Longer-term exposure

A knowledge of physiology and pharmacokinetics is needed (Fanis et al. 1993 Monteiro and Furness 2001). Levels of mercuiy normally vary among internal tissues, and the time to equilibrate within each tissue varies. For example, blood mercury levels normally reflect veiy recent exposure, while brain and liver levels reflect longer-term exposure. Tissue-specific mechanisms of detoxification and seqnestration, among other processes, must be understood to define the bioactive moiety in observed tissue bmdens before a clear expression of toxicity can be derived (Woodetal. 1997). 

The liver is sensitive to hexachloroethane following both acute and longer term exposure scenarios. Evidence of effects on the liver include increased weight and centrilobular necrosis in rats and rabbits and increased serum levels of liver enzymes in sheep. There can also be fatty degeneration of the tissues and hemorrhage when damage is severe. 

Acute studies are summarized in Table 2-4. These studies and effects following longer-term exposures are described in the following text. 

In longer-term exposures, two rhesus monkeys were exposed to PGDN vapors for 125 d at concentrations that were increased in increments from 0.3 to 4.2 ppm (Mattsson et al. 1981). Two monkeys served as controls. Daily testing involving either the cued or free operant avoidance tests showed no effects on either type of avoidance performance, and there was no disruption of the ability to discriminate between the two avoidance schedules. 

Results of acute exposures are summarized in Table 4 1. These studies and studies involving longer-term exposures are discussed below. 

Studies in animals indicate that acute exposures to levels of 160-980 ppm may be lethal (Alexeeff et al. 1985 Eustisetal. 1988 Flonmaetal. 1985 Flurtt et al. 1987a Irish etal. 1940 Katoetal. 1986). Several studies reveal there is an extremely narrow margin between lethal and nonlethal exposures. For example, Kato et al. (1986) found no deaths in rats exposed to 700 ppm for 4 hours, but 100% lethality in animals exposed to 800 ppm. Similarly, Irish et al. (1940) found 100% survival in rats exposed to 100 ppm for 24 hours, and 100% lethality at 220 ppm. Longer-term exposures of animals can lead to death after exposure to levels as low as 66-120 ppm (Drew 1984 Flaber 1987 Flardin et al. 1981 Irish et al. 1940 Reuzel et al. 1987). 

Cresols may be lethal to animals when inhaled (Campbell 1941 Uzhdavini et al. 1972). The inhalation exposure levels and durations that kill animals have not been reliably documented. Lethality has been reported in mice exposed to approximately 178 mg/m of o-cresol aerosol for an unspecified acute duration, suggesting that the minimal lethal exposure level for cresol aerosols may be less than 178 mg/m (Uzhdavini et al. 1972). For longer-term exposure, the minimal lethal level may exceed 50 mg/m, since exposure to this concentration of o-cresol for 1 month had no effect on mouse mortality (Uzhdavini et al. 1972). 

Of the phytotoxic air pollutants and mixtures tested, O3 or combinations of SO2+NO2 are most likely to occur in ambient atmospheres in sufficiently high concentrations to acutely depress apparent photosynthesis. Ambient HP concentrations of the magnitudes which inhibited CO2 uptake rates in an acute, reversible manner would be rare. Studies into longer-term exposures (several days or weeks) to HP concentrations in the low ppb range have suggested that reduced photosynthesis under these conditions correlated with the amount of necrosis that developed (, ). 

Longer term exposure caused effects on respiratory macrophages (Haley et al. 1990 Morimoto et al. 1995 Spiegelberg et al. 1984). An increase in the production of tumor necrosis factor by alveolar macrophages was observed in rats exposed to nickel oxide at 9.2 mg/m, 8 hours/day, 5 days/week, for... 

Dose-response data for dermal exposure of humans or animals to nickel were not identified. The thresholds for nickel sensitivity identified for acute dermal exposure of humans (Menne and Calvin 1993 Menne et al. 1987) should be protective for longer term exposure. 

Evidence accumulating from various laboratories points to a role for PKC in mediating the action of lithium in a number of cell systems and the brain (Manji and Lenox 1994, in press]. Currently available data suggest that short-term lithium exposure facilitates a number of PKC-mediated responses, whereas longer-term exposure results in an attenuation of phorbol ester-mediated responses, which may be accompanied by a downregulation of PKC (S. M. P. Anderson et al. 1988 J. A. Bitran et al. 1990 M. S. Evans et... 

A number of patients have been exposed to clozapine for several years and TD has not developed. Studies have also investigated patients with TD who were switched to clozapine for periods of 3 weeks to 6 months (461, 462, 463 and 464). Some appeared to improve, but these findings are difficult to interpret because control groups would be needed to demonstrate conclusively that clozapine does not cause TD. Theoretically, if clozapine does not cause acute EPS, then it should not cause TD. Other novel agents such as risperidone, olanzapine, quetiapine, and ziprasidone await longer term exposure to assess their propensity to induce TD. Thus, we agree with Casey, who wrote it is possible that compounds associated with a low rate of EPS may also produce less TD, but prospective studies are needed to confirm this premise (465). 

Histological changes in the mucous membranes of the mouth and susceptibility to death among pregnant females during birth are also possible following longer term exposure. 

Each practice indicates its limitations, and these are important to keep in mind. As with all accelerated tests, what is actually tested is the resistance of these alloys to IGA in the specific test environment. One must be very careful to be sure that these results correlate with longer term exposures to the field environment of interest. In addition, these tests are only useful for evaluating the susceptibility of these alloys to IGA, not to pitting or general corrosion or SCC. 

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