Veterans and Agent Orange Update 2010 (2012) / Chapter Skim
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6 Immune-System Disorders
6 Immune-System Disorders
Pages 240-264
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From page 240... ...
The current committee elected to comprehensively revisit the limited epidemiologic evidence concerning association of immune disease with herbicide exposure in light of the substantial volume of toxicologic evidence of 2,3,7,8-tetrachlorodibenzo- pdioxin's (TCDD's) impairment of the immune systems of laboratory animals.
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From page 241... ...
It is often difficult to diagnose such diseases, so they may or may not be medically catego rized as immune disorders. Immune Suppression Suppression of immune responses can reduce resistance to infectious disease and increase the risk of cancer.
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From page 242... ...
Immune suppression can also result from exposure to chemicals in the workplace or in the environment and be manifested as recurrent infections, op portunistic infections, a higher incidence of a specific category of infections, or a higher incidence of cancer. However, unless the immune suppression is severe, it is often difficult to obtain clinical evidence that directly links chemically induced changes in immune function to increased infectious disease or cancer, because many confounding factors can influence a person's ability to combat infection.
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From page 243... ...
For example, the autoimmune reaction in multiple sclerosis is directed against the myelin sheath of the nervous system; in Crohn disease, the intestine is the target of attack; in type 1 diabetes mellitus, the insulin-producing cells of the pancreas are destroyed by the immune response; rheumatoid arthritis arises from immune attack on the joints. More generalized forms of autoimmune diseases also occur.
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From page 244... ...
It is one component of the normal host response to infection and is mediated by innate immune cells. Inflammatory responses have evolved to speed the traffick ing of macrophages, granulocytes, and some lymphocytes to the area of infection, where they produce toxic metabolites that kill pathogens.
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From page 245... ...
, serum Ig, or autoantibodies Michalek et al., Participants in 1997 No change in surface markers for B and 1999a examination cycle, T cells, no change in serum Ig, no change Ranch Hands vs in autoantibodies (antinuclear antibody, comparisons -- incidence smooth muscle autoantibody, parietal cell autoantibody, rheumatoid factor, and monoclonal immunoglobulins) and no dose related change in DTH response Wolfe et al., 1990 Participants in 1987 No change in surface markers for B and T examination cycle, cells Ranch Hands vs comparisons -- morbidity Wolfe et al., 1985 Participants in 1985 No change in surface markers for B and T examination cycle, Ranch cells Hands vs comparisons -- morbidity and mortality US CDC Vietnam Experience Study (VES)
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From page 246... ...
diseases Kahn et al., 1992 New Jersey Agent Orange Depressed response to tetanus in DTH tests, Commission decrease in CD4 and SmIg+ B cells Newell, 1984 Agent Orange Advisory Increase in percentage of active T rosette Committee of Texas forming cells Australian Vietnam Veterans All COIs O'Toole et al., 2009 Australian Vietnam Increase in hay fever, increases in infectious Veterans -- longitudinal and parasitic diseases, increase in arthritis cohort study of 67 conditions in randomly selected Vietnam veterans vs general population CDVA, 1997b National Service Vietnam No change in mortality from infectious Veterans -- mortality (including parasitic) diseases Korean Vietnam Veterans All COIs Kim et al., 2003 Immunotoxicologic study Increase in IgE and IL-4, decrease in IgG1 and IFN-gamma, no change in lymphocyte counts Vietnamese Vietnam Veterans All COIs Chinh et al., 1996 Antinuclear and sperm No change in autoantibodies to sperm, autoantibodies antinuclear bodies OCCUPATIONAL STUDIES Chemical or Industrial Workers Pesticide factories (not specifically Baranska et al., 2008 A prospective multicenter cohort study of 238 TCDD)
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From page 247... ...
TCDD (or TEQs from PCDD/PCDF Jung et al., 1998 192 workers in a German pesticide plant, including exposure) : No significant changes in TCDD 29 highly exposed and and lymphocyte subsets, antibody responses 28 controls compared for to vaccination, lymphocyte proliferation, immune functional tests or autoantibody production; decrease in chromate resistance of PHA-stimulated lymphocytes in highest exposure group TCDD (as a contaminant in chemical Sweeney et al., 1987 cross-sectional study 1997/1998 of 281 chemical-plant production)
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From page 248... ...
: Lymphoid Oh et al., 2005 Comparison of immune measures in 31 waste- subsets, IFN-gamma, and Ig not statistically incineration workers vs 84 different; decrease in IL-4 and increase in controls T-cell activation (measured as combined CD3 and CD69 markers) associated with TCDD exposure Agricultural Health Study (AHS)
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From page 249... ...
; pre-employment samples and samples after 9 months were analyzed for comparison with samples from 31 nonexposed workers Seveso Residential Population TCDD Baccarelli et al., Study of 101 chloracne Persistent increase in TCDD in chloracne 2005b cases vs 211 controls 20 cases; younger people seemed to be more years after the accident; susceptible; no major trends in disease relatively low statistical occurrence power was available because the study examined the occurrence of individual diseases Baccarelli et al., 2002 Study of 62 people from a Plasma concentration of TCDD was highly exposed zone and 53 determined; multivariate regression analysis from noncontaminated areas showed significant decrease in plasma IgG 20 years after the accident with increasing TCDD concentration and no changes in IgM, IgA, or C3 continued
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From page 250... ...
, and only trends were noted in low-risk areas (12 men, 10 women, and 8 children) Quail Run Mobile Home Park (MO)
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From page 251... ...
; TEQ IgE concentrations; history of upper airway values were calculated allergy, and odds of a positive RAST test from serum dioxin-like correlated negatively with serum TEQ; IgA PCB concentrations and concentrations correlated positively with relationships with immune TEQ measures were examined PCDD, exposure from food: The study Lovik et al., 1996 Blood samples from 24 Norwegian hobby fishermen generally lacks experimental details; no were compared with those differences in an NK cell marker or in NK of 10 male referents as activity were seen; apparently, some effects controls on lymphoid markers were observed but specific details are lacking Dioxin in wood preservatives, exposure Wolf and Karmaus, Cross-sectional study of 1995 221 teachers who worked primarily via inhalation: No effects of in German day-care inhaled dioxin were seen on T4 or T8 cell centers treated with wood numbers or on the ratio; some evidence of preservatives vs 189 a dose–response relationship was seen for teachers who worked in risk of anergy (or hypoergy) in the DTH untreated facilities assay continued
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From page 252... ...
and 50 homosexual men as controls ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AFHS, Air Force Health Study; AHS, Agricultural Health Study; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; Con A, concanavalin A; DTH, delayed-type hypersensitivity; IFN-gamma, interferon-gamma; Ig, immunoglobulin; IL, interleukin; MCPA, methyl-4-chlorophenoxyacetic acid; MLR, mixed lymphocyte response; NHANES, National Health and Nutrition Examination Survey; NK, natural killer; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines) ; PCDF, polychlorinated dibenzofurans; PHA, polyhydroxyalkanoates; RAST, radioallergosorbent; SEA, Southeast Asia; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; TCP, trichlorophenol; TEQ, total toxic equivalent; TNF, tumor necrosis factor; VA, Department of Veterans Affairs; VES, Vietnam Experience Study; WBC, white blood cell.
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From page 253... ...
in dioxin-exposed people. As seen Table 6-1, some early studies of the Quail Run Mobile Home Park population exposures reported that dioxin exposure was associated with a re duced cell-mediated immune response, the delayed-type hypersensitivity (DTH)
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From page 254... ...
Prior VAO updates concluded that human data were either insufficient or inconsistent with respect to an increased risk of immunosuppression, allergic disease, or autoimmune disease. UPDATE OF THE EPIDEMIOLOGIC LITERATURE AND HUMAN STUDIES For this update, the committee revisited the entire literature of herbicide– human immune findings from studies of Vietnam veterans, occupationally ex posed people, and environmentally exposed people (Table 6-1)
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From page 255... ...
. It is consistent with its immunosuppressive effects that TCDD exposure suppresses the allergic immune response of rodents, and this in turn results in decreased allergen-associated pathologic lung conditions and has recently been shown to suppress the development of experimental autoimmune disease (Quintana et al., 2008)
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From page 256... ...
No human studies have specifically addressed the influence of TCDD on autoimmune disease, but several animal studies have shown that TCDD suppresses the development of autoimmune diseases. In studying postservice mortality, Boehmer et al.
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From page 257... ...
It is also well known that primary immune responses are easier to alter than sec ondary immune responses. In vivo studies show that exposure to antigens may be important, so the timing of antigen exposure relative to TCDD exposure may be an important variable.
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Future studies should ensure that, whether in animal models or in direct human studies, gene- or sex-specific immune effects are able to be evaluated with sufficient statistical power to support distinctions. Stress Stress produced is a well known modifier of human immune responses.
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From page 259... ...
However, it is critical that the biomarkers used in such studies be those most predictive for risk of disease, and not just those most readily measured. On the basis of extensive animal studies involving TCDD, the most plausible immune alterations expected in dioxin-exposed human adults are suppression of selected adaptive immune responses and misregulated inflammation.
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From page 260... ...
2006. Depression and pesticide exposures in female spouses of licensed pesticide applicators in the Agricultural Health Study cohort.
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2008. Sex differences in autoimmune disease from a pathological perspective.
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2003. Immuno toxicological effects of Agent Orange exposure to the Vietnam War Korean veterans.
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From page 263... ...
2008. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor.
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From page 264... ...
American Journal of Industrial Medicine 11:685–691. Webb KZ, Evans RG, Knutsen AP, Roodman ST, Roberts DW, Schramm WF, Gibson BB, Andrews JS Jr, Needham LL, Patterson DG.
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