Dose-response relationship immunotoxicity

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. 

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). 

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. 

Other forms of immunotoxic expression with occupational Pb exposures have been described. Brazilian Pb workers (Queiroz et al., 1993) had significantly reduced peripheral blood neutrophil populations versus controls, using both chemotaxis and nitroblue tetrazolium reduction. These impairments were seen in workers with PbB <60pg/dl. Mishra et al. (2003) examined immunotoxic effects of Pb in three groups of workers versus controls lead battery plant workers, jewelry makers, and three-wheeler drivers. Phytohemagglutinin-induced lymphocyte proliferation was inhibited versus controls, but no dose—response relationship was seen. T-cell mitogen-stimulated monocytes also showed an increase in IFN- but NK-cell level was unaffected. There was a positive correlation of IFN- with PbB. 

Table 22.2 presents an expanded depiction of dose—toxic response relationships in children at PbB levels at or below 10 p-g/dl. This tabulation particularly focuses on developmental neurotoxic effects in young children, ranging from IQ decrements to deficits in school achievement and neuromuscular function (see Chapter 12 for details). Other systems are affected and include the renal, hematological, and immunological systems. For example, early kidney effects in the form of reduced GFR using cystatin C as the biomarker were noted by Fadrowski et al. (2010), with effects seen in children with a mean PbB of 1.5 p,g/dl and >99% with PbB <10p,g/dl. Immunotoxicity in children due to low Pb exposures is discussed in Chapter 18. 

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