characterized immunotoxic chemicals (Luebke et al., 2006). Modifications to adult testing scenarios have been proposed in response to the concern that adult exposures may not adequately predict the risks of perinatal exposures (Dietert and Piepenbrink, 2006). Because these approaches also rely on data generated in rodents, interpreting the results in terms of human risks remains an issue. As discussed below, several papers published over the last year represent significant progress in closing the gap between rodent data and human risk and indicate that, at least for the developing immune system, the risk is indeed real. |
IMMUNE SUPPRESSION ASSOCIATED WITH DEVELOPMENTAL EXPOSURES TO CIGARETTE SMOKE, ARSENIC, AND POLYCHLORINATED BIPHENYLS |
|---|
|
TOPABSTRACTINTRODUCTIONIMMUNE SUPPRESSION ASSOCIATED...IMPLICATIONS FOR RISK OF...CONCLUSIONSREFERENCES |
|---|
Epidemiologic data indicate that children of mothers who smoke during pregnancy have a greater risk of developing certain types of childhood cancers, including tumors of the nervous system, leukemias, and lymphomas (Filippini et al., 1994
, 2000; Magnani et al., 1990; Schuz et al., 2001). It would be very difficult to use human data to establish a role for immunotoxicity in this increased risk. However, in an elegant study, Ng et al. (2006) exposed pregnant mice to mainstream cigarette smoke by inhalation 4 h/day, 5 days/week, from gestation day 4 to parturition. At a concentration of smoke roughly equivalent to smoking less than a pack of cigarettes per day, male offspring challenged at 5 weeks of age with EL4 lymphoma cells demonstrated a greater than twofold increase in tumor incidence and faster growing tumors compared to offspring from air-exposed mothers. This increased susceptibility to tumor challenge coincided with persistent suppression of cytotoxic T-cell activity. This study provided biological plausibility for the epidemiologic data indicating that children of mothers who smoke during pregnancy have a greater risk of developing childhood cancer and suggested that immune suppression as a result of exposure to cigarette smoke during gestation makes an important contribution to this risk. The authors took advantage of existing epidemiologic studies to develop a link between rodent immunotoxicity data and human health effects. Perhaps, the next step would be to assess T-cell function in children of smoking mothers, similar to the approach taken below with arsenic.
Human populations exposed environmentally to arsenic have a high incidence of bladder, kidney, liver, and skin cancer (Kitchin, 2001). Arsenic exposure in mice suppressed the IgM and IgG antibody–forming cell response, inhibited antigen-driven T-cell proliferation and macrophage activity, decreased CD4+ splenic cell number, and suppressed contact hypersensitivity responses (Burns and Munson, 1993; Patterson et al., 2004; Sikorski et al., 1989). Unlike the example above, there is not a specific link between arsenic-induced suppression of immune responses and susceptibility to tumor challenge in rodents. Although gallium arsenide decreased resistance of mice to challenge with B16F10 melanoma cells, in that particular study responses of natural killer, B, and T cells, most likely to account for such an effect, were not suppressed (Sikorski et al., 1989). Nevertheless, one possible mechanism for enhanced tumorigenesis in arsenic-exposed populations is that damage to the immune system impairs the responses to transformed cells (Andres, 2005). In fact, inhibition of lymphocyte proliferation in response to phytohemaglutinin (PHA) stimulation has been reported in adult human populations exposed to arsenic-contaminated drinking water. Now, Soto-Pena et al. (2006) have demonstrated that proliferation of peripheral blood mononuclear cells in response to PHA was significantly decreased in association with an increase in arsenic concentration in urine of children 6–10 years of age exposed chronically to arsenic. Release of interleukin-2 (a T-cell growth factor) from these cells was also significantly suppressed. Studies that demonstrate significant immune suppression in children exposed to environmentally relevant levels of a toxicant are not a common occurrence, and this case is particularly notable given the relatively small cohort (90 children). Continued surveillance of this population for increased risk of infection and tumors and/or responses to vaccines (as described below) is certainly warranted. In addition, animal studies might be extended to include challenge with skin tumors, mimicking tumor types observed in arsenic-exposed humans rather than the tumor metastasis model represented by intravenous injected B16F10 melanoma cells.
The most common assay used to assess immunotoxicity in rodents is the antibody response to sheep red blood cells (SRBCs) because it was found to be the most predictive single assay for immunotoxicity (Luster et al., 1992) and requires cooperation between B, T, and antigen-presenting cells. This exact response cannot be duplicated in humans for ethical reasons because humans cannot be injected with SRBCs. However, humans are routinely injected with a number of other antigens in the form of vaccinations, a cornerstone of public health and disease prevention. Thus, studies on effects of human toxicant exposures on vaccine responses and effectiveness have been suggested as the best way to demonstrate that rodent tests predict human responses (Luster et al., 2005; Van Loveren et al., 2001). There is general agreement that testing the response of the immune system to antigen challenge is the best way to identify deficits in the immune response; however, for logistical reasons, this is not an approach that has been applied frequently in humans. Heilmann et al. (2006) described just such a study in which the antibody responses to diphtheria and tetanus toxoids were measured in two birth cohorts in the Faroe Islands, where exposures (both pre- and postnatal) to polychlorinated biphenyls (PCBs) vary widely because traditional diets may include whale blubber which is contaminated with PCBs. The antibody response to diphtheria toxoid decreased at age 18 months by 24% for each doubling of the cumulative PCB exposure at the time of examination. At 2 years of age, 21% of children had diphtheria toxoid antibody concentrations below the limit for long-term protection. The tetanus toxoid antibody response at age 7 decreased by 16% for each doubling of the prenatal exposure. This study is consistent with rodent studies that demonstrate suppression of the antibody response to SRBCs in adult animals treated with PCBs (Davis and Safe, 1990; Wierda et al., 1981) and decreased resistance to infection (Imanishi et al., 1984; Loose et al., 1978) and also with a study showing decreases in T and B cells in offspring following gestational and lactational exposure to PCBs (Arena et al., 2003). It is also consistent with studies showing suppression of the antibody response to SRBCs in both adult and infant monkeys treated with PCB (Arnold et al., 1999; Tryphonas et al., 1991). The Heilmann study suggests that children exposed to PCBs in utero or soon after birth are at greater risk of infection, and in fact, studies have shown an increased frequency of childhood infections in children who have been exposed to PCBs and other organochlorine pollutants via their mother's contaminated diet (Dallaire et al., 2006; Dewailly et al., 2000; Nagayama et al., 1998; Weisglas-Kuperus et al., 2000). In addition, the prospect that the protection afforded by common childhood vaccinations may be compromised is alarming.
The above examples have several things in common. They all show that suppression of immune responses in rodents is predictive of suppression of immune responses in humans, and they all show a relationship between immune suppression following developmental exposure to the toxicants and enhanced risk of infectious or neoplastic disease in humans. A number of years ago, Selgrade (1999) proposed a parallelogram model to relate rodent and human immunotoxicity (Fig. 1). At that time, it was rare to have data for the human side of the model, particularly host resistance data, and we were dependent on extrapolating from the remaining corners of the parallelogram. In the preceding examples for in utero PCB and childhood arsenic exposure, we now have at least qualitative human data for both host resistance and immune function and for cigarette smoke we have human data on host resistance. Moreover, the arsenic and PCB studies actually demonstrate a quantitative relationship between exposure and immune suppression. These three cases are also remarkable in that they all deal with real-world environmental exposures that represent different media—air, water, and food—and constitute very real risks.
|
|
IMPLICATIONS FOR RISK OF ALLERGIC DISEASE |
|---|
|
TOPABSTRACTINTRODUCTIONIMMUNE SUPPRESSION ASSOCIATED...IMPLICATIONS FOR RISK OF...CONCLUSIONSREFERENCES |
|---|
Immune suppression with decreased resistance to infectious and neoplastic disease is not the only risk associated with modulation of the immune system. Immune stimulation resulting in enhanced risk of allergic and autoimmune disease is also a concern. The incidence of asthma, which has a significant immune component, has increased dramatically over the last three decades, and the reasons for this increase are unclear. The time frame of the increase is too short to represent a change in genetic susceptibility, and there is general consensus that the increase must be related to changes in the lifestyle or the environment of western societies (Selgrade et al., 2006
). In this regard, in utero exposure to toxicants has received some attention. Germaine to this discussion is the observation that in utero exposure to cigarette smoke has been strongly associated with increased risk of developing asthma (Gold et al., 1999; Jaakkola and Gissler, 2004), and in the arsenic example above (Soto-Pena et al., 2006), a tendency toward increased incidence of allergies and asthma was noted among individuals with arsenic values higher than 50 g/l of urine (though not statistically significant in the relatively small number of subjects tested). An obvious hypothesis is that suppression of certain components of the immune system, while sparing others, removes regulatory components that ordinarily suppress or prevent the development of allergic responses. As with the studies above, the role that the immune system may play in mediating the enhanced risk of asthma associated with in utero exposures will have to be elucidated using animal models. For tobacco smoke, this research is already underway (Doherty et al., 2007). Unlike immune suppression, we do not currently have well-validated methods for testing chemical exposure for these adjuvant-type effects in rodent models; however, this area of research is beginning to receive some attention (Hamada et al., 2007). There is evidence in both humans and animal models that certain air pollutant exposures may act as adjuvants and increase the risk of allergic sensitization and asthma (Gilmour et al., 2006). In the meantime, controlling risks associated with immune suppression, in some cases, might fortuitously control risks associated with asthma as well. It should be noted, however, that exposure to PCBs was associated with less shortness of breath and wheeze (Weisglas-Kuperus et al., 2000). The authors speculated that increased prevalence of infectious disease in early life might account for the lower prevalence of allergic disease in these children (i.e., the hygiene hypothesis). However, rodent data demonstrated suppressed allergic responses to house-dust mite in rats exposed to 2-,3-,7-,8-tetrachlorodibenzo-p-dioxin (TCDD) (Luebke et al., 2001), and TCDD suppressed the induction of autoimmune diabetes in nonobese diabetic (NOD) mice (Kerkvliet, personal communication), suggesting that dioxin and chemicals with similar immunotoxic modes of action may simply be immunosuppressive across the board. Thus, chemical immunosuppressants may or may not be associated with allergic risks. This is clearly a topic that deserves further exploration.
It would be highly desirable to have tests for developmental immunotoxicity that would be predictive of both immune suppression and increased risk of allergenicity. It should be noted that children and laboratory rodents make IgE as well as IgG to tetanus and diphtheria toxoid (Dannemann et al., 1996; Gruber et al., 2001; Naito et al., 1995; Samore and Siber, 1996). In studies such as the PCB study cited above, testing the collected sera for toxoid-specific IgE would be a relatively simple addition to the study and might yield very useful information. Assessment of cord blood or peripheral blood eosinophils might also be a useful marker. Elevated eosinophil counts in peripheral blood of apparently healthy infants at 3 months of age were associated with a subsequent diagnosis of atopic disease (Borres et al., 1995). It would be important to include clinical follow-up in these studies to determine the predictive value of these end points. Likewise, it would be highly desirable to design rodent developmental immunotoxicity-testing protocols in a way that would allow for assessment of IgE as well as IgG and IgM responses and the exploration of other potential biomarkers. Given the economic impact associated with asthma and allergic disease, this is an area that immunotoxicologists should be pursuing vigorously.
|
CONCLUSIONS |
|---|
|
TOPABSTRACTINTRODUCTIONIMMUNE SUPPRESSION ASSOCIATED...IMPLICATIONS FOR RISK OF...CONCLUSIONSREFERENCES |
|---|
In conclusion, those who were expecting an obvious AIDS-like epidemic to occur as the result of exposure to chemical immunosuppressants have suggested that the human population is not at serious risk from exposure to immunotoxicants. However, clinical studies in humans at the extremes of age, in transplant patients, and in those exposed to chronic stress provide evidence that mild to moderate immune suppression in humans increases the risk of infections with pathogens commonly encountered in the general population (Luebke et al., 2004
). The studies cited above indicate that the same is true for toxicant-induced immune suppression. Clearly, if one makes more than a casual attempt to assess the human population for risk associated with immunotoxicity, such risks do in fact exist. These types of studies are expensive and have to contend with wide variability in the normal human response as well as uncertainties related to the level of exposure. In spite of those difficulties, the studies above have demonstrated effects that were predicted by our rodent assays and have concerned some immunotoxicologists for more than 20 years. We will not be able to generate these types of data for every immunotoxicant in the environment, but we should be encouraged that our rodent assays are predictive of effects in humans. And yes, the risk is real.
|
NOTES |
|---|
Disclaimer: This paper has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency and mention of trade names or commercial products does not constitute endorsement or recommendation for use.
|
ACKNOWLEDGMENTS |
|---|
Thanks to Linda Birnbaum, Dori Germolec, Robert Luebke, and Judy Zelikoff for thoughtful review of this manuscript.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONIMMUNE SUPPRESSION ASSOCIATED...IMPLICATIONS FOR RISK OF...CONCLUSIONSREFERENCES |
|---|
Andres A. Cancer incidence after immunosuppressive treatment following kidney transplantation. Crit. Rev. Oncol. Hematol. (2005) 56:71–85.[Web of Science][Medline]
Arena SM, Greeley EH, Halbrook RS, Hansen LG, Segre M. Biological effects of gestational and lactational PCB exposure in neonatal and juvenile C57BL/6 mice. Arch. Environ. Contam. Toxicol. (2003) 44:272–280.[CrossRef][Web of Science][Medline]
Arnold DL, Bryce F, Mes J, Tryphonas H, Hayward S, Malcolm S. Toxicological consequences of feeding PCB congeners to infant rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) monkeys. Food Chem. Toxicol. (1999) 37:153–167.[CrossRef][Web of Science][Medline]
Borres MP, Odelram H, Irander K, Kjellman NI, Bjorksten B. Peripheral blood eosinophilia in infants at 3 months of age is associated with subsequent development of atopic disease in early childhood. J. Allergy Clin. Immunol. (1995) 95:694–698.[CrossRef][Web of Science][Medline]
Burns LA, Munson AE. Gallium arsenide selectively inhibits T cell proliferation and alters expression of CD25 (IL-2R/p55). J. Pharmacol. Exp. Ther. (1993) 265:178–186.
Dallaire F, Dewailly E, Vezina C, Muckle G, Weber JP, Bruneau S, Ayotte P. Effect of prenatal exposure to polychlorinated biphenyls on incidence of acute respiratory infections in preschool Inuit children. Environ. Health Perspect. (2006) 114:1301–1305.[Web of Science][Medline]
Dannemann A, van Ree R, Kulig M, Bergmann RL, Bauer P, Forster J, Guggenmoos-Holzmann I, Aalberse RC, Wahn U. Specific IgE and IgG4 immune responses to tetanus and diphtheria toxoid in atopic and nonatopic children during the first two years of life. Int. Arch. Allergy Immunol. (1996) 111:262–267.[Web of Science][Medline]
Davis D, Safe S. Immunosuppressive activities of polychlorinated biphenyls in C57BL/6N mice: Structure-activity relationships as Ah receptor agonists and partial antagonists. Toxicology (1990) 63:97–111.[CrossRef][Web of Science][Medline]
Descotes J. Methods of evaluating immunotoxicity. Expert Opin. Drug Metab. Toxicol. (2006) 2:249–259.[CrossRef][Web of Science][Medline]
Dewailly E, Ayotte P, Bruneau S, Gingras S, Belles-Isles M, Roy R. Susceptibility to infections and immune status in Inuit infants exposed to organochlorines. Environ. Health Perspect. (2000) 108:205–211.[Web of Science][Medline]
Dietert RR, Piepenbrink MS. Perinatal immunotoxicity: Why adult exposure assessment fails to predict risk. Environ. Health Perspect. (2006) 114:477–483.[Web of Science][Medline]
Doherty SP, Hoffmann C, Brush E, Zelikoff JT. Exposure of mice to cigarette smoke in utero induces airway hyper-responsiveness (AHR) in exposed offspring later in life. Toxicologist (2007) 96:68.
Filippini G, Farinotti M, Ferrarini M. Active and passive smoking during pregnancy and risk of central nervous system tumours in children. Paediatr. Perinat. Epidemiol. (2000) 14:78–84.[CrossRef][Web of Science][Medline]
Filippini G, Farinotti M, Lovicu G, Maisonneuve P, Boyle P. Mothers' active and passive smoking during pregnancy and risk of brain tumours in children. Int. J. Cancer (1994) 57:769–774.[Web of Science][Medline]
Gilmour MI, Jaakola MS, London SJ, Nel AE, Rogers CA. How the indoor and outdoor environments influence the incidence and severity of asthma. Environ. Health Perspect. (2006) 114:627–633.[Web of Science][Medline]
Gold DR, Burge HA, Carey V, Milton DK, Platts-Mills T, Weiss ST. Predictors of repeated wheeze in the first year of life: The relative roles of cockroach, birth weight, acute lower respiratory illness, and maternal smoking. Am. J. Respir. Crit. Care Med. (1999) 160:227–236.
Gore ER. Immune function tests for hazard identification: A paradigm shift in drug development. Basic Clin. Pharmacol. Toxicol. (2006) 98:331–335.[CrossRef][Web of Science][Medline]
Gruber C, Lau S, Dannemann A, Sommerfeld C, Wahn U, Aalberse RC. Down-regulation of IgE and IgG4 antibodies to tetanus toxoid and diphtheria toxoid by covaccination with cellular Bordetella pertussis vaccine. J. Immunol. (2001) 167:2411–2417.
Hamada K, Suzaki Y, Leme A, Ito T, Miyamoto K, Kobzik L, Kimura H. Exposure of pregnant mice to an air pollutant aerosol increases asthma susceptibility in offspring. J. Toxicol. Environ. Health (2007) 70:688–695.[CrossRef][Web of Science]
Heilmann C, Grandjean P, Weihe P, Nielsen F, Budtz-Jorgensen E. Reduced antibody response to vaccinations in children exposed to polychlorinated biphenyls. PLoS Med. (2006) 3:e311.[CrossRef][Medline]
Imanishi J, Oku T, Oishi K, Kishida T, Nomura H, Mizutani T. Reduced resistance to experimental viral and bacterial infections of mice treated with polychlorinated biphenyl. Biken J. (1984) 27:195–198.[Web of Science][Medline]
Jaakkola JJ, Gissler M. Maternal smoking in pregnancy, fetal development, and childhood asthma. Am. J. Public Health (2004) 94:136–140.
Kitchin KT. Recent advances in arsenic carcinogenesis: Modes of action, animal model systems, and methylated arsenic metabolites. Toxicol. Appl. Pharmacol. (2001) 172:249–261.[CrossRef][Web of Science][Medline]
Loose LD, Silkworth JB, Pittman KA, Benitz KF, Mueller W. Impaired host resistance to endotoxin and malaria in polychlorinated biphenyl- and hexachlorobenzene-treated mice. Infect. Immun. (1978) 20:30–35.
Luebke RW, Chen DH, Dietert R, Yang Y, King M, Luster MI. The comparative immunotoxicity of five selected compounds following developmental or adult exposure. J. Toxicol. Environ. Health B (2006) 9:1–26.[CrossRef]
Luebke RS, Parks C, Luster MI. Suppression of immune function and susceptibility to infections in humans: Association of immune function with clinical disease. J. Immunotoxicol. (2004) 1:15–24.[CrossRef]
Luebke RW, Copeland CB, Daniels M, Lambert AL, Gilmour MI. Suppression of allergic immune responses to house dust mite (HDM) in rats exposed to 2,3,7,8-TCDD. Toxicol. Sci. (2001) 62:71–79.
Luster MI, Johnson VJ, Yucesoy B, Simeonova PP. Biomarkers to assess potential developmental immunotoxicity in children. Toxicol. Appl. Pharmacol. (2005) 206:229–236.[CrossRef][Web of Science][Medline]
Luster MI, Munson AE, Thomas PT, Holsapple MP, Fenters JD, White KL Jr, Lauer LD, Germolec DR, Rosenthal GJ, Dean JH. Development of a testing battery to assess chemical-induced immunotoxicity: National toxicology program's guidelines for immunotoxicity evaluation in mice. Fundam. Appl. Toxicol. (1988) 10:2–19.[CrossRef][Web of Science][Medline]
Luster MI, Portier C, Pait DG, Rosenthal GJ, Germolec DR, Corsini E, Blaylock BL, Pollock P, Kouchi Y, Craig W, et al. Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fundam. Appl. Toxicol. (1993) 21:71–82.[CrossRef][Web of Science][Medline]
Luster MI, Portier C, Pait DG, White KL Jr, Gennings C, Munson AE, Rosenthal GJ. Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fundam. Appl. Toxicol. (1992) 18:200–210.[CrossRef][Web of Science][Medline]
Magnani C, Pastore G, Luzzatto L, Terracini B. Parental occupation and other environmental factors in the etiology of leukemias and non-Hodgkin's lymphomas in childhood: A case-control study. Tumori (1990) 76:413–419.[Web of Science][Medline]
Nagayama J, Tsuji H, Iida T, Hirakawa H, Matsueda T, Okamura K, Hasegawa M, Sato K, Ma HY, Yanagawa T, et al. Postnatal exposure to chlorinated dioxins and related chemicals on lymphocyte subsets in Japanese breast-fed infants. Chemosphere (1998) 37:1781–1787.[Medline]
Naito S, Takahashi M, Ishida S, Uchida T. Induction of IgE antibody production in mice with different DPT-vaccine preparations. Jpn. J. Med. Sci. Biol. (1995) 48:117–122.[Medline]
Ng SP, Silverstone AE, Lai ZW, Zelikoff JT. Effects of prenatal exposure to cigarette smoke on offspring tumor susceptibility and associated immune mechanisms. Toxicol. Sci. (2006) 89:135–144.
Patterson R, Vega L, Trouba K, Bortner C, Germolec D. Arsenic-induced alterations in the contact hypersensitivity response in Balb/c mice. Toxicol. Appl. Pharmacol. (2004) 198:434–443.[CrossRef][Web of Science][Medline]
Samore MH, Siber GR. Pertussis toxin enhanced IgG1 and IgE responses to primary tetanus immunization are mediated by interleukin-4 and persist during secondary responses to tetanus alone. Vaccine (1996) 14:290–297.[CrossRef][Web of Science][Medline]
Schuz J, Kaletsch U, Meinert R, Kaatsch P, Spix C, Michaelis J. Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany. J. Clin. Epidemiol. (2001) 54:702–709.[CrossRef][Web of Science][Medline]
Selgrade M. Immunotoxicity. In: A Textbook of Modern Toxicology—Hodgson E, ed. (2004) 3rd ed. Hoboken, NJ: John Wiley & Sons. 327–342.
Selgrade MK. Use of immunotoxicity data in health risk assessments: Uncertainties and research to improve the process. Toxicology (1999) 133:59–72.[CrossRef][Web of Science][Medline]
Selgrade MK, Lemanske RF Jr, Gilmour MI, Neas LM, Ward MD, Henneberger PK, Weissman DN, Hoppin JA, Dietert RR, Sly PD, et al. Induction of asthma and the environment: What we know and need to know. Environ. Health Perspect. (2006) 114:615–619.[Web of Science][Medline]
Sikorski EE, McCay JA, White KL Jr, Bradley SG, Munson AE. Immunotoxicity of the semiconductor gallium arsenide in female B6C3F1 mice. Fundam. Appl. Toxicol. (1989) 13:843–858.[CrossRef][Web of Science][Medline]
Soto-Pena GA, Luna AL, Acosta-Saavedra L, Conde P, Lopez-Carrillo L, Cebrian ME, Bastida M, Calderon-Aranda ES, Vega L. Assessment of lymphocyte subpopulations and cytokine secretion in children exposed to arsenic. FASEB J. (2006) 20:779–781.
Tryphonas H, Luster MI, Schiffman G, Dawson LL, Hodgen M, Germolec D, Hayward S, Bryce F, Loo JC, Mandy F, et al. Effect of chronic exposure of PCB (Aroclor 1254) on specific and nonspecific immune parameters in the rhesus (Macaca mulatta) monkey. Fundam. Appl. Toxicol. (1991) 16:773–786.[CrossRef][Web of Science][Medline]
Van Loveren H, Van Amsterdam JG, Vandebriel RJ, Kimman TG, Rumke HC, Steerenberg PS, Vos JG. Vaccine-induced antibody responses as parameters of the influence of endogenous and environmental factors. Environ. Health Perspect. (2001) 109:757–764.[Web of Science][Medline]
Weisglas-Kuperus N, Patandin S, Berbers GA, Sas TC, Mulder PG, Sauer PJ, Hooijkaas H. Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. Environ. Health Perspect. (2000) 108:1203–1207.[Web of Science][Medline]
Wierda D, Irons RD, Greenlee WF. Immunotoxicity in C57BL/6 mice exposed to benzene and Aroclor 1254. Toxicol. Appl. Pharmacol. (1981) 60:410–417.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Ramos, A. Y. Limon-Flores, and S. E. Ullrich JP-8 Induces Immune Suppression via a Reactive Oxygen Species NF-{kappa}{beta}-Dependent Mechanism Toxicol. Sci., March 1, 2009; 108(1): 100 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. E. Keil, W. D. McGuinn, A. C. Dudley, J. G. EuDaly, G. S. Gilkeson, and M. M. Peden-Adams N,N,-Diethyl-m-Toluamide (DEET) Suppresses Humoral Immunological Function in B6C3F1 Mice Toxicol. Sci., March 1, 2009; 108(1): 110 - 123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Calderon-Garciduenas, M. Macias-Parra, H. J. Hoffmann, G. Valencia-Salazar, C. Henriquez-Roldan, N. Osnaya, O. C.-d. Monte, G. Barragan-Mejia, R. Villarreal-Calderon, L. Romero, et al. Immunotoxicity and Environment: Immunodysregulation and Systemic Inflammation in Children Toxicol Pathol, February 1, 2009; 37(2): 161 - 169. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||