|
Arsine
CASRN 7784-42-1
Contents
0672
Arsine; CASRN 7784-42-1
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Arsine
File On-Line 03/01/1994
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) on-line 03/01/1994
Carcinogenicity Assessment (II.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Arsine
CASRN -- 7784-42-1
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Arsine
CASRN -- 7784-42-1
Last Revised -- 03/01/1994
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- ----------------------- ----- --- ---------
Increased hemolysis, NOAEL: 0.08 mg/cu.m 300 1 5E-5
abnormal RBC NOAEL(ADJ): 0.014 mg/cu.m mg/cu.m
morphology, and NOAEL(HEC): 0.014 mg/cu.m
increased spleen
weight LOAEL: 1.6 mg/cu.m
LOAEL(ADJ): 0.28 mg/cu.m
13-Week Rat and Mouse LOAEL(HEC): 0.28 mg/cu.m
and 28-Day Hamster
Inhalation Study
Blair et al., 1990a,b
Increased hemolysis, NOAEL: 0.08 mg/cu.m
increased spleen NOAEL(ADJ): 0.014 mg/cu.m
weight, and impaired NOAEL(HEC): 0.014 mg/cu.m
compensatory
erythropoiesis LOAEL: 1.6 mg/cu.m
LOAEL(ADJ): 0.28 mg/cu.m
12-Week Mouse LOAEL(HEC): 0.28 mg/cu.m
Inhalation Study
Hong et al., 1989
*Conversion Factors and Assumptions -- Assuming 25 C and 760 mmHg, LOAEL
(mg/cu.m) = 0.025 ppm x 77.93/24.45 = 0.08 x 6 hours/24 hours x 5 days/7 days
= 0.014 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extrarespiratory
effect, assuming periodicity was attained. Because the b:a lambda values are
unknown for the experimental species (a) and humans (h), a default value of
1.0 is used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x [b:a lambda(a)/b:a
lambda(h)] = 0.014 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Blair, P., M. Thompson, R. Morrissey et al. 1990a. Comparative toxicity of
arsine gas in B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters:
System organ studies and comparison of clinical indices of exposure. Fund.
Appl. Toxicol. 14(4): 776-787.
Blair, P., M. Thompson, M. Bechtold et al. 1990b. Evidence of oxidative
damage to red blood cells in mice induced by arsine gas. Toxicology. 63(1):
25-34.
Hong, H., B. Fowler, and G. Boorman. 1989. Hematopoietic effects in mice
exposed to arsine gas. Toxicol. Appl. Pharmacol. 97(1): 173-182.
Arsine gas is a potent hemolytic agent and a recognized industrial hazard.
Typical cases of acute poisonings, predominantly in workers accidentally
exposed, resulted in hemoglobinuria, jaundice, and hemolytic anemia. The
rapid and unique hemolysis caused by arsine can progress to oliguric renal
failure, which can be fatal without proper therapy (Levinsky et al., 1970;
Fowler and Weissberg, 1974). It has been reported that a half-hour exposure
to 25-50 ppm can be lethal (Blackwell and Robins, 1979). Hemolytic anemia,
however, is the most consistent clinical finding in humans. Observed
hemolytic effects in humans are consistent with effects observed in laboratory
animals and include increased Hgb concentrations; reticulocytosis;
leukocytosis; and altered RBC morphology characterized by basophilic
stippling, anisocytosis, poikilocytosis, red-cell fragments, and ghost cells
(Levinsky et al., 1970; Fowler and Weissberg, 1974; Wald and Becker, 1986).
Species differences are expected to be relatively few with respect to
hematologic effects for this direct-acting hemolytic agent. This was
confirmed in a series of comparative toxicity studies in B6C3F1 mice, Fischer
344 rats, and Golden Syrian hamsters (Blair et al., 1990a; Hong et al., 1989).
Although the reactive form of arsine and the specific sequence of events
that precede hemolysis are not fully known, the general mechanism of RBC
damage caused by arsine is understood. In vitro studies (Blair et al., 1990b)
show that the concentration of reduced glutathione falls during incubation
with arsine. It is likely that this is due to an oxidized metabolite of
arsine because arsine does not lyse RBCs in the absence of molecular oxygen
(Blair et al., 1990b; Pernis and Magistretti, 1960). Maintenance of
glutathione in the reduced state via the hexose monophosphate shunt in
erythrocytes is essential for the maintenance of sulfhydryl groups in membrane
proteins and Hgb. With oxidation and cross-linking of sulfhydryl groups on
Hgb, denaturation of the protein occurs and aggregates of the precipitated
molecule bind to the inner surface of the red cell membrane (Heinz bodies).
In the process of preventing the oxidation of Hgb, glutathione levels are
decreased and may not be adequate to inhibit membrane sulfhydryl oxidation
(Jacob and Jandl, 1962). Both the formation of Heinz bodies and membrane
sulfhydryl oxidation increase the fragility of the cell membrane and
predispose cells to fragmentation (Weed and Reed, 1966). Hematologic effects
observed in exposed animals by Blair et al. (1990a,b) and Hong et al. (1989),
such as increased hemosiderosis, Heinz bodies, low RBC counts, low Hgb
concentrations, and low HCTs, would be consistent with this pathogenesis.
Blair et al. (1990a) exposed 8-10-week-old (90-105-g) Fischer 344 rats
(15-16/sex/group) 6 hours/day for 14 consecutive days and 5 days/week for 4
and 13 weeks. Exposure concentrations were 0, 0.025, 0.5, or 2.5 ppm arsine
(equivalent to 0, 0.08, 1.6, or 8.0 mg/cu.m, respectively) for the 13-week
study and 0, 0.5, 2.5, and 5.0 ppm for the other studies. Duration-adjusted
concentrations for the 13-week study were 0.014, 0.28, or 1.4 mg/cu.m for the
low-, mid-, and high-exposure groups, respectively. Blood and tissue samples
were collected 1 and 3 days after the final exposure for rats exposed over 14
days and 4 weeks, respectively. Samples were collected 3 and 4 days after the
final exposure for rats exposed over 13 weeks. In addition, interim samples
were collected in the 13-week study to monitor the time course of hematologic
changes.
In addition, Blair et al. (1990a) exposed 8-10-week-old (20-30-g) B6C3F1
mice (15-16/sex/group) 6 hours/day for 1 day (females only), 14 consecutive
days, and 5 days/week for 13 weeks. Exposure concentrations were 0, 0.025,
0.5, or 2.5 ppm arsine (equivalent to 0, 0.08, 1.6, or 8.0 mg/cu.m,
respectively) for the 13-week study and 0, 0.5, 2.5, and 5.0 ppm for the other
studies. Duration-adjusted concentrations for the 13-week study were 0.014,
0.28, or 1.4 mg/cu.m for the low-, mid-, and high-exposure groups,
respectively. Mice exposed for a single day were sacrificed 0, 1, 2, 4, or 7
days after exposure to track postexposure recovery. Mice exposed for 14 days
were sacrificed 1 or 2 days after the final exposure, whereas mice exposed for
13 weeks were sacrificed 3 or 4 days after the final exposure.
Blair et al. (1990a) also exposed 8-10-week-old (130-150-g) Golden Syrian
hamsters (15-16/sex/group) to 0, 0.5, 2.5, or 0.5 ppm arsine (equivalent to 0,
1.6, 8.0, or 16 mg/cu.m, respectively), 6 hours/day, 5 days/week (duration-
adjusted to 0.28, 1.4, or 28 mg/cu.m) for 4 weeks. Blood samples were
collected 3 and 4 days after the final exposure.
Histopathology and packed cell volumes (PCV) determinations were performed
on all animal species. Histopathologic examinations were performed for 31
male and 29 female tissues. Respiratory tract tissues examined included the
nasal cavity (three sections), esophagus, lungs, and bronchi. Hematological
measurements were conducted only in the rats at interim time points (1, 3, and
11.5 days) and 3 and 4 days postexposure. Amino levalinic acid dehydratase
(ALAD) activity in RBCs was assayed in all three species to determine the
effects of arsine on the heme synthetic pathway.
Microscopic examinations revealed no pathology of the nasal cavity or
lower respiratory tract in any of the species studied. Treatment-related
lesions, as discussed below, were noted only in the spleen (all species),
liver (mice only), and bone marrow (rats only). No clinical effects were
reported in any of the species.
In rats, enlarged spleens and significantly increased relative spleen
weights (p < 0.05) were observed in the 0.5- and 2.5-ppm males and females at
28 and 90 days. Despite a 3-day recovery period, male and female rats exposed
to 0.5 ppm arsine for 28 or 90 days experienced an average increase in
relative spleen weight of approximately 50% over controls. Increased
hemosiderosis and extramedullary hematopoiesis in the spleen and bone marrow,
as well as hyperplasia of bone marrow, were present in the high-concentration
rats. Significantly decreased RBC counts, Hgb concentrations, and HCTs were
present in blood collected at 80 or 81 days of exposure in all exposed females
and in 0.5- and 2.5-ppm exposed males. The mean corpuscular volume (MCV) and
mean corpuscular hemoglobin (MCH) were elevated significantly in male and
female rats of the mid- and high-concentration groups, whereas platelet count
increased only in the high-concentration group. Increased ALAD activity and
reduced PCV occurred in the mid- and high-concentration groups. Increased
ALAD activity is consistent with the increase in the number of immature RBCs
observed by Hong et al. (1989) and supports the existence of a compensatory,
regenerative response to RBC hemolysis at the lowest (0.025 ppm) arsine
exposure level.
In mice, intracanalicular bile stasis was reported in the liver of 2.5-ppm
males and females, and increased relative liver weight was reported in the
2.5-ppm males. The male and female mice exposed to 2.5 ppm and the males
exposed to 0.5 ppm exhibited an elevated relative spleen weight after 90 days
of exposure to arsine. Relative spleen weight increase over controls in the
males exposed to 0.5 ppm was 75% after 14 days and 32% after 90 days exposure.
This corresponded to histopathological findings of enlarged, darkened spleens
with increased hemosiderosis and extramedullary hematopoiesis at these
exposure levels. Mean PCVs were decreased in all exposure groups of female
mice (6/group) subjected to 90 days exposure and a 4-day recovery period.
However, little significance is placed on these results given the small number
of animals involved and the fact that no change relative to controls was
observed in female mice given 90 days exposure and a 3-day recovery period.
In addition, a PCV effect was seen only in males at the 2.5-ppm (90-day)
exposure level. Amino levalinic acid dehydratase activity was significantly
increased in the 0.5-ppm male and female mice at 14 days, but not at 90 days.
Increased ALAD activity was sustained for 90 days at the 2.5-ppm exposure
level.
Similar effects were observed in Golden Syrian hamsters exposed to 0, 0.5,
2.5, or 5.0 ppm arsine, 5 days/week, for 28 days. The PCV was reduced
significantly in the high-concentration group for both females and males.
Spleen weights of the mid- and high-exposure groups (males and females) were
markedly increased relative to controls. Amino levalinic acid dehydratase
activity was significantly increased at all exposure levels for males and at
the mid and high levels for the females. Splenomegaly similar to that
observed in the rats and mice was observed in both females and males of the
mid- and high-exposure groups.
Blair et al. (1990b) further investigated the hypothesis that hemolytic
effects of arsine gas involve oxidative stress by arsine on erythrocytes,
which results in denaturation of Hgb and cell lysis. B6C3F1 mice
(10/sex/group) were exposed to 0, 0.025, 0.5, or 2.5 ppm arsine (equivalent to
0, 0.08, 1.6, or 8.0 mg/cu.m, respectively), 6 hours/day, 5 days/week
(duration adjusted to 0.014, 0.28, or 1.4 mg/cu.m), for 13 weeks. Blood
samples were collected after 5, 15, and 90 days of exposure, and hematological
measurements were made. Red blood cell counts, Hgb concentrations, and HCTs
were decreased in the 2.5-ppm animals (also 0.5-ppm males for Hgb
concentration). Mean corpuscular volume was significantly increased in
females of the 0.5-ppm group, and MCVs and MCHs were significantly increased
in males and females of the 2.5-ppm group at the 90-day sacrifice. A
significant increase in the mean corpuscular Hgb concentration (MCHC) and
platelets also occurred in 2.5-ppm males. Some of these hematological
parameters were also significantly affected on days 5 and 15 of exposure.
White cell count was affected only in the earlier time points (5 and 15 days)
in the high-concentration males. Methemoglobin levels were elevated
significantly (p < 0.01) in the 2.5-ppm group after 90 days of exposure to
arsine gas. Significant increases in absolute reticulocyte counts occurred in
animals in the 2.5-ppm exposure groups (p < 0.01), and small (not
statistically significant) increases occurred in the 0.5-ppm exposure groups.
Morphological evaluation of RBCs revealed polychromasia, anisocytosis,
poikilocytosis, increased number of Howell-Jolly bodies, and numerous
acanthocytes in the 2.5-ppm animals. These effects were apparent but less
severe in the 0.5-ppm group.
In another subchronic mouse bioassay, 8-week-old female B6C3F1 mice
(36/group) inhaled 0, 0.025, 0.5, or 2.5 ppm arsine (equivalent to 0, 0.077,
1.54, or 7.7 mg/cu.m, respectively), 6 hours/day, 5 days/week (duration
adjusted to 0.014, 0.27, or 1.37 mg/cu.m), for 12 weeks (Hong et al., 1989).
Arsine in argon was introduced into the process air stream, which flowed
through the mixing element and into the Rochester-type inhalation chambers.
Hematology and histopathology were performed, and body and spleen weights were
measured. No clinical symptoms were reported. Hematological parameters were
affected (i.e., decreased RBC, Hgb concentration, and HCT; increased MCV and
WBC) in a concentration-related manner. The effects were significant (p <
0.05) at the 2.5-ppm level for all indices. A significant (p < 0.01) increase
in MCV and WBC was observed in mice exposed to 0.5 ppm, and MCV was increased
(p < 0.05) in mice exposed to 0.025 ppm arsine. All blood parameters measured
returned to normal by 20 weeks postexposure. Splenomegaly and increased
relative spleen weight were observed after the 12-week exposure (25, 50, and
172% increased weight in the 0.025-, 0.5-, and 2.5-ppm groups, respectively).
This concentration-related effect, along with the increased MCV, suggests the
presence of significant extramedullary erythropoiesis in mice. By 21 days
postexposure, spleen weight remained significantly elevated in the two high-
concentration groups. Microscopic examination of the spleen from exposed mice
revealed smaller splenic follicles, concentration-related hematopoiesis,
sequestration of RBCs within red pulp, and hemosiderin accumulation within
macrophages in animals of all exposure groups.
Hong et al. (1989) also evaluated the effects of arsine on the
hematopoietic progenitor cells in the bone marrow of mice. Erythropoiesis, as
measured by quantitation of erythroid precursors in culture, revealed a
significant (p < 0.05) bone marrow reduction of colony-forming unit
erythroids/femur cells (CFU-E/femur) in the 2.5-ppm group (14%) and a slight
but nonsignificant reduction in the 0.5-ppm group (10%) at 6 days
postexposure. At 21 days postexposure, CFU-E/femur was not significantly
reduced in the 0.5-ppm exposure group but was still reduced by 11% in the
high-exposure group. Colony-forming unit granulocyte-macrophage/femur cells
(CGU-GM/femur) were not affected, suggesting that erythroid precursors in the
bone marrow of mice are more susceptible to arsine than granulocyte-macrophage
progenitors. Because arsine reacts strongly with Hgb, it is unlikely that the
arsine would survive in circulation to reach bone marrow and to interact with
it directly. However, relatively high doses of arsenic have been reported to
cause bone marrow suppression in humans (Hesdorffer et al., 1986).
In summary, from the Blair et al. (1990a,b) and Hong et al. (1989) studies
it is apparent that there were no differences in the types of effects produced
by arsine in the three species examined. Although concentration-response
information is lacking for humans, similar effects have been reported in case
studies, primarily involving acute occupational exposures (Hesdorffer et al.,
1986; Parish et al., 1979; De Palma, 1969; Teitelbaum and Kier, 1969). One
exception is that renal effects commonly observed as a consequence of acute
human exposures have not been observed following subchronic exposures to
laboratory animals. However, the survival rates in all laboratory animal
exposure groups were comparable with controls (i.e., the MTD was not
exceeded). Thus, it is reasonable to assume that, as has been suggested by
some authors (Levinsky et al., 1970), renal effects are secondary to hemolysis
and would have been observed in laboratory animals at higher exposure levels.
The greater susceptibility of rats to the hematologic effects of arsine may be
due to the fact that mice may have a greater capability for erythrocyte
regeneration because of a superior capacity for splenic extramedullary
hematopoiesis (Blair et al., 1990a). The splenomegaly and increased spleen
weight observed in all three species were likely the result of increased
removal of damaged RBCs (fragments), hemosiderosis, and increased splenic
hematopoiesis. The impact of these effects on normal splenic function is not
completely known but is of concern given the reported alterations in
immunocompetency of mice exposed to 2.5 ppm arsine for just 14 days (Rosenthal
et al., 1989). The studies did not identify a NOAEL or LOAEL for
splenomegaly; however, relative spleen weight was unchanged at the 0.025-ppm
exposure level and markedly increased in mice and rats at the 0.5-ppm exposure
level. With respect to RBC morphology, abnormalities consistent with those
observed in humans following arsine poisonings (Fowler and Weissberg, 1974)
were observed in mice at both 0.5 and 2.5 ppm. The case for impaired
erythropoiesis is not as strong, but Hong et al. (1989) did identify a trend
for reduced CFU-E/temur beginning at the 0.5-ppm exposure level. Thus, these
studies taken together support a 0.025-ppm NOAEL (HEC = 0.014 mg/cu.m) and a
0.5-ppm LOAEL (HEC = 0.28 mg/cu.m) for increased hemolyisis, altered RBC
morphology, increased spleen weight, and impaired erythropoiesis.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- An uncertainty factor of 10 is applied to account for sensitive
populations, and a factor of 3 is applied to account for interspecies
extrapolation based on the use of default dosimetry adjustments and because
large species differences are not expected for these direct hemolytic effects.
A composite factor of 10 is applied to account for both subchronic duration
extrapolation and database deficiencies, specifically the lack of a two-
generation reproductive study. A reduced uncertainty factor for subchronic-
to- chronic duration is applied because the principal studies do not suggest
that duration of exposure is a key determinant of the critical effects (14-
and 28-day exposures caused similar hematologic effects as 90-day exposures in
all three species tested).
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
The toxicologic literature on human exposures to arsine consists
principally of case studies of arsine gas poisonings in various occupational
settings and investigations of health hazards (particularly reproductive
toxicity) within the microelectronics industry. After the initial
demonstration of its toxicity in 1815, 454 cases of poisoning had been
documented by 1974. Of 207 cases of arsine toxicity between 1928 and 1974
(4.5 cases/year), 25% were fatal (Fowler and Weissberg, 1974). Between 1974
and 1986, 24 additional cases were reported (2 cases/year) with no fatalities
(Wald and Becker, 1986). This decline in case reports/year and fatalities
from acute poisonings is not necessarily an indication that a problem no
longer exists. Prior to 1974, anuria was a common cause of death following
acute exposures to high concentrations of arsine. With the ready availability
of hemodialysis, patients should not die from renal failure (Hesdorffer et
al., 1986; Wald and Becker, 1986). Further, the importance of treatment via
exchange transfusions (Hesdorffer et al., 1986) or some other method such as
penicillamine chelation (Risk and Fuortes, 1991) for the adequate removal of
arsine and significant amelioration is now recognized. Less severe cases may
not cause hematuria (Risk and Fuortes, 1991) and may go unrecognized and
untreated as the attending medical staff may not be aware of the possibility
of arsine gas poisoning. In fact, most cases of arsine poisoning have not
resulted from the manufacture or use of the gas itself, but from formation of
arsine as a by-product of a chemical reaction involving a base metal, an
arsenic impurity, and an acid (ACGIH, 1986).
In humans, clinical signs of acute exposures to arsine are abdominal pain,
hematuria, and jaundice. Other symptoms that have been reported following
acute (Wald and Becker, 1986) and subchronic exposures (Risk and Fuortes,
1991) include headache, malaise, weakness, and gastrointestinal distress
accompanied by nausea and vomiting. Hemolytic anemia, however, is the most
consistent clinical finding in humans. Observed hemolytic effects in humans
are consistent with effects observed in laboratory animals and include
increased Hgb concentrations, reticulocytosis, leukocytosis, and altered RBC
morphology characterized by basophilic stippling, anisocytosis,
poikilocytosis, red-cell fragments, and ghost cells (Levinsky et al., 1970;
Fowler and Weissberg, 1974; Wald and Becker, 1986). Bone marrow suppression
by arsenic may give the impression that no or minimal hemolysis is taking
place. In a recent case, a patient did not receive immediate exchange
transfusion because initial reticulocyte counts suggested that severe
continuous hemolysis was not occurring (Hesdorffer et al., 1986). Hematuria
is a symptom generally associated with acute exposure to arsine (Wald and
Becker, 1986). However, it was not observed following longer term, presumably
lower level, exposure despite the occurrence of both hepatic and renal
impairment (Risk and Fuortes, 1991).
The semiconductor industry makes use of many toxic materials, including a
variety of solvents, acids, and metals such as arsenic. The semiconductor
manufacturing process involves extensive use of dopant gases, primarily
arsine, phosphine, and diborane (LaDou, 1983; Pastides et al., 1988). The
California Department of Industrial Relations reported a higher rate of
occupational illness in the electronics industry between 1977 and 1980, and
that the semiconductor industry accounts for a large part of the difference
(LaDou, 1983). Two processes, the "photolithurgic" process and the
"diffusion" process, were investigated as potential sources of general illness
and spontaneous abortions (Pastides et al., 1988). The photolithurgic process
involves coating wafers with a photosensitive material containing glycol
ethers and, often, xylene, toluene, and hexamethyldisilazane. The diffusion
process involves heating the wafer at very high temperatures in a chamber
containing arsine, phosphine, and diborane (dopants). Three groups of workers
were selected for participation in this study: (1) all current workers with
more than 1 month of employment in the photolithurgic area, (2) workers
employed primarily in the diffusion area (but also workers from other areas
exclusive of photolithurgy), and (3) administrative staff not exposed to any
of the process chemicals. Spontaneous abortion ratios, defined as the number
of fetal losses prior to 29 weeks gestation divided by the number of total
pregnancies, were increased in both exposure groups. The spontaneous abortion
ratios observed for women in the photolithurgic, diffusion, and nonexposed
groups were 31.3% (5/16), 38.9% (7/18), and 17.8% (71/398), respectively. An
increased relative risk of 2.18 for the diffusion group vs. the nonexposed
group (95% confidence interval = 1.11-3.60) was calculated. This observation
persisted even after controlling for a variety of risk factors including age
at pregnancy, gravidity, consumption of caffeine during pregnancy, smoking
during pregnancy, and consumption of alcohol during pregnancy. The elevated
ratio among women in the photolithurgic group was not statistically
significant; however, the risk of spontaneous abortion in the photolithurgic
and diffusion groups relative to the nonexposed group remained consistent,
regardless of which risk factors were considered. This study was subject to
several limitations. First, the authors acknowledge that many semiconductor
workers have exposures to chemicals found in both the photolithurgic and
diffusion areas, and workers were sometimes involved in work in both areas
during their tenure with the company. Second, spontaneous abortion rates were
based on a small sample size (34 pregnancies in both manufacturing groups).
These limitations, along with the lack of quantifiable exposure data for any
individual chemical, preclude making any kind of determination regarding the
role of arsine in the observed increased spontaneous abortion rate.
Female B6C3F1 mice (36/group) inhaled 0, 0.5, 2.5, or 5.0 ppm arsine (0,
1.6, 8, or 16 mg/cu.m) 6 hours/day for 14 days (Hong et al., 1989).
Concentration-related decreases in RBC count, Hgb, and HCT values were found
after exposure, but values returned to normal levels by 3 weeks postexposure.
Significant concentration-related splenomegaly was observed in mice. The
relative spleen weight was significantly increased (38-236% increase) in all
exposed groups compared to controls at 2 days postexposure and remained at 24
days postexposure (12-48% increase). Histopathology revealed a concentration-
related hematopoiesis in spleens of exposed mice. To evaluate the effect of
arsine on erythropoiesis, quantitation of erythroid precursors in culture were
examined. In the bone marrow, colony-forming unit granulocyte-
macrophage/femur cells (CGU-GM/femur) (8-13% decrease compared with control)
and colony-forming unit erythroids/femur cells (CFU-E) (11-27% decrease) were
significantly reduced in all exposed groups on day 2 or 3 postexposure.
Values returned to normal levels after 3 weeks except for the CFU-E values in
the high-concentration group (9% decrease). Therefore, the changes in
hematological parameters and the reduction in CFU-E in the bone marrow suggest
that fewer bone marrow cells divide or that extramedullary erythropoiesis in
sites such as spleen compensate for deficit in bone marrow cells.
Rosenthal et al. (1989) examined immunological parameters in groups of
female B6C3F1 mice that inhaled 0, 0.5, 2.5, or 5 ppm arsine (0, 1.6, 8, or 16
mg/cu.m) 6 hours/day for 14 days. Marked changes in splenic cellular
populations were observed in exposure groups. The percentage of splenic
lymphocytes fell significantly and in a dose-related fashion in all exposure
groups, from 83.4% in air controls to 45.6% in animals exposed to 5.0 ppm
arsine. At the same time, there was a concomitant increase in percentages of
immature erythrocytes (rubricytes). Splenic T-cell percentages were
significantly decreased at all arsine concentrations, whereas the percentage
of B-cells was depressed only at the 5.0-ppm exposure level. In vitro
analysis showed a concentration-dependent decrease in natural killer cell and
cytotoxic T-lymphocyte function (significant at the 2.5- and 5.0-ppm exposure
levels). Increased susceptibility to Listeria and Plasmodium yoelii was
observed at all concentrations. As previous studies have shown, these data
suggest that the spleen represents a target of arsine manifested by altered
cellular populations. The decreases in certain host resistance parameters
suggest that arsine exposure also results in immunosuppression. For
immunotoxic effects, based principally on decreased cytotoxic T-lymphocyte
function and increased susceptibility to Listeria, a NOAEL of 0.5 ppm and a
LOAEL of 2.5 ppm are identified from this study.
The concentration-response curve for effects from acute exposure to arsine
has been shown by Peterson and Bhattacharyya (1985) to be steep. The
investigators exposed B6CF1/Anl female mice (8/group) to 0, 5, 9, 11, 15, or
26 ppm arsine for 1 hour. Blood samples were taken for hematologic evaluation
1, 5, and 11 days after exposure. No alterations in HCT, erythrocyte,
leukocyte, or reticulocyte levels were noted in the 5-ppm group. Significant
hemolytic responses were seen in the other groups. Hematocrit values were
98.8, 80.2, 79.7, 61.4, and 21.7% of controls 1 day after exposure for the 5-,
9-, 11-, 15-, and 26-ppm groups, respectively. At the 26-ppm exposure level,
all five mice that remained after the first 24-hour sampling period died
within 4 days.
Pregnant Fischer 344 rats and CD-1 mice were exposed to 0, 0.025, 0.5, or
2.5 ppm arsine (0, 0.08, 1.6, or 8 mg/cu.m, respectively), 6 hours/day, on
gestational days 6-15 (Morrissey et al., 1990). Mice were killed on
gestational day 17 and rats on gestational day 20. Significant increases in
absolute and relative spleen weights were observed in the 2.5-ppm exposed
mice, but no significant differences in the developmental indices were
observed. In the 2.5-ppm rats, enlarged spleen was noted in >80% of the
animals at necropsy (changes in spleen weight were not reported). A
significant increase in the average fetal body weight per litter was evident
in the 2.5-ppm group. No other developmental or reproductive effects were
observed. In further experiments by these investigators, pregnant rats (13-
15/group) were exposed to 0 or 5 ppm arsine (0 or 16 mg/cu.m) during
gestational days 4-15 (Morrissey et al., 1990). Exposed rats developed
splenomegaly and displayed significant changes in all hematological values
(i.e., increased leukocyte and platelet counts, MCV, MCH, and MCHC; decreased
RBC, Hgb concentration, and HCT) compared with those of the control group.
Therefore, a NOAEL of 0.5 ppm arsine (HEC = 1.6 mg/cu.m) was determined for
maternal toxicity (increased spleen weight in rats and mice), and a NOAEL of
0.5 ppm (HEC = 1.6 mg/cu.m) was determined for developmental effects (increase
in average fetal body weight per litter in rats).
The ACGIH (1986) recommends a TLV-TWA of 0.05 ppm (0.2 mg/cu.m) based on
hemolytic anemia.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- High
Data Base -- Medium
RfC -- Medium
The studies by Blair et al. (1990a,b) and Hong et al. (1989) indicate that
the most sensitive endpoints of arsine exposure in rats are increased
hemolysis, altered RBC morphology, increased spleen weight, and impaired
erythropoiesis. These effects result in splenic changes due to increased
removal of damaged RBCs and splenic hematopoiesis. Taken together, the
studies are given high confidence because the sample sizes were adequate,
statistical significance was reported, critical endpoints were consistent with
one another or replicated across studies, concentration-response relationships
were documented, three species were investigated, and both a NOAEL and LOAEL
were identified. These findings are corroborated by subacute inhalation
exposure studies conducted by the same investigators. Supporting evidence
also is provided by a reproductive study (Morrissey et al., 1990) in which
similar effects were observed in pregnant rats exposed to arsine. The data
base is given medium confidence because there are three inhalation subchronic
animal studies (two species) and a developmental/reproductive study that
reported the same critical endpoint; however, there is a lack of data on human
exposure, a lack of chronic inhalation studies, and no two-generation
reproductive study. A medium confidence in the RfC follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1984a,b
Agency Work Group Review -- 02/11/1993
Verification Date -- 02/11/1993
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Arsine
CASRN -- 7784-42-1
This substance/agent has not undergone a complete evaluation and determination
under US EPA's IRIS program for evidence of human carcinogenic potential.
_VI. BIBLIOGRAPHY
Substance Name -- Arsine
CASRN -- 7784-42-1
Last Revised -- 03/01/1994
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1986.
Documentation of TLVs. Arsine. Cincinnati, OH. p. 39.
Blackwell, M. and A. Robins. 1979. Arsine (arsenic hydride) poisoning in the
workplace. NIOSH Current Intelligence Bulletin 32. Am. Ind. Hyg. Assoc. J.
40: A-56-60.
Blair, P., M. Thompson, R. Morrissey et al. 1990a. Comparative toxicity of
arsine gas in B6C3F1 mice, Fischer 344 rats, and Syrian golden hamsters:
System organ studies and comparison of clinical indices of exposure. Fund.
Appl. Toxicol. 14(4): 776-787.
Blair, P., M. Thompson, M. Bechtold et al. 1990b. Evidence of oxidative
damage to red blood cells in mice induced by arsine gas. Toxicology. 63(1):
25-34.
De Palma, A.E. 1969. Arsine intoxication in a chemical plant. J. Occup.
Med. 11(11): 582-587.
Fowler, B.A. and Weissberg. 1974. Arsine poisoning. N. Eng. J. Med.
291(22): 1171-1174.
Hesdorffer, C.S., F.J. Milne, J. Terblanche, and A.M. Meyers. 1986. Arsine
gas poisoning: The importance of exchange transfusions in severe cases. Br.
J. Ind. Med. 43: 353-355.
Hong, H., B. Fowler, and G. Boorman. 1989. Hematopoietic effects in mice
exposed to arsine gas. Toxicol. Appl. Pharmacol. 97(1): 173-182.
Jacob, H.S. and J.H. Jandl. 1962. Effects of sulfhydryl inhibition on red
blood cells. I. Mechanism of hemolysis. J. Clin. Invest. 41(4): 779-792.
LaDou, J. 1983. Potential occupational health hazards in the
microelectronics industry. Scand. J. Work. Environ. Health. 9: 42-46.
Levinsky, W.J., R.V. Smalley, P.N. Hillyer, and R.L. Shindler. 1970. Arsine
hemolysis. Arch. Environ. Health. 20: 436-440.
Morrissey, R., B. Fowler, M. Harris et al. 1990. Arsine: Absence of
developmental toxicity in rats and mice. Fund. Appl. Toxicol. 15(2):
350-356.
Parish, G.G., R. Glass, and R. Kimbrough. 1979. Acute arsine poisoning in
two workers cleaning a clogged drain. Arch. Environ. Health. 34(4): 224-227.
Pastides, H., E.J. Calabrese, D.W. Hosmer, Jr., and D.R. Harris, Jr. 1988.
Spontaneous abortion and general illness symptoms among semiconductor
manufacturers. J. Occup. Med. 30(7): 53-73.
Pernis, B. and M. Magistretti. 1960. A study of the mechanism of acute
hemolytic anemia from arsine. Med. Lavoro. 51(1): 37-41.
Peterson, D. and M. Bhattacharyya. 1985. Hematological responses to arsine
exposure: Quantitation of exposure response in mice. Fund. Appl. Toxicol.
5: 499-505.
Risk, M. and L. Fuortes. 1991. Chronic arsenicalism suspected from arsine
exposure: A case report and literature review. Vet. Hum. Toxicol. 33(6):
590-595.
Rosenthal, G.J., M.M. Fort, D.R. Germolec et al. 1989. Effect of subchronic
arsine inhalation on immune function and host resistance. Inh. Toxicol. 1:
113-127.
Teitelbaum, D.T. and L.C. Kier. 1969. Arsine poisoning. Report of five
cases in the petroleum industry and a discussion of the indications for
exchange transfusion and hemodialysis. Arch. Environ. Health. 19(1):
133-143.
U.S. EPA. 1984a. Health Assessment Document for Inorganic Arsenic. Office
of Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Research Triangle Park, NC. EPA/600/8-83/021F.
U.S. EPA. 1984b. Health Effects Assessment for Arsenic. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH. EPA/540/1-86/020.
Wald, P.H. and C.E. Becker. 1986. Toxic gases used in the microelectronics
industry. Occup. Med. 1(1): 105-117.
Weed, R.I. and C.F. Reed. 1966. Membrane alterations leading to red cell
destruction. Am. J. Med. 41: 681-698.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
None
_VII. REVISION HISTORY
Substance Name -- Arsine
CASRN -- 7784-42-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1993 I.B. Inhalation RfC now under review
03/01/1994 I.B. Inhalation RfC on-line
03/01/1994 VI.B. Inhalation RfC references on-line
VIII. SYNONYMS
Substance Name -- Arsine
CASRN -- 7784-42-1
Last Revised -- 03/01/1993
7784-42-1
Arsine
UN2188
Agent SA
Arsenic hydride
ARSENIC HYDRIDE (ASH3)
Arsenic trihydride
ARSENIURETTED HYDROGEN
Arsenous hydride
Arsenowodor [Polish]
Arsenwasserstoff [German]
Arsina [Spanish]
HSDB 510
Hydrogen arsenide
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0672.HTM
|
