Veterans and Agent Orange Update 2014 (2016) / Chapter Skim
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7 Immune-System Disorders
7 Immune-System Disorders
Pages 263-286
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From page 263... ...
The current 1 espite loose usage of "Agent Orange" by many people, in numerous publications, and even in the D title of this series, this committee uses "herbicides" to refer to the full range of herbicide exposures experienced in Vietnam, while "Agent Orange" is reserved for a specific one of the mixtures sprayed in Vietnam.
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From page 264... ...
Each type has many specialized cell populations that are responsible for specific functions connected to the production of specific mediators, such as immune hormones, cytokines, and other secreted factors. Imbalances in those specialized populations or in their level of functional activity can result in inadequate or improper immune responses, which may lead to pathologic outcomes.
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From page 265... ...
It is often difficult to diagnose such diseases, so they may or may not be medically categorized as immune disorders. Immune Suppression The suppression of immune responses can reduce resistance to infectious disease and increase the risk of cancer.
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From page 266... ...
. Genetic predisposition, age, hormone status, and environmental factors, such as the presence of infectious diseases and stress, are known to affect the risk of developing autoimmune diseases, and different autoimmune diseases tend to occur in the same person and to cluster in families.
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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 movement 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 268... ...
A few studies also included disease or condition end points, such as rheumatoid arthritis, SLE, immune suppression, and sensitivity to fungal infection. Ex vivo analyses included measures of NK activity, lymphoid mitogen-induced proliferation, and the mixed lymphocyte response (MLR)
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From page 269... ...
(including parasitic) diseases et al., 1995 New Jersey Agent Orange Commission Depressed response to tetanus in DTH Kahn et al., tests, decrease in CD4 and SmIg+ B cells 1992b Texas Agent Orange Advisory Increase in percentage of active T rosette- Newell, Committee forming cells 1984 Sample of 1,000 Male Australian All COIs Vietnam Veterans–prevelance Australian Vietnam Veterans -- Increase in hay fever, increases in O'Toole longitudinal cohort study of 67 infectious and parasitic diseases, increase et al., 2009 conditions in randomly selected in arthritis Vietnam veterans vs general population continued
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From page 270... ...
; no difference for other cell Hosnijeh counts and lymphocyte subsets et al., 2012b Decrease in B cells with increasing serum TCDD Soluble CD27 and CD30 levels not Saberi related to TCDD levels; Hosnijeh With exclusion of chronically ill subjects, et al., 2013a IL1RA decreased with increasing TCDD levels IARC Phenoxy Herbicide Cohort -- Dioxins, phenoxy herbicides German production workers (2,479 workers at 4 plants, in IARC as of 1997) Cross-sectional study of 153 male TCDD (during production of TCP)
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From page 271... ...
138 surviving workers from a larger TCDD: Among 14 immune measures; Ott et al., cohort of 254 exposed workers after regression analysis of TCDD 1994 an accident in a BASF TCP production concentration suggested marginal positive facility associations with IgG, IgA, C3, and C4; marginal reductions in some lymphocyte population were also reported IARC Phenoxy Herbicide Cohort -- Dioxins, 2,4,5-T; 2,5-DCP; 2,4,5-TCP German production workers at Boehringer-Ingelheim Plant in Hamburg (1,144 men working > 1 month in 1952–1984; generation of TCDD reduced after chloracne outbreak in 1954) Updated and expanded evaluation of TCDD (or "TCDD toxic equivalents" Neubert 158 workers in a German chemical from PCDD/PCDF)
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From page 272... ...
of hepatitis B vaccination among exposed 238 pesticide-exposed workers vs 198 workers carrying a specific IL-1 allele unexposed workers OCCUPATIONAL -- HERBICIDEUSING WORKERS (not related to IARC sprayer cohorts) Agricultural Health Study (AHS)
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From page 273... ...
Other Studies of Herbicide-Using Workers Longitudinal study of 10 farmers 2,4-D and MCPA formulations: Faustini during 1994 within 7 days before Decreases in percentages of CD4, CD8, et al., 1996 and 1–12 days and 50–70 days after CTL, CD8-DR, and NK cells and in exposure NK activity and mitogen-stimulated lymphoproliferation; CD4/CD8 ratio was unaltered; CD3 and CD8 percentages had recovered by the second assessment period; no significant correlations between immune changes and amount of pesticides applied ENVIRONMENTAL STUDIES Seveso Cleanup Workers TCDD Prospective study using analysis of No differences in WBC counts and Ghezzi samples from 36 cleanup workers (divided platelet counts et al., 1982 into three groups based on time spent in the contamination area) ; pre-employment samples and samples after 9 months were analyzed for comparison with samples from 31 unexposed workers Seveso, Italy Residential Cohort -- TCDD Industrial accident July 10, 1976 (723 residents Zone A; 4,821 Zone B; 31,643 Zone R; 181,574 local reference group)
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From page 274... ...
, and only trends were noted Quail Run Mobile Home Park (MO) TCDD Cohort A subset of the previously anergic Retesting of DTH failed to produce the Evans et al., persons in the Stehr-Green et al.
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From page 275... ...
; TEQ values were increasing TEQ; IgE concentrations; et al., 2002 calculated from serum dioxin–like PCB history of upper airway allergy, and concentrations, and relationships with odds of a positive RAST test correlated immune measures were examined negatively with serum TEQ; IgA concentrations correlated positively with TEQ Finland -- 123 men and 132 women from TEQ for dioxins, furans, and PCBs: Tururen high–fish consumption group CRP was not associated with overall TEQ et al., 2012 for men (p = 0.29) or women (p = 0.94)
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From page 276... ...
-- telephone Chemical exposures, including Hardell interviews concerning environmental and pesticides, and Agent Orange: No et al., 1987 occupational chemical exposures were significant differences were reported in a conducted with 50 AIDS patients (with small study that generally lacked focus Kaposi sarcoma) and 50 homosexual men as controls ABBREVIATIONS: 2,4-D, 2,4-dichlorophenoxyacetic acid; 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid; AHS, Agricultural Health Study; CATI, computer-assisted telephone interview; CDC, Centers for Disease Control and Prevention; CI, confidence interval; COI, chemical of interest; Con A, concanavalin A; CRP, C-reactive protein; DLC, dioxin-like compound; DTH, delayed-type hypersensitivity; IARC, International Agency for Research on Cancer; ICD, International Classification of Diseases; IFN-gamma, interferon-gamma; Ig, immunoglobulin; IL, interleukin; IL1RA, interleukin one receptor agonist; MCPA, methyl-4-chlorophenoxyacetic acid; MLR, mixed lymphocyte response; MO, Missouri; NHANES, National Health and Nutrition Examination Survey; NIOSH, National Institute for Occupational Safety and Health; NK, natural killer; OR, odds ratio; PCB, polychlorinated biphenyl; PCDD, polychlorinated dibenzo-p-dioxin (highly chlorinated, if four or more chlorines)
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From page 277... ...
in dioxin-exposed people. As seen in Table 7-1, some early studies of the Quail Run Mobile Home Park population exposures reported that dioxin exposure was associated with a reduced cell-mediated immune response, the DTH response (Andrews et al., 1986; offman et al., 1986; Knutsen et al., 1987; Stehr-Green et al., 1987)
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Having generated results consistent with immune suppression being associated with TCDD exposure, Saberi Hosnijeh et al.
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, which are associated with autoimmune disorders. Among the women, after adjustments for mercury blood level, race, menopausal status, diet, and BMI, total TEQs for PCBs were significantly associated with positivity for ANA (intensity ≥ 3)
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TCDDinduced immunotoxicity is due primarily to changes in adaptive immune responses resulting in the suppression of both antibody-mediated and cell-mediated immunity. Dioxin and other AHR agonists may also reduce the clearance of infections and promote tumor growth through alterations in immune function.
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From page 281... ...
Data from animal models and cell culture indicate that exposure to dioxin and DLCs alters the development of autoimmune disorders. For example, antagonism of the AHR represses the expression of cytokines and chemokines in primary human synovial fibroblasts (Lahoti et al., 2013)
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From page 282... ...
However, several studies of various measures of human immune function failed to reveal consistent correlations with TCDD exposure, probably because the exposures were inadequate to produce immune suppression or because the characteristics measured were not among those most relevant with respect to biologic plausibility. No clear pattern of an increase in infectious disease has been documented in the studies of veterans exposed to TCDD or to the herbicides used in Vietnam.
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From page 283... ...
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. The study of people who had allergic asthma or controlled asthma strengthened the data and suggested that the AHR (and thus dioxin exposure)
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From page 284... ...
Magnitude and Timing of Exposure In general, the TCDD exposures used in animal studies have been orders of magnitude higher than the exposures that Vietnam veterans are likely to have received during military service. It is well known that the immune system is highly susceptible to xenobiotic exposure during critical stages of development, such as gestation, and that primary immune responses are easier to alter than secondary immune responses.
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From page 285... ...
In considering the potential effects of the COIs on the immune system and the risk of disease, sex-based differences in chemically induced adverse immune outcomes need to be investigated. Future studies should ensure that -- whether in animal models or in human studies -- gene-specific or sex-specific immune effects are able to be evaluated with sufficient statistical power to support distinctions.
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