Immunotoxicity relationship

Bartlett A, Dearden JC, Sibley PR. Quantitative structure-activity relationships in the prediction of penicillin immunotoxicity. Quant Struct-Act Relat 1995 14 258-63. 

This chapter presents specific information with regard to the effects of environmental and occupational exposure to arsenic on inflammatory processes, the immune system, and host defense. While the focus is on the in vivo and in vitro effects of arsenic on host immune responses (e.g., immunotoxicity and hypersensitivity) and their relationship to clinically observed manifestations of arsenic toxicity (e.g., inflammation and skin cancer), information on the potential mechanisms through which arsenic may exert its biological effects is also provided. 

Most immunotoxic responses express a clear dose-response relationship that can be used for human risk assessment. However, it is more difficult to extrapolate in vitro concentrations than in vivo animal doses (plasma concentrations) to the clinical dose. 

Immunotoxicity. There are currently no data on the effects of 2-hexanone on the human immune system via any route of exposure. Animal data included an inhalation study in which there was a 40% decrease in peripheral white blood cells in rats exposed to 2-hexanone (Katz et al. 1980). In addition, 2,5-hexanedione, a metabolite of 2-hexanone, was shown to adversely affect lymphoid organs of the immune system in rats and to cause impairment of immunity in mice (Upreti and Shanker 1987). Immunological assessments, including analysis of peripheral blood components and effects on lymphoid tissue, conducted as part of intermediate-or chronic-duration studies and skin sensitization tests would be useful in developing a dose-response relationship and assessing the potential risk to chronically exposed persons in the vicinity of hazardous waste sites or to exposed workers. 

Usually both sexes should be used in these studies, excluding non-human primates. The high dose should be above the no observed adverse effect level (NOAEL) but below a level inducing changes secondary to stress. Multiple dose levels are recommended in order to determine dose-response relationships and the dose at which no immunotoxicity is observed. 

Immunotoxicity. There are numerous studies of the immune system in workers (active or retired) exposed to asbestos in workplace air (deShazo et al. 1988 Froom et al. 2000 Kagan et al. 1977 Pemis et al. 1965 Sprince et al. 1991, 1992 Warwick et al. 1973). These studies indicate that the immune system may be depressed in individuals who have developed clinical signs of injury, such as asbestosis or cancer. However, the cause-effect relationship between the immunological changes and the asbestos-related diseases is not certain. Also, it is not known if similar effects occur after oral exposure, or if the effects are inhalation specific. Prospective studies on this subject may be useful, both in discerning the importance of... 

A large number of acute intraperitoneal and in vitro studies have inveshgated congeneric structure-activity relationships for the purpose of elucidating mechanisms of immunotoxicity and relative potencies of individual congeners and their potential interactive effects. As summarized in Section 3.4.2 (Mechanisms of Toxicity), there is evidence from various test systems that noncoplanar as well as... 

Another panelist agreed with Dr. Tryphonas arguments. He added that his experience as a researcher for EPA on Aroclor 1254 has found that immunotoxicity is a critical adverse effect associated with exposure to PCBs. This panelist noted that the Levinskas study found a dose-response relationship for clinical manifestations of PCB-related immunotoxicity in rhesus monkeys (Levinskas et al. 1984). Based on this study and other studies, this panelist was also convinced that basing the MRL on immunotoxic effects was appropriate. 

There is usually no dose-response relationship for immune responses, as the magnitude of the response is dependent on the type of reaction of the endogenous immune system, not on the concentration of the foreign compound. However, there may be a relationship between the frequency of occurrence of an immunotoxic response and the exposure as occurs with hydralazine (see Chapter 7). 

The mechanism of penicillin immunotoxicity relies on the formation of a covalent conjugate with soluble or cellular protein. There is a clear relationship between conjugation to proteins and cells and the... 

Epidemiological and Human Dosimettv Studies. Acute high-level exposure to zinc by inhalation resulted in respiratory irritation and metal fume fever (Blanc et al. 1991 Hjortso et al. 1988 Johnson and Stonehill 1961 Linn et al. 1981 Schenker et al. 1981 Sturgis et al. 1927). Welders are a subpopulation of workers who have a high potential for exposure to zinc oxide. Most of the available studies did not report exposure levels or used a small number of subjects. Studies that correlate occupational exposure to zinc with health effects would be useful. A number of human oral exposure studies have shown that excess levels of zinc can result in anemia, pancreatic damage, decreased serum HDL cholesterol levels, and immunotoxicity (Black et al. 1988 Chandra 1984 Hooper et al. 1980). There are insufficient data for establishing dose-response relationships. 

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