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   Health Advisory

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                                                             March 31, 1987
                  CONTROL OF LEGIONELLA IN PLUMBING SYSTEMS

                               Health Advisory
                           Office of Drinking Water
                     U.S. Environmental Protection Agency


     The Health Advisory (HA) Program, sponsored by the Office of Drinking
Water (ODW), provides information on the health effects, analytical methodology
and treatment technology that would be useful in dealing with the contamination
of drinking water.  Most of the Health Advisories prepared by the Office of
Drinking Water are for chemical substances.  This Health Advisory is different
in that it addresses contamination of drinking water by a microbial pathogen
and examines pathogen control rather than recommending a maximum allowable
exposure level.  Thus,  for a variety of reasons, the format and contents of
this Health Advisory necessarily vary somewhat from the usual Health Advisory
document.

     Health Advisories serve as informal technical guidance to assist Federal,
State and local officials responsible for protecting public health when
emergency spills or contamination situations occur.  They are not to be
construed as legally enforceable Federal standards.  The HAs are subject to
change as new information becomes available.

         This Health Advisory (HA) is based upon information presented in the
Office of Drinking Water's Criteria Document (CD) for Legionella.  Individuals
desiring further information should consult the CD.  The CD is available for
review at each EPA Regional Office of Drinking Water counterpart (e.g., Water
Supply Branch or Drinking Water Branch), or for a fee from the National
Technical Information Service,  U.S.  Department of Commerce, 5285 Port Royal
Rd., Springfield,  VA 22161, PB # 86-117843/AS.  The toll-free number is (800)
336-4700; in the Washington, D. C.  area:  (703) 487-4650.

INTRODUCTION
         Legionellae are bacteria that have been identified as the cause of
legionellosis.  Based upon an attack rate of about 1.2 cases of legionellosis
per 10,000 persons per year (Foy et al., 1979), it has been estimated that
more than 25,000 cases of this disease occur annually within the United
States", and are caused primarily by one of the 23 currently recognized species
of the genus Legionella.  Most people who have developed Legionnaires Disease,
the pneumonia form of legionellosis, were immunosuppressed or appeared to be
more susceptible because of an underlying illness, heavy smoking, alcoholism,
or age (more than 50 years old).  In contrast, while some apparently healthy
individuals have developed Legionnaires Disease, outbreaks involving healthy
people have been limited mostly to the milder non-pneumonia form of the
disease called Pontiac Fever.

     Legionellae are widespread in lakes and rivers (Fliermans et al., 1979,
1981).  There is some indication that these organisms may be either very
sparse or absent in groundwater (Fliermans et al., 1982; Spino et al., 1984).
Spino et al. ("1984) was unable to isolate legionellae after aeration of
groundwater through a redwood-slat aerator.  The possibility that humans may

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Legionella                                                       March 31, 1987

                                         -2-
    be exposed transiently to legionellae because of their high rate of contact
    with water is highly probable, given the high frequency of seropositivity to
    legionellae in healthy populations (Wentworth et al., 1984) and the widespread
    occurrence of legionellae'in water environments.

         In a number of outbreaks of legionellosis that have occurred in the
    United States, aerosols of water documented to contain the specific type of
    legionellae that was recovered from the patient have been identified as the
    vehicle for transmission (Cordes et al., 1981; Stout et al., 1982; Garbe
    et al., 1985).  It has been hypothesized that legionellae enter buildings
    in very low numbers via the treated drinking water.  These bacteria may
    proliferate in warm water when factors not yet fully determined allow them.
    Even when this occurs, as has been shown in numerous buildings, disease
    usually does not result.  Cases and outbreaks of legionellosis occur only
    when aerosols containing legionellae possessing specific virulence factors
    (not as-yet determined) are inhaled (possibly ingested) by susceptible
    individuals.  Foodborne outbreaks or secondary spread have not been reported.

         This Health Advisory discusses the control of legionellae in drinking
    water.  This includes finished water at the treatment facility, the distri-
    bution system, and plumbing systems.  Plumbing systems include hot water
    tanks, taps, showerheads, mixing valves, the faucet aerators, all of which
    have been associated with the proliferation of legionellae.  This guidance
    does not discuss legionellae control for whirlpools, respirators, or heat-
    rejection equipment such as cooling towers and air conditioners.  These have
    all been associated with cases of Legionnaires Disease.

    Presence of Legionellae in the Distribution System and Plumbing Systems

         Legionellae are found in raw water, in treated waters, and in plumbing
    systems (Fliermans et al., 1981; Hsu et al., 1984; Witherell et al., 1984),
    but the occurrence and fate of these organisms in the distribution system
    between these points are unknown.  The organism may survive the treatment
    and disinfection process and pass intact through the distribution system.
    In addition, opportunities exist for their introduction into the system by
    means of broken or corroded piping, repair of existing mains, installation of
    new mains, back siphonage and cross connections, any of which may result in
    contamination of the water supply.  In older distribution systems, especially
    those dependent on gravity flow, deterioration of piping may be so severe
    that the treated water comes in intimate contact with soil and is subject
    to infiltration by surface water.  Thus, legionellae may be introduced into
    potable water by these routes.

         Legionellae surviving initial water treatment may colonize pipe joints
    and corroded areas or adhere to the surface or sediment of storage tanks,
    especially those constructed of wood.  Here, they may find a habitat suitable
    for survival and growth  (Engelbrecht, 1983).  Cul-de-sacs, intermittently
    used storage tanks and other sites in which waterflow is absent or restricted
    also may be appropriate habitats for legionellae.

         New distribution systems or their components that were not appropriately
    cleaned and disinfected before being put into use may introduce legionellae
    into the system.  Although this has not been documented, it may not be

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Legionella                                                       March 31, 1987

                                         -3-
    coincidence that some of the serious outbreaks of Legionnaires Disease have
    occurred in newly-opened institutions or buildings (Haley et al., 1979; Marks
    et al., 1979; Helms et al., 1983).  Construction activities may have included
    intervention into the water supply mains with introduction of contaminated
    water or, possibly, disturbance of sediment and sloughing of scale bearing
    high concentrations of legionellae by means of hydraulic shock or other
    perturbations.

         There are numerous reports of legionellae occurring in plumbing systems,
    especially in hot water systems.  Most of these investigations have been
    carried out in hospitals,  and many were prompted by outbreaks of nosocomial
    (hospital-acquired) Legionnaires Disease.  The primary reservoirs in hospitals
    are apparently hot water tanks in which water is maintained at temperatures
    below 55°C.  Legionellae also have been found in showerheads, rubber fittings,
    aerator screens, faucet spouts, and other plumbing fixtures.  This group of
    organisms has also been found in residential plumbing systems such as apartment
    buildings and homes (Wadowsky, 1982; Arnow and Weil,  1984), but disease has
    not been associated with these findings.

    Control at the Water Treatment Facility

         Only a few studies have been published on the effectiveness of various
    types of treatment for eradicating or reducing legionellae numbers at the
    water treatment utility.  In one study, Tison and Seidler (1983) examined raw
    water and three kinds of distribution water supplies:  (1) those treated by
    chlorine (free residual 0.2-0.6 mg/L); (2) those treated by sand filtration
    and chlorination (free residual O.Q-0.4 mg/L); and (3) those treated by
    flocculation, mixed media filtration, and chlorination (free residual
    0.5-2.0 mg/L).  Legionella were enumerated by direct fluorescent antibody
    (DFA) tests and all distribution waters contained about one order of magnitude
    fewer Legionella-like cells than did the raw waters,  i.e., 10^-104 per liter.
    While the evidence suggests that legionellae are common in treated water, the
    significance of these results is questionable because the authors were unable
    to isolate any legionellae by animal inoculation or culture procedures, and
    there are uncertainties about the specificity of the DFA technique used for
    legionellae detection.

         Most water treatment plants in the United States use chlorine disinfection.
    Although extrapolation of laboratory studies to treatment plant situations is
    somewhat tenuous,  Kuchta et al. (1983) reported that both L_. pneumophila and
    L_. micdadei (laboratory-adapted environmental and clinical strains) were much
    more resistant to chlorine than was Escherichia coli.  At 21°C,  pH 7.6, and
    0.1 mg/L of free chlorine residual, a 99 percent kill was achieved in less
    than one minute for Jj. coli compared to 40 minutes for L. pneumophila.  Under
    the same conditions,  0.5 mg/L of  free chlorine resulted in a 99.9 percent
    legionellae kill in about 5 minutes.  The contact time for a 99 percent kill
    of L_. pneumophila  at 4°C was twice as long as it was  at 21 °C.  The authors
    concluded that legionellae can survive low levels of chlorine for rather long
    periods of time.  In a subsequent study,  Kuchta et al. (1984) compared agar-
    passaged (laboratory-adapted) and tap water-grown strains of L_. pneumophila
    with respect to chlorine.- resistance,  and showed that the latter were consid-
    erably more resistant.  At 0.25 mg/L free residual chlorine, 21°C,  and pH
    7.6-8.0, a 99 percent kill of agar-passaged L_. pneumophila was usually

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Legionella                                                       March 31, 1987

                                         -4-
    achieved within 10 minutes, compared to 60 to 90 minutes for tap water-
    maintained strains.  These data suggest that normal chlorination practices
    at treatment facilities may not control legionellae.

         In contrast to these data,  Hsu et al. (1984) reported that survivals of
    L_. pneumophila and _E. coli in various concentrations of chlorine were similar.
    In an in vitro study, laboratory-adapted strains of L_. pneumophila Flint 1
    serogroup 1 and E. coli B were inoculated into several dilutions of sodium
    hypochlorite in sterile tap water,  and incubated at 24°C.  At 0.2 mg/L residual
    chlorine, about an order of magnitude reduction occurred in two hours for both
    organisms.  Neither organism could be recovered after two hours at concentration?
    equal to or exceeding 2.0 mg/L.   The pH values were not reported.  The reason
    for the discrepancy between this study and the Kuchta et al. (1983, 1984)
    studies may be due to strain or pH differences.

    Control of Legionellae in Plumbing Systems

         Chlorine and Heat

         Studies on controlling legionellae in plumbing systems have examined
    primarily the effectiveness of heat and chlorine.  The results of several of
    these are described below.

         In an attempt to eradicate L. pneumophila from showers in a transplantation
    unit experiencing cases of Legionnaires Disease, Tobin et al. (1980) emptied
    the hot and cold water tanks and filled them with water containing 50 mg/L
    free chlorine.  After three hours, this process was repeated.  Shower fittings
    were removed and held at 65°C for 18 hours before replacement.  Legionellae
    were not isolated from the shower samples after six months, but were found
    again at nine months.

         Massanari et al. (1984) controlled a nosocomial outbreak of L_. pneumophila
    infection by shock chlorination (15 mg/L) of both hot and cold water supplies
    for 12 hours.  The system then was flushed and the hot water temperature
    raised from 41°C to 64°C for 41  days.  These measures significantly reduced
    the frequency of positive cultures, but 3/35 of the outlets were still positive.
    Thereafter, a continuous-flow proportional chlorination unit was installed
    that provided free chlorine levels of 8 and 7.3 mg/L in hot and cold water,
    respectively.  During the first 16 months of its use, virtually no samples
    (N=355) contained L_. pneumophila and no new cases of legionellosis were
    identified.  The few positive samples were obtained from rooms which had been
    vacant for at least 32 days.  In this hospital, water is distributed in
    copper pipes.

         Baird et al. (1984) hyperchlorinated their hospital water supply at a
    constant level of 4 mg/L of free chlorine.  The rate of nosocomial Legionnaires
    Disease decreased by almost two-thirds and the total numbers of legionellae
    decreased, but the organisms persisted.

         Witherell et al. (1984) attempted to eradicate L_. pneumophila in hospital
    plumbing by adding chlorine to the cold water make-up that supplied the hot
    water heating system, in proportion to the water demands on the system.  This
    was to avoid corrosion damage resulting from constant feed chlorination units

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Legionella                                                   March 31,  1987

                                     -5-
during periods of low demand.  A free chlorine residual of  3.0 mg/L was
maintained in the hot water system for 10 days and then reduced to 1.5 mg/L.
The organism was not detected by direct culture methods subsequent to disin-
fection.  The corrosivity of the hot water increased slightly (Langelier
index = -0.3).

     Fisher-Hoch et al.  (1981) used hypochlorite to obtain  a level of
1-2 mg/L of free chlorine at all cold water outlets in Kingston Hospital
where legionellae were present in both cold and hot water.  The free chlorine
levels in the hot water  could not be maintained above 0.2 mg/L and legionellae
were recoverable at this level.  The water temperature was  45°C, which was
warm enough to volatilize the chlorine and cool enough to allow growth of
legionellae.  Eradication was accomplished successfully by  maintaining the
hot water temperature at 55°-60°C, in addition to disinfection of cold water.
Subsequently, these investigators reported that when a disconnected hot water
tank containing stagnant water was turned on again, L. pneumophila was found
in the water and a case  of nosocomial Legionnaires Disease  occurred (Fisher-Hoch
et al., 1982).  A second disconnected tank which had been drained incompletely
contained a thick brown  liquid deposit at the bottom.  This deposit contained
5.4 x 108 _L. pneumophila/L.  Filling the second tank with water containing
50 mg/L of chlorine for  24 hours followed by descaling did  not successfully
eliminate the legionellae.  Maintaining a constant water temperature of 70°C
throughout the tank for  1 hour, however, eliminated the organism.  Ciesielski
et al. (1984) also noted that legionellae can proliferate in stagnant water
inside hot water tanks.

     Dennis et al. (19.82) examined water samples from the plumbing of 52
hotels, none of which was associated with cases of legionellosis.  Ten
isolates of L_. pneumophila were obtained from water samples from eight hotels.
Seven of these were from hot water taps or hot-cold mixer showers with water
temperatures ranging from 40° to 54°C at the time of sampling.  Evidence that
these temperatures are not sufficient for Legionella control was also provided
by Meenhorst et al, (1983).  In their study, guinea pigs exposed to aerosolized
legionellae from contaminated hot tapwater (48°C) contracted pneumonia.  The
strain of I,, pneumophila used was isolated from a series of patients in the
Netherlands.

     Beam et al. (1984) attempted to control legionellosis  outbreaks in two
state development centers for the severely handicapped.  In one center, hot
water tanks that were positive for legionellae were heated  to 71°C for 72
hours, followed by flushing for 15 minutes.  Because of legionellae regrowth,
a monthly heating schedule was established.  Subsequently,  the chlorine level
was raised from 0.5 mg/L to 2 mg/L.  This approach was successful in eradi-
cating legionellae from water sources, but this chlorine level caused leaching
from the iron pipes and consequent discoloration of the water, and was thus
discontinued.  Cement liners were installed in the hot water tanks and the
first samples were positive for legionellae.  The water temperature was not
reported.  Soon after, an outbreak of legionellosis occurred.

     Plouffe et al. (1983) examined the relationship between the presence of
J^. pneumophila in potable water, nosocomial Legionnaires Disease, and hot
water temperatures in six buildings.  L. pneumophila was found in the hot
water of all four buildings in which hot water was maintained at 43-49°C

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Legionella                                                   March 31, 1987

                                     -6-
(110°-120°F), and nosocomial Legionnaires Disease was found in three of these
buildings.  No organism and no disease was found in the two buildings where
hot water was maintained at 57-60°C (135°-140°F).  When the plumbing system
of one of the buildings experiencing both 1^. pneumophila and Legionnaires
Disease was flushed with 71°C water and the hot water then maintained at
57-60°C, no L^. pneumophila and no new cases of Legionnaires Disease occurred
for at least six months.  The authors concluded that colonization and nosocomial
Legionnaires Disease can be ^evented by maintaining the hot water at 57-60°C.

     In another attempt to eradicate L. pneumophila and nosocomial Legionnaires
Disease, Yu et al. (1982) raised the temperature in the hot water storage
tanks from 45° to 60°C for 72 hours and flushed 50 showers and 360 faucets
for 20 minutes with the 60°C water to eliminate the organism from the sediment.
A substantial reduction in counts occurred.  After three months, colony counts
increased rapidly from four colonies/mL to over 300 colonies/mL and nosocomial
Legionnaires Disease again appeared.  The authors concluded that a periodic
schedule of short-term temperature elevation of the hot water system may
control nosocomial Legionnaires Disease.

     Stout et al. (1986) tested 75 legionellae isolates for their ability to
withstand high temperatures.  Tubes containing buffered yeast extract broth,
sterile water, or hot water tank water plus sediment were inoculated and
placed in 60°C, 70°C or 80°C water baths.  At 60°C, four minutes were required
for a one log reduction of L_. pneumophila in the water plus sediment tube.
Approximately 25 minutes were required at this temperature to sterilize a
suspension of _L. pneumophila which contains 1Q8 colonies/mL.  The authors
recommend that when flushing distal outlets,, that a flush temperature exceeding
60°C should be maintained for at least 30 minutes.

         Muraca et al. (1987) compared the relative efficacies of heat
(608C)," ozone (1-2 mg/L), UV (30,000 uW-scm2 at 254 run) and hyperchlorinatiori
(4-6 mg/L) to eradicate JL. pneumophila in a model plumbing system.  Non-turbid
water at 25°C and 43°C and turbid water at 25°C were tested.  When samples
were taken of the circulated water, a 5-log kill of a 107 bacteria/mL concen-
tration was achieved with all treatments within six hours.  However, it is
noteworthy that heat completely eradicated the Legionella in less than three
hours, whereas UV light had produced its 5-log decrease in 20 minutes and
no further inactivation was seen during the six-hour observation period.
Chlorine and ozone required five hours to effect a similar 5-log decrease and
chlorine achieved complete eradication only in the non-turbid samples during
the six hours, while ozone killed the organisms in both turbid and non-turbid
water in four to five hours.

     Ozone Treatment

     Edelstein et al. (1982) used ozone in an attempt to eradicate legionellaie
from the potable water supply of an unused wing of a hospital that was known
to be contaminated with bacteria.  The results were inconclusive because the
organisms were eliminated from both the experimental wing and the control
wing that was untreated.  The latter was thought to be due to excess mechanical
flushing and an unexpected rise in. the chlorine content of the main water supply^
The in vitro susceptibility of L. pneumophila to ozone was on the order of
0.36 mg ozone/L, but was not consistent.  The ozone mean residual concentration'
used in the hospital water system was 0.79 mg/L.

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Legionella                                                   March 31, 1987

                                     -7-


     Ultraviolet Radiation Treatment

     Antopol and Ellner (1979) reported that 90 percent of L^. pneumophila
cells in distilled water were killed by 920 microwatt-sec/cm2 of UV radiation.
This could be compared with exposures ranging from 2,100 to 5,000 microwatt-
sec/cm2 for killing of E. coli, Salmonella, Serratia and Pseudomonas.  If
the latter values were obtained under the same conditions as those used for
L^. pneumophila, it would indicate that legionellae may be more than twice as
susceptible to UV radiation than are the other organisms.

     Gilpin (1984) reported laboratory and field experiments using UV radiation
to inactivate Legionella spp. in standing and recirculating water systems.
Times of exposure to one microwatt/cm2 of UV radiation to produce 90 percent
killing of six species of Legionella ranged from 17 to 44 minutes.  A commer-
cial UV apparatus killed 99 percent of the organism in less than 30 seconds
in a three-liter recirculating water system.

     In addition, Knudson (1985) reported that when agar plates seeded with
_L« pneumophila were exposed to 240 microwatt/cm2 for 25 seconds or less, a
reduction of six to seven orders of magnitude was observed.  However, when
UV-irradiated legionellae were exposed to indirect sunlight for 60 minutes,
the recovery rates were two orders of magnitude greater than those not exposed
to sunlight, due to photoreactivation.

     Ethylene Oxide Treatment

     Cordes et al. (1981) sterilized Legionella-contaminated showerheads with
ethylene oxide but they were soon recontaminated.


Design of Hot Water Tanks

     Legionellae often have been reported in hot water tanks,  particularly in
the bottom sediment.  The design of these tanks is important in the control
of these bacteria.  Most residential hot water tanks are heated from the
bottom near the cold water entrance pipe and are more likely to maintain a
bottom temperature high enough (>55°C) to prevent growth of legionellae.
However, if thermostats in homes have been set low (<55°C) as an energy
conservation measure,  growth of legionellae may result.  Thermostats for hot
water heaters in hospitals and other health care facilities are usually set
at lower temperatures  in conformity with the recommendations of the Joint
Commission on Accreditation of Hospitals that the water temperature be "safe"
(JCAH, 1985).  This practice,  which is done to prevent scalding of patients
using the hot water, may promote the growth of legionellae.  Larger institu-
tional tanks also are heated more often by internal steam coils or by other
heaters located midway from top to bottom of the tank.  The water at the
bottom may not be heated sufficiently to kill legionellae.  Periodic partial
draining of these tanks from the bottom to eliminate sediment may control
legionellae proliferation.  This is especially important,  since environmental
microflora in the sediment are known to produce metabolites, possibly including
cysteine, which stimulate legionellae growth (Stout et al., 1985).  Removal
from other areas of the plumbing system where water stagnates may also prevent
or control legionellae growth (Stout et al., 1985).

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Legionella                                                   March 31, 1987

                                     -8-


Type of Water Fittings

     Information on the specific types of gaskets and fittings that support
the colonization of legionellae is not well documented.  One study of water
fittings as sources of L_. pneumophila in a hospital plumbing system was
carried out by Colbourne et al. (1984a, 1984b).  In well-controlled experiments,
I». pneumophila was isolated from rubber washers and gaskets, but not from
liber ur plastic fittings.  The ability of the bacteria to multiply when in
contact with the rubber fittings was demonstrated.  When the rubber fittings
were replaced with plastic fittings, 1^. pneumophila could not be isolated up
to one year later.  The authors concluded that shower and tap fittings that
support growth of legionellae provide habitats protected from chlorine and
heat.  These foci may be seeded constantly or intermittently with legionellae
from hot water tanks or other amplifiers within the distribution system.


When to Control Legionellae in Plumbing Systems

     Legionellae are often found in the plumbing systems of hospitals which
have not experienced any cases of Legionnaires Disease.  One reason may be
that some strains are more virulent than others.  Currently, there is no
practical method for distinguishing the virulent strains from avirulent
strains.  For this reason, some experts feel that the mere presence of
legionellae in the absence of the disease is not sufficient grounds to under-
take control measures (Jakubowski et al., 1984).  They believe that health
care institutions should focus initially on surveillance for respiratory
illness, especially in high risk patients, rather than to control legionellae
in plumbing systems.  If nosocomial legionellosis is identified and environ-
mental strains match patient isolates, then control in plumbing systems is
indicated.

     In contrast, Edelstein (1985) states that most authorities would probably
agree that disinfection of a contaminated site is indicated when:

     0  it is implicated as a source of an outbreak of Legionnaires Disease
        or Pontiac Fever;

     0  it is present in a hospital ward housing especially high-risk patients,
        such as an organ transplantation unit, regardless of epidemiological
        findings; in this case, selective decontamination of certain ward
        areas may be feasible; and when

     0  it is found in a building which has not been used for some time and
        in which the water has stagnated.

     Because of the virulence of some of these strains and the fact that at
least 25,000 cases/year or more occur in the U.S., a stronger preventive
approach could also be supported.

     In summary, there is no consensus on when measures should be undertaken
to control legionellae in the plumbing system of health care institutions.
Once virulence factors can be identified and virulent strains differentiated
from avirulent strains, routine monitoring of the plumbing system may become
more practical.

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Legionella                                                   March 31, 1987

                                     -9-
Until then, the Office of Drinking Water recommends that, on the basis of the
high incidence and mortality rate, health care institutions consider preventive
measures for the control of legionellae in their plumbing systems.  'These
measures could also control other opportunistic pathogens in the system which
might cause nosocomial infections.
Summary

     Legionellae are abundant in ambient water, and may survive water treat-
ment, especially since they are relatively resistant to chlorine.  Once in
the treated water,  they then pass, probably at low levels, through the
distribution system.  It is also possible that legionellae enter the distri-
bution system through broken or corroded piping,  repair of existing mains,
installation of new mains, back siphonage, and cross connections.  When
legionellae enter hot water tanks, they settle to the bottom and, under
certain circumstances, will proliferate.  If they proliferate, plumbing
fixtures such as aerators, water fittings, and showerheads may be seeded,
resulting in colonization and growth at these sites.

     Inhalation of aerosolized potable water has been suggested from outbreak
investigations as a primary route of infection, although ingestion is also
a possibility.  The most susceptible individuals are those with underlying
diseases, especially those involving immunosuppression therapy.  In several
outbreaks, however, apparently healthy individuals have developed legionellosis.
Other risk factors include alcohol abuse, surgery and smoking.

     In order to reduce legionellae levels in drinking water, the presence of
organic matter and growth of algae and protozoa should be minimized in storage
reservoirs.  Moreover, newly-repaired or constructed components of the water
distribution system should be flushed thoroughly and disinfected before being
put into operation.  Even after flushing and disinfection, one cannot assume
legionellae have been controlled, since design factors in the distribution
system may impede the efficiency of these measures.

     In order to control legionellae growth in hot water plumbing, several
approaches may be considered.  Most of the published data have examined the
effectiveness of chlorine and/or heat.  The maintenance of free chlorine has
been found effective for controlling legionellae.  Shock chlorination also
is effective, but unless free chlorine is maintained within a system, the
organism may reappear.  Control probably can be achieved if free chlorine
levels in the hot water are maintained at 8 mg/L, but at this level corrosion
of pipes may occur.  In some cases, control may be achieved at 1.5-2 mg/L
free chlorine.  Undoubtedly, the level of chlorine found effective will
depend, in part, on the design criteria of the plumbing system.  A pertinent
facet in controlling legionellae is the difficulty of controlling batch
chlorination and of maintaining a chlorine residual in hot water.  This
problem can be minimized by using a continuous-flow proportional chlorinator
in the hot water system.

     Heat shock may eradicate legionellae in hot water tanks, if the temperature
at the bottom of the tank is maintained at 70°C for one hour, but this is a
temporary measure which must be done routinely to be effective.  Maintenance

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Legionella                                                   March 31, 1987

                                     -10-
of hot water at 55°C or higher apparently controls the organism, while lower
temperatures may not.  If legionellae are controlled by heat, care must be
taken to prevent scalding of persons using the water, especially in health
care institutions.

     Disinfection of a plumbing system by heat treatment or chlorine treatment
alone may not be as effective as a combination of the two.  For example,
growth of legionellae may theoretically be enhanced on the cold water side of
a hot-cold, water mixing valve in a heat-treated plumbing system, a location
where chlorine may be effective.

     Effective disinfection of legionellae by ozone, ultraviolet radiation
or ethylene oxide has not been demonstrated by field tests.

     In addition to chemical and heat disinfection, other procedures may be
effective in controlling legionellae.  Hot water tanks should be designed
to give uniform temperatures throughout.  Hot or cold water tanks used
intermittently should be disconnected from the system, drained, flushed,
and disinfected before being reconnected.  Hot water tanks should be drained
regularly or at least bled to remove accumulated sludge that may serve as
a substrate for growth of legionellae and other microorganisms.  Taps and
showers in unused areas of health care facilities should at least be flushed
before patients are exposed to them.  Finally, faucet sieves and aerators,
and rubber washers and gaskets in the plumbing system should be used with
caution, especially in institutions housing physically compromised individuals
and where hot water is maintained at temperatures lower than 55°C.

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Legionella                                                   March 31, 1987

                                     -11-


REFERENCES

Antopol, S.C. and P.O. Ellner.  1979.  Susceptibility of Legionella pneumophila
     to ultraviolet radiation.  Appl. Environ. Microbiol.  38:347-348.

Arnow, P.M. and D. Weil.  1984.  Legionella pneumophila contamination of
     residential tap water.  In:  C. Thornsberry, A. Balows, J.C. Feeley and
     W. Jakubowski, eds. Legionella:  Proceedings of the 2nd international
     symposium, June 19-23, 1983; Atlanta, GA.  Washington, DC:  American
     Society for Microbiology; pp. 240-241.

Baird, I.M., W. Potts, J. Smiley, N. Click, S. Schleich, C. Connole and
     K. Davidson.  1984.  Control of endemic nosocomial legionellosis by
     hyperchlorination of potable water.  In:  C. Thornsberry, A. Balows,
     J.C. Feeley and W. Jakubowski, eds.  Legionella:  Proceedings of the 2nd
     international symposium, June 19-23, 1983; Atlanta, GA.  Washington, DC:
     American Society for Microbiology; pp. 333.

Beam, T.R., D. Moreton, T.A. Raab, W. Heaslip, M. Montes, J. Hanrahan,
     M. Best and V.L. Yu.  1984.  Epidemiology and control of Legionellaceae
     in state developmental centers.  In:  C. Thornsberry, A. Balows,
     J.C. Feeley and W. Jakubowski, eds.  Legionella: Proceedings of the 2nd
     international symposium, June 19-23, 1983; Atlanta, GA.  Washington, DC:
     American Society for Microbiology; pp. 236-237.

Ciesielski, C.A., M.J. Blaser and W-L.L. Wang.  1984.  Role of stagnation and
     obstruction of water flow in isolation of Legionella pneumophila from-
     hospital plumbing.  Appl, Environ. Microbiol.  48:984-987.

Colburne, J.S., M.G. Smith, S.P. Fisher-Hoch and D. Harper.  1984a.  Source
     of Legionella pneumophila infection in a hospital hot water system:
     materials used in water fittings capable of supporting I*, pneumophila
     growth.  In:  C. Thornsberry, A. Balows, J.C. Feeley and W. Jakubowski,
     eds.  Legionella: Proceedings of the 2nd international symposium,
     June 19-23, 1983; Atlanta, GA.  Washington, DC:  American Society for
     Microbiology; pp. 305-307.

Colburne, J.S., D.J. Pratt, M.G. Smith, S.P. Fisher-Hoch and D. Harper.  1984b.
     Water fittings as sources of Legionella pneumophila in a hospital plumbing
     system.  Lancet 1:210-213.

Cordes, L.G., A.M. Wiesenthal,  G.W. Gorman,  J.P. Phair,  H.M. Sommers,
     A. Brown, V.L. Yu, M.H. Magnussen, R.D. Meyer, J.S. Wolf, K.N. Shands
     and D.W. Fraser.  1981.  Isolation of Legionella pneumophila from hospital
     shower heads.  Ann. Intern. Med.  94(2):195-197.

Dennis, P.J., J.A. Taylor,  R.B. Fitzgeorge,  C.L.R. Bartlett and G.I. Barrow.
     1982.  Legionella pneumophirla in wa-ter—plumbing syoteams.—Lancat—I-t-949-951 .

Edelstein,  P.H.  1985.  Environmental aspects of Legionella.  ASM News
     51:460-467.

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Legionella                                                   March 31,  1987

                                     -12-
Edelstein, P.H., R.E. Whittaker,  R.L. Kreiling and C.L. Howell.  1982.
     Efficacy of ozone in eradication of Legionella pneumophila from hospital
     plumbing fixtures.  Appl. Environ. Microbiol.  44:1330-1334.

Engelbrecht,  R.S.  1983.  Source,  treatment,  and distribution.   In:
     P.S. Berger and Y. Argaman,  eds.  Assessment of microbiology and turbidity
     standards for drinking water.  EPA 570/9-83-001.  U.S.  Environmental
     Protection Agency, pp. 1-68.

Fisher-Hoch,  S.P., C.L.R. Bartlett,  J.O'H. Tdbin, M.B. Gillett, A.M. Nelson,
     J.E. Pritchard, M.G. Smith,  R.A. Swann,  J.M. Talbot and J.A. Thomas.
     1981.  Investigation and control of an outbreak of legionnaires' disease
     in a district general hospital.  Lancet 1:932-936.

Fisher-Hoch,  S.P., M.G. Smith, and J.S, Colbourne,  1982.  Legionella pneumo-
     phila in hospital hot water cylinders [Letter].  Lancet 1:1073.

Fliermans, C.B., W.B. Cherry, L.H. Orrison and L. Thacker.   1979.  Isolation
     of Legionella pneumophila from nonepidemic-related aquatic habitats.
     Appl. Environ. Microbiol.  37:1239-1242.

Fliermans, C.B., W.B. Cherry, L.H. Orrison, S.J. Smith, D.L. Tison and
     D.H. Pope.  1981.  Ecological distribution of Legionella pneumophila.
     Appl. Environ. Microbiol.  41:9-16.

Fliermans, C.B., G.E. Bettinger and A.W. Fynsk.  1982.  Treatment of cooling
     systems containing high levels of Legionella pneumophila.   Water Res.
     16:903-909.

Foy, H.M., P.S. Hayes, M.K. Cooney,  C.V. Broome, I. Allan and R. Tobe.  1979.
     Legionnaires' Disease in a.prepaid medical-care group in Seattle, 1963-756
     Lancet 1:767-770.

Garbe, P.L.,  B.J. Davis, J.S. Weisfeld, L. Markowitz, P. Miner, F. Garrity,
     J.M. Barbaree and A.L. Reingold.  1985.  Nosocomial Legionnaires Disease:
     epidemiologic demonstration of cooling towers as a source.  J. Amer.
     Med. Assoc.  254:521-524.

Gilpin, R.W.  1984.  Laboratory and field applications of ultraviolet light
     disinfection on six species of Legionella and other bacteria in water.
     In:  C. Thornsberry, A. Balows, J.C. Feeley and W. Jakubowski,  eds.
     Legionella:  Proceedings of the 2nd international symposium, June 19-23,
     1983; Atlanta, GA.  Washington, DC:  American Society  for  Microbiology;
     pp. 337-339.

Haley, C.E.,  M.L. Cohen, J. Halter and R.D. Meyer.  1979.  Nosocomial
     legionnaires' disease:  a continuing common-source epidemic at Wadsworth
     Medical Center.  Ann. Intern. Med.  90:583-586.

Helms, C.M.,  R.M. Massanari, R. Zeitler, S. Streed, M.J.R.  Gilchrist, N.  Hall,
     W.J. Hausler, J. Sywassink,  W. Johnson,  L. Wintermeyer and W.J. Hierholzer.
     1983.  Legionnaires' disease associated with a hospital water system:   a
     cluster of 24 nosocomial cases.  Ann. Intern. Med.  99(2):172-178.

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Legionella                                                   March 31, 1987

                                     -13-
Hsu, S.C., R. Martin and B.B. Wentworth.  1984.  Isolation of Legionella
     species from drinking water.  Appl. Environ. Microbiol. 48:830-832.

Jakubowski, W., C.V. Broome, E.E. Geldreich and A.P. Dufour.  1984.  Trans-
     mission and control.  In:  C. Thornsberry, A. Balows, J.C. Feeley and
     W. Jakubowski, eds.  Legionella:  Proceedings of the 2nd international
     symposium, June 19-23, 1983; Atlanta,  GA.  Washington,  DC:   American
     Society for Microbiology; pp. 351-355.

JCAH.  1985.  Joint Commission on Accreditation of Hospitals.  Accreditation
     manual for hospitals; Chapter on plant, technology, and safety management.
     JCAH, Chicago.

Knudson,  G.B.  1985.  Photoreactivation of  UV-irradiated Legionella pneumophila
     and other Legionella species.  Appl. Environ. Microbiol.  49.:975-980.

Kuchta, J.M., S.J. States, J.E. McGlaughlin, R.M. Wadowsky,  A.M. McNamara,
     R.S. Wolford and R.B. Yee.  1984.  Enhanced chlorine resistence of
     tapwater grown Legionella pneumophila  as compared with agar-passaged
     strains.  Abstracts, annual meeting of the American Society for Micro-
     biology, St. Louis; Paper No. Q2.

Kuchta, J.M., S.J. States, A.M. McNamara, R.M. Wadowsky and R.B. Yee.  19.83.
     Susceptibility of Legionella pneumophila to chlorine in tapwater.
     Appl. Environ. Microbiol.  46:1134-1139.

Marks, J.S., T.F. Tsai, W.J. Martone, R.C.  Baron, J. Kennicott,  F.J. Holtzhauer,
     I. Baird, D. Fay, J.C. Feeley, G.F. Mallison, D.W. Fraser and T.J. Halpin.
     1979.  Nosocomial legionnaires'  disease in Columbus, Ohio.  Ann. Intern.
     Med.  90(4):565-569.

Massanari, R.M.,  C. Helms, R. Zeitler, S. Streed, M. Gilchrist,  N. Hall,
     W. Hausler,  W. Johnson, L. Wintermeyer, J.S. Muhs and W.J. Hierholzer.
     1984.  Continuous hyperchlorination of potable water system for control
     of nosocomial Legionella pneumophila infections.  In:  C. Thornsberry,
     A. Balows, J.C. Feeley and W. Jakubowski, eds.  Legionella:  Proceedings
     of the 2nd international symposium, June 19-23, 1983; Atlanta, GA.
     Washington,  DC:  American Society for  Microbiology; pp. 334-336.

Meenhorst, P.L.,  A.L. Reingold, G.W.  Gorman, J.C. Feeley, B.J. van Cronenburg,
     C.L.M. Meyer and R. van Furth.  1983.   Legionella pneumonia in guinea
     pigs exposed to aerosols of concentrated potable water from a hospital
     with nosocomial legionnaires' disease.  J. Infect. Dis.  147(1):129-132.

Muraca, P, J.E. Stout and V.L. Yu.  1987.  Comparative assessment of chlorine,
     heat, ozone and UV light for killing Legionella pneumophila within a
     model plumbing system.  Appl. Environ. Microbiol.  53:447-453.

Plouffe,  J.F., L.R. Webster, B. Hackman and M. Macynski.  1983.  Hot water
     temperature, Ij. pneumophila (LP) and nosocomial legionnaires; disease
     (LD).  Abstracts, annual meeting of the American Society for Microbiology,
     New Orleans; paper L16.

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Legionella                                                   March 31,  1987

                                     -14-
Spino, D.F., E.w. Rice and E.E.  Geldreich.   1984.   Occurrence of Legionella
     spp. and other aquatic bacteria in chemically contaminated ground water
     treated by aeration.   In:   C. Thornsberry,  A. Balows,  J.C. Feeley and
     W. Jakubowski, eds.  Legionella:  Proceedings of the 2nd international
     symposium, June 19-23,  1983;  Atlanta,  GA.  Washington,  DC:  American
     Society for Microbiology;  pp. 318-320.

Stout, J.E., M.G. Best and V.L.  Yu.   1986.   Susceptibility  of members  of the
     family Legionellaceae to thermal stress: implications  for heat eradication
     methods in water distribution systems.  Appl. Environ.  Microbiol.
     52:396-399.

Stout, J., V.L. Yu, R.M. Vickers,  J. Zuravleff,  M. Best,  A.  Brown,  R.B. Yee
     and R. Wadowsky.  1982.  Ubiquitousness of Legionella  pneumophila in the
     water supply of a hospital with endemic Legionnaires Disease.   New Eng.
     J. Med.  306:466-468.

Stout, J.E., V.L. Yu and M.G. Best.   1985.   Ecology of Legionella pneumophila
     within water distribution systems.  Appl. Environ. Microbiol.  49:221-228.

Tison, D.L. and R.J. Seidler.  1983.  Legionella incidence  and density in
     potable drinking water supplies.  Appl. Environ. Microbiol.  45:337-339.

Tobin, J.O'H., J. Beare, M.S. Dunnill, S. Fisher-Hoch, M. French, R.G. Mitchell,
     P.J. Morris and M.F. Muers.  1980.  Legionnaires' disease in a transplant
     unit: isolation of the causative agent from shower baths.  Lancet 11:118-121|

Wentworth, B.B., W.A. Chadwick,  H.E. Stiefel and D.S. Benge.  1984.  Preva-
     lence of antibody to various  Legionella species in ill and healthy
     populations in Michigan.  In:  C. Thornsberry, A. Balows, J.C. Feeley
     and W. Jakubowski, eds.  Legionella: Proceedings of the 2nd international
     symposium, June 19-23, 1983;  Atlanta,  GA.  Washington, DC:  American
     Society for Microbiology:   pp.  255-257.

Wadowsky, R.M., R.B. Yee, L. Mezmar, E.J. Wing and J.N. Dowling.  1982.  Hot
     water systems as sources of Legionella pneumophila in  hospital and
     nonhospital plumbing fixtures.  Appl.  Environ. Microbiol.  43:1104-1110.

Witherell, L.E., L.A. Orciari,  R.W.  Duncan, K.M. Stone and  J.M. Lawson.  1984.,
     Disinfection of hospital hot water systems containing  Legionella pneumo-
     phila .  In:  C. Thornsberry,  A. Balows, J.C. Feeley and W. Jakubowski,
     eds.  Legionella: Proceedings of the 2nd international symposium,
     June 19-23, 1983; Atlanta,  GA.   Washington, DC:  American Society for
     Microbiology:  pp. 336-337.

Yu, V.L., M. Best, J. Stout, A. Brown and A. Goetz.  1982.   Effectiveness of
     intermittent short-term temperature elevation of the hospital water supply
     in controlling nosocomial Legionnaires' Disease (LIU.—Ahstrsnts, annual—
     meeting of the American Society for Microbiology, Atlanta; paper L19.

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                                                             March 31,  1987
                                       BARIUM

                                  Health Advisory
                              Office of Drinking Water
                        U.S.  Environmental  Protection Agency
I. INTRODUCTION
        The  Health Advisory  (HA)  Program,  sponsored  by  the Office of Drinking
   Water (ODW),  provides  information on the health effects, analytical method-
   ology  and treatment  technology  that would be useful  in dealing with the
   contamination of  drinking water.   Health Advisories  describe nonregulatory
   concentrations of drinking water  contaminants at  which adverse health effects
   would not be  anticipated  to occur over specific exposure durations.  Health
   Advisories contain a margin of safety  to protect  sensitive members of the
   population.

        Health Advisories serve as informal technical guidance to assist Federal,
   State and local officials responsible  for protecting public health when
   emergency spills  or  contamination situations occur.   They  are not to be
   construed as  legally enforceable  Federal standards.   The HAs are subject to
   change as new information becomes available.

        Health Advisories are developed for One-day,  Ten-day,  Longer-term
   (approximately 7  years, or 10% of an individual's  lifetime)  and Lifetime
   exposures based on data "describing noncarcinogenic end points of toxicity.
   Health Advisories do not  quantitatively  incorporate  any potential carcinogenic
   risk  from such exposure.   For  those substances  that  are known or probable
   human carcinogens, according to the Agency  classification  scheme (Group A  or
   B),  Lifetime  HAs  are not  recommended.   The  chemical  concentration values for
   Group A or B  carcinogens  are correlated  with carcinogenic  risk estimates by
   employing a cancer potency (unit  risk)  value together with assumptions for
   lifetime  exposure and  the consumption  of drinking water.  The cancer unit
   risk  is usually derived from the  linear  multistage model with 95% upper
   confidence limits.   This  provides a low-dose estimate of cancer risk to
   humans that is considered unlikely to  pose  a carcinogenic  risk in excess
   of  the stated values.   Excess  cancer risk estimates  may also be calculated
   using the One-hit, Weibull,  Logit or Probit models.   There is no current
   understanding of  the biological mechanisms  involved  in cancer to suggest that
   any one of these  models is able to predict  risk more accurately than another.
   Because each  model is  based  on differing assumptions,  the  estimates that are
   derived can differ by  several  orders of  magnitude.

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    Barium
                                March 31,  1987
                                         -2-
         This Health Advisory  is  based  on information presented in the Office
    of Drinking Water's Health Effects  Criteria Document (CD)  for barium (U.S.
    EPA,  1985).  The HA and  CD formats  are similar for easy  reference.  Individuals
    desiring further information  on the toxicological data base or rationale for
    risk  characterization should  consult the CD.   The CD is  available for review
    at each EPA Regional Office of Drinking Water counterpart (e.g.,  Water Supply
    Branch  or Drinking  Water Branch), or for a fee from the  National  Technical
    Information Service, U.S. Department of Commerce, 5285 Port Royal Rd.,
    Springfield,  VA 22161, PB #86-118031/45.  The toll-free  number is (800)
    336-4700; in the Washington,  D.C. area:  (703) 487-4650.
II.  GENERAL INFORMATION AND  PROPERTIES
    CAS No.
         0  Barium —
            Barium Chloride — 10361-37-2
            Barium Sulfate — 7727-43-7
    Synonyms
            Barium Sulfate;  Barite (Windholz,  1976)
    Uses
         0  Depending upon the specific compound,  barium salts are used for a
            number of purposes including drilling mud (Kirkpatrick, 1978),  pigment
            (Miner,  1969), and as x-ray contrast nedium  (Miner,  1969).  Other
            uses are summarized by Pidgeon (1964).

    Properties  (Pidgeon,  1964; Preisman,  1964;  Miner,  1969;  Chilton,  1973;
                 Kirkpatrick,  1978; Reeves,  1979)

         0  The properties of  barium compounds vary  with the  specific  compound;
            some examples  are  as follows:
    Chemical Formula
    Atomic/Molecular Weight
    Physical State
    Boiling Point
    Melting Point
    Density (20°C)
    Vapor Pressure
    Water Solubility (pph)
    Log Octanol/Water
      Partition Coefficient
    Taste Threshold
    Odor Threshold
                              Barium
                    Barium
                    Chloride
Ba                  Bad 2
137.33              208.24
Silver-white solid  White solid
1637-1 638°C
729-7308C
3.6 g/cm3
1810 x 10-5 mm Hg
reacts
1560°C
960°C
3,856 g/cm3

31  (0°C)
Barium
Sulfate

BaS04
233.40
Colorless solid

1580°C
4.50 g/cm3

0.000285 (30°C)

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     Barium                                                    March 31,  1987

                                          -3-


     Occurrence

          0  Barium is  a reactive metal  which is  not found  free in nature but
             exists as  a number of salts.   Barium occurs in nature chiefly as the
             mineral barite (33804)  and  ^-n mucn smaller amounts as witherite
             (83003).   TJie ">ineral forms are relatively insoluble in water,  having
             high melting and  boiling  points and  very  low vapor pressures (Preisman,
             1964'.  Barium compounds  occur in most geologic materials at levels
             of 300-500 ppm.   Barium occurs at low levels in most surface and
             ground waters with reported levels of less than 340 ug/L.  While
             barium compounds  are used commercially in a number of processes,
             contamination of  drinking water is usually the result of naturally -
             occurring  barium  and not  industrial  releases (U.S. EPA, 1987).

          0  There are  limited survey  data on the occurrence of barium in drinking
             water.  Most supplies contain less than 200 ug/L of barium.   Currently,
             60 ground  water supplies  and  1 surface water supply exceed the  interim
             maximum contaminant level (MCL) of 1,000  ug/L.  Barium also occurs  in
             most foods as a low level contaminant.  Based  upon the limited  infor-
             mation available  on barium  exposure,  food is the major source of
             barium exposure  (U.S. EPA,  1987).


III. PHARMACOKINETICS

     Absorption

          0  In laboratory animals,  the  absorption of  barium varies with  a number
             of factors including the  species of  animal (U.S. EPA, 1985),  the
             compound tested (McCauley and Washington,  1983), the age of  the animal
             (Taylor et al., 1962) and the composition of the diet (Lengemann,  1959),

             While no definitive human barium absorption studies were found  (U.S.
             EPA,  19851, barium absorption has been estimated to be approximately
             5% in the  adult (ICRP,  1973).  However, other  data (Harrison et al.,
             1967) suggest that barium absorption probably  is greater than this.
             While data in laboratory  animals (Lengemann, 1959) suggest that barium
             absorption in children may  be significantly greater than in  adults,
             there is currently inadequate information to resolve this issue.

     Distribution

          0  In the mouse,  intravenously injected  barium (133BaCl2)  is distributed
             widely throughout the organism, but  is localized principally  in the
             bone (Dencker et  al., 1976).

          °  Based on autopsy  data,  barium levels  in human  bone are relatively
             constant and do not appear  to increase with age, ranging from an
             average value of  7.0 ppm  in bone at  age 0 to 3 months to an  average
             of 8.5 ppm at age 33 to 74  years (Sowden  and Stitch, 1957).

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    Barium                                                    March 31,  1987

                                         -4-


    Metabolisrn

         0  The skeletal metabolism of barium in humans is qualitatively similar
            to that of calcium,  although the incorporation of these two elements
            is quantitatively  very  different (Bauer et al., 1956,1957).
    Excretion
            In humans,  ingested barium is eliminated principally  via fecal excretion
            (approximately  72%) following oral exposure (Tipton et al., 1966).
IV. HEALTH EFFECTS
    Humans
            Acute barium toxicity  is associated with hypokalemia and electrocar-
            diographic changes as  well as other symptoms (Diengott et al., 1964;
            Gould et al.,  1973; Talwar and Sharma,  1979).

            NAS (1977) has concluded that: "The fatal dose of barium chloride for
            man has been reported  to be about 0.8 - 0.9 g,  or 550 - 600 mg of
            barium."

            Schroeder and  Kraemer  (1974)  concluded  that there was a significant
            negative correlation between barium,in  drinking water and athero-
            sclerotic heart disease.

            In an epidemiology study,  Brenniman et  al. (1981) concluded that
            there was no statistically significant  difference in blood pressure
            between those  ingesting drinking water  containing barium at 7.3 mg/L
            as compared to 0.1 mg/L.  A concentration of 7.3 mg/L corresponds to
            a dose of 0.20 mg/kg/day (assuming a 70-kg adult drinks 2 L per day).
            The duration of exposure was not identified.
    Animals
    Short-term Exposure
            The acute oral LD50 of barium varies markedly with species,  compound,
            age and other factors (U.S. EPA,  1985).  For example, the acute oral
            LD50 of barium chloride is 220 mg/kg in weanling rats and 132 rag/kg in
            adult rats (Tardiff et al., 1980).
    Long-term Exposure
            Tardiff et al. (1980) exposed rate to barium at 0,  10, 50, or 250
            ppm in drinking water for 4, 8 and 13 weeks.  The barium concentrations
            were approximately 0, 2.75,  13.7 and 66.25 mg/kg/day at the beginning
            of the study and 0,  1.7,  6.6 and 31.5 mg/kg/day at the end of the
            study.  Although the barium body burden increased with increasing
            barium dosage, no conclusive signs of barium toxicity were observed
            in these animals.  A weakness of this study is that, unlike Perry
            et al. (1983) below, blood pressure was not measured.

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   Barium                                                    March 31,  1987
        0  Perry et al. (1983)  exposed weanling rats to barium at 1,  10 or 100
           ppm in drinking water for up to 16 months (average daily  barium doses
           of 0.051,  0.51  and 5.1  mg/kg,  respectively).  With the exception of
           an increase in blood pressure, there were no signs of toxicity at
           any barium dose level.   Systolic blood pressure measurements revealed
           no increase in pressure in animals exposed to 1 ppm for 16 months,
           an increase of  4 mm Hg  (p  ~.01) in animals exposed to 10 ppm barium
           for 16 months,  and an increase in systolic pressure of 16 mm Hg (p
           <0.001) in animals exposed to 100 ppm barium for 16 months.  The
           animals in this study were maintained in a special contaminant-free
           environment and fed  a diet designed to reduce exposure to trace
           metals.  It is  possible that the restricted intake of certain beneficial
           metals (e.g.,  Ca and K) may have predisposed the test animals to the
           hypertensive effects of barium (U.S. EPA, 1985).

        0  Schroeder and  Mitchener (1975a,b)  exposed rats and mice to 5 mg/L
           barium in drinking water for a lifetime (approximately 0.25 mg/kg/day
           for rats and 0.825 mg/kg/day for mice).  No compound related adverse
           effects were observed.  A weakness  of this study is that,  unlike
           Perry et al.  (1983) above, blood pressure was not measured.

   Reproductive Effects

        0  No adequate mammalian study on the potential reproductive effects
           of barium was  identified (U.S. EPA, 1985).

   Developmental Effects

        0  No adequate mammalian study on the potential developmental effects of
           barium was identified (U.S. EPA, 1985).

   Muta^enicity

        0  No adequate studies  on  the mutagenicity of barium were identified
           (U.S. EPA, 1985).

   Carcinogenicity

        0  No adequate studies  on  the carcinogenicity of barium were identified
           (U.S. EPA, 1985).


V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories  (HAs) are generally determined for One-day, Ten-day,
   Longer-term (approximately 7 years) and Lifetime exposures if adequate data
   are available that identify  a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic  toxicants  are  derived using the following formula:

                 HA = (NOAEL or LOAEL) x  (BW) = 	   „  (	    „ ,
                        (OF) x  (	 L/day)

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Barium                                                    March 31,  1987

                                     -6-
where:

        NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                         in rag/kg bw/day.

                    BW = assumed body weight of a child (10 kg) or
                         an adult (70 kg .

                    UF = uncertainty factor (10,  100 or 1,000), in
                         accordance with NAS/ODW guidelines.

             	 L/day = assumed daily water consumption of a child
                         (1  L/day)  or an adult (2 L/day).

One-day Health Advisory

     The available data are insufficient to develop a One-day HA for barium.
It is recommended that the modified DWEL of 0.51  mg/L (adjusted for a 10-kg
child) be used as the One-day HA for the 10-kg child.

Ten-day Health Advisory

     The available data are insufficient to develop a Ten-day HA for barium.
It is recommended that the modified DWEL of 0.51  mg/L (adjusted for a 10-kg
child) be used as the Ten-day HA for the 10-kg child.

Longer-term Health Advisory

     The available data are insufficient to develop Longer-term HAs for barium.
It is recommended that the DWEL of 1.8 mg/L be used as the Longer-term HA
for the 70-kg adult and the modified DWEL of 0.51 nig/L (adjusted for a 10-kg
child) be used as the Longer-term HA for the 10-kg child.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The Lifetime HA
is derived in a three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic  (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%

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Barium                                                    March 31, 1987

                                     -7-
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     Considering the kind,  nature and partially contradictory results of the
various barium studies, ODW does not believe that it is appropriate to use
any simplistic formula to determine a Lifetime HA for barium in drinking
water.  Rather:

0  No single study, considered alone, is appropriate to calculate a Lifetime
   HA for barium.

0  A barium HA must be based on the weight of all the pertinent data,
   considered together.

     In the Perry et al. (1983) rat drinking water study, 10 ppm barium
(0.51 mg/kg/day) produced a small (4 to 7 mm Hg) but statistically significant
increase in blood pressure by 8 to 16 months; 100 ppm barium (5.1 mg/kg/day)
produced clear hypertension and cardiotoxic effects.

     A major shortcoming of the Perry, et al. (1983) study is that the animals
were maintained in a special environment and received both a special diet and
special water, all intended to reduce exposure to trace metals.  Because of
the beneficial effects of some metals (i.e., cadmium) and the interactions
of barium with other metals, it is possible that the restricted intake of
other metals may have contributed to the apparent toxicity of barium.  In
addition, the results of the Perry, et al. (1983) rat study clearly contradict
the results of the Brenniman, et al. (1981) human study which suggests that
barium in drinking water has no appreciable effect upon blood pressure in
humans,  at least at a level of 7.3 ppm (0.20 mg/kg/day) in drinking water.

     While the 4 to 7 mm Hg increase in blood pressure observed at 10 ppm
barium (0.51  mg/kg/day) in the Perry, et al. (1983)  study may be a compound
related effect,  ODW has serious doubts as to whether this 4 to 7 mm Hg increase
in rat blood pressure should be considered an adverse effect in the light of
the negative effects observed in the Brenniman, et al. (1981) human study.
Considering the contradiction between the rat and human data, it was ODW's
judgment that it was not prudent either to ignore the results of Perry et al.
(1983) or to treat the results with the same seriousness they would warrant,
had they been observed in humans.

     In ODW's judgment, the most appropriate way to balance the contradiction
between the Perry, et al. (1983) rat study and the Brenniman, et al.  (1931)
human study is to use the results of the Perry, et al. (1983) study, with a
reduced uncertainty factor of 10x and to treat the 0.51 mg/kg/day value as
if it were a NOAEL.

     Thus, based on the previous discussion, the Lifetime Health Advisory
is derived as follows:

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Barium                                                    March 31, 1987

                                     -8-

Step 1:   Determination of the Reference Dose (RfD)

                   RfD = (0.51  mg/kg/day) = 0>051 mg/kg/day
                               (10)
where:

        0.51 mg/kg/day = NOAEL (see discussion above).

                    10 = uncertainty factor, chosen in accordance with NA3/ODW
                         guidelines for use with a NOAEL from an animal study•
                         However, as previously discussed, ODW believes that
                         an uncertainty factor of 10 is appropriate in this
                         specific case (see discussion above).

Step 2:   Determination of the Drinking Water Equivalent Level (DWEL)

           DWEL = (0.051 mg/kg/day) (70 kg) = K8 mg/L (T,800 ug/L,
                         (2 L/day)

where:

        0.051 mg/kg/day = RfD.

                  70 kg = assumed body weight of an adult.

                2 L/day = assumed daily water consumption of an adult.

Step 3:   Determination of the Lifetime Health Advisory

            Lifetime HA = (1.8 mg/L)  (33%) =1.5 mg/L (1,500 ug/L)

where:

        1.8 mg/L = DWEL.

             83% = assumed relative source contribution from water  (Federal
                   Register, November 13, 1985).

Evaluation of Carcinogenic Potential

     "  Due to the absence of toxicological evidence to classify barium as
        a potential carcinogen, a quantification of carcinogenic risks for
        barium is not appropriate.

     0  No information was located in the available literature regarding  the
        carcinogenic potential of barium in humans nor were any animal studies
        found which were adequate to evaluate the carcinogenic potential  of
        barium.

      0  Applying the criteria described in EPA's guidelines for assessment of
        carcinogenic risk  (U.S. EPA,  1986) barium is classified in  Group  0:
        Not classified.  This category is for agents with inadequate animal
        and human evidence.

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      Barium                                                    March 31,  1987

                                           -9-
           0  The International Agency for Research on Cancer has not evaluated the
              carcinogenic potential of barium.


  VI. OTHER CRITERIA,  GUIDANCE AND STANDARDS

           0  The National Interim Primary Drinking Water Regulations of 1975
              established a Maximum Contaminant Level (MCL)  drinking water standard
              for barium of 1  mg/L (U.S.  EPA,  1976).

           0  The National Academy of Sciences (NAS,  1982) derived a 1-day Suggested
              No-Adverse-Response Level (SNARL) for barium of 6.0 mg/L.

           0  The National Academy of Sciences (NAS,  1982) derived a chronic Sug-
              gested No-Adverse-Response Level (SNARL) value for barium  of 4.7 mg/L.

           0  The American Conference of Governmental Industrial Hygienists estab-
              lished an occupational threshold limit value (TLV) of 0.5  mg/m3 for
              barium nitrate in air (ACGIH,  1980).

           8  The USSR standard for waterborne barium is  4 mg/L (NAS,  1977).

           0  The OSHA 8-hour time-weighted  average exposure limit for soluble
              barium compounds is 0.5 mg/m3  in workplace  air (OSHA,  1985).


 VII. ANALYTICAL METHODS

           0  Determination of barium is  by  atomic  absorption (AA) using either
              direct aspiration into a flame (U.S.  EPA,  1979a)  or a furnace technique
              (U.S.  EPA,  1979b).

           0  The direct aspiration AA procedure  is a physical  method based on the
              absorption of radiation at 553.6 nm by  barium.  The sample is
              aspirated into an air-acetylene  flame and atomized.  A light beam is
              directed through the flame  into  a monochromator,  and onto  a detector
              that measures the amount of light absorbed.   Absorbance is proportional
              to the concentration of barium in the sample.   The detection limit is
              100 ug/L using this procedure.

           0  The furnace AA procedure is similar to  direct  aspiration AA except a
              furnace, rather  than a flame,  is used to atomize  the sample.   The
              detection limit  is  2 ug/L using  this  procedure.

VIII. TREATMENT  TECHNOLOGIES
              Experience  indicates  that  ion  exchange,  lime  softening  and  reverse
              osmosis  are effective to remove barium  from drinking  water.   Conven-
              tional  coagulation/filtration  processes  are not  effective  to  remove
              barium  from drinking  water (U.S.  EPA,  1977).

              Weinberg (1973)  and Logsdon et al.  (1974)  reported  that ion exchange
              softening systems  are highly efficient  (93 to 98 percent)  for reducing

-------
Barium                                                    March  31,  1987

                                     -10-
        barium in water,  even after water hardness  breakthrough.   Field
        data from two Midwestern full-scale ion exchange softening plants
        showed that barium  removal was  comparable  to hardness  removal on well
        water containing  11-19 mg/L of  barium and  225-230 mg/L of hardness as
        CaCo3 (BIF, 1970).   When these  softening units were performing ef-
        ficiently and removing all of the hardness  from the water, they  also
        removed all of the  barium.

     0  Experience indicates that lime  softening is very effective in removing
        barium from drinking water.  Lime softening achieved greater than
        90 percent removal  in the 10-11  pH range on well water containing
        7-8.5 mg/L of naturally occurring barium.   Removals decreased below
        and above this range.  Pilot plant studies  conducted at the EPA
        Municipal Research  Laboratory and full-scale treatment information on
        similar types of  ground water verified the  laboratory  data.  Pilot
        plant test runs on  water containing 10-12  mg/L of barium  at pH 9.2,
        10.5 and 11.6 resulted in removals of 84,  93 and 32 percent, respec-
        tively.  Grab samples from two  full-scale  lime softening  plants
        showed removals of  88 and 95 percent.  These plants operated at  pH
        10.5 and 10.3; the  raw water barium concentrations were measured
        at 7.5 and 17.4 mg/L,  respectively (BIF, 1970).

     0  A number of studies indicate that reverse  osmosis membranes can  remove
        more than 90 percent of the barium from drinking water.  In an experi-
        mental long term  study, 99 percent barium  removal was  obtained using
        cellulose acetate membrane at 400-800 psi  operating pressures (3IF,
        1970).  Other studies by Sorg et al. (1980) achieved similar results,
        where 95-99 percent removals were obtained  by passing  water containing
        7 mg/L barium through cellulose acetate membranes at 165-180 psi
        operating pressures.

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    Barium                                                     March 31,  1987

                                         -1 1-


IX. REFERENCES

    ACGIH.   1980.   American Conference  of Governmental  Industrial Hygienists.
         Threshold limit values  for chemical substances and physical agents in
         the workroom  environment with  intended  changes for 1980.  Cincinnati,
         Ohio:  American Conference of  Governmental Industrial Hygienists.  p. 35.

    Bauer,  G.C.H.,  A.  Carlsson and B. Lindquist.   1957.  Metabolism of  140ga in
         man.  Acta.  Orth.  Scand.  26:241-254.

    Bauer,  G.C.H.,  A.  Carlsson and B. Lindquist.   1956.  A comparative  study of
         the metabolism of  140Ba and 45Ca in rats.   Biochem. J.  63:535-542.

    BIF.   1970.  Chemicals  Used  on Treatment of  Water and Waste Water Engineering
         Data.  (Unit  of General Signal Corp.,  Providence, RI) brochure.   May.

    Brenniman, G.R., W.H. Kojola, P.S.  Levy,  B.w.  Carnow and T. Namekata.   1981.
         High barium  levels in public drinking  water and its association  with
         elevated  blood pressure.  Arch.  Environ.  Health.  36(1):28-32.

    Dencker, L., A. Nilsson,  C.  Ronnback  and G.  Walinder.  1976.  Uptake  and
         retention of  133ga and  140Ba-T4C>La  in  mouse tissue.  Acta Radiol.
         15(4):273-287.

    Diengott, D.,  O. Rozsa,  N. Levy  and S. Muammar.  1964.  Hypokalemia  in
         barium poisoning.   Lancet 2:343-344.

    Federal Register,  November 13,  1985,  Vol. 50,  No. 219,  pp 46936-47022.

    Gould,  D.B., M.R.  Sorrell and A.D.  Luperiello.   1973.  Barium sulfide  poison-
         ing.  Arch. Intern.  Med.  132:891-894.

    Harrison, G.E.,  T.E.F.  Carr  and A.  Sutton.   1967.  Distribution of  radioactive
         calcium,  strontium,  barium  and radium  following intravenous injection
         into a healthy man.   Int. J. Radiat. Biol.  13(3):235-247.

    ICRP.   1973.   International  Commission on Radiological Protection.  Alkaline
         earth metabolism in  adult man.  ICRP Publication 20.  Health Phys.
         24:125-221.

    Kirkpatrick, T.  1978.  Barium compounds.   In:   Kirk-Othmer encyclopedia of
         chemical  technology,  3rd ed.,  Vol.  3.   New York:  John Wiley and  Sons.
         pp. 463-479.

    Lengemann, F.W.  1959.  The  site of action  of  lactose in the enhancement of
         calcium utilization.  J. Nutrition,  69:23-27.

    Logsdon, G.S.,  Sorg, T.J. et al.  1974.  Removal of Heavy Metals by Conven-
         tional  Treatment.   Proceedings,  16th Water Quality  Conference.   Trace
         Metals  in Water Supplies:   Occurrence,  Significance and Control.
         University of Illinois.

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Barium                                                    March 31, 1987

                                     -12-
McCauley, P.T., and I.S. Washington.  1983.  Barium bioavailability as the
     chloride, suifate or carbonate salt in the rat.  Drug Chem. Toxicol.
     6(2):209-217.

Miner,  S.  1969.  Air pollution aspects of barium and its compounds.  Techni-
     cal Report.  Bethesda, Md.:  Litton Systems, Inc.  Contract No. PH-22-
     68-25.  69 pp.

NAS.  1977.  National Academy of Sciences.  Drinking Water and health.
     Vol. 1.  Washington, D.C.:  National Academy Press, pp. 207-305.

National Academy of Sciences.  1982.  Drinking Water and Health, Vol. 4.
     Washington, D.C.:  National Academy Press, pp. 167-170.

OSHA.  1985.  Occupational Safety and Health Administration.  Code of Federal
     Regulations.  Title 29 - Labor.  Part 1910 - Occupational Safety and
     Health Standards.  Subpart Z - Toxic and Hazardous Substances.  Section
     1910.1000 - Air Contaminants.  U.S. Government Printing Office,
     Washington, DC.

Perry,  R.H., and C.H. Chilton.  1973.  Chemical engineers' handbook, 5th ed.
     New York:  McGraw-Hill Book Co.  pp. 3-8 - 3-9.

Perry,  H.M., S.J. Kopp, M.W. Erlanger and E.F. Perry.  1983.  Cardiovascular-
     effects of chronic barium ingestion.  In: Hemphill, D.D., ed.  Trace
     substances in environmental health-XVII.  Proceedings of University of
     Missouri's 17th annual conference on trace substances in environmental
     health, Columbia, MO:  University of Missouri Press.   pp. 155-164.

Pidgeon, L.M.  1964.  Barium.  In:  Kirk-Othmer encylopedia of chemical
     technology.  2nd ed.  Vol. 3.  John Wiley and Sons, New York.  pp. 77-80.

Preisman, L.  1964.  Barium compounds.  In:  Kirk-Othmer encylopedia of
     chemical technology.  2nd ed. Vol 3.  John Wiley and Sons, New York.
     pp. 80-98.

Reeves, A.L.  1979.  Barium.  In:  L. Friberg, G.F. Nordberg and V.B. Vouk,
     eds.  Handbook on the toxicology of metals.  Amsterdam:  Elsevier/Nortii
     Holland Biomedical Press,  pp. 321-328.

Schroeder, H.A., and L.A. Kraemer.  1974.  Cardiovascular mortality, municipal
     water and corrosion.  Arch. Environ. Health.  28:303-311.

Schroeder, H.A., and M. Mitchener.  1975a.  Life-term effects of mercury,
     methyl mercury and nine other trace metals on mice.  J. Nutr.  105:452-458,

Schroeder, H.A., and M. Mitchener.  1975b.  Life-term studies in rats:  effects
     of aluminum, barium, beryllium and tungsten.  Jo Nutr.  105:421-427.

Sorg, T.J., and Logsdon, G.S.  1980.  Treatment technology to meet the interim
     primary drinking water regulations for inorganics:  Part 5.  AWWA.
     72(7):411-22.

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Barium                                                    March 31, 1987

                                     -13-
Sowden, E.M., and S.R. Stitch.  1957.  Trace elements in human tissue.  2.
     Estimation of the concentrations of stable strontium and barium in
     human bone.  Biochem. J.  67:104-109.

Talwar, K.K., and B.K. Sharma.  1979.  Myocardial damage due to barium chlond«
     poisoning.  Indian Heart J.  31(4):244-245.

Tardiff, R.G., M. Robinson and N.S. Ulmer.  1980.  Subchronic oral toxicity
     of BaCl2 in rats.  J. Environ. Path. Tox.  4:267-275.

Taylor, D.M., P.M. Bligh and M.H. Duggan.  1962.  'The absorption of calcium,
     strontium, barium and radium from the gastrointestinal tract of the rat.
     Biochem. J.  83:25-29.

Tipton, I.H., P.L. Stewart and P.G. Martin.  1966.  Trace elements in diets
     and excreta.  Health Phys.  12:1683-1689.

U.S. EPA.  1976.  U.S. Environmental Protection Agency.  National interim
     primary drinking water regulations.  EPA 570/9-75-C03.  Washington, D.C.:
     U.S.  Environmental Protection Agency.

U.S. EPA.  1977.  U.S. Environmental Protection Agency.  Manual of treatment
     techniques for meeting the interim primary drinking water regulations,
     revised.  U.S. Environmental Protection Agency,  EPA-600/8-77-005.

U.S. EPA.  1979a.  U.S. Environmental Protection Agency.  Method 208.1.
     Atomic Absorption, direct aspiration, In:  Methods for Chemical Analysis
     of Water and Wastes.  EPA-600/4-79-020,  March.

U.S. EPA.  1979b.  U.S. Environmental Protection Agency.  Method 208.2.
     Atomic Absorption, furnace technique, In:  Methods for Chemical Analysis
     of Water and Wastes.  EPA-600/4-79-020,  March.

U.S. EPA.  1983.  U.S. Environmental Protection Agency.  Barium occurrence in
     drinking water,  food, and air.  Office of Drinking Water.

U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Draft health effects
     criteria document for barium.  CSD,  Office of Drinking Water.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogenic risk assessment.  Federal Register.  51(185):33992-34003.
     September 24.

U.S. EPA.  1987.  U.S. Environmental Protection Agency.  Estimated national
     occurrence and exposure to barium in public drinking water supplies.
     CSD.  Office of  Drinking Water.

Weinberg, L.M.  1973.  Report of analytical evaluation and treatability
     study.  For Wight Consulting Engineers on Lake Zurich Water Well *5.
     CHEMED Corp., Dearborn Environmental Engineers,  July.

Windholz, M., ed.  1976.  The Merck-Index:  An encyclopedia of  chemicals and
     drugs, 9th ed.  Rahway, NJ:  Merck and Co., Inc.  p. 995.

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                                                             March 31,  1S87
                                      CADMIUM

                               Health Advisory  Draft
                              Office of Drinking Water
                        U.S.  Environmental Protection Agene/
I. INTRODUCTION
        The Health  Advisory  (HA)  Program,  sponsored by  the Office of Drinking
   Water (ODW),  provides information on the health effects, analytical method-
   ology  and treatment technology  that would be useful  in dealing with the
   contamination of drinking water.   Health Advisories  describe nonregulatory
   concentrations of drinking water  contaminants at which adverse healtn effects
   would not be  anticipated  to occur over  specific exposure durations.  Health
   Advisories contain a margin of  safety  to protect sensitive members of the
   population.

        Health Advisories serve as informal technical guidance to assis.t Federal,
   State and local  officials responsible for protecting public health when
   emergency spills or contamination situations occur.   They  are not to be
   construed as  legally enforceable  Federal standards.   The HAs are subject to
   change as new information becomes available.

        Health  Advisories are developed for One-day,  Ten-day,  Longer-term
   (approximately 7 years, or 10%  of an individual's  lifetime) and Lifetime
   exposures based  on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not  quantitatively  incorporate  any potential carcinogenic
   risk  from such exposure.   For  those substances  that  are known or probable
   human carcinogens,  according to the Agency  classification scheme (Group A or
   B),  Lifetime  HAs are not  recommended.   The  chemical  concentration values for
   Group A or B  carcinogens  are correlated  with carcinogenic  risk estimates by
   employing a cancer potency (unit  risk)  value together with assumptions for
   lifetime exposure and the consumption of drinking water.  The cancer unit
   risk  is usually  derived from the  linear  multistage model with 95% upper
   confidence limits.   This  provides a low-dose estimate of cancer risk to
   humans that is considered unlikely  to pose  a carcinogenic  risk in excess
   of  the stated values.  Excess cancer risk estimates  may also be calculated
   using the One-hit,  Weibull,  Logit or Probit models.   There is no current
   understanding of the biological mechanisms  involved  in cancer to suggest that
   any one of these models is able to predict  risk more accurately than another.
   Because each  model  is based  on differing assumptions,  the  estimates that are
   derived can differ  by several orders of  magnitude.

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    Cadmium
                                March 31, 1987
                                         -2-
         This Health Advisory  (HA)  is  based  on information presented  in the Office
    of Drinking Water's Health Effects Criteria Document (CD)  for cadmium (U.S.,
    EPA,  1985).  The HA and  CD formats are similar for easy reference.   Individuals
    desiring further information on the toxicological data base or rationale for
    risk  characterization should consult the CD.   The CD is available for review
    at each EPA Regional Office of Drinking  Water counterpart (e.g.,  Water Supply
    Branch or Drinking Water Branch),  or for a fee from the National  Technical
    Information Service, U.S. Department of  Commerce, 5285 Port Royal Rd.,
    Springfield,  VA 22161,  ?B #86-117942/AS.  The toll-free number is (800)
    336-4700; in the Washington, D.C.   area:  (703) 487-4650.
II.  GENERAL INFORMATION AND PROPERTIES
    CAS No.
            Cadmium — 7440-43-9
            Cadmium Chloride — 10108-64-2
            Cadmium Oxide — 1306-19-0
         0  Cadmium is  used  for a number of  purposes  including the following
            (Stubbs,  1978):   batteries,  electroplating,  stabilizer,  pigments,
            and as  an alloy  with other metals.

    Properties  (Schindler,  1967; Weast, 1971;  IARC,  1976;  Parker, 1978)

         0  The properties of cadmium compounds vary  with the specific compound;
            some examples are as follows:
    Chemical Formula
    Physical State
    Boiling Point
    Melting Point
    Density
    Vapor Pressure (400°C)
    Water Solubility
    Log Octanol/Water
      Partition Coefficient
    Taste Threshold
    Odor Threshold
                              Cadmium
Cd
    Atomic/Molecular Weight   112.40
Cadmium
Chloride

CdCl2
183.32
Soft white solid  Solid
765°C
320.9°C           568°C
8.642 g/cm3       4.047 g/cm3
1.4 mmHg
                  Soluble
Cadmium
Oxide

CdO
128.40
Solid
1,559°C
900°C
8.15 g/cm3

Insoluble

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     Cadmium                                                   March 31,  1987

                                          -3-


     Occurrence

          0  Cadmium is a naturally-occurring metallic element, present in most of
             the earth's crust at levels below 1  ppm.   Cadmium is commercially
             obtained as a byproduct during the production of zinc.   Commercial
             uses of cadmium and its compounds include metal plating, electronics,
             paints,  and pigments.   Cadmium is released to the environment during
             its uses and from other commercial activities.  However, these releases
             have not resulted in the contamination of ground and surface waters
             (U.S. EPA, 1987).

          0  Naturally  occurring levels  of  cadmium in  surface and ground  water
             normally fall in the range  of  1-10 ug/L.   State monitoring data have
             reported that 21 ground water  supplies and 4 surface water supplies
             currently  exceed 10 ug/L.  Cadmium occurs at low levels in food and
             air.  The FDA Total Diet Study reports that adults currently receive
             34 ug/day  of cadmium from their diets. Based upon this information
             food appears to be the  major route of exposure for cadmium (U.S. EPA,
             1987).

          0  Cadmium is found in both cigarettes  and cigarette smoke and  as the
             absorption of inhaled  cadmium  can approach levels as high as 96%
             (CEC, 1978), smoking can account for a substantial fraction  of the
             body burden of cadmium  (Ellis  et al., 1979)


III. PHARMACOKINETICS

     Absorption

          0  The absorption of cadmium following  oral  administration to laboratory
             animals, and presumably humans, is modified by many factors  including
             dose (Engstrom and Nordberg,  1979),  age (Kostial et al., 1983),  diet
             (Suzuki et al., 1969)  and by  the presence of other metals such as
             calcium (Washko and Cousins,  1976).

          0  Cadmium does not readily cross the skin (CEC, 1978).

          0  Cadmium is very readily absorbed following inhalation;  as much as  96%
             of the cadmium deposited in the lungs may be absorbed (CEC,  1978).

     Distribution

          0  In both rats (Sabbioni  et al., 1978)  and  humans (Sumunio et  al.,
             1975), cadmium distributes  throughout the body and accumulates in
             the kidney and liver where  it  may attain  levels 10 to 100 times
             greater than those of other tissues.

     Metabolism

             Whole cadmium is not metabolized to  other compounds as  is the typical
             organic drinking water  contaminant;  once  within the body, cadmium
             readily  combines with the the  low molecular weight protein(s)
             metallothionein (Foulkes, 1982).

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    Cadmium                                                   March  31,  1987

                                         -4-
    Excretion
            Once absorbed,  cadmium  is  eliminated in humans  principally  via the
            urine (U.S.  EPA,  1985).

            Cadmium  is  eliminated very  slowly  in humans;  a  half-life for elimina-
            tion of  cadmium has been estimated to be 10 to  33 years (Ellis et al.,
            1979).   The  long  half-life  of  cadmium in humans is principally accounted
            for by  the  marked accumulation and retention of cadmium in the kidney
            and liver (Friberg et al.,  1974)

            In humans, average body retention  of radiolabelled cadmium  chloride,
            measured one to five weeks  post exposure,  was approximately 4.6%
            (McLellan et al.,  1978).
IV.  HEALTH EFFECTS

    Humans
            In humans,  the symptoms  of  cadmium  toxicity  following acute exposure
            include nausea,  vomiting,  diarrhea,  muscular cramps and salivation
            (Arena, 1963).  In the case of  severe intoxication, sensory distur-
            bances, liver injury  and convulsions may  result,  which, in fatal
            intoxications, are followed by  shock and/or  renal failure and cardio-
            pulmonary depression  (CEC,  1978).

         1   The estimated acute lethal  dose of  cadmium is 350 to 35,000 mg for a
            70-kg adult (CEC,  1978).

         '   For emesis,  the NOAEL for  cadmium  in adults  is 0.043 mg/kg/day followin:
            an acute oral exposure to  cadmium  salts  (Lauwerys, 1979).

            Chronic non-occupational oral exposure to very high levels of cadmium
            has resulted in such  adverse health effects  as the Itai-Itai disease
            observed in Japan  (principally  in  multiparous women), which is
            characterized by pain, osteomalacia, osteoporosis, proteinuria,
            glucosuria,  and anemia (U.S. EPA,  1985).

         '   While it has been  suggested that cadmium  may play a role in hyper-
            tension, there is  considerable  uncertainty concerning what, if any,
            role cadmium may play in this disease.  (Perry et al., 1977a and b;
            Kopp et al., 1982,  1983).

          0 Renal toxicity (e.g.  proteinuria)  following  low level chronic oral
            exposure to cadmium is believed to be the most sensitive manifestation
            of cadmium toxicity (CEC,  1978;  U.S. EPA,  1985).   It has been estimated
            that the concentration at  which 10% of the population is likely  to
            display signs of renal dysfunction is 180 to 220  ug Cd/g renal cortex.
            Individuals with values  over 285 ug/g usually display signs of renal
            dysfunction (U.S.  EPA, 1985).

         3   Friberg et al. (1974) hypothesized  that renal damage may occur when,
            over a 50 year period, a person's  daily cadmium intake equals or
            exceeds 0.352 mg/day.

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                                     -5-


Animals

Short-term Exposure

     0  The acute oral LDjQ of cadmium compounds in the rat varies with the
        compound and ranges from 16 mg/kg for cadmium cyanide to > 5,000 mg/kg
        for cadmium sulfide (CEC, 1978).

     0  Toxic effects, resulting from oral exposure to various cadmium compounds,
        have been observed in a variety of animal tissues (U.S. EPA, 1985)
        including the nervous system (Gabbiani et al., 1967), kidney (CEC,
        1978), liver  (Stowe et al., 1972), bone (Larsson and Piscator, 1971),
        hematopoietic system (Stowe et al., 1972), cardiovascular system
        (Kopp et al., 1978) and immune system (Koller, 1973).

Long-term Exposure

     0  Cadmium-induced renal toxicity (e.g. proteinuria) has been observed
        in animals in the absence of renal histopathology (CEC, 1978).

     0  In a 24-week male rat drinking water study, animals exposed to 2.15
        and 6.44 mg cadmium/kg/day developed a significant level of proteinuria
        (P <0.05), while animals exposed to the lowest level tested, 0.84 mg
        cadmium/kg/day (NOAfiL), did not develop proteinuria (Kotsonis and
                      ).

             12 month rat drinking water study,  no adverse effects were
        observed in animals exposed to 0.008, 0.035, 0.181,  0.361  or 0.375
        (NOEL) mg cadmiumAg/day .  However, at three months, the animals
        exposed to the highest level tested, 3.04 mg cadmium/kg/day, developed
        anemia and did not gain weight normally (Decker et al., 1958).

Reproductive Effects

     0  In a rat oral study, cadmium was administerted at 0, 0.1,  1.0 and
        10.0 mg cad mi urn/kg/day (as CdC^) respectively, to groups  of male and
        female adult rats for six weeks;  males and females were mated for
        three weeks, and cadmium was administered during the mating period;
        pregnant females were given cadmium during the gestation period.  In
        the 10 mg/kg group,  the number of total implants and live  fetuses
        decreased significantly (p <0.05) while resorptions increased signifi-
        cantly (p <0.01); fetuses showed decreased body weight (p  <0.05) and
        delayed ossification of the sternebrae and caudal vertebrae.  No
        effects were observed at 0.1 or 1.0 mg cadmium/kg/day (Sutou et al.,
        198°).

Developmental Effects

     8  In a rat drinking water study, fetal growth retardation was observed
        in animals whose dams were exposed to 100 mg cadmium/L but not in
        those exposed to 0.1 or 10 mg cadmium/L during gestation (Ahokas
        et al., 1980).

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   Cadmiam                                                  March  31,  1987

                                        -6-


   Mutagenicity

        0  While cadmium has been observed to cause chromosomal aberrations in
           several in vitro studies (e.g., Watanabe et al.,  1979,  and Di Paolo
           and Casto,  1979), strong evidence of  mutagenic effects  following oral
           ingestion is not available (U.S. EPA, 1985).

   Carcinogenicity

        0  Cadmium and cadmium compounds  have been shown to  induce  sarcomas at
           local injection sites (Haddow et al., 1964; Gunn  et al., 1967).  In
           addition,  cadmium chloride administered to rats by  aerosol for 18
           months has produced lung tumors (Takenaka et al.,  1983).  These data
           are not believed relevant to the consumption of cadmium  in drinking
           water (U.S. EPA, 1985).

        0  Although cancers of the prostate and  lung have been noted in cadmium
           smelter workers in an epidemiological study (Lenten  et al., 1976),
           evidence regarding the carcinogenicity of cadmium in humans following
           oral exposure is largely conjectural  (U.S. EPA, 1985).

        0  No evidence of cadmium oncogenicity has been found  in chronic oral
           animal studies (Schroeder et al., 1965; Kanisawa  and Schroeder,
           1969; Loser, 1980).


V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories (HAs)  are generally determined for One-day, Ten-day,
   Longer-term (approximately 7 years) and Lifetime exposures  if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants  are derived using the following formula:

                 HA =  (NOAEL or LOAEL) x  (BW) =  	   /L (	    „ j
                        (UF) x (	 L/day)
   where:
           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effeet-Level
                            in mg/kg bw/day.

                       BW = assumed body weight of a child (10 kg)  or
                            an adult (70 kg).

                       UF = uncertainty factor (10,  100 or 1,000),  in
                            accordance with NAS/ODW guidelines.

                	 L/day = assumed daily water consumption of a child
                            (1 L/day)  or an adult (2 L/day).

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                                     -7-


One-day Health Advisory

     The study by Lauwerys (1979) was selected to serve as the basis for the
One-day HA for cadmium.  In this study, the NOAEL for cadmium-induced emesis
in adult humans following a single dose of cadmium was 0.043 mg cadmium/kg/day.
This study was selected because it is of appropriate duration and was conducted
in the most appropriate species, humans; more suitable data are not available.

     The HA for a 10-kg child is calculated as follows:

        One-day HA = (0.043 mg/kg/day)  (10 kg) = 0.043 mg/L (43 ug/L)
                          (10)  (1 L/day)
where:
        0.043 mg cadmium/kg/day = NOAEL for emesis following acute exposure
                                  to adults (Lauwerys, 1979).

                          10 kg = assumed body weight of a child.

                             10 = uncertainty factor, chosen in accordance with
                                  NAS/ODW guidelines for use with a NOAEL from
                                  a human study.

                        1 L/day = assumed daily water consumption of a child.

Ten-day Health Advisory

     A 24-week oral exposure study in rats (Kotsonis and Klaassen, 1978) was
considered for use as the basis of the Ten-day HA.  In this study a NOAEL of
0.84 mgAg/day was identified for proteinuria.  If this NOAEL and an uncertainty
factor of 100 were used, the Ten-day HA value would be 0.08 mg/L.  This value
is not markedly different from the One-day HA of 0.043 mg/L (based on a study
which demonstrated cadmium-induced emesis in adult humans). However, since
the Ten-day HA value of 0.08 mg/L would be greater than the One-day HA value,
it is recommended that the more conservative One-day HA of 0.043 mg/L (43 ug/L)
be used as the Ten-day HA.

Longer-term Health Advisory

     The available data are insufficient to develop Longer-term HAs for
cadmium.  It is recommended that the DWEL of 18 ug/L be used as the Longer-
term HA for the 70-kg adult and the modified DWEL of 5 ug/L (adjusted for a
10-kg child) be used as the Longer-term HA for the 10-kg child.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The Lifetime HA
is derived in a three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without

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Cadmium                                                   March 31, 1987

                                     -8-
appreciable risk of deleterious effects over a lifetime,  and is derived from
the NOAEL (or LOAEL),  identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that mediam,  at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is  determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     There are no adequate oral exposure studies in humans which provide a
NOAEL for the chronic effects of cadmium.  Friberg et al. (1974) concluded
that the critical concentration of cadmium in the renal cortex of humans
associated with renal dysfunction is 200 ug/g wet weight; this is supported
by the recent reassessment by Kjellstrom et al. (1984).  The 200 ug/g critical
concentration was based on a comprehensive review of evidence from animal
experiments and from analyses of kidneys from workers occupationally exposed
to cadmium.  The 200 ug/g value is probably the most widely accepted estimate
of the critical concentration for renal dysfunction (NA3, 1977; CEC, 1978).
However, Roels et al.  (1983) reported that the critical concentration in the
human renal cortex is 216 ug/g tissue wet weight and that less than 10% of
occupationally exposed males may develop renal dysfunction at this concentration,

     Several models have been proposed to estimate the daily intake (exposure)
of cadmium required to produce the critical concentration in the renal cortex.
Each model has inherent limitations.  Friberg et al. (1974)  estimated that a
daily cadmium intake of 0.352 mg/day for 50 years would result in a renal
cortex concentration of 200 ug/g.  This model assumes 4.5% absorption of the
daily oral dose and 0.01% excretion per day of the total body burden, both
reasonable estimates.   Thus, 0.352 mg of cadmium per day in a 70-kg adult
(0.005 mgAg/day) is a reasonable estimate of the daily cadmium intake that
would result in renal dysfunction.  In that the Friberg et al., (1974) value
of 0.005 mg/kg/day is associated with renal dysfunction,  0.005 mg/kg/day is a
LOAEL value which normally would require that an uncertainty factor of 100 be
used.  However, considering the relatively low level of uncertainty concerning
cadmium toxicity in this case, it is judged that an uncertainty factor of 100
is unreasonably high and that an uncertainty factor of 10 is more appropriate.

     As previously discussed, the study by Friberg et al.,  (1974) is the
most appropriate from which to derive the Lifetime Health Advisory.  From
these results, a LOAEL of 0.005 mg/kg was identified.  Using this LOAEL, the
Lifetime Health Advisory is derived as follows:

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Cadmium                                                   March 31,  1987

                                     -9-


Step 1:  Determination of the Reference Dose (RfD)

                  RfD = (0.005 mg/kg/day) = 0.0005  mgAg/day
                              (10)

where:

        0.005 mgAg/day = LOAEL based on renal dysfunction in humans.

                     10 = uncertainty factor; this  uncertainty factor, while
                          smaller than would normally be required by NA3/ODW
                          guidelines, was judged to best reflect the uncertainty
                          concerning cadmium toxicity in humans.

Step 2:  Determination of the Drinking Water Equivalent Level (DWEL)

           DWEL = (0*0005 mgAg/day) (70 kg) _ 0.018 mg/L (18 ug/L)
                          (2 L/day)

where:

        0.0005 mgAg/day = RfD.

                   70 kg = assumed body weight of an adult.

                 2 L/day = assumed daily water consumption of an adult.

Step 3:  Determination of the Lifetime Health Advisory

            Lifetime HA = (0.018 mg/L) (25%) = 0.005 mg/L (5 ug/L)

where:

        0.018 mg/L = DWEL.

               25% = assumed relative source contribution from water.

Evaluation of Carcinogenic Potential

     0   A quantitative evaluation of the carcinogenicity of cadmium  has  not
        been conducted since there is no conclusive evidence that cadmium is
        carcinogenic following oral exposure.

     0   U.S. EPA has recommended that cadmium not be considered a suspect
        human carcinogen for the purpose of calculating an ambient water
        quality criterion (U.S. EPA, 1980).

     0   Based on exposure to cadmium via inhalation,  IARC (1982) has
        classified cadmium and certain cadmium compounds in Group 2B: Limited
        evidence for carcinogenicity in humans,  sufficient evidence  for
        carcinogenicity in animals.

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    Cadmium                                                   March  31,  1987

                                         -10-
         0  Applying the criteria  described  in EPA's  guidelines  for  assessment of
            carcinogenic risk (U.S.  EPA,  1986),  cadmium,  on the  basis  of  inhalation
            data,  may be classified  in Group B1:   Probable  human carcinogen.   This
            category is for agents for which there is inadequate evidence from
            human  studies and sufficient  evidence from animal  studies. However,
            as there are inadequate  data  to  conclude  that cadmium is carcinogenic
            via ingestion,  cadmium is  dealt  with here as  Group D:  Not classified.
            This category is for agents with inadequate animal evidence of
            carcinogenicity.


VI. OTHER CRITERIA,  GUIDANCE, AND  STANDARDS

         0  The National Academy of  Sciences (NAS,  1982)  has calculated a one-day
            Suggested No-Adverse Response Level (SNARL) of  0.150 mg/L  for cadmium
            in drinking water for  70-kg adults.

         0  The National Academy of  Sciences (NAS,  1982)  has calculated a seven-day
            SNARL  of 0.021  mg/L  of drinking  water for 70-kg adults.

         0  The National Academy of  Sciences (NAS,  1982)  has calculated a chronic
            exposure SNARL of 0.005  mg/L  for cadmium  in drinking water for 70-kg
            adults;  this value is  based on the assumption that water contributes
            20% of the daily cadmium intake.

         0  A FAO/WHO expert committee has proposed a provisional tolerable weekly
            standard of no more  than 57.1  to 71.4 ug  Cd/week (WHO,  1972).

         0  The World Health Organization (WHO,  1984) has recommended  that the
            concentration of cadmium in drinking water not  exceed 0.005 mg/L.

         0  The Commission of the  European Communities (CEC, 1975) has recommended
            that the concentration of  cadmium in drinking water  not  exceed O.OOE mg/1.

         0  The current U.S. EPA primary drinking water standard for cadmium is
            0.010  mg/L of drinking water  (U.S. EPA,  1976).

         0  The recommended threshold  limit  values (TLVs) for  cadmium  dusts,
            salts  and oxide fumes  for  occupational eight hour  time-weighted
            average  exposure is  0.05 mg/m3 (ACGIH,  1980).

         0  The OSHA 8-hour time-weighted average exposure  limit for cadmium fume
            is 0.1 mg/m3 in workplace  air; the acceptable ceiling concentration
            for cadmium fume is  0.3  mg/m3 (OSHA,  1985).

         0  The OSHA 8-hour time-weighted average exposure  limit for cadmium dust
            is 0.2 mg/m3 in workplace  air; the acceptable ceiling concentration
            for cadmium dust is  0.6  mg/m3 (OSHA,  1985).

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      Cadmium                                                   March  31,  1987

                                           -1 1-


 VII. ANALYTICAL METHODS

           0   Determination  of  cadmium  is  by  atomic  absorption  (AA)  using  either
              direct aspiration into  a  flame  (U.S. EPA,  1979a)  or  a  furnace  technique
              (U.S.  EPA,  19795).

           0   The direct  aspiration AA  procedure  is  a physical  method  based  on  the
              absorption  of  radiation at 228.8 nm by cadmium.   The sample  is
              aspirated into an air-acetylene flame  and  atomized.  A light beam is
              directed  through  the  flame into a monochromator and  onto a detector
              that measures  the amount  of  light absorbed.   Absorbance  is proportional
              to the concentration of cadmium in  the sample.  The  detection  limit
              is 5 ug/L using this procedure.

           0   The furnace AA procedure  is  similar to direct aspiration AA  except a
              furnace,  rather than a  flame, is used  to atomize  the sample.   The
              detection limit is  0.1  ug/L  using this procedure.


VIII. TREATMENT TECHNOLOGIES

           0   Effective removal of cadmium from source waters may  be achieved with
              treatment methods such  as coagulation  with alum or iron  salts, lime
              softening,  ion exchange and  reverse osmosis.  Laboratory experiments
              and pilot plant studies indicate that  the  effectiveness  of cadmium
              removal by  coagulation  is pH dependent. Ferric sulfate coagulation
              studies on  river  water  containing 0.3  mg/L of cadmium  showed removals
              to increase from  20 % at  pH  7.2 to  above 90  % at  pH  8  and above.
              Alum coagulation  results  on  river water also  increased with  pH, but
              the data indicated  that,  above  pH 8, removals may depend on  che
              turbidity of the  raw water.   In  some tests with low  turbidity  water
              (1-10  jtu), removals decreased  as the  pH increased (U.S.  EPA,  1978).

           0   Experience  indicates that lime  softening is  capable  of achieving
              cadmium removal from water greater  than 98 \  in the  pH range in
              well water  containing 0.3 mg/L  of cadmium.  Removals equally as good
              were obtained  at  pH 11.2-11.3 when  the initial cadmium concentration
              was increased  up  to 10  mg/L  (U.S. EPA, 1978).

           0   There  are limited performance data  on  the  use of  ion exchange  as  a
              treatment method  for removal of  cadmium from  drinking  water.   The
              plating industry  uses ion exchange  for reducing cadmium  in wastewaters
              and other wastewater streams studied have  successfully used  ion
              exchange  for removing cadmium (Lindstedt et  al.,  1976; Nippon, 1976;
              Amax,  1977; Laszlo, 1977;  Ameron, 1978).   However, there is  one report
              of 99  % removal efficiency for  cadmium from drinking water using  a
              home ion exchange softener (Personal communications, Ciccone
              Engineering, V.J. from  Culligan  Co., 1982).   Tap  water spiked
              with 0.10 mg/L of cadmium chloride  and used  as feed  water to a cation
              exchanger on the  sodium cycle produced product water with a  cadmium
              level  less  than 0.01 mg/L.

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Cadmium                                                   March 31,  1987

                                     -12-
        Experience indicates that reverse osmosis can effectively remove
        cadmium from drinking waters.  A study by Mixon (1973) showed a 90
        and 9.8% cadmium removal, respectively,  from 0.10 mg/L and 0.98 mg/L
        spiked water samples, using three laboratory-scale cellulose acetate
        membranes operated at 400 psi.   No difference in cadmium rejection
        was noted when barium, chromium, copper, lead and zinc were introduced.
        Another study by Hindin et al.  (data)  indicated a 70 percent removal
        for cadmium concentrations of 0.097,  0.959 and 9.25 mg/L using a
        laboratory size reverse osmosis cellulose acetate cell.  A study
        performed by Huxstep (1982) in Florida related to inorganic con-
        taminant removal from potable water by reverse osmosis resulted in a
        96-98 % removal of cadmium.

        Protection against cadmium from corrosion of water distribution
        systems, in general, may be achieved by a number of methods including
        pH adjustment,  addition of lime, increasing alkalinity, or addition
        of phosphates or silicates.  The extent and type of treatment
        selection is dependent on the characteristics of the water and the
        compatibility of existing treatment with regard to various materials
        used to convey the water through the distribution system.

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    Cadmium                                                   March  31,  1987

                                         -13-


IX. REFERENCES

    ACGIH.   1980.   American Conference  of  Governmental  Industrial  Hygienists.
         Documentation of  the  threshold limit values,  4th ed.  Cincinnati,  OH:
         American Conference of  Governmental  Industrial Hygienists,  pp.  59-61.

    Ahokas, R.A.,  P.V. Dilts and E.B.  LaHaye.  1980.   Cadmium-induced fetal
         growth  retardation:   protective  effect  of  excess dietary  zinc.  Am. J.
         Obstet. Gynecol.   136:216-226.

    Amax,  Inc.   1977.   Removal of  metal ions  from wastewater.   U.S.  Patent
         4,025,430, submitted  January  12,  1976.   May  24.

    Ameron, Inc.  1978.  System  for  removal of  toxic heavy metals  from drinJcing
         water.   U.S.  Patent 4,096,064, submitted April 5, 1976.   June 20.

    Arena,  J.M.   1963.   Poisoning:   chemistry,  symptoms and treatment.  Spring-
         field,  IL: Charles C.  Thomas, p. 127.

    CEC.   1975.  Commission of the European Communities.  Proposal for a council
         directive  relating to the quality of water human consumption.  J. Official
         European Communities.  18:2-17.

    CEC.   1978.  Commission of the European Communities.  Criteria (dose/effect
         relationships")  for cadmium.  Oxford:   Permagon Press,  pp. 1-198.

    Decker, C.F., R.U.  Byerrum and C.A. Hoppert.  1957.   A study of the distribution.
         and retention  of  cadmium-115  in  the  albino rat. Arch.  Biochem.  Biophys.
         66:140-145.

    DiPaolo,  J.A.,  and  B.C. Casto.   1979.   Quantitative studies of in vitro
         morphological  transformation  of  Syrian  hamster cells  by inorganic
         metal salts.  Cancer  Res. 39:1008-1013.

    Ellis,  K.J., D. Vartsky, I.  Zanzi,  S.H. Cohn and S. Yasumura.   1979.  Cadmium:
         in vivo measurement in  smokers and nonsmokers.  Science.   205:323-325.

    Engstrom, B., and  G.F. Nordberg.  1979.   Dose dependence of gastrointestinal
         absorption and  biological half-time  of  cadmium in mice.   Toxicology.
         13:215-222.

    Foulkes,  B.C.,  ed.   1982.  Biological  roles  of  metallothionein.   New York:
         Elsevier/North-Holland.

    Friberg,  L., M. Piscator,  G.F. Nordberg and  T.  Kjellstrom.  1974.  Cadmium
         in the  environment, 2nd ed. Boca  Raton,  Florida:   CRC  Press Inc.

    Gabbiani, G., A. Gregory and D.  Baic.   1967.  Cadmium-induced  selective
         lesions of sensory ganglia.   J.  Neuropath. Exp. Neur.  26:498-506.

    Gunn, S.A.,  T.C. Gould and W.A.D. Anderson.   1967.   Specific response  of
         mesenchymal tissue to carcinogenesis  by cadmium,   Arch. Pathol.
         83:493-499.

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                                     -14-
Haddow, A., F.J.C. Roe,  C.E. Dukes and B.C.V. Mitchley.  1964.  Cadmium
     neoplasia:   Sarcomata at the site of injection of cadmium sulphate in
     rats and mice.  Brit. J. Cancer.  ,18:667-673.

Hindin, E., G.H. Dunstan et al.   Water reclamation by reverse osmosis.
     Bulletin 310, Washington State University.

Huxstep,  M.R.  1982.   Inorganic  contaminant removal from potable water by
     reverse osmosis (Task 49AS, Treatment of Small Community Water Supplies
     by Reverse Osmosis).  Charlottee Harbor (FL)  Water Association,  Inc.,
     Progress Report, January 1  - March 31, 1982.   U.S. Environmental
     Protection Agency.

IARC.  1976.  International Agency for Research on Cancer.   Monographs on tne
     evaluation of carcinogenic  risk of chemicals  to man.  Cadmium, nickel,
     some epoxides, miscellaneous industrial chemicals and  general considera-
     tions on volatile anesthetics, Vol. 11.  Lyon:  International Agency for
     Research on Cancer, pp. 39-74.

IARC.  1982.  International Agency for Research on Cancer.   IARC monographs on
     the evaluation of the carcinogenic risk of chemicals to humans.   Suppl.
     4: 133-135.

Kanisawa, M., and H.A. Schroeder.  1969.  Life term studies on the effect
     of trace elements on spontaneous tumors in mice and rats.  Cancer Res.
     29:892-895.

Kjellstrom, T.,  C.G.  Blinder and L. Friberg.  1984.  Conceptual problems in
     establishing the critical concentration of cadmium in  human kidney
     cortex.  Env. Res.   33:284-295.

Roller, L.D.  1973.  Immunosuppression produced by lead, cadmium and  mercury,,
     Am. J. Vet. Res. 34:1457-1458.

Kopp, S.J., V.W. Fisher, M. Erlanger, E.F. Perry and H.M. Perry.  1978.
     Electrocardiographical, biochemical and morphological  effects of chronic
     low level cadmium feeding on rat heart.  Proc. Soc. Exp. Biol. Med.
     159:339-345.

Kopp, S.J., T. Glonek, H.M. Perry, M. Erlanger and E.F. Ferry.  1982.
     Cardiovascular actions of cadmium at environmental exposure levels.
     Science.  217:837-839.

Kopp, S.J., H.M. Perry,  E.F. Perry and M. Erlanger.  1983.   Cardiac physio-
     logic and tissue metabolic  changes following  chronic low-level cadmium
     and cadmium plus lead ingestion in the rat.  Toxicol.   Appl. Pharmacol.
     69:149-160.

Kostial, K., I. Simonovic, I. Rabar, M. Blanusa and M. Landeka.  1983.
     Age and intestinal retention of mercury and cadmium in rats.  Environ.
     Res.  31:111-115.

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Cadmium                                                   March 31,  1987

                                     -15-
Kotsonis, F.N.,  and C.D. Klaassen.  1978.  The relationship of metallonthionein
     to the toxicity of cadmium after prolonged oral administration to rats.
     Toxicol. Appl. Pharmacol.  46:39-54.

Larsson, S.E., and M. Piscator.  1971.  Effect of cadmium on skeletal tissue
     in normal and cadmium-deficient rats.  Isr.  J. Med. Sci.  7:495-498.

Laszlo, M.  1977.  Process for removing heavy metals from fluid media.
     U.S. Patent 4,060,410,  submitted July 7,  1975.  November 29.

Lauwerys, R.  1979.  Cadmium in man.  In:  Webb,  ed.  The chemistry, biochem-
     istry and biology of cadmium.  Elsevier/North Holland Biomedical Press,
     pp. 433-453.

Lemen,  R.A., J.S. Lee, J.K.  Wagoner and H.P. Blejer.  1976.  Cancer mortality
     among cadmium production workers.  Ann. NY Acad. Sci.  271:273-279.

Loser,  E.  1980.  A 2-year oral carcinogenicity study with cadmium on rats.
     Cancer Lett.  9:191-198.

Linstedt, K.D.,  C.P. Houck et al.   1971.  Trace element removals in advanced
     wastewater treatment processes.  Journal WPCP.  43(7):1507-13.

McLellan, J.S.,  P.R. Flanagan, M.J. Chamberlain and L.S. Valberg.   1978.
     Measurement of dietary cadmium absorption in humans.  J. Toxicol. Environ.
     Health.  4:131-138.

Mixon,  F.O.  1973.  Removal  of toxic metals from  water by reverse  osmosis.
     R&D Progress Report No. 889.   U.S. Department of Interior, Office of
     Saline Water.

NAS.  1977.  National Academy of Sciences.  Drinking Water and Health.  Volume 1.
     Washington, DC:  National Academy Press,  p.  939.

NAS.  1982.  National Academy of Sciences.  Drinking Water and Health.  Volume 4.
     Safe Drinking Water Committee.  Washington,  D.C.:   National Academy Press,
     pp. 170-174.

Nippon  Electric  Co., Ltd.  1976.  Improvements in or relating to the extraction
     of heavy metals from industrial wastewaters.  British Patent  1,457,528,
     submitted December 19,  1972.   December 1, 1976.

OSHA.  1985.  Occupational Safety  and Health Administration.   Code of Federal
     Regulations.  Title 29  - Labor.  Part 1910 - Occupational Safety and
     Health Standards.  Subpart Z  - Toxic and Hazardous Substances.  Section
     1910.1000 - Air Contaminants.  U.S. Government Printing  Office,
     Washington, DC.

Parker,  P.O.  1978.  Cadmium compounds.  In:   Kirk-Othmer,  encyclopedia  of
     chemical technology.  3rd ed., Vol. 4.  New  York:   John  Wiley & Sons.
     pp. 387-411.

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Cadmium                                                   March 31,  1987

                                     -16-
Perry, H.M.,  M. Erlanger and E.F.  Perry.   1977a.   Elevated systolic pressure
     following chronic low-level cadmium feeding.  Am. J. Physiol.  232:H114-
     H121.

Perry, H.M.,  M. Erlanger and E.F.  Perry.   1977b.   Hypertension following
     chronic, very low dose cadmium feeding.  Proc. Soc. Exp. Biol. Med.
     156:173-176.

Personal communication between V.J.  Ciccone Engineers  and Culligan, August 4,
     1982.

Ribelin, W.E.  1963.   Atrophy of rat testis as index of chemical toxicity.
     Arch. Pathol.  75:229-235.

Roels, R., R. Lauwerys and A.N. Dardenne.  1983.   The critical level of
     cadmium in human renal cortex:   a re-evaluation.  Toxicol. Letters.
     15:357-360.

Sabbioni, E., E. Marafante,  L. Amantini,  L. Ubertalli and R.  Pietra.  1978.
     Cadmium toxicity studies under long term-low level exposure (LLE) con-
     ditions.  I.   Metabolic patterns in rats exposed to present environmental
     dietary levels of Cd for two years.  Sci. Total Environ.  10:135-161.

Schindler, P.w.  1967.  Heterogenous equilibria involving oxides,  hydroxides,
     carbonates and hydroxide carbonates.  In:  American Chemical Society.
     Equilibrium concepts in natural water systems.  Adv. in Chem. Series 67,
     pp.  196-221.

Schroeder, H.A., J.J. Balassa and W.H. Vinton.  1965.  Chromium, cadmium and
     lead in rats:  effects on life span, tumors and tissue levels.  J. Nutr.
     86:51-66.

Stowe, H.Do,  M. Wilson and R.A. Goyer.  1972.  Clinical and morphologic
     effects of oral cadmium toxicity in rabbits.  Arch. Pathol.  94:389-405=

Stubbs, R.L.  1978.  Cadmium - the metal of benign neglect.  Proceedings of
     the  1st International Cadmium Conference.  Metal Bulletin Ltd., London,
     England, pp.  7-12.

Sumino, K., K. Hayakawa, T. Shibata and S. Kitamura.  1975.  Heavy metals in
     normal Japanese tissues.  Arch. Environ. Health.  30:487-494.

Sutou, S., K. Yamamoto, H. Sendota and M. Sugiyama.  1980.  Toxicity,  fer-
     tility, teratogenicity and dominant lethal tests in rats and administered
     cadmium subchronically.  III.  Fertility, teratogenicity and dominant
     lethal test.  Ecotoxicol. Environ. Safety.  4:51-56.

Suzuki, S., T. Taguchi and G. Yokohashi.  1969.  Dietary factors influencing
     upon the retention rate of orally administered 115Cd C12 in mice with
     special reference  to calcium and protein concentrations in diet.   Industr,
     Health.  7:155-162.

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Cadmium                                                   March 31,  1987

                                     -17-
Takenaka, S., H. Oldiges, H. Konig, 0. Hochrainer and G. Oberdorstar.  1983.
     Carcinogenic!ty of cadmium chloride aerosols in W rats.  JNCI.  70:367-373,

U.S. EPA.  1976.  U.S. Environmental Protection Agency.  National interim
     primary drinking water regulations.  Office of Water Supply.  Washington,
     D.C.  pp. 59-62.

U.S. EPA.  1978.  U.S. Environmental Protection Agency.  Manual of treatment
     techniques for meeting the interim primary drinking water regulations,
     revised.  EPA-600/8-77-005.

U.S. EPA.  1979a.  U.S. Environmental Protection Agency.  Water Method 213.1.
     Atomic Absorption, direct aspiration.  In:  Methods for chemical analysis
     of water and wastes.  EPA-60/4-79-020,  March.

U.S. EPA.  1979b.  U.S. Environmental Protection Agency.  Method 213.2,
     Atomic Absorption, furnace technique.  In: Methods for chemical analysis
     of water and wastes.  EPA-600/4-79-020,  March.

U.S. EPA.  1980.  U.S. Environmental Protection Agency.  Ambient water quality
     criteria for cadmium.  Washington,  DC:   EPA-440/5-30-025.

U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Final draft of the
      drinking water criteria document on cadmium.  Office of Drinking Water.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogen risk assessment.  Federal Register.  51(185):33992-34003.
     September 24.

U.S. EPA.  1987.  U.S. Environmental Protection Agency.  Occurrence of cadmium
     in public water supplies.  CSD.  Office of Drinking Water.

Washko,  P.W., and R.J. Cousins.  1976.  Metabolism of 109Cd in rats fed normal
     and low-calcium diets.  J. Tox. Environ. Health.  1:1055-1066.

Watanabe, T., T. Shimada and A. Endo.  1979.   Mutagenic effects of cadmi am
     on mammalian oocyte chromosomes.  Mutation Res. 67:349-356.

Weast,  R.C.,  ed.  1971.  CRC handbook of chemistry and physics,  52nd ed.
     Cleveland, OH:   The Chemical Rubber Co.

WHO.  1972.  World Health Organization.   Evaluation of certain food additives
     and the contaminants mercury, lead, and cadmium.  Sixteenth Report of
     the Joint FAO/WHO Expert Committee on Food Additives.  Geneva, Switzer-
     land:  WHO Technical Report Series No.  505, FAO Nutrition Meetings Report
     Series No. 51.

WHO.  1984.  World Health Organization.   Guidelines for drinking water quality
     — recommendations.  Volume 1.  Geneva:   World Health Organization.

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                                                             March  31,  1987
                                      CHROMIUM

                                  Health  Advisory
                              Office  of Drinking Water
                        U.S.  Ehvironmental  Protection Agency
I. INTRODUCTION

        The  Health Advisory  (HA)  Program,  sponsored  by  the  Office  of  Drinking
   Water (ODW),  provides  information  on the  health effects, analytical  method-
   ology and  treatment  technology that  would be  useful  in dealing  with  the
   contamination of  drinking water.   Health  Advisories  describe  nonregulatory
   concentrations of drinking water contaminants at  which adverse  health  effects
   would not  be  anticipated  to  occur  over  specific exposure durations.   Health
   Advisories contain a margin  of safety to  protect  sensitive  members of  the
   population.

        Health Advisories serve as informal  technical guidance to  assist  Federal,
   State and  local officials responsible for protecting public health when
   emergency  spills  or  contamination  situations  occur.   They are not  to be
   construed  as  legally enforceable Federal  standards.   The HAs  are subject to
   change as  new information becomes  available.

        Health Advisories are developed for  One-day, Ten-day,  Longer-term
   (approximately 7  years, or 10% of  an individual's lifetime) and Lifetime
   exposures  based on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not  quantitatively incorporate  any  potential  carcinogenic
   risk  from  such exposure.   For  those  substances that  are  known or probable
   human carcinogens, according to the  Agency classification scheme (Group A or
   B),  Lifetime  HAs  are not  recommended.   The chemical  concentration  values for
   Group A or B  carcinogens  are correlated with  carcinogenic risk  estimates by
   employing  a cancer potency (unit risk)  value  together with  assumptions for
   lifetime exposure and  the consumption of  drinking water. The cancer unit
   risk  is usually derived from the linear multistage model with 95%  upper
   confidence limits.   This  provides  a  low-dose  estimate of cancer risk to
   humans that is considered unlikely to pose a  carcinogenic risk  in  excess
   of  the stated values.   Excess  cancer risk estimates  may  also  be calculated
   using the  One-hit, Weibull,  Logit  or Probit models.   There  is no current
   understanding of  the biological mechanisms involved  in cancer to suggest that
   any one of these  models is able to predict risk more accurately than another.
   Because each  model is  based  on differing  assumptions,  the estimates  that are
   derived can differ by  several  orders of magnitude.

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    Chromium                                                  March  31,  1987

                                         -2-
         This Health  Advisory  is  based  on  information  presented  in  the  Office
    of  Drinking Water's  Health Effects  Criteria  Document  (CD)  for chromium  (U.S.
    EPA,  1985).  The  HA  and CD formats  are similar  for easy  reference.   Individuals
    desiring further  information  on  the toxicological  data base  or  rationale for
    risk  characterization  should  consult the CD.  The  CD  is  available for  review
    at  each EPA Regional Office of  Drinking Water counterpart (e.g.,  Water  Supply
    Branch  or Drinking Water Branch), or for a fee  from the  National  Technical
    Information Service, U.S.  Department of Commerce,  5285  Port  Royal Rd.,  Spring-
    field,  VA 22161,  PB  #86-113072/AS.   The toll-free  number is  (800) 336-4700;
    in  the  Washington, D.C. area:   (703) 487-4650.


II.  GENERAL INFORMATION  AND PROPERTIES

    CAS NO.

         0   Chromium  —  7440-47-3
            Chromium  (III) Chloride  —  10025-73-7
            Chromic Acid,  Dtpotassium Salt — 7789-00-6

    Synonyms

         0   None

    Uses

         Chromium and its  salts have a  variety of uses including the  following
    (for  additional information see  Hartford, 1979):

         0   Hexavalent chromium compounds  are used  widely in industry for  chrome
            alloy and chromium metal production,  for metal finishing  and corrosion
            control  (Love, 1947)  and as mordants  in the textile  industry (Her,
            1954).

         0   Chromium  salts are used  as  anticorrosive agents  in cooling  waters, in.
            the leather  tanning industry,  in the  manufacture of  catalysts,  in
            pigments  and paints,  and in fungicides  and wood  preservatives  (Hartford,
            1979).

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 Cn r om i urn
                                                          March  31,  1987
                                      -3-
 Properties   (Hem,  1970;  Weast,  1971;  Windholz,  1976}

      "  The properties of chromium compounds vary with  the  specific  compound;
        some  examples are as  follows:
                          Chromium
                  Chromium (III)
                  Chloride
                  Chromic Acid,
                  Dipotassium Salt
Chemical Formula
Atomic/Molecular Weight
Physical State
Boiling Point
Melting Point
Density
Vapor Pressure
Water Solubility
Log OctanoI/Water
  Partition Coefficient
Taste Threshold
Odor Threshold

Occurrence
Cr
51.996
blue-white solid
2,642°C
1,900°C
7. 1 4 gm/cm3

0.5 ug/L
CrCl3
122.90
solid

83 °C
194.20
solid

968. 3 °C
2.76 g/cm3 (15°C) 2.732 g/cm3 (18°C)

inslouble         62.9 g/100 mL (20°C)
        Chromium is a relatively rare, naturally occurring element in the
        earth's crust.  Chromium occurs in most rocks and minerals at levels
        of 200 ppm.  A few minerals contain chromium at levels of 2-3,000
        ppm.  Chromium is not mined in the U.S. commercially; it is imported.
        Chromium is released to the environment during industrial activities.
        However, current data suggest that surface and ground water levels of
        chromium are the result of naturally-occurring chromium leaching from
        mineral deposits.  Soluble chromium has been reported to occur in
        surface waters at levels up to 84 ug/L and in ground water at levels
        of 50 ug/L (U.S. EPA, 1987).

        Federal surveys of surface and ground water drinking water supplies
        have reported that most supplies contain less than 5 ug/L.  Currently,
        17 ground water supplies and one surface water supply exceed the
        interim standard of 50 ug/L (U.S. EPA, 1987).
III. PHARMACOKINETICS

Absorption

     In general,  with the exception of the Cr III glucose tolerance factor
(GTF),  Cr VI is more readily absorbed than Cr III:

     0   In humans and experimental animals, gastrointestinal absorption of
        inorganic salts of Cr III is low (from 0.5% to 3°s).  However, Cr VI
        and organic complexes of Cr III are more readily absorbed (approxi-
        mately 2% to 10% for Cr VI and 10% to 25% for organic complexes of
        Cr III) (U.S. EPA,  1985).

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Chromium                                                  March 31,  1987

                                     -4-


     0  In humans administered 20 ng of Cr III as 51CrCl3 in water,  0.5% of the
        dose was recovered in the urine, indicating little absorption (Donald-
        son and Berreras, 1966).  In rats, Mertz et al.  (1965) reported 2% to
        3% absorption of Cr(III) based on total body counting of animals admin-
        istered ^CrCl^ by intubation at doses ranging from 1.5 to 100 ug/kg.

     0  GTF,  an organic complex of Cr III with nicotinic acid and an ami no
        acid that is found in brewer's yeast, was absorbed in rats at 10% to
        25% of the administered dose (Mertz,  1976;  Mertz et al., 1978).

     0  An estimate of 2.1% absorption of Cr VI based on recovery in urine was
        reported for humans administered 20 ng of Na251Cr04 in water (Donaldson
        and Barreras, 1966).

     0  Rats administered drinking water containing 25 mg/L Cr III as chromic
        chloride had 12.5 times greater tissue levels of chromium than rats
        whose drinking water contained 25 mg/L Cr VI as  potassium chromate
        (Mackenzie et al., 1958).

Distribution

     Depending on the particular compound (e.g., GTF) Cr III and Cr VI
differ in their distribution within an organism; in general Cr III crosses
membranes much more slowly than Cr VI (U.S. EPA, 1985):

     0  Chromium circulates in the plasma primarily.in a nondiffusible form.
        A small fraction (9% to 12%) is in a more diffusible form which is
        filtered and partially reabsorbed in the kidney (Collins et al.,
        1961).  An approximate plasma half-life of 6 hours for 51cr III in
        rats was reported by Hopkins (196S) after intravenous administration
        of either 0.1 or 1.0 ug/kg.

     0  Cr III has an affinity for iron-binding proteins (Gray and Sterling,
        1950; Hopkins and Schwarz, 1964).

     0  The spleen and kidneys were shown to have the highest concentrations
        of chromium when rats were administered Cr III as chromium chloride
        in intravenous doses of 0.1 or 1.0 ug/kg (Hopkins, 1965).  Similar
        results were reported by Mackenzie et al.  (1958) when rats received
        drinking water containing 25 mg/L of either Cr III as chromic
        chloride or Cr VI as potassium chromate.  The calculated doses were
        1.87 mg/kg/day for males and 2.41 mg/kg/day for  females.

     0  The placenta appears to be highly selective in its permeability to
        the various forms of chromium.  Inorganic Cr III administered as
        51CrCl3 (chromium chloride) intravenously or by stomach intubation
        does not cross the placental barrier to an appreciable extent in rats
        (Mertz et al., 1969).  However, Cr III administered by stomach
        intubation to pregnant rats in the form of GTF (obtained from yeast)
        is recovered readily from the fetus  (Mertz and Roginski, 1971).  The
        dosages in these two studies were unspecified.

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    Chromium                                                  March 31,  1987

                                         -5-
         0  Cr VI  traverses  biological  membranes  by  diffusion or facilitated
            transport,  possibly via an  anion transport system (Alexander  at al.,
            1982).  It  is  reduced  to Cr III intracellularly by the cytochrome
            P-450 system in  the presence of NADPH.   Cr ill reacts with nucleophilic
            ligands  and cellular macrocnolecules  (Gruber and Jennette,  1978).

    Metabolism

         0  The metabolism of  chromium  in mammalian  species is not well under-
            stood  and is complicated by the presence of the two oxidation states,
            Cr III and  Cr  VI (U.S.  EPA,  1985).

    Excretion

         The kidney  appears  to be  the principal  route of excretion of  chromium
    compounds:

         0  The urinary system is  the major excretory route for absorbed  chromium,
            accounting  for 80% or  more  of chromium excretion (Kraintz  and Talmage,
            1952).  Very little is  known about  the form in vhich chromium is
            excreted.

         0  After intravenous  administration, chromium is also excreted in the
            feces, although  reports in  the literature vary considerably on the
            percentage.  Hopkins (1965) reported  that 0.5% to 1.7% of  the initial
            dose of  Cr  III was excreted in the  feces of rats eight hours  after
            intravenous administration  of 51CrCl3 at 0.1 ug/100 g.


IV. HEALTH EFFECTS

    Humans

         In general,  Cr VI compounds are more toxic  than Cr III compounds:

         0  The toxicity of  chromium has been attributed primarily to  Cr  VI,  which
            has been shown to  produce liver and  kidney damage,  internal hemorrhage,
            dermatitis  and respiratory  problems.   The immediate symptoms  are
            generally nausea,  repeated  vomiting  and  diarrhea (U.S. EPA, 1985).

         0  Doses  of 0.5 to  1.5 g  of K2Cr2O7 have been fatal in humans.  The
            estimated LDLO for K^r2O7  in children is 26 mg/kg (Cr VI  at  9.2
            mg/kg) (NIOSH, 1983).

         0  Subchronic  and chronic  dermal exposure to Cr VT in the form of chromic
            acid may cause contact  dermatitis and ulceration of the skin  (Barrows,
            1978).  For example, Denton et al.  (1954) reported information on an
            individual  who was patch-tested on  three occasions with 0.005%
            potassium dichromate solution and the filtrate of two cement  samples
            which contained  0.0001% and 0.0004%  Cr VI.  The individual repeatedly
            showed a positive  erythematous, edematous, papulovesicular patch-test
            reaction to each test  solution.

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Chromium                                                  «arch 31,  1987

                                     -6-

     0  Chronic inhalation of dust or air containing Cr VI may cause respira-
        tory problems including perforated or ulcerated nasal septa and
        decreased spirometric values (U.S. EPA,  1985).  For example, Bloomfield
        and Blum (1928) reported perforated/ulcerated nasal septa and inflamed
        nasal mucosa in workers exposed to chromic acid (Cr VI)  (0.1 to  5.6
        mg/m3 air) for one week to three years.

Animals

Short-term Exposure

     In general, Cr VI compounds are more toxic than Cr III compounds:

     0  The oral LD5g for various salts of Cr III range from 600 to 2,600 mg/kg
        (Smyth  et al., 1969).

     0  The oral LD50 of Cr  VI  (as Na2Cr2O7) in rats is 19.8 mg/kg  (NIOSH,  1983),

     0  Rats were exposed to drinking water containing Cr VI  (K2CrC>4) at levels
        of both 80 and 134 rag Cr VI/L for 60 days (8.3 and 14.4  mg  Cr Vl/kg/day
        respectively)  without adverse effect  (Gross and Heller,  1946).

Long-term Exposure

     0  In a one year  rat drinking water study, consumption of water containing
        0 to 25 mg/L of either  Cr III   (CrCl3) or Cr VI   (K2Cr04)  (0 to  1.87
        mgAg/day for  male rats and  0 to 2.41 mg/kg/day for female  rats)
        produced no significant differences in weight gain, appearance or
        pathological changes in the  blood or  other  tissues (Mackenzie et al.,
        1958).  NOAELs of 1.87  mg/kg/day  (males) and 2.41 mg/k-j/day (females)
        can be  identified from  the  results  of this  study.

      0  In  a  rat drinking water study in  which   5 mg/L Cr  III  (about  0.42
        mg/kg/day) was administered  from  the  time of weaning  until  death,  no
         adverse effects were observed  (Schroeder et al.,  1965).   A  NOAEL of
         0.42  mg/kg/day can be  identified  from the results  of  this study.

      0   In  a  four  year female  dog drinking  water study (five  dose groups with
         two  animals  per group), Cr  VI  (K2CrO5) at 0.45 to  11.2 mg/L (0.012 to
         0.30  mg/kg Cr  VI) was  without effect  in  terms  of  changes in physical
         condition,  food consumption, growth rate, organ  weights, urinalysis
         results and  hematological analyses.  Therefore, a  NOAEL of  0.30 mg/kg/day
         can be identified from the  results  of this  study (Anwar et al.,  1961).

 Reproductive Effects

      0   No information was  found  in the available  literature on the reproductive
         effects of chromium.

 Developmental Effects

      0  No information was  found  in the available  literature on the develop™
         mental effects of chromium.

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   Chromium                                                  March 31,  1987

                                        -7-


   Mutagenicity

        0  The genotoxic effects of chromium are well documented both in in vivo
           and In vitro studies.  The pathway by which chromium exerts  these
           effects is believed to involve penetration of the cell membrane by
           Cr VI, followed by intracellular reduction to Cr III.  Extracellular
           Cr III crosses the cell membrane, but less efficiently.  Once inside
           the cell, Cr III can form tight complexes with DNA, accounting for
           its mutagenic potential (U.S.  EPA,  1985).

        0  Compounds of both Cr III and Cr VI increase non-complementary nucleo-
           tide incorporation into DNA (Raffetto et al., 1977; Ma j one and Rensi,
           1979), with Cr VI producing effects at lower doses.  Exposure of cells
           from rat liver and kidney to Cr VI leads to increased cross-linking
           in DNA.  Petrilli and De Flora (1978) reported positive Ames tests
           for Cr VI.  However, Cr III exerted no effect at relatively  high
           concentrations (presumably because of its inability to penetrate
           cells).  Similar results were reported by Gentile et al.  (1981).

        0  The difficulty of observing mutagenic effects of Cr III may be related
           to its slight uptake by cells  under most conditions.  Warren et al.
           (1931), studied the mutagenicity of a series of hexacoordinate Cr III
           compounds and concluded that,  in the proper ligand environment, the
           metal possesses considerable genetic toxicity.

   Carcinogenicity

        There is inadeqaate evidence to determine whether or not oral exposure
   to chromium can lead to cancer:

        0  No increase in tumor rates over that of the control animals  was
           observed in rats exposed rats  to Cr III (chromium oxide pigments)
           at 293, 586 or 1,466 mg/kg/day in the diet for two years  (Ivankovic
           and Preussmann, 1975).

        0  While the carcinogenicity of inhaled Cr VI is well established for
           occupational exposure of humans (Hayes et al., 1979), the effects
           are observed only in the respiratory passages and in the  lungs, and
           are believed to have no bearing on carcinogenic risk following oral
           exposure to the metal (U.S.  EPA,  1985).


V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories (HAs) are generally determined for One-day,  Ten-day,
   Longer-terni (approximately 7 years)  and Lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs  for noncarcinogenic toxicants  are derived using the following formula:
                 HA =        or LOAEL)  X (BW)  = _   „  ( _   „ ,
                        (UF)  x  (     L/day)

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Chromiu-n                                                  March 31,  1987

                                     -8-


where:

        NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                         in mg/kg bw/day.

                    BW = assumed body weight of a child (10 kg) or
                         an adult (70 kg).

                    UF = uncertainty factor (10,  100 or 1,000), in
                         accordance with NAS/ODW guidelines.

             	 L/day = assumed daily water consumption of a child
                         (1  L/day)  or an adult (2 L/day).

      In considering the toxicity of chromium compounds, it is important to
realize that chromium III is an essential nutrient required in trace quantities
for normal glucose metabolism - i.e. GTF.  Some forms of chromium may also be
important,in the metabolism of lipids and other carbohydrates (U.S.  EPA, 1935).

      The Health Advisories will be determined on the basis of the effects of
Cr VI measured as total chromium.  Separate Health Advisories will not be
established for Cr III for the following reasons:

      1.  Based on the work of Schroeder and Lee (1975), there is reason to
         believe that oxidizing agents (e.g. due to chlorination of water)
         may accelerate the normal conversion of Cr III to Cr VI at the
         point of consumption (i.e., the tap).

      2.  Health Advisories based on total chromium will allow for the possible
         conversion of Cr III to Cr VI.

      3.  As discussed in this document, there is reason to believe that Cr
         VI is more toxic than Cr III.  Thus Health Advisories base! on th»
         effects of Cr VI will conservatively protect against the toxic
         effects of any Cr III not converted to Cr VI.

One-day Health Advisory

      The available data are insufficient to develop a One-day HA for chromium.
It is recommended that the Ten-day HA of 1.4 mg/L be used as the One-day HA
for the 10 kg child.

Ten-day Health Advisory

      Gross and Heller (1946) exposed both male and female rats for 60 days
to drinking water containing K2Cr04 at either 300 or 500 mg/L (Cr VI at
80 mg/L and 134 mg/L, respectively).  Using reported average body weights of
270 and 260 g, respectively, and assuming consumption of 28 mL water per day,
tne average ingested doses of Cr VI are calculated to be 8.3 and 14.4 "ijAg/day,
respectively.  After two months, the rats receiving Cr VI at 8.3 mg/kg/day were
described as normal.  A "slight roughness of coat" «M-> noted in rats receiving
14.4  mg/kg/day, but this is not considered to be an adverse health effect; this
observation is not associated with other adverse health effects.  Therefore,
14.4  mg/kg/day represents the NOAEL for Cr VI in this study.

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Chromium                                                  March 31, 1987

                                     -9-


     The Ten-day HA for a 10-kg child is calculated as follows:

         Ten-day HA = H 4.4 mg/kg/day) (10 kg) = 1.4 mg/Ij (1400 ug/L)
                          (100) (1 L/day)

where:

        14.4 mg/kg/day = NOAEL based on the absence of adverse effects in
                         rats exposed to chromium in drinking water.

                 10 kg = assumed body weight of a child.

                   100 = uncertainty factor, chosen in accordance with NAS/ODW
                         guidelines for use with a NOAEL from an animal study.

               1 L/day = assumed daily water consumption of a child.

Longer-term Health Advisory

     Mackenzie et al. (1958) studied the effects of chronic ingestion of
Cr III and Cr VI in rats.  Both male and female Sprague Dawley rats (34 days
old) were supplied with drinking water containing Cr as CrCl3 (Cr III) or as
K^CrO^ (Cr VI) in a series of doses up to 25 mg/L for a period of one year.
Assuming an average weight of 375 g for males and 290 g for females, and an
average daily water intake of 28 mL (Arrington, 1972), the average dose for
males and females receiving 25 mg/L is calculate-1 to be 1.87 and-2.41  mg
Cr Vl/kg/day, respectively.  No significant adverse effects on appearance,
weight gain, food consumption or blood chemistry were noted at any of the
dose levels.  However, the animals receiving the highest dose (25 mg/L) of
Cr VI showe? da approximate 20% reduction in water consumption.

     Cr VI at 2.41 mg/kg/day was identified as the NOAEL in this study.  The
Longer-term HAs are calculated as follows:

   For a 10-kg child:

       Longer-term HA = (2.41  mg/kg/day) (10 kg) = Q 24   /L (240   /T ,
                             (100M1  L/day)
where:
        2.41  mg/kg/day = NOAEL based on the absence of adverse effects in
                         rats exposed to chromium in drinking water.

                 10 kg = assumed body weight of a child.

                   100 = uncertainty factor, chosen in accordance with NAS/ODW
                         guidelines for use with a NOAEL from an animal study.

               1  L/day = assumed daily water consumption of a child.

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Chromium                                                  March 31, 1987

                                     -10-


   For a 70-kg adult:

       Longer-term HA = (2.41 mg/kg/day) (70 kg) = 0<84   /L  (840   /L }
                             (100) (2 L/day)

where:

        2.41 mg/kg/day = NOAEL based on the absence of adverse effects in
                         rats exposed to chromium in drinking water.

                 70 kg = assumed body weight of an adult.

                   100 = uncertainty factor, chosen in accordance with NAS/ODW
                                  s for use with a NOAEL from an animal study.
               2 1,/day = assumed daily water consumption of an adult.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual1 s  total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adversu 'vjilth effects over a lifetime exposure.  The  Lifetime HA
is derived vi  t three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely  to be without
appreciable risk of -ieleterious effects over a lifetime, and  is  derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic)  study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water  Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific  (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinog'eni. • 'le-tlth effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consu.no ti D-L jf an
adult.  Tie Lifetime HA is determined in Step 3 by factoring  in  other sources
of exposure, the relative sonrr-i contribution (RSC).  The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should  be  exercised in
assessing the  risks associated with lifetime exposure to this chemical.

     The study by MacKenzie et al. (1958)  (described under the Lo-vjer-term HA)
is considered appropriate to serve as the basis for the Lifetime HA.  The
Anwar et al. (1961) study was not selected because only two animals per dose
group were used.
         j th-i NOAEL of 2.41 mg/kg/day, the Lifetime HA is derived as follows:

St-sp  1:  Determination of the Reference Dose  (RfD)

                  RfD =  (2.41 mg/kg/day) = Q.0048 mg/kg/day
                            (100)  (5)

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Chromium                                                  March 31, 1987

                                     -1 1-
where:

        2.41 mg/kg/day = NOAEL based upon the absence of adverse effects in
                         rats exposed to chromium in drinking water.

                   100 = uncertainty factor, chosen in accordance with NAS/ODW
                         guidelines for use with a NOAEL from -vi i-iinal study.

                     5 = additional uncertainty factor to compensate for less-
                         than-lifetime exposure.

Step 2:   Determination of the Drinking Water Equivalent Level (DWEL)

                   DWEL = (0-0048 mg/kg) (70 kg) = ., 70   „
                                (2 L/day)

where:

        0.0048 mrj/k'j = RfD.

               70 kg = assumed body weight of an adult.

             2 L/day = assumed daily water consumption of an adult.

Step  3:   Determination of Lifetino Health Advisory

                  Lifetime HA = (170 ug/L)  (71%) = 120 ug/L

where:

        170 ug/L = DWEL.

             71% = assumed relative source contribution from water.

Evaluation of Carcinogenic Potential

     0  There is no evidence of carcinogenic effects following oral exposure
        to chromium.  Thus,  no assessments for carcinogenic risks from oral
        exposure to chromium have been conducted.  Inhalation of chromium,
        however, is associated with an increased frequency of lung cancer in
        humans.

     0  EPA's CAG has estimated the lifetime cancer risk due to >\ constant
        exposure to air containing 1  ug/m3 of elemental chromium to be
        1.2 x 10~2 (U.S. EPA, 1983).

     0  Based on exposure to chromium via inhalation,  IARC (1982) has classified
        chromium and certain chromium compounds in Group *  (Chromium VI);
        sufficient evidence  for carcinogenicity in humans and ani.nal?.

      0  Applying the criteria described in EPA's guidelines for assessment
        of carcinogenic risk (U.S. EPA,  1986), chromium may be classified in
        Group A:  Human carcinogen.  This category is for agents for which

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     Chromium                                                   March 31, 1987

                                          -12-
             there is sufficient evidence to support the causal associatioa '.i-jtwtjen
             exixDsure to- the agents and cancer.  However, as there are inadequate
             data to conclude that chromium is carcinogenic via ingestion, chromium
             is dealt with here as Groan D:  Not classified.  This category is for
             agents with inadequate animal evidence of carcinogenicity .


 VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

          Recommended or established standards for chromium in the United States
     include:
          0  50 ug Cr VI per litur for drinking water (U.S. PHS,  1962).

          0  50 ug total chromium per liter for drinking water (NAS, 1974;
             U.S.  EPA,  1976).

          0  1  ug/m3 for carcinogenic forms of Cr VI in workplace air (NIOSH,  1975)

          0  25 ug/m3 TWA or 50 ug/m3 ceiling for non-carcinogenic forms of Cr VI
             in workplace air (NIOSH, 1975).

          0  The recourieri ]-.• 1 Ambient water quality criterion for Cr VI is 50 ug/L
             (U.S. EPA,  1980).

          0  An estimated adequate and safe intake for chraaium of 50 to 200 ug/day
             for adults has been established  (NAS, 1980a,b).  This range is based
             on the absence of  sujns of chromium deficiency in the major portion
             of the U.S. population which consumes a.-i 'U--rage of 60 ug of chromium
             per day.

          0  The OSHA 8-hour time-weighted average exposure limit for ciir- >irL'i>a,
             soluble chromic, and chromous salts as chromium is 0.5 mg/m3 (03HA,
             1985).
VII. ANALYTICAL METHODS
          0  Determination of chromium is by atomic absoro!;; m (AA) using either
             direct aspiration into a flame (U.S. EPA, 1979a) or a furnace technique
             (U.S. EPA,  1979b).

          0  The direct aspiration AA procedure is a physical method based on the
             absorption of radiation at 357.9 nm by chromium.  Tha s-inple is
             aspirated into an air-acetylene flame and atomized.  A 1i
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      Chromium                                                  March  31,  1987

                                           -13-


VIII.  TREATMENT TECHNOLOGIES

           0  The  treatment technologies  that are available  to  remove  chromium  from
             water  include coagulation/filtration,  lime  softening,  ion  exchange  and
             reverse  osmosis.   However,  the  type of treatment  that may  be applied
             is dependent on the species of chromium present.

           0  Laboratory and pilot  plant  studies indicated  that using  ferric sulfate,
             Cr III removals were  near 100 percent  in the range of  pH 6.5  to 9.5.
             Alum was less effective between pH 7.5 and  8.5, with  removals around
             90 percent or better.  Above and below this pH range,  removals were
             slightly lower, 80 to 90 percent.  In  removing Cr VI,  laboratory  and
             pilot-plant tests  confirmed that of the three  coagulants used, only
             ferrous  sulfate was effective.  With alum and  ferric  sulfate,  Cr  VI
             removals did not exceed 30 percent.  By comparison, ferrous  sulfate
             coagulation achieved  90 percent removal or  better (U.S.  EPA,  1977).

           0  Results  of jar and pilot-plant tests indicate  that Cr  III  removal
             efficiencies with  lime softening were  approximately  72 percent at pH
             8.5  to 9.5 and greater than 99 percent at pH  11 to 11.5.   Results
             with Cr  VI in the  same tests in all cases were less  than 10  percent
             (U.S.  EPA,  1977; Sorg, 1979).

           0  Since  Cr in occurs in cationic species and Cr VI in  anionic  species,
             a cation exchanger in series with an anion  exchanger  may be  required
             for  their removal.  Removal of Cr VI from sewage  (Sorg,  1979), industrial
             wastewater, rinse  waters from chromium plating operations  (Miller
             and  Mindler, 1978), cooling tower blowdown  (Richardson et  al., 1963;
             Miller and Mindler, 1978), and metal recovery  (Sussman et  al., 1945)
             has  been demonstrated.  Laboratory tests on a  simulated  Arizona well
             water  (TDS 174 mg/L,  pH 7.85) having 0.019  mg/L of Cr  VI showed a
             breakthrough of Cr VI at roughly 12,000 bed volumes  (U.S.  EPA, 1932).
             Reports  concerning  industrial wastewater treatment indicate  that  ion
             exchange can successfully remove Cr III to below  0.05  mg/L (Patterson,
             1975).   Strong acid cationic resins have been  used for removing Cr
             III  as a contaminant  from metal plating rinse  waters  and from  chromate
             treated  cooling waters.  Vendor information indicates  that operating
             pH levels  of between  6 and 8 are adequate for  C~  III removal  with pH
             above  7  being slightly better than pH  below 7  (Rohm and  Haas  Co.,
             1980).   Ion exchange  softening using standard  strong acid  synthetic
             resins operating in the sodium cycle should effectively  remove Cr
             III  with 90 percent or greater efficiency (Amore,  1977).   in  tests
             of home  softeners with tap water spiked with 1 mg/L of chromium
             nitrate,  the chromium  content continued to be  reduced  to 0.020 mg/L
             after  192 cycles,  at  which point the test was  discontinued.

           0  Reverse  osmosis (RO)  membranes can efficiently remove  from 82  to  99
             percent  of the chromium in a feed water source (Fox,  no  date;  Mixon,
             1973;  Johnston et  al., 1978).  Pilot plant  tests  using both  cellulose
             acetate  and hollow fiber (polyamide) membranes demonstrated  their
             effectiveness in removing both Cr III  and Cr VI.  Cr  III removal
             ranged from 90 to  98  percent and Cr VI removal ranged  from 82 to  97
             percent.   Slightly better removal was  achieved with the  hollow fiber
             than with  the cellulose acetate membranes (Fox, no date).

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    Chromium                                                   March  31,  1987

                                         -14-



IX.  REFERENCES
    Alexander,  J.,  J.  Aseth  and  T.  Norseth.   1982.   Uptake  of  chromium  by rat
         liver  mitochondria.  Toxicol.   24:115-122.

    Amore,  F.   1977.   Technical  Letter  20:   Removal  of  Water Supply  Contaminants
         -- Chromium.   Illinois  State Water  Survey,  1977.

    Anwar,  R.A.,  R.F.  Langham, C.A.  Hoppert,  B.V. Alfredson and  R.U.  Byerrum.
         1961.   Chronic toxicity studies:   III.   Chronic toxicity of cadmium and
         chromium in dogs.   Arch.  Environ. Health.   3:456-460.

    Arrington,  L.R.  1972.   The  laboratory animals.   In:   Introductory  laboratory
         animal science.  The  breeding,  care and  management of experimental
         animals.  Interstate  Printers  and  Publishers,  Danville,  IL.  pp.  9-11.

    Burrows,  D.  1978.  Chromium and  the skin.  Br.  J.  Dermatol.   99:587-595.

    Collins,  R.J.,  P.O. Fronm  and W.D.  Collings.   1961.  Chromium excretion in
         the  dog.   Am.  J. Physiol.   201:795-798.

    Davids,  H.W., and  M.  Lieber.  1951.   Underground water  contamination  by chromium
         wastes.   Water Sewage Works.   98:528-534.

    Donaldson,  R.M., Jr., and  R.F.  Barreras.  1966.   Intestinal  absorption of
         trace  quantities of chromium.   J. Lab. Clin. Med.  68:484-493.

    Fox,  K.R.  (No Date).   Removal of inorganic contaminants  from drinking water
         by reverse osmosis.  U.S.  Environmental  Protection Agency (unpublished).

    Gentile,  J.M.,  K.  Hyde  and J.  Schubert.   1981.   Chromium  genotoxicity as
         influenced by complexation  and  rate effects.   Toxicol.  Lett.  7:439-445.

    Gray,  S.J., and K. Sterling.  1950.   The tagging of red cells and plasma
         proteins with radioactive  chromium.  J.  Clin.  Invest.  29:1604-1613.

    Gross,  W.G.,  and V.G. Heller.   1946. Chromates  in  animal  nutrition.   J. Ind,
         Hyg. Toxicol.   28:52-56.

    Gruber,  J.E.,  and  K.W.  Jennette.   1978.   Metabolism of  the carcinogen chromate
         by rat liver  microsomes.   Biochem.  Biophys. Res. Commun.  82:700-706.

    Hartford, W.H.  1979.   Chromium  compounds.  In;   M. Grayson  and  D.  Eckroth,
         eds.   Kirk-Othmer  encyclopedia  of chemical  technology,  Vol.  6.   New
         York,  NY:  John Wiley and  Sons. pp. 82-120.

    Hayes,  R.B.,  A.M.  Lilienfeld and  L.M. Snell.   1979.  Mortality in chromium
         chemical production workers:   a prospective study.  Int. J.  Epidemiol.
         8:365-374.

    Hem,  J.D.   1970.   Study  and  interpretation of  the chemical characteristics of
         natural water, 2nd ed.   U.S. Geological  Survey Water-Supply Paper 1473.
         p. 199.

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                                      -15-
Hopkins, L.L.   1965.  Distribution in the rat of physiological amounts of
     injected Cr51(III) with time.  Am. J. Physiol.   209:731-735.

Hopkins, L.L., and K. Schwarz.  1964.  Ch
     specifically siderophilin.   Biochem. Biophys. Acta

IARC.   1982.  International Agency for Research on Cancer.  IARC monographs on
     the evaluation of the carcinogenic risk of chemicals  to humans.   Suppl.
     4: 133-135.

Her, R.K.  1954.  Process for the production of Verner type chromium complexes.
     U.S. Patent No. 2,683,156.

Ivankovic, S., and R. Preussman.  1975.  Absence of toxic and carcinogenic
     effects after administration of high doses of chromic oxide pigment in
     subacute and long term feeding experiments in rats.  Food Cosmet. Toxicol.
     1 3:347-351.

Johnston, J.K., and H.S.  Lim.  1978.  Removal of persistent contaminants from
     municipal effluents by reverse osmosis.  Environmental Protection Service,
     Environment Canada.

Kraintz, L., and R.V. Talmage.  1952.  Distribution of radioactivity following
     intravenous administration of trivalent chromium-51 in the rat and
     rabbit.  Proc. Soc.  Exp. Biol. Med.  81:490-492.

Love, C.H.  1947.  German production of some of the more important inorganic
     pigments.  Washington, DC:  Hobart Publishing Co.  pp. 47-63.

MacKenzie, R.D., R.U. Byerrum, C.F. Decker,  C.A. Hoppert and R.F. Langham.
     1958.  Chronic toxicity studies.  II.  Hexavalent and trivalent chromium
     administered in drinking water to rats.  AMA Arch. Ind. Health.  18:232-234.

Majone, F., and D. Rensi.  1979.  Mitotic alterations, chromosome aberrations
     and sister chromatid exchanges induced by hexavalent and trivalent
     chromium on mammalian cells in vitro.  Caryologia.  32:379-392.

Mertz, W., E.E. Roginski and R.C. Reba.  1965.  Biological activity and fate
     of trace quantities  of intravenous chromium (III) in the rat.  Am. J.
     Physiol.  109:489-494.

Mertz,  W., E.E. Roginski,  F.J. Feldman and D.E.  Thurman.  1969.  Dependence
     of chromium transfer into the rat embryo on the chemical form.  J. Nutr.
     99:363-367.

Mertz,  W., and E.E. Roginski.  1971.  Chromium metabolism:  The glucose
     tolerance factor.  In;  W. Mertz and W.E. Cornatzer, eds.  Newer trace
     elements in nutrition.  New York, NY:   Marcel Dekker.  pp. 123-151.

Mertz, W.  1976.  Chromium and its relation to carbohydrate metabolism.  In;
     R.E. Burch and J.F.  Sullivan, eds.  Symposium on trace elements.  Med.
     Clin. North Am.  60:739-744.

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                                     -16-
Mertz, W., R.A. Anderson, W.R. Wolf and E.E. Roginski.  1978.  Progress in
     chromium nutrition research.  In:  M. Kirchgessner, ed.  Trace element
     metabolism in man and animals.  Proc. Third Int. Symp. Freising, July,
     1977.  pp. 272-278.

Miller, W.S., and A.B. Mindler.  1978.  Ion exchange separation of metal ions
     from water and waste waters.  Permutit R&D Center.

Miller, W.S.  1978.  Removal and recovery of chromates from cooling tower
     blowdown.  In:  Ion Exchange for Pollution Control, Vol. I.  CRC Press,
     Inc.

Mixon, F.O.  1973.  The removal of toxic metals from water by reverse osmosis.
     U.S. Department of the Interior, INT-OSWRDPR-73-899.

NAS.   1974.  National Academy of Sciences.  Water quality criteria 1972.
     Washington, DC:  National Academy Press,  p. 62.

NAS.   1980a.  National Academy of Sciences.  Recommended dietary allowances,
     9th rev. ed.  Washington, DC:  National Academy Press,  pp. 159-161.

NAS.   1980b.  National Academy of Sciences.  Drinking Water and Health.
     Volume  3.  Washington, DC:  National Academy Press,  pp. 266, 364-369,
     374-375.

NIOSH.  1975.  National Institute for Occupational Safety and Health.  Occu-
     pational exposure to chromium VI.  Criteria document HEW(NIOSH).  76-129.

NIOSH.  1983.  National Institute for Occupational Safety and Health.  Registry
     of Toxic Effects of Chemical Substances (RTECS).  Vol. 2, p. 72.

OSHA.  1985. Occupational Safety and Health Administration.  Code of Federal
     Regulations.  Title 29 - Labor.  Part 1910 - Occupational Safety and
     Health Standards.  Subpart Z - Toxic and Hazardous Substances.  Section
     1910.1000 - Air Contaminants.  U.S. Government Printing Office,
     Washington, DC.

Patterson, J.w.  1975.  Wastewater Treatment Technology.  Ann Arbor Science
     Publisher, Inc.

Petrilli, F.L., and S. De Flora.  1978.  Oxidation of inactive trivalent
     chromium to the mutagenic hexavalent form.  Mutat. Res.  58:167-173.

Raffetto, G., S. Parodi, C. Parodi, M. DeFarrari, R. Troiano and G. Brambilla..
      1977.   Direct interaction with cellular targets as the mechanism for
     chromium carcinogenesis.  Tumori.  63:503-512.

Richardson,  E.W., E.D. Stobbe et al.  1968.  Ion exchange traps chromates  for
     reuse.  Environmental Science and Technology.  2(11):1006-16.

Rohm and  Haas Co.  1980.  Amber lite Ion Exchange Resins.  Technical Bulletins
     for IR-120 and IRA-402.

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Chromium                                                  March 31, 1987

                                     -17-
Schroeder, H.A., J.J. Balassa and W.H. Vinton, Jr.  1965.  Chromium, cadmium
     and lead in rats:  Effects on life span, tumors and tissue levels.
     J. Nutr.  86:51-66.

Schroeder, D.C., and G.F. Lee.  1975.  Potential transformations of chromium
     in natural waters.  Water Air Soil Pollut.  4:355-365.

Smyth, H.F., C.P. Carpenter, C.S. Weil, U.C. Pozzani, J.A. Striegel and
     J.S. Nycum.  1969.  Range finding toxicity data:  List  VII.  Am.  Ind.
     Hyg. Assoc. Journal.   30:470.

Sorg, T.J.  1979.  Treatment technology to meet the interim primary drinking
     water regulations for  inorganics:  part 4.  JAWWA.  71(8):454-66.

Sussman, S., F.C. Nachod et al.  1945.  Metal recovery by anion exchange.
     Industrial and Engineering Chemistry.  37(7):618-22.

U.S. EPA.  1976.  U.S. Environmental Protection Agency.  National interim
     primary drinking water regulations.  EPA 570/9-76-003.  Washington, DC:
     pp. 63-64.

U.S. EPA.  1977.  U.S. Environmental Protection Agency.  Manual of treatment
     techniques for meeting the interim primary drinking water regulations,
     revised.  EPA-600/8-77-005.

U.S. EPA.  1979a.  U.S. Environmental Protection Agency.  Method 218.1.  Atonic
     Absorption, direct aspiration.  In:  Methods for Chemical Analysis of
     Water and Wastes.  EPA-600/4-79-020,  March, 1979.

U.S. EPA.  1979b.  U.S. Environmental Protection Agency.  Method 218.2.  Atomic
     Absorption, furnace technique.  In:  Methods for Chemical Analysis of
     Water and Wastes.  EPA-600/4-79-020,  March, 1979.

U.S. EPA.  1980.  U.S. Environmental Protection Agency.  Ambient water
     quality criteria for chromium.  EPA 440/5-80-035.  Washington, D.C.

U.S. EPA.  1982.  U.S. Environmental Protection Agency.  Personal communication.
     Municipal Environmental Research Laboratory.

U.S. EPA.  1983.  U.S. Environmental Protection Agency.  Health assessment
     document for chromium.  Review Draft.  EPA 600/8-82-014A.  Washington, D.C,

U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Health Effects
     Criteria Document for C' romium.  Criteria and Standards Division.  Office
     of Drinking Water.  Washington, DC.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogen risk assessment. Federal Register.  51(185):33992-34003.
     September 24.

U.S. EPA.  1987.  U.S. Environmental Protection Agency.  Estimated national
     occurrence and exposure to chromium in public drinking water supplies.
     CSD.  Office of Drinking Water.

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Chromium                                                    March  31,  1987

                                     -18-
U.S. PHS.  1962.  U.S. Public Health Service.  Drinking water standards.
     U.S. Public Health Service Publication No. 956.  Washington, DC:  U.S.
     Government Printing Office, pp. 36-39.

Warren, G., P. Schultz, D. Bancroft, K. Bennett,  E.H. Abbot and S. Rogers.
     1981.  Mutagenicity of a series of hexacoordinate chromium  (III) com-
     pounds.   Mutation Res.  90:111-118.

Weast, R.C., ed. 1971.  Handbook of Chemistry and Physics. 52nd ed. CRC  Press
     Cleveland, OH pp. B-65,  B-83-84,  B-1 22, B-137.

Windholz, M., ed.  1976.  The Merck Index:  An encyclopedia of chemicals and
     drugs, 9th ed.  Rahway,  NJ:  Merck and Co.,  Inc.  pp. 228-289.

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                                                           March 31,  1987
                                      CYANIDE

                                  Health Advisory
                              Office of Drinking Water
                        U.S.  Environmental  Protection Agency
I. INTRODUCTION

        The Health Advisory  (HA)  Program,  sponsored  by  the  Office  of  Drinking
   Water (ODW),  provides  information on the health effects, analytical method-
   ology and treatment  technology that would be  useful  in dealing  with the
   contamination of  drinking water.   Health Advisories  describe  nonregulatory
   concentrations of drinking water  contaminants at  which adverse  health effects
   would not be  anticipated  to  occur over  specific exposure durations.  Health
   Advisories  contain a margin  of safety to protect  sensitive  members of the
   population.

        Health Advisories  serve as informal technical guidance to  assist Federal,
   State and local officials responsible for protecting public health when
   emergency spills  or  contamination situations  occur.   They are not  to be
   construed as  legally enforceable  Federal standards.   The HAs  are subject to
   change as new information becomes available.

        Health Advisories  are developed for One-day, Ten-day,  Longer-term
   (approximately 7  years, or 10% of an individual's lifetime) and Lifetime
   exposures based on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not  quantitatively incorporate  any  potential  carcinogenic
   risk  from such exposure.   For  those substances that  are  known or probable
   human carcinogens, according to the Agency classification scheme (Group A  or
   B), Lifetime  HAs  are not  recommended.  The chemical  concentration  values for
   Group A or  B  carcinogens  are correlated with  carcinogenic risk  estimates by
   employing a cancer potency (unit  risk)  value  together with  assumptions for
   lifetime exposure and  the consumption of drinking water. The cancer unit
   risk  is usually derived from the  linear multistage model with 95%  upper
   confidence  limits.   This  provides a low-dose  estimate of cancer risk to
   humans that is considered unlikely to pose a  carcinogenic risk  in  excess
   of the stated values.   Excess  cancer risk estimates  may  also  be calculated
   using the One-hit, Weibull,  Logit or Probit models.   There  is no current
   understanding of  the biological mechanisms  involved  in cancer to suggest that
   any one of  these  models is able to predict risk more accurately than another.
   Because each  model is based  on differing assumptions,  the estimates that are
   derived can differ by  several  orders of magnitude.

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    Cyanide                                                  March  31,  1987

                                         -2-
         This Health Advisory  (HA)  is  based  on information  presented  in the Office
    of Drinking Water's Health Effects Criteria Document (CD)  for cyanide (U.S.
    EPA,  1985).  The HA and  CD formats are similar for  easy reference.   Individuals
    desiring further information on the toxicological data  base or rationale for
    risk  characterization should consult the CD.   The CD is available for review
    at each EPA Regional Office of  Drinking  Water counterpart  (e.g.,  Water Supply
    Branch or Drinking Water Branch),  or for a fee from the National  Technical
    Information Service, U.S.  Department of  Commerce, 5285  Port Royal Rd.,
    Springfield,  VA 22161, PB  # 86-117793/AS.  The toll free number is  (800)
    336-4700; in the Washington, D.C.   area:  (703) 437-4650.


II. GENERAL INFORMATION AND  PROPERTIES

         0  Cyanides are a group of organic  and inorganic compounds that contain
            the cyano (CN) group.  Free cyanide is defined  as  the sum of cyanide
            present as HCN and as CN~.  The  organic cyanides are called nitriles
            and few of them  dissociate to yield CN~ or  HCN. In this  Health
            Advisory, only a few widely used industrial inorganic cyanides will
            be discussed.

    CAS No.

         0  Hydrogen Cyanide — 74-90-8
            Sodium Cyanide —  143-  33-9
            Potassium Cyanide  — 151-50-8

    Synonyms

         0  Hydrogen Cyanide:  Prussic  Acid

    Uses   (U.S. EPA, 1985)

         0  Cyanide is used  in rat  and pest  poisons,  silver and metal polishes,
            photographic solutions, fumigating products, in the production of
            various resins such as  acrylates, methyl acrylate  and nitriles and
            in electroplating.

         0  Although there are a number of organic and  inorganic compounds that
            contain the CN group, in this document only a few  widely  used indus-
            trial inorganic  cyanides will be considered.

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     Cyanide
                            March 31, 1987
                                          -3-
     Properties  (Weast,  1980;  Towill et al., 1978)

          0  The properties  of  cyanide compounds  vary with the specific compound;
             some examples are  as follows:
     Chemical Formula
     Molecular Weight
     Physical State
Hydrogen
Cyanide

HCN
27.03
colorless gas
or liquid
25.70°C
-13.24°C
0.688 (20°C)
     Boiling Point
     Melting Point
     Densi ty {g/cm 3)
     Vapor Pressure              —
     Water Solubility (g/100 mL)  miscible
     Octanol/Water               0.66
       Partition Coefficient
     Taste Threshold
     Odor Threshold
     Conversion Factor           1.123
Sodium
Cyanide

NaCN
49.01
colorless solid

14.96°C
563.7°C
1.60-1.62

48 (10°C)
-0.44
                  2.037
Potassium
Cyanide

KCN
65.12
colorless solid
634.5°C
1.553 (20°C)

71.6 (20°C)
                  2.707
     Occurrence
             In 1978,  cyanide  production in  the United  States  exceeded  700 million
             pounds.  Cyanide  wastes are released from  the pyrolysis  of natural and
             synthetic materials  (Towill et  al.,  1973).

             Despite numerous  potential sources of pollution,  cyanide is relatively
             uncommon in U.S.  drinking water.   In 1970, a  survey of  969 water
             supplies failed to reveal cyanide  concentrations  above  0.2 mg/L.  Of
             2,595 samples examined, the highest cyanide concentration  found was
             8 ug/L and the average concentration was 0.09 ug/L (McCabe et al.,
             1970).
III. PHARMACOKINETICS
     Absorption
             Free  cyanides  are  absorbed  readily  from  the  lungs,  the  gastrointestinal
             tract and the  skin by animals  and humans.   Inhalation exposure to
             HCN provides the most rapid route of  entry  (U.S.  EPA, 1985).

             Dogs  treated with  KCN at single gavage doses equivalent to 20, 50
             and 100 mg HCN (1.57,  4.42  or  8.40  mg HCN/kg bw)  absorbed 72%, 24%
             and 16.6%, respectively, through the  GI tract (Gettler  and Baine, 1938)
             The dogs died  within 155,  21 and 8  minutes,  respectively, after dosing.

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Cyanide                                                 March 31,  1987

                                     -4-


Distribution

     0  Once cyanide is absorbed,  it is distributed rapidly by the blood
        throughout the body.  Distribution patterns vary with the route of
        exposure (U.S. EPA, 1985).

     0  High levels of cyanide were found in brains and livers of 3 human
        subjects who ingested fatal doses of cyanide (Gettler and Baine, 1938).

     0  In rabbits, intramuscular injection of HCN gave higher levels of CN
        in blood and tissues than did KCN administration (Ballantyne et al.,
        1972).

     0  When radiolabeled KCN (5 mgAg) was administered orally to rats over
        24 hours, a rapid decline of radioactivity from whole blood and plasma
        was observed with a small increase in the levels in erythrocytes
        (Farooqui and Ahmed, 1982).  The majority of the radioactivity in the
        erythrocytes (94.3%) was found in the hemolysate rather than the
        membranes.  The heme fraction contained 70% of the radioactivity while
        14 to 25% and 5 to 10% were found in the globin and cell membrane,
        respectively.

     0  Cyanide does not accumulate in blood and tissues following chronic
        exposure.  Virtually no cyanide was found in the plasma or kidneys of
        rats treated with dietary concentrations of 100 and 300 ppm (mgAg
        diet) for two years (Howard and Hanzal, 1955).  Low levels were found
        in erythrocytes (mean of 1.97 ug).  Increased levels of~ thiocyanate
        were found in plasma (1123 ug), erythrocytes (246 ug), liver (665 ug)
        and kidney (1188 ug).

     0  Yamamoto et al. (1982)  found that rats on oral (gavage) exposure to
        cyanide (NaCN) (7 and 21 mg CN/kg/bw) showed higher levels of cyanide
        in lungs and liver compared to blood.  On inhalation exposure to HCN
        at concentrations of 356 and 1,180 ppm (392 and 1,298 mg/m3), concen-
        tration in the lungs exceeded that in the blood.

Metabolism

     0  Cyanide is detoxified by an intramitochondrial enzyme, rhodanese,
        which catalyzes the transfer of sulfur from a donor to cyanide to form
        the less toxic thiocyanate.  Rhodanese is widely distributed throughout
        the body; high doses are found in the liver (U.S. EPA, 1985).

     0  Other minor detoxification pathways include spontaneous reaction with
        cystine to form 2-imino-4-thiozolidene carboxylic acid and with hydroxy-
        cobalamine to form cyanocobalamine - i.e. vitamin B-|2 (U.S. EPA, 1985) =
Excretion
        The major route of cyanide elimination is as the thiocyanate in the
        urine, although some cyanide enters the metabolism of one-carbon
        compounds and C02 is eliminated in expired air.  A small amount of
        HCN is eliminated in expired air (U.S. EPA,  1985).

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    Cyanide
March 31, 1987
                                         -5-
            Rats eliminated 80% of subcutaneously-injected cyanide as thiocyanate
            in the urine,  while 15% was eliminated as urinary 2-imino-thiozolidine
            carboxylic  acid (Wood and  Cooley,  1956).

            A man who had  ingested 3 to 5 g KCN (at least 1 .2 g HCN was present in
            the blood 3 hours  later) eliminated a total of 237 mg thiocyanate in
            72-hour urine  (Liebowitz and Schwartz, 1948).
IV. HEALTH EFFECTS
    Humans
            The enzyme  cytochrome  oxidase enables  cells  to utilize oxygen.
            Cyanide inhibits this  enzyme thus resulting  in effective cellular
            anoxia (U.S.  EPA,  1985).
            Acute exposure  to  cyanide  by  the oral  route has  usually  occurred from
            suicide attempts (NIOSH,  1976).   Signs of acute  poisoning by cyanide
            include rapid breathing, gasping,  tremors,  convulsions and death
            (DiPalma,  1971).

            The fatal  oral  doses  of cyanide  compounds range  from 50  to 200 mg (0.7
            to 2.9 mg  CN'/kg 'bw)  (U.S. EPA,  1985).  Within 20 minutes of ingestion
            of fatal doses,  events progress  from hyperventilation, vomiting,
            unconsciousness, convulsions,  rapid and irregular heart  rate,  gasping,
            vascular collapse  and cyanosis,  to death.

            Although data regarding chronic  oral exposure of humans  to HCN,  KCN
            or NaCN are not available,  there are a number of reports on the etiology
            of thyroid disorders  and  neuropathies  characterized by optic atrophy,
            nerve deafness  and spinal  ataxia in people living in certain tropical
            areas of Africa where the  staple diet  consists largely of cassava.
            Cassava contains a high level  of the cyanogenic  glycoside,  linamarin,
            which releases  cyanide on  metabolism or acid hydrolysis  in vivo
            (Osuntokun et al., 1969; Makene  and Wilson,  1972).

            Case studies and epidemiological studies of case-hardeners, electro-
            platers, metal  polishers,  photographic material  workers  and HCN
            fumigators have revealed effects in workers typical of sublethal
            cyanide poisoning,  including headache,  dizziness and thyroid enlarge-
            ment (NIOSH, 1976).
    Animals
    Short-term  Exposure
            The  acute  oral LD5Q  for  KCN was  10  mgAg  (4  mg CN~/*g)  in  rats  (Hayes,
            1967;  Gaines, 1969)  and  8.5 mg KCN/kg  (3.4 mg CN~/*g)  in mice  (Sheehy
            and  Way,  1968).   The LD5Q  of  intraperitoneally administered NaCN for
            mice was  3.2  mg CN~/kg  (Kruszyna et al.,  1982).

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Cyanide                                                 March 31,  1987

                                     -6-
        Mice administered 1  or 2 mg KCN/kg (0.4 or 0.8 mg/CN~/kg) intra-
        peritoneally showed minimal or no effects, while 3 to 5 mg KCN/kg
        (1.2-2.0 mg CN~/kg)  resulted in signs of toxicity (convulsions,  agi-
        tation) (Isom et al., 1982).  A dose of 6 mg KCN/kg (2.4 mg CN~/*g)
        resulted in 20% mortality.

        Doses that are fatal to one species may be harmless to others.  An
        oral dose of 3.8 mg KCN/kg (1.5 mg CN-/kg) was fatal to a dog in 155
        minutes (Gettler and Baine, 1938) but a higher dose of 8 mg KCN/kg
        (3.2 mg CN~/kg), equal to the ^050 in mice, had only minimal effects
        on guinea pigs  (Basu, 1983).

        Rats tolerated higher doses of cyanide (80 mg CN~/kg bw/day) when
        mixed in the diet (Kreutler et al., 1978) than when administered by
        gavage (4.0 mg CN~/kg bw)  (Ferguson,  1962).

        Rats tolerated 25 daily doses of 1 0 mg KCN/kg bw (4 mg CN-/kg bw)
        when the chemical was mixed in the diet; each of these doses was
        equal to the acute oral LDsg (Hayes,  1967).
        Rats tolerated higher oral doses of KCN (approximately 30 mg KCN/kg
        bw/day or 1 2 mg CN~/kg bw/day for 21 days) when administered in
        drinking water (Palmer and Olsen, 1979) than when KCN was administered,
        in a bolus (approximately 10 mg/kg bw KCN; 4.5 mg CN~/kg bw) by
        gavage with water as the vehicle (Hayes, 1967; Gaines, 1969).

        Rats receiving approximately 12 mg CN-/kg bw/day for 21  days in
        drinking water had significantly increased liver weights compared
        with controls, while rats receiving approximately 8 mg CN~/kg bw/day
        in the diet did not (Palmer and Olsen, 1979).

        Beagle dogs  consuming 3 mg CN-/kg bw/day in the diet for 30 days showed
        no clinical  signs of toxicity,  effects on body weight, hematology or
        histopathologic lesions (American Cyanamid Co., 1959).
Long-term Exposure
        Animals can tolerate higher doses of cyanide when administered in the
        diet or in the drinking water during longer-term exposures (Hayes,
        1967; Palmer and Olsen,  1979) than as a bolus dose by gavage.

        Pigs (sows) maintained on diets containing cyanide (30.3,  276.6
        and 520.7 mg CN~/kg diet) throughout gestation and lactation
        showed hyperplasia of kidney glomerular cells and accumulation
        of colloid and morphological changes in follicular cells of the
        thyroid (Tewe and Maner,  1981b). (See also discussion under
        Developmental Effects, below.)

        Weanling rats maintained on a diet containing 1,500 ppm KCN for 11.5
        months (approximately 30 mg CN-/kg bw/day) had a significantly reduced
        body weight gain, increased excretion of thiocyanate at 4  months
        and at 11 months, decreased plasma thyroxine levels, and decreased
        thyroxine secretion rates at 4 months (Philbrick et al., 1979).  The

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Cyanide                                                 March  31,  1987

                                      -7-
        effects appeared to be greater in the animals on  the vitamin B-j 2~ and
        methionine-deficient diet.  There were no definitive histopathologic
        lesions in the optic or CNS tissues, thyroid or sciatic tissues;
        however, vacu'olization and myelin degeneration were observed in
        spinal cord sections.

      0  Dogs receiving _>. 0.27 mg CN-/k9 bw/day, administered in a capsule for
        15 months, had degenerative changes in ganglion cells of the CNS
        (Hertting et al.,  1960).  These effects may be due to the fact  that
        CN- was administered in a capsule (similar to a bolus dose by gavage).

      0  Rats maintained for 104 weeks on diets that had been fumigated with
        HCN to give average dose levels of 76 mg/kg diet  and 190 mg/kg diet
        (i.e., approximately 3.6 and 7.5 mg CN~/kg bw/day for males and
        4.6 and 10.8 mg CN~/kg bw/day for females) resulted in no effects
        clinically or histologically (Howard and Hanzel,  1955).  The only
        effects of treatment were increased CN~ levels in the red blood
        cells, increased thiocyanate levels in the plasma, red blood cells,
        liver and kidneys of animals from both treatment groups.

Reproductive Effects

      0  No effects were seen on the reproductive performance of pregnant rats
        fed 500 mg CN~/k9 diet (KCN) through gestation and lactation (Tewe
        and Maner, 1981a).  Offspring that were continued on the test diet
        after weaning consumed less food and grew at a significantly reduced
        rate compared to control offspring.

Developmental Effects

      0  Severe teratogenic effects were seen in hamsters administered cyanide
        by subcutaneously implanted osmotic minipumps that delivered cyanide
        at a rate of 3.3-3.4 mg CN-/kg bw/hour (79.2-81.6 mg CW/kg bw/day)
        from day 6-9 of gestation (Doherty et al., 1982).

      0  Piglets born to pigs maintained on diets containing cyanide (30.3,
        276.6 and 520.7 mg CN~/^9 diet) throughout gestation and lactation
        showed reduced organ-to-body weight ratios of the thyroid,  spleen and
        heart in the high and/or medium dose groups relative to the low-dose
        group piglets (Tewe and Maner, 1981b). (See also discussion under
        Long-term Exposure, above.)

Mutagenicity

      0  Potassium cyanide was  not mutagenic  in Salmonella typhimurium with or
        without metabolic activation (De Flora,  1981).

      0  A  study using HCN gas  reported marginally  mutagenic activity in
        S_._  typhimurium strain TA100 (Kushi,  1983).  Addition of S-9 mix
        decreased the mutagenic activity.

      0  Cyanide was negative in a modified rec assay in Bacillus subtilis
        (Karube et al.,  1981).

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   Cyanide                                                 March 31,  1987

                                        -8-


   Carcinogenicity

        0  No information was located in the available literature on the
           carcinogenicity of cyanides.

V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories (HAs)  are generally determined for One-day,  Ten-day,
   Longer-term (approximately 7 years) and Lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following formula;

                 HA = JNOAEL or LOAEL) x (BW) = 	 mg/L (	 ug/L)
                        (UF) x (	 L/day)

   where:

           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effeet-Level
                            in mg/kg bw/day.

                       BW = assumed body weight of a child (10 kg)  or
                            an adult (70 kg).

                       UF = uncertainty factor (10,  100 or 1,000),  in
                            accordance with NAS/ODW guidelines.

                	L/aay = assumed daily water consumption of a child
                            (1 L/day) or an adult (2 L/day).

   One-day Health Advisory

        The available data are insufficient to develop a One-day HA for cyanide.
   It is recommended that the modified DWEL of 0.22 mg/L (adjusted  for the 10-kg
   child) be used as the One-day HA for the 10-kg child.

   Ten-day Health Advisory

        While the study by Palmer and Olsen (1979) was considered as  the basis
   for the Ten-day HA,  it is recommended that the modified DWEL of  0.22 mg/L
   (adjusted for a 10-kg child)  be used as the Ten-day HA for the 10-kg child.
   The NOAEL observed by Howard  and Hanzal (1955) in a two-year rat study (which
   serves as the basis for the DWEL and Lifetime HA) was 10.8 mgAg/day, in good
   general agreement with the NOAEL of 8 mg/kg/day observed by Palmer and Olsen
   (1979) in a 21-day rat study.  As the NOAELs in the two studies  were little
   different and as greater confidence was placed in the Howard and Hanzal (1955)
   study, it was determined that it was appropriate to use the modified DWEL as
   the Ten-day HA.

   Longer-term Health Advisory

        The available data are insufficient to develop Longer-term HAs for cyanide
   It is recommended that the DWEL of 0.77 mg/L be used as the Longer-term HA
   for the 70-kg adult and the modified DEWL of 0.22 mg.L (adjusted for a 10-kg
   child) be used as the Longer-term HA for the 10-kg child.

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Cyanide                                                 March 31, 1987

                                     -9-


Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The Lifetime HA
is derived in a three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime,  and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD,  a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual exposure data or,  if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA,  1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     The study of Howard and Hanzal (1955)  has been selected to serve as the
basis for the DWEL and Lifetime HA.  In this study, rats were maintained for
104 weeks on diets that had been fumigated  with HCN to give average dose
levels of 76 or 190 mg/kg diet (i.e., approximately 3.6 and 7.5 mg/kg/day for
male rats and 4.6 and 10.8 for female rats).  No clinical or histological
effects were observed at either dose level.

     Using the NOAEL of 10.8 mg/kg/day, the DWEL and Lifetime HA are derived
as follows:

Step 1:  Determination of the Reference Dose (RfD)

                  RfD = (10.8 mg/kg/day) =  0.022 mgAg/day *
                           (100) (5)              ^  y/

* NB:  The RfD is in good general agreement  with the observation (NIOSH, 1976)
      that 1 mg HCN/m^ is without effect in humans  via inhalation.
where:
        10.8 mgAg/day = NOAEL for absence of clinical and histological effects
                         in rats exposed to HCN in the diet for 104 weeks.

                   100 = uncertainty factor,  chosen in accordance with NAS/ODW
                         guidelines for use with a NOAEL from an animal study.

                     5 = additional uncertainty factor selected to allow for
                         possibly greater absorption of cyanide from water
                         than from the diet.

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    Cyanide                                                 March 31,  1987

                                         -10-


    Step 2:  Determination of the Drinking Water Equivalent Level (DWEL)

               DWEL = (0.022 mg/kg/day) (70 kg) = 0>77 mg/L (770 ug/L)
                              (2 L/day)

    where:

            0.02 mq/kg/day = RfD.

                     70 kg = assumed body weight of an adult.

                   2 L/day = assumed daily water consumption of an adult.

    Step 3:  Determination of the Lifetime Health Advisory

         The DWEL of 770 ug/L assumes that 100% of the exposure to cyanide is
    via drinking water.  It is probable,  however, that exposure occurs via other
    routes.  Therefore,  if one assumes that drinking water contributes 20% of daily
    exposure to cyanide/ then the Lifetime Health Advisory would be 154 ug/L.
    The Lifetime HA is calculated as follows:

                      Lifetime HA = (770 ug/L) (20%) = 154 ug/L

    where:

            770 ug/L = DWEL.

                 20% = assumed relative source contribution from water.

    Evaluation of Carcinogenic Potential

         0  There is no available information  pertaining  to the carcinogenicity
            of cyanides.

         0  IARC has not calculated the carcinogenic potential  of cyanides«

         0  Applying the criteria described in EPA's final guidelines  for
            assessment of carcinogenic risk (U.S. EPA,  1986), cyanide  may  be
            classified in Group D:  Not classified.  This category is  for  agents
            with inadequate human and animal evidence of  carcinogenicity.
                                                   i

VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

         0  The ambient water quality criterion for cyanide has been proposed at
            3.77 mg/L assuming that a 70 kg human consumes 2 L  of water and 6.5 g
            of fish per day with a bioconcentration factor of  1.0 (U.S. EPA, 1982).

         0  The U.S. PHS (1962)  recommended that concentrations of cyanide in
            water supplies not exceed 0.2 mg/L in order to protect human health.
            The U.S. PHS (1962) also recommended that concentrations in drinking
            water be kept below 0.01 mg/L since this level or  lower can be achieved
            by proper treatment.

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      Cyanide                                                 March 31,  1987

                                           -11-
           0  ACGIH (1980)  has recommended a TLV for alkali cyanides in workroom air
              of 5 mg CN-/m3'

           0  NIOSH has recommended a TLV of 5 mg/m^ for CN~ which was adopted by
              OSHA (1981).
 VII. ANALYTICAL METHODS

           0  Determination of cyanide is by volumetric titration or colorimetry
              (U.S. EPA, 1979).  The cyanide as hydrocyanic acid (HCN) is released
              from cyanide complexes by means of a reflux-distillation operation
              and absorbed in a scrubber containing sodium hydroxide solution.  The
              cyanide ion in the absorbing solution is then determined by volumetric
              titration or colorimetrically.  The titration procedure uses a standard
              solution of silver nitrate and an indicator.  The detection limit is
              1  mg/L.  In the colorimetric measurement, the cyanide is converted to
              cyanogen chloride, a reagent is added to form a colored complex and
              the absorbance is measured.  The detection limit is 20 ug/L.


VIII. TREATMENT TECHNOLOGIES

           0  Several treatment technologies for the removal of cyanide are avail-
              able, although most of what has been reported in the literature
              involves wastewater applications.  The treatment of high concentrations
              of cyanide (and cyanide complexes) in industrial waste streams and
              mine drainage runoff has been studied extensively,  but only limited
              information is available on reductions of low cyanide levels in
              drinking water supplies.

           0  The general treatment technologies that may be practical for reducing
              cyanide levels in drinking water include oxidation by chlorine or
              ozone,  ion exchange and reverse osmosis.

           0  Oxidation by chlorine may be the cheapest and most practical method to
              remove  cyanide from the water.  In addition to the removal of cyanide,
              chlorine oxidation may cause secondary beneficiary effects.  These
              include disinfection of the water,  oxidation of iron and manganese,
              oxidation of taste and odor causing compounds.  Practical experience
              in the  wastewater industry and the laboratory indicate that chlorine
              oxidation is capable of removing 99% or more of the cyanide from the
              water (Gott,  1978; Smith et al., 1980).

           0  Oxidation by ozone may be used to destroy cyanide in water if the
              formation of trihalomethanes is to be avoided.  The use of ozone
              oxidation for cyanide is a relatively new technique.  Laboratory and
              pilot studies by Cullivan (Cullivan,  no date) indicated that complete
              destruction of cyanide in water required a 1.3 to 1 ozone to cyanide
              molar ratio.   These results were achieved with 5 to 15 mg/L of cyanide
              in the  influent water.  However, the results of study indicated that
              at cyanide concentrations of less than 5 mg/L, the rate of destruction
              is decreased.

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Cyanide                                                 March 31,  1987

                                     -12-
        Although reverse osmosis and ion exchange can reduce cyanide levels in
        the water, their application may not be practical in the economical
        sense if cyanide is the only contaminant to be removed.  Experience
        by Moore  (1976) and Trachtenberg et al. (1979) indicates that a
        well-designed ion exchange facility can remove over 99% of the cyanide
        present in the water.  Pilot plant studies performed by Rosehart
        (1973) treating mine-waters by reverse osmosis, resulted in cyanide
        removal ranging from 28.7 to 81.6 percent, respectively.

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    Cyanide                                                 March 31,  1987

                                         -13-


IX. REFERENCED

    ACGIH.   1980.   American Conference  of  Governmental  Industrial Hygienists.
         Documentation of the threshold limit values for substances in workroom
         air,  4th  ed.,  with supplements through  1981.   Cincinnati,  OH.   pp.  109-110.

    American Cyanamid Co.  1959.   Report on sodium cyanide:   30-day repeated
         feedings  to dogs.   Central Med.  Dept.   Report  Number 59-14.

    Ballantyne,  B., J.  Bright,  D.W.  Swanston and P.  Williams.  1972.   Toxicity
         and distribution of free  cyanides given intramuscularly.  Med.  Sci. Law.
         12:209-219.

    Basu, T.K.   1983.   High-dose ascorbic  acid decreases detoxification  of cyanide
         derived from amygdalin (laetrile):   studies in guinea pigs.   Can. J.
         Physiol.  Pharmacol.  61(11):1426-1430.

    Cullivan,  B.M. No date .  Industrial Toxics  Oxidation:   An Ozone-Chlorine  Compar-
         ison.   Presented at the 33rd Purdue Industrial Waste Conference.

    De Flora,  S.  1981.  Study  of  106 organic and inorganic  compounds  in the
         Salmonella/microsome test.   Carcinogenesis.  2(4):283-298.

    DiPalma, J.R., ed.   1971.  Noxious  gases and vapors:   I.   Carbon monoxide,
         cyanides, methemoglobin and  sulfhemoglobin.  In;  Drill's  Pharmacology
         in Medicine.   McGraw-Hill Book Co.,  NY.  pp. 1189-1205.

    Doherty,  P.A., V.H. Perm and R.P.  Smith.   1982.  Congenital malformations
         induced by infusion of sodium cyanide in the golden  hamster.  Toxicol.
         Appl. Pharmacol.  64:456-464.

    Farooqui, M.Y.H., and A.E.  Ahmed.   1982.  Molecular interaction of acrylonitrile
         and potassium  cyanide  with rat blood.   Chem. Biol.  Interact.   38:145-159.

    Ferguson,  H.C.  1962.  Dilution of  dose  and  acute oral toxicity.   Toxicol.
         Appl. Pharmacol.  4:759-762.

    Gaines,  T.B.  1969.  Acute  toxicity of pesticides.   Toxicol.  Appl. Pharmacol.
         14:515-534.

    Gettler,  A.O.,  and  J.O.  Baine,  1938.  The toxicology of  cyanide.  Am.  J.  Med.
         Sci.  195:182-198.

    Gott, R.D.   1978.   Development of  waste  water treatment at the Climax  Mine.
         Mining  Congress Journal 64(4):28-34.

    Hayes,  W.T.   1967.   The  90-dose LD50 and  a chronicity factor  as measurer of
         toxicity.  Toxicol. Appl.  Pharmacol.  11:327-335.

    Hertting, G.,  0. Kraupp,  E. Schnetz  and  S. Wieketich.  1960.   Untersuchungen
         uber die  Folgen einer  chronischen Verabreichung akut toxischer  Dosen  von
         Natriumcyanid  an Hunden.  Acta. Pharmacol.  Toxicol.   17:27-43.

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Cyanide                                                 March 31, 1987

                                     -14-
Howard, J.W., and R.F. Hanzal.  1955.  Chronic toxicity for rats of food
     treated with hydrogen cyanide.  J. Agric. Food Chem.  3s325-329.

Isom, G.E., G.E. Burrows and J.L. Way.  1982.  Effect of oxygen on the
     antagonism of cyanide intoxication-cytochrome oxidase, in vivo.
     Toxicol. Appl. Pharmacol.  65(2):250-256.

Karube, I., T. Matsunaga, T. Nakahara, S. Suzuki and T. Kata.   1981.  Pre-
     liminary screening of mutagens with a microbial sensor.  Anal. Chem.
     53(7):1024-1026.

Kreutler, P.A., V. Varbanov, W. Goodman,  G. Olaya and J.B. Stanbury.  1978.
     Interactions of protein deficiency,  cyanide and theocyanate on thyroid
     function in neonatal and adult rats.  Am. J. Clin. Nutrit.  31:282-289.

Kruszyna, R., H. Kruszyna and R.P. Smith.  1982.  Comparison of hydroxylamine,
     4-dimethylaminophenol and nitrite protection against cyanide poisoning
     in mice.  Arch. Toxicol.  49:191-202.

Kushi,  A., T. Matsumoto and D. Yoshida.  1983.  Mutagen from the gaseous
     phase of protein pyrolyzate.  Agric. Biol. Chem.  47(9):1979-1982.

Liebowitz, D., and H. Schwartz.  1948. Cyanide poisoning:  Report of a case
     with recovery.  Am. J. Clin. Pathol.  18:965-970.

Makene, W.J., and J. Wilson.  1972.  Biochemical studies in Tanzanian patients
     with ataxic tropical neuropathy.  J. Neurol. Neurosurg. Psychiatry.
     35:31-33.

McCabe, L.J., J.M. Symons, R.D. Lee and G.G. Robeck.  1970.  Survey of com-
     munity water supply systems.  J. AWWA.  62:670-687,

Moore,  F.L.  1976.  An improved ion exchange resin method for  removal and
     recovery of zinc cyanide and cyanide from electroplating wastes.
     J. Environ. Sci. Health.  7:459-467.

NIOSH.  1976.  National Institute for Occupational Safety and  Health.  Criteria
     for a recommended standard...occupational exposure to hydrogen cyanide and
     cyanide salts (NaCN, KCN and Ca(CN)2).  NIOSH Publ. No. 77-108.  Dept.
     Health, Educ. & Welfare.  U.S. Govt. Printing Office, Washington, D.C.

OSHA.  1981.  Occupational Safety and Health Administration.  General Industry
     OSHA Safety and Health Standards (29 CFR 1910).  OSHA 2206.  U.S. Dept.
     of Labor, Washington, D.C.

Osuntokun, B.O., G.L. Monekosso and J. Wilson.  1969.  Relationship of a
     degenerative tropical neuropathy to diet, report of a field study.  Br.
     Med. J.  1:547-550.

Palmer, I.S., and O.E. Olson.  1979.   Partial prevention by cyanide of selenium
     poisoning in rats.  Biochem. Biophys. Res. Commun.  90(4):1379-1386.

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Cyanide                                                 March 31, 1987

                                     -15-
Philbrick, D.J., J.B. Hopkins, D.C. Hill, J.C. Alexander and R.G. Thomson.
     1979.  Effects of prolonged cyanide and thiocyanate feeding in rats.
     J. Toxicol. Environ. Health.  5:579-592.

Rosehart, R.G.  1973.  Mine water purification by reverse osmosis.  Can. J.
     Chem. Eng.  51(12):788-789.

Sheehy, M.,  and J.L.  Way.  1968.  Effect of oxygen on cyanide intoxication.
     III.  Mithridate.  J. Pharmacol. Exp. Ther.  161:163-168.

Smith,  R., M.S. Siebert and W.H.J. Hattingh.  1980.  Removal of inorganic
     pollutants from waste water during reclamation for potable reuse.  Water
     SA.  6(2):92-95.

Tewe, O.O.,  and J.H.  Maner.  1981a.  Long-term and carry-over effect of dietary
     inorganic cyanide (KCN) in the life cycle performance and metabolism of
     rats.  Toxicol.  Appl. Pharmacol.  58(1):1-7.

Tewe, O.O.,  and J.H.  Mkner.  1981b.  Performance and pathophysiological changes
     in pregnant pigs fed cassava diets containing different levels of cyanide.
     Res. Vet. Sci.  30(2):147-151.

Towill, L.E.,  J.S. Arury, B.L. Whitfield, E.B. Lewis, E.L. Galyan and A.S
     Hammone.   1978.   Reviews of the environmental fate of pollutants: V.
     Cyanide.   U.S. EPA Report No. EPA 600/1-78-027.  Health Effects Research
     Laboratory, Office of Research and Development, U.S EPA Cincinnati, OH.
     Available through NTIS, Order No. PB 289920; Springfield,  VA.

Trachtenberg,  J.J., and M.A. Murphy.  1979.  Removal of iron cyanide complexes
     from waste water utilizing and ion exchange process.  Light Metals J.

U.S. EPA.  1979.  U.S. Environmental Protection Agency.  Method 335.2. Titri-
     metric;  Spectrophotometric. In:  Methods for Chemical Analysis of Water
     and Wastes.  EPA600/4-79-020, March 1979.

U.S. EPA.  1982.  U.S. Environmental Protection Agency.  Ambient water quality
     criteria  for cyanides, with errata for ambient water quality criteria
     documents dated  June 9, 1981 (Updated: February 23, 1982).  Environmental
     Criteria  and Assessment Office.  Cincinnati, OH.  NTIS PB 81-117483.

U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Health effects
     criteria  document for cyanide.  Office of Drinking Water.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Final guidelines
     for carcinogen risk  assessment.  Federal Register.  51(185):33992-34003.
     September 24, 1986.

U.S. PHS.  1962. U.S. Public Health Service.  Drinking water standards.
     U.S. Govt.  Printing Office, Washington, D.C.  PHS Publ. No. 956.

Weast,  R.C.,  ed. 1980. CRC handbook of chemistry and physics.   61st ed.
     CRC Press, Inc., Boca Raton, FL. pp. B-98,  B-133, B-147.

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Cyanide                                                 March 31, 1987

                                     -16-
Wood, J.L., and S.L. Cooley.  1956.  Detoxication of cyanide by cystine.
     J. Biol. Chem.  218:449-457.

Yamamoto, K., Y. Yamamoto, H. Hattori and T. Samori,  1982.  Effects of routes
     of administration on the cyanide concentration distribution in the various
     organs of cyanide-intoxicated rats.  Tohoku J. Exp. Med.  137:73-78.

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                                                                March 31 ,  1987
                                      MERCURY

                                  Health Advisory
                              Office of Drinking Water
                        U.S. Environmental Protection Agency
I. INTRODUCTION

        The Health Advisory (HA)  Program,  sponsored by the Office of Drinking
   Water (ODW), provides information on the health effects, analytical method-
   ology and treatment technology that would be useful in dealing with the
   contamination of drinking water.   Health Advisories describe nonregulatory
   concentrations of drinking water  contaminants at which adverse health effects
   would not be anticipated to occur over  specific exposure durations.  Health
   Advisories contain a margin of safety to protect sensitive members of the
   population.

        Health Advisories serve as informal technical guidance to assist Federal,
   State and local officials responsible for protecting public health when
   emergency spills or contamination situations occur.  They are not to be
   construed as legally enforceable  Federal standards.  The HAS are subject to
   change as new information becomes available,

        Health Advisories are developed for One-day,  Ten-day, Longer-term
   (approximately 7 years,  or 10% of an individual's  lifetime) and Lifetime
   exposures based on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not quantitatively incorporate any potential carcinogenic
   risk from such exposure.  For  those substances that are known or probable
   human carcinogens, according to the Agency classification scheme (Group \ or
   B),  Lifetime HAs are not recommended.  The chemical concentration values for
   Group A or B carcinogens are correlated with carcinogenic risk estimates by
   employing a cancer potency (unit  risk)  value together with assumptions for
   lifetime exposure and the consumption of drinking  water.  The cancer anit
   risk is usually derived from the  linear multistage model with 95% upper
   confidence limits.  This provides a low-dosi= estimate of cancer risk to
   humans that is considered unlikely to pose a carcinogenic risk in excess
   of  the stated values.  Excess  cancer risk estimates may also be calculated
   using the One-hit, Weibull, Logit or Probit models.  There is no current
   understanding of the biological mechanisms involved in cancer to suggest that
   any one of these models is able to predict risk more accurately than another.
   Because each model is based on differing assumptions, the estimates that are
   derived can differ by several  orders of magnitude.

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    Mercury
                                       March 31,  1937
                                         -2-

         This Health Advisory (HA)  is based on information presented in the Officl
    of Drinking Water's Health Effects Criteria Document (CD)  for Mercury (U.S.
    EPA,  1985).  The HA and CD formats are similar for easy reference.   Individuals
    desiring further information on the toxicological data base or rationale for
    risk characterization should consult the CD.   The CD is available for review
    at each EPA Regional Office of  Drinking Water counterpart (e.g., Water Supply
    Branch or Drinking Water Branch), or for a fee from the National Technical
    Information Service, U.S. Department of Commerce, 5285 Port Royal Rd.f
    Springfield, VA 22161, PB # 86-117827/AS.  The toll-free number is  (800)
    336-4700; in the Washington, D.C. area: (703) 487-4650.
II. GENERAL INFORMATION AND PROPERTIES
    CAS Nos.
            Mercury — 7439-97-5
            Mercury (II) Chloride — 7437-94-7
            Mercury (II) Sulfate  — 7783-36-0
    Synonyms

         0  Mercury (II)  chloride:   mercuric bichloride;  mercury perchloride.
            Mercury (II)  sulfate:   mercuric sulfate.

    Uses  (U.S. EPA, 1985)

         0  While this document is  concerned with the toxic effects of ionic
            mercury, it is metallic mercury that has  the  most uses.  Some uses
            of metallic mercury include use as a cathode  in the electrolytic
            preparation of chlorine and caustic soda, and in electrical apparatuse--,
            dental amalgams,  catalysts and in pulp and paper manufacture.

    Properties  (Weast, 1971)

         0  The properties of  inorganic mercury compounds vary with the specieLc
            compound;  some examples are as follows:
    Chemical Formula
                              Mercury
Hg
    Atomic/Molecular Weight   200.59
Mercury (II)
Chloride

HgCl2
271.49
    Physical State
    Boiling Point
    Melting Point
    Density
    Vapor Pressure
    Water Solubility
    Log Octano I/Water
      Partition Coefficient
    Taste Threshold
    Odor Threshold
Silver liquid   White powder
356.53°C
-38.87°C
13.5939
Insoluble
302°C
276°C
5.44

6.9 g/100
        Mercury  (II)
        Sulfate   	

        HgS04
        296.65
        White powder

        Decomposes
        6.47

(20°C)   Decomposes

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     Mercury                                                          March 31, 1937

                                          -3-


     Occurrence
             Mercury, although a relatively rare element, is ubiquitous in the
             earth's crust, occurring at levels from 10 to 500 ppb as a sulfide,
             chloride or oxide.  However,  mercury can form organic compounds that
             can bioaccumulate in the food chain and become a significant toxico-
             logical concern.  Only a small fraction of mercury in ground and
             surface waters occurs in the  organic form (U.S. EPA, 1987).

             The majority of mercury used  commercially in the United States is
             imported.  These commercial Uses have resulted in releases of mercury
             and its compounds to surface  waters.  Naturally occurring levels of
             mercury in ground and surface water are less than 0.5 ug/L, although
             higher levels may occur in ground water from local mineral deposits.
             Ground water surveys have found mercury at levels above 0.5 ug/L in
             15 to 30% of wells tested.  Surface water surveys report that about
             20% of surface waters exceed  0.5 ug/L.  State compliance data report
             that 16 ground water and 16 surface water wells currently exceed the
             maximum contaminant level of  2 ug/L (U.S. EPA, 1987).
III. PHARMACOKINETICS
     Absorption
             It is estimated that between 7 and 15% of orally administered inorganic
             mercury is absorbed by humans (Rahola et al.,  1971;  Task Group on Metal
             Accumulation,  1973).
     Distribution
          0  Rothstein and Hayes (1960)  administered a single c^ose of 203Hg (as
             Hg(N03)2/'  °'2 '"SA?)  by intravenous injection to seven male Wistar
             rats.   Distribution of mercury was primarily to kidney,  liver, blood,
             skin and muscle.   Other tissues contained only fractional percentages
             of the administered dose.   In general,  each tissue except the kidney
             showed a maximum  value four hours or one day post-treatment, followed
             by rapid clearance.  The kidney continued to accumulate mercury with
             maximum concentrations reached at 6 to 1 5 days.  For example, after
             four hours,  only  9% of the  body burden of mercury was found in the
             kidney; by the fifteenth day post-treatment 86% of the remaining
             mercury was  in the kidney.

          0  Jugo (1976)  administered single intravenous injections of 203^g (ag
             HgCl2;  0.15  Tig/kg)  to 2- or 21-week old female albino rats (strain
             not specified).   Approximately 28 and 51% of the administered dose
             was present  in the kidneys  of the 2- and 21-week old rats, respectively,
             after 144 hours.   Approximately 9% of the dose was present in the liver
             of 2-week old rats,- less than 1% was present in the liver of older
             rats.   In both groups of rats,  the blood and brain contained less
             than 1% of the administered dose.

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    Mercury                                                          March 31, 1987

                                         -4-


    Metabolism
            No information was found in the available literature on the metabolism
            of inorganic mercury.
    Excretion
            Rahola at al.  (1971)  administered single oral doses of protein bound
            methyl mercury (14 ug/subject)  and inorganic mercury (6 ug/subject)
            to human volunteers.   Approximately 85% of the administered inorganic
            mercury was eliminated in the feces within 4 to 5 days; only about
            0.2% was excreted in  the urine.  After 50 days the daily excretion of
            inorganic mercury in  the urine and feces was about 0.02% of the admin:i
            stered dose.  Approximately 6% of the administered dose of methyl
            mercury was eliminated in the feces within 3 to 4 days; excretion in
            the urine was  negligible at first, but increased slowly.  After 100
            days, 20% of the daily excretion of mercury was via the urine.

            Rothstein and  Hayes (1960) reported on the excretion of mercury in
            rats administered single intravenous injections of    Hg (as HgfNO^),;
            0.2 mg/kg). These authors indicated that the clearance of mercury
            from rats occurred in three phases:  a rapid phase invoking 35% of
            the dose lasting for  a few days; a slower phase involving 50% of the
            dose with a half-time of 30 days,- and a slow phase involving 15% of
            the dose with  a half-time of approximately 100 days.  Since mercury
            was found to accumulate in the kidney in the first few days following
            dosing, the two slow  phases of excretion represent primarily clearance
            from the kidney.
IV. HEALTH EFFECTS
    Humans
    Short-term Exposure
            Gleason, et al. (1957)  estimated that the lethal oral dose for mercuri<
            salts in humans is 1  to 4 g (equivalent to 14 to 57 mg/kg body weight)

            Ingestion of a dose of 1.5 g of mercuric chloride (HgCl2) produced
            emesis after 5 minutes, followed by severe abdominal pain with a
            brief period of loss of consciousness (Pesce et al., 1977).
    Long-term Exposure
            No information was found in the available literature on the human
            health effects of long-term exposure to inorganic mercury.

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Mercury                                                          March 31, 1987

                                     -5-
Animals

Short-term Exposure

     0  Male and female Brown-Norway rats (varying numbers per dose group)
        were given subcutaneous injections of mercuric chloride, three times
        per week for a maximum of 12 weeks.  The dose levels administered
        were 0, 0.05, 0.1, 0.25, 0.5, 1.0 or 2.0 mg/kg/injection.  Rats that
        received doses of 0.1 mg/kg/injection or higher developed renal
        disease characterized by antiglomerular basement membrane antibodies
        and the appearance of deposits in the glomerular tufts and in the
        small renal arteries.  Proteinurea and a nephrotic syndrome were also
        observed in these rats.  Based on these results, a NOAEL of 0.05
        mg/kg/injection is identified (Druet et al., 1978).

Long-term Exposure

     0  Male and female rats (strain not specified; 20 to 24/group) were
       ' administered mercury (as mercuric acetate) in the diet for up to 2
        years at concentrations of 0, 0.5, 2.5, 10, 40 or 160 ppm.  Assuming
        that 1  ppm in the diet of rats is equivalent to 0.05 mg/kg/day (Lehman,
        1959),  these dose levels correspond to 0, 0.025, 0.125, 0.50, 2.0 or
        8.0 mg/kg/day.  At the highest dose level (3.0 mg/kg/day), body
        weight was slightly depressed in male rats only (statistical significance
        not specified).  Kidney weights were significantly increased (p < 0.05)
        in the 2.0 and 8.0 mg/kg/day dose groups.  Pathological changes
        originating in the proximal convoluted tubules were also noted at
        these dose levels, with more severe effects in females than in males.
        Based on these results, a NOAEL of 10 ppm (0.5 mg/kg/day) is identifier!.
        A number of deficiencies limit the usefulness of this study.  These
        deficiencies include the small number of animals surviving past 18
        months, lack of information on the number of animals in each group
        having detectable pathological changes and the absence of statistical
        analysis of body weight changes in males (Fitzhugh et al., 1950).

Reproductive Effects

     0  No information was found in the available litsature on the reproductive
        effects of inorganic mercury.

Developmental Effects

     0  Oral dosing of Syrian golden hamsters with mercuric acetate on day 3
        of gestation at levels ranging from 4 to 100 mg/kg produced a dose-
        related response in numbers of resorptions and abnormal embryos.
        While these findings were evident at the 4 mg/kg dose lovel, the
        percentage of change was not significantly different from controls
        at this low level (Gale, 1974).

Mutagenicity

     0  No evidence is currently available to indicate that the mercuric
        salts are mutagenic.

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   Mercury                                                          March 31, 1987

                                        -6-

                                                                               •
   Carcinogenic!ty

        0  No evidence was found in the available literature on the carcinogenic!ty
           of inorganic mercury.


V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories (HAs) are generally determined for One-day, Ten-day,
   Longer-term (approximately 7 years) and Lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity,
   The HAs for noncarcinogenic toxicants are derived using the following formula:
   where:
                 HA = (NOAEL or LOAEL) x (BW) = __ mg/L ( __ ug/L >
                        (UF) x ( ___ L/day)
           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Sffeet-Level
                            in mg/kg bw/day.

                       BW = assumed body weight of a child (10 kg) or
                            an adult (70 kg).

                       UF = uncertainty factor (10, 100 or 1,000), in
                            accordance with NAS/ODW guidelines.

                	 L/day = assumed daily water consumption of a child
                            (1 L/day) or an adult (2 L/day).

   One-day Health Advisory

        The available data are insufficient to develop a One-day HA for mercury.
   It is, therefore, recommended that the modified DWEL (1.58 ug/L) be used at
   this time as a conservative estimate of the One-day HA value.

   Ten-day Health Advisory

        The available data are insufficient to develop a Ten-day HA for mercury<
   It is, therefore, recommended that the modified DWEL (1.58 ug/L) be used at
   this time as a conservative estimate of the Ten-day HA value.

   Longer-term Health Advisory

        The available data are insufficient to develop Longer-term HAs for mercurv,
   It is, therefore, recommended that the modified DWEL (1.58 uq/L) be used at
   this time as a conservative estimate of the Longer-term HA value for the
   10-kg child.

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Mercury                                                          March 31, 1987

                                     -7-


Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The Lifetime HA
is derived in a three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium,  at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).   The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     The study by Druet et al. (1978) has been selected to serve as the basis
for the Lifetime Health Advisory.  In this study,  Brown-Norway rats were given
subcutaneous injections of mercuric chloride, three times per week for up to
12 weeks at dose levels of 0,  0.05, 0.1, 0.25, 0.5, 1.0 or 2.0 mg/kg/injection.
Kidney damage, characterized by proteinurea and a nephrotic syndrome, was
observed in rats that received doses of 0.1 mg/kg/injection or higher.
Based on these results, a NOAEL of 0.05 mg/kg/injection is identified.

     Using this NOAEL, the Drinking Water Eguivalent Level and Lifetime Health
Advisory are derived as follows:

Step 1:  Determination of the Reference Dose (RfD)

       RfD = (100) (0.05 mg/kg/injection) (0.739)  (36) = 0.153 ug/kg/day
                      (10)  (84 days) (1,000)

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Mercury                                                          March 31, 1987,

                                     -8-


where-.

   0.05 mg/kg/injection = NOAEL for absence of renal effects in rats.

                     36 = number of doses.

                  0.739 = percentage of mercury in mercuric chloride.

                84 days = exposure period.

                  1,000 = uncertainty factor, chosen in accordance with NAS/ODW
                          guidelines for use with a NOAEL from an animal study
                          of less-than-lifetime duration.

                 100/10 = assumed subcutaneous absorption factor relative
                          to ingestion.

Step 2:   Determination of the Drinking Water Equivalent Level (DWEL)

                  DWEL = (0.158 ug/kg/day)(70 kg) = 5<5 ug/L
                                (2 L/day)

where:

        0.158 ug/kg/day = RfD.

                  70 kg = assumed body weight of an adult.

                2 L/day = assumed daily water consumption of. an adult.

Step  3:  Determination of the Lifetime Health Advisory

                 Lifetime HA = (5.5 ug/day)  (20%) = 1 .1 ug/L

where:

        5.5 ug/L = DWEL.

             20% = assumed relative source contribution from water.

Evaluation of Carcinogenic Potential

      0  The International Agency for Research on Cancer has not evaluated the
        carcinogenic potential of mercury.

      0  Applying the criteria described in EPA's guidelines for assessment of
        carcinogenic risk (U.S. EPA, 1986), mercury may be classified in
        Group D:  not classified.  This group is for substances with  inadequate
        animal evidence of carcinogenicity.

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    Mercury                                                       March 31,  1987

                                         -1 1-


IX. REFERENCES
    Druet,  P.,  E.  Druet,  F.  Potdevin and C.  Sapin.   1978.   Immune type glomerulo-
         nephritis induced by HgCL2 in the brown Norway rat.   Ann.  Immunol.
         1290:777-792.

    Ebersole,  G. ,  and J.T. O'Connor.  1972.   The removal of mercury from water by
         conventional water treatment processes.  Presented at 92nd Annual
         Conference,  American Water Works Association,  Chicago,  IL,  June.

    Fitzhugh,  O.G.,  A.  Nelson, E.  Laug and F. Junze.   1950.  Chronic oral
         toxicants of mercuric-phenyl and mercuric  salts.   Arch.  Ind.  Occup.  Med,
         2:433-442.

    Gale,  T.F.   1974.  Embryopathic effects  of different routes  of  administration
         of mercuric  acetate in the hamster.  Environ.  Res.  8:207-213.

    Gleason,  M.N., R.E. Gosselin and H.C. Hodge.  1957.  Clinical Toxicology  of
         Commercial Products.  Baltimore, MD:  Williams and wilkins Co.,  p.  154.
    Jugo,  S.   1976.   Retention and distribution of     HgCl,  in suckling and- adult-
         rats.   Health Physics.  30:240-241.

    Lehman,  A.J.  1959.   Appraisal of the safety of  chemicals  in foods,  drugs  and
         cosmetics.   Assoc.  Food Drug Off.  U.S.,  Q.  Bull.

    Logsdon,  G.S.,  and J.M.  Symons.   1973.   Mercury  removal  by conventional  water
         treatment techniques.  J. Amer.  Water Works Assoc.  65(8) :554-562.

    Pesce,  A.J., I.  Hanenson and K.  Sethi.   1977.  B% microglobulinuria in a
         patient with nephrotoxicity secondary to mercuric chloride  ingestion.
         Clin.  Toxicol.   1 1 (3) : 309-31 5.

    Rahola,  T. ,  T.  Hattula,  A. Korlainen  and J.K. Miettinen.   1971.   The biologi-
         cal halftime of inorganic mercury (Hg'"*") in man.  Scand.  J.  Clin. Invest.
         27{suppl.  116) :77.   (Abstract)

    Rothstein,  A.,  and A.D.  Hayes.  1960.  The metabolism  of mercury in the  rat
         studied by isotope  techniques.   J. Pharmacol.   130:166-176.

    Sigworth, E.S.,  and S.3. Smith.   1972.   Adsorption of  inorganic  compounds  by
         activated carbon.   J. Amer. Water Works Assoc. 64(6) : 386-91 .

    Sorg,  T.J.   1977.  Manual of treatment techniques for  meeting the interim
         primary drinking water standards.   U.S.  Environmental Protection Agency,
         EPA-600/8-77-005.

    Sorg,  T.J.   1979.  Treatment technology to meet  the interim primary drinking
         water  regulations  for organics:   Part 4.  J. Amer.  Water Works Assoc.
         71 :454-66.

    Task Group  on Metal Accumulation.   1973.   Accumulation of  toxic  metals with
         special reference  to their absorption, excretion  and  biological halftimes.
         Environ. Phys.  Biochem.  3:65-67.

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Mercury                                                       March 31,  1987

                                     -12-
Theim, L.,  D. Badorek et al.  1976.  Removal of mercury from drinking water
     using activated carbon.  J.  Amer. Water Works Assoc.   need volume 445-51 .

U.S. EPA.  1973.  U.S. Environmental Protection Agency.  Water Quality Criteria,
     1972.   Ecol. Res. Ser. Rep.  Comm. of Water Quality Criteria.   MAS, U.S.
     GPO, Washington, DC.  EPA R3/73/033.

U.S. EPA.  1979a.  U.S. Environmental Protection Agency.  Method 245.1.  Manual
     cold vapor technique.  In:  Methods for Chemical Analysis of Water and
     Wastes, SPA-600/4-79-020.

U.S, EPA.  1979b.  U.S. Environmental Protection Agency.  Method 245.2.
     Automated cold vapor technique.  In:  Methods for Chemical Analysis of
     Water and Wastes, EPA-600/4-79-020.

U.S. EPA.  1980.  U.S. Environmental Protection Agency.  Ambient water quality-
     criteria for mercury.  EPA 440/5-80-05b.  Office of Water Regulations
     and Standards, Washington, DC.

U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Drinking water
     criteria document for mercury (draft report).  Office of Drinking Water,
     Washington, DC.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for car-
     cinogen risk assessment.  Fed. Reg.  51(185) :33992-34003.  September 24.

U.S. EPA.  1987.  U.S. Environmental Protection Agency.  Estimated national
     occurrence and exposure to mercury in public drinking water supplies.
     Criteria and Standards Division.  Office of Drinking Water, Washington,  n •":,

Weast, R.C., ed.  1971.  CRC handbook of chemistry and physics, 52nd ed.
     Cleveland, OH:  The Chemical Rubber Co.

WHO.  1971.  World Health Organization.  International standards for drinking
     water.  Geneva, Switzerland.

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      Mercury
March 31,  1937
                                           -9-
  VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

           °- The U.S. EPA has recommended an ambient water quality criterion for
              the protection of health of 144 ng/L (U.S. EPA, 1980) and for drinking
              water of 2 ug/L (U.S. EPA, 1973).

           0  A WHO expert group has recommended an international standard for
              mercury in drinking water at 1 ug Hg/L (WHO, 1971).
 VII. ANALYTICAL METHODS

           0  Determination of mercury is by flameless atomic absorption using
              either a manual cold vapor technique (U.S. EPA, 1979a) or an automated
              cold vapor technique (U.S. SPA,  1979b).

           0  The flameless atomic absorption procedure is a physical method based
              on the absorption of radiation at 253.7 rnn by mercury vapor.  The
              mercury is reduced to the elemental state and aerated from solution in
              a closed system.  The mercury vapor passes through a cell positioned
              in the light path of an atomic absorption spectronhotorneter.  Absorbance
              is measured as a function of mercury concentration.  The detection
              limit for mercury is 0.2 ug/L using either the manual or automated
              technique.
VIII. TREATMENT TECHNOLOGIES

           °  Laboratory and pilot plant studies indicate that coagulation/filtration
              is moderately effective in removal of inorganic mercury from drinking
              water.  Ferric sulfate coagulation achieved 66% removal at pH 7 and
              97% removal at pH 8 from water containing 0.05 mg/L of inorganic
              mercury.  Alum coagulation was shown to be much less effective:  47%
              of the mercury was removed at pH 7 and 33% at pH 8. • It has been
              found that coagulation/filtration is less effective for removal of
              organic mercury.  However, the mercury removal efficiency of existing
              coagulation/filtration systems can be improved by the addition of
              powdered activated carbon (PAC) to the raw water influent.  Laboratory
              tests by Logsdon and Symons (1973) have shown that each milligram
              per liter of PAC added removes 0.0001 mg/L of either inorganic or
              organic mercury.

           0  Lime softening is essentially ineffective for removal of organic
              mercury taut moderately effective for removal of inorganic mercury,
              depending on the pH of the water.  Laboratory studies by Logsdon and
              Symons (1973) have shown that in the 10.7-11.4 pH range, lime softening
              removed 60 to 80% of the inorganic mercury, wheraas only about 30%
              removal was achieved at oH 9.4.
              The use of activated carbon as a process to remove mercury from
              drinking water has been reported by various investigators (Logsdon
              and Syrnons,  1973;  Sigworth and Smith,  1972;  Sorg,  1979:  Theim et al.,
              1976).  Laboratory tests were performed by pumping solutions of tap

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Mercury                                                    March 31, 1987

                                     -10-
        water and either soluble inorganic or organic mercury through columns
        of granular activated carbon for extended periods of time.  The
        results showed that «0 to 99% of the mercury may be removed from the
        water by this technology (Sigworth, et al. 1972; Logsdon and Symons,
        1973) .

        Limited pilot-plant studies have been reported by Sorg (1977) on the
        use of reverse osmosis for mercury removal.  One study investigating
        the removal of heavy metals, pesticides and other toxic chemicals
        from secondary wastewater effluent resulted in inorganic and organic
        mercury removals of 82 and 83%, respectively.  Another test involved
        a hollow fiber membrane with raw water flow of 1.25 gpm, 170 to 200
        psi, and 40 to 50% water recovery.  The spiral wound membrane system
        showed a 25% mercury removal, while the hollow fiber system efficien'-,
        removal was 79 to 81%.

        Several preliminary ion exchange experiments have been carried out
        by Ebersole and O'Connor (1972) to investigate organic and inorganic
        mercury removal from drinking water.  These studies showed that as
        much as 98% of inorganic mercury added to distilled water could be
        removed by cation and anion exchange resins operated in series.
        Although these experiments were very preliminary, the results indi-
        cated that ion exchange may be an effective method for inorganic
        mercury removal.

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                                                           March 31,  1987
                                       NICKEL

                                  Health  Advisory
                              Office of Drinking Water
                        U.S.  Environmental  Protection Agency
I. INTRODUCTION

        The  Health  Advisory  (HA)  Program,  sponsored  by  the  Office  of  Drinking
   Water (ODW),  provides  information on the  health effects, analytical method-
   ology and treatment  technology that  would be  useful  in dealing  with the
   contamination of drinking water.   Health  Advisories  describe nonregulatory
   concentrations of  drinking water  contaminants at  which adverse  health  effects
   would not be anticipated  to  occur over  specific exposure durations.  Health
   Advisories  contain a margin  of safety to  protect  sensitive  members of  the
   population.

        Health  Advisories  serve as informal  technical guidance to  assist  Federal,
   State and local  officials responsible for protecting public health when
   emergency spills or  contamination situations  occur.   They are not  to be
   construed as legally enforceable  Federal  standards.   The HAs are subject to
   change as new information becomes available.

        Health  Advisories  are developed for  One-day, Ten-day,  Longer-term
   (approximately 7 years, or 10% of an individual's lifetime)  and Lifetime
   exposures based  on data describing noncarcinogenic end points of toxicity.
   Health Advisories  do not  quantitatively incorporate  any  potential  carcinogenic
   risk  from such exposure.   For those  substances that  are  known or probable
   human carcinogens, according to the  Agency classification scheme (Group A  or
   B), Lifetime HAs are not  recommended.  The chemical  concentration  values for
   Group A or  B carcinogens  are correlated with  carcinogenic risk  estimates by
   employing a  cancer potency (unit  risk)  value  together with  assumptions for
   lifetime  exposure  and  the consumption of  drinking water. The cancer unit
   risk  is usually  derived from the  linear multistage model with 95%  upper
   confidence  limits.   This  provides a  low-dose  estimate of cancer risk to
   humans that is considered unlikely to pose a  carcinogenic risk  in  excess
   of  the stated values.   Excess  cancer risk estimates  may  also be calculated
   using the One-hit, Weibull,  Logit or Probit models.   There  is no current
   understanding of the biological mechanisms involved  in cancer to suggest that
   any one of  these models is able to predict risk more accurately than another.
   Because each model is  based  on differing  assumptions,  the estimates that are
   derived can  differ by  several orders of magnitude.

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    Nickel
                            March 31,  1987
                                         -2-
         This  Health  Advisory  (HA)  is  based  on information presented  in the Office
    of  Drinking  Water's  Health Effects Criteria Document (CD)  for Nickel (U.S.
    EPA,  1985).   The  HA  and  CD formats are similar  for  easy reference.   Individuals
    desiring further  information on the toxicological data base or rationale for
    risk  characterization should consult the CD.  The CD is available for review
    at  each EPA  Regional Office of  Drinking  Water counterpart  (e.g.,  Water Supply
    Branch  or  Drinking Water Branch),  or for a fee  from the National  Technical
    Information  Service, U.S.  Department of  Commerce, 5285 Port Royal Rd.,
    Springfield,  VA 22161, PB  # 86-1 17801/AS.  The toll-free number is (800)
    336-4700;  in the  Washington, D.C.  area:  (703) 487-4650.
II.  GENERAL INFORMATION  AND  PROPERTIES
    CAS  No.
         0   Nickel — 7440-02-0
            Nickel Chloride -- 7718-54-9
            Nickel Oxide  — 1313-99-1
    Synonyms
         0   Nickel  Chloride:  Nickelous  Chloride
            Nickel  Oxide:  Bunsenite

    Uses  (U.S.  EPA,  1985)

         0   While  this  document  is concerned  with  the  toxic  effects  of  ionic  nickel,
            it is  metallic  nickel which has  the  most uses.   Some uses of metallic
            nickel  include  use in the manufacture  of stainless  steel, various
            other  alloys  and  in  electroplating.

    Properties  (Weast,  1971)

         0   The  properties  of nickel  compounds vary  with  the specific compound;
            some examples are as follows:
    Chemical Formula
    Atomic/Molecular Weight
    Physical State
    Boiling Point
    Melting Point
    Density
    Vapor Pressure
    Water Solubility
    Log OctanoI/Water
      Partition Coefficient
    Taste Threshold
    Odor Threshold
Nickel

Ni
58.71
silver metal
2,732°C
1,453°C
8.90

insoluble
Nickel
Chloride

NiCl2
129.62
yellow solid
973°C (sublimes)
1,001°C
3.55
Nickel
Oxide

NiO
74.71
green-black solid

1,990°C
6.67
64.2 g/100cc (20°C) --

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      Nickel                                                  March 31,  1987

                                           -3-


      Occurrence
           0  Nickel is a metallic element which is  not found free in nature but
              exists as a number of salts.  Nickel compounds are found in most
              geologic materials at levels up to several thousand ppm.  Nickel
              occurs at low levels in most surface and ground waters.  Because
              nickel compounds  are relatively insoluble,  the levels of nickel in
              most surface and ground waters are less than 100 ppb.  Since nickel
              compounds are used commercially in a number of industries,  contamination
              of drinking water is the result of naturally occurring nickel compounds
              proliferated during industrial activities (U.S. EPA, 1979a; 1983a).

           0  Nickel is a component of some plumbing material.  When pipes and other
              materials corrode, nickel can be released to drinking water.  However,
              available information suggests that releases from this source are small
              (U.S.  EPA,  1979a;  1983a).

           0  There  are limited survey data on the occurrence of nickel in drinking
              water.  Based upon these data,  most supplies contain less than 40 ug/L
              of nickel.   The highest level reported for a drinking water supply was
              490 ug/L.  Nickel also occurs at low levels in food.  Based upon the
              limited information available,  diet is the major source of  nickel
              exposure with water making only a minor contribution (U.S.  EPA,  1979a;
              1983a).
Ill.  PHARMACOKINETICS
              The major routes  of  nickel  intake  for  both  humans  and  animals  are
              inhalation and ingestion, and to a lesser extent percutaneous
              absorption.    The extent of nickel absorption  is dependent  not only
              on the concentration of inhaled or ingested nickel,  but also on the
              chemical and  physical forms of  nickel  (U.S. EPA, 1985).  Since inhala-
              tion and percutaneous exposures are not relevant to  drinking water,
              emphasis will be  placed on  studies using the oral  route of  exposure.
      Absorption
              Very little of  the nickel  ingested  in  food  is  absorbed.   Total dietary
              intake  of  nickel ranges  from  107  to 900  ug/day with  average  values  of
              160-500 ug daily (U.S.  EPA,  1985);  about 1-10% of this  is absorbed
              (Horak  and Sunderman,  1973).
              In  rats,  intubation  of  6%i  in  dilute  acid  solutions  resulted  in  3-5%
              absorption  of  radiolabelled  nickel  (Ho and  Furst,  1973).

              There  was no uptake  of  nickel in rats  chronically  exposed  to drinking
              water  at  levels  of  5 ppm  over the lifetime  of  an animal (Schroeder
              et  al.,  1974).

              Transplacental transfer of nickel to the  fetus takes  place  in  both
              humans and  animals.   Newborn rats of mothers  fed  1000 ppm  Ni in
              the diet  showed  whole body levels of 22-30  ppm nickel (Phatak  and

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     Nickel                                                  March  31,  1987

                                          -4-
             Patwardhan,  1950).   Also,  similar levels  of  nickel  (0.04-2.8  ppm)
             were seen in the  liver,  heart and muscle  of  fetuses  as  were seen in
             adult humans (Casey  and  Robinson,  1978).

          0  Absorption from inhalation exposure to nickel carbonyl  is both rapid
             and extensive.   Sunderman  and Selin (1968) exposed  rats to nickel
             carbonyl  at  100 mg Ni/L  of air for 15  minutes.   It was  estimated that
             half of the  inhaled  amount was initially  absorbed.   On  the other
             hand,  inhalation  exposure  to  insoluble particulate  nickel (e.g., the
             oxide or  the subsulfide) results  in very  little  absorption.

     Distribution

          0  The tissue distribution  in animals orally exposed  to Ni is dependent
             upon the  concentration of  the compound.  Calves  fed  supplemental
             nickel in the diet at levels  of 62.5,  250 or 1000 ppm showed  somewhat
             elevated  levels of nickel  in  pancreas, testes and  bone  at 250 ppm;
             pronounced increases were  seen in these tissues  at  1000 ppm (O'Dell
             et al., 1971).

          0  Weanling  rats exposed to nickel (acetate)  in diet up to levels of
             1000 ppm  showed increased  levels  of nickel in kidney, liver,  heart
             and testes as nickel concentration was increased, with  the greatest
             accumulation in the  kidneys (Whanger,  1973).

     Metabolism

          0  Serum albumin is  the main  carrier protein for nickel in the sera of
             humans, rabbits,  rats and  bovine  species. In the sera  of rabbits and
             humans the nickel-rich metalloproteins ^ •]-macroglobulin (nickeloplasmin)
             and 9.5 S C<"1-glycoprotein, respectively  have been  identified (NAS,
             1975).
     Excretion
             The main excretory  route  of  absorbed  nickel  in  humans  and  animals
             appears to be the urine (Ho  and Furst,  1973)  with  biliary  excretion
             also occurring in experimental  animals  (Onkelinx et  al.,  1973).   The
             deposition of nickel in hair of humans  also  appears  to be  an excretory
             mechanism (Nechay and Sunderman,  1973).   Unabsorbed  dietary  nickel  is
             excreted in the feces.
IV.  HEALTH EFFECTS
     Humans
             No clinical or epidemiologic  studies  dealing  with  the toxicity of
             nickel following oral exposure were found in  the available literature.

             The toxicity of nickel to humans and  animals  is  a  function of the
             chemical form of the element and the  route of exposure.  There has
             been a suggestion of a correlation between chronic inhalation exposure

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Nickel                                                  March 31,  1987

                                     -5-


        to nickel carbonyl and respiratory tract cancer from epidemiclogical
        studies which have been confirmed in experimental animals.  Dermatitis
        (nickel itch) is another frequent effect of exposure to nickel (SPA,
        1983b).  However, these data are not pertinent to the effects due to
        ingestion of nickel in drinking water.

Animals

Short-term Exposure

     0  The oral LD50 values converted to mg nickel/kg bw range from 105  mg/kg
        bw for nickel chloride in male rats to  186 mg/kg for nickelocene  in
        mice (U.S. EPA, 1985).

     0  Nickel chloride administered orally to  rats at doses of 0.5 to 5.0
        mg/kg/day for 2 to 4 weeks led to a significantly decreased thyroid
        absorption of iodine  (Lestrovoi et al., 1974).

     0  Nickel acetate in the diet of weanling  OSU brown rats for  six weeks at
        concentrations of 100, 500 or 1000 ppm  (i.e.,  10,  50 or 100 mg Ni/kg
        bw) resulted in a significantly reduced weight gain at 500 ppm; rats
        exposed to 1000 ppm lost weight.  At 500 and 1000 ppm,  there was  a
        dose-related decrease in blood hemoglobin concentration, packed cell
        volume and plasma alkaline phosphate activity.  Cytochrome oxidase
        activity was decreased significantly (p< 0.005) in both heart and liver
        in the high-dose group.  Iron concentration was increased  significantly
        (p< 0.05) in red blood cells, heart, kidney, liver and testes in  the
        1000 ppm group; elevated levels of iron concentration also were seen
        in the 500 ppm group.  No significant effects  were seen on body weights,
        mineral content and enzyme activity in  the 100 ppm group in comparison
        with control levels.  The 100 ppm (10 mg Ni/kg bw)  is considered  a
        NOAEL while 500 ppm (50 mg Ni/kg bw) is a LOAEL (Whanger,  1973).

Long-term Exposure

     *  Nickel added to the diet of mice resulted in reduced body  weight  gain
        in females at a dietary concentration of 1100 ppm nickel and reduced
        body weight gain in both males and females at  1600 ppm  (Weber and
        Reid, 1969b).

     0  Studies in chicks (Weber and Reid,  1968a;  Ling and Leach,  1979) and
        calves (O'Dell et al., 1970) have shown adverse effects at dietary
        levels ranging from 250 to 700 mg Ni/kg diet.

     0  Nickel (as nickel chloride) administered to rats at a concentration
        of 225 ppm in drinking water (17.6 mg Ni/kg bw)  for four months led
        to a significant reduction in body weight (p<  0.05) compared with
        controls (Clary,  1975).  Daily urinary  volume  and  urinary  zinc and
        calcium concentrations were reduced significantly.  Also,  at sacrifice,
        serum lipid and cholestrol concentrations were reduced  significantly
        (p< 0.05).

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Nickel                                                  March 31,  1987

                                     -6-
        Daily doses of 25 mg/kg bw of nickel sulphate administered by oral
        intubation to male rats for 120 days caused degenerative cellular
        changes in the liver and kidney (von Waltschewa et al.,  1972).  In
        the treated rats, testes were smaller than in controls.   Other testicular
        changes included interstitial cell proliferation,  transparent vessel
        walls, reduced number of spermatozoa and their precursors and decreased
        concentrations of succinodehydrogenase and steroid 3-a-dehydrogenase.

        Rats fed a diet containing nickel acetate at concentrations of 0.1 to
        10% (16.6-166 mg Mi/kg bw) for 10-190 days led to  a high rate of
        mortality, hypoplasia of bone marrow, thymus and spleen, progressive
        renal tubular degeneration,  mural exudative pulmonary alveolar lesions
        and noninflammatory lysis of pancreatic exocrine cells (Ashrof and
        Sybers, 1974).

        In a chronic study with mice fed a diet devoid of  cadmium and Low in
        other metals with 5 ppm nickel added to their drinking water (approxi-
        mately 0.85 mg Ni/kg bw/day) no significant effects were observed.
        Only body weights of animals dying after one year  were depressed by
        4% to 13% over controls (Schroeder et al., 1964).

        The mean body weights of both male and female rats were  reduced
        significantly (p<0.025) compared to controls at 18 months in a study
        where rats were administered 5 ppm nickel (average daily dose estimated
        to be 0.41 mg Ni/kg bw) in drinking water for life (Schroeder et al.,
        1974).  Lifespan was not affected.  Histopathology revealed an increased1
        incidence (p<0.025) of focal myocardial fibrosis (13.3%) in the experi-
        mental group compared to the control.

        In a two-year feeding study with beagle dogs administered nickel
        sulfate hexahydrate at dietary levels of 0, 100, 1,000 or 2,500 pom
        (0, 3, 29 or 70 mg Ni/kg bw), no significant effects on  body weight,
        hematology, urinalysis, organ-to-body weight ratios or histopathology
        were noted at 100 or 1,000 ppm.  At 2,500 ppm, body weight gain was
        depressed, hemoglobin and hematocrit values tended to be lower and
        kidney- and liver-to-body weight ratios were significantly higher
        (p <0.05).  Pathological changes in the lungs and  granulocytic hyper-
        plasia of the bone also were noted in the high dose group.  Based on
        these findings, the NOAEL from this study is 1,000 ppm (29 mg/kg bw)
        (Ambrose et al., 1976).

        In a two-year feeding study in rats given 0, 100,  1,000  or 2,500 ppm
        nickel sulfate in milk (0, 5, 50 and 125 mg Ni/kg  bw), no significant
        effects were reported at 100 ppm (Ambrose et al.,  1976).  Body weight
        was reduced significantly (p<0.05) in both male and female rats fed
        2,500 ppm nickel when compared with controls.  At 1,000 ppm, body
        weight also was reduced in both sexes.  Animals fed 1,000 or 2,500 ppm
        nickel diets had significantly higher (p<0.05) heart-to-body weight
        ratios and significantly lower liver-to-body weight ratios than
        controls.  The 1,000 ppm (50 mg/kg bw) represents  a LOAEL from this
        study and 100 ppm (5 mg/kg bw) is a NOAEL.

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Nickel                                                  March 31, 1987

                                         -7-


Reproductive Effects

     0  In a three-generation reproduction study in rats, nickel sulfate
        hexahydrate fed at levels of 0, 250, 500 or 1,000 ppm (0, 12.5, 25 or
        50 mg Ni/kg/day) led to a slight decrease in adult body weight at
        mating and weaning in the 1000 ppm group over controls.  Fertility,
        gestation, viability and lactation indices were not affected.  The
        body weights of weanlings from the 1,000 ppm group were reduced in all
        generations.  The incidence of stillborn pups was 19%, 12% and 15% in
        the F-|a and 4%, 20% and 25% in the F-|b generations in the 250, 500 and
        1000 ppm groups, respectively, compared to 4% and 2% in the control
        F1a and F-JJ-, generations.  Elevated incidence of fetal mortality was not
        observed in the F2 and F3 generations (Ambrose et al., 1976).

     0  In another three-generation reproduction study, rats were provided
        drinking water containing 5 ppm nickel (salt not specified, estimated
        total daily dose was 0.43 mg/kg) (Schroeder and Mitchener,  1971).
        Neonatal mortality was increased significantly (p <0.025) in all
        generations of exposed rats compared to controls.  The number of
        runts were increased significantly in the first (p <0.025)  and third
        (p <0.0001) generations.  Average litter size was reduced somewhat
        in the F3 generation.  In this study, the diet was found to be deficient
        in trace metals (particularly chromium).

     0  No significant differences were observed in the litter size and
        initial body weight of pups when male and female rats were  fed diets
        containing 250, 500 or 1,000 ppm nickel (daily dose of 10,  20 or 40 mg
        Ni/kg bw) for 8 weeks before breeding and continuing through lactation
        (Phatak and Patwardhan,  1950).

Developmental Effects

     0  Transplacental transfer of nickel is well documented in laboratory
        animals  (U.S.EPA, 1985).

     0  In a three-generation reproduction study in rats (Ambrose et al.,  1976)
        (described above) no evidence of teratogenicity was seen in weanlings
        of rats fed nickel sulfate hexahydrate at levels of 0,  250,  500 or
        1,000 ppm (0,  12.5,  25 or 50 mg Ni/kg/day).

Mutagenicity

     0  Nickel chloride was  not mutagenic in Escherichia coli and Bacillus
        subtilis (U.S. EPA,  1985).

     0  Nickel chloride and  nickel sulfate were mutagenic or weakly mutagenic
        in eukaryotic test systems (U.S. EPA,  1985).

        Nickel induced chromosomal aberrations in cultured mammalian cells
        and sister chromatid exchanges in both cultured mammalian cells and
        in human lymphocytes (U.S. EPA, 1985).

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    Nickel                                                 March  31,  1987

                                         -8-


    Carcinogenicity

         0  It has  been demonstrated  that the  incidence  of  respiratory tract
            cancers in nickel refinery workers is  statistically significantly
            elevated (NIOSH,  1977;  IARC,  1976;  NAS,  1975);  these data  are not,
            however, relevant to the  consumption of  nickel  in drinking water.

         0  Repeated i.p.  injections  of nickel acetate at a dose of  360 mg/kg
            have induced lung carcinomas  in mice (Stoner et al., 1976).  This is
            not,  however,  relevant  to the consumption of nickel in drinking water.
         0  No evidence of carcinogenicity has been  found in  those chronic  studies
            in which nickel was  administered orally  to laboratory  animals (Schroedsr
            et al., 1964,  1974;  Schroeder and  Mitchner,  1975).

V.  QUANTIFICATION  OF TOXICOLOGICAL EFFECTS

         Health Advisories (HAs)  are  generally determined for One-day, Ten-day,
    Longer-term (approximately 7 years) and Lifetime exposures if  adequate  data
    are available that identify  a sensitive noncarcinogenic end point  of  toxicity.
    The HAs for noncarcinogenic  toxicants are  derived using the following formula:

                  HA = (NOAEL or LOAEL) x (BW) = 	 mg/L (	 ug/L)
                         (UF) x  (	 L/day)

    where:

            NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                             in  mg/kg bw/day.

                        BW = assumed  body weight of  a child (10 kg)  or
                             an  adult (70 kg).

                        UF = uncertainty  factor (10,  100 or 1,000),  in
                             accordance with NAS/ODW guidelines.

                 	 L/day = assumed  daily water consumption  of a  child
                             (1  L/day) or an adult (2 L/day).

    One-day Health Advisory

         The available data are  insufficient  to develop  a One-day  HA for  nickel.
    It is recommended that the Ten-day HA of  1.0 mg/L be used as the One-day  HA
    for the 10-kg child.

    Ten-day Health Advisory

         The study by Whanger (1973)  has  been  selected  for  the derivation of  a
    Ten-day HA.  Dose-response relationships  were  observed  in this 6-week dietary
    study defining a NOAEL for nickel of  100 ppm in  diet (10  mg/kg bw/day)  and a
    LOAEL of 500 ppm in diet (50 mg/kg bw/day). The biological endpoints  included
    body weight gain, hematology parameters and cytochrome oxidase activity.

         The Ten-day HA for Ni for a 10-kg child is  calculated as  follows:

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Nickel                                                  March 31, 1987

                                     -9-
         Ten-day HA =  (10 mg/kg/day) (10 kg) = T.0 mg/L (1,000 ug/L)
                          (1 L/day)  (100)
where:
        10 mg Ni/kg bw/day = NOAEL for absence of effects on weight gain,
                             hematology parameters and cytochrome oxidase
                             activity in rats following 6-week oral exposure.

                     10 kg = assumed body weight of a child.

                       100 = uncertainty factor, chosen in accordance with
                             NAS/ODW guidelines for use with a NOAEL from an
                             animal study.

                   1 L/day = assumed daily water consumption of a child.

Longer-term Health Advisory

     The available data are insufficient to develop Longer-term HAs for nickel.
It is recommended that the OWEL of 0.35 mg/L be used as the Longer-term HA
for the 70-kg adult and the modified DWEL of 0.1 mg/L (adjusted for a JO-kg
child) be used as the Longer-term HA for the 10-kg child.

     The Agency is in the process of reviewing a draft report of a 90-day
gavage study in rats (Mayhew, 1987).  The final report is expected to be
available in July or August, 1987.  After the official final report has been
reviewed and considered,  it may serve as the basis for a longer-term health
advisory.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health  effects over a lifetime exposure.  The Lifetime HA
is derived in a three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure  to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime,  and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined  (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure  level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from  the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is  determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual  exposure data or,  if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic  chemicals.  If the contaminant is classified as a
Group A or B carcinogen,  according to the Agency's classification scheme of

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Nickel                                                  March 31, 1987

                                     -10-
carcinogenic potential (U.S. EPA,  1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     Because of various problems with the two teratogenicity/reproductive
toxicity studies of Schroeder and Mitchner (1971) and Ambrose et al.,
(1976), the two-year rat feeding study of Ambrose et al.,  (1976) is used for
the derivation of the Lifetime HA.  In this study, rats were given 0, 100,
1,000 or 2,500 ppm nickel sulfate (approximate daily dose  was 0, 5, 50 or
125 mg Ni/kg bw)  in their diet.   No significant effects were reported at
100 ppm.  Body weight was reduced significantly (p <0.05)  in both male and
female rats fed 2500 ppm nickel  compared to controls.  At  1000 ppm also, the
body weight was reduced for the  male and female rats.  The NOAEL identified
in this study is 100 ppm (5 mg/kg bw) .

     Using this NOAEL, the Lifetime Health Advisory is derived as follows:

Step 1:  Determination of the Reference Dose (RfD)

                    RfD = (5 mg/kg/day) = 0.01  mg/kg/day
                             (100) (5)          y/ ^   y

where:

        5 mg/kg/day = NOAEL for  absence of effects on weight gain in rats.

                100 = uncertainty factor, chosen in accordance with NAS/ODW
                      guidelines for use with a NOAEL from an animal study.

                  5 = additional uncertainty factor selected to allow for
                      possibly greater absorption of nickel from water than
                      from the diet.

Step 2:  Determination of the Drinking Water Equivalent (DWEL)

            DWEL = (0-01 mg/kg/day) (70 kg) = 0>35 mg/L (350 ug/L)
                          (2 L/day)

where:

        0.01 mg/kg/day = RfD.

                 70 kg = assumed body weight of an adult.

               2 L/day = assumed daily water consumption of an adult.

Step 3:  Determination of the Lifetime Health Advisory

     The DWEL of 350 ug/L assumes 100% of the exposure to nickel occurs via
drinking water.  The available data indicate that the estimated intake of
nickel from food and air are 400 ug/day and 0.6 ug/day (negligible), respec-
tively.  Factoring in these data on human exposure, a Lifetime  HA of
0.150 mg/L  (150 ug/L) would result.

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       Nickel                                                  March  31,  1987

                                            -11-


       Evaluation of Carcinogenic  Potential

            0  Nickel has not been shown to  be carcinogenic through oral  exposure.
              Data are not available concerning the potential carcinogenic effects
              of ingested nickel  compounds  in humans.

            0  A relative high degree of evidence exists to demonstrate that certain
              nickel compounds or mixtures  of nickel compounds are carcinogenic to
              humans via inhalation.  Nickel refinery dust and nickel subsulfide
              (which is believed  to be the  major nickel component of the refinery
              dust) are classified in Group A: Human carcinogen, based on the EPA
              final guidelines for assessment of carcinogen risk (U.S. EPA, 1986).
              In the case of nickel carbonyl, while there is insufficient evidence
              from epidemiological studies, there is sufficient evidence from
              animal studies to classify it in Group B2:  Probable human carcinogen.

            0  Based upon an evaluation of the carcinogenic potential of nickel from
              inhalation and intramuscular  injection,  IARC has concluded that nickel
              and certain nickel compounds  are group 2A chemicals (IARC,  1976).
              However, at the present time  there is insufficient evidence to classify
              nickel as a carcinogen following oral exposure.

            0  Applying the criteria described in EPA's final guidelines for assess-
              ment of carcinogenic risk (U.S. EPA,  1986),  nickel via inhalation or
              intramuscular injection may be classified in Group B:  Probable human
              carcinogen.   This category is for agents for which there is inadequate
              evidence from human studies and sufficient evidence from animal
              studies.  However,  as  there are inadequate data to conclude that
              nickel is carcinogenic via ingestion, nickel is dealt with  here as
              Group D:   Not classifiable as to human carcinogenicity.  This category
              is for agents with inadequate human and  animal evidence of  carcino-
              genicity.


 VI.  OTHER CRITERIA,  GUIDANCE AND STANDARDS

              ACGIH (1983)  has  established  a TWA-TLV of  1.0  mg Ni/m3 for  metallic
              nickel salts  and  0.1 mg  Ni/m3 for soluble  nickel salts.

           0  The NIOSH (1977)  criterion for occupational  exposure  to nickel  is  a
              TWA of 15 ug  Ni/m3.

           0  EPA  (U.S. EPA,  1980; 1982)  derived an ADI  of 1.46  mg Ni/day and
              established an  ambient water  quality  criterion  of  0.632 mg  Ni/L.


VII.  ANALYTICAL METHODS
              Determination  of  nickel  is by  atomic  absorption  (AA)  using  either
              direct aspiration into a flame (U.S.  EPA,  1979b)  or a furnace  technique
              (U.S.  EPA,  1979c).

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       Nickel                                                 March  31,  1987

                                            -12-
            0  The direct aspiration AA procedure  is  a physical  method  based  on  the
               absorption of radiation at 232.0 nm by nickel.   The sample is  aspirated
               into an air-acetylene flame and  atomized.   A  light  beam  is directed
               through the flame into a monochromator and onto a detector that
               measures the amount of light absorbed. Absorbance  is  proportional to
               the concentration of nickel in the  sample.  The detection limit is
               40 ug/L using this procedure.

            0  The furnace AA procedure is similar to direct aspiration AA except a
               furnace, rather  than a flame,  is used  to  atomize  the sample.   The
               detection limit  is 1  ug/L using  this procedure.


VIII.  TREATMENT TECHNOLOGIES

            0  Treatment techniques that may  be capable  of removing nickel from
               drinking water include lime softening, ion exchange and  reverse osmosis.
               Conventional coagulation is moderately effective  in removing nickel
               from drinking water.  Although the  removal of nickel from drinking
               water supplies by these technologies have  not been  extensively studied,
               some information is available  from  waste  water  technology surveys.

            0  Gulp et al. (1978) reported excellent  removal of  nickel  with lime
               softening, ranging from 90.9 to  99.9 percent, for wastewater with
               nickel concentrations from 5 mg/L to 160 mg/L.  Maruyama et al.
               (1975) reported  removal efficiencies of 95 percent  with  low lime
               softening (260 mg/L lime dosage) and 98 percent with high lime softening
               (600 mg/L dosage)  from domestic  wastewater containing  5  mg/L of nickel.

            0  Cation exchange  has been used  extensively in  the  plating industry to
               recover nickel.   Normally,  these operations have  employed cation  resins
               in the hydrogen  cycle because  of the need  to  recover both acid and
               metal for recycle.  Nickel was eluted  with sulfuric acid,  6 to 10 Ib
               H^SO^/ft^ of resin in 10 percent solution. The reported efficiencies
               of removing nickel from plating  industry  wastewater are  96 to  100
               percent (Keramida and Etzel, 1982).

            0  Reverse osmosis  (RO)  membranes have been  tested and shown to remove
               nickel effectively from source water.  A  laboratory scale study evalu-
               ating the performance of cellulose  acetate membrane with plating  rinse
               showed that cellulose acetate  has a rejection efficiency for Ni+2 Of
               99.6 percent.  Other membranes are  commercially available: cellulose
               acetate butyrate,  nylon hollow fibers, polyurethanes (Golomb,  1972).
               These membranes, however, have not  been tested  for  their efficiencies
               to remove nickel.  The cellulose acetate  membrane was  field tested on
               a small industrial automatic plating line.  The wastewater nickel
               concentration was varied: 1,700  mg/L,  50  mg/L,  12 mg/L.   Tests by
               Golomb  (1974) have shown that  cellulose acetate membrane can be used
               to remove effectively 99+ percent of nickel from  the waste rinse streams.

            0  Pilot plant studies evaluating the  efficiency of  coagulation indicated
               that alum was only 25-45 percent effective to remove nickel from  water
               (Maruyama et al., 1975; Hannah et al., 1977).

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Nickel                                                  March 31, 1987

                                     -13-
        Another study by Uillson (1978),  investigating the removal on trace
        metals from tap water and municipal wastewater,  determined the effi-
        ciency of calcium hydroxide proved to be 91.3 percent effective in
        removing nickel from tap water and 63.3 percent effective in removing
        nickel from wastewater at a pH of 9.5.

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     Nickel                                                  March 31,  1987

                                          -14-


IX.  REFERENCES

     ACGIH.  1983.   American Conference  of  Governmental  Industrial Hygienists.
          TLVs.  Threshold limit values  for chemical substances and physical agents
          in the work environment with intended changes  for 1983-84.   Cincinnati,
          OH.  p. 27.

     Ambrose, A.M.,  P.S.  Larson,  J.R.  Borzelleca and G.  R.  Hennigar,  Jr.   1976.
          Long-term toxicologic assessment  of nickel in  rats and dogs.  J. Food
          Sci. Technol.   13:181-187.

     Ashrof,  M.,  and H.D.  Sybers. 1974.   Lysis of pancreatic exocrine cells and
          other lesions  in rats fed nickel  acetate.   Amer.  J. Pathol. 74:102a.

     Casey, C.E.  and M.F.  Robinson.   1978.   Copper,  manganese,  zinc,  nickel,
          cadmium,  and lead in human foetal tissues.  Br.  J. Nutr.  39:639-646.

     Clary, J.J.   1975.   Nickel chloride -  induced metabolic changes  in the rat
          and guinea pig.   Toxicol.   Appl.   Pharmacol.   31:55-65.

     Gulp, R.J.,  G.M. Wesner et al.   1978.   Handbook of  Advanced Wastewater
          Treatment.  2nd.  Van Nostrand Reinhold Co.

     Golomb,  A.  1972.  Application of reverse osmosis to  electroplating  waste
          treatment.  Plating 59(4):316-19.

     Golomb,  A.  1974.  Application of reverse osmosis to  electroplating  waste
          treatment.  Plating 61(5):432-42.

     Hannah,  S.A,,  M. Telus and J.M.  Cohen.  1977.  Removal of  uncommon trace
          metals by physical and chemical treatment  processes.   Journal WPCF
          49(11):2297-309.

     Ho,  W.,  and A.  Furst.  1973.  Nickel excretion  by rats following a single
          treatment.  Proc. West. Pharmacol. Soc.  16:245-248.

     Horak, E., and P.M. Sunderman,  Jr.  1973. Fecal  nickel  excretion by healthy
          adults. CLin.  Chem. 19:429-430.

     IARC.  1976.  International Agency  for Research on  Cancer.  Nickel and nickel
          compounds.  IARC Monographs.  2:75-112.

     Keramida, V.,  and J.E. Etzel.  1982.   Treatment of  metal plating wastewater
          with a disposable ion exchange material.  In:  Proceedings of the 37th
          Industrial Waste Conference.  Purdue University.

     Lestrovoi, A.P., A.I. Itskova and I.N. Eliseev.  1974.  Effect of nickel on
          the iodine fixation of the thyroid gland when  administered perorally  and
          by inhalation.  Gig. Sanit.  10:105-106.

     Ling, J.R., and R.M. Leach. 1979. Studies on nickel metabolism:  Interaction
          with other mineral elements.  Poultry Sci. 58(3):591-596.

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Nickel                                                  March 31, 1987

                                     -15-
Maruyama, T., S.A. Hannah and J.M. Cohen,  1975.  Metal removal by physical
     and chemical treatment processes.  Journal WPCF 47(5):962-75.

Mayhew, D.A.  1987.  Ninety-day gavag« study in albino rats  using nickel.
     Draft final report by American Biogenics Corp., Decatur, IL.

NAS. 1975.  National Academy of Sciences.  Nickel.  National Academy of
     Sciences Committee on Medical and Biological Effects of Environmental
     Pollutants.  Washington, DC.
   i
Nechay, M.W., and F.W. Sunderman, Jr.  1973.  Measurements of nickel in hair by
     atomic absorption spectrometry.  Ann. Clin. Lab. Sci.  3:30-35.

Nillson, R.  1978.  Removal of metals by chemical treatment  of municipal
     waste water.  Water Research.  5:51-60.

NIOSH.   1977.  National Institute of Occupational Safety and Health.  Criteria
     for a recommended standard.. .occupational exposure to inorganic nickel.
     NIOSH Publ. No. 77-164.  Washington, DC.

O'Dell, G.D., W.J. Miller, A, King, S.L. Moore and D.M. Blackmon.  1971.
     Effect of dietary nickel level on excretion and nickel  content of tissues
     in male calves.  J. Anim. Sci.  32:769-7730.

Onkelinx, C.  1973.  Compartmental analysis of the metabolism of 6%i(II) in
     rats and rabbits.  Res. Comm. Chem. Pathol. Pharmacol.  6:663.

Phatak, S.S., and V.N. Patwardhan.  1950.  Toxicity of nickel.   J. Sci. Ind. Res
     9B:70-76.

Schroeder, H.A., J.J. Balassa and W.H.  Vintin,  Jr.  1964.  Chromium,  lead,
     cadmium, nickel and titanium in mice:   Effect on mortality, tumors and
     tissue levels.  J.  Nutr.  83:239-250.

Schroeder, H.A., and M.  Mitchener.  1971.  Toxic effects of  trace elements  on
     the reproduction of mice and rats.   Arch.  Environ. Health.   23:102-106.

Schroeder, H.A., M. Mitchener and A.P.Mason. 1974.  Life-term effects of
     nickel in rats:  survival, tumors,  interactions with trace  elements and
     tissue levels.  J.  Nutr. 104:239-243.

Schroeder, H.A., and M.  Mitchener.  1975. Life-term effects  of  mercury, methyl
     mercury and none other trace metals on mice. J. Nutr. 105:452-458.

Stoner, G.D., M.B. Shimkin,  M.C. Troxell, T.L.  Thompson and  L.S. Terry.
     1976.  Test for carcinogenicity of metallic compounds by the pulmonary
     tumor response in strain A mice. Cancer Res.  36:1744-1747.

Sunderman, F.W., Jr., and C.E. Selin.  1968.  The metabolism of  nickel-63
     carbonyl.  Toxicol. Appl. Pharmacol.  12:207.

U.S. EPA.  1979a.  U.S.  Environmental Protection Agency.   Water  related
     environmental fate of 129 priority pollutants.  Office  of  Water Planning
     and Standards.  EPA-440/4-79-029.

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Nickel                                                  March 31, 1987

                                     -16-
U.S. EPA.  1979b.  U.S. Environmental Protection Agency.  Method 249.1.
     Atomic Absorption, direct aspiration.  In: Methods for Chemical Analysis
     of Water and Wastes.  EPA-600/4-79-020.

U.S. EPA.  1979c.  U.S. Environmental Protection Agency.  Method 249.2.
     Atomic Absorption, furnace technique.  In: Methods for Chemical Analysis
     of Water and Wastes.  EPA-600/4-79-020.

U.S. EPA.  1980.  U.S. Environmental Protection Agency.  Ambient water quality
     criteria document for nickel.  Environmental Criteria and Assessment
     Office,  Cincinnati, OH.  EPA 440/4-80-060.  NTIS PB 81-117715.

U.S. EPA.  1982.  U.S. Environmental Protection Agency.  Errata for ambient
     water quality criteria documents.  February 23.  p. 14.

U.S. EPA.  1983a.  U.S. Environmental Protection Agency.  Nickel occurrence
     in drinking water, food and air.  Office of Drinking Water.

U.S. EPA.  1983b.  U.S. Environmental Protection Agency.  Health assessment
     document for nickel.  Office of Research and Development.  Environmental
     Criteria and Assessment Office.  Research
     Triangle Park,  NC.  EPA-600/8-83-012.

U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Drinking water
     criteria document for nickel.  Environmental Criteria and Assessment
     Office,  Cincinnati, OH.  EOA-600/X-84-193-1.

U.S. EPA. 1986. U.S. Environmental Protection Agency.  Guidelines for
     carcinogen risk assessment.  Federal Register. 51 (1 85): 33992-34003.
     September 24.

Von Waltschewa, W.,  M. Slatewa and I. Michailow.  1972.  Hodenveranderungen
     bei weissen Ratten durch chronische Verabreichung von Nickel sulfat.
     (Testicular changes due to long-term administration of nickel sulphate
     in rats.)  Exp. Pathol.  6:116-120.  (Ger. with Eng. Abstr.)

Weast,  R.C.,  ed.  1971.  CRC handbook of chemistry and physics, 52nd ed.
     Cleveland, OH:   The Chemical Rubber Co.

Weber,  C.W.,  and B.L. Reid.  1969a.  Nickel toxicity in young growing chicks.
     J. Nutr. 95:612-616.

Weber,  C.W.,  and B.L. Reid.  1969b.  Nickel toxicity in young growing mice.
     J. Anim. Sci.  28:620-623.

Whanger, P.O.  1973.  Effects of dietary nickel on enzyme activities and
     mineral content in rats.  Toxicol. Appl. Pharmacol.  25:323-331.

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                                                             March 31,  1987
                                  NITRATE/NITRITE

                                  Health Advisory
                              Office of Drinking Water
                        U.S.  Environmental Protection Agency
I. INTRODUCTION
        The Health Advisory  (HA)  Program,  sponsored fay  the Office of Drinking
   Water (ODW),  provides information on the health effects, analytical method-
   ology and treatment technology that would be useful  in dealing with the
   contamination of drinking water.  Health Advisories  describe nonregulatory
   concentrations of drinking water contaminants at which adverse health effects
   would not be  anticipated  to occur over specific exposure durations.  Health
   Advisories contain a margin of safety  to protect sensitive members of the
   population.

        Health Advisories serve as informal technical guidance to assist Federal,
   State and local officials responsible  for protecting public health when
   emergency spills or contamination situations occur.   They are not to be
   construed as  legally enforceable Federal standards.   The HAs are subject to
   change as new information becomes available.

        Health Advisories are developed for One-day, Ten-day, Longer-term
   (approximately 7 years, or 10% of an individual's lifetime) and Lifetime
   exposures based on data describing noncarcinogenic end points of toxicity.
   Health Advisories do not  quantitatively  incorporate  any potential carcinogenic
   risk from such exposure.   For those substances that  are known or probable
   human carcinogens,  according to the Agency classification scheme (Group A or
   B),  Lifetime  HAs are not  recommended.   The chemical  concentration values for
   Group A or B  carcinogens  are correlated  with carcinogenic risk estimates by
   employing a cancer potency (unit risk)  value together with assumptions for
   lifetime exposure and the consumption  of drinking water.  The cancer unit
   risk is usually derived from the linear multistage model with 95% upper
   confidence limits.   This  provides a low-dose estimate of cancer risk to
   humans that is considered unlikely to  pose a carcinogenic risk in excess
   of the stated values.  Excess  cancer risk estimates  may also be calculated
   using the One-hit,  Weibull, Logit or Probit models.   There is no current
   understanding of the biological mechanisms involved  in cancer to suggest that
   any  one of these models is able to predict risk more accurately than another.
   Because each  model is based on differing assumptions, the estimates that are
   derived can differ by several orders of magnitude.

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    Nitrate/Nitrite                                           March  31,  1987

                                         -2-


         This Health Advisory  (HA)  is based on information presented in the Office
    of Drinking Water's Health Effects Criteria Document (CD) for nitrate and
    nitrite (U.S. EPA,  1985).   The  HA and CD formats are similar for easy reference.
    Individuals desiring further information on the toxicological data base or
    rationale for risk  characterization should consult the CD.  The CD is available
    for review at each  EPA Regional Office of Drinking Water counterpart (e.g.,
    Water Supply Branch or Drinking Water Branch),  or for a fee from the National
    Technical Information Service,  U.S. Department of Commerce, 5285 Port Royal
    Rd.,  Springfield, VA 22161,  PB  #86-117959/AS.  The toll-free number is (800)
    336-4700; in the Washington, D.C. areas  (703)  487-4650.


II. GENERAL INFORMATION AND PROPERTIES

    CAS tio.

         0  Potassium Nitrate — 7757-79-1
            Potassium Nitrite -- 7758-09-0

    Synonyms

         0  Potassium Nitrate: Saltpeter  (Windholz, 1976)

    Uses

         Among other uses, nitrate and nitrite have a variety of uses including
    the following  (U.S. EPA, 1985):

         0  The major use of nitrate is in inorgaiic fertilizers.

         0  Nitrate is used in the manufacture of explosives, glassmaking and  as
            a heat-transfer fluid and a heat-storage medium for solar heating
            applications.

         0  Both nitrate and nitrite are  used in curing meats.

    Properties   (Weast, 1974)

         e  The properties of nitrate and nitrite compounds vary with the specific
            compound; some examples  are  as follows:

                                       Potassium                 Potassium
                                       Nitrate                   Nitrite

    Chemical  Formula                   KNO3                      KNO2
    Molecular Weight                   101.11                    85.11
    Physical  State 	solid	... _    solid
    Boiling Point                      400°C  (decomposes)        decomposes
    Melting Point                      334°C                     440°C
    Density                           2.109  (16 C)              1.915
    Vapor  Pressure                   ' —
    Water  Solubility (0°C)             13.3 g/100cc              281 g/100cc
    Log  Octanol/Water
       Partition Coefficient
    Taste  Threshold                   —
    Odor Threshold                    —

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     Nitrate/Nitrite
     Occurrence
March 31, 1987
                                          -3-
             Nitrate and nitrite are naturally occurring inorganic ions which make
             up part of the nitrogen cycle.  Wastes containing organic nitrogen
             enter the soil and are decomposed first to ammonia which is subsequently
             oxidized to nitrite and nitrate.  Because nitrite is easily oxidized
             to form nitrate,  nitrate predominates in ground and surface waters.
             Nitrate then is taken up by plants during their growth and converted
             back to organic form.   Levels  of nitrate in water can be raised as
             the result of the contamination by nitrogen containing fertilizers or
             human and animal wastes.  Nitrate and nitrite ions are very mobile in
             soil and readily move with ground water (U.S. EPA, 1987).

             Surveys of naturally occurring levels of nitrate and nitrite in ground
             and surface water have found that levels normally do not exceed 1 to 2
             mg/L for nitrate and 0.1 mg/L for nitrite.  Surface waters generally
             contain lower levels of nitrate and nitrite than ground water.
             Nitrate has been included in a number of drinking water surveys.
             Nitrates occur at levels of less than 1  mg/L in most surface and
             ground water supplies.  Nitrates occur at levels exceeding 5 mg/L in
             about 3% of surface waters and 6% of ground waters.  Currently, 40
             surface water supplies and 568 ground water supplies exceed the
             nitrate MCL of 10 mg/L.  Systems which exceed the MCL are usually
             contaminated by nitrates from the use of fertilizers or from animal
             wastes or septic systems.  Nitrite levels have not been surveyed in
             drinking water supplies but are expected to be much lower than  1 mg/L
             (U.S. EPA, 1987).

             Nitrates occur naturally in a  number of  foods, particularly vegetables.
             Nitrates also are added to meat products as a preservative.  For
             adults,  the major source of nitrates appears to be from dietary
             sources.  For infants, water appears to be the major source of  exposure
             (U.S. EPA, 1987).
III. PHARMACOKINETICS

     Absorption

          Both nitrate and nitrite  are  readily  and  completely  absorbed  following
     oral administration:

          0  Nitrate is absorbed by active  transport from the  upper small intestine
             and nitrite is absorbed by diffusion across  the gastric mucosa and
             also through  the wall  of the intestinal tract (U.S.  EPA, 1985).

          0  Following oral administration,  both nitrate  and nitrite are readily
             and completely absorbed: both  13N05 and 1^O^ were completely
             absorbed within ten minutes after  administration  of  10 to  100 mgAg
             in mice (Parks et  al., 1981).   Similar results for nitrate (dose not
           •  specified) in rats were reported by Witter.et al.  (1979).

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Nitrate/Nitrite                                           March 31,  1987

                                     -4-


Distribution

     Both nitrate and nitrite readily distribute throughout the tissues
but do not bioaccumulate:

     0  Rapid,  homogeneous distribution of nitrate (dose unspecified) was
        observed in rats 45 to 60 minutes after dosing by gavage (Witter
        et al., 1979) .
     0  Both 1%03~ and 1 ^NC^" achieved transient equilibrium in mice within
        five minutes after intratracheal administration of 10 to 100 mg/kg
        (Parks et al., 1981).  Equilibrium between the intravascular and
        extravascular compartments of rabbits was reached within five minutes
        after injection of either radiochemical into rabbits.

     0  Nitrate secretion in saliva by humans was reported by Spiegelhalder
        et al. (1976) after ingestion of vegetables and vegetable juices.
        Secretion of nitrate by the gastric mucosa in rats was observed by
        Bloomfield et al. (1962) following intraperitoneal doses of sodium
        nitrate ranging from 60 to 200 mg/kg.

     0  In rats,  nitrite has been shown to cross the placenta (Shuval and
        Greuner,  1977).

     0  No evidence was found for bioaccumulation of nitrate or nitrite in
        any tissue (U.S. EPA, 1985).

Metabolism

     While nitrate is not directly metabolized to other compounds in humans,
nitrate is metabolized by bacteria in humans - particularly infants - to nitri t .
which, by reacting with hemoglobin, can markedly decrease the ability of blood
to carry oxygen to the tissues:

     0  While there is no evidence that mammals metabolize nitrate into other
        compounds (Parks et al.,1981), the bacteria found in human saliva
        and the stomach can reduce nitrate to nitrite (U.S. EPA, 1985).

     0  Due to decreased acidity (increased pH), particularly in the stomach
        of the bottle-fed infant, bacteria capable of reducing nitrate to
        nitrite may proliferate in the stomach thus leading to an increased
        formation of nitrite in infants 3 months old or less (U.S. EPA, 1985) .

     0  Nitrite reacts with the hemoglobin (the chemical responsible for the
        ability of blood to transport oxygen to the tissues) in erythrocytes
        to form methemoglobin which is unable to transport oxygen (Parks
        et al., 1981).

     0  The enzyme methemoglobin reductase converts methemoglobin to hemoglobin
        and nitrate, thus, reversing the process induced by nitrite  (Smith and
        Beutler,  1966).

     0  Bacteria in the saliva reduce 5% of absorbed nitrate into nitrite
         (Spiegelhalder et al.,      ^.

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    Nitrate/Nitrite                                            March  31,  1987

                                         -5-


         In animals:

         0  Gruener  et al.  (1973)  observed that the activity of  methemoglobin
            reductase in rat fetuses was nearly ten times higher than that of
            adult rats.

         0  Nitrite  in the  stomach can  react with secondary  amines and other amine
            substrates to form N-nitroso compounds that may  be oncogenic (Sander
            et al.,  1968;  Oshima and Bartsch,  1981).  Vitamin C  and  vitamin E
            can inhibit the formation of nitrosamines (Archer et al., 1975;
            Kamm et  al., 1977).

    Excretion
         0  Nitrate is  readily  excreted by  the kidneys  (U.S.  EPA,  1985).

         0  In humans,  about 25% of the nitrate absorbed is secreted in saliva
            (Spiegelhalder et al.,  1976). •

         0  While  it has  been suggested that appreciable amounts  of  nitrate are
            eliminated  in human (Donahoe,  1949) and cows milk (Davison et al.,
            1964),  there  are inadequate data to support this  conclusion.

         0  The half-life for elimination of nitrite in dogs, sheep  and Shetland
            ponies  (0.5-0.6 hrs)  is too rapid to be accounted for by renal excre-
            tion,  thus  suggesting that metabolism may be significant (Schneider
            and Yeary,  1975).
IV. HEALTH EFFECT^

    Humans
            The lethal  dose of  potassium nitrate  for an adult ranges  from 54 to
            462 mgAg;  the lethal dose  of sodium  nitrite ranges  from  32 to 154
                  (Burden,  1961).
            The  toxicity  of  nitrate  in  humans  is due  to  the  reduction of  nitrate
            to nitrite.   By  reacting with hemoglobin,  nitrite forms methemoglobin
            which  will not transport oxygen  to the  tissues and thus can lead  to
            asphyxia (see Metabolism, above) (U.S.  EPA,  1985).

            The  normal methemoglobin level in  humans  has been shown to range
            between 1 and 2\ (Shuval and Greuner,  1977).  A  level greater than
            3% is  defined as methemoglobinemia.  However,  there is a consistent
            elevation of  the methemoglobin concentration in  pregnant women from
            the  14th week through  delivery (Skrivan,  1971).

            Walton (1951) published  a survey by the American Public Health Associ-
            ation  which found that more than 278 cases of  cyanosis in infants
            were associated  with nitrate-contaminated water.  No cases of cyanosis
            in infants were  associated  with  water containing 10 mg/L or less  of
            nitrate-nitrogen.  See also the  discussion under Ten-day HA,  below.

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Nitrate/Nitrite                                           March 31,  1987

                                     -6-
        Winton et al.  (1971)  compared methemoglobin levels  with nitrate ion
        intake in 111  infants younger than six months old.   Only three infants
        had methemoglobin levels above 2.9%.  They were the youngest of five
        infants who had received more than 10 mgAg/day of  nitrate ion.

        Craun et al. (1981) conducted an epidemiologic study of 102 children
        aged one to eight years in Washington County,  Illinois.  Of the study
        subjects,  64 consumed water with high nitrate levels (22 to 111 mg/L
        nitrate-nitrogen) and 38 consumed water with low nitrate levels (less
        than 10 mg/L nitrate-nitrogen).  Ingestion of water containing 22 to
        111 mg/L nitrate-nitrogen did not produce abnormal  mean methemoglobin
        levels and was not related to increased methemoglobin levels in com-
        parison to controls.  See also the discussion under  Ten-day HA,  below*

        Hegesh and Shiloah (1982) demonstrated that nitrites were synthesized
        in infants with acute diarrhea.  See also the discussion under Ten-day
        HA, below.

        In pregnant woman, the level of methemoglobin increases from the normal
        methemoglobin  level  (between 0.5 and 2.5% of total  hemoglobin) to a
        maximum, 10.5%, at the 30th week of pregnancy and subsequently declines
        to normal after delivery (Skrivan, 1971).  Thus,  pregnant women may
        be more sensitive to the induction of clinical methemoglobinemia by
        nitrite at approximately the 30th week of pregnancy.
Animals
Short-term Exposure
        In the rabbit and rat,  acute oral LDsg values for potassium nitrate
        of 1,166 mgAg and 1,986 mgAg/  respectively, have been reported
        (Windholz, 1976; WHO, 1962).  The acute oral LD50 of sodium nitrate
        in the rabbit has been reported to be 1,955 mgAg (Windholz, 1976).

        In the rat, reported acute oral LD50 values for sodium nitrate range
        from 46 to 120 mgAg (Druckery et al., 1963; Imaizumi et al.,  1980;
        Windholz, 1976; WHO, 1962).

        Unlike humans, in which nitrite toxicity relates to the formation of
        methemoglobin (see Metabolism, above), the immediate toxic effect of
        nitrite in some species (e.g. the horse) is due to nitrite induced
        vasodilation which results in cardiovascular collapse and shock
        (U.S. EPA, 1985).

        In a three week mouse drinking water study, elevated methemoglobin
        levels were observed in 50-day-old mice administered nitrite ion (as
        sodium nitrite) at levels of 133 and 178 mgAg/day but not at 88
                  (Shuval and Greuner, 1977).
Long-term Exposure
        In a six month rat feeding study, 2,500 mg nitrate/kg/day produced a
        marked diuretic effect within two months when compared with rats fed

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Nitrate/Nitrite                                           March 31,  1987

                                     -7-
        equimolar levels of sodium chloride; 250 mg nitrate/kg/day caused no
        diuresis and is identified as the NOAEL in this study (Fritsch
        et al., 1980).

     0  In a six month rat feeding study, both 250 and 2,500 mg nitrate/kg/day
        as well as 25 and 250 mg nitrite/kg/day induced hemorrhagic areas in the
        spleen (Fritsch et al. , 1980).  Therefore, 250 mg nitrate/kg/day and
        25 mg nitrite/kg/day are identified as LOAELs in this study.

     0  Two long-term studies using ICR mice reported increases in amyloidosis
        (starchy deposits) and hemosiderosis after ingestion of very high doses
        of sodium nitrate (2,500 and 5,000 mg nitrate/kg/day: Sugiyama et al.,
        1979) and sodium nitrite (208,  416 and 833 mg nitrite/kg/day:  Inai,  et
        al., 1979).  LOAELs of 2,500 mg nitrate/kg/day and 208 mg nitrite/kg/day
        can be identified from the results of these studies.

Reproductive Effects

     0  In a developmental toxicity study reported by Globus and Samuel (1976)
        (described below) no evidence of sodium nitrite-induced adverse
        reproductive effects was observed.

Developmental Effects

     0  Groups of mice were intubated with sodium nitrite at 16.7 mg/kg/day
        on days 0 through 14, 16 or 18 of gestation  (Globus and Samuel, 1978).
        Analysis of fetal livers indicated that maternally administered sodium
        nitrite stimulated fetal hepatic erythropoiesis.  No evidence of a
        nitrite related effect upon fetal mortality, resorptions, mean weight,
        number of offspring or incidence of skeletal malformation was observed.

     0  The nitrosation of amides or amines in the stomach produces N-nitroso
        compounds which may pass through the placenta to exert teratogenic or
        fetotoxic effects (Ivankovic, 1979; Teramoto et al., 1980).

Mutagenicity

     0  Both sodium nitrite and sodium nitrate were negative in host-mediated
        assays in mice (FDA, 1972a and b).  Other host mediated assays did
        not find sodium nitrite to be mutagenic in mice (Couch and Friedman,
        1975) or in either rats or mice (Whong et al., 1979).

     0  Dominant lethal gene tests in rats were negative for both sodium
        nitrate and nitrite (FDA, 1972a and b); a cytogenetic assay in rat
        bone marrow cells was also negative for both compounds.

     0  Kodama et al. (1976) reported that sodium nitrite induced mutations
        to azaquanine resistance in cultured FM3A cells (a C3H mouse mammary
        carcinoma cell line).  Sodium nitrite was mutagenic in Salmonella
        typhimurium (FDA, 1972a,b) and _E. coli Sd-4 (Hussain and Ehrenberg,

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   Nitrate/                                                        31,  1987

                                        -8-


   Carcino^enicity

        0  It was judged (U.S.  EPA,  1985)  that the available  animal studies
           (Newberne 1978,  1979;  Maekawa et al.,  1982)  provided inconclusive
           evidence regarding  the carcinogenicity  of  nitrate  and nitrite
           administered orally  in the absence of  nitrosatable compounds .

        0  Many  studies have documented carcinogenesis  (ouuit and prenatal) in
           which both nitrite  and nitrosatable compounds were orally administered
           to animals  (NAS, 1981);  tumors were induced in many organs  including
           the stomach, esophagus and nasal cavity.

        0  More than 120 N-nitroso compounds have been  tested for carcinogenicity
           and greater than 75% of these compounds have been  shown to be carcino-
           genic (Shank and Magee, 1981).   These  compounds have been demonstrated
           to be carcinogenic  in at least 22 species  and carcinogenic transpla-
           centally in at least five species (Schmahl and Habs, 1980).   All
           species  tested have  shown tumor formation  following treatment with
           at least one of  the  N-nitroso compounds tested. Tumors have been
           induced  in every organ and tissue and  most cell types.  While organ
           specificity is observed within a species even after administration by
           different routes, clear differences in target tissue have been noted
           between  species  (Lijinsky et al., 1975).


V. QUANTIFICATION OF- TOXICOLOGICAL EFFECTS

        Health Advisories (HAs) are generally determined for  One-day, Ten-day,
   Longer-term (approximately  7 years) and Lifetime exposures if adequate data
   are available that identify  a. sensitive noncarcinogenic end point of toxicity «
   The HAs for noncarcinogenic toxicants are derived  using the following formulas

                 HA = INOAEL or LOAEL) x (BW) =	mg/L (	u /L)
                        (UF) x  (	 L/day)

   where:

           NOAEL or LOAEL - No- or Lowest-Observed-Adverse-Effect-Level
                            in mg/kg bw/day.
                           •
                       BW » assumed body weight of a  child (10 kg) or
                            an adult (70 kg).

                       UF » uncertainty factor (10, 100 or 1,000), in
                            accordance with NAS/ODW guidelines.

                	 L/day = assumed daily  water consumption of a child
                            (1  L/day) or an adult (2  L/day).

        The available data suggest that calculation of  the HA values for nitrate/
   nitrite should:                   • •

        8  Recognize the newborn infant as the population group at greatest

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Nitrate/Nitrite                                           March 31, 1987

                                     -9-
     0  Recognize and consider the conversion of orally ingested nitrate to
        nitrite.

     0  Utilize human data wherever possible due to the extreme species varia-
        tion (both quantitative and qualitative) observed in nitrate and
        nitrite toxicity.

     HA values are presented below for a 4-kg infant (assumed to consume
0.64 L of formula per day) and a 70-kg adult.  Normally, HAs are determined
for the 1 0-kg child and the 70-kg adult.  However, newborn infants (assumed
to weigh 4 kg) are the population subgroup at greatest risk and thus HAs are
provided for the 4-kg infant.

     While no separate HAs for the 10 kg child are provided, the HAs for the
70-kg adult will be protective for all age groups other than the 4-kg infant,
in that they are based upon data obtained in children (Craun et al., 1981).

     Nitrate is toxic because it is converted to nitrite and thus the toxicity
of nitrate and nitrite must be additive.  Thus,  nitrate and nitrite cannot be
considered independently.  Each HA is presented in terms of both mg nitrate-
nitrogen/L drinking water and mg nitrite-nitrogen/L drinking water.  Appropriate
use of these values requires information on both the nitrate and nitrite
content of drinking water so that a total "effective" nitrate concentration
can be calculated and used as follows :

     0  The "effective" nitrate-nitrogen concentration (mg/L) for all age
        groups is equal to nitrate-nitrogen + 10x nitrite-nitrogen.

     0  The "effective" nitrate-nitrogen concentration (mg/L) should not
        exceed the appropriate nitrate standard for the appropriate group
        (4-kg infant or 70-kg adult) or exposure period.

One-day Health Advisory

     The available data are insufficient to develop One-day HAs for nitrate
and nitrite.  The Ten-day HA should be protective of one-day exposures.

Ten-day Health Advisory

     Populations other than the 4-kg infant:

     Craun et al. (1981) conducted an epidemiologic study of 102 children
aged one to eight years in Washington County, Illinois.  Of the study subjects,
64 consumed water with high nitrate levels (22 to 111 mg/L nitrate-nitrogen)
and 38 consumed water with low nitrate levels (less than 10 mg/L nitrate-
nitrogen).  Ingestion of water containing 22 to 111 mg/L nitrate-nitrogen
did not result in abnormal mean methemoglobin levels and was not related to
increased methemoglobin levels in comparison to controls.  In the entire
study group of 102 children, only five had methemoglobin levels greater than
2% (maximum of 3.1% in a child from the low exposure group).

     For a 70-kg adult and all age groups other than the 4-kg infant, the
Ten-day nitrate HA value is 111 mg/L nitrate-nitrogen,  the NOAEL observed by

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Nitrate/Nitrite                                           March 31, 1987

                                     -10-
Craun et al. (1981).  Since the study was based on observations in humans
and since the most sensitive subgroup (i.e., infants) is considered separately,
no uncertainty factor has been employed in deriving the Ten-day nitrate HA
from the NOAEL.

     There are no studies that provide a direct measure of the NOAEL for
nitrite in children. The Ten-day nitrite HA for a 70 kg adult and all other
age groups other than the 4 kg infant can be calculated from the NO?,EL for
nitrate, assuming 10% conversion of nitrate to nitrite, as follows:

         (111 mg/L nitrate-nitrogen)(0.10) = 11 mg/L nitrite-nitrogen

where:

        111 mg/L = NOAEL for nitrate based on the absence of methemoglobinemia
                   in children.

            0.10 = assumed 10% conversion of nitrate to nitrite by 10-kg
                   child.

     For a 4-kg infant:

     Walton (1951) published a survey by the American Public Health Asso-
ciation which found more than 278 cases of cyanosis in infants that were
definitely associated with consumption of nitrate-contaminated water by the
infant or the nursing mother.  No cases associated with water containing 10
mg/L or less of nitrate-nitrogen were found.  As previously noted, Hegesh
and Shiloah (1982) demonstrated that nitrites were synthesized in infants
with acute diarrhea.  Nitrites are responsible for methemoglobinemia and
thus it is possible that infants with diarrhea may be the population most
sensitive to the toxic effects of both nitrate and nitrite.  As diarrhea is
relatively common in infants, it is believed that at least some of the infants
noted in Walton (1951) had diarrhea (U.S. EPA, 1985).  Thus it was concluded
that Walton (1951) could serve as a basis for the protection of all infants
including those with diarrhea.

     Based on the previous discussion, the Ten-day nitrate HA for 4-kg infants
is 10 mg/L nitrate-nitrogen, the NOAEL for methemoglobinemia observed by
Walton  (1951).  Studes by Donahoe (1949), Winton, et al. (1971) and Toussaint
and Wurkert (1982) support this HA.

     No study provides a direct measure of the NOAEL for nitrite in infants.
However, the Ten-day nitrite HA for the 4-kg infant can be calculated from
the NOAEL for nitrate as follows:

          (10 mg/L nitrate-nitrogen)(100%) = 1 mg/L nitrite-nitrogen
                         10

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Nitrate/Nitrite                                           March 31, 1987

                                     -11-
where:

        10 mg/L = NOAEL for nitrate-nitrogen based on the absence of methemo-
                  globinemia in infants.

           100% = assumed 100% conversion of nitrate to nitrite by 4-kg
                  infant.

             10 = uncertainty factor, chosen in accordance with NAS/ODW
                  guidelines for use with data from a study in humans.

Longer-term Health  Advisory

     The available data are insufficient to develop Longer-term HAs for
nitrate and nitrite.  However, for both nitrate and nitrite, it is judged that
the Ten-day HA for the 4-kg infant will offer protection against the formation
of methemoglobin induced by the ingestion of either nitrate or nitrite in all
age groups.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.  The Lifetime HA
is derived in a three step process.  Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the Human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty" factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual exposure data or, if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.  If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA,  1986), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     No suitable studies for calculation of a Lifetime Health Advisory were
located.  However, for both nitrate and nitrite, it is judged that the Ten-day
HA for the 4-kg infant (10 mg/L nitrate-nitrogen and 1 mg/L nitrite-nitrogen)
will offer protection againisTTthe^ formation of methemoglobin induced by the
ingestion of either nitrate or nitrite in all age groups.
     As previously discussed, the 4-kg infant is the most sensitive member of
the population with respect to the formation of methemoglobin induced by
either nitrite directly or by the in vivo reduction of nitrate to nitrite.

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     Nitrate/Nitrite                                           March 31,  1987

                                          -12-

     In addition,  as the 4-kg infant ages,  e.g.,  to a 10-kg child,  the sensitivity
     to the effects of methemoglobin as well as the amount of nitrate reduced to
     nitrite decrease, thus rendering the older child and the adult less  sensitive
     to the effects of both nitrate and nitrite.   Thus,  it has been concluded that
     the Ten-day HA for the 4-kg infant for both  nitrate and nitrite (10  mg/L
     nitrate-nitrogen and 1 mg/L nitrite-nitrogen)  will  offer adequate protection
     against methemoglobin formation in all other age groups as well.

     Evaluation of Carcinogenic Potential

          0  A number of animal studies provided  inconclusive evidence regarding
             the carcinogenicity of nitrate and nitrite  administered in the absence
             of nitrosatable compounds (U.S. EPA, 1985).

          °  Applying the criteria described in EPA's guidelines for assessment
             of carcinogenic risk (U.S. EPA, 1986), both nitrate and nitrite may
             be classified in Group D:  Not classified.   This category is for
             agents with inadequate animal evidence of carcinogenicity.


VI.  OTHER CRITERIA, GUIDANCE AND STANDARDS

          0  The interim Maximum Contaminant Level  for nitrate-nitrogen is 10 mg/L
             (U.S. EPA, 1976b).

          0  The U.S. Public Health Service recommended  a' limit of  10 mg/L nitrate-
             nitrogen or 45 mg/L nitrate ion (U.S.  PHS,  1962).

          0  The Committee on Water Quality Criteria of  the National Academy of
             Sciences recommended that nitrate-nitrogen  concentration-in  public
             water supplies not exceed 10 mg/L and nitrite-nitrogen not exceed
             1 mg/L (NAS, 1972).

          0  The EPA Quality Criteria for Water (U.S. EPA, 1976a) suggested that
             the maximum concentrations of nitrate-nitrogen and nitrite-nitrogen in
             domestic water supplies not exceed 10 mg/L  and 1 mg/L, respectively.


VII. ANALYTICAL METHODS
             Determination of nitrite alone, or nitrite and nitrate combined, is
             by colorimetry or spectrophotometry (U.S. EPA, 1979a;b).  In these
             methods, a sample is passed through a column containing granulated
             copper-cadmium to reduce nitrate to nitrite.  The nitrite (that
             which was originally present plus reduced nitrate) is determined by
             diazotizing with sulfanilamide and coupling with N-(1-naphthyl)-
             ethylenediamine dihydrochloride to form a highly colored azo dye
             which then is measured colorimetrically or spectrophotometrically.
             Separate, rather than combined, nitrate-nitrite values are obtained
             by carrying out the procedure first with, and then without, the copper-
             cadmium reduction step.  The applicable range of the colorimetric and
             spectrophotometrie methods is 0.05 to 10 mg/L nitrate-nitrogen and
             0.01 to 1 mg/L nitrite-nitrogen, respectively.

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      Nitrate/Nitrite
March 31, 1987
                                           -13-
              An alternative reduction procedure may be used (U.S. EPA,  1979c).
              this method,  nitrate is reduced to nitrite with hydrazine  sulfate.
              The applicable range of this method is 0.01 to 10 mg/L.
                 In
VIII. TREATMENT TECHNOLOGIES
           0  Ion exchange and reverse osmosis  are the practical methods currently
              in use to remove nitrates from water.   Conventional coagulation and
              lime softening are not effective  treatment methods for the removal of
              this contaminant (U.S. EPA,  1977;  Laverentz,  1974).

           0  The application of ion exchange resins for nitrate removal has  a well
              established history and is recognized  as a practical treatment for
              drinking water systems (U.S.  EPA,  1977;  Gillies,  1978; Sorg,  1978;
              Sorg, 1980).

           0  Laboratory experiments and pilot  plant studies  have shown that some
              strong base and weak base ion exchange resins are nitrate selective
              and can reduce the nitrate concentration from as  high as  50 mg/L
              (as N) to 0.5 mg/L (Holzmacher, 1971;  Gregg,  1973; Korngold,  1973;
              Gaundett,  1975; Kuelow et al.,  1975).   One full-scale ion exchange
              plant has  been operating successfully  on Long Island,  New York,  since
              1974.  This plant lowers the  nitrate level of 20-30 mg/L  in the raw
              water to 0.5 mg/L.  The finished  water is a blend of treated  and raw
            .  water and contains about 5 mg/L of nitrate (as  N).  Other installations
              removing nitrate include a 40,000 gpd  plant at Curryville, Pennsylvania
              and the 2,500 gpd plant in the  Virgin  Islands.

           0  An important feature of the commercial nitrate -ion exchange resin
              is that nitrate is not the most preferred ion in  jthe exchange but
              rather the sulfate ion.  However,  field studTes™by Guter  (1982)  in
              McFarland,  California have shown  that  nitrates  can be removed effec-
              tively in the presence of sulfates as  high as 380 mg/L.

           0  Although reverse osmosis (RO)  systems  have not been installed to remove
              specifically nitrates,  removal  efficiencies of  67 to 95%  (high  pressure)
              have been demonstrated.  There  are two plants currently operating
              which can provide data on nitrate  removal. Laverentz (1974)  reported
              that in Greenfield,  Iowa,  nitrate  is reduced  from 0.2 mg/L NO3-N to
              0.014 ng/L NOj-N.  In San Diego Country  Estates,  Romona,  California,
              the nitrate is reduced from 12.4  mg/L  NO3-N to  4.2 mg/L N03-N.
              However,  there are considerable experimental  field data obtained
              when cellulose acetate was the  only commercial  membrane as well  as
              more recent field tests that  indicate  nitrate rejection ranges  for
              cellulose  acetate membranes from  70 to 80% (Sourirajan, 1977),  80 to
              90% (Metcalf and Eddy,  Inc.,  1979),  and  58 to 86% (Weber,  1972).

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    Nitrate/Nitrite                                           March  31,  1987

                                         -14-


IX. REFERENCES

    Archer,  M.C.,  S.R.  Tannenbaum,  T-Y.  Fan and M.  Weisman.   1975.   Reaction
         of  nitrite with ascorbate and its relation to nitrosamine  formation.
         J.  Natl.  Cancer Inst.   54:1203-1205.

    Bloomfield,  R.A., J.R. Hersey,  C.W.  Welsch, G.B. Garner and M.E. Muhrer.
         1962.  Gastric concentration of nitrate in rats.   J.  Anim.  Sci.  21:1019.

    Burden,  E.H.W.J.  1961.  The toxicology of nitrates and nitrites with particu-
         lar reference  to the potability of water supplies.   Analyst.  86:429-433.

    Couch,  D.B., and M.A. Friedman.  1975.  Interactive mutagenicity of sodium
         nitrite,  dimethylamine, methylurea and ethylurea.   Mutat.  Res.
         31:109-114.

    Craun,  G.F., D.G. Greathouse and D.H. Gunderson.  1981.   Methemoglobin levels
         in  young children consuming high nitrate well water in the United States..
         Int. J. Epidemiol.  10:309-317.

    Davison, K.L., W. Hansel, L. Crook,  K. McEntee and M.J.  Wright.   1964.
         Nitrate toxicity in dairy  heifers.  I.  Effects on reproduction, growth,
         lactation and  vitamin  A nutrition.  J. Dairy Sci.   47:1065-1073.

    Druckery, H.,  D. Steinhoff,  H.  Beuthner, H. Schneider and P. Klarner.  1963.
         Screening of nitrate for chronic toxicity  in rats.   Arzneim. Forsch.
         13s320-323.  (In German? summary in English)

    FDA. -1972a.  Food  and Drug Administration.  Stanford Research  Institute.
         Study of mutagenic effects of sodium nitrate (71-7).  Menlo Park, CA.
     ~Contract FDA 71-267.  Rept. No.  FDABF-GRAS-083.   103 pp.

    FDA.  1972b.  Food  and Drug Administration.  Stanford Research  Institute.
         Study of mutagenic effects of sodium nitrate (71-9).  Menlo Park, CA.
         Contract FDA 71-267.  Rept. No.  FDABF-GRAS-084.   103 pp.

    Fritsch, P., M. Canal, G. Saint-Blanquat and E. Hollande.  1980.  Nutritional
         and toxicological impacts of nitrates and nitrites chronically admini-
         stered (6 months) in rats.  Ann. Nutr. Alim.  34:1097-1114.

    Gaundett, R.B.  1975.  Nitrate Removal from Water by Ion Exchange.  Water
         Treat.  Exam.  24(3):172-190.

    Gillies, M.T.  1978.  Drinking Water Detoxification.  Noyes Data Corporation.

    Globus,  M.,  and D.  Samuel.   1978.  Effect of maternally administered sodium
         nitrite on hepatic erythropoiesis in fetal CD-1 mice.  Teratology.
         18:367-377.

    Gregg,  J.C.  1973.   Nitrate Removal at Water Treatment Plant. Civ. Eng.
         43(45:45-47.

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                                     -15-
Gruener, N., H.I. Shuval, K. Behroozi, S. Cohen and H. Shechter.  1973.
     Methemoglobinemia induced by transplacental passage of nitrites in rats.
     Bull. Environ. Contain. Tox.  9:44-48.

Guter, G.A.  1982.  Removal of nitrate from contaminated water supplies for
     public use.  Final Report. U.S. Environmental Protection Agency.
     EPA-600/82-042.

Hegesh, E., and J. Shiloah.  1982.  Blood nitrates and infantile methemo-
     globinemia.  Clinica Chimica Acta.  125:107-115.

Holzmacher, R.G.  1971.  Nitrate removal from a ground water supply.  Water
     Sewage Works.  118(7):210-213.

Hussain, S., and L. Ehrenberg.  1974.  Mutagenicity of primary amines combined
     with nitrite.  Mutation Res.  26:419-422.

Imaizumi, S., I. Tyuma, K. Imai, H. Kosaka and Y. Ueda.  1980.  In vivo
     studies on methemoglobin formation by sodium nitrite.  Int. Arch. Occup.
     Environ. Health.  45:97-104.

Inai, K., Y. Aoki and S. Tokuoka.  1979.  Chronic toxicity of sodium nitrite
     in mice, with reference to its tumorigenicity.  Gann.  70:203-208.

Inui, N., Y. Nishi, M.M. Hasegawa, M. Taketumi, M. Yamamoto and A. Tanimura.
     1980.  Induction of 8-azaguanine-resistant mutation and neoplastic trans-
     formation of hamster embryonic cells by coadministration of sodium
     nitrite and aminopyrine.  J. Cancer Res. Clin. Oncol.  97:119-128.

Ivankovic, S.  1979.  Teratogenic and carcinogenic effects of some chemicals
     during prenatal life in rats, Syrian golden hamsters, and guinea pigs.
     Natl. Cancer Inst. Monogr.  51:103-115.

Kamm, J.J., T. Dashman, H. Newmark and W.J. Mergens.  1977.  Inhibition of
     amine-nitrite hepatotoxicity by alpha-tocopherol.  Tox. Appl. Pharmacol.
     41:575-583.

Keulow, R.W., K.L. Kropp, J. Withered and J.M. Symons.  1975.  Nitrate removal
     by anion-exchange resins.  JAWWA.  67(9):528-534.

Kodama, F., M. Umeda and T. Tsutsui.  1976.  Mutagenic effect of sodium
     nitrite on cultured mouse cells.  Mutat. Res.  40:119-124.

Korngold, E.  1973,  Removal of nitrates from potable water by ion exchange.
     Water, Air, Soil Pollut.  2:15-22.

Laverentz, D.L.  1974.  Economic feasibility of desalting systems for municipal
     water supply in Iowa.  U.S. Department of the Interior.

Lijinsky, W., G.M. Singer and H.W. Taylor.  1975.  Carcinogenic N-nitroso
     compounds.  Proc. XI International Cancer Congress.  3:44-47.

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                                     -16-
Maekawa, A., T. Ogiu, H. Onodera et al.  1982.  Carcinogenicity studies of
     sodium nitrite and sodium nitrate in F344 rats.  Food Cosmet. Tox.
     20:25-33.

Metcalf and Eddy, Inc.  1979.  Wastewater Engineering:  Treatment, disposal
     reuse, 2nd ed.  McGraw-Hill Co.

NAS.  1972.  National Academy of Sciences.  Water quality criteria.  National
     Academy Press.  Washington, DC.  EPA R3-73-033, 1973.

NAS.  1978.  National Academy of Sciences.  Nitrates:  an environmental assess-
     ment.  National Academy Press.  Washington, DC.

NAS.  1981.  National Academy of Sciences.  The health effects of nitrate,
                   nitroso compounds.  National Academy Press.  Washington, DC,

          P.M.  1978.  Dietary nitrite in the rat.  Final Report or. Contract
     FDA-74-2181, Food and Drug Administration, Public Health Service, U.S.
     Department of Health, Education and Welfare, Rockville, MD.

Newberne, P.M.  1979.  Nitrite promotes lymphoma incidence in rats.  Science.
     204: 1079-1081 .

Ohshima, H., and H. Bartsch.  1981.  Quantitative estimation of endogenous
     nitrosation in humans by monitoring N-nitrosoproline excreted in the
     urine.  Cancer Res.  41:3658-3662.

Parks, N.J., K.A. Krohn, C.A. Mathis, J.H. Chasko, K.R. Geiger, M.E. Gregor
     and N.F. Peek.  1981.  Nitrogen-13-labeled nitrite and nitrate:  Distri-
     bution and metabolism after intratracheal administration.  Science.
     212:58-61.

Sander, J., and F. Schweinsberg. 1972. Interrelationships between nitrate,
     nitrite and carcinogenic N-nitroso-compounds.   1. Communication:
     nitrate, nitrite and nitrosable amino-compounds in food and drugs,
     chemistry of N-nitroso compounds.  Zentralbl. Bakteriol. Parasitenkd.
     Infektionsk. Hyg. Abt. 1: Orig. Reihe B 156:299-340. (In German;
     summary in English).

Schmahl, D., and M. Habs.  1980.  Carcinogenicity of N-nitroso compounds.
     Species and route differences in regard to organotropism.  Oncology.
     37:237-242.

Schneider, N.R., and R.A. Yeary .  1975.  Nitrite and nitrate pharmacokinetics
     in the dog,-sheep, and pony.  Am. J. Vet. Res.  36:941-947.

Shank, R.Ci, and P.N. Magee.  1981.  Toxicity and Carcinogenicity of N-nitroso
     compounds.  In;  R.C. Shank, ed., Mycotoxins and N-nitroso compounds:
     environmental risks, Vol. I.  CRC Press.  Boca  Raton, FL.  pp. 185-217.

Shuval, H.I., and N. Gruener.  1977.  Health effects of nitrates in water.
     Cincinnati, OH:  Health Effects Research Laboratory, U.S. Environmental
     Protection Agency.  EPA 600/1-77-030.

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                                     -17-


Skrivan, J.  1971.  Methemoglobin in pregnancy.  Acta Univ. Carol. Med.
     17:123-161.

Smith, J.E., and E. Beutler.  1966.  Methemoglobin formation and reduction' in
     man and various animal species.  Am. J. Physiol.  210:347-350.

Sorg, T.J.  1978.  Treatment technology to meet the interim primary drinking
     water regulations for inorganics.  JAWWA.  70(2):105-12.

Sorg, T.J.  1980.  Compare nitrate removal methods.  Water and Wastes
     Engineering.  17(12):26-31.

Sourirajan, S.   1977.  Reverse osmosis and synthetic membranes.  National
     Research Council Canada.  NRCC No. 15627.  Ottawa,  Canada.

Spiegelhalder,  B., G. Eisenbrand and R. Preussmann.  1976.  Influence of
     dietary nitrate on nitrite content of human saliva:   possible relevance
     to in vivo formation of N-nitroso compounds.  Pood Cosmet. Tox.
     14:545-548.

Sugiyami, K., T. Tanaka and H. Mori.  1979.  Carcinogenicity examination of
     sodium nitrate in mice.  Gifu Daigaku Igakubu Koyo.  27:1-6.  (In Japanese;
     summary in English)

Teramoto, S., R. Saito and Y. Shirasu.  1980.  Teratogenic effects of com-
     bined administration of ethylenethiourea and nitrite in mice.  Teratology.
     21:71-78.

Toussaint, V.W., and K. Wurkert.  1982.  Methamoglobinamie im Sauglingsalter.
     In;  F. Selenka, ed.  Nitrat - Nitrit - Nitrosamine in Gewassern.  Bonn,
     Germany:  Deutsche Forschungsgemeinschaft, pp. 136-142.

U.S. EPA.  1976a.  U.S. Environmental Protection Agency.  Office of Water
     Planning and Standards.  Quality criteria for water.  Washington, DC.
     EPA 440/9-76-023. '

U.S. EPA.  1976b.  U.S. Environmental Protection Agency.  National interim
     primary drinking water regulations.  EPA 570/9-76-003.  Washington, DC.

U.S. EPA.  1977.  U.S. Environmental Protection Agency.   Manual of treatment
     techniques for meeting the interim primary drinking water regulations,
     revised.  EPA-600/8-77-005.

U.S. EPA.  1979a.  U.S. Environmental Protection Agency.  Method 353.2.
     Colorimetric, Automated, Cadmium Reduction.  In:  Methods for Chemical
     Analysis of Water and Wastes.  EPA-600/4-79-020.  March.

U.S. EPA.  1979b.  U.S. Environmental Protection Agency.  Method 353.3.
     Spectrophotometric,  Cadmium Reduction.  In:  Methods for Chemical Analysis
     of Water and Wastes.  EPA-600/4-79-020.  March.

U.S. EPA.  1979c«  U.S. Environmental Protection Agency.  Method 353.1.
     Colorimetric, Automated, fydrazine Reduction.  Methods for Chemical
     Analysis of Water and Wastes.  EPA-600/4-79-020.  March.

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                                     -18-
U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Health effects
     criteria document for nitrate/nitrite.  Criteria and Standards Division,
     Office of Drinking Water.  Washington, DC.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogenic risk assessment. Federal Register.  51(185):33992-34003.
     September 24.

U.S. EPA.  1987.  U.S. Environmental Protection Agency.  Estimated national
     occurrence and exposure to nitrate and nitrite in public drinking water
     supplies.  CSD.  Office of Drinking Water.

U.S. PHS.  1962.  U.S. Public Health Service.  U.S. Public Health Service
     drinking water standards.  U.S. Department of Health, Education and
     Welfare.  Rockville, MD.

Walton, G.  1951.  Survey of literature relating to infant methemoglobinemia
     due to nitrate contaminated water.  Am. J. Pub. Health.  41:986-996.

Weber, W.J.  1972.  Physicochemical processes for water quality control.
     Wiley-Interscience.

WHO.  1962.  World Health Organization.  Evaluation of the toxicity of a
     number of antimicrobials and antioxidants.  Sixth report of the Joint
     FAO/WHO Expert Committee on Food Additives, World Health Organization
     Technical Report Series No. 228.

Whong, W.Z., N.D. Speciner and G.S. Edwards.  1979.  Mutagenicity detection
     of in vivo nitrosation of dimethylamine by nitrite.  Environ. Mutagenesis.
     1:277-282.

Windholz, M., ed.  1976.  The Merck Index.  Ninth Edition.  Rahway, NJ:
     Merck and Co. Inc.

Winton, E.F., R.G. Tardiff and L.J. McCabe.  1971.  Nitrate in drinking water.
     JAWWA.  63:95-98.

Witter, J.P., S.J. Gatley and E. Balish.  1979.  Distribution of nitrogen-13
     from labeled nitrate (13N03~) in humans and rats.  Science.  204:411-413.

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