Methemoglobin levels

Duration depends on dapsone half-life ( 20-30 h but prolonged with cimetidine use) and methemoglobin levels... 

Blood transfusions may be indicated with methemoglobin levels >50% and evidence of tissue hypoxia... 

No accidental inhalation exposures to aniline in which concentrations were known were identified in the available literature. However, methemoglobin levels were measured after accidental exposures to liquid aniline or aromatic... 

Human toxicity data are limited to secondary citations. Because these citations provided no experimental details, they cannot be considered reliable. Deaths have occurred from aniline ingestion and skin absorption, but doses were unknown. Reviews of the older literature indicate that a concentration of 5 ppm was considered safe for daily exposures, concentrations of 7 to 53 ppm produced slight symptoms after several hours, a concentration of 40 to 53 ppm was tolerated for 6 h without distinct symptoms, a concentration of 130 ppm may be tolerated for 0.5 to 1 h without immediate or late sequalae, and 100 to 160 ppm was the maximum concentration that could be inhaled for 1 h without serious disturbance. In studies of accidents with unknown exposure concentrations, methemoglobin levels of up to 72% were measured. Recoveries occurred with a minimum of medical intervention following cessation of exposure. 

Statistical analyses were not performed on the data however, it can be seen from the data in Table 1-6 that the methemoglobin levels following exposures to 0, 10, and 30 ppm for 8 h are not different. An additional 4 h of exposure (12 h of exposure) at the higher concentrations resulted in only slightly higher methemoglobin levels. 

In rats exposed at concentrations of 30 or 50 ppm for 8 h for up to 5 d, methemoglobin levels returned to control values after overnight recovery (10 ppm was identified by the authors as a no-effect level), whereas in the groups exposed at 150 ppm for 8 h or 50 or 150 ppm for 12 h for a maximum of 4 d, methemoglobin levels increased with increasing days of exposure. Hematocrit levels, measured 1 w after the start of exposure, were reduced at concentrations of >30 ppm. Signs of aniline intoxication either did not occur or were not reported. 

TABLE 1-6 Methemoglobin Levels in Rats Following 8 or 12 h of Exposure to Aniline... 

Further details of the above study were discussed in U.S. EPA (1994). After the last exposure, methemoglobin levels were elevated in a dose-dependent manner 17 ppm, 0% to 2.9% (no different from controls) 45 ppm, 2.2% to 5.4% and 87 ppm, 4.2% to 23%. The animals exposed at 45 and 87 ppm were anemic with decreases in RBC counts, hemoglobin content, MCHb concentration, and hematocrit, and accompanying increases in erythropoietin foci, reticuloendothelial cell hypertrophy, and hemosiderin deposition in the spleen. The animals in the 87-ppm exposure group were judged cyanotic. In the 17-ppm exposure group, effects were limited to mild splenic congestion. 

In an in vitro study in which phenylhydroxylamine (0.5 milligram per milliliter (mg/ mL)) was added to samples of rat and human blood, blood from the human subjects produced less methemoglobin in the human subjects than in the rats (approximately 35% in human blood and 60% in rat blood) (Jenkins et al. 1972). There was no more variation in methemoglobin levels among the cells from different humans than among the cells from different rats. 

Mier (1988) reported on the ingestion of aniline by a 4.5-y-old child weighing 16 kg. Ingestion of approximately 1 teaspoon (approximately 0.3125 mg/kg) produced a methemoglobin level of 68% by 6 h after ingestion. At this time, treatment consisted of intravenous methylene blue to which she was poorly responsive followed by blood exchange 13 h after ingestion. 

As noted, during exposure to a constant concentration, the level of methemoglobin does not approach equilibrium until 6-8 h after initiation of exposure (Figure 1-1). Therefore, methemoglobin levels at the shorter exposure durations are lower than those at 8 h (e.g., the level is 10.5% at 3 h for a constant exposure to 100 ppm), and any effect used as an endpoint at 8 h may not be present at the shorter exposure duration. Because of the 6-8 h lag time before... 

The concentration of 100 ppm for 8 h in the study by Kim and Carlson (1986) was used as the basis for the AEGL-1. This exposure results in a methemoglobin level of 22% but no hypoxic signs in rats. A review of the literature revealed that methemoglobin levels of 15-20% in humans results in clinical cyanosis, but no sign of clinical hypoxia (Kiese 1974 Seger 1992). Although inhalation data for comparison purposes are not available, oral... 

FIGURE 1-2 Measured and projected methemoglobin levels in rats exposed to aniline for 8 h. Source Data from Kim and Carlson 1986. 

An aniline concentration of 250 ppm, which is projected to result in a methemoglobin level between 70% and 80% after an 8-h exposure was identified as the basis for the AEGL-3. The same uncertainty factors and scaling procedure (the value of k in the formula C1xt=k is 1,200 ppm-min) as used for the AEGL-1 were applied to calculations of the AEGL-3. Calculations are in Appendix B, and values appear in Table 1-10. 

Endpoint/Concentration/Rationale Because the exposures did not result in effects consistent with the definition of an AEGL-3, the concentration vs percent hemoglobin formation data presented by the authors was graphed and projected to a methemoglobin level of 70-80%, which was considered the threshold for lethality in humans. This value was approximately 250 ppm. An 8-h exposure to 250 ppm was chosen as the basis for the AEGL-3 calculations. 

No data on lethality following acute exposures of <1 day were available. Squirrel monkeys exposed to PGDN at concentrations of 70-100 ppm for 6 h exhibited vomiting, pallor, cold extremities, semiconsciousness, and clonic convulsions. Rats exposed at 189 ppm for 4 h exhibited no overt signs of intoxication, although the mean methemoglobin level was increased to 23.5% (Jones et al. 1972). 

Few data on acute exposures with effects that meet the definition of an AEGL-2 were located. No clinical signs of intoxication were observed in rats exposed to PGDN at 189 ppm for 4 h. The methemoglobin level was 23.5% (Jones et al. 1972). Exposure of monkeys to PGDN at a concentration of 33 ppm for 4 h failed to affect performance in an operant avoidance behavioral test but altered the VER (Mattsson et al. 1981). 

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