Biologic Markers in Immunotoxicology (1992) / Chapter Skim
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5 The Capacity of Toxic Agents to Compromise the Immune System (Biologic Markers of Immunosuppression)
5 The Capacity of Toxic Agents to Compromise the Immune System (Biologic Markers of Immunosuppression)
Pages 63-82
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From page 63... ...
Adverse effects on humans treated wit mmunosuppress~ve drugs, numerous studies employing expenment~ animals, and, to a lesser extent, Elated cases of altered immune function in humans inadvertently or occupationally exposed to xenobiotic substances support these concerns. There is no definitive e~ndence, as yet, that persons who live near contaminated sites or chem~cal-manufacturing plants have been immunologically compromised to the extent that they are at increased risk of ~ease.
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From page 64... ...
Studies of human ~mmunodefic~ency diseases and the counterpart animal models emphasize the potentially serious consequences of immunosuppression, whether it occurs as a result of heredity, aging, or nutrition or is ace as a result of exposure to xenobiotics. For some time, immunosuppressive agents have been used in treadng autoimmune diseases and as adjunctive therapy in organ transplantation procedures to prevent rejection by the recipient.
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From page 65... ...
deficiency Chediak-~gashi syndrome Chronic granulomatous din Complement deficient C1C8 Increased bacterial infections Increased bacterial infections Increased bacterial infections Increased bacterial and viral infections Inc reased bacterial and Cal infusions Creased bacterial and veal infusions Leuto~gtes cells (direct) ; B cells (into)
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From page 66... ...
It Is an immunosuppressive drug widely used to reduce transplant rejection, a cad-mediated immune response (Klaus and Hawrylow~cz, 1984~. The effects of CsA on Waft survive and on the generation of an immune response have been studied ~ AIRS IN IMMUNOTO~COLOGY animal models of many species to predict the effects of an ~mmunoto~cant on the human immune system.
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From page 67... ...
DNCB' d~itrochlorobenzene; DNFB, dinitrofluorobenzene; DNP, d~trophenol; DNP-KLH, D~P-k~yhole limpet hemopyanin; DTH, delayed~type hypersens~dvitr? GVH, graft versus host; MHC, major histocompat~b~ity complex antigens; OVA, ovalbumin; SRBC, sham red blood eel}.
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From page 68... ...
Adverse effects after low-level chronic exposure remain to be confirmed ENVIRONMENTAL CONTAMINANTS Human Studies Although they are not as well established as are the effects of therapeutic drugs, enwronment~ to~ncants are implicated ~ a number of reports that Rescue increased rates of neoplastic disease or infection in humans associates! tenth immune-system cages.
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From page 69... ...
In addition to env~ronmenta] chemicals, a large number of therapeutic substances, as wed as abused recreational Mugs, can alter Although most of the xenobiotics that alter the human immune system also can affect e~enment~ gals, clinical studies often have been critic zed for incomplete or inconsistent diagnosis of ~mmunodefic~ency, lack of clinical changes, small group she, inability to establish exposure levels, or lacl: Of reprodumbiliW.
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From page 70... ...
1n em ~ryogenesls, many ·mmUDosuppresslve xenobiotics would be expected to be developmental toxicants. To date, animal data have not been used to any significant event in the assessment of human risk resuldng from exposure to ~mmunosuppressive environmental pollutants.
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From page 71... ...
Regardless of age at the time of exposure or the target tissue examined' immunosu~ pression by TCDO, as well as by PCBs, is believed to be mediated through stereospecific and irreversible binding to an int~acellular receptor proteus (the Ah genotype) found ~ the cellular targets for TCDD, including lymphoid tissue, bone marrow cells, and the thymic epit}leli~ (Ihomas and Faith, 1985)
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From page 72... ...
In humane and experimental animals, the predominant hemopathy associated ante benzene exposure is pan~topenia, with assoaated bone marrow hypoplasia Alaskan and Goldstein, lo. Although hematopoietic progenitor cells are particularly susceptible to benzene, the mature c~culadng lymphm carte also responds to benzene in an antiprm Eferative response (Snyder et al., 19803.
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From page 73... ...
Organotm compounds, used as heat stabilizers, bioades, and Fiducial catalysts the production of foams and rubber, also are ~mmunotomc ~ ram. These compounds target the thymes, caused severe thymic atrophy and suppression of ceD-mediated immune responses (Seinen and Perk, 1~9)
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From page 74... ...
The mixture Table 543 was administered to the my n their drinking water over a period of 1~90 days and was found, at least at the high levels, to suppress the number of granulogyte-macrophage pros gewtor cells in the bone marrow, the generation of specific antibody-form~ cells ~ the spleen, and the ability of the mice to fight an infection of Plasmodium yeelii, Without it did not affect other indicators of targetorgan today. The authors note that although several of Me components of this complex mixture had been shown to have timid immunologic and myeloto~c effects, earlier studies tenth the ~n&v~dual comply nents suggest that none of We m~vidual con~i~tS was present at sufficient concentrations to be solely responsible for the observed effects.
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From page 75... ...
Injection or inhalation of ~sobul:y} mtrite suppresses sple~c and penpheral blood ~K activ~W ~otzovi et al., 1984~. Subchromc inh~ation e~osure to isobutyl n~tnte also results ~n decreased thymus wei~t, decreased 1iYer weigllt, decreased white-blood-cell colmts, mild focal hyperplasia, and vacuolizadon of the epithelium lining bronchi and bronchioles (Lynch et al., 1985)
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From page 76... ...
Phosgene exposure results in decreased levels of prostaglandin E-2 and leukotrienes in rat BALF. Production of arachidonic acid metabolites was measured by rat and human alveolar macrophages after in vitro exposure to phosgene (Madden et al., 1991)
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From page 77... ...
Within the marrow microenvironment, these seE-renewmg ceDs mature into committed progenitor cells, which can be found in peripheral blood and tissues. The continued development of these cells is under the control of venous growth factors, many of which or~nate In bone marrow stromal cells, which also pros vice a supporting matrix for development of hematopoiedc cells.
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From page 78... ...
In laboratory animals, many halogenated aromatic hydrocarbons, including chiormated dibenz~p-dio~nns and biphenyls, produce myeloto~cit~r at relatively low dose levels (Vos and Luster, 1989~. PAHs, such as B[a]
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From page 79... ...
When TCDD Is administered to adult animals, suppression of the celD-mediated and hum oral immune responses occurs and lasts for 1-2 months. However, the effects of TCDD on the thymus and on une-system responses are more severe and long-lasdug if TCDD is aclm~ni~tered both before =d after birth rather than only after birth (Vos and Moore, 1974; Faith and Moore, 1977; Luster et al., 1979~.
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From page 80... ...
When parable, mechanistic studies should be conducted with the appropriate consideration of the biolog~caDy effective dose and temporal susceptibility of the target site. Most studies on die mechanisms of immunoto~cant action are performed to allow a further understanding of the effects a compound can have on the human immune system and to show potential differences AIRS IN IMMlJNOTOX[COLOaY between animal models and humus.
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From page 81... ...
When possible, mechanistic studies should be conducted tenth the appropriate consideration of biolog~caBy effective doses. Animal immunologic bioassays are useful to identify possible hazards associated with human exposure to xenobiotics; to explain possible differences in susceptibility between m~ividuals and species; and to develop a rational basis for the management of nsk In medicine, in tile workplace, and among members of the general public.
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From page 82... ...
These differences should be taken into account and mininl~zed wherever possib: le in the interpretation of data Also, wherever possible, mech~mctic studies should be incorporated into the risk-assessment profile of an immunotoxicant Once the point of action of a xenobiotic is estate fished, it can be determined whether the Dame site is present In the human immune system. Mechanistic data also can allow a determination of whether a given xenobiotic can induce increased susceptibility to human &ease by Hating the importance of the mechanism to human defense against disease.
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