Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 1 (2000) / Chapter Skim
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Arsine: Acute Exposure Guideline Levels
Arsine: Acute Exposure Guideline Levels
Pages 65-112
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From page 65... ...
values for arsine. AEGL values derived with animal data which had complete exposure data were more scientifically valid than AEGEs estimated Tom limited anecdotal human data.
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From page 66... ...
A less sensitive species, the rat, was used to calculate the AEGL levels because the data exhibited clear exposure-response relationships and the reduced hematocrit can be considered a sensitive indicator of arsine toxicity. Uncertainty regarding intraspecies variability was limited to a factor of 3-fold, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals.
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From page 67... ...
The steep exposure-response curves from animal data also affirm the limited variability in response. Furthermore, the AEGL-2 values were developed using an exposure resulting in no significant hemolysis in mice exposed to arsine at 5 ppm for ~ h, and, therefore, additional reduction of the values was unwarranted.
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From page 69... ...
2. OMAN TOXICITY DATA Human data for arsine are compromised by deficiencies in exposure concentration and duration data and by concurrent exposures to other materials.
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From page 70... ...
, provided the following anecdotal information regarding human responses to arsine exposure: immediately fatal following exposure at ~ ,530 ppm (no duration specified) , fatal within 30 min following exposure at 250 ppm, immediately fatal following exposure at 15.5 ppm for 30-60 min.
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From page 71... ...
A case of oliguric renal failure following acute exposure to arsine was reported by Uldall et al.
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From page 72... ...
produced toxic effects characterized by abdominal cramping, thoracic discomfort, and hematuria. Over the next week, the patient's hematocrit declined from 42.5 to 27.1 and hemoglobin dropped from 14.1 to 9.5 g/dL even with medical intervention (blood transfusions and mannitol diuresis)
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From page 73... ...
One case involved acute hemolysis followed by acute renal failure requiring dialysis, and the other involved acute hemolysis and cytolytic hepatitis; a definitive etiology for the hepatitis was not found but was thought to be possibly related to the arsine exposure. Arsine levels were subsequently found to be at or below the ACGTH Threshold Limit Value (TEV)
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From page 74... ...
The extreme acute toxicity of arsine gas precludes the relevance of carcinogenic potential for acute exposures. Therefore, a carcinogenicity assessment based upon elemental equivalence has not been carried out.
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(as cited in Flury and Zernik ~931) noted that the dog was similar to the cat regarding arsine toxicity.
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From page 76... ...
(as cited in Flury and Zernik 1931) provided data on the acute lethality of arsine in cats, noting the following for 1-h exposures: no observable signs oftoxicity following exposure to 43-50 ppm, sickwithrecovery following exposure to 50-100 ppm, and death (12-40 h post-exposure)
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From page 77... ...
All mate rats exposed at 400 ppm died and all female rats exposed at 350 or 400 ppm died. In the 1-h LCso experiments, rats were exposed to arsine concentrations of 120, 160, 190, or 220 (two groups)
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From page 78... ...
A 100% mortality was noted for groups of eight female B6C3F~ mice exposed to arsine for 1 h at a concentration of 26 ppm (three died immediately following exposure, and the remaining five died within 4 d. At 24 h post-exposure, there was a significant exposure-related decrease (21.7% relative to sham-exposed controls)
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From page 79... ...
Rats exposed at the two highest concentrations exhibited significantincreases in relative river weighs end relative spleen weight. Relative spleen weight was also significantly increased in the 0.5-ppm group (except 14~ females)
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From page 80... ...
The study focused on assessing hematologic responses, specifically hematocrit levels, numbers of erythrocytes, leukocytes andreticulocytes, and erythrocyte fragility. In this study, groups of eight female B6C3F~ mice were exposed to arsine for ~ h at concentrations of 0, 5, 9, ~ I, ~ 5, or 26 ppm.
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From page 81... ...
Relative spleen weight and packed cell volume were assessed at termination of exposure and after 1, 2, 4, and 7 ~ of recovery. At 2, 4, and 7 ~ post-exposure, the 5.0-ppm arsine exposure group exhibited significantly increased relative spleen weight relative to sham-exposed controls.
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From page 82... ...
. Relative liver weight, relative spleen weight, packed cell volume, and wholeblood aminolevuTinic acid dehydratase (ALAD)
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From page 83... ...
Based upon proposed mechanisms of action and the known interaction with RBCs and hemoglobin, metabolism per se may of limited importance relative to acute exposures to arsine. Delayed toxicity and lethality are observed in both humans and animals following acute exposure to arsine, and it is known that increased
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From page 84... ...
weight and decrease in packed l 990a cell volume Minor hematologic alterations Peterson and (reduced erythrocyte count) Bhattacharyya 1985 Minor hematologic alterations Peterson and (reduced erythrocyte count, Bhattacharyya decreased hematocrit, 1985 increased reticulocyte count)
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From page 85... ...
(199Ob) noted increased levels of circulating methemogiobin and decreased reduced glutathione levels in erythrocytes of mice exposed to arsine, and hypothesized that oxidative stress may be a key mechanism in arsine toxicity.
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From page 86... ...
4.4. Other Relevant Information Delayed neurologic and psychiatric disorders following acute arsine exposures have been reported (Frank 1976~.
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However, these data are not consistent with similar or Tower exposures resulting in lethality (see Table 2-3~. Numerous case reports are available documenting effects of varying severity following acute exposures of humans to arsine, but these reports lack definitive exposure data.
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From page 88... ...
The uncertainty factor of 3 for intraspecies variability was applied because of the extreme toxicity of arsine and because the mechanism of toxicity (hemolysis and subsequent renal failures is not likely to vary greatly among individuals. The basis for this assumption was that physiologic parameters (e.g., absorption, distribution, metabolism, structure ofthe erythrocyte and its response to arsine, and renal responses)
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From page 89... ...
, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = ~ when extrapolating to longer time points using the Cn x t = k equation. The human data from the earlier reports appears to be equivocal and unverifiable.
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From page 90... ...
indicated hematologic involvement. Cumulative exposures of 540-1,800 ppm min produced decreases in hematocrit levels, RBC counts, packed cell volumes, and increases in absolute and relative spleen weights (consistent with erythrocyte damage)
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From page 91... ...
justifies the approach used for derivation of the AEGL-2. Data from mice were used to calculate the AEGL levels because these data exhibited a good exposure response relationship, and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity.
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From page 92... ...
Although these reports verify the extreme toxicity of arsine, with the erythrocyte as the primary target, and the propensity for delayed lethality due to renal failure, valid exposure data are lacking. Human lethality has been documented for cumulative exposures ranging from 375 to 7,500 ppm min.
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From page 93... ...
The relationship among the three tiers of proposed AEGEs reflects the steep exposure-response relationship and extreme toxicity documented for arsine. It is apparent from the AEGL values that it is difficult to quantitatively differentiate a lethal exposure from one that produces serious but nonlethal effects.
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From page 94... ...
along the continuum of arsine toxicity and the approach employed for time scaling are considered sufficient for AEGLs that are protective of human health. Selection of uncertainty factors (10-fold for interspecies variability and 3-fold for protection of sensitive populations)
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perioU prior to renal faiTure. Quantitative animal data are available from several well-conducted peer-reviewed studies that demonstrate a toxic response similar to that observed for humans.
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From page 96... ...
This is likely a function of the rapid progression of arsine-induced toxicity from essentially no observable effects to that of a lethal response and the consequent steep exposure-response relationship. Additionally, studies addressing exposure concentration-duration relationships would allow for more precise temporal extrapolation for the development of AEGL values of varying exposure time durations.
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1989. Hematopoietic effects in mice exposed to arsine gas.
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From page 98... ...
Standing Operating Procedures for Developing Acute Exposure Guideline Levels forAirbome Chemicals. Washington, DC: National Academy Press.
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1950. Arsine poisoning: Epidemiological studies of outbreak following exposure to gases from metallic dross.
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Appendixes
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From page 103... ...
. Male and female B6C3F~ mice ex posed to arsine at 0.5 ppm for 6 h exhibited no change in relative spleen weights or hematologic parameters and exhibited no overt signs of toxicity.
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From page 104... ...
Uncertainty factors: An uncertainty factor of 10 was used for interspecies vari ability to account for possible variability in arsine-induced hemolysis and progression to renal effects. Uncertainty regarding intraspecies variability was limited to 3, because the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals.
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From page 105... ...
An uncer tainty factor for intraspecies variability of 3 was used, be cause the hemolytic response is likely to occur to a similar extent and with similar susceptibility in most individuals. This was based on the consideration that physiologic param eters (e.g., absorption, distribution, metabolism, structure of
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From page 106... ...
Individual variability (i.e., variability in erythrocyte structure/function or response of the kidney to hemolysis) is not likely to have a significant impact on any of the proposed subcellular mechanisms of arsine toxicity.
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From page 107... ...
, and to obtain AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = ~ when extrapolating to longer time points using the Cn x t = k equation.
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From page 108... ...
The mechanism of arsine toxicity (hemolysis and subsequent renal failure) and the fact that toxicity has been demonstrated at or below the odor threshold justify the inappropriateness of AEGL- ~ values for any exposure period.
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From page 109... ...
Uncertainty Factors/Rationale: Totaluncertainty factor 30 Interspecies: 10 - The 10-min LCso value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity.
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From page 110... ...
Because of these considerations and the fact that the AEGL-2 values were developed using a toxic response indicative of no significant hemolysis in mice exposed for 1 h to arsine at 5 ppm, an additional reduction of the values would seem unwarranted. Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn x t = k, where n = ~ or 3.
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From page 111... ...
The mouse data were used to caTculate the AEGL levels, because the data exhibited a good exposure-response relationship curve, and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship giving little margin between no effects and lethality.
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From page 112... ...
The steep exposure-response curves derived from animal data also affirm the limited variability in response. Because of these considerations and the fact that the AEGL 2 values were developed using a toxic response indicative of no significant hemolysis in mice exposed for ~ h to arsine at 5 ppm, additional reduction of the values would seem unwarranted.
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