Office of Emergency and
                                            Remedial Response
                                            Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                       HEALTH  EFFECTS ASSESSMENT
                       FOR  HEXAVALENT  CHROMIUM

                                                                          September  1984
                                     HEALTH  EFFECTS ASSESSMENT
                                      FOR HEXAVALENT CHROMIUM
                                  U.S. Environmental Protection Agency
                                   Office of Research and Development
                              Office of Health  and Environmental  Assessment
                              Environmental Criteria and Assessment Office
                                          Cincinnati,  OH  45268
                                  U.S. Environmental Protection Agency
                                Office of Emergency and Remedial  Response
                              Office of Solid Waste and Emergency Response
                                          Washington,  DC  20460
                                U.S. Environmental Protection Agency
                                Region 5, Library (PL-12J)
                                77 West Jackson Boulevard, 12th Floor
                                Chicago, IL  60604-3590


    This  report  has  been  funded  wholly  or  1n  part by  the  United  States
Environmental  Protection  Agency under  Contract  No.  68-03-3112  to  Syracuse
Research Corporation.  It has been  subject  to  the Agency's peer and adminis-
trative review, and  1t has  been  approved  for  publication as an EPA document.
Mention of  trade  names or  commercial  products  does  not  constitute  endorse-
ment or recommendation for use.

    This  report  summarizes  and evaluates Information  relevant  to  a prelimi-
nary Interim assessment  of  adverse  health  effects  associated with hexavalent
chromium.   All  estimates   of  acceptable  Intakes   and carcinogenic  potency
presented  In  this  document should  be  considered as preliminary  and  reflect
limited  resources   allocated   to  this  project.   Pertinent   toxlcologlc  and
environmental  data  were located  through  on-Hne literature  searches  of  the
Chemical  Abstracts, TOXLINE,  CANCERLINE  and  the CHEMFATE/DATALOG data bases.
The  basic literature  searched supporting  this document  1s  current up  to
September,  1984.   Secondary  sources  of  Information  have  also been  relied
upon  1n  the  preparation of  this  report  and  represent  large-scale  health
assessment  efforts  that  entail   extensive   peer   and  Agency  review.   The
following  Office of  Health  and Environmental Assessment  (OHEA)  sources  have
been extensively utilized:

    U.S.  EPA.    1980b.   Ambient  Water Quality  Criteria  for  Chromium.
    Environmental Criteria  and Assessment Office,   Cincinnati,  OH.   EPA
    440/5-80-035.  NTIS PB  81-117467.

    U.S.  EPA.   1983a.   Reportable  Quantity  Document  for Chromium  (and
    Compounds).  Prepared by  the  Environmental  Criteria  and Assessment
    Office,  Cincinnati,  OH,  OHEA  for  the  Office  of  Solid Waste  and
    Emergency Response, Washington, DC.

    U.S.   EPA.    1984.   Health   Assessment  Document   for   Chromium.
    Environmental  Criteria   and  Assessment   Office,  Research  Triangle
    Park, NC.  EPA 600/8-83-014F.   NTIS PB 85-115905.

    The Intent 1n these assessments  1s  to  suggest  acceptable exposure levels
whenever  sufficient data were available.   Values were not derived  or  larger
uncertainty  factors  were employed  when  the  variable data  were limited  1n
scope tending  to generate conservative (I.e.,  protective) estimates.   Never-
theless,  the Interim values  presented  reflect the  relative  degree  of  hazard
associated with exposure or  risk to the chemlcal(s) addressed.

    Whenever possible,  two categories  of values  have  been estimated for  sys-
temic toxicants (toxicants  for which cancer  1s  not  the endpolnt of  concern).
The  first,  the AIS  or acceptable  Intake  subchronlc,  1s an estimate of  an
exposure  level  that would  not  be  expected  to cause  adverse effects  when
exposure  occurs  during a limited  time  Interval  (I.e., for  an  Interval  that
does not  constitute a  significant  portion of  the Hfespan).  This  type  of
exposure  estimate  has  not   been  extensively  used  or  rigorously defined,  as
previous  risk  assessment   efforts  have  been  primarily  directed  towards
exposures from toxicants 1n  ambient air or water where  lifetime  exposure  1s
assumed.   Animal  data  used  for  AIS  estimates  generally Include  exposures
with durations of  30-90 days.  Subchronlc  human data are rarely  available.
Reported  exposures are  usually  from chronic  occupational  exposure  situations
or from reports of  acute accidental exposure.

    The  AIC,  acceptable  Intake  chronic,  1s  similar in  concept  to  the  ADI
(acceptable  daily  intake).   It  is  an  estimate  of an  exposure  level  that
would  not  be expected  to cause  adverse effects  when  exposure occurs  for  a
significant portion  of  the lifespan  [see  U.S.  EPA  (1980a)  for a discussion
of  this  concept].   The  AIC  1s  route specific   and  estimates   acceptable
exposure  for  a  given  route with  the  Implicit  assumption that  exposure  by
other routes is insignificant.

    Composite  scores  (CSs)  for  noncardnogens  have  also  been  calculated
where data  permitted.   These  values  are used for  ranking  reportable quanti-
ties; the methodology for their development is explained  in U.S.  EPA (1983).

    For  compounds for which there  is  sufficient  evidence of  carclnogenlclty,
AIS  and AIC values  are  not derived.   For a  discussion of risk assessment
methodology  for  carcinogens refer  to U.S. EPA  (1980a).   Since  cancer  is  a
process  that  is  not characterized by a threshold,  any  exposure  contributes
an  increment of  risk.   Consequently,  derivation of  AIS  and  AIC  values would
be  inappropriate.   For  carcinogens,  q-|*s  have been  computed  based  on  oral
and inhalation data if available.


    In  order  to  place the  risk  assessment  evaluation  1n  proper  context,
refer  to  the preface  of   this  document.   The  preface outlines  limitations
applicable to all documents of  this  series as  well  as  the appropriate Inter-
pretation and use of the quantitative estimates presented.

    Chromium exposure has   been  shown  to contribute  to  Increased  Incidence of
respiratory  cancers  1n  occupatlonally  exposed  workers.   The  particular
form(s) of chromium responsible  1s not  clear.   Increases  In  cancer  Incidence
1n  experimental  animals  following  chromium  Inhalation has  not been  demon-
strated.   However,  Intrapleural and  Intrabronchlal  Implantation of  hexava-
lent chromium compounds has  resulted 1n tumors at  the  site  of  Implantation.
Hexavalent chromium  has  been  shown   to  be mutagenlc  1n   bacterial  systems.
Using human  ep1dem1olog1cal  data,  a  unit  risk of 41  (mg/kg/day)"1  has  been
estimated  for  Inhalation   exposure.   Data are  not available  to assess  the
potential cardnogenlcHy  of hexavalent chromium following oral  exposure.

    Data  are  Inadequate  to  consider  chromium  as a carcinogen  by  the  oral
route.  Using data  from a 1-year rat drinking  water exposure study,  an  oral
AIC of 0.35 mg/day 1s estimated.

    The  Initial  draft  of  this  report  was  prepared  by Syracuse  Research
Corporation under  Contract No.  68-03-3112  for EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,  OH.   Dr.  Christopher  DeRosa and  Karen
Blackburn were the Technical Project Monitors  and  Helen Ball  was^the Project
Officer.  The final documents  1n  this  series  were  prepared  for the Office of
Emergency and Remedial Response, Washington, DC.

    Scientists from  the  following U.S. EPA offices  provided  review  comments
for this document series:

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment Group
         Office of A1r Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document series was provided by:

    Judith Olsen and Erma Durden
    Environmental Criteria and Assessment Office
    Cincinnati, OH

Technical support services for the document series  was provided by:

    Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
    Environmental Criteria and Assessment Office
    Cincinnati, OH





3.1.1. Oral 	 ,
3.1.2. Inhalation 	 ,
3.2.1. Oral 	
3.2.2. Inhalation 	 ,
3.3.1. Oral 	 ,
3.3.2. Inhalation 	


4.1.1. Oral 	
4.1.2. Inhalation 	
4.2.1. Oral 	
4.2.2. Inhalation 	
, . . 4
, , 5
. . . 5
, , , 12
. . . 12
. . . 14
. . . 15
. . . 16
. . . 18
. . . 18
. . . 19

                           TABLE OF CONTENTS (cont.)




            6.1.1.   Oral	    21
            6.1.2.   Inhalation	    21


            6.2.1.   Oral	    21
            6.2.2.   Inhalation	    21

     6.3.   CARCINOGENIC POTENCY (q-|*)	    21

            6.3.1.   Oral	    21
            6.3.2.   Inhalation	    21

 7.  REFERENCES	    23

APPENDIX: Summary Table for Hexavalent  Chromium	    37

                               LIST OF  TABLES

No.                               Title                                Page

1-1     CAS Numbers and Aqueous Solubilities  of Selected Hexavalent
        Chromium Compounds	     2

3-1     Subchronlc Oral Toxldty of Hexavalent Chromium 1n Rats  ...     6

3-2     Perforation of Nasal  Septum 1n  Chromate Workers 	     8

3-3     Nasal Lesions 1n a Chromium-Plating Plant 	     9

3-4     Chronic Toxldty of Hexavalent  Chromium to Animals
        Exposed by Inhalation 	    13

5-1     Standards for Occupational Exposure to Cr(VI)  	    20

                             LIST  OF  ABBREVIATIONS

ADI                     Acceptable dally Intake

AIC                     Acceptable Intake chronic

AIS                     Acceptable Intake subchronlc

BCF                     B1oconcentrat1on factor

CAS                     Chemical Abstract Service

CS                      Composite score

LOAEL                   Lowest-observed-adverse-effect level

LOEL                    Lowest-observed-effect level

MED                     Minimum effective dose

NOAEL                   No-observed-adverse-effect level

NOEL                    No-observed-effect level

ppm                     Parts per million

RVj                     Dose-rating value

RVe                     Effect-rating value

TWA                     Time-weighted average

                     1.   ENVIRONMENTAL CHEMISTRY AND FATE

    In the  hexavalent  state,  chromium exists  as  oxo species  (such  as  Cr03>
    ~  and   Cr02Cl2)   that   are  strongly  oxidizing   (Cotton   and   Wilkin-
son,  1980).   The  CAS   Registry  numbers  and  the  solubilities  of  a  few
Important hexavalent chromium compounds are given 1n Table 1-1.
    In  solution,   hexavalent   chromium   exists   as  hydrochromate  (HCrO^),
               2                               2-
chromate    (CrO'  )    and   dlchromate    (Cr^O-,  )    1on1c    species.     The
proportion  of  each  1on  1n  solution 1s pH  dependent.   In basic  and neutral
pH, the chromate  form  predominates.   As  the pH 1s  lowered  (6.0  to 6.2),  the
hydrochromate  concentration  Increases.    At   very   low  pH,  the  dlchromate
species predominate  (U.S. EPA, 1984).
    The primary  sources of  hexavalent chromium  1n the atmosphere  probably
are chromate chemicals used as  rust Inhibitors  1n  cooling  towers and emitted
as  mists,  partlculate matter  emitted during  manufacture and  use  of  metal
chromates,  and chromic  add  mist  from  the  plating  Industry.   Hexavalent
chromium  1n  air  could eventually react with  dust  particles  or  other  pollu-
tants  to  form  trlvalent chromium (NAS, 1974);  however, the  exact  nature of
such  atmospheric  reactions  has not been  studied extensively.   Both hexava-
lent and  trlvalent  chromium are removed  from air by atmospheric fallout  and
precipitation  (Flshbein, 1981).   The  atmospheric half-life  for  the  physical
removal mechanism  1s  expected  to  depend  on  the  particle size  and  particle
density.   Chromium  particles   of  small   aerodynamic diameter   (<10 pm)  may
remain airborne for  a  long  period  (U.S. EPA,  1984).
    Hexavalent  chromium  may  exist  In  aquatic  media  as water  soluble complex
anlons and  may persist   1n water for  a long time.   Hexavalent chromium is  a
moderately strong oxidizing agent and  may  react with organic matter  or  other

                                  TABLE  1-1

               CAS Numbers and Aqueous Solubilities of Selected
                        Hexavalent Chromium Compounds*
      Compound                   CAS No.                Water Solubility

Ammonium chromate                7788-98-9            40.5 g/100 ma at 30C
  (NH4)2 Cr04

Calcium chromate                13765-19-0            2.23 g/100 mil at 20C
Sodium chromate
Chromic acid
9 g/100
3 g/100
7 g/100
at 0

*Sources: Weast, 1980; Hartford, 1979

reducing  agents  to  form trlvalent  chromium.   The  trlvalent chromium  will

eventually  be  precipitated  as  Cr(L'xH_0.    Therefore,   1n  surface  water
                                   I- O   (L

rich  1n  organic content,  hexavalent chromium  will  exhibit  a much  shorter

lifetime (Callahan  et al., 1979).

    Any hexavalent  chromium 1n soil  1s  expected  to be reduced  to  trlvalent

chromium by the  organic  matter 1n soil.  The primary  processes  by  which the

converted trlvalent  chromium  1s  lost from soil are  aerial  transport  through

aerosol  formation   and  surface water  transport  through  runoff  (U.S.  EPA,

1984).  Very  little chromium  Is  leached  from  soil  because  1t 1s present  as

Insoluble CrO,,.xH00 (Flshbeln, 1981).

    The BCF for  hexavalent  chromium In  fish muscle  appears  to be <1.0 (U.S.

EPA,  1980b),  but values  of 125  and  192 were  obtained  for  oyster and  blue

mussel, respectively (U.S. EPA, 1980b).

2.1.   ORAL
    Absorption  of   Ingested  hexavalent  chromium  1s  estimated   to  be  <5%.
Donaldson  and Barreras  (1966)  fed  Na2slCrO.  to  rats  and  humans.   Based
on  mean  urinary  excretion of  51Cr,  absorption was  estimated  to be  2.1% 1n
humans.  In  rats,  -2% of  the  administered  dose  was absorbed based  on  fecal
excretion   of  51Cr.    When   Na.51CrO.   was  administered   Intraduodenaly
(1n humans)  or  Intrajejunally (1n  rats),  however,  absorption was  estimated
to -50 and -25%,  respectively.
    MacKenzle  et   al.   (1959)  administered   Na251CrO.  to  rats  by  gavage.
Based on urinary excretion, absorption was estimated to  be  6% 1n fasted rats
and 3% 1n nonfasted rats.
    A study by Langard et  al.  (1978)  Indicates  that water-soluble hexavalent
chromium  1s.  absorbed  rapidly  by  Inhalation.   Rats  were  exposed  to  zinc
chromate dust at  a level  of 7.35 mg/m3.   After  0,  100, 250 and  350 minutes
of  exposure,  the   concentrations  of  chromium  1n  the  blood  (yg/ms,)  were
0.007, 0.024, 0.22 and 0.31,  respectively.
    In  the  second  part of this  study, rats  were  exposed  to the  same  level
for 6 hours on 4 consecutive days.   Blood  concentrations  appeared to peak at
the end of  the second  exposure and  then  began to decline slowly.  Mean blood
chromium values measured  at  the  end  of  each exposure  period  averaged  0.03,
0.56,  0.46 and 0.34  yg/ma,  for   exposures  1-4,  respectively.    No  signifi-
cant  differences  1n absorption  as  reflected by  blood chromium  levels  were
noted between the  sexes or between day and night exposures.

3.1.1.   Oral.  Data from  two  subchronlc  studies Involving  oral  exposure  to
hexavalent chromium are summarized 1n Table 3-1.
    MacKenzle et al.  (1958)  exposed  groups  of  rats,  both  male and female,  to
potassium dlchromate (0-25 ppm of hexavalent chromium)  1n  drinking water  for
1  year.   Since  no effects were  observed  at any  level  of treatment,  a  NOEL
can be  established based  on body weight,  gross  external condition,  hlsto-
pathologlcal  analysis  and  blood  chemistry.  Converting 25 ppm  to mg/kg/day,
25  ppm  (mg/a, water)  1s multiplied  by  the  average water  consumption/day  for
a rat  (0.035 8,/day),  and  divided by the  weight  of  an average  rat (0.35  g),
to give a value of 2.50 mg/kg/day.
    The  study  by  Gross  and Heller  (1946),  lacking detailed  pathological
analysis and  sufficiently  large  sample sizes  (two  animals/treatment  level),
cannot be used for quantitative risk assessment.
3.1.2.   Inhalation.    Pertinent  data   regarding   subchronlc  exposure   of
animals  to  hexavalent chromium  by   Inhalation  could not  be located  1n  the
available literature;  however, there are  many  studies regarding occupational
exposure of humans to hexavalent  chromium.
    Bloomfleld  and Blum   (1928)   examined  23  men  from  6   chromium  plating
plants 1n the United  States.  Fourteen of  these  workers  typically spent  2-7
hours/day over  vats  of  chromic  add,  which  generated airborne  hexavalent
chromium  ranging  from 0.12-5.6  mg/m3.   These men   experienced nasal  tissue
damage.  Including  perforated septum (2),  ulcerated  septum (3), chrome holes
(6),  nosebleed  (9) and  Inflamed mucosa  (9).    In  general,  the  9 remaining
workers examined, not  directly exposed  to  chromium  vapors, had  only Inflamed

                                                 TABLE 3-1

                           Subchronic Oral Toxlclty of Hexavalent Chromium  In Rats
Number of Animals
Dose and Compound
Period of
Endpolnts Monitored and Effect
9 females, 12 males
  at 25 ppm
10 males, 10 females
  at 0 ppm
8 males, 8 females
  at other treatment

1 male, 1 female per
  level of treatment
0, 0.45,  2.2,  4.5,
7.7, 11,  25 ppm as
potassium dlchromate
In drinking water
0, 0.036,  0.072,
0.143, 0.2854 Cr(VI)
as zinc chromate  or
0, 0.033,  0.067,
0.134 or 0.268%
Cr(VI) as  potassium
chromate In feed
1 year       No effect based on body weight,
             gross external condition, hlsto-
             pathologlcal analysis and blood
2-3 months   Animals were "subnormal" and
             sterile at all doses of zinc
             chromate and at 0.134 and
             0.268% potassium chromate.
et al., 1958
Gross and
Heller, 1946

    Several  other  studies  report  nasal  tissue  destruction  resulting  from
hexavalent chromium.   The United  States Health  Public  Service conducted  a
study of workers 1n seven chromate-produdng plants  1n  the  early 1950s.   The
results Indicated  severe nasal tissue  destruction  but exposure levels  were
not measured;  hence,  the data  are of  limited  usefulness  (Federal  Security
Agency, 1953).
    Mancuso  (1951) reported  on physical examinations  of  a random  sample  of
97 workers from  a  chromate-chemlcal plant.   The  results, presented  in  Table
3-2, Indicated that 61  of the 97 workers (63%)  had  septal  perforation.   The
data suggested to  the  author that Cr(III) may  be partly  responsible for the
perforations;  however,   later  studies  have  not  provided  support   for  this
    The results  of examinations  of nine workers  In a chrome-plating  plant
are shown  1n  Table 3-3.  Analyses of air samples showed  chromium  concentra-
tions  of  0.18-1.4 mg/m3.   Some  degree  of  nasal  septal ulceratlon  was  seen
1n  7  of the  9 men, with 4  of 7  demonstrating  frank perforations  (Kleinfeld
and Russo, 1965).  The  effects of chromium  exposure  for  a specific  length of
time at a fixed concentration were not studied.
    Vigllani  and  Zurlo  (1955) reported  nasal  septal perforation 1n workers
exposed  to   chromic  acid  and  chromates  In  concentrations  of   0.11-0.15
mg/m3.  The   lengths of exposure were  not  known.   Otolaryngologic  examina-
tions  of  77  persons exposed to  chromic  add aerosol during  chrome plating
revealed  19%  to  have   septal  perforation  and   48% to  have  nasal  mucosal
irritation.   These people averaged  6.6 years  of  exposure  to  an  air chromium
concentration  of  0.4  mg/m3.   In  14  persons,  paplllomas  of the oral  cavity
and  larynx  were  found.   The  diagnosis  of papilloma was  confirmed  by  hlsto-
loglc  examination.  There  were   no signs  of  atypical  growth  or  malignant
degeneration  (Hanslian  et al., 1967).


                                  TABLE  3-2

               Perforation of Nasal  Septum 1n Chromate Workers*
Ratio of
Insol Cr+3 Chromium concentration, No. Workers
to sol Cr+6 yg/fn3 (as Cr) Examined
Workers 1n plant

1.1 to 4.9:1


Office workers

0.26 - 0.51
0.26 - 0.51
0.26 - 0.51


Workers with
Septal Perforation


*Source:   Mancuso,  1951

Insol  = Insoluble;  sol  = soluble

                                  TABLE 3-3

                  Nasal  Lesions  In  a  Chromium-Plating  Plant*
Case Age
1 30
2 19
3 19
4 18
5 47
6 45
7 23
8 20
9 48
Duration of
perforated septum
perforated septum
perforated septum
perforated septum
ulcerated septum
ulcerated septum
ulcerated septum
moderate Injection of
septum and turblnates
moderate Injection of
*Source:  Klelnfeld and Russo,  1965

    The literature suggests  that  chromium  compounds  are also responsible for
a wide  variety of other  respiratory effects.  German  studies  demonstrating
mixed results  from exposure  to chromium compounds were  reviewed  by the U.S.
EPA (1984).  Because In all  of  these studies  no correlation between symptom-
atology, physical  signs,  length of  exposure  and  dose  of  chromium compounds
was available,  they  are  not  useful  for risk  assessment and are not reviewed
    In  the  United States, 897  workers In  chromate-produclng plants   had  a
higher  Incidence of  severely red  throats and  pneumonia, but did not show any
Increase 1n  the Incidence of  other  respiratory diseases when  compared with
control groups.   Although bilateral hllar enlargement  was  observed,  there
was  no  evidence of  excessive  pulmonary flbrosls  1n these  workers  (Federal
Security Agency, 1953).  The various lung  changes  described 1n  these workers
may  represent  a nonspecific reaction to  Irritating  material or  a  specific
reaction  to  chromium  compunds.   Many  of  the  conditions  mentioned  occur
widely  In the general population (NAS, 1974).
    Gomes  (1972)  examined  303  employees   who  worked  1n   81  electroplating
operations 1n  Sao  Paulo,  Brazil.   Over two-thirds of  the  workers had mucous
membrane  or  cutaneous  lesions,   with  many  of  them  having  ulcerated  or
perforated nasal  septa.   The  duration  of   exposure  was not  stated,  but  the
author  mentioned  that  the harmful  effects  were noted  1n <1  year.   A direct
correlation  between  workers exposed to  a given  airborne  concentration  of
chromium (VI) and the development of harmful effects  could  not be made.
    Cohen and  Kramkowskl  (1973)  and Cohen   et al.  (1974) examined 37 workers
employed  by  a  chromium-plating  plant.    Within  1  year  of employment,  12
workers experienced  nasal  ulceratlon or perforation.   The  airborne chromium
(VI) concentrations ranged from <0.71-9.12

    In  a  chromium plating  plant where  the maximum  airborne chromium  (VI)
concentration was  3  yg/m3,  no  ulcerated  nasal  mucosa  or perforated  nasal
septa were  found;  however,  half of  the  32 employees had  varying  degrees  of
mucosal Irritation (Markel  and Lucas, 1973).  The  authors did  not  consider
this  to be  significant, because the  survey was  carried  out  at the  peak  of
the 1972-1973 Influenza epidemic.
    Machle  and   Gregorlus   (1948)   reported an  Incidence  of  nasal  septa!
perforation  of  43.5% In  354  employees  who worked 1n a  chromate-produdng
plant that  manufactured  sodium chromate  and bichromate.   At  the  time of the
study,  airborne  chromate   concentrations   ranged   from  10  to  2800  yg/m3.
The  plant  had been  1n  operation for at least 17  years,   and  some employees
probably worked 1n the  plant when  reverberatory  furnaces,  a  prominent source
of high chromate exposure,  were used.
    In  a more recent study,  lung function,  the condition  of  the nasal septum
and  subjective  symptoms  related  to  respiratory  health  (data obtained  by
questionnaire)  were  compared  In unexposed controls  (119) and  workers  (43)
exposed   to  chromic  add   1n  chrome  plating  operations   (Undberg  and
Hedenstlerna, 1983).   Workers  were  further divided Into  low (<2)  and  high
(>2  yg  Cr* /m3)   exposure  groups.   Complaints   of diffuse  nasal  symptoms
("constantly  running nose,"   "stuffy  nose" or  "a  lot  to  blow  out")  were
registered  by 4/19 workers  1n  the  low group and  half  of the  24  workers  1n
the  high  group.   Complaints  were  not  registered  by  workers exposed  to  <1
yg/m3.   The frequency  of  throat  and chest symptoms  did not  appear  to  be
related to  treatment.
    Examination of the nasal  septum revealed  that damage was  significantly
greater  1n  exposed  workers  than  1n  unexposed  controls  and  appeared  to  be
somewhat more severe 1n the high group  than the low group.   Measurements  of

lung function revealed  a  detrimental  effect due to  exposure  to  chromic  add
fumes,   but  significant  differences  between  low and  high  groups  were  not
observed.  There  was  a  tendency  for  lung  function  parameters to  return  to
normal  over  a 2-day weekend.
    Various  other  disease  states  have been  attributed to chromium,  but,  In
most cases,  the etlologlc  relation  to  chromium  1s  doubtful because  of  the
presence  of  other  chemicals  (NAS,  1974).   These studies,  reviewed  by  the
U.S. EPA (1984), will  not be reviewed  here.
3.2.   CHRONIC
3.2.1.    Oral.  Only  one chronic study  pertaining  to  the oral   toxldty  of
hexavalent chromium was located 1n the  available literature.  Anwar  et  al.
(1961)   exposed  dogs  orally to potassium  chromate  1n  drinking  water for  4
years.    Treatment  levels  were 0, 0.45,  2.25,  4.5,   6.75 and  11.2 ppm potas-
sium chromate;  there  were  two dogs/group.   No  effects  were observed  with
regard  to  gross and  microscopic  analysis  of  all  major  organs,  urlnalysls,
and weights  of  spleen,  liver  and  kidney.   The exposure  of  11.2 ppm  can  be
converted to units  of mg/kg/day by multiplying 11.2  ppm by the average dally
water consumption  for a dog  of  average  weight (0.0275  i/kg/day)  to produce
a NOEL  of 0.31  mg  potassium chromate/kg/day.   This  1s  equivalent to 0.089 mg
3.2.2.    Inhalation.   Data  regarding  the  chronic  toxldty  of  hexavalent
chromium administered  by Inhalation  are  summarized 1n Table 3-4.
    Netteshelm  et  al.  (1971)  exposed  mice  to  an  aerosol  of  calcium chromate
at  levels  of   either   10  mg/m3  (4.33  mg  Cr(VI)/m3)  or  30 mg/m3   (10  mg
Cr(VI)/m3)  for  5  hours/day,  5 days/week  for  life.    Based  on  epithelial
necrosis,  marked   hyperplasla  and  atrophy   of   the   pulmonary   bronchi,
emphysema-like  changes, and atrophy  of  the spleen and  liver,  a  LOAEL can be

                                                                              TABLE 3-4

                                               Chronic  Toxlclty of Hexavalent Chromium  to Animals Exposed by Inhalation
Number of Animals
136 total (male
and female);
unspecified number
of controls
Dose and Compound
13 or 30 mg calcium
chromate aerosol/m3
[4.33 or 10 mg Cr(Vl)/m,
Period of
5 hours/day,
5 days/week
for life
Endpolnts Monitored and Effect
At 6-month Intervals, bacteriological.
parasltologlcal, vlrologlcal and htsto-
pathologlcal analyses were performed.
Netteshelm et
al.. 1971
2 mg calcium chromate           S89/B91  days
aerosol/m [0.67  Cr(Vl)/m]
            Hamsters      100
                                                                                                10  mg/m  level:
                                                                                                4.33 mg/m'  level:
                                                                                        early death, rapid
                                                                                        weight loss, fatty
                                                                                        liver, distended and
                                                                                        atrophlc Intestines

                                                                                          epithelial necro-
                                                                                          sis, marked hyper-
                                                                                          plasla and atrophy
                                                                                          of pulmonary
                                                                                          bronchi, alveolar
                                                                                          scarring after 6
                                                                                          months; after 2
                                                                                          years, atrophy of
                                                                                          spleen and liver
Laryngeal hyperplasla (2) and laryn-
geal metaplasia (3) were found upon
examination Immediately after treat-
ment was stopped.

Squamous metaplasia (8) and laryngeal
hyperplastas (8) were found Immedi-
ately after treatment was stopped.
No other details were provided.
                                                                                                                                          Laskln.  1972

established at  4.33 mg  Cr(VI)/m3.   Adjusting  to units  of mg/kg/day,  4.33
mg/m3 is  multiplied  by the product  of  5 hours/24 hour  day times  5  days  of
exposure/week  times   the   average   Inhalation  rate/day  for  a  mouse  (0.05
mVday).  This  value  1s  subsequently divided  by  the average body  weight  of
a mouse (0.03 kg) to yield a value of 1.07 mg CR(VI)/kg/day.
    Laskin (1972) exposed  rats and  hamsters  to calcium  chromate  aerosol  at a
level of  2 mg/m3  (0.67  mg Cr(VI)/m3)  for  589 of  891  days.  Although  some
laryngeal hyperplaslas and metaplasias were  observed  1n  both species  tested,
details pertaining to controls were not given 1n  the  available review.
3.3.1.   Oral.   Pertinent  data  regarding  the  teratogenidty   of   orally
administered  hexavalent   chromium   could  not  be   located   in  the  available
3.3.2.   Inhalation.   Pertinent   data   regarding   the   teratogenicity   of
inhaled hexavalent chromium could not be located  in the available literature.
    Pertinent data  regarding  the  toxicant  Interactions of  hexavalent  chro-
mium with other compounds could not be located in  the available literature.

                             4.  CARCINOGENICITY
4.1.1.   Oral.    Pertinent  human  data  regarding'  the  cardnogenlcHy  of
Ingested hexavalent chromium  could  not be  located  1n the available  litera-
4.1.2.   Inhalation.    Occupational   exposure   to   chromium  compounds  via
Inhalation  has   been  studied  1n  the   chromate,  chrome-plating  and  chrome
pigment Industries.
    Workers In the chromate Industry are exposed to both  tMvalent  and hexa-
valent  compounds  of  chromium.   Ep1dem1olog1cal  studies  of chromate  produc-
tion plants 1n Japan, Great Britain, West Germany and the  United  States  have
revealed a  correlation  between  occupational  exposure to  chromium and  lung
cancer, but  the  specific etlologlcal  agent was not  Identified  (Machle and
GregoMus, 1948;  Brlnton et al., 1952;  Baetjer,  1950a,b; Mancuso  and  Hueper,
1951; Mancuso, 1975;  Taylor, 1966; Enterllne, 1974; Hayes  et  al.,  1979;  H111
and  Ferguson,  1979;  Bldstrup,  1951;   Bldstrup  and  Case,  1956;  Alderson et
al., 1981; Todd,  1962; Watanabe  and Fukuchi, 1975;  Ohsakl  et  al.,  1978;  Sano
and  MHohara, 1978;  Satoh et al.,  1981;  Korallus  et  al., 1982).   Of  these,
the  studies by Mancuso and Hueper (1951) and Mancuso  (1975) are of  Interest,
since they were  used  by  the Carcinogen Assessment Group to derive  a  cancer-
based criterion  for  lifetime exposure  to chromium (U.S. EPA, 1984).
    Mancuso and  Hueper  (1951)  analysed the  vital  statistics  of a  cohort of
chromate workers  (employed  for  >1 year  from 1931-1949 1n a  Pa1nesv1lle, OH
chromate plant)  In order  to Investigate lung cancer associated  with chromate
production.  Of  the  2931  deaths of males 1n  the county  where the  plant was
located, 34  (1.2%) were  due to  respiratory cancer.   Of  the  33 deaths  among
the  chromate  workers,  however,   6  (18.2%)  were  due  to respiratory  cancer.

The difference  between  these  groups 1s significant at  p<0.01.   Furthermore,
two of  these workers exposed  primarily to  Insoluble  chromlte had -390  and
250 yg  chromium/10 g of  lung tissue,  respectively.   By contrast,  chromium
levels 1n the lungs of nonexposed Individuals were nearly zero.
    In  an  update  of the  Mancuso  and  Hueper  (1951)  study,  Mancuso  (1975)
followed 332  of the  workers  employed  from  1931-1951  until 1974.  By  1974,
>50%  of  this cohort  had  died.   Of  these  men, 63.6,  62.5  and 58.3% of  the
cancer  deaths  for  men  employed  from  1931-1932,  1933-1934  and  1935-1937,
respectively, were  due  to lung  cancer.  Mancuso  (1975) reported  that  these
lung  cancer  deaths were  related  to Insoluble  (tMvalent), soluble  (hexava-
lent)  and  total  chromium  exposure, but the  small  numbers  involved make this
relationship questionable (U.S. EPA, 1984).
    In  two  studies derived from the chrome  pigment  industry, workers  were
exposed  only  to  hexavalent  chromium.   In both  studies,  exposure  to  chromium
was correlated  with  lung  cancer  (Langard  and  Norseth, 1975;  Davies,  1978,
    Studies  from the chrome-plating industry  either demonstrated  a  correla-
tion  between  lung  cancer and  exposure  to  chromium compounds  (Royle,  1975),
or were  inconclusive  (Silversteln et al., 1981; Okubo and Tsuchlya, 1979).
4.2.1.   Oral.   Pertinent  data  regarding  the  carclnogenlcity  of  orally
administered  hexavalent  chromium in animal  systems  could  not  be  located in
the available literature.
4.2.2.   Inhalation.  To  date, It has  not  been possible to Induce tumors  in
laboratory animals  by exposing  them  to chromium (either tMvalent  or  hexa-
valent)  via  inhalation.

    Baltjer et al.  (1959)  chronically  exposed three strains of  mice  (Strain
A,  Swiss,   C57B1)   and  mixed-breed  rats  to  ~1  mg  chromium  dust/m3,  and
reported  no  Increase  In  the  Incidence  of  lung  tumors  with  respect  to
untreated  controls.   Similar results  were obtained by  Steffee and  Baetjer
(1965) for  Wlstar rats,  rabbits  and guinea pigs exposed  to chromium dust.
    Netteshelm et al. (1971)  exposed  C57B1 mice to 4.33  mg  calcium chromate
dust/m3, 5 hours/day,  5  days/week  for  life,  and  reported  an Increase  1n
the  number of  lung  tumors  with  respect  to controls.   Since  statistical
analysis was  not performed,  however,  the significance  of  these  results  1s
unclear.   In  a  review of this  study,  IARC (1980)  concluded that  a signifi-
cant excess of treatment-related tumors was not observed.
    There  1s  some  evidence   that  hexavalent  chromium  may  be  carcinogenic
following  Intrapleural  Implantation  of  calcium  chromate (Hueper  and  Payne,
1962) or 1ntrabronch1al Implantation of  strontium chromate,  calcium chromate
or  zinc chromate  (Levy  and Martin,  1983).   These  tumors,  however,  were
observed at the  site  of Implantation.   In addition, Stelnhoff  et  al.  (1983)
have  shown that  Intratracheal  administration  to  rats  both  Na?Cr?07  and
CaCrO.  produced  Increased  Incidences  of  lung  tumors  following 30  months  of
    In  contrast, zinc  chromate  was not  carcinogenic following  Intratracheal
Implantation  (Steffee  and Baetjer,  1965; Baetjer  et  al.,  1959), nor  were
barium  chromate, chromium  dust,  lead  chromate, chromlte  ore,  powdered chro-
mium  metal,  potassium  chromate  and   sodium  dlchromate  following  1ntra-
bronchlal,   Intrapleural or  Intratracheal Implantation  (Steffee  and Baetjer,
1965;  Baetjer  et al..  1959;  Hueper,   1955,  1958;  Payne,  1960;   Hueper  and
Payne, 1962; Levy and Venltt, 1975).

    Hexavalent chromium has been  shown  to  be mutagenlc 1n bacterial  systems
1n  the  absence  of  a  mammalian  activating  system (VenHt  and  Levy,  1974;
N1sh1oka,  1975; Nakamuro et a!.,  1978; Green et al.,  1976; Kanematsu  et al.,
1980; Lofroth  and  Ames,  1978; Newbold  et  al., 1979;  Bonattl  et al.,  1976;
Fukanaga et al., 1982), and not mutagenlc when a mammalian activating system
1s present  (Lofroth, 1978; PetrllH and Deflora, 1977,  1978a,b).  Hexavalent
chromium 1s also mutagenlc 1n eucaryotlc test  systems  (Bonattl et al.,  1976;
Newbold et  al., 1979;  Fukanaga  et  al.,  1982) and  clastogenlc  In cultured
mammalian  cells  (Raffetto,  1977;  Levls and  Majone,  1979;  Umeda and  N1shi-
mura, 1979;  Tsuda  and  Kato,  1977;  Newbold  et al.,  1979;  Nakamuro et al.,
1978; Stella  et al.,  1982;  Ohno  et  al.,  1982; Gomez-Arroyo  et al.,  1981;
Wild, 1978; Sarto et al.,  1982).
    IARC (1980)  has  concluded  that  there  1s  sufficient evidence of respira-
tory cardnogenlcHy  1n men occupatlonally  exposed during  chromate  produc-
tion;  however,   the  ep1dem1olog1cal  data  do  not  allow  elucidation  of  the
relative contributions  to carcinogenic  risk  of metallic  chromium,  tMvalent
chromium,   hexavalent  chromium,   or  of  soluble  versus  Insoluble  chromium
compounds.    Furthermore,   the  animal  studies   using   non-natural  routes   of
administration  have  provided  sufficient evidence  that certain  compounds  of
hexavalent  chromium  (sintered  calcium chromate,   lead  chromate,   strontium
chromate,   sintered  chromium trioxlde  and  zinc chromate) are carcinogenic.
Therefore,   IARC  (1982)  classified chromium and chromium compounds as  Group  I
chemicals.    Applying  the criteria  proposed  by   the  Carcinogen Assessment
Group  of  the  U.S.  EPA for  evaluating the  overall weight  of  evidence  for
cardnogenlcHy  to  humans (Federal  Register,  1984),  hexavalent  chromium  1s
most appropriately designated  a Group A -  Human Carcinogen.


                     5.   REGULATORY  STANDARDS  AND  CRITERIA

    Recommended  standards  for occupational  exposure to hexavalent  chromium
compounds are summarized 1n Table 5-1.
    The  U.S.  EPA (19805)  has  recommended a  criterion  of  0.05 mg/8.  for  the
concentration  of hexavalent  chromium  1n  water.   They  also  established  an
Interim ADI of 0.175 mg/man/day  for  chronic  1ngest1on  of  hexavalent  chromium
based  on  the  study  of  MacKenzle  et  al.   (1958).    These  levels  are  not
Intended  to  protect against  potential  carcinogenic  effects of  chromium  VI
compounds.  The  considered opinion when these levels were  suggested  was  that
Cr(VI)  would  potentially  be  reduced   In  the  gastrointestinal  tract   to
Cr(III).  Although  this  1s a plausible assumption,  conclusive data  are  not

                                  TABLE 5-1
                Standards for Occupational Exposure to Cr(VI)
Noncardnogenlc chromium VI*

Carcinogenic chromium
Soluble chromic or chromous salt
Insoluble salts
Water soluble compounds of
chromium (VI) (noncarclnogenlc)
Insoluble compounds of chromium
(VI) (carcinogenic potential)
0.025 TWA
0.050 ceiling
0.001 TWA
0.500 TWA
1.000 TWA
0.05 TWA

0.05 TWA
NIOSH, 1975

NIOSH, 1975
OSHA, 1978
OSHA, 1978
ACGIH, 1983

ACHIH, 1983
*Monochromates  and  dichromates  of  hydrogen,  lithium,  potassium,  rubidium,
 cesium, ammonium and chromic oxide

                              6.  RISK ASSESSMENT
6.1.1.   Oral.   A  1-year  oral  study  has established  a  NOEL  for  hexavalent
chromium  in  rats  of  2.5  mg/kg/day (MacKenzle  et al.,  1958)  (see  Section
3.1.1.).   Applying  an  uncertainty  factor  of  100  (10  for  Interspedes
extrapolation and  10  for  1nter1nd1v1dual variability) and assuming a  70  kg
body weight results 1n an estimated oral AIS of 1.75 mg/day.
6.1.2.   Inhalation.   Hexavalent   chromium  has  been   shown  to  be  a   human
carcinogen  by  the  Inhalation route   for  which  data  are  sufficient  for
computation  of   a  q,*.   It  1s  Inappropriate,  therefore,  to calculate  an
Inhalation AIS for hexavalent chromium.
6.2.1.   Oral.   Using the  oral  AIS of 1.75  mg/day   and  applying an  addi-
tional  uncertainty  factor  of 5 to  adjust  for  a  study  which 1s  of  Inter-
mediate duration between  subchronlc and chronic  results  in an  .estimated oral
AIC of 0.35 mg/day.  This 1s  the approach recommended by U.S. EPA (1985).
6.2.2.   Inhalation.   Hexavalent   chromium  has  been  shown  to  be  a   human
carcinogen  for  which data  are sufficient  for  computation of  a q  *.   It  is
inappropriate,  therefore,  to  calculate an  Inhalation   AIC  for  hexavalent
6.3.1.   Oral.   The  lack  of  data  regarding  the  carcinogeniclty   of  orally
administered hexavalent chromium precludes assessment of carcinogenic risk.
6.3.2.   Inhalation.  Based  on the epidem1olog1cal study  of Mancuso  (1975),
the  Carcinogen   Assessment  Group   has   derived  a  cancer-based  criterion for
exposure  to  chromium by  Inhalation (U.S.  EPA,  1984).  Assuming  a lifetime

exposure  to  1  yg  elemental  chrom1um/m3,   the  upper  limit  unit  carcino-
genic   risk   was   estimated   to  be   1.16xlO~2   (yg/m3)"1   1n   units   of
lifetime  risk per  1   yg/m3  exposure  for  humans.   This  unit risk  may  be
transformed  to  units  of  (mg/kg/day}"1  as  follows:   the  concentration  of
1  yg/m3  Is  equivalent  to  20  yg/day  or   0.02   mg/day   assuming  a   human
respiratory  rate  of  20  mVday.   Assuming  an  average  human  weighs  70  kg,
the  dosage  becomes   2.857xlO~4  mg/kg/day.    The   unit  risk   of   1.16xlO"2
(yg/m3)"1  *   2.857xlO~4   mg/kg/day   results   1n   an   expression  of   unit
risk of 41 (mg/kg/day)'1.

                                7.   REFERENCES

ACGIH  (American  Conference  of  Governmental  Industrial  Hyglenists).   1983.

Threshold Limit  Values  for  Chemical  Substances  and  Physical  Agents 1n  the

Workroom Environment  with  Intended Changes  for  1983-1984.  Cincinnati,  OH.

p. 15.

Alderson, M.R.,  N.S.  Rattan  and  L. Bldstrup.   1981.   Health  of workmen  1n

the  chromate-platlng  Industry In  Britain.   Br.  J.  Ind.  Med.   38:  117-124.

(Cited 1n U.S. EPA, 1984)

Anwar, R.A.,  C.F.  Langham,  C.A.  Hoppert, B.V.  Alfredson  and  R.U.  Byerrum.

1961.   Chronic  toxlclty   studies.   III.  Chronic   toxldty  of  cadmium  and

chromium 1n dogs.  Arch. Environ.   3:  456.  (Cited  1n U.S.  EPA,  1984)

Baetjer,  A.M.  1950a.   Pulmonary carcinoma 1n  chromate workers.   I.  A review

of  the  literature and  report of  cases.  Arch.  Ind. Hyg.  Occup.   Med.   2:

487-504.   (Cited 1n U.S. EPA, 1984)

Baetjer,  A.M.   1950b.  Pulmonary  carcinoma  In chromate workers.   II.  Inci-

dence  on  basis  of   hospital  records.   Arch.  Ind.  Hyg.  Occup.  Med.   2:

505-516.   (Cited 1n U.S. EPA, 1984)

Baetjer,   A.M.,  J.F.  Lowney, H.  Steffee and  V.  Budacz.   1959.   Effect  of

chromium on  Incidence of   lung tumors  In mice and rats.   Arch.  Ind. Health.

20:  124-135.   (Cited in IARC, 1980; U.S. EPA, 1984)

Bldstrup, P.L.   1951.   Carcinoma of  the  lung  In  chromate workers.  Br.  J.
Med.  8: 302-305.  (Cited In U.S. EPA,  1984)

Bldstrup, P.L. and  R.A.M.  Case.   1956.   Carcinoma of the  lung  1n  workmen  1n
the bichromates-producing  Industry  1n  Great  Britain.   Br.  J. Ind.  Med.   13:
260-264.  (Cited In U.S. EPA, 1984)

Bloomfleld,   O.J.  and W.  Blum.   1928.   Health  hazards  1n chromium plating.
Public Health Rep.  43: 2330-2351.  (Cited 1n U.S.  EPA,  1984)

Bonatti, S., M.  Melnl  and  A.  Abbondandolo.   1976.   Genetic effects of potas-
sium  dlchromate  1n  Schlzosaccharomyces  pombe.   Mutat.  Res.   38:  147-150.
(Cited 1n U.S. EPA, 1984)

BMnton, H..P.,  E.S.  Rasler and  A.L.  Koven.   1952.  Morbidity  and mortality
experience  among chromate  workers.   Public Health  Rep.   67:  835-847.  (CHed
In  U.S.  EPA, 1984)

Callahan, M.A.,  M.W.  Sllmak and N.W.  Bagel,  et  al.    1979.   Water-Related
Environmental Fate  of  129  Priority  Pollutants,  Vol.  II.  U.S.  EPA, Office of
Water  Planning and  Standards,  Office  of Water and  Waste Management, Washing-
ton,  DC.  EPA 440/4-79-029.

Cohen,  S.R. and R.S.  Kramkowsl.  1973.   Health  Hazard  Evaluation Determina-
tion,  Report No. 72-118-104.  Cincinnati, OH,  U.S. DHEW, NIOSH.   (CHed  In
U.S.  EPA, 1984)

Cohen, S.R., O.M. Davis and R.S. Kramkowsk!.   1974.   Clinical  manifestations

of chromic  add  toxlclty  -- Nasal  lesions  1n electroplate workers.   Cutls.

13: 558-568.  (Cited 1n U.S.  EPA,  1984)

Cotton,  F.A.   and   G.  Wilkinson.   1980.   Advanced  Organic  Chemistry.    A

Comprehensive Test,  4th ed.   John  Wiley  and  Sons,  NY.   p.  719-736.

Davles,  J.M.   1978.   Lung-cancer  mortality  of  workers  making chrome pig-

ments.  Lancet.  1:  384.   (Cited 1n U.S. EPA,  1984}

Davles,  J.M.   1979.  Lung cancer  mortality  In workers  1n chromate  pigment

manufacture: An  ep1dem1olog1cal  survey.  J.  011  Chem. Assoc.   62:  157-163.

(Cited 1n U.S.  EPA,  1984)

Donaldson,  R.M.  and R.F.  Barreras.  1966.   Intestinal  absorption of  trace

quantities  of  chromium.   J.  Lab   CUn.  Med.   68:  484-493.   (Cited  1n U.S.

EPA, 1984)

Enterllne,  P.E.    1974.   Respiratory   cancer  among  chromate  workers.   J.

Occup. Med.  16:  523-526.   (Cited  1n U.S. EPA, 1984)

Federal  Register.   1984.   Environmental Protection Agency.   Proposed guide-

lines for carcinogenic  risk  assessment.   Federal  Register.  49:  46294-46299.

Federal  Security Agency.   1953.    Health  of   Workers  1n   Chromate  Producing

Industry.   A  Study.   U.S.   Public  Health  Service  Publication   No. 192.

Washington,  DC.   U.S.  Government  Printing Office.   131  p.   (Cited  1n U.S.

EPA, 1984)


F1shbe1n, L.   1981.   Source, transport  and  alterations of metal  compounds:
An Overview.  I. Arsenic, beryllium, cadmium, chromium  and  nickel.   Environ.
Health Perspect.  40:  43-64.

Fukanaga, M., Y. Kurachl and Y. M1zuguch1.   1982.   Action  of  some metal  Ions
on yeast  chromosomes.   Chem. Pharm.  Bull.   30:  3017-3019.   (Cited 1n  U.S.
EPA,  1984)

Gomes, E.R.  1972.  Incidence of  chromium-Induced  lesions  among  electroplat-
ing workers 1n  Brazil.   Ind.  Med.   41:  21-25.  (Cited In U.S.  EPA, 1984)

Gomez-Arroyo, S., M.  Altamlrano and R.  V1llalobos-P1etr1n1.   1981.  Slster-
chromatld exchanges Induced  by  some chromium compounds  1n  human  lymphocytes
1n vitro.  Mutat. Res.   90:  425-431.  (Cited  In  U.S. EPA, 1984)

Green, M.H.L.,  W.J.  Muriel  and  B.A.  Bridges.   1976.   Use  of a  simplified
fluctuation test to detect  low  levels  of mutagens.   Mutat. Res.   38:  33-42.
(Cited 1n U.S.  EPA,  1984)

Gross, W.G. and  U.G.  Heller.   1946.  Chromium 1n animal  nutrition.  J.  Ind.
Hyg.  Toxlcol.  28:  52.   (Cited  1n  U.S.  EPA,  1984)

Hansllan, L., J. Nauratll, J. Jurak  and  M. Kotrle.   1967.   Upper  respiratory
tract  lesions   from  chromic  add aerosols.   Pracovnl.  Lekar.   19:294-298.
(Czech.,  English Abstr.) (Cited  1n U.S. EPA,  1984).

.Hartford,  W.H.   1979.   Chromium Compounds.   .In.:  K1rk-0thmer  Encyclopedia of

 Chemical  Technology,  3rd ed.,  Vol.  6,  M. Grayson and  D.  Eckroth,  Ed.  John

 Wiley and  Sons,  Inc., NY.  p. 82-120.

 Hayes,  R.B.,  A.M.  L1l1enf1eld and L.M.  Snell.   1979.   Mortality 1n chromium

 chemical  production workers: A prospective  study.   Internat.  J. Ep1dem1ol.

 8:  365-374.

 H111,  W.J. and  W.S. Ferguson.   1979.   Statistical  analysis of ep1dem1olog1-

 cal  data  from  chromium chemical manufacturing  plant.   J. Occup.  Med.   21:

 103-106.   (Cited 1n U.S.  EPA, 1984)

 Hueper,  W.C.   1955.    Experimental  studies  1n  metal  cardnogenesls.  VII.

 Tissue  reactions  to  parenterally  Introduced powdered  metallic chromium and

 chromlte ore.   J.   Natl.  Cancer Inst.   16(2): 447-469.   (Cited 1n U.S. EPA,


 Hueper,   W.C.    1958.   Experimental  studies  1n  metal  cancerogenesls.   X.

 Cancerogenlc  effects of  chromlte  ore  roast  deposited 1n  muscle tissue and

 pleural  cavity  of  rats.   Am.  Med.  Assoc. Arch.  Ind.  Health.   18: 284-291.

 (Cited  1n U.S.  EPA,  1984)

 Hueper,  W.C.  and W.W.  Payne.   1962.   Experimental  studies 1n  metal cardno-

 genesls      Chromium,  nickel   Iron  arsenic.   Arch.  Environ.  Health.   5:

 445-462.  (Cited In IARC,  1980; U.S.  EPA,  1984)

IARC  (International  Agency  for  Research  on  Cancer).   1980.   Chromium  and
Chromium  Compounds.   In:  Some  Metals  and Metallic  Compounds.   IARC  Mono-
graphs on  the Evaluation  of  the  Carcinogenic  Risk  of Chemicals to  Humans.
IARC, WHO, Lyon,  France.   23:  205-323.

IARC  (International  Agency  for  Research  on  Cancer).   1982.   Results  and
Conclusions.  Ln:  Chemicals,  Industrial  Processes and  Industries  Associated
with  Cancer  1n  Humans.   IARC  Monographs  on  the  Evaluation of  the  Carcino-
genic Risk  of Chemicals  to Humans.   IARC, WHO, Lyon,  France.   1-29  (Suppl.
4): 18.

Kanematsu,  N.,  M.  Hara  and  T.  Kada.  1980.   Rec  assay  and  mutagenldty
studies  on  metal  compounds.   Mutat.  Res.  77:  109-116.   (Cited  1n  U.S.  EPA,

Klelnfeld,  M. and A.  Russo.  1965^   Ulceratlons  of the  nasal septum due to
Inhalation  of chromic  acid mist.  Ind.  Med.  Surg.  34:  242-243.   (Cited In
U.S.  EPA, 1984)

Korallus,  V., H.  Lange,  A.  Ness,  E.  Wuestefeld and  T.  Zwlngers.   1982.
Relationships between  precautionary  measures  and  bronchial  carcinoma mortal-
ity   1n  the  chromate-produdng  Industry.   Arbe1tsmed1z1n,  Soda!  Medlzln
Prevent1vmed1z1n.  17(7):  159-167.   (Cited 1n U.S. EPA, 1984)

Langard,  S.  and  T. Norseth.  1975.   A cohort  study  of bronchial  carcinomas
1n  workers  producing  chromate  pigments.   Br.  J.   Ind.  Med.   32:  62-65.
(Cited 1n U.S. EPA, 1984)

Langard, S., NJ. Gundersen,  D.L.  Tsalev  and B. Glyseth.  1978.  Whole blood
chromium  level  and  chromium  execretlon  1n   the  rat  after  zinc  chromate
Inhalation.  Acta.  Pharmacol.  Toxlcol.   42:142-149.   {Cited  In  U.S.  EPA,

Laskln,  S.  1972.   Research  1n  Environmental  Sciences,  Washington,  DC.,
Institute of Environmental  Medicine,   p.  92-97.   (Cited  In IARC,  1980)

Levls,  A.G.  and F.  Majone.   1979.   Cytotoxlc  and  clastogenlc  effects  of
soluble chromium compounds  on  mammalian  cell  cultures.   Br. J.  Cancer.  40:
523-533.   (Cited In U.S.  EPA, 1984)

Levy,  L.S.  and P.A.  Martin.  1983.   The effects of  a  range  of  chromium-
containing materials  on rat lung.   Dye Color Manufacturers Assoc.

Levy,  L.S.  and S.  VenHt.  1975.   Carcinogenic  and mutagenlc  activity  of
chromium  containing  materials.   Br.  J.  Cancer.   32:  254-255.   (CHed  1n
IARC, 1980)

Llndberg,  E. and G. Hedenstlerna.  1983.  Chrome plating:   Symptoms, finding
1n the upper airways, and  effects  on  lung functions.  Arch.  Environ. Health.
38(6): 367-374.

Lofroth, G.  1978.   The  mutagenldty of  hexavalent  chromium Is  decreased by
mlcrosomal  metabolism.   Naturwlssenschaften.   65:  207-208.   (CHed In U.S.
EPA, 1984)

Lofroth, G.  and  B.N. Ames.   1978.   Mutagenlcity of  Inorganic  compounds  1n
Salmonella  typhlmurlum:  Arsenic,  chromium and  selenium.   Am. Environ.  Mut.
Soc. 8th Meeting, February  13-17,  1977,  Colorado Springs.  Mutat. Res.   53:
65-66.   (Cited In U.S.  EPA,  1984)

Machle, W.  and F. GregoMus.   1948.  Cancer of  the respiratory system  1n  the
United   States chromate-produdng  Industry.    Public  Health  Rep.    63(35):
1114-1127.   (Cited In U.S.  EPA, 1984)

MacKenzle,  R.D.,   R.U.  Byerrum, C.F.  Decker,  C.A.  Hoppert and F.L.  Langham.
1958.   Chronic   toxldty studies.   II.   Hexavalent  and  trlvalent  chromium
administered  1n  drinking water  to  rats.   Am. Med. Assoc. Arch.  Ind.  Health.
18: 232-234.  (Cited In U.S. EPA,  1984)

MacKenzle,  R.D.,   R.A.  Anwar,  R.U. .Byerrum and  C.A. Hoppert.  1959.   Absorp-
tion and  distribution  of  51Cr  1n the albino rat.   Arch. Blochem.  Blophys.
79: 200-250.  (Cited 1n U.S. EPA,  1984)

Mancuso, T.F.   1951.   Occupational  cancer  and  other  health hazards  1n  a
chromate plant:   A  mdelcal appraisal.   I.  Lung cancer 1n chromate  workers.
Ind. Med. S1ng.  20: 358-363.  (Cited 1n  U.S. EPA, 1984)

Mancuso,  T.F.   1975.    International  Conference on  Heavy  Metals  1n  the
Environment,  loronto,  Canada, Oct.  27-31.   (Cited 1n Towlll et al.,  1978;
U.S. EPA, 1984)

Mancuso, T.F. and W.C.  Hueper.   1951.   Occupational cancer and  other  health
hazards  1n  a  chromate plant: A  medical  appraisal.   I. Lung cancer  1n  chro-
mate workers.   Ind.  Med.  Surg.   20:  358-363.   (Cited in NIOSH,  1975;  U.S.
EPA, 1984}

Markel,  H.L.,  Jr.  and  J.B.  Lucas.   1973.   Health  Hazard Evaluation  Report
72-106.   Cincinnati,  OH, U.S. OHEW,  NIOSH,  Division  of  Technical  Services,
Hazard Evaluation Services  Branch.   (Cited 1n NIOSH, 1975; U.S.  EPA, 1984)

Nakamuro,  K.,  K. Yoshlkawa,  Y.   Sayato  and  H.  Kurata.   1978.   Comparative
studies  of  chromosomal  aberration and mutagenldty  of  trlvalent  and hexava-
lent chromium.  Mutat. Res.  58:  175-181.  (Cited In U.S.  EPA,  1984)

NAS  (National  Academy of  Sciences).   1974.   Medical  and  Biological Effects
of  Environmental  Pollutants:  Chromium.   National Academy  Press, Washington.,
DC.  (Cited 1n U.S.  EPA, 1984)

Netteshelm,  P.,  M.G.  Hanna,  Jr., D.6.  Doherty,  R.F.  Newell and A. Hellman.
1971.   Effect  of calcium  chromate  dust,  Influenza vlrum, and  100 R  whole-
body  X-rad1at1on on  lung tumor  Incidence 1n mice.   J.   Natl.  Cancer  Inst.
47: 1129-1144.   (Cited 1n IARC, 1980; U.S. EPA, 1984)

Newbold,  R.F.,  J. Amos  and  J.R. Connell.   1979.    The cytotoxlc, mutagenlc
and  clastogenlc  effects of chromium-containing  compounds  on  mammalian cells
1n  culture.  Mutat. Res.  67: 55-63.  (Cited  1n U.S. EPA,   1984)

N1sh1oka,  H.   1975.   Mutagenlc  activities  of  metal  compounds  1n  bacteria.
Mutat.  Res.  31: 185-189.   (Cited 1n U.S. EPA, 1984)


NIOSH (National  Institute  for  Occupational  Safety  and Health).  1975.  Cri-
teria for  a  Recommended Standard...Occupational Exposure  to Chromium  (VI).
U.S. DHEW,  PHS, CDC,  Rockvllle,  MD.

Ohno, H., F.  Hanaoka and M. Yanada.  1982.  IndudbllHy of  slster-chromatid
exchanges by heavy-metal  Ions.   Mutat.  Res.  104:  141-145.   (Cited 1n U.S.
EPA, 1984)

Ohsakl,   Y.,  S.  Abe,  K. Klmura,  Y.  Tsunlta, H.  M1kam1  and  M.  Murao.   1978.
Lung cancer  In  Japanese chromate  workers.   Thorax.   33: 372-374.   (CHed 1n
U.S. EPA, 1984)

Okubo,  T. and  K.  Tsuchlya.   1979.   Ep1dem1olog1cal  study of chromium plater
1n Japan.  B1ol. Trace Element  Res.   1:  35-44.   (Cited 1n U.S.  EPA,  1984)

OSHA (Occupational  Safety  and   Health Administration).   1978.   A1r  contaml-
nents.   29  CFR. 1910.1000.   p.  99-100.   (CHed In U.S. EPA,  1984)

Payne,  W.W.  1960.   Production  of trace elements  1n  whole blood by photon-
Induced  x-ray  fluorescence.   Eur.  J.  Nucl.  Med.   2:  277-279.   (Cited  In
IARC, 1980)

PetrllH, F.L.  and S.  DeFlora.   1977.   Toxlclty and  mutagenlclty of hexava-
lent chromium  on  Salmonella  typhlmurlum.   Appl.   Environ.  M1crob1ol.   33:
805-809.  (CHed In U.S. EPA,  1984)

PetrlTM,  F.   and  S.  DeFlora.   1978a.   Oxidation  of   Inactive, tMvalent
chromium  to  the  mutagenlc  hexavalent  form.   Mutat.   Res.    58:  167-178.
(Cited In U.S. EPA,  1984)

PetrHH, F.L. and S. DeFlora.  1978b.  Metabolic deactlvatlon of hexavalent
chromium mutagenlcHy.   Mutat.  Res.   54: 139-147.  (Cited  1n U.S.  EPA, 1984)

Raffetto, G.  1977.  Direct  Interaction with  cellular  targets  as the mecha-
nism  for  chromium  carclnogenesls.   Tumor1genes1s.  63:  503-512.   (CHed 1n
U.S. EPA, 1984)

Royle, H.   1975.  Toxldty of  chromic  add In the chromium plating Industry
(2).  Environ. Res.   10:  141-163.   (CHed  1n U.S.  EPA, 1984)

Sano,  T.  and  I.   MHohara.    1978.    Occupational  cancer  among  chromium
workers.  Jap. J.  Chest  Disorders.   37:  90-101.   (CHed 1n U.S. EPA, 1984)

Sarto, F.,  I.  Cemlnato,  V.  B1an1h1 and A.G.  Lewis.   1982.   Increased Inci-
dence of  chromosomal  aberrations  and  sister  chromatld  exchanges  1n workers
exposed  to  chromic  acid  (Cr03) 1n electroplating factories.  Carclnogenesls
(London).  3:  1011-1016.   (CHed 1n  U.S. EPA,  1984)

Satoh, H.,  Y.  Fukuda,  K.  Terll and  N.  Chlka  Katsuno.   1981.   Ep1dem1olog1c
study of  workers  engaged  1n  the  manufacturing  of  chromium  compounds.   J.
Occup. Med.   23(12:  835-838.   (Cited  In  U.S. EPA,  1984)

S1lverste1n,  M.,  F.  Mirer,  D.  Kotelchuck,   B.  S1verste1n  and  M.  Bennett.
1981.   Mortality  among workers  1n a  die-casting  and electroplating  plant.
Scand. J. Work Environ. Health.  7(4):  156-165.   (Cited 1n U.S.  EPA,  1984)

Stella, M., A.  Mentaldl,  R.  Rossi, 6.  Rossi  and A.G.  Levls.   1982.   Clasto-
genlc effects of chromium on human  lymphocytes  \t  vitro  and j_n  vivo.   Mutat.
Res.  101: 151-164.   (Cited In  U.S. EPA,  1984)

Steffee,  C.H.  and  A.M. Baetjer.   1965.   H1stopatholog1cal effects of  chro-
mate  chemicals.  Report  of studies 1n rabbits,  guinea pigs, rats and  mice.
Arch. Environ. Health.  11: 66.  (Cited in U.S.  EPA,  1984)

Stelnhoff,  S.,  C.   Gud,  G.K.   Hatfield  and U.  Mohr.   1983.  Listing  sodium
dlchromate and  soluble calcium chromate  for  carcinogenicity  1n  rats.   Bayer
AG Institute of Toxicology.  (Sept., Unpublished)   (Cited 1n U.S. EPA,  1984)

Taylor, F.H.  1966.   The relationship and  duration of  employment as  reflect-
ed  by a  cohort  of  chromate workers.   Am.  J.  Public  Heath.   56:  218-229.
(Cited in U.S. EPA,  1984)

Todd,  G.E.   1962.    Tobacco   manufacturer's  standing   committee  research
papers.   No.   1.  Statistics   of  Smoking  In  the  United  Kingdom,  3rd  ed.
Tobacco Research Council,  London.  (Cited 1n U.S.  EPA,  1984)

Towlll,  I.E.,  C.R.  Shrlner,  J.S.  Drury, A.S.  Mammons  and  J.W.  Holleman.
1978.   Reviews  of  the  environmental effects  of  pollutants:  III.  Chromium.
Prepared  for  Health  Effects  Research  Laboratory,  Office of  Research  and
Development,  U.S.   EPA,  Cincinnati,  OH.    Report  No.   ORNL/EIS-80  and  EPA
600/1-78-023.   (Cited In U.S.  EPA, 1984)

Tsuda,  H.  and  K.   Kato.   1977.   Chromosomal  aberrations and  morphological
transformation 1n  hamster embryonic  cells  treated with  potassium dichromate.
Mutat. Res.  46:  87-94.   (Cited In U.S.  EPA,  1984)

Umeda, M.  and  M.  N1sh1mura.  1979.  Indudbllity  of  chromosomal  aberrations
by metal  compounds 1n cultured mammalian  cells.   Mutat. Res.   67:  221-229.
(Cited 1n U.S. EPA, 1984)

U.S.  EPA.   1980a.   Guidelines  and  Methodology  Used 1n  the  Preparation  of
Health  Effects  Assessment  Chapters  of  the  Consent  Decree  Water  Quality
Criteria.  Federal Register.  45:  79347-79357.

U.S.  EPA.   1980b.   Ambient  Water Quality  Criteria for  Chromium.   Environ-
mental  Criteria  and  Assessment  Office,  Cincinnati,  OH.  EPA  440/5-80-035.
NTIS PB 81-117467.

U.S.  EPA.   1983.   Methodology and Guidelines  for  Reportable  Quantity  Deter-
minations  Based  on  Chronic  Toxicity  Data.    Prepared  by the  Environmental
Criteria and Assessment  Office, Cincinnati,  OH, OHEA  for  the  Office  of Solid
Waste and Emergency Response,  Washington,  DC.

U.S. EPA.   1984.   Health  Assessment Document  for  Chromium.   Environmental

Criteria and  Assessment  Office, Research Triangle  Park,  NC.   EPA  600/8-83-

014F.  NTIS PB 85-115905.

U.S. EPA.   1985.   Acceptable Dally  Intakes  for Volatile Organic  Chemicals,

Inorganic Chemicals and Synthetic Organic Chemicals.   Criteria  and  Standards

Division, Office of Drinking Water.   (Federal  Register  Draft)

Venltt, S. and  L.S.  Levy.   1974.   Mutagenltlcy of chromates  1n bacteria  and

Us relevance to chromate cardnogenesls.  Nature.  250: 493-495.   (Cited  1n

U.S. EPA, 1984)

V1gl1an1,  E.C.  and N.  Zurlo.   1955.   Efahrung der CUnlca  del Lavoro  m1t

elnlgen  maxlmalen  Arb1tsplatzkonzentrat1onen  (MAk)   von   Industr1eg1ften.

Arch. Gewerbepath.  Gewerbhyg.  13:528-534.   (Ger.)   (Cited  In U.S.  EPA,  1984)

Watanabe,  S.  and  Y.  Fukuchl.   1975.   An  ep1dem1olog1cal   survey  on  lung

cancer   1n  workers  of  a  chromate-produdng  Industry In  Hokkaido,  Japan.

Presented at  International  Congress  on  Occupational Health.  (Cited  1n  U.S.

EPA, 1984)

Weast,   R.C.,  Ed.   1980.  Handbook  of Chemistry and  Physics,  61st  ed.   CRC

Press,  Boca Raton,  FL.  p.  873-166.

Wild,  D.   1978.  Cytogenetlc effects  1n the  mouse  of 17 chemical  mutagens

and  carcinogens  evaluated   by  the  mlcronucleus  test.   Mutat.  Res.    56:

319-327.  (Cited 1n U.S.  EPA, 1984)


                                        Summary Table for Hexavalent Chromium

                     lung tumors
               41 (mg/kg/day)
                                                                                           U.S.  EPA,  1984;
                                                                                           Mancuso,  1975
                                                                     Acceptable Intake
                                                                       (AIS or AIC)

                                                  Systemic Toxiclty
0-25 ppm In          none
drinking water
for 1 year
(2.5 mg/kg)

0-25 ppm In          none
drinking water
for 1 year
(2.5 mg/kg)
               1.75 mg/day
               0.35 mg/day
                                                                                           et al..  1958
                                                                                           et al.,  1958
     ND =  Not  derivable