PB87-235586
HEALTH ADVISORIES FOR LEGIONELLA AND SEVEN  INORGANICS
U.S. Environmental Protection Agency
Washington,  DC
Mar 87
              U.S. DEPARTMENT OF COMMERCE
           National Technical Information Service

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4. TITLE AMD SUBTITLE
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March, 1987

Health Advisories for Legionella and Seven Inorganics '"OOOAN,AT,O.,COOI
,.AUTHOR,S> UoS> Environmental protection Agency  PERFORMING ORGANIZATION REPORT NO
Office of Drinking Water
1. PERFORMING ORGANIZATION NAME AND AOOMESS
U.S. Environmental Protection Agenc)
Office of Drinking Water (WH-550D)
401 M St., S.W.
Washington, D.C. 20460
12. SPONSORING AGENCY NAME AND ADDRESS
Same as box 9>
10. PROGRAM ELEMENT NO.
ft. CONTRACT/GRANT NO


13. TYPE Of REPORT AND PERIOD COVERED
1. SPONSORING AGENCY CODE
#

16 SUPPLEMENTARY NOTES
16. ABSTRACT
" These- document* summarize, the health effect
including: barium, cadmium, chromium, cyan]
Topics discussed include: general Informatj
Health Effects in Humans and Animals, oXiant
Criteria guidance and ^tandards, Analytical
.s of TJe SATI Field 'Group
Legionella 1
Inorganics
Drinking Water REPRCOUCEDBY
Health Advisory u-s DEPAFTTMENTOF COMMERCE
TV,v -1 r -1 1- NATONAL TECHNICAL
loxicicy ^ INFORMATION SERVICE
SPRWGFIELD.VA 22161
1. DISTRIBUTION STATEMENT
Open Distribution
It. SECURITY C'.*SS (T>ut Ktfori/ J1 NO Of PAGES
non-sensitive | 2 (A
SO SECURITY CLASS (Ttuipfffl 22 PRICE
non- sen s i t ive
If A Pra 2220.1 (. 4-77)    *ioui COITION it OOLIT

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AS NOTED IN THE NTIS ANNOUNCEMENT, PORTIONS
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COPY SENT TO NTIS,

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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 (300)
    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

    Sy nony ms

         0  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  bariura compounds vary with the specific  compound;
            some examples  are  as follows:
    Chemical Formula
    Physical State
    Boiling Point
    Melting Point
    Density (20C)
    Vapor Pressure
    Water Solubility  (pph)
    Log Octanol/Water
      Partition Coefficient
    Taste Threshold
    Odor Threshold
                              Barium
3a
    Atomic/Molecular Weight   137.33
Barium
Chloride

3aCl2
208.24
Silver-white solid  White solid
1637-1 638C
729-730C
3.6 g/cm3
1810 x 10-5 mm Hg
reacts
1560C
960C
3.856 g/cm3

31 (0C)
Barium
Sulfate

BaS04
233.40
Colorless solid

1580C
4.50 g/cm3

0.000235 (30C)

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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 (BaS04)  and  in much smaller amounts as  withente
             (83003).  Tne mineral forms are relatively insoluble in  water,  having
             high melting and boiling  points and  very  low vapor pressures (Preisman,
             1964V.  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 foodsas 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, 1985\ 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  (1^3BaCl2) is distributed
             widely throughout the organism, but  is  localized principally in the
             bone (Dencker et al., 1976).

          0  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. ppm at age 33 to 74  years (Sowden and Stitch,  1957).

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    Barium                                                    March  31,  1987
    Metabolism
            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).

            MAS (.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  ale (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 LDjg f barium varies markedly with species,  compound,
            age and other factors (U.S. EPA,  1985).  For example,  the acute oral
            LD5Q of barium chloride is 220 mg/kg in weanling rats  and 132 mg/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

                                        -5-
        8   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
          iany 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  0825  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).

   Mutagenicity

        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) =  	   /L (	     ,
                        (UF) x (     L/day)

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Barium                                                    March 31,  1987

                                     6
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 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 mg/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 oarium 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  tne 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.
                     I
      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 NAS/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) , 1>8 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.

             33% = assumed relative source contribution from water (Federal
                   Register, November 13, 1985).

Evaluation of Carcinogenic Potential

     0  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 h-imans 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 D:
        Not classified.  This category is for agents with inadequate animal
        and human evidence.
     9

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      Barium                                                    March 31, 1987

                                          -9-
           0   The  International Agency for Research on Cancer has not evaluated tne
              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).

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

           0   The  OSHA 8-hour time-weighted  average exposure limit for soluble
              bariam  compounds is 0.5 mg/m^  m  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

           0   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).

           8   Weinberg  (1973) and Logsdon et al.  (1974)  reported that ion exchange
              softening  systems are highly efficient  (93 to 98 percent) for reducing
                                                                                10

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 Barium                                                    March 31, 1987

                                     -10-
        banum 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 waterc  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 82 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, 1970K

      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 (BIF,
        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.
11

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    Barium                                                     March  31,  1937

                                         -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  148a  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  133ea and 140Ba-140La  in  mouse tissue.  Acta Radiol.
         15(4):273-287.

    Diengott, D.,  0.  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.
                                                                              1 *>
                                                                              -L /<*

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Barium   '                                                 March 31,  1987

                                     -12-
McCauley, P.T., and I.S. Washington.  1983.  Barium bioavailability as the
     chloride, sulfate 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
     1910clOOO - 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 Ca.  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/North
     Holland Biomedical Press,  pp. 321-328.

Schroeder, H.A., and L.A. Kraemer.  1974.  Cardiovascular mortality, municipal
     water and corrosion.  Arch. Environ. Health.  28:303-31'.

Schroeder, H.A., and M. Mitchener.  1975a.  Life-term effects of mercury,
     methyl mercury and nine othet 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.  J. 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.
 13

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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 chloride
     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 570/9-76-003.  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-600/3-77-005.

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:   Metnods 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.
                                                                          14

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                                                            March  31,  1937
                                      CADMIUM

                               Health Advisory  Draft
                              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.
                                                                               15

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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 CD0   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 #86-117942/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
    Synonyms

         8  None

    Uses
         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
    Atomic/Molecular Weight
    Physical State
    Boiling Point
    Melting Point
    Density
    Vapor Pressure (400C)
    Water Solubility
    Log Octanol/Water
      Partition Coefficient
    Taste Threshold
    Odor Threshold
Cadmium

Cd
112.40
Soft white solid
765c
320.9C
8.642 g/cm3
1 .4 mmHg
Cadmium
Chloride

CdCl2
183.32
Solid

568C
4.047 g/cm3

Soluble
Cadmium
Oxide

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

Insoluble
    16

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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. PKARMACOKINETICS

     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
         0  Once absorbed,  cadmium is eliminated in humans  principally  via tne
            urine (U.S.  EPA,  1985).

         0  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)

         0  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

         0  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).

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

         0  For emesis,  the NCAEL for cadmium  in adults is  0.043 mg/kg/day following
            an acute oral exposure to cadmium  salts  (Lauwerys, 1979).

         0  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).

         0  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 alo, 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).

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

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Cadmium                                                   *<*  31'  198?

                                     -5-


Animalo

Short-term Exposure

     0  The acute oral LD5Q 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, ^85)
        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
        cadmiumAg/day  (NOAEL), did not develop  proteinuria  (Kotsonis and
                       ).

              12 month rat  drinking water  study,  no  adverse  effects were
        observed  in animals  exposed  to 0.003,  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 cadmiurn/kg/day  (as CdCl2) 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 cadmiurn/kg/day  (Sutou et al.,
         198).

 Developmental Effects

      0  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
         tnose exposed to 0.1 or 10 mg cadmium/L during gestation (Anokas
         et al., 1980).

                                                                      -   19

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   Cadmium                                                  March  31, 1987

                                        -6-


   Mutagenicity

        0  While  cadmium  has  been  observed to  cause  chromosomal aberrations in
           several in vitro studies  (e.g., Watanabe  e't  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  Altnough cancers of  the prostate and lung have  been noted in cadmam
           smelter workers in an epidemiological  study  (Lemen 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 EFFECT^

        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)  = _   /L  { _   /L)
                        (UF)  x  (     L/day)
           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).
     20

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Cadmium                                                   March  31,  1987

                                     -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 1 0-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 witn
                                  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 tne Ten-day HA.  In this study a NOAEL of
0.84 mg/kg/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 dally exposure to the human population that is likely to be without


                                                                         21

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   Cadmium                                                   March 31, T987

                                       -3-
  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 RfQ, a Drinking Water Equivalent Level
  (DWEL) can be determined (Step 2).  & DWET. 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 ^"4 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 OK, 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, 19S6), 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
  tnat the critical concentration of cadmium in tne 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.'(1934).  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 tro 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 foe 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 mgAg/day is associated with renal dysfunction, 0.005 mgAg/day is a
  LOAEL value which normally would requira 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 vss identified.  Using this LOAL, the
  Lifetime Health Advisory is derived as follows:
22

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Cadmium                                                   March  31,  1987

                                     -9-


Step 1:  Determination of the Reference Dose (RfD)

                  RfD = (0.005 mg/kg/day)  = o.OOOS  mgAg/day


where:

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

                     10 = uncertainty factor;  this  uncertainty factor,  while
                          smaller than would normally  be  required  by NAS/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 = (0.0035 mg/kg/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:  Lmited
        evidence for carcinogenicity in humans, sufficient evidence for
        carcinogenicity in animals.
                                                                         23

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    Cadmium                                                  March  31,  198?

                                         -10-
           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  cnronic
            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 cadnium 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/Lo

         0  The Com-nission  of the European Communities  (CEC, 1975) has  recommended
            that the concentration of  cadmium in drinking water  not  exceed 0.005 mg/L.

         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).
       24

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      Cadmium                                                   March  31,  1987

                                           -1 1-


 VII. ANALYTICAL METHODS

           0   Determination  of  cadmium  is  by  atomic absorption  (AA) using  eitner
              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 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  oy 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 the
              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.
                                                                               25

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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/u  and 0.98 mg/u
        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  925 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 tae
        compatibility of existing treatment with  regard to  various materials
        used to convey the  water through the distribution system.
   26

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    Cadnium                                                   March  31,  1987

                                         -1 3-


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     Series No. 51.

WHO.  1984.  World Health  Organization.   Guidelines for  drinking water quality
     -- recommendatibns  Volume 1.   Geneva:   World Health Organization.
                                                                          31

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                                                             March  31,  1987
                                      CHROMIUM

                                  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 sub3ect 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 maltistage 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  #86-1 13072/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, Dipotassium  Salt    7789-00-6

    S_ynonyms

         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  Cnromium  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).
      33

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

     0  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 Octanol/Water
  Partition Coefficient
Taste Threshold
Odor Threshold

Occurrence
Cr
51.996
blue-white solid
2,642C
1,9008C
7.14 gm/cm3

0.5 ug/L
CrCl3
122.90
solid

83 8C
194.20
solid

968.3C
2.76 g/cm3 (15C) 2.732 g/cm3 (1SC)

inslouble         62.9 g/100 rnL  (20C)
        Chromiun 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%).  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).
                                                                               34

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Chromium                                                  March  31,  7987

                                     -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 ammo
        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 Na2^1Cr04 in water (Donaldson
        and Barreras, 1966).

     0  Rat3 administered drinking water containing 25 mg/L Cr  III as chromic
        chloride had 12.S 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 for-n.
        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  n
        rats was reported by Hopkins  (t96M <=ifter intravenous administration
        of either 0.1 or 1.0 ug/kg.

     0  Cr III has an affinity for iron-binding protein.3 (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 10 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  Ln its permeability to
        the various forms of chromium.  Inorganic Cr III administered as
        '1CrCl3 (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 fatus  (Mertz and Roginski, 1971).   The
        dosages in these two studies were unspecified.
   35

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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  et al.,
            1982).  It  is  reduced  to Cr III  intracellularly by the  cytochrome
            P-450 system in  the presence of  NADPH.  Cr  III  reacts with  nucleophulic
            ligands  and cellular macromolecules  (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 systen xs  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  which  chromium is
            excreted.
         o
            After intravenous administration,  chromium  is  also  excreted  in the
            feces, although reports in the literature vary considerably  on the
            percentage.   Hopkins (1965)  reported  tnat 0.5% to  1.7% of  tne initial
            dose of Cr III was excreted  in the feces  of rats eight hours after
            intravenous  administration of   CrClj 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
            nas 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. EP^,  1985).

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

         0  Subchronic and chronic dermal exposure to Cr VI in  the form  of chromic
            acid may cause contact dermatitis  and ulceration of the skin (3um*/s,
            1978).  For  example, Denton  et al. (1954) reported  information on an
            individual who was patch-tested on three  occasions  with 0.005%
            potassium dichrotnate 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.
                                                                                 36

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Chromium                                                  March 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,  198.5).  For example, Bloomfield
        and Blum (1928) reported perforated/ulcerated nasal septa and i-nflamed
        nasal mucosa in workers exposed to chromic acid (Cr VI)  (0.1 to 5.6
        mg/m^ 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 LD50 for various salts of Cr III range from 600 to 2, 600 nig/kg
        (Smyth et al., 1969).

     0  The oral LD50 of Cr VI (as Na2Cr2C>7) in  rats is 19.8 mg/kg (NIOSH,  1983).

     0  Rats vere exposed to drinking water containing Cr VI (K2CrC>4) at levels
        of both 80 and 134 mg 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
        mgA9/3ay for male rats and 0 to 2.41 mg/kg/day for female rats)
        produced no significant differences in weight gain, appearance or
        patholo-jical changes in the blood or other tissues (Mackenzie et al.,
        1958).  NOAELs of 1.87 mg/kg/day (males) and 2.41 mg/kj/day (females)
        can be identified from the results of this study.

     8  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 1eath, 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  (K^rOg)  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-
 37
mental effects of chromium.

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   Ch'romium                                                  March  31,  1987

                                        -7-


   Mutaqenicity

        0  The genotoxic  effects of  chromium  are well documented  both in in vivo
           and iji 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 botn Cr III  and Cr VI increase non-complementary nucleo-
           tide incorporation into DNA (Raffetto et al.,  1977; Majone 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  reporte.1 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.
           (19311, 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 inadeqj^te evidence to determine whether or not  oral exposure
   to chromium can lead to cancer:

        0  No increase in tumor rates o\/
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Chromiu-n                                                  March 31, 1987

                                     -8-


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 NA3/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 importa-it 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. EP=i,  1935).

      The Health Advisories will be determined on the basis of the effects o'"
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 (-i tie
         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 c1ir.>niu.-u.
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 consunption of 28 mL water per  day,
tne average ingested doses of Cr VI are calculated to be 3.3 and 14.4 -ij/kg/day,
respectively.  After two months, the rats receiving Cr VI at 3.3 mg/kg/day were
described as normal.  A "slight roughness of coat" WM-S a.ite-1 in rats  receiving
1 4. 4^ mg/kg/day, but this is not considered to be an adverse health effect; tnis
observation is not associated with other adverse health effects.  Therefore,
14.4  mg/kg/day represents the NOAEL for Cr VI in this study.
39

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Chromium                                                  March 31,  1987
     The Ten-day HA for a 10 -kg child is calculated as follows:
         Ten-day HA = JJ4.4 mg/kg/day) HO kg) = 1>4 mg/L (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 ingestioi 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
l^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 av.jca<.ji ,3ose for
male? and females receiving 25 mg/L is calculate! 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 "loteu at any of the
dose levels.  However, the animals receiving the highest dose (25 mg/L) of
Cr VI s'i i/e-? an 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)  MOJaJ. = 0.24 mg/L (240 ug/L)
                             (100H1 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 aa animal study.

               1 L/day = assumed daily water consumption of a child.
                                                                            40

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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
                         jiuielLnes for use with a NOAEL from an animal study.

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

Lifetime Health Advisory

     The Lifetime HA represents that portion of an i ndi vi i  ->f an
alult.  Tie Lifetime HA is determined in Step 3 by factoring in other sources
of exposure, the relative sourr- 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 ^n-1 a value :> 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 expos'!^ to this chemical.

     The study by MacKenzie  et al. (1958)  (described under thn :.,,;>.ij-er-tera 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.

     Usivj t'\i NOAEL of 2.41 mg/kg/day, the Lifetime HA is derived as follows:

3t-j  1:  Determination of the Reference Dose  (RfD)
                  RfD =  (2-41 mg/kg/day) = 0.0048 mg/kg/day
                            (100)  (5)
  41

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Chromium                                                  March 31, 1937

                                     -11-


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 fron -i -runal study.

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

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

                   DWEL = (0-0048 mq/kg) (70 kg) = ,70 ug/L
                                (2 L/day)

where:

        0.004S '/j/v-.-j = HfD.

               70 kg = assumed body weight  of an adult.

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

Step  3:  Determination of Lifetii'-' -*>-lfi 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 carcinogen!c 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 freja-;ac/ of lung cancer in
        humans.

      0  EPA's CAG has estimated the lifetime cancer risk due to *  constant
        exposure to air containing 1 ug/m^  of elemental chromium to be
         1.2 x 10~2 (U.S. EPA, 1933).

      0  Based on exposure to chromium via inhalation, IARC (1982)  has classified
        chromium and certain chromium compounds in GrDuo ' (rhromiu.-n  VI);
        sufficient evidence for carcinogenici ty in humans and a n i n - 1 =;.

      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 carcinojen.  This category is for agents  for  vhicn

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     Chromium                                                   March 31,  1987

                                          -12-
             there is  sufficient evidence to support the causal associateja '-i-f-.^^an
             exposure  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 lity Fjr drinking water (U.S. PHS,  1962).

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

          *  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 recoinuer.1-.-l Ambient water  quality criterion for Cr VI is 50 ug/L
             (U.S. EPA,  1980).

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

          0  The OSHA  8-hour time-^eiyhted  average exposure limit for OH- Mit'i-i,
             soluble chromic, and chromous  salts as chromium is 0.5 mg/m3 (OSHn,
             1985).
VII. ANALYTICAL METHODS
          0  Determination of chromium is by atomic ab^'>r-n'.; n\ (AA) using eitner
             direct aspiration into a flame (U.S. EPA, 1979a) or a furnace technique
             (U.S.  EPA,  1979D).

          0  The direct aspiration AA procedure is a physical method based on the
             absorption of radiation at 357.9 nm by chromium.  Th 3 single is
             aspirated into an air-acetylene flame and atomized.  A IHJ'T-.  i-i-im is
             directed through the flame into a monochromator, and onto a detector
             that measures the amount of light aosorbed.  Absorbance is proportional
             to the concentration of chroii. in , <\ the sample.  The detection limit
             is 50 ug/L using this procedure.

           0  The furnaco AA j- -'><1 ice is similar to direct aspiration AA except
             that a furnace,  rather than a flame, is used to atomize th-j s-imple.
             The detection limit is 1 ug/L using this procedure.
         43

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      Chromium                                                  March  31,  1987

                                           -13-


VIII. TREATMENT TECHNOLOGIES
              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.

              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,t 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).

              Results of jar and pilot-plant  tests indicate  that  Cr III  removal
              efficiencies witn  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).

              Since Cr Hi 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.

              Reverse osmosis (RO) membranes can efficiently remove from 82 to  99
              percent of th,e 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.   7:439-448.

    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 aninal  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.  Ec^roth,
         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.


       45

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Chromium                                                  March 31,  1987

                                     -15-
Hopkins, L.L.  1965.  Distribution in the rat of physiological amounts of
     injected Cr51(HI) 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.
     13:347-351.

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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Chromium                                                  March 31,  1987

                                     -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.

NA3.   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.

NI03H.  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. ^roiano 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 chronates for
     reuse.  Environmental Science and Technology.  2(11 ): 1006-1 6.

Rohm and Haas Co.  1980.  Amberlite Ion Exchange Resins.  Technical Bulletins
     for IR-120 and IRA-402.
     47

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Chromium                                                  March 31, 1987

                                     -1 7-
Schroeder, H.A., J.J. Balassa and W.H. Vinton, Jr.  1965.  Chromium, cadmiun
     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 213.1.  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
     Adsorption, 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.
     C3D.  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.So 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:M1-118.

Weast,  R.C.,  ed. 1971.  Handbook, of Chemistry and Physics. 52nd ed. CRC Press
     Cleveland, OH pp. B-65,  B-SJ-84,  3-122,  3-1 37.

Windholz, M., ed.  1976.  The Merck Index:   An encyclopedia of chemicals and
     drugs,  9th ed.  Rahway,  NJ:  Merck and Co.,  Inc.  pp. 228-289.
     49

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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 informa-tion 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 ri.sk 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.
                                                                                 50

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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

         "  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.
     51

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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
25.70C
-13.24C
0.688 (20C)
     Boiling  Point
     Melting  Point
     Density  (g/cm^)
     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

14.96C
563.7C
1.60-1.62

48 (10C)
-0.44
                  2.037
Potassium
Cyanide

KCN
65.12
colorless solid
634.5C
1.553 (20C)

71.6 (20C)
                  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., 1978).

             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.
                                                                                   52

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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 mg/kg) 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/m^),  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 8^2 (U.S. EPA, 1985).

Excretion

     0  The major route of cyanide elimination is as the thiocyanata 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).
   53

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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

         0  The enzyme cytochrome oxidase enables  cells  to utilize oxygen.
            Cyanide inhibits this enzyme thus resulting  in effective cellular
            anoxia (U.S. EPA,  1985).
    Humans
            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 ^D5Q for KCN was 10 mgAg (4 mg CN~/kg) in rats (Hayes,
            1967; Gaines,  1969) and 8.5 mg KCN/kg (3.4 mg CN~/kg) in mice (Sheehy
            and Way, 1968).  The LD5Q of intraperitoneally administered NaCN for
            mice was 3.2 mg CN-/k9 (Kruszyna et al., 1982).

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                                     -6-


     0  Mice administered 1  or 2 mg KCN/kg (0.4 or 0.8 mg/CN'/^g)  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'/kg)
        resulted in 20% mortality.                  ,

     0  Doses that are fatal to one species may be harmless to others.  An
        oral dose of 3.8 mg  KCN/kg (1o5 mg CN-/fccj)  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~/^g) equal to the LD^Q in mice,  had only minimal effects
        on guinea pigs  (Basu,  1983).

     0  Rats tolerated higher doses of cyanide (80 mg CN-/k9 bw/day) when
        mixed in the diet (Kreutler et al., 1978) than when administered by
        gavage (4.0 mg CN-/k<3 bw) (Ferguson, 1962).

     0  Rats tolerated 25 daily doses of 10 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 LD5Q (Hayes, 1967).

     0  Rats tolerated higher oral doses of KCN (approximately 30 mg KCN/kg
        bw/day or 12 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-/*9 bw) by
        gavage with water as the vehicle  (Hayes, 1967; Gaines, 1969).

     0  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~/k9 bw/day
        in the diet did not (Palmer and Olsen, 1979).

     0  Beagle dogs consuming 3 mg CN-/*9 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

     0  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.

     0  Pigs  (sows) maintained on diets containing cyanide  (30.3, 276.6
        and 520.7 mg CN~/^9 diet) throughout gestation and lactation
        showed hyperplasia of kidney glomerular cells and accumulation
        of colloid and  morpholog_cal changes in follicular cells of  the
        thyroid  (Tewe and Maner, 1981b).  (See also discussion under
        Developmental Effects, below.)

     0  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

        55

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Cyanide                                                 March  31,  1987

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

     0  Dogs receiving 2. 0.27 mg CN'/kg 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 mgAg 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-/*9 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~/kg 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
                            v
     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~Ag bw/hour (79.2-81.6 mg  CN-/*g 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~/*g 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).

        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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                                        -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:
   where:
                 HA = (NOAEL or LOAEL)  x (BW)   _   /L ( _ u  /L)
                        (UF) x ( _ L/day)
           NOAEL or LOAEL = No- or Lowes t-Observed-Adverse-Ef feet-Level
                            in mgAg bw/day.

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

                       UF = uncertainty factor (10,  1 00 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 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 1 0-kg child) be used as the Ten-day  HA for  the 1 0-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 1 0-kg
   child) be used as the Longer-term HA for the 10-kg child.

     57

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                                     -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 = HP'S mg/kg/day) = Q.022 mg/kg/day *
                            (100) (5)

* NB: The RfD is in good general agreement with the observation (NIOSH, 1976)
      that 1 mg HCN/m3 is without effect in humans via inhalation.
where:
        10.8 mg/kg/day = NOAEL for absence of clinical and histological effects
                         in rats exposed to HCN in the diet for 104 weeks.
                       I
                   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.

                                                                                 58

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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   /L (770   /L)
                              (2 L/day)                 *

    where:

            0.02 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 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 vould 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.


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.
       59

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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-/ro3'

           0  NIOSH has recommended a TLV of 5 mg/m3 for CN~ which was adopted by
              OSHA (1981).
 VII. ANALYTICAL METHODS
              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
              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.

              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.

              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).

              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.
                                                                                   60

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                                     -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.
    61

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    Cyanide                                                 March 31, 1987

                                         -13-


IX. REFERENCES

    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.  Ferm and R.P. Smith.  1982.  Congenital malformations
         induced by infusion of  sodium cyanide in the golden hamster.  Toxicol.
         Appl. Pharmacol.  64:456-464.
I
'    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.
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    Games,  T.B.  1969.  Acute toxicity of pesticides.  Toxicol. Appl. Pharmacol.
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    Gettler, A.O., and J.O. Baine.  1938.  The toxicology of cyanide.  Am. J. Med.
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    Gott, R.D.  1978.  Development of waste water treatment at the Climax Mine.
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    Hayes, W.T.  1967.   The 90-dose LD^Q and a chronicity factor as measurer of
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                           i
    Hertting, G., O. Kraupp, E.  Schnetz and S. Wieketich.   1960.  Untersuchungen
         uber die Folgen einer chronischen Verabreichung akut toxischer  Dosen  von
         Natnumcyanid 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 Chera.  3:325-329.

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-
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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,
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     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
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Makene, W.J., and J. Wilson.  1972.  Biochemical studies in  Tanzanian patients
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McCabe, L.J., J.M. Symons, R.D. Lee and G.G. Robeck.  1970.   Survey of com-
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Moore,  F.L.  1976.  An improved ion exchange resin method for  removal and
     recovery of zinc cyanide and cyanide from electroplating wastes.
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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
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\
Osuntokun, B.O., G.L. Monekosso and J. Wilson.  1969.  Relationship of a
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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.
       63

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                                     -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.  Maner.  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.
                                                                              64

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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.
      65

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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 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-dost3 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 estimatss that are
   derived can differ by several orders of magnitude.
                                                                            66

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    Mercurv
                                       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 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.,
    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  7439-97-6
            Mercury (II)  chloride  7437-94-7
            Mercury (II)  Sulfate   7733-36-0
    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 apparatuses,
            dental amalgams,  catalysts and in pulp and paper manufacture.

    Properties  (Weast, 1971)

         0  The properties  of  inorganic mercury compounds vary with  th-? specicic
            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
Mercury

Hg
200.59
Silver liquid
356.59C
-33.37C
13.5939

Insoluble
Mercury (II)
Chloride

HgCl2
271.49
White powder
302SC
276C
5.44
                                                                    Mercury (II)
                                                                    Sulfate
296.65
White powder

Decomposes
6.47
6.9 g/100 cm3 (20C)  Decomposes
      67

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     Mercury                                                          March 31, _1 937

                                          -3-


     Occurrence

          0  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).

          0  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 watar surveys report that about
             20% of surface  waters exceed  0.5 ug/L.  State compliance data report
             that 15 ground  water and 16 surface watar wells currently exceed the
             maximum contaminant level of  2 ug/L (U.S. SPA, 1987).


III. PHARMACOKINETICS

     Absorption

          0  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 r*ose of 203Hg (as
             Hg(N03)2; 0.2 tig/kg) by intravenous injection to seven male Wistar
             rats.  Distribution of mercury was primarilv to kidney, liver, blood,
             skin and  muscle.   Other tissues contained only fractional p--rce-ita*7<2s
             of tne administered dose.  In general, each  tissue except  the kilnev
             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 15 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  36% of the renaming
             mercury was in the kidney.

          0  Jugo (1976) administered single intravenous  injections of 203Hg  (as
             HgCl2; 0.15 tig/kg) to 2- or 21-week old female albino rats  (strain
             not specified).  Approximately 28 and 51% of the administers 1 dose
             was present in the kidneys of the 2- and 21-week old rats,  respectively,
             after 144 hours.  Approximately 9% of tne dose was present  in the  liver
             of 2-week old rats; less than 1% was present in the  liver of oldsr
             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

         0  No information was  found  in the available  literature  on  the  metabolism
            of inorganic mercury.

    Excretion

         0  Rahola et al.  (1971)  administered  single oral  doses of protein bound
            methyl mercury (14  ug/subject) and inorganic mercury  (6  ug/sub^ect)
            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 0.0?% of  the admini-
            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.

         0  Rothstein and Hayes (1960)  reported on the excretion  of  mercury in
                                                              203
            rats administered single  intravenous injections of   Hg (as HgfNOj^;
            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_

         0  Gleason, et al. (1957) estimated  that the  lethal oral dose for mercuric
            salts in humans is  1  to 4 g (equivalent to 14  to 57 mg/kg body weight).

         0  Ingestion of a dose of 1.5  g of  mercuric chloride (HgC^) produced
            emesis after 5 minutes, followed  by severe abdominal  pain witn a
            brief period of loss  of consciousness (Pesce et al.,  1977).

    Long-term Exposure

         0  No information was  found  in the  available  literature  on  the  human
            health effects of long-tarm exposure to inorganic mercury.
        69

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Mercury                                                          March 31, 1937

                                     -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/injaction.  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 identifle.-i.
        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 liteature on the reproductive
        effects of inorganic mercury.

Developmental Effects

     0  Oral dosing of Syrian golden hamsters with mercuric acetate  :>n 3av 3
        of gestation at levels ranging from 4 to 100 mg/kg produced a .lose-
        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 .tiatagenic.

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   Mercury                                                          March 31,  1937

                                        -6-


   Carcinogenicity

        0  No evidence was found in the available literature on the carcinogenicity
           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 noncarcinoqenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following formula:

                 HA = (NOAEL or  LOAEL)  X (BW) =	mg/Tj (	 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 mercury.
   It is,  therefore, recommended tnat the modified DWEL (1.53 ug/L)  be uso-1 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.

   L_pnger-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)  oe use-i at
   this time as a conservative estimate of the Longer-term HA value for ths
   10-kg child.
    71

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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 ofnoncar-
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 chis 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/in^ection.
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 Equivalent Level and Lifetinp 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/OOW
                          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:

        0.153 ug/kg/day = Rf D.

                  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 Potentiaj.

     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.
  73

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      Mercury                                                          March 31,  1937

                                           -9-


  VI. OTHER CRITERIA,'GUIDANCE AND STANDARDS

           0  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  Hq/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. EPA, 1979b).

           0  The flameless atomic absorption procedure is  a physical method based
              on the absorption of radiation at  253.7 nm 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 spectrophotometer.  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 nas 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 Synons (1973) have shown that each milligram
              per liter of PAC added removes 0.0001 mg/L of either inorganic or
              organic mercury.

              Lime softening is essentially ineffective for removal of organic
              mercury but 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, whereas only about 30%
              removal was achieved at pH 9.4.

              The use of activated carbon as a process to remove mercury from
              drinking water has been reported by various investigators  (Logsdon
              and Symons, 1973; Sigworth and Smith, 1972; Sorg, 1979; Theim et ai. ,
              1976).  Laboratory tests were performed by pumping solutions of tap

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Mercury                                                    March 31,  1937

                                     -10-
        water and either soluble inorganic or organic mercury through columns
        of granular activated carbon for extended periods of time.   The
        results showed that SO 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.1  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 32 and 83%,  respectively.  Another test involved
        a hollow fibar 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 efficiency
        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.
  75

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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.  3:207-213.

    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.  82 microglobulinuria  in a
         patient with nephrotoxicity secondary to mercuric chloride ingestion.
         Clin. Toxicol.  11(3):309-315.

    Rahola, T., T. Hattula,  A. Korlainen and J.K. Miettinen.   1971.  The oiologi-
         cal halftime of inorganic mercury (Hg-"1") in man.   Scand.  J. Clin. Invest.
         27(suppl. 116):77.    (Abstract)

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

    Sigworth, E.S., and S.B. Smitn.  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 tieeting the interim
         primary drinking water standards.  U.S. Environmental Protection Agencv,
         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
         special reference to their absorption, excretion and biological halftimes.
         Environ. Phys. Biochem.  3:65-67.

                                                                              76

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Mercury                                                       March  31,  1937

                                     -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.  Comn.  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, EPA-600/4-79-020.

U.S. EPA.  I979b.  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.  1936.  US. Environmental Protection  Agency.  Guidelines for car-
     cinogen risk assessment.  Fed.  Reg.   51(135):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, D.C.

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 irinkin7
     water.  Geneva, Switzerland.
 77

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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  lew-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.
                                                                               78

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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 # 86-117801/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.
            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:

                                                 Nickel             Nickel
                                Nickel           Chloride           Oxide
    Chemical Formula            Ni                NiCl2
    Atomic/Molecular Weight     58.71             129.62              74.71
    Physical State              silver metal     yellow solid        green-black solid
    Boiling Point               2, 732C          973C (sublimes)
    Melting Point               1,453C          1,001C             1,990C
    Density                     8.90             3.55                6.67
    Vapor Pressure
    Water Solubility            insoluble        64.2 g/1 OOcc (20C)  
    Log Octano I/Water                                             
      Partition Coefficient
    Taste Threshold
    Odor Threshold
 79

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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 drinxing  water supply was
              490 ug/L.   Nickel also occurs at low levels in food.   Based upon tne
              limited information available, diet is the major source  of nickel
              exposure with water making only  a minor contribution (U.S. EPA,  1979a;
              1983a).


III.  PHARMACOKINETICS

           0  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

           0  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 S^Ni  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 levels1 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).

             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
             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 pen;
             pronounced  increases  were seen in  these  tissues  at 1000  ppm (.3'Dell
             et al.,  1971).

             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
             Serum  albumin  is  the  main carrier protein  for  nickel  in  the  sera  of
             humans,  rabbits,  rats and bovine species.   In  the  sera of  raobits and
             humans the  nickel-rich metalloproteins <^ )-macroglobulin (nickeloplasmin)
             and 9.5 S <~i-glycoprotein,  respectively have  been identified  (NAS,
             1975).
     Excretion
             The  main excretory  route  of  absorbed  nickel  in humans  and  ani-als
             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
      81
             Mo 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 epidemiological
        studies which have been confirmed in experimental animals.   Dermatitis
        (nickel itch) is another frequent effect of  exposure to nickel (EPA,
        1983b).  However, these data are not pertinent to the effects due to
        ingestion of nickel in drinking water.
Animals
Short-term Exposure
        The oral LD5g 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).

        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).

        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  weighc 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).

        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.

        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).
                                                                                  86}
                                                                                  4,

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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-B-dehydrogenase.

        Rats fed a diet containing nickel acetate at concentrations of  0.1  to
        10% (16.6-166 mg Ni/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)o

        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  increased
        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 ppm
        (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 fas
        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.
     83

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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
        Fla and F1b 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) (Schrceder 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., 1975.
        (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 coll  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).
                       t
        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).
                                                                               84

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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.po  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  (Schroeder
            et al., 1964,  1974;  Schroeder and  Mitenner,  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)  = 	  /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  oody weight of  a cnild (10 kg)  or
                             an  adult (70 kg),

                        UF = uncertainty factor (10,  100 or 1,OOOJ,  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 cy'tochrome  oxidase activity.

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


          85

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Nickel                                                  March  31,  1987

                                     -9-
         Ten-day HA =  (10 mg/kg/day)  (10 kg)  =1.0 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 DWEL of 0.35 mg/L oe used as the Longer-term HA
for the 70-kg adult and the modified DWEL of 0.1  mg/L (adjusted for a 10-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-
cinoge-nic adverse health  effects over a lifetime exposure.  The Lifetme  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
                                                                                86

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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)

wheres

        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 T.g/kg/day) (70 kg) = 0.35   /L (350   /L,
                          (2 L/day)

where:

        0.01 mg/kg/day = RfD.

                 70 kg = assumed body weight of an adult.

               2 L/day = assumed iaily 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.
 87

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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 a-re 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:   Probacle human carcinogen.

           0  Based upon an evaluation of the carcinogenic potential of nickel from
              inhalation and intramuscular infection,  IARC has concluded that nickel
              and certain nickel compounds are group 2A chemicals (IARC, 1975).
              However, at the present time there is insufficient evidence to classify
              nickel as a carcinogen following oral exposure.

              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).
                                                                                    -88

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       Nickel                                                 March  31,  1937

                                            -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 c  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.


VI 1 1 .  TREATMENT TECHNOLOGIES

            0  Treatment techniques that may  be capable of removing nickel from
               drinking water include lime softening, ion exchange  and  reverse osnosis.
               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  Culp et al. (1978) reported excellent  removal of  nickel  with li.-ne
               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 line
               softening (260 mg/L lime dosage)  and 93  percent with high lime softening
               (600 mg/L dosage)  from domestic  wastewater containing  5  mg/L of ni
            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 lo
               H,S04/ft^ of resin  in 10 percent  solution.  The  reported efficiencies
               ot removing nickel  from plating industry  vastewater  are  96 to  1JO
               percent (Keramida and Etzel,  1932).

            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+- 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).
           89

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Nickel                                                 March 31,  1987

                                     -13-
        Another study  by  Uillson  (1978), investigating the removal of 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.
                                                                               90

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     Nickel                                                  March  31,  1937

                                          -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.  Re Hennigar,  Jr.   1976.
          Long-term toxicologic assessment of  nickel  in  rats and dogs.   J. Food
          Sci. Technol.   13s 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) s 31 6-1 9.

     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):2297-309c

     Ho,  w.,  and A.  Furst.  1973.  Nickel excretion by rats  following a  single
          treatment.  Proc. West. Pharmacol. Soc. 16:245-248.

     Horak, E., and F.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  tne 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.
        91

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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 gavage 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.

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 nickelx.
     NIOSH Publ. No. 77-164.  Washington, DC.

O'Dell, G.D., W.J. Miller, A. King, 3.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 63Ni(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. Kitchener.  1971.  Toxic effects of trace elements on
     tne reproduction of mice and rats.  Arch. Environ. Health.  23:102-136.

Schroeder, H.A., M. Mitchener and A.P.Nason. 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. Thompsom 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.
                       I
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.  D.S. Environmental Protection Agency.  Ambient water quality
     criteria document for nickel.  Environmental Criteria and Assessment
     Office,  Cincinnati,  OH.   EPA 440/4-80-060.   NTI3 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): 33992-34303.
     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 .-nice.
     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.
   93

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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 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 modelse   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.
                                                                                  94

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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. area:  (703) 487-4650.


 II.  GENERAL  INFORMATION  AND PROPERTIES

     CAS  No.

         .    Potassium Nitrate   7757-79-1
             Potassium Nitrite   7758-09-0

     Sy nony ms

          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 inorganic 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)

          *   The properties  of  nitrate and nitrite compounds vary with the specific
             compound; some  examples  are as follows:

                                       Potassium                Potassium
                                       Nitrate                   Nitrite

     Chemical Formula                   KN03                      KNO2
     Molecular  Weight                   101.11                    85.11
     Physical State                    solid                     solid
     Boiling  Point                      400C  (decomposes)       decomposes
     Melting  Point                      334C                     440C
     Density                            2.109  (16 C)               1.915
     Vapor Pressure
     Water Solubility  (0C)             13.3 g/100cc              281 g/100cc
     Log Octanol/Water
Q K   Partition  Coefficient
     Taste Threshold
     Odor Threshold

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     Nitrate/Nitrite                                           March  31,  1987

                                          -3-


     Occurrence

          0  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).

          0  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).

          0  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 13NC>3 and 1 3NO^  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:                          ,

     8  Rapid,  homogeneous distribution of nitrate (dose unspecified)  was
        observed in rats 45 to 60 minutes after dosing by gavage (Witter
        et al., 1979).

     8  Both 13N03~ and 13N02~ 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.

     8  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).

     8  No evidence was found for bioaccumulation of nitrate or nitrite in
        any tissue (U.S. EPA, 198S).

Metabolism

     While nitrate is not directly metabolized to other compounds in humans,
nitrate is metabolized by bacteria in humans - particularly infants -  to nitrite,
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).

        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 EFFECTS
    Humans
            The lethal dose of  potassium nitrate for an adult ranges  from 54 to
            462 rngAg; the lethal dose of sodium nitrite ranges  from  32 to 154
            mg/kg (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 mg/kg/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 LDso values  for potassium  nitrate
        of 1,166 mgAg and 1,986 mg/kg,  respectively,  have been  reported
        (Windholz, 1976; WHO,  1962).  The acute oral LDso of sodium  nitrate
        in the rabbit has been reported  to be 1,955 mg/kg (Windholz,  1976).
        In the rat, reported acute oral LDsg values for sodium nitrate range
        from 46 to 120 mgAg (Druckery et al.,  1963;  Imaizumi  et al.,  1980;
        Windholz, 1976; WHO, 1962K

        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 mg/kg/3ay but not at 88
        mgAg/day (Shuval and Greuher, 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
   99

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                                     -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).

     Q  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.

     *  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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                                            -8-


       Carcinogenicity

            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 (adult  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 formula:

                    HA - (NOAEL or LOAEL) x (BW) = 	 mg/L  (	  u  /Lj
                           (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 a. 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:

 101         Recognize  the  newborn  infant  as the  population group  at  greatest risk.

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                                     -9-
     0  Recognize and consider the conversion of orally ingested nitrate to
        ni tri te .

     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 10-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 + 1 0x 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 1 1 1 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
                                                                             102

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                                       -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 NOAEL 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" toxTcTef fects 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 nicrate  as follows:'

            (10 mg/L nitrate-nitrogen)(100%) =  1 mg/L  nitrite-nitrogen
                          10
103

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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, against the 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.
                                                                            104

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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).

          0  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

          0  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.
     105

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      Nitrate/Nitrite                                           March 31,  1987

                                           -13-
           0  An alternative reduction procedure may be used (U.S.  EPA,  1979c).   In
              this method,  nitrate is reduced to nitrite with hydrazine  sulfate.
              The applicable range of this method is 0.01  to 10 mg/L.

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 die 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 the exchange but
              rather the sulfate ion.  However, field studies 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 N03~N to
              0.014 ng/L NOj-N.  In San Diego Country Estates,  Romona, California,
              the nitrate is reduced from 12.4 mg/L NO^-N to 4.2 mg/L NOj-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).
                                                                              106

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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.
          13;320-323.   (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. Alinu  34s1097-1114.

     Gaundett, R.B.  1975.   Nitrate Removal from Water by Ion Exchange.  Water
          Treat.  Focanu  24(35:172-190.

     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(4):45-47.
107

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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. Contam. 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
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Inai, K., Y. Aoki and  S. Tokuoka.  1979.  Chronic toxicity of sodium nitrite
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Ivankovic, S.  1979.  Teratogenic and carcinogenic effects of some chemicals
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Kamm, J.J., T. Dashman, H. Newmark and W.J. Mergens.  1977.  Inhibition of
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Keulow, R.W., K.L. Kropp, J. Withered and J.M. Symons.  1975.  Nitrate removal
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Kodama, F., M. Uraeda and T. Tsutsui.  1976.  Mutagenic effect of sodium
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Laverentz, D.L.  1974.  Economic feasibility of desalting systems for municipal
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       Nitrate/Nitrite                                           March  31,  1987

                                            -16-
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Nitrate/Nitrite                                           March 31, 1987

                                     -17-
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ill

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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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                                         -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 cuts 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
   113

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                                         -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 55C.  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 0.0-0.4 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 21C, pH 7.6, and
    0.1 mg/L of free chlorine residual, a 99 percent kill was achieved in less
    than one minute for . 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 4C was twice as long as it was  at 21C.  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, 21C, and pH
    7.6-8.0, a 99 percent kill of agar-passaged L_. pneumophila was usually
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                                         -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_o 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 . coli B were inoculated into several dilutions of sodium
    hypochlorite in sterile tap water,  and incubated at 24C.  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 concentrations
    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 bs 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 I.,  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 65C 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 41C to 64C 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
 115

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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 45C, 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 55-60C, 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, JL. 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 70C
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. (1982) 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 54C at the time of sampling.  Evidence that
these temperatures are not sufficient for Legionella control was also provided
Jby Meenhorst et al. (1983).  In their study, guinea pigs exposed to aerosolized
legionellae from contaminated hot tapwater (48C) contracted pneumonia.  The
strain of JL. 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 71C 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
I*, pneumophila in potable water, nosocomial Legionnaires Disease, and hot
water temperatures in six buildings.  I,, pneumophila was found in the hot
water of all four buildings in which hot water was maintained at 43-49C
                                                                           116

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 Legionella                                                   March 31,  1987

                                      -6-
 (110-120F),  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 57-60C (135-140F).  When the plumbing system
 of one of the  buildings experiencing both Ij. pneumophila and Legionnaires
 Disease was flushed with 71C water and the hot water then maintained at
 57-60C, 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 prevented by maintaining the hot water at 57-60C.

      In another attempt to eradicate L_. pneumophi la and nosocomial Legionnaires
 Disease, Yu et al. (1982) raised the temperature in the hot water storage
 tanks from 45 to 60C for 72 hours and flushed 50 showers and 360 faucets
 for 20 minutes with the 60C 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. (1936) 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 60C, 70C or 80C water baths.  At 60C, 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 10^ colonies/mL.  The authors
 recommend that when flushing distal outlets, that a flush temperature exceeding
 60C should be maintained for at least 30 minutes.

          Muraca et al. (1987) compared the relative efficacies of heat
 (60C), ozone  (1-2 mg/L), UV (30,000 uW-scm2 at 254 run) and hyperchlorination
 (4-6 mg/L) to  eradicate 1^. pneumophila in a model plumbing system.  Non-turbid
 water at 25C and 43C and turbid water at 258C 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 legionellae
 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.
117

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                                     -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
. 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 (>55C) to prevent growth of legionellae.
However, if thermostats in homes have been set low (<558C) 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 tank,s 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).
                                                                              118

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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,
     _L.  pneumophila was  isolated from  rubber  washers  and  gaskets, but not from
     fiber or plastic fittings.  The ability  of the bacteria  to  multiply wher. in
     contact with the rubber  fittings  was  demonstrated.   When the rubber fittings
     were replaced with  plastic fittings,  L.  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 whens

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

          e  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
     approacheeuld aloo bo aupported-	

          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.
119

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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 70C for one hour, but this is a
temporary measure which must be done routinely to be effective.  Maintenance
                                                                             120

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     Legionella                                                   March 31, 1987

                                          -10-
     of hot water at 55C 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,
                                                        I

          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 ta.nks 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 55Cc
d21

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 Legionella                                                   March 31, 1987

                                     -11-


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