POLYCHLORINATED BIPHENYLS
Ambient Water Quality Criteria
            Criteria  and  Standards  Division
            Office of Water  Planning  and  Standards
            U.S. Environmental  Protection Agency
            Washington, D.C.

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                     CRITERION DOCUMENT


                  POLYCHLORINATED BIPHENYLS


Criteria


                        Aquatic  Life


     For polychlorinated biphenyls the criterion to protect
               i

freshwater aquatic life as derived using the Guidelines


is 0.0015 jug/1 as a 24-hour average and the concentration


should not exceed 6.2 ;ug/l at any time.


     For polychlorinated biphenyls the criterion to protect


saltwater aquatic life as derived using the Guidelines is


0.024/ig/l as a 24-hour average and the concentration should


not exceed 0.20 ;ag/l at any time.


                        Human Health


     For the maximum protection of human health from the


potential carcinogenic effects of exposure to PCBs through


ingestion of water and contaminated aquatic organisms, the


ambient water concentration should be zero.  Concentrations


of PCBs estimated to result in additional lifetime cancer


risks ranging from no additional risk to an additional risk


of 1 in 100,000 are presented in the Criterion Formulation


section of this document.   The Agency is considering setting


criteria at an interim target risk level in the range of


10" , 10  , or 10~  with corresponding criteria of 0.26 ng/1,


0.026 ng/1 and 0.0026 ng/1 respectively.

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Introduction
     Polychlorinated biphenyls (PCBs)  are the chlorinated
derivatives of a class of aromatic organic compounds called
biphenyls and are manufactured by the direct chlorination
of the biphenyl ring system.  The commercial products are
complex mixtures of chlorobiphenyls and are marketed for
various uses according to the percentage of chlorine in
the mixture.  Currently there is no production of PCBs in
the United States but the sole producer of PCBs in the United
States previously marketed four mixtures containing 21 percent,
41 percent, 42 percent and 54 percent chlorine for use only
in closed electrical systems under the trademark "Aroclor."
Prior to 1971 mixtures containing up to 68 percent chlorine
were used in a number of other applications, including plasti-
cizers, heat transfer fluids, hydraulic fluids, fluids in
vacuum pumps and compressors, lubricants, and wax extenders.
     In 1974 approximately 65 to 70 percent of domestic
sales were to manufacturers of capacitors and the remainder
to manufacturers of transformers while approximately 450,000
pounds of PCBs were imported primarily for use in non-closed
systems.  U.S. production appeared to be one-half of the
world total.
     As a result of the long life of many products containing
PCBs, it is believed that a substantial portion of the PCBs
manufactured before 1971 are still in service and thus represent
potential pollution through possible future discharge into
the environment.
                              A-l

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     During the period 1972 to 1974 domestic production of



PCBs averaged approximately 40 million pounds per year with



33 million pounds representing the annual domestic marketed



consumption during that period.



     Although the environmental behavior and biological



activity of a number of individual chlorobiphenyl isomers



have been studied in recent years, it is still difficult



to evaluate the potential toxicity of the complex mixtures



actually found in the environment since their composition



often changes.  In making this evaluation it is necessary



to weigh carefully the results of studies of individual



compounds, and to compare critically the environmental and



toxicological properties of the commercial mixtures.



     A further complication is that several commercial PCB



mixtures have been reported to contain small quantities



of highly toxic contaminants, polychlorinated dibenzofurans



(PCDFs).  Certain of the toxic effects observed in animals



and humans exposed to PCBs appear to be attributable to



PCDFs, while others appear to be caused by PCBs themselves.



There  is also some evidence that small quantities of PCDFs



may be formed from PCBs while  in service or as a result



of metabolic changes in certain organisms.



     PCBs consist of a mixture of chlorinated biphenyls



which  contain a varying number of substituted chlorine atoms



on the aromatic rings.  The biphenyl molecule has a total



of ten sites where chlorine substitution can be accommodated



as shown in the following structure:
                              A-2

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The potential positions for chlorine substitution are numbered
according to the American Chemical Society standard notation.
Chlorinated biphenyls having the same number of chlorine
      • f,    •  .   .  •
atoms per molecule are referred to as a specific class of
chlorobiphenyls, with a suitable numerical prefix to define
the number of substituted chlorines.  Hence/ there are classes
varying from monochlorobiphenyls to decachlorobiphenyl.
All compounds within the same class have the same molecular
weight and are structural isomers of each other.  They differ
only in terms of the location of the chlorine atoms in the
biphenyls ring.  The ten classes of chlorobiphenyls, comprissing
209 possible isomers, are summarized in Table 1.
     Chlorobiphenyls with five or more chlorine atoms are referred
to as "higher chlorobiphenyls."  This distinction is made
in recognition of the fact that the former group of compounds
is much more persistent in the environment than the latter
group.  The tetrachlorobiphenyls are intermediate in persistence.
     The physical properties of individual chlorinated biphenyls
are known (Cook, 1972).  The physical properties of the
Aroclor mixtures are summarized in Table 2.  Lower chlorinated
Aroclors (1221, 1232, 1016, 1242, and 1248) are colorless mobile
oils.  Increasing chlorine content results in mixtures taking
on the consistency of viscous liquids (Aroclor 1254) or
sticky resins  (Aroclors 1260 and 1262).  Aroclors 1268 and
1270 are off white-white powders.  With the exception of
Aroclors 1221 and 1268, Aroclors do not crystallize upon
                                                                - /
                              A-3

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                           TABLE 1

          Emperical Formulation, Molecular Weights
               and Chlorine Percentage in PCBs
Empirical formula
chlorobiphenyls
C12H10
C12H9C1
,*
C12H8C12
C12H9C13
C12H6C14
C12H5C15
C12H4C16.
C12H3C17
C12H2C18
C12H1C19
C12C110
Molecular
weight*
154
188
222
256
290
324
358
392
426
460
490
Percent
chlorine*
0
18.6
31.5
41.0
48.3
54.0
58.7
62.5
65.7
68.5
79.9
No. of
isomers
1
3
12
24
42
46
42
24
12
3
1
*Based on Cl
                              A-4

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                                                    TABLE 2

                               Physical Properties of Commercial PCBs  (Aroclors)
i
Ul
Property
Chlorine, percent
Specific Gravity
Distillation Range
C Corrected
Vapor Pressure
(mm/HS)
Evaporation loss (%)
100 C 6 hr.
USTA D-6 Mod.
160 C, 5 hr.
Pour Point C
(WTM E97) F
1221
20.5-21.5
1.182-1.192
(25°/15.5°C)
275-320

1.0-1.5


1 (Crystal)
34 (Crystal)
1232
31.4-32.5
1.270-1.280
(25°/15.5°C)
290-325

1.0-1.5


-35.5
-32
1016 1242
41 42
1.362-1.372 1.391-1.392
(25°/15.5°C) (25°/15.5°C)
323-356 325-366
4.06xlO~4
0-0.4
3.0-3.6

-19
2
1248
48
1.405-1.415
(65°/15.5°C)
340-375
4.94xlO~4
0-0.3
3.0-4.0

-7
19.4
        Water Solubility
          at 25 C(ug/l)
               >200
225-250
        Reference:
Versar, Inc.  (1976)
Hammond, et al.  (1972)
Hutzinger, et al.  (1974)
Mieuer, et al. (1976)
Tucker, et al. (1975)
Mackay and Wolkoff  (1973)
240
54

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                                         TABLE 2  (cont)

                       Physical Properties of Commercial PCBs  CAroclors)
Property
Chlorine/ percent
Specific Gravity
Distillation Range
C Corrected
Vapor Pressure
(nun/HS)
Evaporation loss (%)
100 C 6 hr.
USTA D-6 Mod.
160 C/ 5 hr.
Pour Point C
(WTM E97) P
1254
54
1.495-1.555
(65°/15.5°C)
365-390
7.71xlO~5
0-0.2
1.1-1.3

10
50
1260
60
1.555-1.566
(90°/15.5°C)
385-420
4.05xlO~5
0-0.1
0.5-0.8

31
88
1262
61.5-62.5
1.572-1.583
(90°/15.5°C)
390-425

0-0.1
0.5-0.2

35-38
99
1268
68
1.604-1.611
(25°/25°C)
435-450

0-0.6
0.1-0.2



1270
71
1.944-1.960
(25°/25°C)
450-460






Water Solubility
  at 25 C(ug/l)
12
2.7

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heating or cooling but at a specific temperature, definesd
as a "pour point," change into a resinous state.
     It is known from the studies of pesticides that soil
moisture and evaporation of water have a strong influence
on the rate of chlorinated hydrocarbon volatilization from
soils and sand.  Haquef et al (1974) demonstrated that the
periodic evaporization of water from Ottawa sand enhanced
         t      ' . •
the total volatilization of Aroclor 1254 but reduced the
degree of differentiation in the volatility of the higher
chlorinated biphenyls  (7,6, and 5 chlorine aroms) from the
tetrachlorobiphenyls.  However, when Aroclor 1254 was heated
in water at 100°C the total volatilization of this Aroclor
was reduced compared to equivalent dry isothermal conditions
but the differentiation in volatility between the higher
and lower chlorinated biphenyls was increased (Bowes, et
al. 1975a) .
     Mackay and Wolkoff (1973) calculated theoretical evapora-
tion rates for various Aroclors from water and predicted
very rapid volatilization rates.  Under laboratory conditions,
PCBs appear to volatilize fairly rapidly from water in aquaria
(Uhlken, et al. 1973) and even from flasks plugged with
glass wool (Oloffs, et al. 1972).  Under the same conditions,
volatilization was markedly reduced in the presence of sedi-
ments  (Oloffs, et al. 1973).  Hence in natural waters, it
would seem likely that absorption to sediments would limit
the rate of volatilization.
                              A-7

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     Solubilities of the individual chlorinated biphenyls
in water have been studied by several workers and an inverse
correlation between solubility and degree of chlorination
has been reported (Wollnofer, et al. 1973; Hague and Schmedding,
1975; Metcalf, et al. 1975).  The problem in obtaining true
solution equilibria data for PCBs in water has been explained
by Schoor (1975) who has given evidence that solutions of
PCBs in water are in fact stable emulsions of PCB aggregates
and that the true solubility of Aroclor 1254 is less than
0.1" >ig/l in fresh water and 0.04 jig/1 in marine water.
     Chlorobiphenyls are freely soluble in relatively nonpolar
organic solvents  (Hutzinger, et al. 1974) and lipids in
biological systems (Hammond, et al. 1972; Metcalf, et al.
1975) .  Metcalf, et al.  (1975) have reported parition coeffi-
cients between octanol and water in the range of 10,000
to 20,000 for representative tri-, tetra-, and pentachloro-
biphenyls.  Partition coefficients with this biphasic solvent
system have been found to correlate well with ecological
magnification factors in aquatic organisms (Metcalf, et
al. 1975).
     PCBs are strongly adsorbed on solid surfaces, including
glass and metal surfaces in laboratory apparatus  (Schoor,
1975) and soils, sediments, and particulates in the environment
(Haque, et al. 1974; Oloffs, et al. 1973; Crump-Wiesner,
et al. 1974; Dennis, 1976; Munson, et al. 1976; Pfister,
et al. 1969).
     In aquatic environments, PCBs are associated with sediments
and are usually found at much higher concentrations in sediments
than in water in contact with them  (Young, et al. 1976;
                               A-8

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Crump-Weisner, et al. 1974; Dennis,  1976).  As  with  other
chlorinated  hydrocarbons, PCBs are probably associated  partic-
ularly  strongly with micro-particulates  of 0.15 pm diameter
or  less (Pfister, et al. 1969).
      PCBs  are  commercially produced  by the chlorination
of  the  biphenyl ring with anhydrous  chlorine  in the  presence
of  iron filings pr  ferric chloride as the catalyst.   The
crude product  is purified to  remove  color, traces of the
byproduct  hydrogen  chloride,  and  the catalyst by treatment
with  alkali  and subsequent distillation.  The purified  product
is  a  complex mixture of  the chlorobiphenyls,  the precise
composition  depending on the  conditions  under which  the
chlorination occurred.
      It has  been reported that foreign PCB mixtures  are
similar in composition to one of  the 10  Aroclor products
previously manufactured  in the U.S.  Gas liquid chromatograms
of  Phenoclor DP6  (France), Clopen A60  (Germany), and Aroclor
1260  (U.S.), all mixtures containing 60  percent chlorine,
Show  that  these mixtures are  virtually identical (Tas. and
de  Vos, 1971).  Jensen and Sundstron (1974) have shown  that
Clophen A60  and A50 (Germany) are very similar  in isomer
composition  to Aroclors  1260  and  1254  (U.S.)  respectively.
„Table 3 lists  the distribution of the various classes of  chloro
biphenyls  in seven  major Aroclor  mixtures as  reported by
Mieure, et al.  (1976) Webb and McCall  (1973), and Hirwe,
et  al.  (1974)..  The,small differences in analytical  results
reported for Aroclors 1242 and 1254  may  reflect either  dif-
ferences in  analytical methods or variations  in sample  constitu
tion.

                               A-9

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                                         TABLE  3

                      Approximate Molecular Composition of  A'roclors
Chlorobiphenyl
1221 1232 1242 1248 1254 1261
M W W M M W H W M W H W
C12H
C12H10C1
C12H9G12
C12H8C13
G12H7G14
C12H6C15
C12H5G16
GI2H4C17
11 7 6 Tr Tr Tr
51 51 26 1 1 • 1 Tr . - Tr
32 38 29 20 16 17 4 1 0.5 -
4 3 24 57 49 40 39 23 1 - 0.5
2 - 15 21 25 32 42 50 21 16 36
0.5 0.5 1 8 10 14 20* 48 60 45 12
- Tr 1 0.5 1 23 23 18' 46
- - Tr - - 61 1 36
Tr - Trace (less than Ovl percent)  Letters refer  to  references

Reference:  Micure, et al.  (1976)
            Webb and McCall  (1973)
            Hirwe, et al. (1974)

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     Certain substitution patterns are believed  to  influence
the biological activities of chlorobiphenyls.  The  presence
of two adjacent carbon atoms without chlorine  substitution
in one or both rings is believed to facilitate metabolism
because  it permits the formation of arene oxide  intermediates
(Safe, et al. 1975).  Essentially all chlorobiphenyls with
five or  fewer chlorine atoms have at least one pair of adjacent
unsubstituted carbon atoms because of the rarity of 3,5-
substitution in the natural mixtures.
     Jensen and Sundstrom  (1974b) presented evidence that
chlorobiphenyls with three or four chlorine atoms in the
ortho-positions (2- and 6- positions) are more easily meta-
bolized  by humans than those with only one or  two ortho-
chlorines.  Compounds with three or four ortho-substituted
chlorines are virtually absent from Aroclors 1016 and 1242
but are  fairly well represented in Aroclors 1254 and 1260
(Clopens A50 and A60 respectively).
     McKinney (1976) has suggested that chlorobiphenyl isomers
with chlorine substitution in both the 4- and  41 positions
tend to  be biologically active and well retained in tissues.
The number and proportion of these isomers increase with
increasing mixture chlorination.
     McKinney, et al.  (1976a) have shown an association
.between  biological activity and substitutions  in the 3,4-,
or 3,4,5- positions on one or both rings.  The first pattern
is frequently found in PCB mixtures but the second  is found
only as part of the 2,3,4,5-pattern which is found  in only
trace amounts in PCBs.
                               A-ll

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     Toxic materials other than chlorinated biphenyls have
been found in commercial PCS mixtures.  Vos, et al. (1970);
Bowes, et al. (1975a), Roach and Pomerantz  (1974), Nagayama,
et al. (1976), and Kuratsume, et al.  (1976) have detected
polychlorinated dibenzofurans (PCDFs) in a number of domestic
and foreign PCB mixtures at levels of 0.8 to 33 mg/kg.
While 119 structurally different PCDF isomers are possible,
only two have been precisely identified to date, the 2,3;7;8-
tetrachloro- and the 2,3,4,7,8-pentachlorodibenzofurans
(Bowes, et al. 1975).
     Polychlorinated naphthalenes  (PCNs) have also been
identified in small quantities in Clopen A60 and Phenochlor
DP 6  (both corresponding to Aroclor  1260), Aroclor 1254>
and KC-400 (corresponding to Aroclor  1248)  (Vos, et al.
1970; Roach and Pomerantz, 1974; Bowes, et al. 1975).
     There appear to be no authenticated reports of poly-
chlorinated dibenzo-p-dioxins (PCDDs) in commercial PCBs
(Bowes, et al. 1975a).  The presence  of potentially toxic
compounds other than polychlorinated  biphenyls in commercial
PCB mixtures complicates both analytical and toxicological
evaluation of such mixtures.
     PCBs are considered to be inert  to almost all of the
typical chemical reactions.  PCBs do  not undergo oxidation,
reduction, addition, elimination, or  electrophilic substitu-
tion reactions except under extreme  conditions.  Chlorines
can be replaced by reductive dechlorination with any metal
hydride such as lithium aluminum hydride but temperatures
of 245°C or greater  are required to  effect chlorine displacement;
                               A-12

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     The reactions of environmental importance that PCBs
appear to undergo include alkali- and photochemically-catalized
nuceleophilic substitutions and photochemical free radical
substitutions, all of which occur with alkali and water.
     Photolysis generally has been found to give one type
of product under environmental conditions (Hutzinger, et
al. 1974; Ruzo, et al. 1972; Ruzo, et al. 1974a; Ruzo and
Zabik, 1975; Hutzinger, et al. 1972c; Herring, et al. 1972).
Chlorine is replaced by hydroxy groups in aqueous systems.
     A marked increase in rate of PCB photolysis was observed
when solvents were degassed prior to irradiation (Ruzo,
et al. 1974a).  Oxygen is known to act as a free radical
quencher by accepting energy from free radicals before any
chemical change can occur.  This increase in rate therefore
implies that a free radical process is occurring and in
the environment these photochemical transformations will
be enhanced under anaerobic conditions.
     The photochemical behavior of higher chlorobiphenyls
appears similar to that of the tetrachlorobiphenyls  (Hutzinge'r,
et al. 1972c; Herring, et al. 1972).  Irradiation of Aroclor
1254 in aqueous solution gave rise to dechlorinated and
hydroxylated products  (Hutzinger, et al. 1972c).  Hexa- and
octachlorobiphenyls are more photochemically reactive than
tetrachlorobiphenyls  (Hutzinger, et al. 1972c), so that
under irradiation the higher components of Aroclor 1254
are selectively degraded (Hutzinger, et al. 1972c; Herring,
et al. 1972).
                              A-13

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     The creation of free radicals by sunlight allows the
environmental replacement of chlorines by hydroxy groups
from water without the intervention of alkali.  When this
occurs at the ortho position (found to the the most preferred
for chlorine loss) the resulting 2-hydroxychlorobiphenyl
is perfectly positioned to allow oxygen to bond to an ortho
position of the other ring.  This results in the creation
of potentially the most important class of contaminant in
commercial mixtures of PCBs, the chlorodibenzofurans (CDFs).
     Irradiation studies on either Aroclor 1254 or 2,5,2', 51-
tetrachlorpbiphenyl (Hutzinger, et al. 1972c) in hydroxylic
solvents have shown the formation of phenolic compounds,
carboxylic compounds, and polymers along with dechlorination.
Activation of the phenyl rings by metals or metallic salts
make them more susceptible to hydroxylation.  Thus in the
environment, either heat, light, or metals and metal salts
in water could theoretically accelerate the transformation
of PCBs to PCDFs.  The ultraviolet component of sunlight
is sufficiently energetic to generate free radicals from
both phenols and PCBs.  The energies required to break the
Ar-Cl bond to form hydroxy-PCBs in a hydroxylic solvent
and ArO-H bond to form CDFs correspond to wavelengths near
360 to 320 nm, respectively.  These wavelengths are clearly
within the sunlight region.
     Irradiation experiments with five pure 2-chlorinated
biphenyls as 5 mg/1 aqueous suspensions, showed that traces
of 2-chlorodibenzofuran were detectable although only the
•2,5-dichloro- and the 2,5,2',5'-tetrachlorobiphenyls provided
identifiable amounts or approximately a 0.2 percent yield
                               A-14

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during a seven-day irradiation (Crosby, et al. 1973; Crosby


and Moilanen, 1973).   The environmental significance of


this is four fold: (1)  ortho-chlorobiphenyls can be hydroxy-


lated by radiation similar to sunlight when they are suspended


in aqueous media; (2)  the product(s) are converted to CDFs;


(3) rates of CDF formation by this process are approximately


the same as their rates of degradation, leading to an approxi-


mately steady concentration.  The fourth point of significance


is illustrated by irradiation studies on 2,8-dichlorobenzo-


furan (Crosby and Moilanen, 1973).  Decomposition of this


material was found to be very slow in aqueous suspension


but dehalogenation did not take place to form the relatively


photdlytically stable 2-chlorodibenzofuran.


     In addition to photochemical and metallic/metallic


salt formations of PCDFs from PCBs, a third route of formation
     •*

has been suggested.   Kanechlor KC-400  (analogous to Aroclor
     •» i

1248) having an intitial PCDF content of 20 mg/kg, was shown


to undergo conversion as the heat transfer fluid in a heat


exchanger to give PCBs with a PCDF content of 4975-11765


mg/kg '(Nagayma, et al.  1976; Kuratsune, et al. 1976).  This
                     V
material was identified as the agent which poisoned a large


number of Japanese in 1968.  A general disadvantage of PCBs


in many of their applications including electrical capacitor

   '.*'  *•
and transformer uses as well as heat transfer uses is their


tendency to decompose under the action of heat or electrical


arcing to form potentially more toxic products (Broadhurst,
                              A-15

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                          REFERENCES


Bowes, G.W., et al. 1975a.  Identification of chlorinated
dibenzofurans in American polychorinated biphenyls.  Nature
256: 305.


Broadhurst, M.G. 1972.  Use and replaceability of polychlori-
nated biphenyls.  Environ. Health Perspect. 2: 81.


Cook, J.W. 1972.  Some chemical aspects of polychlorinated
biphenyls  (PCBs).  Environ. Health Perspect. 1: 1.


Crosby, D.H., and K.W. Moilanen. 1973.  Photodecomposition
of chlorinated biphenyls and dibenzofurans.  Bull. Environ.
Contam. Toxicol. 10: 372.
                                           '

Crosby, D.G., et al. 1973.  Environmental generation and
degradation of dibenzodioxins and dibenzofurans.  Environ.
Health Perspect. 5: 259.


Crump-Wiesner, H.J., et al. 1974.  Pesticides in water:
a study of the distribution of polychlorinated biphenyls
in  the aquatic environment.  Pestic. Monitor. Jour. 8: 157.


Dennis, D.S.  1976.  Polychlorinated biphenyls in the surface
waters and bottom sediments of the major basins of the United
States.  Proceed. Nat. Conf. on Polychlorinated Biphenyls:
193-196.
                              A-16

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Hague, R.,  et al. 1974.  Aqueous solubility, adsorption,
and vapor behavior of polychlorinated biphenyl Aroclor 1254.
Environ. Sci. Tech. 8: 139.

Hague, R.,  and D. Schmedding. 1975.  A method of measuring
the water solubility of hydrophobia chemicals: solubility
of five polychlorinated biphenyls.  Bull. Environ. Contam.
Toxicol. 14: 13.

Herring, J.L., et al. 1972.  UV irradiation of Aroclor 1254.
Bull. Environ. Contam. Toxicol. 8: 153.

Hirwe, S.N., et al. 1974.  Gas-liquid chromatography-mass
spectrometric characterization of Aroclor 1242 and 1254
components.. Bull. Environ. Contam. Toxicol. 12: 135.

Hutzinger,  O., et al. 1972.  Photochemical degradation of
chlorobiphenyls  (PCBs).  Environ. Health Perspect. 1: 15.

Hutzinger,  0., et al. 1974.  The Chemistriy of PCB's. CRC
Press, Cleveland, Ohio. 77 pp.

Jensen, S., and G. Sundstrom. 1974.  Structures and levels
of most chlorobiphenyls in two technical PCB products and
in human adipose tissue.  Ambio 3: 70.

Kuratsune,  M., et al. 1976.  Some of.the recent findings
concerning Yusho.  Proc. Nat. Conf. on Polychlorinated Biphenyls:
15-37.
                              A-17

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Mackay, D., and A.W. Wolkoff. 1973.  Rate of evaporation


on low-solubility contaminants from water bodies to atmosphere.


Environ. Sci. Tech. 7: 611.





McKinney, J.D. 1976.  Toxicology of selected symmetrical


hexachlorobiphenyl isomers: correlating biological effects


with chemical structure.  Proc. Nat. Conf. on Polychlorinated


Biphenyls: 99-104.





McKinney, J.D., et al. 1976.  Toxicology of hexachlorobiphenyl


isomers and 2,3,7,8-tetrachlorodibenzofuran in chicks.


I. Relationship of chemical.parameters.  Toxicol. Appl.


Pharm., in press.





Metcalf, R.L., et al. 1975.  Laboratory model ecosystem


studies of the degradation  and fate of radiolabeled tri,-


tetra-, and pentachlorobiphenyl compared with DDE.  Arch.


Environ. Contam. Toxicol. 3: 151.





Mieure, J.P., et al. 1976.  Characterization of polychlorihated


biphenyls. Proc. Nat. Conf. on Polychlorinated Biphenyls:


112-125.





Munson, T.O.y et al. 1976.| Transport of chlorinated hydro-


carbons in the Upper Chesapeake Bay.  Proc. Nat. Conf. on
                         .. i
                       •' •«

Polychlorinated Biphenyls:  223-235.





Nagayama, J.,,et al. 1976.  Determination of chlorinated


dibenzofurans in Kanechlors and "Yusho Oil".  Bull.


Environ. Contam. Toxicol. 15: 9.




                               A-18

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Oloffs, P.C., et al. 1972.  Fate and behavior of five chlor*i-


nated hydrocarbons in three natural waters.  Can. Jour.


Microbiol.  18: 1393.




Oloffs, P.C., et al. 1973.  Factors affecting the behavior


of five chlorinated hydrocarbons in the two natural waters


and their sediments.  Jour. Fish. Res. Board Can. 30: 1619.




Pfister, R.M., et al. 1969.  Microparticulates: isolation


from water and identification of associated chlorinated


pesticides.  Science 166: 878.

                     .'


Roach, J.A.G., and I.H. Pomerantz. 1974.  The finding of chlori-


nated dibenzofurans in a Japanese polychlorinated biphenyl


sample.  Bull. Environ. Contam. Toxicol. 12: 338.
                    s •



Ruzo, L.O., and M.J. Zabik. 1975.  Polyhalogenated biphenyls:


photolysis of hexabromo and hexachlorobiphenyls in methanol


solution.  Bull. Environ. Contam. Toxicol. 13: 181.




Ruzo, L.O., et al. 1972.  Polychlorinated biphenyls: photol-
    %

ysis of 3,4,3',4'-tetrachlorobiphenyl and 4,4'-dichlorobiphenyl


in solution.  Bull. Environ. Contam. Toxicol. 8: 217.




Ruzo, L.O., et al. 1974.  Photochemistry of bioactive compounds


photo-products and kinetics of polychlorinated biphenyls.


Jour. Agri. Food Chem.  22: 199.




Safe, S., et al. 1975.   The mechanism of chlorobiphenyl


metabolism.  Jour. Agri. Food Chem. 28: 851.
                              A-19

-------
Schoor, W.P. 1975.  Problems associated with low-solubility
compounds in aquatic toxicity tests: theoretical model and
solubility characteristics of Aroclbr 1254 in water.  Water
Res. 9: 937.

Tax, A.C., and R.H. deVos. 1971.  Characterization of four
major components in a technical polychlorinated biphenyl
mixture.  Environ. Sci. Tech. 5: 1216.

Tucker, E.S., et al. 1975.  Migration of polychlorinated
biphenyls in soil  induced by percolating water.  Bull. Environ,
Contain. Toxicol. 13: 86.

Uhlken, L.D., et al. 1973.  Apparent volatility of PCB's
as used in continuous flow bioassays.  PCB Newsletter 5: 4.

Versar, Inc. 1976.  Final Report.  PCBs in the United States:
Industrial use ^id environmental distribution.  Report to
U.S. Environmental Protection Agency.  Task I: Contract
No. 68-01-3259.

Vos, J.G., and J.H. Koeman. 1970.  Comparative toxicologic
study with polychlorinated biphenyls in chickens with special
reference to porphyria, edema formation, liver necrosis,
and tissue residues.  Toxicol. Appl. Pharm. 17: 656.

Webb, R.G., and A.C. McCall. 1973.  Quantitative PCB standards
for electron capture gas chromatography.  Jour. Chromatog.
Sci. 11: 366.
                              A-20

-------
Wollnofer, P.R., et al. 1973.  The solubilities of twenty-



one chlorobiphenyls in water.  Analabs Research Notes 13: 14







Young, D.R., et al. 1976.  Marine inputs of polychlorinated



biphenyls off southern California.  Proc. Nat. Conf. on



Polychlorinated Biphenyls: 197-209.
                              A-21

-------
AQUATIC LIFE TOXICOLOGY*



                       FRESHWATER ORGANISMS



Introduction



     Most data  for polychlorinated  biphenyls  (PCB's)  are for



studies concerned with tissue  levels  in  fish,  mammals,  and birds,



without correlation with  source  or  exposure  concentrations.  Many



studies dealing with various physiological parameters are also



available, but  again, are  such that they are  of little  use here..



Also, PCB's often do not  appear  to  be  very acutely toxic to



juvenile and adult freshwater  fish  and invertebrate species due to



solubility problems in static  tests,  and this  can lead  to



erroneous judgments as to  the  actual  toxicity  of the  compounds.



     PGB.'s occur as mixtures of  chemical isomers that differ in



the amount of chlorination of  the biphenyl structure, they have



been treated herein as a  single  entity.   They  are highly



lipophilic and  bioconcentrate  to high  tissue  concentrations from
*The reader  is  referred  to  the Guidelines  for Deriving Water



Quality Criteria for  the Protection  of  Aquatic Life [43 FR 21506



(May 18, 1978)  and 43  FR 29028  (July 5,  1978)]  in order to better



understand the  following discussion  and  recommendation.  The



following tables contain the  appropriate data that were found in



the literature, and at the  bottom  of each  table are the calcula-



tions: for deriving various  measures  of  toxicity as described iVi



.the Guidelines.
                              B-l

-------
water concentrations that are below the usual detection  limits*

Acute Toxicity
     Only three 96-hour LC50 values are available and these are
for the fathead minnow (Table 1).  Newly-hatched fish were more.
sensitive than juveniles with LC50 values of 15 ug/1 and 300 ug/1,
respectively, for Aroclor 1242 (A-1242).  A-1254 was more toxic
with an LC50 of 7.7 ug/1 for newly-hatched fish.  No adjustments
to the data were necessary as all values were from flow-through
tests with measured concentrations.  Other 96-hour LC50 values in
the literature exceeded the solubility of PCB's and were not used.
The solubility of PCB's is, at most, 250 ug/1 and 96-hour LC50
values such as 50,000 ug/1 are meaningless.
     The acute toxicity data base for invertebrate species (Table
2) contains 12 values for three species.  These values were from
static and flow-through tests and showed an LC50 range from 10
ug/1 for the scud, Garamarus fasciatus, to 200 to 400 ug/1 for the
damselfly, Ischnura verticalis.  The higher chlorinated  isomers,
such as Aroclor 1254 which contains 54 percent chlorine, were more
toxic to Gammarus pseudolimnaeus, than they were to fish, with
LC50 values of 73 ug/1;for A-1242 and 29 ug/1 for A-1248.
     Acute toxicity tests with polychlorinated biphenyls have
established that these compounds can be toxic to aquatic life at
low concentrations once they are in solution.  The data  indicate
that the more highly chlorinated compounds are more toxic to fish
and invertebrate species.:  The Final Fish Acute Value is 7.7 ug/1
and the Final Invertebrate Acute Value is 6.2 ug/1 which also
                              B-2

-------
becomes the Final Acute Value.





Chronic Toxicity



     Four flow-through chronic tests have been conducted with



polychlorinated biphenyls and fathead minnows.  Test



concentrations were measured.  The fish were most sensitive to



A-1248 with a chronic value of-0.2 ug/1 (Table 3).  Chronic values



for A-1242, A-1254, and A-1260, were 9.0, 2.9, and 2.3 ug/1,



respectively.  The geometric mean (1.86 ug/1) of the four chro(nic



concentrations divided by the species sensitivity factor  (6.7)



results in a value of 0.28 ug/1.  Since the lowest chronic value



is 0.20 ug/1, it becomes the Final Fish Chronic Value.



     Results from 14 chronic tests with 2 invertebrate species,



Daphnia magna and Gammarus pseudolimnaeus, are shown in Table 4.



The low chronic values for Daphnia magna, 1.14 ug/1 for A-1242,



1.4 ug/1 for A-1248, and 0.73 ug/1 for A-1254 were from flow-



through tests with measured concentrations; the other values were



from static tests, and were much higher due to loss of PCB's from



the test containers.  The two chronic values for Gammarus



pseudolimnaeus, 4.9 ug/1 for A-1242 and 3.3 ug/1 for A-1248, were



from flow-through tests with measured concentrations.  The



geometric mean of the 14 tests was 8.1 ug/1 which, after division



by the species sensitivity factor (5.1) results in a concentration



of 1.6 ug/1.  Since there is a lower chronic value (0.73 ug/1 for



Daphnia magna), this latter value becomes the Final Invertebrate



Chronic Value.
                              B-3

-------
Plant Effects
     Results from six tests with four different algal species
are shown in Table 5.  In general the data show that plants were
less sensitive than the fish and invertebrate species, but
reduction in the rate of carbon fixation in Scenedesmus
quadricauda occurred at 0.1 ug/1 A-1254 which is lower than the
Final Fish and Invertebrate Chronic Value.  Therefore, the Final
Plant Value is 0.1 ug/1.
   i
Residues
     Table 6 contains results of 25 laboratory residue studies and
47 field studies of fish residues where information on water
concentrations was also available.  The studies include laboratory
and field data for invertebrate and fish species and show a wide
range of bioconcentration factors (BCF's).  For invertebrate
species the BCF ranged from 740 for stoneflies exposed for 21 days
to 125,000 for mysids collected from Lake Superior.  The BCF for
fish ranged from 3,500 for field collected bass to 4,125,000 for
field-collected siscdwet, a race of lake trout.  For laboratory
exposures, the BCF ranged from 5,500 for white sucker exposed for
30 days to 540,000 for minnows exposed for 240 days.
     The residue limit established by the Food and Drug
Administration (FDA) for polychlorinated biphenyls in edible fish
and shellfish is 5.0 mg/kg.  Significant effects on reproduction
oE mink were observed when fed food containing 0.64 mg/kg; this
figure was used to calculate the Residue Limited Toxicant
                              B-4

-------
Concentration (RLTC).  Since fish is one of the principal foods of
mink, the mink-effect concentration of 0.64 mg/kg was divided by
the geometric mean fish bioooncentration factor of 427,000 to give
an RLTC of 0.0000015 mg/kg or 0.0015 ug/1.
     The lowest of the .Final Fish Chronic Value (0.2 ug/1), Final
Invertebrate Chronic Value (0.73 p.g/1) , Final Plant Value (0.1
ug/1) and the RLTC (0.0015 ug/1) is used to determine the Final
Chronic Value.  For polychlorinated biphenyls the Final Chronic
Value is 0.0015 ug/1.

Miscellaneous
     Data presented in Table 7 do not conflict with the selection
of 0.0015 ug/1 as the Final Chronic Value.
                           B-5

-------
Criterion Formulation
                   Freshwater Aquatic Life
Summary of Available Data
     Final Fish Acute Value + 7.7 pg/1
     Final Invertebrate Acute Value = 6.2 pg/1
          Final Acute Value = 6.2 pg/1
     Final Fish Chronic Value =0.20 pg/1
     Final Invertebrate Chronic Value = 0.73 pg/1
     Final Plant Value = 0.10 pg/1
     Residue Limited Toxicant Concentration = 0.0015 pg/1
         . Final Chronic Value = 0.0015 pg/1
          0.44 x Final Acute Value = 2.7 pg/1
     The maximum concentration of polychlorinated biphenyls
is the Final Acute Value of 6.2 pg/1 and the 24-hour average
concentration is the Final Chronic Value of 0.0015 pg/1.
    '' \
No important adverse effects on freshwater aquatic organisms
have been reported to; be caused by concentrations lower
than the 24-hour average concentration.
     CRITERION: For polychlorinated biphenyls the criterion
to protect freshwater aquatic life as derived using the
Guidelines is 0.0015 pg/1 as a 24-hour average and the concen-
trations should not exceed 6.2 pg/1 at any time.
                               B-6

-------
                                Table  1.  Freshwater fish acute values for polychlorinated biphenyls (Nebeker. et al. 1974)
03
I


Organism
Fathead minnow
(juvenile),
Pimephales promelas
Fathead minnow
(newly hatched) ,
Pimephales promelas
Fathead minnow
(newly hatched) ,
Pimephales promelas

Bioassay Test • .
Mfctnod* Cone .**
FT M


FT M


FT M



Chemical
Description
A-1242


A-1242


A-1254


Adjusted
Time LC&u LCio
(hrs) (uq/JL) (uq/i)
96 300 300
t

96 15 15


96 7.7 7.7


*  FT = flow-through
*.*  M = measured
    Geometric mean of adjusted  values -  33 vg/1 39 =8.4 pg/1
    Lowest value from a flow-through test with measured concentrations =7.7 yg/1
                                                               33

-------
                                       Table  2.  Freshwater invertebrate acute values  for polychlorinated biphenyls
09
I
oo
Or nanism
Scud.
Gammarus
Scud,
Gammarus
Scud,
Gammarus
Scud,
Gammarus
Scud,
Gammarus
Scud,
Gammarus
Scud,
Gammarus
Scud,,
Gammarus
Scud,
Gammarus
Scud,
Gammarus
Bioassay
Method*
..-..-. .FT
fasciatus '-•••.-;
fasciatus
fasciatus
pseudolinmaeus
p s eudo 1 imnaeus
pseudolinmaeus
pseudolinmaeus
pseudolinmaeus
pseudolinmaeus
pseudolimnaeus
Damselfly,
Ischnura verticalis
Damselfly,
Ischnura verticalis


S
S
FT
FT
S
S
S
S
S
FT
FT
Test
Cone. *
M
U
U
M
M
U
U
U
U
U
M
M'
Chemical Time
* . Description (hrs)
A-1242 96
A-1248 •
A-1254
A-1242
A-1248
2.3,4- tri-
chlorobiphenyl
4,4 - dichloro-
biphenyl
2,4- dichloro-
biphenyl
2. 4, 6,2', 4', 6-
hexachloro-
biphenyl
2452' 5 -
£, H, j , £ , j -
pentachloro-
biphenyl
A-1242
A-1254
96
96
96
96
96
96
96
96
96
96
96
Adjusted
LCbo LCiu
(gq/1^ (ua/1)
10
52 •',:.;.'•
2,400
73
29
70
100
120
150
210'
400
200
10
44
2,032
73
29
59
85
101
127
178
400
200
Reference
Mayer ,
Mayer,
Mayer,
Nebeker
1974
Nebeker
1974
Mayer,
Mayer.
Mayer,
Mayer,
Mayer,
Mayer ,
Mayer,
et
et
et
&
&
et
et
et
et
et
et
et
al.
al.
al.
1977
1977
1977
Puglisi.
Puglisi,
al. 1977
al.
al.
al.
al.
al.
al.
1977
1977
1977
1977
1977
1977
                    *  S =• static, FT » flow-through


                    ** U = unmeasured, M = measured


                       Geometric mean of adjusted  values = 131- ng/1  21 - 6.2  jig/1


                       Lowest value from a flow-through test with measured concentrations
131
                       10 pg/1

-------
                           Tacle 3.  Freshwater fish chronic values for poiychlorinated biphenyls
                                                              Chronic
                                                    Limits     Value
Organism
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,.
Pimephales promelas
Test*
LC
LC
LC
LC
taq/H
0.1 - 0.4
A- 1248
1.3 - 4.0
A- 1260
5.4 - 15
A-1242
1.8 - 4.6
A-1254
(uq/i)
0.2
2.3
9.0
2.9
Reference
DeFoe, et al, .In
DeFoe, et al. in
Nebeker, et al.
Nebeker, et al.

press
press
1974
1974
             * LC » Life cycle or partial life cycle
                                                            1.86
 I              Geometric mean of chronic values = 1.86 ug/1  6.7 = 0.28 wg/1
vo
               Lowest  chronic value  =0.2 pg/1

                                         Application Factor Values (Nebeker,  et  al.  1974)

                                    96-hr LC50      MATC
             Species                  (pg/1)        (ug/1)        AF


             Fathead minnow,            15.0         '9.0       0.6
             Pimephales promelas     (A-1242)      (A-1242)

             Fathead minnow,             7.7          2.9       0.38
             Pimephales promelas     (A-1254)      (A-1254)
             Geometric mean AF - 0.48                     Geometric mean LC50 = 10.75 pg/1
                                  0.48  S7.7 pg/1  x 10.75  pg/1  =  4.4 pg/1

-------
Table 4. Freshwater invertebrate chronic values for polychlorinated biphenyls






CO
M
O







Organism
Cladoceran,
Daphnia m'agna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran.
Daphnia magna
Cladoceran.
Daphnia magna
Cladoceran,
Daphnia magna
Scud,
Gamma r us pseudolimnaeus
'Scud,
Cammarus .pseudolimnaeus

Test*
LC
LC
LC
LC
.LC
LC
LC
LC
LC
LC
LC
LC
LC
LC
Limits
10-24
89-125
53-66
48-63
16-24
18-28
22-33
24-41
162-206
1.0-2.1
0.48-1.1
1.0-1.3
2.8-8.7
2.2-5.1
Chronic
Value
(uq/1)
15 '" "''•••
A-1254
105 '
A-1221
59
A-1232
55
A-1242
19
A-1248
22
A-1254
27
A-1260
31
A-1262
182
A-1268
1.4
A-1248
0.73
A-1254
1.14
A-1242
.4.9
A-1242
3.3
A-1248
Reference
Maki & Johnson, 19 75-
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
Nebeker
&
&
&
&
&
&
&
&
&
&
&
&
&
Puglisi ,
Puglisi,
Puglisi.
Puglisi.
Puglisi.
Puglisi.
Puglisi.
Puglisi.
Puglisi.
Puglisi,
Puglisi,
Puglisi,
Puglisi,
1974
1974
1974
1974
1974
,1974
1974
1974
•1974
.1974
1974
.1974
1974
                                     8.1
* LC = Life cycle or "partial life cycle
  Geometric mean of chronic values -8.1. pg/1     « 1.6  ug/1
  Lowest chronic value - 0.73

-------
                          Table  5.   Freshwater  plant  effects  for  polychlorinaced biphenyls
            Organism
                        Effect
Cone e n tr at i on
(ug/j.)	
Reference
            Alga.''
            Chlamydompnas
            reinhardt-ii
                        Reduced
                        growth
    2.000
   A-1242
 Morgan, 1972
BJ
I
Alga.
Chlorella
pyrenoidosa

Alga,
Chlorella
pyrenotdosa

Alga,
Euglena gracilis

Alga,  .
Scenedesmus
obtusiusculus

Alga,
Scenedesmus
quadricauda
                                     Depressed           1,000
                                     cell produc-      A-1268
                                     tivlty

                                     Reduced             1,000
                                   population         A-1254
                                     growth

                                     48 hr              4,400
                                     ID50             A-1221

                                     Growth              300
                                     inhibition        A-1242
                                    Reduction  in          0.1
                                    rate  of  carbon     A-1254
                                    fixation
                     Hawes, et al.  1976b
                     Hawes, et al.  1976a
                     Ewald, et al.  1976
                     Larsson & Tillberg, 1975
                     Luard, 1973
           Lowest plant value  =  0.1  vig/1

-------
              Table 6. Freshwater residues for polychlorinated biphenyls
Organism
Snail.
Physa sp.
Snails,
Cladoceran,
Daphnia magna
Mysid,
Mysis relicta
Scud,
Garamarus pseudolimnaeus
Scud,
Gamma rus pseudolinmaeus
Amphipod ,
W Pohtiporeia affinis
1
lyj Glass shrimp,
Palaemonetes kadiakensis
Crayfish,
Orconectes nais
Stonefly,
Pteronarcys dorsata
Mosquito,
Culex tarsalis
Phantom midge,
Chaoborus punctipennta
Dobsonf ly ,
Corydalus cornutus
Gizzard shad.
Dorosoma cepedianum
Alewife,
Bioconcentration factor
59,600
45,000
3,800
125,000
6.200
108,000
1,709
2,600
750
740
3.500
2,700
1.500
150,300
270,000
Time
(days)
33
Field data
4
Field data
21
60
Field data
21
21
21
7
14
7
Field data
Field data
Reference
Sanborn, 1974
Nadeau &.\f)avis
Mayer, et al.

. 1976
1977
Veith, et al. 1977
Mayer, et al. 1977
Nebeker & Buglisi, 1974
Halle, et al.
Mayer, et al.
Mayer , et al .
Mayer, et al.
Mayer, et al.
Mayer, et al.
Mayer, et al.
Hesse, 1973
Hesse. 1973
1975
1977
1977
1977
1977
1977
1977

Alosa pseudoharengus

-------
              Table 6.  (Continued)
Organism
Bioconcentratidn Factor
 Time
(days)      Reference
Alewife,
Alosa pseudoharengus
Alewife,
Alosa pseudoharengus
Chub,
Coregonus j oh anna e
Me nominee,
Pros opium cylindraceum
Lake whitefish,
Coregonus clupeaformis
Lake whitefish,
Coregonus clupeaformis
CD
jL Bloater,
oj Coregonus hoyi
Bloater,
Coregonus hpyi
Lake herring,
Coregonus artedii
Rainbow trout,
Salmo gairdneri
Rainbow trout ,
Salmo gairdneri
Rainbow trout,
Salmo gairdneri
Steelhead trout,
Salmo gairdneri
Brook trout,
Salvelinus fontinalis
Brook trout,
89,000
42,700
850,000
120,000
110., 000
875,000
1,162,500
81,000
250,000
120,000
46,000
5,850
600,000
47 , 000
60,000
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
30
42
Field data
118
500
Veith, 1975'
Haile, et al. 1975
Hesse, 1973
Hesse, 1973
Hesse, 1973
Veith, et al. 1977
Veith, et al. 1977
Veith, et al. 1977
Veith. et al. 1977
Veith, 1975
Bills & Marking, 1977
Branson, et al. 1975
Hesse, 1973
Mauck, et al. In presi
Snarski & Puglisi, 19
Salvelinus fontinalis

-------
              Table  6.   (Continued)



a
i
M
*>.




Organism
Brown trout,
Salmo trutta
Lake trout,
Salvelinus namaycush
Lake trout,
Salvelinus namaycush
Lake trout,
Salvelinus namaycush
Lake trout.
Salvelinus namaycush
Siscowet,
S. namaycush siscowet
Chinook salmon,
Oncorhynchus tschawytscha
Chinook salmon.
Oncorhynchus tschawytscha
Coho salmon,
Oncorhynchus kisutch
Rainbow smelt,
Osmerus mordax
Rainbow smelt,
Osmerus mordax
Rainbow smelt,
Osmerus mordax
Pike,
Esox lucius
•— — .^— *^» •^••H^W^^^^B^to
Carp,
Cyprinus carp to
Carp,
Bioconcentration Factor
119,000
1,110,000
212,000
2,333,000
1,625,000
4,125,000
1,240,000
240,000
173,000
462,500
32,000
48,000
15,000
43,600
390,000
Time
(days)
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Reference
Veith, 1975
Hesse, 1973
Veith, 1975
Parejko, et al.
Veith, et al.
Veith, et al.
Veith, et al.
Hesse, 1973
Veith, 1975
Veith, 1975
Veith, et al.
Veith. 1975
Haile, et al.
Hesse. 1973
Hesse, 1973
Hesse, 1973

. 1975
1977
1977
1977
1977
1975


Cyprinus'carpio

-------
              Table  6.  (Continued)
Organism
'
Carp,
Cyprinus carpio
Fathead minnow.
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead mtnow,
Pimephales promelas
Fathead minnow,
Pimephales promelas
03 	 	 * 	
t_i Fathead minnow.
tn Pimephales promelas
Fathead minnow,
Pimephales promelas
Fathead minnow.
Pimephales promelas
Common shiner,
Notropis cornutus
Longnose sucker,
Catostomus catostomus
Longnose sucker,
Catostomus catostomus
Redhorse sucker,
Moxostoma sp.
White sucker,
Catostomus cotnmersoni
Bioconcentration Factor

110,000

240,000

120,000

270,000

540,000

274,000

107,000

235,000 .

238,000

> 78, 000

150,000

1,125,000

32,000

106,000

Time
(days)
• • v
Field data

240

240

240

240

255

255

240

240

Field data

Field data

Field data

Field data

Field data

Reference
";; '
Veith, 1975

DeFoe, et al.

Defoe, et al.

DeFoe, et al.

DeFoe, et al.

Nebeker, et al

Nebeker, et al

Nebeker, et al

Nebeker, et al

Nadeau & Davis

Hesse, 1973

Veith, et al.

Veith, 1975

Veith, 1975





In 'press

la press

In 'press

In press

. 1974

. 1974

. 1974

. 1974

, 1976



1977





White sucker,
Catostomus commersoni
5,500
30
Frederick, 1975

-------
                          Table 6.  (Continued)
09
            Organism
Bioconcentration Factor
Time
(days)      Reference
Channel catfish,
•Ictalurus punctatus
Burbot,
Lota lota
Rock bass,
Ambloplites rupestris
Bluegill.
Lepomis macrochirus
Largemouth bass ,
Micropterus salmoides
Yellow perch,
Perca flavescens
Yellow perch,
Perca flavescens
Yellow perch,
Perca flavescens
Yellow perch,
Perca flavescens
Slimy sculpin.
Cottus cognatus
Slimy sculpin,
Cottus cognatus
Fourhorn sculpin,
49,000
1,162,500
117,000
52,000
3,500
14,800
50.000
109.000
154,000
300,000
84,000
337.500
, ^hMH^H^^H^-M^B*
77
Field data
«' ^
Field data
77
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Field data
Stalling. 1971
Veith, et al.
Nadeau & Davis ,
Stalling. 1971
Martell, et al.
Hesse. 1973
Hesse, 1973
Veith, 1975
Nor strora, et al
Veith. et al.
Haile, et al.
Veith, et al.

1977
1976
1975


. 1976
1977
1975
1977
            Myoxocephalus quadricornis

-------
                         Table 6.   (Continued)

                                     Maximum Permissible Tissue Concentration
            Organism
            Man
            Mink.
            Mustela vison

            Mink,
            Mustela vison
                              Concentration
  Action Level or Effect          (mg/kg)
                                  *

Edible fish and shellfish           5
    FDA action level

    Reduced reproduction            1


    No- reproduction, mortality     0.64
Reference


21 CFR Part 122.10


Ringer, et al.  1972


Platonow & Karstad, 1973
CO
I
            Geometric mean fish bioconcentration factor = 427,000

            Lowest residue concentration = 0.64 mg/kg

            42°;000 • 0.0000015 mg/kg or 0.0015 yg/1

-------
Table  7.   Other freshwater data for polychlorinated biphenyls

Organism
Cladoceran,
Daphnia pulex
Cladoceran, „"".'
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Ostracod,
Cypridopsis vidua
03 	 	
!_, Glass shrimp,
oo Palaemonetes kadiakensis
Crayfish,
Orconectes nais
Dragonfly ,
Macromia sp .
Midge,
Tanytarsus dissimilis
Mosquito.,
Culex tarsalis
Rainbow trout,
Salmo gairdneri
Rainbow trout.
Salmo gairdneri
'Rainbow trout.
Salmo gairdneri
Rainbow trout.
Salmo gairdneri
Test
Duration
4
days
2 •-,
wks
2
wks
3
wks
2
wks
3
days
7
days
7
days
7
days
3
wks
7
days
—

25
days
25
days
25
days

Ett'ect
Significant
mortality
LC50

LC50

LC50

LC50

Significant
mortality
LC50

LC50

LC50

50% death
of pupae
No adult
emergence
Inhibit ATPase
activity
LC50

LC50

LC50

Result
tuq/1)
2,000
A-1242
2.6
A-1248
1.8
A-U54
1.3
A-1254
24
A-1254
2,000
A-1242
3
A-1254
30
A-1242
800
A-1242
0.45
A-1254
1.5
A-1254
4 pg/g
A-1242
12
A-1242
3-4
A-1248
27
A-1254
                                                  Reference





                                                   Morgan, 1972





                                                   Nebeker & Puglisi.. 1974





                                                   Nebeker & Puglisi. 1974





                                                   Nebeker & Puglisi, 1974





                                                   Maki & Johnson, 1975





                                                   Morgan, 1972





                                                   Mayer, et al.  1977





                                                   Mayer, et al.  1977





                                                   Mayer, etal.. 1977





                                                   Nebeker£ Puglisi, 1974





                                                   Sanders & Chandler. 1972





                                                   Davis, et al.  1972





                                                   Mayer, et ,al.  1977





                                                   Mayer, et al.  1977





                                                   Mayer, et al.  197.7

-------
                   Table  7.   (Continued)
Organism
Test
Duration  Etfect
                                                           flesult
Rainbow trout,
Salmo gairdneri
Rainbow trout,
Salmo gairdneri

Rainbow trout,
Salmo gairdneri
Rainbow trout ,
Salmo gairdneri
Rainbow trout,
Salmo gairdneri
QJ Rainbow trout,
1 Salmo gairdneri
*° Steelhead trout,
Salmo gairdneri
Coho salmon,
Oncorhynchus kisutch
Coho salmon,
Oncorhynchus kisutch

Coho salmon,
Oncorhynchus kisutch

V
Coho salmon,
Oncorhynchus kisutch

Atlantic salmon,
Salmo salar
Atlantic salmon,
Salmo salar
25
days
21
days
30
days
330
days
5
days
5
days
24
days
embryo-
larval
72
hrs
68
days

72
days
96
hrs
192
hrs
.1 i • • — T ••
LC50
Induce fish.
hepatic micro-
somal enzymes
75% mortality. '70%
deformed fry
Kidney pathology
LC50
LC50
Bioconcentration
factor
MATC
Stimulated
thyroid
activity
Induced fish
hepatic AHH
microsomal
enzymes

Induction of aryl
hydrocarbon
hydroxylase
Bioconcentration
factor
Mortality
mm m -J • mm
49
A-1260
31 yg/g "'
Clophen
A-50
0.39 yg/g
PCB
10 yg/g
A-1254
67
A- 1242
54
A-1254
38.000
times
<4.4
0.48 yg/g
A-1254
1 ng/g
A-1242

12 yg/g
PCBYs
600
times
>2 yg/g
A-1254
Mayer,
Lidman
et al.
, et al.
Hogan & Brauhn.
Nestel
Mayer ,
Mayer,
Halter
Halter
Mayer ,
Gruger

Gruger
Zitko
Zitko,
& Budd,
et al.
et al.
. 1974
1977
1976
1975
1974
1977
1977

& Johnson, 1974
et al. 1977
, et al.

, et al.
& Carlson
1970
1977

1976
, 1977


-------
Table  7.   (Continued)
Organism
Brook trout,
Salvel-inus fontinalis
Brook trout,
Salvelinus fontinalis
Brook trout,
Salvelinus fontinalis
Brook trout,
Salvelinus fontinalis
Brook trout,
Salvelinus fontinalis
03
1 Brown trout,
ro Salmo trutta
o
Northern pike (fry).
Esox lucius
Carp.
Cyprinus carpio
Carp,
Cyprinus carpio
Fathead minnow0,
Pimephales promelas
Fathead minnow, .
Pimephales promelas
Fathead minnow.
Pimephales promelas
Test
Duration
embryo-
. larval
71
wks
fert. .-.-
to
hatch
21
days
21
days
43
days
field
data
20
days
21
days
30
days
• 30 ;?••
days
30
days
Ettect
Result
(uq/ll
MATC <0.43
.V" • ' •
No effect on survival 0.94
growth or reproduction A-1254
No egg hatch 200 .
A-1254
Stimulated 200
hydroxylation A-1254
of testosterone
Bioconcentration 164
factor times .
Anaemia 10 pg/g in
hyperglycaemia food Clophen
altered cholestrol A-50
metabolism
Possible
mortality
Altered plasma
0-glucoronidase
activity
Hjtabolic
changes
30- day LC50
';• - •
Reduced growth
1.41 yg/g
tissue
1.8 pg/g
eggs
A-1248
5 yg/g
A-1248
250 pg/g
A-1248
28
A-1242
28
A- 1016
23
A- 1016
RetereiiCfe
Mauck, et al," In
Snarski & Puglisi
Freeman & Idler,
Freeman & Idler,
Freeman & Idler,
Johansson, et al
Waybrant. 1974
ltd. 1973

press
.1976
1975
1975
1975
1972


Ito & Murata, 1974
Veith. 1976
Veith. 1976
Veith. 1976




-------
                            Table  7.   (Continued)
         Organism
                        Test
                        Duration  Effect
                                                                    Result
                                                                    (ug/l)  ... Reference
03
I
to
Fathead minnow,            30
Pimephales promelas       days

Fathead minnow,            30
Pimephales promelas       days

Fathead minnow,            30
Pimephales promelas       days

Fathead minnow,            30
Pimephales promelas       days

Fathead minnow,             4
Pimephales promelas        mos

Fathead minnow,             4
Pimephales promelas        mos

Channel catfish,           30
Ictalurus punctatus       days

Channel catfish,           30
Ictalurus punctatus       days

Channel catfish,           30
Ictalurus punctatus       days

Channel catfish,           72
Ictalurus punctatus        hrs

Channel catfish,           30
Ictalurus punctatus       days

Channel catfish,           20
Ictalurus punctatus        wks

Channel catfish,            2
Ictalurus punctatus        wks
         Channel catfish,            4
         Ictalurus punctatus        wks
                                              LC50
                                              LC50
Significant
 mortality

Significant
 mortality

Inhibition of
ATPase activity

Inhibition of
APTase activity

   LC50
                                              LC50
                                            .  LC50
                                           Stimulated thyroid
                                           activity

                                              LC50
Weight loss and
liver hypertrophy

Increased trans-
aminase, lower
cortisol

Induced fish
hepatic microsomal
enzymes
  4.7
 A-1248

  3.3
 A-1260

  23
 A-1242

  44  !
 A-1016

  0.31
 A-1242

  0.31
 A-1254

  75
 A-1248

  139
 A-1254

  433
 A-1260

2.4 yg/g
 A-1254

  8.7
 A-1242

20 wg/g
 A-1242

   8
 A-1254
DeFoe, et al. In press


DeFoe, et al. In press  ;


Herraanutz & Puglisi,-1976


Hermanutz & Puglisi, 1976


Cutkomp, et al.. 1972


Koch, et al.  1972


Mayer, et al.  1977


Mayer, et al.  1977


Mayer, et al.  1977


Mayer, et al.  1977


Mayer, et al.  1977


Hansen, et al.  1976


Camp, et al.  1974
                                                            1.000     Hill,  et al.   1976
                                                            A-1254

-------
                   Table  7.    (Continued)
Organism
Test
Duration  Etfe
Result
(ug/i)    Reterencfe
Flagfish,
Jordanella floridae
Mosquitofish,
Gambusia affinis
Mosquitofish.
Gambusia affinis
Guppy.
Poecilia formosa
Bluegill.
Lepomis macrochirus
Bluegill,
M Lepomis macrochirus
ro Bluegill.
to Lepomis macrochirus
Bluegill.
Lepomis macrochirus
Bluegill.
Lepomis macrochirus
Bluegill.
Lepomis macrochirus
Bluegill.
Lepomis macrochirus
Mink .
Mustela visbn
Mink.
Mustela vison

30
days
6
days
1.5
hr
1
day
5
days
•» w
^ •»
30
days
30
days
30
days
30
days
1
yr
Fin erosion
*
Bioconcentration
factor
Avoidance
Significant
mortality
LC50
Inhibit (150)
ATPase
Inhibition
of ATPase
LC50
LC50
LC50
LC50
Reduced
reproduction
Depressed
growth
37
A-1242
v 12,100
times
0.1
A-1254
200
A-1242
136
A-124S
0.6 yg/g
A-1242
30
A-1254
84
A-1242
78
A-1254
177
A-1254
400
A-1260
2 yg/g
10 pg/g
Hermanutz & Puglisi, 1976
Sanborn. 1974
Hansen, et al. 1974
Morgan, 1972
Mayer, et al. 1977
Desaiah, et al. . 1972
Yap. et al. 1971
Mayer, et al. 1977
Mayer, et al. 1977
Mayer, et al. 1977
Mayer, et al. 1977
Aulerich & Ringer, 1977
Aulerich, et al. 1973
Avoidance at 0.1 wg/1

-------
                       SALTWATER ORGANISMS

Introduction

     Polychlorinated biphenyls (PCB's) were manufactured by the

direct chlorination of biphenyl; production in the United States

has now ceased.  These mixtures were  identified under the trade

name Aroclor and sold on the basis of percentage chlorine (e.g.,

21, 42,.54, and 60 percent).  Since each component of the mixtures

differs in its physical, chemical, and biological properties, and
                                                    '^
since a possible 209 different chlorobiphenyls may be produced,

th,e .evaluation of the potential impact of the various mixtures on

the environment is complicated.

     When an evaluation of the impact of PCB's on the environment

is performed, it is necessary to relate the data gathered in

laboratory, experiments with relatively pure mixtures to what

happens to the mixtures in nature.  There is evidence that

percentages of chlorine change with time and location as the

mixtures are transported through the  environment.  For example,

the proportion of major peaks of Aroclor 1254 in shrimp and fish

captured from Escambia Bay, Florida differed from each other

(Nimmo et al., 1971).  The major peaks in these organisms and in

organisms from laboratory studies (Hansen et al., 1971) also

differed from the standard used to calculate the amounts of the

chemical in tissues.  Results of environmental monitoring by

Butler and Schutzmann (1978) showed that PCB's identified in

fishes, Pacific staghorn sculpin and  English sole from the

Duwamish River, Washington State, during the period of fall 1972
                              B-23

-------
to spring 1976, changed from those resembling Aroclor 1254, to



those resembling Aroclor 1260, and later, Aroclor 1242.





Acute Toxicity



     Acute toxicity tests of PCB mixtures to saltwater fishes have



not produced data that can be used to obtain 9.6-hour LC50 values



because concentrations tested were not sufficiently high (Table



12).  Pinfish were not affected in 48 hours by 100 ug Aroclor



1254 per liter of water (Duke et al., 1970).  Eighteen percent of



the pinfish died after 96 hours, compared to 2 percent of the



control fish, in water to which 100 ug Aroclor/1 was added  (Hansen



et al., 1974a).  Additional tests with saltwater fishes at



slightly higher concentrations might have given data necessary to



calculate 96-hour LC50 values.  However, possible problems  could



exist in validity of acute tests with PCB's because of their low



solubility in water (Schoor, 1975).



     Available data suggest that saltwater  invertebrate species



may be more acutely sensitive to PCB's than fishes (Table 8).  The



adjusted LC50:or EC50 values for invertebrate species ranged from



2.8 to 12.0 ug/1; an unusually low variability in adjusted  LC50



values.  Because there was little difference in the toxicity of



different Aroclors, the geometric mean was  calculated from  all



adjusted LC50 values and divided by the species senstivity  factor



of 49 to obtain a Final Invertebrate Acute Value of 0.14 ug/l«



The narrow range in adjusted LC50 values suggests that (1)  a



species sensitivity factor of 49 is too great or  (2) the more
                              B-24

-------
likely probability, based on freshwater invertebrate LC50 values



is that not enough species have been tested to establish the



variability, in sensitivity of saltwater invertebrate species.



Since there are too few data for PCB's and saltwater invertebrate



species to calculate a specific species sensitivity factor, the



guidelines value (49) is used.  The Final Invertebrate Acute Value



is used as the Final Acute Value because, although LC50 values are



not available for fishes, they are not likely to produce a lower



acute value.





Chronic Toxicity



     No life-cycle tests have been reported using saltwater



organism's.  In an embryo-larval test (Table 9) with the sheepshead



minnow, fertilization was not affected by Aroclor 1254, but



significantly fewer embryos survived to hatching in a measured



concentration of 3.48 ug/1 (Schimmel et al., 1974).  Survival of



fish during the two weeks following hatching was significantly



less in 0.16 ug/1 but not different from controls in 0.06 ug/1.



     In a second study to determine the effect of PCB's in fish



eggs on survival, Hansen et al. (1973) exposed adult sheepshead



minnows for four weeks to Aroclor 1254 (Table 12).  Adult fish



exposed to 5.6 ug/1 died but those in 1.1 ug/1 or lower apparently



were not affected.  Embryos from adult fish were placed in



PCB-free flowing saltwater and observed for four weeks.



Fertilisation success was not affected by PCB's in eggs, but



survival of embryos and the resulting fry was reduced.  Fry from



eggs containing 7.0 ug/g or more of PCB began dying a few hours
                              B-25

-------
after hatching.  The concentration in eggs calculated to be lethal



to 50 percent of the fish was 6.1 ug/g.  If PCS affects other



species similarly/ then other fish species with equally high



concentrations of Aroclor 1254 in their eggs may be endangered.



     The effect of another PCB, Aroclor 1016, in water on fry,



juvenile or adult sheepshead minnows was determined in a four-week



exposure (Hansen et al., 1975).  Survival of all three life-stages



was reduced in 15 u.g/1 but not in 5.5 ug/1 or less.  Unlike



Aroclor 1254, as much as 77 u,g of Aroclor 1016/g of eggs



apparently did not affect survival of embryos and fry in water



free of this PCB.



     Chronic exposure of fishes to Aroclor produced pathological



effects not observed in acute tests.  Hansen et al. (1971)



reported signs of poisoning in pinfish exposed to Aroclor 1254,



such as fungus-like lesions on the body, hemorrhagic areas around



the mouth, ragged fins, etc.  Signs of poisoning in sheepshead



minnows exposed to Aroclor 1254 included lethargy, reduced



feeding and fin rot (Hansen et al., 1973; Schimmel et al., 1974).



     Spot exposed to Aroclor 1254 for two weeks or longer showed



fatty changes in their livers (Nimmo et al., 1975).  In inter-



mediate stages of liver pathogenesis in fish exposed to Aroclor



1254, there were extreme fatty changes characterized by the



presence of large vacuoles within hepatocytes and disorientation



of liver cord distribution.  In advanced stages of pathogenesis in



a moribund fish, there were intracellular PAS-positive bodies



(ceroid), congestion of blood sinuses, and severe vacuolation.
                              B-26

-------
     Life-cycle tests with the fathead minnow and Aroclors 1242,
        - 
-------
alterations:'in the vesicular connective tissue  (parenchyma) around

the digestive diverticular of the hepatopancreas.

     Aroclor 1254 was toxic to the saltwater amphipod, Gammarus
 •
oceanicus,. at a nominal concentration of 10.0 ug/1  (Wildish,
          *. •.
1970) .  Molting animals were particularly vulnerable  to  the PCS.

Necrotic branchia were found in some animals exposed  for about 6

days to a nominal concentration of 1.0 ug/1.

     Arpclor 1254 affected the species composition  of communities

of estuarine animals that developed from planktonic larvae in salt'

water that flowed for four months through small aquaria  (Table 12;.

Hansen, 1974) .  The number of arthropods decreased  while the

number of :;ehordates increased in aquaria receiving  0.6 ug/1 of the

PCS.  Numbers of phyla, species and individuals were  decreased by

this PCB, but there was no apparent effect on the abundance of

annelids, brachiopods, coelenterates, echinoderms,  or nemerteans. '

This study showed that a PCB can have marked effects  on  community

structure at concentrations not much different  from those that

produced chronic effects on single species.

     No Final Invertebrate Chronic Value can be obtained because

no appropriate chronic"tests on saltwater invertebrate species

were found in the literature.  However, extended exposures of

saltwater species and life-cycle tests with freshwater inverte*-

brate species.(Table 4) demonstrate that acute  tests  underestimate
       * .  *  •*
the chronic toxicity of PCB's (Table 12).  Therefore, knowledge of

the chronic effects of this PCB are .critical to the generation of

a criterion.
                              B-28

-------
Plant Effects


     Information concerning the sensitivity of plants  is


restricted to unicellular algae (Table 10).  Fisher and Wurster


.(1973) found that the growth of the diatom, Rhizosolenia setigera,


was reduced in a medium to whch 0.1 u.g/1 Aroclor 1254 was added.


Likewise, Fisher et al. (1974) demonstrated that 0.1 ug Aroclor


1254 added per liter of water changed the species ratio of the


alga,fDunaliella tertiolecta, and the diatom, Thalassiosira


pseudonana.  Fisher et al. (1974) also showed a decrease in


species diversity and species ratio change in natural phytoplank-


ton communities at 0.1 ug/1 Aroclor 1254.  In summary, some data


suggest that unicellular plants are affected by concentrations of


PCB's similar to concentrations that are chronically toxic to


animals.  Unfortunately no data using measured concentrations were


presented and it is difficult to interpret the ecological


significance of these studies.



Bioconcentration


     The bioconcentration factors (BCF's) of PCB's in saltwater


species in laboratory tests are shown in Table 11.  The diatom,


Cylindrotheca closterium,  had a bioconcentration factor of 1,000


(Keil et al., 1971);  Eastern oyster, up to 168,000 times (Lowe et


al., 1972); grass shrimp,  Palaemonetes pugio, 42,000 times (Nimmo
     • ' '     *-

et al., 1974),  and in the  three fishes listed, Leiostomus


xanthurus, Cyprinodon variegatus, and Lagodon rhomboides, as high
                              B-29

-------
as 44,000 times (Hansen et al., 1971; 1974a, and 1974b).
Bioconcentration factors for PCB's in six of seven species of
freshwater fishes in laboratory tests were generally similar,
ranging from 5,000 to 60,000.
     Bioconcentration factors calculated from data from Escambia
Bay, Florida were greater than 230,000 for blue crabs  (Nimmo et
al., 1975), and greater than 100,000 for oysters; :and 670,000 for
speckled trout (Duke et al., 1970).  These data, and field data on
freshwater fishes, suggest that bioconcentration factors from
laboratory studies underestimate bioconcentration potentials of
PCB's in the environment (Hansen, 1975).
     The bioaccumulation of PCB's into aquatic organisms from
PCB's in food and in water and the effects of PCB's on mammals
that feed on fish and shellfish are important.  The lowest maximum
permissible tissue concentration (0.64 ug/1) is based on the
effect of dietary PCB's on mink (Platonow and Karstad, 1973).
Using the geometric mean fish bioconcentration factor  (27,000) a
Residue Limited Toxicant Concentration of 0.024 ug/1 is obtained.
Effects on mink were seen at a dietary PCB concentration of 0.64
ug/g and a "no-effect" dose was not determined.  A criterion
calculated from these data may not be protective because the
dietary concentration was not protective and the BCF based on
laboratory studies may underestimate BCF's in saltwater animals
since field-observed bioconcentration factors were higher but
could not be used in the calculations.  When field data were used
for freshwater fish, a much higher BCF (427,000) was derived.
                              B-30

-------
Miscellaneous
    , No other data exist that suggest any more sensitive effects
(Table 12).
                              B-31

-------
CRITERION FORMULATION
                    Saltwater Aquatic Life
Summary of Available Data                           .c -^r_?:.I*z,-=•
     The concentrations below have be'en  rounded  to  twd  signif-
icant figures.                                         -
     Final Fish Acute Value  = not available
     Final Invertebrate Acute Value  =  6.20'jag/1
          Final Acute Value  = 0.20 jig/I
     Final Fish Chronic Value = 0.049  ug/1
     Final Invertebrate Chronic Value  =  not available
     Final Plant Value =0.1 ug/1
     Residue Limited Toxicant Concentration = 0.024 jig/I
          Final Chronic Value = 0.024  ug/1
          0;44 x Final Acute Value = 0.087 jig/1
     The maximum concentration of polychlorinated biphenyls
is the Final Acute Value of  0.20 ug/1  and the 24-hour average
concentration is the Final Chronic Value of 0.024 pg/1.
No important adverse effects on saltwater aquatic organisms
have been reported to be caused by concentrations lower
than the 24-hour average concentration.
     CRITERION: For polychlorinated  biphenyls the criterion
to protect saltwater aquatic life as derived using  the Guide-
lines is 0.024 ug/1 as a 24-hour average and the concentration
should not exceed 0.20 pg/1  at any time.
                               B-32

-------
                  Table  8.  Marine invertebrate acute values for polychloririated biphenyls
                                                                              Adjusted













00
1
u>



• Or nanism
Eastern oyster,
Crassostrea virginica
Eastern oyster,
Crassostrea virginica
Eastern oyster.
Crassostrea virginica
Eastern oyster.
Crassostrea virginica
Brown shrimp,
Penaeus aztecus
Grass shrimp,
Palaemonetes pugio

Pink shrimp.
Penaeus duorarum
Pink shrimp.
Penaeus duorarum

Bicxissay
Method*
FT

FT

FT
•
FT

FT

FT

FT

FT

Test
cone . **
^MIMWri^V^B
U

u

u

u

u

u

u

u

Chemical
Description
A- 1016

A- 1248

A- 1254

A-1260

A- 1016

A- 1016

A- 1248

A-1254
•
Time
(hrs)
96

24

24

24

96

96

48

48

LCbO
(qq/1)
10.2***

17. ***

14.0***

60. ***

10.5

12.5

32. ***

32.0***

LCbu
(uq/1)
7.8

3.4

2.8

12.0

8.1

9.6

10.5

10.5


Reference
Hansen, et
al. 1974a
Lowe, undated

Lowe, undated

Lowe, undated

Hansen, et
al. 1974a
Hansen, et
al. 1974a
Lowe, undated

Lowe, undated

*  FT =» flow-through
** U = unmeasured
***EC50:   Decreased growth of oysters;  loss of equilibrium or death of shrimp.
   Geometric mean of adjusted  values =9.67 ug/1    ^T    =0.20 ug/1

-------
                         Table   9.   Marine  fish chronic values for polychlorinated biphenyls
''Organism'

 Sheepshead minnow,
 Cyprinodon variegatus

 Sheepshead minnow,
 Cyprinodon variegatus
                                        Test* ;
                                        E-L
                                       Limits
                                       (uq/Jl>
                                                            Chronic
                                                            Value
                                       3.4-15.0** 3.6


                                      0,06-0.16   0.049
Reference

Hansen. et al.  1975


Schimmel, et al.  1974
u»
*  E-L = embryo- larval test

** Aroclor 1016

***Aroclor 1254

   Geometric mean = 0.42 pg/l


   Lowest chronic value «• 0.049 pg/1
                                                   0.060 ng/1

-------
                         Table 10. Marine plant effects for polychlorinated biphenyls
CO
I
(jj
ui
           Organism

           Diatom,
                        Effect
                        No growth in
               Concentration
               (aq/il	
                  0.1*
          Rhizosolenia setigera   48 hr.  Reduced
                                  growth thereafter
          Diatom.
          Thalassiosira
          pseudonana

          Diatom,
          Skeletonema costatum

          Diatoms,
          Thalassiosira
           §seudonana7
           keletonema
                        Reduced growth    25-100*
costatum

Diatom,
Cylindrotheca
closCerium '

Phytoplankton
populations

Green alga.
                        Reduced growth
                        Reduced growth
                        and carbon
                        fixation in
                        48 hr
                                  Reduced growth
Toxicity in
24 hr
                                  Species ratio
          Dunaliella tertiolecta/ change
          Diatom
          Thalassiosira pseudonana
          (mixed culture)

          Green alga,             Species ratio
          Dunaliella tertiolecta/"change
          Diatom
          Thalassiosira pseudonana
          (mixed culture;

          Natural phytoplankton   Decrease  in
                    10*
                    10*
                   100**
15*. 6.5**
                     1*
                                          0.1*
                                          0.1*
          community
          Alga.
                        species diversity,
                        species ratio
                        change

                        Reduction in rate  100*
          Dunaliella  tertiolecta  of carbon fixation
                  Reference

                  Fisher & Uurster. 1973



                  Mosser, et al. 1972a



                  Mosser, et al. 1972a


                  Fisher, 1975
                  Keil, et al. 1971
Moore & Harriss, 1972
                  Mosser, et al. 1972b
                                   Fisher, et al. 1974
                                   Fisher, et al. 1974
                                   Luard, 1973
          *  Aroclor  1254
          ** Aroclor  1242
             Lowest plant value v 0.1  pg/1

-------
                          Tatle 11.  Marine residues for polychlorinaced biphenyls
00
I
            Organism
Diatom,
Cylindrotheca closterium

Eastern oyster,
Crassoscrea virginica

Eastern oyscer,
Crassostrea virginica

Eastern oyster,
Crassostrea virginica

Grass shrimp,
Palaemonetes pugio

Blue crab,
Callinectes sapidus

Spot,
Leiostomus xanthurus

Sheepshead minnow,
Cyprinodon variegatus

Pinfish,
Lagodon rhotnboides

Speckled trout,
Cynoscion nebrelosus

Fishes

Invertebrates
Bioconcentration factor

          1,000*


         13,000**


        101,000***


       >100,000*****


         27,000***


       >230,000*****


         37,000***


         30,000***


         17,000*


       >670,000*****


       >133.000****

        >27,000****
  Time
 (days)

   14
                                                                             84
                                                                            245
 neference

Keil, et al. 1971


Parrish. et al. 1974


Lowe, et al. 1972
                                                                          Field data  Duke, et al. 1970
   16


Field data


   28


   28


 21-28


Field data


Field data

Field data
Nimmo, et al. 1974


Nimmo, et al. 1975


Hansen, et al. 1971


Hansen, et al. 1973


Hansen, et al. 1974a


Duke, et al. 1970


Nimmo, et al. 1975

Nimmo, et al. 1975
            *     Aroclor 1242

            **    Aroclor 1016

            ***   Aroclor 1254

            ****  Averages from field data from Escambia Bay, Fl., based on 27 water samples, 101 invertebrate
                  samples, and 17 fish samples expressed, as Aroclor 1254.

            ***** Greatest bioconcentration factor of Aroclor 1254 in moHusks, crustaceans, or fishes from
                  Escambia Bay, Florida.

-------
                           Table 11 (continued)
             Organism
                                  Bioconcentratlon Factor
                                                                             Time
                                                                            (days)
                                                                                        i
-------
                            Table  12.  Other marine data for polychlorinated biphenyls
03
I
LJ
00
Organism

Ciliate protozoans,
Tfctrahymena pyriformis

Ciliate protozoan,
Tetrahymena pyriformis

Ciliate protozoan,
Tetrahymena pyriformis

Ciliate protozoan,
Tetrahymena pyriformis

Eastern oysters,
Crassostrea virginica

Eastern oysters,
Crassostrea virginica

Horseshoe crab,
LimuLus polyphemas

Amphipod,
Gammarus oceanicus

Grass shrimp,
Palaemonetes pugio

Pink shrimp,
Penaeus duorarum

Pink shrimp,
Penaeus duorarum

Pink shrimp,
Penaeus ouorarum

Fiddler crab,
Uca pugilator

Communities of
organisms

Spot,
Leiostomus xanthurus
                                 Test
                                 Duration  Ettect

                                  7 days   Bioconcentration
                                           factor = 60*

                                  96 hrs   Reduced growth
                                  96 hrs   Reduced growth
                                  96 hrs   Reduced growth
                                  2 days   Bioconcentration
                                           factor = 8,100*

                                  24 wks   Reduced growth
96 days   Bioconcentration
          factor = 1.298****

30 days   Mortality
                                   Result
                                    tug/it    Reference
                                  1 hr
          Avoidance
                                 15 days   51% mortality
                                 15 days   LC50
                                  2 days   Bioconcentration
                                           factor = 140*

                                 38 days   Inhibited molting*****


                                  4 mos    Affected composition
                                 12 days   50% mortality
                                             Cooley,  et al.  1972
                                   1000.**   Cooley, et al.  1973
                                      1.0*   Cooley, et al.  1972
                                   1000.***  Cooley, et al., 1973
                                             Duke, et al.  1970
                                      5.0*   Lowe, et al.  1972
          Neff & Giam, 1977
 >10.0*   Wildish. 1970
<100.0*

  10.0*   Hansen, et al. 1974b
                                      0.94*  Nimmo, et al.  1971
                                      1.0*   Nimmo & Bahner,  1976
                                             Duke, et al.  1970
                                      8.0*   Fingerman & Fingerman,
                                             1977

                                      0.6*   Hansen. 1974
                                      5.0*   Hansen, et al.  1971

-------
           Organism

           Pinfish.
           Lagodon rhomboldes

           Pinfish.
           Lagodon rhomboides

           Pinfish,
           Lagodon rhomboides

           Pinfish.
           Lagodon rhomboides
                   Table  12.  (Continued)


                        Test
                        Duration  Etfect

                       •  1 hr     Avoidance


                        18 days   50% mortality
                         2 days   Bioconcentration
                                  factor = 980*

                        42 days   507. mortality
Result
Jua/il  •  Reference
10.0*     Hansen. et al. I974b


 5.0*     Hansen. et al.  1971


          Duke, et al.  1970


21.0****  Hansen, et al.  1974a
           Sheepshead minnow.      28 days   Affected reproduction***  0.14*    Hansen, et al.  1973
           Cyprinodon variegatus
00
I
W
vo
*    Aroclor 1254

**   Aroclor 1248

***  Aroclor 1260

**** Aroclor 1016

*****Aroclor 1242                           '

******significantly affected hatching of eggs or the survival of fry from exposed adults.

-------
                  POLYCHLORINATED BIPHENYLS

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and solubility characteristics of Aroclor®' 1254 in water.


Water Research.   9: 937.



                           •   .                             t>
Snarski, V.M., and F.A. Puglisi.  1976.  Effects of Aroclor


1254 on brook trout, Salvelinus fontinalis.  Ecol. Res.


Ser. EPA 600/3-76/112.  U.S. Environ. Prot. Agency, Duluth,


Minn.




Stalling, D.L.  1971.  PCS residues in bluegills and channel


catfish exposed to A-1248 and A-1254 for 11 weeks.  PCB


Newslett. July 28. Duluth, Minn.




Veith, G.  1975.  Baseline concentrations of polychlorinated


biphenyls and DDT in Lake Michigan fish, 1971.  Pestic.


Monitor. Jour.  9: 21.




Veith, G.  1976.  Comparative toxicity of A-1016 and A-1242


to the fathead minnow.  Environ. Res. Lab.  U.S. Environ.


Prot. Agency, Duluth, Minn.  (Manuscript.)



                                B-51

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Veith, G.D., et al.  1977.  Residues of PCB's and DDT in
the Western Lake Superior ecosystem.  Arch. Environ. Contain.
Toxicol.  5: 487.

Waybrant, R.  1974.  Northern pike fry mortalities attributed
to PCB's polychlorinated biphenyls. Mich* Dep. Nat. Resour.
(Unpublished document.)

Wildish, D.J.  1970.  The toxicity of pblycibrinated biphenyls
(PCB) in seawater to Gammarus oceanicus.  Bull. Environ.
Contarn. Toxicol.  5: 202.

Yap, H.H., et al.  1971.  Sensitivity of fish ATPases to
polychlorinated biphenyls.  Nature  233: 61.

Zitko, V,  1970.  Polychlorinated biphenyls  (PCB) sblubilized
in water by nonionic surfactants for studies of toxicity
to aquatic animals.  Bull. Environ. Contarn. Toxicol.  5:
279.

Zitko, V. and W.Q. Carson.  1977.  A comparison of the uptake
of PCB's and Isopropyl-PCB's  (chloralkylene 12 ) by
Chemosphere No. 2/3.  Pergammon Press.

-------
                            .PCBS

Mammalian Toxicology and Human Health Effects
                           SUMMARY  .,

     Polychlorinated biphenyls (PCBs) have been used com-
mercjLadly since 1929 as dielectric and heat exchange fluids
and in a variety of other applications.  They have become
widely disseminated in the environment worldwide.  Like
many organochlorine pesticides, they are highly persistent
and accumulate in food webs.  Human exposure to PCBs has
resulted largely from the consumption of contaminated food
but also from inhalation and skin absorption in work environ-
ments.  PCBs accumulate in the fatty tissues and skin of
man and other mammals.  Metabolism occurs by hydroxylation
and dihydrodiol formation with arene oxides as probable
intermediates.  The rate of metabolism and excretion slows
dramatically as the chlorination of the biphenyl nucleus
increases.  Arrangement of chlorines which eliminate adjacent
unsubstituted carbons greatly increase resistance to metabolism.
PCBs have caused profound toxic effects in man and animals,
particularly if repeated exposures occur.  The skin and
liver are major sites of pathology with the gastrointestinal
tract and nervous systems also being targets.  Polychlorodi-
benzofurans which contaminate commercial PCB mixtures may
contribute significantly to their toxicity.  Several studies
in rodents suggest strongly that some PCBs are carcinogenic
                              C-l

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and that they can enhance the carcinogenic!ty of other chemi-
cals.  A linear model for risk assessment has been used
to estimate maximum safe levels in water and fish which
will establish a level of risk for the human population
from cancer.  A maximum level of PCBs in water projected
to result in no more than 1 cancer in 10  individuals with
lifetime exposure of 0.26 ng/liter is suggested by the analysis.
                              C-2

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                          EXPOSURE



Introduction



     PCB's have t>ecome widespread in the environment since



the introduction of their commercial use in 1929 (Peakall,



1975).   The magnitude of the dispersal of these chemicals



is revealed by their detection in the tissues of plants



and animals in all parts of the world.  PCB residues have



been observed in wildlife in Sweden, North America, Great



Britain, the Netherlands, and even the Arctic  (Risebrough



and de Lappe, 1972).  Because PCBs are not naturally occurring



substances, their dissemination is entirely the result of



human activity.  Their entry into the environment has occurred



by vaporization into the atmosphere, and by spilling or



dumping into water or onto land.  It has been estimated



that of the 1970 sales of PCBs in North America only 20



percent represented a net increase in the total amount in



service.  Estimated sources of loss for that year were 1



- 2 x 10  tons for evaporation; 4 - 5 x 10  tons for leaks



and disposal of fluids; and 22 x 10 tons from disposal by



incineration and burial  (Nisbet and Sarofim, 1972).  The



cumulative input to the environment between 1930 and 1970


                          4                    4
was estimated to be 3 x 10  tons to air, 6 x 10 tons to



fresh and coastal waters, and 3 x 10  tons to dumps and



landfills.  In that time, up to 1/3 of the PCBs released



to air and 1/2 of that released to water were probably degrad-



ed.  Degradation in landfills is more difficult to estimate



(Nisbet and Sarofim, 1972).  PCBs have been found repeatedly



to be widespread in analyses of human tissues.  For example,



detectable levels of PCBs have been reported in adipose
                               C-3

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tissue samples of  up  to  91  percent of  individuals  sampled
in a survey of the United States population  (Kutz  and Strassraan,
1976; see Table  12).   This  finding suggests  that environmental
contamination may  be  a significant source of human exposure.
Likely routes of exposure for  the general population are
water and particularly food while inhalation and dermal
icontact are likely to be more  significant routes in occupa-
tional exposure.
                               C-4

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Ingestion from Water
     The solubility of PCBs in water is very low, decreasing
as the percent chlorination is raised.  Solubilities of
Aroclors in water at 20° vary from 200 >ug/l for 1242 to
about 25 ;ug/l for 1260 (Nisbet and Sarofim, 1972).  The
major factors in the dynamics of PCB distribution in water
are its low solubility, high specific gravity, and its high
affinity for solids.  Most PCBs discharged into water are
found in bottom sediments near the site of discharge (Nisbet
and Sarofim, 1972).  Evaluation of PCB levels in surface
waters and bottom sediments of the major drainage basins
of the United States was conducted between 1971 and 1974
(Dennis, 1976).  The data were derived from the U.S. Geological
Survey study of 1971-72 (Crump-Weisner, et al. 1974) and
from additional data collected by the USGS between 1972
and 1975 (PCB data base 1972-75).  It  is summarized in detail
in the Criteria Document for PCBs (U.S. EPA, 1976a).  The
highest concentrations in both water and sediment were found
in the basins east of the Mississippi River.  The highest
levels were found in 1971 in the lower Mississippi basin
with a median concentration for the region of  3 ug/1 and
positive detections at 100 percent of  stations tested.
Over the time period of the study the concentrations and
incidences of PCBs detected in all basins have decreased
substantially.  By 1974 the median level in the lower Missis-
sippi basin had dropped to 0.1 jug/1 and the incidence of
detection to 2.6 percent of stations tested.  The levels
in sediments however, have persisted at much higher levels
                               c-5

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over this period of  time.   In 1971 median sediment levels
for the Mississippi  basin were 30 jug/kg and the  incidence
of detection 100 percent.   By 1974 the incidence had dropped
to 9.9 percent and the median level was 10.5 jug/kg.
     Although PCBs are widespread in aquatic environments
(Peakall, 1975) their low solubility generally prevents
them from reaching high concentrations in drinking water
.supplies.  The persistence  of PCBs and their accumulation
in sediments increase the significance of water  as a source
of human exposure by providing a reservoir of material which
can continue to contaminate water long after the addition
of PCBs has ceased.  In combination with these factors,
the lipophilicity of PCBs results in their continued intro-
duction to, and accumulation in, the food chain.  As a con-
sequence, fish and other foods obtained from aquatic environ-
ments may become important  sources of exposure even if PCB
levels in the water  are low.
     The ability of  PCBs discharged from a manufacturing
facility to contaminate a drinking water system  has recently
been highlighted.  Billings, et al.   (1978) determined the
levels of PCBs in the Easley-Central Water District, Pickens
County, South Carolina.  They observed that PCBs discharged
by a capacitor manufacturing facility 12 km upstream from
the water district's treatment plant were entering the water
system.  Finished potable water supplies were contaminated
to levels as high as 818 ng/1.
                               C-6

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Ingestion from Foods



     Contamination of food with PCBs occurs primarily by



three mechanisms.  The first is contamination of human food



as a consequence of accumulation in the food chain. The



contamination of freshwater fish as a consequence of the



contamination of the aquatic environment is a particularly



significant route of PCB entry into the human diet which



will be discussed in more detail below.  The second mechanism



occurs by the direct contamination of feeds or foodstuffs



with PCBs.  This may occur as a result of accidental spills



or equipment malfunctions as was the case in the episode



of rice oil contamination in Japan which led to the outbreak



of Yusho or rice oil disease in 1968 (Kuratsune, et al.



1976).  In this instance leaks in a heat exchanger used



to process rice bran oil resulted in the contamination of



the oil by the exchanger fluid (Kanechlor 400) .  Discovery



of the contamination was made only after numerous cases



of chlorinated hydrocarbon intoxication in Fukuoka prefecture,



Japan.  The oil was found to contain 2,000 to 3,000 ppm



Kanechlor 400 which was contaminated with polychlorodibenzo-



furans (1.6 to 5 ppm).  Average consumption of PCBs among



affected individuals was estimated to be 2 g  (Kuratsune,



et al. 1972).  By 1975 the total number of known individuals



affected was 1,291.  Elevated PCB levels in fat were still



observed four years after the exposure, and dermatological



symptoms were found in up to 89 percent of a group of 72



patients examined in 1973 or 1974.  Another example of acci-



dental PCBs contamination in animal feed occurred as a result
                              C-7

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of the use of PCBs in silo coatings (Willett and Hess, 1975),



The third significant source of PCBs in foodstuffs was food



packaging made from recycled paper containing PCBs (Jelinek



and Corneliussen, 1976).



     A special case of  human exposure via food which must



be considered is human  breast milk.  Adverse effects have



been observed in breast fed infants of women with Yusho



(Kuratsune, et al. 1976) and in infant Rhesus monkeys ingest-



ing breast milk containing 7 to 16 ppm PCBs  (fat basis)



(Allen, 1975; Allen and Barsotti, 1976).  Preliminary survey



data indicate average PCB levels in human breast milk of



1.8 ppm (fat basis) (42 FR 17487) and a study of PCB exposed



nursing mothers in Germany indicated average PCB levels



of 3.5 ppm (Tombergs, 1972).  The proximity of these values



to the toxic levels in  infant monkeys (7 to 16 ppm) suggests



that human breast milk  must be considered a significant



source of PCB exposure.



     The extent of contamination of the U.S. food supply



has been the subject of Food and Drug Administration  (FDA)



and Department of Agriculture  (USDA) monitoring programs



since 1969.  Results of these studies have been summarized



by Jelinek and Cornelliussen (1976).  The initial analysis



of 15,000 food samples  between 1969 and 1971 is summarized



in Table 1.  The results of monitoring programs in fiscal



years 1973, 1974, and 1975 are summarized in Table 2.  Over



the monitored period the incidence and levels of PCBs have



dropped in all food classes.  By 1975 the only significant



food sources were fish, meat, and dairy products. Fish were
                              C-8

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                                TABLE  1

                       Summary of PCB's in Food
                       Nov., 1969 - June, 1971a
Food
commodity
Finf ish
Oysters
Fish byproducts
Cheese
Milk
Eggs
Potato
byproducts
Miscellaneous
Positive
findings
317
12
6
44
60
17
12

11
Avg. of
positives
(ppm)
2.1
Trace
1.8
0.3b
2.5b
Trace
1.1

1.9
Max. level
(ppm)
35.3
Trace
5.0
1.0b
22. 8b
0.5
4.2

6.5
Approximately 15,000 samples examined.

 Fat basis.

°Detection limits: fish 0.5 ppm, other foods 0.05 ppm (P.E. Corneliusser
 personal communication).

From:  Jelinek and Corneliussen (1976).
                             C-9

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                                     TABLE 2

                   Summary of PCBs  in Foods.  FY73,  74  and  75
Food
Commodity
Fish
Milk
Eggs
Cheese
Feed components
Animal feeds
Processed fruits
Infant & jr. foods

Meats & poultry
(USDA)
FY '
Percent
positive
60.4
2.2
1.1
0.9
12.7
7.2
4.5
1.1
Percent
positive
1.9
73
Max.
(ppm)
123.0
1.6
Trace
0.5
9.0
199.5
19.2
Trace
Percent
above
5 ppma
0.19
FY
Percent
positive
44.0
2.6
4.2
2.6
0.0
0.0
0.0
0.0
Percent
positive
1.2
'74
Max.
(ppm)
16.8
2.3
11.0
2.8
N.D.
N.D.
N.D.
N.D.
Percent
above
5 ppma
0.07
FY
Percent
positive
17.8
0.7
0.0
0.0
0.3
0.0
0.0
0.0
Percent
positive
0.3
'75
Max.
(Ppm)
9.0
1.9
N.D.
N.D.
0.9
N.O.
N.D*
N.D.
PercVr
above .
5 ppm'
0.06
aMilk, cheese, meats and poultry reported as ppm, fat basis.

 Detection limits:  fish 0.5 ppm, other foods 0.05 ppm.   (P.E. Corneliussen,
 personal communication).

From:  Jelinek and Corneliussen  (1976).
                                    C-10

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by far the most significant source.  The findings for the
1969-71 period led to the establishment of regulations for
PCB levels in food (38 FR 18096).   The temporary tolerances
established at that time and new tolerances recommended
in 1977 (42 FR 17487) are given in Table 3.  The enforcement
of those tolerances and restriction of PCB use in open systems
after 1970 probably account for the general decline of PCB
levels in foodstuffs.
     Comprehensive fish surveys conducted by the FDA in
fiscal years 1973 and 1974 indicated a drop in the incidence
of PCB detection in fish from less than 30 percent in 1973
to less than 20 percent in 1974.  In 1973 three percent
contained over 1 ppm and 0.5 percent contained over 5 ppm
PCBs.  The data from all FDA studies in the fiscal years
1973, .1974, and 1975 are summarized in Figure 1.  While
the incidence of PCBs in fish dropped over the period the
fraction of positive fish containing over 5 ppm PCBs increased
from less than five percent to over ten percent.  The samples
containing more than 5 ppm were from the Great Lakes.  Because
the study involved different sources and objectives from
year to year no conclusion as to whether a significant trend
existed was drawn.  It should be noted that these surveys
were conducted with fish in commerce and provide no information
about sport fish per se.  The studies indicated that signi-
ficant levels of PCBs generally do not occur in salt water
fish.
                              C-ll

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            60
            50
            10
            30
          S 20-
            10
                   n


                                           i
                                                        yj



                                                                g\
               FISCAL YEAR '/J
FISCAL YEAR '7<4
FISCAL YEAR '75 »
Figure  1:  PCBs  in fish FY73,  74, 75  a  level of detection:
            0.5 ppm.

Prom:   Jelinek and Corneliussen (1976).
                                C-12

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                                  TABLE 3

                         FDA Regulations for PCBs
I.
Commod i ty
Milk (fat basis)
Dairy products (fat basis)
Poultry (fat basis)
Eggs
Finished animal feed
Animal feed components
Fish (edible portion)
Infant and junior foods
Temporary tolerances
PCB cone.
(ppm)
2.5
2.5
5.0
0.5
0.2
2.0
5.0
0.2
Proposed Guidelines
1977
1.5
1.5
3.0
0.3
0.2
2.0
2.0
pending
Paper food-packaging material 10. Oa
without PCB-impermeable barrier
II. Use prohibited in food,
food packaging plants
feed,
 Administrative guideline, pending hearing.

From:  Jelinek and Corneliussen (1976)
       42 FR 17487
                                C-13

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The impact of sport fish consumption was examined in a study



of a group of sports fishermen who consumed an average of



24 to 25 pounds of fish annually  (highest individual exposure



180 Ibs/year over a two-year period).  PCS residues in cooked



fish ranged from 0.35 - 5.38 ppm.  Plasma PCB levels ranged



from a high of 0.366 ppm in the exposed group to control



levels 0.007 ppm (less than six Ibs consumed per year) (42



FR 17487) -.



     A bioconcentration factor (BCF) relates the concentration



of a chemical in water to the concentration in aquatic organisms,



but BCF's are not available for the edible portions of all



four major groups of aquatic organisms consumed in the United



States.  Since data indicate that the BCF for lipid-soluble



compounds is proportional to percent lipids, BCF's can be



adjusted to edible portions using data on percent lipids



and the amounts of various species consumed by Americans.



A recent survey on fish and shellfish consumption in the



United States (Cordle, et al. 1978) found that the per capita



consumption is 18.7 g/day.  From  the data on the nineteen



major species identified in the survey and data on the fat



content of the edible portion of  these species (Sidwell,



et al. 1974) , the relative consumption of the four major



groups and the weighted average percent lipids for each



group can be calculated:
                              C-14

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          Group
     Freshwater fishes
     Saltwater fishes
     Saltwater molluscs
     Saltwater decapods
Consumption
 (Percent)
    12
    61
     9
    18
Weighted Average
 Percent Lipids
       4.8
       2.3
       1.2
       1.2
     Using the percentages for consumption and lipids for each
     of these groups, the weighted average percent lipids is
     2.3 for consumed fish and shellfish.
          Measured bioconcentration factors were obtained in
     tests lasting over 200 days with three species using Aroclor
     1242, 1248, 1254, and 1260:
Organism
Brook trout
Salvelinus fontinalis
fillets, A-1254
whole body, A-1254
Average
BCF
2,800
12,000
Percent
lipids
0.65
2.8
Adjusted
BCF
9,900
9,900
Reference
Snarski &
Puglisis,
1976
Fathead minnow
Pimephales promelas
females, A-1248
males, A-1248
males, A-1260
females, A-1260
Fathead minnow
Pimephales promelas
males, A-1242
females, A-1242
males, A-1254
females, A-1254
240,000
120,000
270,000
540,000
123,000
75,000
181,000
283,000
10.4
4.2
3.3
9.7
3.8
10.0
3.8
10.0
53,000
66,000
188,000
128,000
74,000
17,000
109,000
49,000
                             DeFoe, et al.
                             1978
                                                           Nebeker, et
                                                           al. 1974
                                   C-15

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Eastern oyster                                             Lowe, et al,
Crassostrea yirginica                                      1972

A-1254                    93,000    1.5        142,000

     Only tests lasting over 200 days were used since long exposures

     are necessary to reach steady-state.  The percent lipids

     for mature fathead minnows were obtained from DeFoe, et

     al. (Personal communication).  The percent lipids for oysters

     was obtained from Sidwell, et al. 1974.  Each of these average

     measured BCF's was adjusted from the percent lipids of the

     test species to the  2.3 percent lipids that is the weighted

     average for consumed fish and shellfish.  The geometric

     mean was obtained for each species, and then for all species.

     Thus, the weighted average bioconcentration factor for PCB's

     and the edible portion of all aquatic organisms consumed

     by Americans is calculated to be 46,000.

          Higher BCF values apparently can be achieved in field

     exposures  (Haile, et al. 1975; Norstrom, et al. 1976; Duke,

     et al. 1970; Nimmo et al. 1975; Veith, 1975; Veith, et al.

     1977) , but those values cannot be considered quantitative

     because the exposure of the organism cannot be adequately

     documented and integrated over a long enough period of time.

          In order to estimate human dietary PCB intake the FDA

     conducts a continuing survey of the total diet.  Composites

     of 12 different food categories are analyzed for PCB content.

     Table 4 summarizes the results of the survey from 1971 through

     the first half of 1975.  While contamination was observed

     in most categories in 1972 the number of positive categories

     had dropped by 1973.  In 1974 and 1975 only meat, fish,

     and poultry were observed to contain PCBs and fish was almost


                                   C-16

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                                    TABLE 4
                    Percent of Composites Containing PCBs,
                        From the FDA Total Diet  Studies
Fiscal Year


1971


1972


1973


1974


1975  (1st half)
 6


10
•
CO
•o
£ 0
CO >,
••-1 Vl
fa 4J
iH
•• 3
JJ 0

(U <1)
J >
(0
0)
__J
^^
X!
(0
-U
4J (U
O CT
O (U
« >



C CO
0) -U
T3 -iH
>-i 3
(Q W
O fa
                                                                     C
                                                                   (0 —i
                                                                   4J C
                                                O
                                                x:
                                      m to
                                       4J
                                      to o
                                      Vi C
                                      ro =1
                                      cr>Ti
                                      3-D
                                      co <
17


 3
From:  Jelinek  and  Corneliussen.  1976.
                                  C-17

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always the contributor of positive results in that category



(Jelinek and Corneliussen, 1976).  Most of the contamination



noted in the other categories in earlier years was thought



to result from exposure during processing or packaging be-



cause the raw foods were rarely found to contain PCBs.



Total daily intake, calculated from the composite figures



for a young adult male over the period 1971-1975, is sum-



marized in Table 5.  Total daily intake dropped by almost



50 percent over the period but intake in the meat-fish-poultry



category changed very little.  By 1974 almost all of the



dietary intake resulted from the ingestion of PCB-contami-



nated fish.  The measures taken in the early 1970's to limit



the release of PCBs into the environment and to remove them



from food processing environments effectively reduced direct



contamination of foodstuffs to a minimum level.  The per-



sistence of PCBs in aquatic environments and in fish has



maintained a residual dietary exposure level in the diet.



Further reduction of PCB levels in the diet will require



that entry of PCBs into waterways be more tightly controlled



and that monitoring of fish and other foods for PCB contami-



nation be continued (Jelinek and Corneliussen, 1976).  The



recently recommended reduction of allowable PCB levels in



fish to 2.0 ppm may further reduce dietary intake (42 PR



17487).



     Two special situations should be mentioned which must



be avoided to prevent unnecessary PCB ingestion.  First,



accidental contamination of foodstuffs or feeds with PCBs



must be avoided.  Although PCB manufacture is now stopping
                               c-18

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                             TABLE 5
                 Estimates of daily PCB  intakes
                (Total Diet; Study - Teenage Male)
Average daily intake of PCB' sa
Fiscal
year
1971
1972
1973
1974
1975. (1st half)
Total diet
(jug/day)
15.0
12.6
13.1
8.8
8.7
Meat-fish- poultry
food class (jug/day)
9.5
9.1
8.7
8.8
8.7
aLower limit of quantitative reporting =
 0.05 ppm with analytical method employed.

From:  Jelinek and Corneliussen (1976)
                           C-19

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and distribution will cease in the near future, many PCB


containing products remain in service.  Failure to exercise


care in the maintenance and disposal of these units could


result in the contamination of food or water.  The tragic


results of the episode of rice oil contamination in Japan


(Kuratsune, 1972) provides ample evidence of the need for


care and continued surveillance of foods.  Second, although


occupational exposure to PCBs will decline over the next


several years, the possibility of food contamination as


a consequence of transfer from workers tools' or clothing


must be considered as a possible route of dietary exposure.


Inhalation


     PCBs can enter the atmosphere by vaporization and may


be found in either gaseous form or adsorbed to airborne


particulates.  Prior to the restriction of PCB use, substan-


tial losses to the atmosphere resulted from evaporation


of plasticizers and from improper incineration (Nisbet and


Sarofim, 1972) .  In 1972 terrestrial input from fallout


was estimated to be 1000 to 2000 tons/year.  Annual emission


rates were estimated at 1500 to 2500 tons.  (Nisbet and Sarofim,


1972).  In 1975 a study of PCB content in air in suburban


areas in Florida and Colorado indicated that average atmos-


pheric levels were approximately 100 ng/m  (Kutz and Yang,


1976) .  Rates of fallout along the southern California Coast

                                                       2
were estimated to average 1800 kg/year over a 50,000 km


area (Young, et al. 1976).  The distribution of PCBs in


air is non-uniform, being more highly concentrated in urban


areas.  The aerial fallout survey in southern California
                               C-20

-------
indicated that sectors in the urban areas around Los Angeles

had fallout rates of up to 180 kg/yr while less industrialized

sectors had rates as low as 30 kg/yr.  A study of PCS levels

in soil samples showed that they were rarely detectable

in agricultural soils but were found in 63 percent of urban

samples from 19 cities (Carey and Gowan, 1976).  General

human exposure to inhaled PCBs probably varies with the

local conditions.  Relative to the 9 /ig/day intake estimated

from the diet (Jelenek and Corneliussen, 1976) non-occupa-

tional exposures by inhalation are probably small.

     While inhalation of PCBs is not and most likely will

not be a major route of general human exposure, it is a

highly significant route of occupational exposure.  Early

in its commercial use an association was observed between

occupational exposure to PCB vapors and chloracne (Jones

and Alden, 1936; Schwartz, 1936).  The benefits of control-

ling leaks from closed systems into work environments were

noted by Meigs, et al. (1954).

     A study of occupational exposure in Japan found PCB

vapors at levels between 13 and 540 jug/m  and airborne par-

ticulates between 4 and 650 jug/m  in a survey of six indus-

trial plants.  An additional finding of 6,270 jjg/m  PCB

particulates was associated with a spill.  Blood PCB levels

of 99 exposed workers averaged 370 ppb as compared to levels

in 32 controls of 20 ppb  (Hasegawa, et al.  1972).  Ouw,

et al. (1976) observed Aroclor 1242 levels between 2.22

and 0.32 mg/m  in different areas of an electrical equipment
                                      I
manufacturing facility in Australia.  Blood Aroclor levels
                              c-21

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were analyzed by gas chromatography and fractions with several
retention times standardized against Aldrin were detected
in exposed workers.  Workers in an impregnation room where
inhalation was a major mode of exposure had higher levels
of PCBs than did workers in another area where exposure
was primarily dermal.  A series of 30 control individuals
were not found to have detectable PCB levels.  The limit
of detection in this study was not reported; however, Finklea,
et al.  (1972) reports American control population blood
levels of 0.3 to 3 ppb.
     It is difficult to differentiate between industrial
exposure by inhalation and dermal absorption (see below).
Animal studies do indicate that animals exposed to PCB aerosols
show rapid increases in liver PCB levels.  Exposure to Pydranl
A 200 for 15 minutes resulted in the accumulation in the
liver of 50 percent of the PCBs accumulated after two hours
(Benthe, et al.  1972).  The lung appears to be a good site
of absorption and certain occupational environments contain
significant levels of airborne PCBs.  The National Institute
of Occupational Safety and Health has recently proposed
an occupational exposure limit of 1.0 jug/m  on a time weighted
average 10-hour day, 40-hour week basis  (Natl. Inst. Occup.
Safety Health, 1977).  Assuming a tidal air volume of 10
m  in an eight-hour day and 100 percent absorption, the
resulting dose at this exposure level would be 10 ^ug/day.
Dermal
     Dermal exposure, like inhalation exposure, is a partic-
ularly significant route in the occupational setting.  With
                               C-22

-------
the restriction of PCS uses to sealed systems, the use of



PCBs in products to which the public might be exposed has



declined markedly, reducing opportunities for general exposure.



Past uses of PCBs in carbonless copy paper, printers inks,



and other products probably contributed to general PCS ex-



posures.  Documented exposures are largely occupational



as exemplified by the results of Ouw, et al.  (1976).  The



authors noted that one group of employees were largely ex-



posed through skin contact and had significantly elevated



blood PCB levels.



     In a variety of animal studies dermal application of



several PCB containing materials has produced both local



and systemic effects including liver degeneration and death



(Miller, 1944; Paribok, 1954; Vos and Beems, 1971).  In



neonatal rats treated by skin application with PCBs, a five-



to ten-fold increase in aryl hydrocarbonhydroxylase activity



occurred in liver, skin, lung, and kidney, indicating signi-



ficant distribution to these tissues after exposure by this



route (Bickers/ 1976; Bickers, et al.  1975).



     The relative contributions of various routes of exposure



can be expected to vary widely.  Occupational exposures



are by far the most severe with inhalation and skin contact



being the major routes of absorption.  A noteworthy by-product



of occupational PCB exposure is the elevated risk of exposure



among other members of workers' families.  An epidemiological



study in Bloomington, Indiana revealed significantly elevated



serum PCB levels among a group of 18 occupationally exposed



workers (mean 71.7 ppb) and a slight elevation among 19
                              C-23

-------
members of their families  (near 33.6 ppb) as compared to


background levels  (5 to 20 ppb) (McCloskey, et al. 1978).


The general public is widely exposed to PCBs but at much


lower levels and primarily through the diet.  Fish living


in contaminated waters are by far the largest contributors


to dietary PCBs (Jelinek and Corneliussen, 1976).


                       PHARMACOKINETICS


Absorption


     The efficiency of PCB absorption in the gut of rats


was shown to be between 92 to 98.9 percent, (Albro and Fishbein,


1972).  Neither degree of chlorination (mono-hexachloro-


biphenyl) nor the dose ingested (5 to 100 mg/kg) markedly


affected the efficiency of uptake.  Matthews and Anderson


(1975b) observed a reduced accumulation of PCBs in adipose


tissues of rats exposed orally as compared to i.v. injection.


The differences were more pronounced with biphenyls of low


chlorine content and were thought to be related to route
                                         \

of absorption and metabolic rates, rather than to the overall


efficiency of transport across the gut.  Absorption via


the gut was also very efficient in adult Rhesus monkeys,


90 percent of a single dose of 1.5 or 3.0 g/kg Aroclor 1248


being absorbed from the gastrointestinal tract  (Allen, et
         L

al. 1974) .


     Efficient absorption via inhalation has been demons-
         i.-
trated in rats by Benthe, et al.  (1972).


     In humans, absorption via the intestine has been best


illustrated by the "Yusho" incident in Japan in 1968.  Among


individuals ingesting less than 720 ml of contaminated rfce
                              C-24

-------
bran oil (equivalent to 1.5 to 2.2 g Kanechlor 400) 39 percent
developed severe symptoms and an additional 49 percent devel-
oped moderate symptoms of PCB intoxication.  The lowest
level of PCB ingestion in an affected individual was estimated
to be 0.5 g (Kuratsune, et al. 1972).  Absorption via the
respiratory tract and skin is also efficient as indicated
by occupational exposures where effects of PCB exposure
can be detected even at doses too low to produce pathology
(Alvares, et al. 1977).
Distribution
     PCBs given to rats by i.v. injection are removed from
the blood rapidly and stored initially in the liver and
muscle.  With time they are redistributed primarily to skin
and adipose tissue (Matthews and Anderson, 1975b).  The
degree to which PCB's are stored or excreted depends on
their susceptibility to metabolism and, therefore, on the
degree of chlorination and availability of adjacent unsub-
stituted carbons.  Tissue levels of mono-, di-, penta- and
hexachloro-biphenyls in rats given a single injected dose
at 0.6 mg/kg were determined by Matthews and Anderson (1975b).
The maximum doses accumulated in each tissue increased with
degree of chlorination as did the half life in each tissue.
The proportion of total PCBs present in tissues as metabolites
was greatest for the mono-and di-chlorobiphenyls.  Hexachloro-
biphenyls in tissues were largely unmetabolized.  The distri-
bution of PCBs in adipose tissue provides a useful example
of the relative accumulation of different isomers.  Tissues
were examined for up to 42 days and a summary of .the results
is presented in Table 6.
                              C-25

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                                TABLE 6

               Storage of PCBs in Adipose Tissue  in Rats
              (Values are Percent  of Total Dose 0.6 mg/kg)
Degree of
Chlorination
mono-
di-
penta-
hexa-
Maximum
11.
52.
23.
85.
63
75
54
18
± 5.
± 14-
± 3-
+ 21.
64
99
0
6
Time of
Maximum
Stored
1
2
1
42
hr
hr
day
days
Amo u n t at
7 Days
0.
1.
13.
56.
234
837
04
08
± °-
± °-
± 2-
+ 15.
055
213
1
72
Adapted from Matthews and Anderson, 1975b.
                              C-26

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     A similar pattern was observed in skin with up to 22
percent of the hexachlorobiphenyl dose being accumulated
there at 1 day and residual levels around 15 percent remaining
at 42 days.
     Single intravenous doses of 0.6 or 6.0 mg/kg 2, 4,
5, 2',5' pentachlorobiphenyl were cleared from the blood
in ten minutes and initially deposited in liver and muscle.
They were subsequently translocated to adipose tissue and
skin as depositories (Matthews and Anderson, 1975a).
     A single administration of approximately 500 mg/kg
2, 5, 2', 51 tetrachlorobiphenyl to rats resulted in a similar
distribution with adipose, skin, and blood being the signifi-
cant storage depots after 24 hours  (Van Miller, et  al.
1975) .
     The significance of chlorine position as well  as number
was addressed in a study of the pharmacokinetics of 3, 5,
3',5' tetrachlorobiphenyl (TCB) by Tuey and Matthews  (1977).
The arrangement of chlorines on this molecule results in
the absence of adjacent unsubstituted sites.  The pattern
of distribution of the compound following a single  i.v.
injection of 0.6 mg/kg was similar to that observed in earlier
studies  (Matthews and Anderson, 1975a,b) with adipose tissue
and skin becoming the major long term storage sites.  However,
loss of 3, 5, 3',5' TCB was slower than earlier observed
for 2, 4, 5, 2', 5' pentachlorobiphenyl (see penta  CB Table
6) with the maximum adipose tissue load reaching 52.9 percent
of total dose on day four and the residual on day seven
                             >
remaining at 45.4 percent.  The distribution of several

                              C-27

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tetrachlorobiphenyl isomers in mice was analyzed by Mizutani,
et al. (1977).  In all cases the accumulation of the compound
was greater in the carcass than in the liver.  A tendency
for those isomers with adjacent unsubstituted carbons to
be rapidly cleared was observed.  2, 6, 2', 6' TCB was very
rapidly cleared from carcass and liver, and 2, 3, 2',3'
TCB was cleared fairly rapidly.  However, 2, 4, 2', 4' TCB
was more resistant to removal than 3, 5, 3', 5' TCB which
might not be anticipated on structural grounds.  The half
life in the carcass of the former was 9.2 days but only
2.1 days fbr the latter.  The degree of accumulation of
the isomers was assessed by the introduction of an index
referred  to as a storage ratio (the daily amount entering
storage/daily oral ingestion).  By this measure 3, 5, 31,
51 TCB and 2, 4, 2',4' TCB were similar with indices of
0.7 and 0.6, respectively, while the more readily metabolized
2, 3, 2', 3' TCB had an index of 0.06.
     The distribution of 2, 5, 21, 5' TCB in infant Rhesus
monkeys was determined after a single dose of tritiated
TCB (500 mg/kg).  At 72 hours the distribution differed
from that in rats in that the label was more widely dispersed
in the monkeys.  Blood levels were lower than observed in
rats and the major storage depots were bone marrow, adrenal
and skin.  Most of the labelled material was associated
with macromolecules although it was largely extractable
and not covalently bound  (Hsu, et al.  1975a).
     Distribution of PCBs in the human body has not been
the subject of systematic experimentation.  Data available
from general population surveys indicate that general patterns
                              C-28

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of distribution are consistent with those found in other
animals.  When detected in the adipose tissue of the general
populace, PCB levels ^are around 1 mg/kg  (Yobs, 1972;, Kutz
and Strassman, 1976; and Grant, et al.  1976).  Plasma levels
detected in the general populace are two to three orders
of magnitude lower than adipose levels (Finklea, et al.
1972) Similarly, Yusho patients exhibited a 100 to 1000
fold greater concentration in the fat of skin, liver and
in adipose tissue than in plasma.  Over several years both
the fat and plasma levels were observed to decline to near
normal levels (Kuratsune, et al.  1976).  The PCBs found
in humaniadipose tissues in the U.S. chromatographically
resemble Aroclor 1254 and 1260, suggesting that less chlorinated
isomers found in Aroclor 1248 are preferentially excreted
(Kutz and Strassman, 1976).
Metabolism
     The metabolism of PCBs has been studied extensively
in several organisms.  A detailed review of PCB metabolism
was written by Sundstrom, et al.  (1976a).  Rather than
attempt to treat the subject exhaustively this section will
summarize the major characteristics of PCB metabolism which
relate to their distribution, accumulation, toxicity, and
possible mechanisms of carcinogenicity.
     the metabolism of PCBs depends on their chlorine content,
and the sites of chlorination on the biphenyl  (Sundstrom,
et al. 1976a; Lutz, et al.  1977).  While the overall mecha-
nisms of metabolism appear to be similar in most vertebrates
examined, the capacity to metabolize PCBs declines from
mammals to birds to fish  (Hutzinger, et al.  1972).  Elucida-

                              C-29

-------
tion of PCB metabolism has been made possible by the use


of individual purified isomers.  Predominantly, the products


of PCB metabolism at all levels of chlorination are biphenylols,


biphenyldiols, and dihydrodihydroxybiphenyls, although the


types and proportions of specific metabolites vary in different


species.  A few biphenyltriols and methoxy derivatives have


also been observed (Sundstrom, et al.  1976a).


     The structures of several PCB metabolites support the


formation of arene oxides as intermediates.  The first evidence


for the formation of arene oxide intermediates was obtained


by Gardener, et al.  (1973).  They isolated trans 3, 4 dihy-


droxy-3, 4-dihydro-2, 2', 5, 5' tetrachlorobiphenyl as a


metabolite of 2, 21, 5, 5' tetrachlorobiphenyl in rabbits.


More direct evidence for the formation of arene oxides was


obtained by Safe, et al.  (1975, 1976).  In rabbits and frogs


the biohydroxylation of 4-chlorobiphenyl was investigated

         2
using 4'- H-4-chlorobiphenyl.  The major metabolite 4' chloro-


4-biphenylol retained 79 percent of the label which is con-


sistent with arene oxide formation (Daly, et al.  1972).


The subsequent isomerization of the arene oxide results


in the migration of the deuterium atom from the ultimate


site of hydroxylation to the adjacent carbon, an NIH shift.


Daly, et al.  (1972) consider the NIH shift of labeled hydro-


gens, halogens or alkyl substituents to be indicative of


enzymatic arene oxide formation.  A subsequent hydroxylation


to 4'chloro-3, 4-biphenyldiol resulted in the loss of half


the remaining deuterium suggesting a direct hydroxylation


rather than a second arene oxide formation (Safe, et al.


1975).  4, 4'-dichlorobiphenyl produced three metabolites



                              C-30

-------
in the rabbit:  4, 4'-dichloro- 3-biphenylol, 3, 4'-dichloro



- 4-biphenylol and 4'-chloro-4-biphenylol.  These products
                                                 \


are consistent with a  mechanism involving 3, 4-arene oxide



formation followed by epoxide ring opening.  Either a 1.2



halogen shift, with or without halogen elimination upon



tautomerization, or 3-ol formation after arene ring cleavage



would produce the ultimate products (Safe, et al. 1976;



Safe, et al. unpublished, quoted in Sundstrom, et al.  1976a).



The reactions are diagrammed in Figure 2.  Other examples



of PCBs for which metabolic pathways are consistent with



are;ne oxide formation include 2, 2', 4, 4', 5, 5' -hexachloro-



biphenyl in rabbits (Sundstrom, et al. 1976b) and 4 chlorobi-



phenyl and 4, 4'-dichlorobiphenyl in rats  (Hass, et al.



1977).  Infant Rhesus monkeys fed 2, 5, 2', 5 tetrachloro-



biphenyl excreted dihydroxy, dihydrodihydroxy and dihydrotri-



hydroxy derivatives in urine (Hsu, et al.  1975b).



     The K region epoxides of polyaromatic hydrocarbons



are known to bind to nucleic acids in vitro  (Grover and



Sims, 1970) and in cultured mammalian cells  (Grover, et



al. 1975).  Furthermore, they are capable of transforming



cells in culture  (Huberman, et al.  1972) although their



significance in tumor induction in animals is in doubt (Grover,



et al. 1975).  It has been suggested that arene oxide metabo-
                                                               r\


lites of PCBs may react with nucleophilic sites in DNA and



other macromolecules and that alkylation of critical sites



may be involved in the induction of tumors (Allen and Norback



1977).
                              C-31

-------

                    urine  2.0
0.2
2.2
2.0
7.5
Figure  2:   Metabolic pathways  for  4,  4'-dichlorobiphenyl
            in the rabbit.

From:   Sundstrom, et al.  (1976a)

-------
Excretion


     The primary routes of PCB excretion are bile (observed


in feces) and urine.  Excretion is closely coupled to meta-


bolism.  In rats less than ten percent of excreted PCBs
             *

were unmetabolized  (Matthews and Anderson, 1975b).  The


rate and efficiency of excretion were highly dependent upon


the degree of chlorination and structure.  Urinary excretion


of PCBs accounted for the removal of 59.8, 33.9, 7.6, and


0.7 percent of total dose of mono, di, penta, and hexachloro-


biphenyl respectively.  Over 60 percent of urinary excretion


occurred within the first 24 hours and all urinary excretion


ceased by the ninth and fourth days, respectively, for penta-


and hexachlorobiphenyl (Matthews and Anderson, 1975b).


All the 2, 4, 5, 2',5' pentachlorobiphenyl excreted in urine


by rats was in the  form of a glucuronide conjugate of a


metabolite (Chen and Matthews, 1974).  While urinary excretion


usually ceases within a few days, biliary excretion continues


for an extended period.  The relative contribution of biliary


excretion to the elimination of PCBs increases with  chlori-


nation.  The kinetics of excretion of mono- and dichlorobi-


phenyl are monophasic while the elimination of penta- and


hexabiphenyl is biphasic.  While 90 percent of PCBs up to


pentachlorobiphenyl were excreted in 42 days or less, hexa-


chlorobiphenyl was  largely retained in the tissues of the


animal.  Extrapolation of the excretion data indicated that


only 20 percent of  2, 4, 5, 21, 41, 5' hexachlorobiphenyl


would even be excreted (Matthews and Anderson, 1975b).
                              C-33

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The- absence of adjacent unsubstituted carbons greatly decreased



excretion as would be expected from the effects of structure



on storage arid metabolism.  3, 5, 31, 51 TCB is excreted



at about the same rate as 2, 4, 5, 2', 5' pentabiphenyl



(Tuey and Matthews, 1977; Matthews and Anderson, 1975a).



While the half-life in fat for 2, 5, 2', 5' TCB was about



33 hours at 500 mg/kg dose in rats (Van Miller, et al.



1975) the half-life for 3, 5, 3', 5' TCB was 12 to 15 days



at dose levels of .6 mg/kg in rats (Tuey and Matthews, 1977).



     The half-lives of the individual PCB isomers in the



rat may be approximated by the fecal half-lives which are



15.7 and 22.2 hours for mono and dichlorobiphenyl respectively.



Penta and hexabiphenyls elimination is biphasic with first



and second component half-lives of 39.2 and 211 hours for



penta-CB and 49 and 642 hours for hexa-CB  (Anderson, et



al. 1977).  Because only 20 percent of the hexa-CB is ulti-



mately excreted its half-life is indefinite.



     Rates of elimination of a series of tetrachlorobiphenyls



in mice were determined by Mizutani, et al. (1977).  Half-



lives for TCB isomers in liver and the carcass ranged from



0.9 days for 2, 3, 2', 3' TCB to 9.2 and 7.8 days for the



loss of 2, 4, 2', 41 from carcass and liver, respectively.



Structure did not influence elimination as markedly as in



the rat.  3, 5, 3', 5' TCB had half-lives of 2.1 and 2.2



days in carcass and liver.  However, stimulation of meta-



bolism by the addition of phenobarbitol did increase the



rate of elimination of 2, 4, 2', 4' TCB more than 3, 5,



3', 5' TCB.  The authors concluded that the rate-limiting
                              C-34

-------
 step in the elimination of the isomers was release from
storage in the tissues of the mouse rather than metabolism.
     Two differences between the elimination of 2, 5, 2',
5' TCB in infant Rhesus monkeys and rats may be of interest
in evaluating human metabolism.  Single doses of 500 mg/kg
to rats resulted in total elimination of about 76 percent
(66 percent feces, 10 percent urine) in 72 hours (Van Miller,
et al. 1975).  In primates only one percent of the same
dose was eliminated in feces and two percent in urine after
72 hours (Hsu, et al. 1975a).  In addition, the major excreted
metabolite in rats appeared to be 3-hydroxy TCB while a
dihydrodiol TCB predominated in monkeys (Van Miller, et
al.  1975; Hsu, et al. 1975b).
     A final comment on the pharmacokinetics of PCBs must
be addressed to transplacental and transmammary movement.
Transplacental uptake of PCBs by a fetus has been documented
in mice (Masuda, et al. 1978), rats (Curley, et al. 1973),
Rhesus monkeys (Allen and Barsotti, 1976), and humans (Yosh-
imura, 1974) .  In mice, transplacental and transmammary
uptake of PCBs were approximately 0.1 to 0.2 and 20 to 35
percent of total dose respectively  (Masuda, et al. 1978).
Similar values were observed in rats (Mizunoya, et al. 1974).
Female monkeys consuming 2.5 ppm Aroclor  1254 transferred
enough via breast milk to produce severe hyperplastic gas-
tritis in nursing infants  (Allen and Barsotti, 1976).  Recently,
a preliminary mathematical model of PCB distribution in
rats has been proposed (Lutz, et al. 1977; Anderson, et
al. 1977).
                              C-35

-------
     It should be noted that most of the laboratory studies
discussed above have been performed with pure isomers, while
toxicity studies and environmental exposures involve commercial
mixtures with possible dibenzofuran contamination.  In addition,
commercial mixtures tend to contain  asymmetrical polychlorinated
biphenyls (Natl. Inst. Occup. Safety Health, 1977).
     The pharmacokinetics of PCBs can be summarized with
the following points:
1.   They are readily absorbed through the gut, respiratory
     system, and skin.
2.   They may initially concentrate in the liver, blood,
     and muscle mass; but long-term storage in mammals is
     primarily in adipose tissue and skin.
3.   The major metabolic products of PCBs are phenolic deriv-
     atives or dihydrodiols which may be formed through
     pathways with arene oxide intermediates or by direct
     hydroxylation.  The susceptibility of individual PCB
     isomers to metabolism is a function of the number of
     chlorines present on the biphenyl and their arrangement.
     Biphenyls which have one or more pairs of adjacent
     unsubstituted carbons are more rapidly metabolized
     than those which do not.
4.   PCBs which are readily metabolized are also rapidly
     excreted in the urine and bile.  Excretion in urine
     is most prominent for the least chlorinated, while
     bile becomes the more significant route of excretion
     for more highly chlorinated isomers.
                              C-36

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5.  "Those isomers which are most refractory to metabolism
     accumulate for increasing periods of time in fatty
     tissues.   Highly chlorinated isomers are accumulated
     almost indefinitely.
6.   PCBs can be transferred either transplacentally or
     in breast milk.
7.   Non-human primates may retain PCBs more efficiently
     than rodents.
                           EFFECTS
Acute,, Sub-acute, and Chronic Toxicity
     Several reviews of the toxic effects of PCBs in animals
and man have appeared in recent years (Kimbrough, 1974;
Fishbein, 1974; Peakall, 1975; Kimbrough, et al. 1978; Cordle,
et al. 1978; Natl. Inst. Occup. Safety Health, 1977 (which
is particularly recommended for human effects)).  This section
will attempt to highlight the most significant toxic effects
observed in animals and man, but will not seek to be compre-
hensive.
     The acute oral and dermal LD^Q  for PCBs in rats, mice,
and rabbits are given in Tables 7, 8, and 9.  In the classi-
fication by the American Hygiene Association the PCBs, are
slightly toxic or almost nontoxic  (Hodge and Sterner, 1949).
In rats, Bruckner, et al. (1973) observed a 14-day LD5Q
of 4.25 g/kg.   Toxic effects of high doses of Aroclor 1242
included diarrhea, chromoacryorrhea, loss of body weight,
unusual stance and gait, lack of response to pain stimuli,
and terminal ataxia.  CNS deterioration and dehydrydration
were thought to be contributing factors.  Histopathologic
changes were observed only in liver and kidney.  Miller

                              C-37

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                                                               TABLE  7

                                    Acute Toxicity of PCD's in Several Strains of Rats and Mice.
    Compound  tested
                                          Species and sex
                                          Route
                            LD
                     g/kg body weight
               Reference
o
 i
U>
00
 Aroclor 1254
 Aroclor 1260
 Aroclor 1254
 Aroclor 1260
 Aroclor 1254
 Aroclor 1221
•Aroclor 1262
 Aroclor 1240
 Aroclor 1254
 Aroclor 1254
 Aroclor 1254
 Aroclor 1254
 Kaneclor-400
 Kaneclor-400
 Kaneclor-400
 Kaneclor-400
 Kaneclor-300
 Kaneclor-300
 nP-200 biphenyls of
  dichloride and below
 2,4' -Dichlorobiphenyl
 Trlchlorobiphenyl
 niphenyl of 'trichloride
  and below
 2,4,3',4'-Tatrachlorobiphenyl
 5-OH derivative of 2,4,3',4'-
  tetrachlorob-phenyl .
 2,3,4,3' ,4' -P-.-atachlorobtphenyl
Rat (adult, Sherman strain)
Rat (adult, Sherman strain)
Rat (weanling, Sherman strain)
Rat (weanling, Sherman strain)
Rat (female, Sherman strain)
Rat (female, Sherman strain)
Rat (female, Sherman strain)
Rat
Rat (Wistar, 30-day-old, M-F)
Rat (Wistar, 60-day-old, M-F)
Rat (Wistar, 120-day-old, M-F)
Rat (Wistar, 120-day-old, F)
Rat (Wistar, M)
Rat (Wistar strain, F)
Mice (CPI strain, M)
Mice (CFI strain, F)
Rat (Wistar strain, M)
Rat (Wistar strain, F)
Mice (dd strain, F)

Mice (dd strain, F)
Mice (dd strain, F)
Mice (dd strain, F)

Mice (DVI strain)
Mice (CFI strain)

Mice (CFI strain)	
     "•"^afcrence  nutnt_    fre**. source.'

       •;:.:   K'.mbrough,  *-   «?..  1578.
      Oral
      Oral
      Oral
      Oral
   Intravenous
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
      Oral
    / Oral

      Oral
      Oral
      Oral

 Intraper itoheal
.Intraperttoneal

 Intrapcrttoneal
4-10
4-10
 1.295
 1.315
 0.358
 4,00
11.3
 4.25
 1.3
 1.4
 2.0
 2.5
   (ml kg)
   (ml kg)
                                                                                                   30
                                                                                                   14
                                                                                                 1.075 (ml kg)
                                                                                                 1.57
   (ml kg)
  ,15
  .05
                                                                                                     6.36

                                                                                                     7.86
                                                                                                  3.0fi - 4.25
                                                                                                     9.27

                                                                                                     2.15
                                                                                                     0.43

                                                                                                     0.65
 (5)
 (5)
 (5)
 (5)
 (5)
 (6)
 (6)
 (7)
 (8)
 (8)
 (8)
 (8)
 (9)'
 (9)
 (9)
 (9)
 (9)
 (9)
(10)

(10)
(10)
(10)

(11)
(11)

(11)

-------
                               TABLE 8

                                         a
                          Oral LD5Q  (rat)
                                                         LD
               Compound tested	g/kg body weight
Aroclor
Aroclor
Aroclor
Aroelor
Aroclor
Aroclor
Aroclor
1221
1232
1242
1248
1260
1262
1268
(Und
(Und
iluted)
iluted)








(Undiluted)
(Und
(50%
(50%
(33.
iluted)
soln in
soln in
3% soln


corn
corn
in


oil)
oil)
corn
oil)
2.
1.
0.
0.
1.
1.
2.
000
26
794
794
26
26
5
- 3.
- 2.
- 1.
- 1.
- 2.
- 3.

169
0
269
269
0
16

aData of Panel on Hazardous Substances (6)

From:  Kimbrough, et al.  (1978)
                               TABLE 9

                                           a
                        Skin LD5Q  (rabbits)
                                                            LD
             Compound tested	  g/kg body weight
Aroclor
Aroclor
Aroclor
Aroclor
Aroclor
Aroclor
Aroclor
1221
1232
1242
1248
1260
1262
1268
(Und
(Und
(Und
(Und
(50%
(50%
(50%
iluted
iluted
iluted
iluted
soln
soln
soln
,
)
)
)
in
in
in




corn oi
corn oi
corn oi




1)
1)
1)
3.
4.
8.
11.
10.
11.
10.
98
47
65
0
0
3
9
aData of Panel on Hazardous Substances (6)
From:  Kimbrough, et al.  (1978)
                             C-39

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(1944) found the guinea pig most sensitive  to Aroclor  1242



followed by the rabbit and rat.  In  the rat, toxicity  de-



creased with increasing degree of chlorination; however,



the effect was not observed with rabbits  (Fishbein,  1972).



     The more significant toxic effects of  PCBs are



observed on repeated exposure over a period of time.   Aroclor



1254 at 1000 ppm in the diet was fatal to 75 percent of



male rats in 43 days with total intakes of  500 to  2000 mg/kg



being lethal (Tucker and Crabtree, 1970).   Phenoclor DP6  "



fed at 2000 ppm to rats resulted in  marked  weight  loss and



death between 12 and 56 days after the initiation  of treatment



(Vos and Koeman, 1970).  Guinea pigs treated dermally  for



11 days with a total of 379.5 mg of  a PCB with 42  percent



average chlorine content died at intervals  up to 21  days



following the first application (Miller, 1944).  Aroclor



1254 at 1000 ppm in the diet killed  5/10 male rats and 8/10



female rats.  At 500 ppm over eight  months  two males and



one female died while  no lethality was observed at 100 or



20 ppm. Aroclor 1260 was less toxic, with 8/10 females but



no males dying at 1000 ppm. No males died at lower doses



and 1/10 and 2/10 females died at 100 and 500 ppm  respec-



tively.  Substantial weight losses were observed at  100



and 500 ppm in both males and females  (Kimbrough,  et al.



1972).  Mink have been shown to be unusually sensitive to



PCBs.  A mixture of Aroclors 1242, 1248 and 1254 at  30 ppm



in the diet for 6 months was 100 percent lethal  (Aulerich,



et al.  1973) as was 3.6 ppm Aroclor 1254 over 105 days



in another study (Plantonow and Karstad, 1973).  Adult Rhesus



monkeys (Macaca mulatta) were particularly  sensitive to
                              C-40

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PCBs.  Aroclor 1248 at 100 or 300 ppm in the diet  for  two
to three months resulted in extreme morbidity within one
month and almost 100 percent mortality within three months.
Total intakes for the two groups were 0.8 to 1.0 g for  100
ppm and 3.6 to 5.4 g for 300 ppm  (Allen, 1975).
     The roost consistent pathological changes occurring
in mammals after PCB exposure are in the liver.  In rats/
                   i
rabbits, and guinea pigs, Miller  (1944) observed fatty  depo-
sits after acute injections and similar changes in rabbits
and guinea pigs after dermal application.  In feeding  experi-
ments, marked fatty metamorphosis was noted in guinea  pig
liver with intracellular hyaline bodies being observed  in
rats.  Less striking changes were noted in the kidneys,
lungs, adrenals, and heart of guinea pigs.  Rats exposed
repeatedly ;to dietary PCBs show increased liver weights
(Kimbrough, et al. 1972; Bruckner, et al. 1973).   Kimbrough,
et al.  (1972) fed rats Aroclor 1254 or 1260 at levels  between
20 and 1000 ppm for eight months.  Light microscopic changes
observed included hypertrophy of liver cells, cytoplasmic
inclusions, brown pigment in Kupffer cells, lipid  accumula-
tion and, at higher doses, adenofibrosis.  Ultrastructural
examination revealed an increase in smooth endoplasmic  retic-
ulum.  The effect of Aroclor 1254 was more pronounced  than
that of 1260.  Porphyria was observed in the livers and,
occasionally, other tissues of animals exposed to  either
mixture.
                             C-41

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     Rats fed 2000 ppm Phenoclor DP6 also had enlarged livers
with vacuolated foamy cells containing pycnotic nuclei (Vos
and Koeman, 1970).  Vacuolization of liver cells was also
noted by Bruckner, et al.  (1973) after dosing rats with
100 rag/kg Aroclor for three weeks although no overt toxicity
was manifest.
     Rats fed 100 ppm Aroclor 1242  (6.6 to 3.89 mg/kg/day)
or Aroclor 1016 (6.9 to 3.5 mg/kg/day) for periods of up
to ten months showed no signs of overt intoxication or gross
liver changes.  Enlarged hepatocytes with vacuolated cyto-
plasms and inclusions were noted.  Aroclor 1242 seemed to
produce more pronounced changes than 1016.  Four and six
months after the discontinuation of exposure hepatocytes
were still enlarged but cytoplasmic vacuoles and inclusions
had diminished, suggesting a degree of reversibility of
effect.  Significant residual levels of PCBs remained in
adipose tissue.  Using electron microscopy, increased smooth
endoplasmic reticulum and  lipid vacuoles as well as atypical
mitochondria were observed.  No significant gross changes
in other organs were noted (Burse, et al. 1974).
     Allen and Abrahamson  (1973) fed rats 1000 ppm of either
Aroclor 1248, 1254, or 1262 for 1, 3, 7, 14, 21, or 28 days
or 6 weeks.  No overt toxicity was observed although weight
gain was retarded in all treated groups.  The effect was
inversely proportional to  percent chlorination.  Increased
liver size, protein, and RNA content were observed.  The
magnitude of changes increased with the percent chlorination.
Hypertrophy was associated with proliferation of the smooth
endoplasmic reticulum, formation of membranous arrays, and
increased lipid droplets.
                             C-42

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     The effect of metabolism on toxicity was explored  •
by giving rats large (1.5 g/kg) single doses of 2, 5, 2',
S'-tetrachlorobiphenyls which produced high mortality within
two to three days (Allen, et al. 1975).  Pretreatment with
phenobarbitol to induce metabolic enzymes allowed survival
without obvious ill effects following a 1.25 g/kg dose,
while treatment with the microsomal enzyme inhibitor SKF
525A lead to 100 percent mortality in four days.  The ability
to metabolize and eliminate TCB appears to protect the animal.
Dietary administration of 100 ppm TCB for three weeks produced
less liver hypertrophy than Aroclor 1248.
     Liver pathology in mice exposed to 1.5 mg PCB/day was
essentailly the same as seen in rats/ including increased
smooth endoplasmic reticulum and increased lipid droplets
(Nishizumi, 1970).
     Rabbits receiving 300 mg orally of Aroclor 1221, 1242,
or 1254 for 14 weeks were examined (Roller and Zinkl, 1973).
Aroclor 1221 and 1242 treated rabbits gained weight at control
rates while 1254 treated rabbits did not gain as much.
Livers of 1254 and 1242 treated animals were enlarged while
livers of 1221 treated animals were smaller than controls.
Gross liver lesions and small uteri were apparent in the
1254 treated animals but not the others.  Liver pathology
in 1254 treated animals included enlarged hepatocytes with
foamy to granular cytoplasms, and subcapsular midzonal necrosis
Aroclor 1242 produced a liver pathology similar to 1254.
Aroclor 1221 treated animals were free of histologic changes.
                             C-43

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     Dermal studies with rabbits using Clophen A60, Phenoclor
DP6 and Aroclor 1260 indicated that the latter was the least
toxic (Vos and Beems, 1971).  The former two mixtures had
been shown to be contaminated with tetra- and penta-chlorodi-
benzofuran (Vos, et al. 1970).  Skin lesions produced included
hyperplasia and hyperkeratosis of the epidermal and follicular
epithelium, and were accompanied by pathological changes
in the liver and kidney.  The chlorodibehzofuran impurities
in the PCBs were thought to be responsible for the skin
lesions.  A comparison of the toxic effects of dermally
applied 2, 4, 5, 2'f 5' hexachlorobiphenyl and Aroclor 1260
demonstrated that the skin lesions appeared sooner and were
more severe after treatment with the commercial mixture.
Liver changes were found in both treatment groups with the
pure isomer inducing the more severe effects.  From this
study it was concluded that the chlorodibenzofuran contaminants
in commercial mixtures probably contribute to the skin lesions
(chloracne), edema formation, and liver damage while PCBs
contribute in lesser degrees to chloracne and liver damage
but are primarily responsible for the hepatic porphyria
observed in PCB intoxication (Vos and Notenboom-Ram, 1972).
     Non-human primates are rather sensitive to PCBs.  Male
Rhesus monkeys were fed 300 ppm Aroclor 1248 for three months.
Effects which began to appear within a month included hair
loss, subcutaneous edema, purulent discharge from the eyes,
acneform eruptions, and liver hypertrophy caused by smooth
endoplasmic reticulum proliferation.  Marked hypertrophy
of the gastric mucosa was a significant finding not usually
                               C-44

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seen in rodents.  Invasion of the submucosa by the mucosal
epithelium with increased cellularity and dysplasia occurred
in the stomach.  The dietary levels used were about tenfold
greater than the contamination levels in foods during the
early 1970's and the gastric changes observed were considered
to be of particular significance to human risk (Allen and
Norback, 1973).  When fed low levels (2.5 and 5 ppm) of
Aroclor 1248 for 52 weeks female monkeys developed periorbital
edema, alopecia, erythema and acneform lesions.  Effects
in males were less pronounced (Barsotti and Allen, 1975) .
The high sensitivity of monkeys to PCBs has been confirmed
and the evaluation of the toxic effects, particularly in
the gastric mucosa, has been extended (McNulty, 1976; Bell,
1976) .  The pathologic effects of PCBs in nonhuman primates
have been reviewed by Allen and Norback (1976) and Allen
(1975).
     The ability of PCBs to induce liver microsomal enzymes
was demonstrated by Street, et al. (1969).  Enzyme induction
by commercial PCBs has been shown in rabbits  (Villeneuve,
et al. 1971a), rats (Litterst and VanLoon, 1972), and primates
(Allen, et al. 1974).  In rats induction is observed following
intraperitoneal injection (Bickers, et al. 1972)  or skin
application  (Bickers, et al. 1975).  Threshold values for
enzyme induction vary between 0.5 and 25 ppm  (Villenueve,
et al. 1971a; Litterst, et al. 1972; Turner and Green, 1974) .
The induction of demethylating activity in rats by Aroclor
1254 was maximum in seven days while cytochrome P450 and
nitroreductase activities continued to rise over four weeks
                              C-45

-------
of treatment.  Activities declined slowly after discontinua-
tion of treatment reaching control levels in about ten days
(Litterst and VanLoon, 1974).  Cutaneous exposure to PCBs
resulted in a maximum induction within two to six days.
(Bickers, et al. 1972, 1975).  Degree of induction of enzyme
activities was found to correspond to increasing chlorine
content of Aroclors  (Litterst, et al. 1972)  and of di, tetra,
and hexachlorobiphenyl mixtures (Schmoldt, et al. 1974).
The effects of chlorine content and position of pure isomers
were examined by Johnstone, et al. (1974), Ecobichon (1975),
and Ecobichon and Comeau  (1975).  More highly chlorinated
isomers and those substituted at the 4 and 4' positions
were most active in  inducing enzymes associated with the
endoplasmic reticulum.  For less localized enzymes, position
was less critical, although chlorinated compounds were more
effective than biphenyl.
     The effects of  dietary exposure to Aroclor 1254 on
enzyme induction were investigated in rats by Bruckner,
et al. (1977).  Aroclor 1254 at 5 or 25 ppm induced dose
dependent increases  in the metabolism of pentobarbitol,
aminopyrine, and acetanilide after 35, 70, and 140 days
of exposure.  Exposure to 1 ppm had little effect on metabolism.
Liver weight and serum triglyceride levels were elevated
only in animals exposed to 25 ppm.  In 15-day experiments
induction of aminopyrine N-demethylation was observed after
the first day of exposure at 5 and 25 ppm, and acetanilide
hydroxylation was induced after two days.  Aminopyrine N-
demethylation returned to normal 15 days after the termination
of exposure.  Consumption of as little as 1 to 2 mg of PCBs
in 24 hours was sufficient to stimulate acetanilide hydroxylation
                              C-46

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     Commercial PCBs have been shown to induce cytochrome
P450 (phenobarbitol type) and cytochrome P448 (3 methylcho-
lanthrene type) (Alvares, et al. 1973).  More recent studies
with purified isomers indicated that ortho-para-substituted
PCBs induce P450 while meta-para-substituted PCBs induce
P448.  Substitution in the ortho-position dominates over
meta and no isomers were found to induce both activities
(Goldstein, et al. 1977).  The induction of both systems
by commercial preparations and some purified isomers has
recently been shown to result from contamination with dibenzo-
furans.  Even "99 percent pure" isomeric PCBs containing
44 ppm tetrachlorodibenzofuran effectively induces P448
while more rigorously purified material does not (Goldstein,
et al. 1978).  This observation serves as a reminder that
the effects of trace contaminants must be kept in mind when
evaluating the toxic effects of PCBs.
     Enzyme inducing effects of PCBs have also been examined
in vivo by the observation of shortened phenobarbitol sleeping
times in PCB treated animals (Bickers,et al. 1972; Johnstone,
et al. 1974;  and Villeneuve, et al. 1972).  PCB induction
of enzyme activities in other tissues has included skin
(Bickers, et al. 1975) placenta and fetus (Alvares and Kappas,
1975), neonatal liver during lactation  (Alvares and Kappas,
1975), and lung and kidney  (Vainio, 1974) .
     Other systemic effects of PCBs in mammals include por-
phyria (Bruckner, et al. 1974), increased thyroxin metabolism
(Bastomsky, 1974) and ultrastructural changes in the thyroid
(Collins, et al. 1977),  inhibition of ATPases (LaRocca and
                               c-47

-------
Carlson, 1975), and interference with oxidative phosphorylation
(Sivalingan, et al. 1973).  Alterations in steroid hormone
metabolism are produced by PCBs in rats (Hitman and Cecil,
1970), mice  (Orberg and Kihlstrom, 1973), and other animals.
Aroclor 1254 appears to reduce liver vitamin A concentrations
in pregnant rabbits (Villeneuve, et al. 1971b).  A more
complete review of these  effects can be found in Matthews,
et al.  (1978).
     PCBs have been shown to have immunosuppressive effects
in rabbits  (Vos and Beems, 1971; Street and Sharma, 1975),
guinea pigs  (Vos and van  Genderen, 1973; Vos and DeRoij,
1972), monkeys, mice (Thomas and Hinsdill, 1978) , and several
birds.  Significant effects were observed in Rhesus monkeys
exposed to dietary levels of Aroclor 1248 as low as 5.0
ppm.
     Effects of Aroclor 1254 and 1260 on reproduction in
Sherman strain rats were  investigated  (Linder, et al. 1974).
Dietary levels of 5 ppm Aroclor 1254 had no effect on repro-
duction in rats exposed through two generations.  Liver
weights were increased in male and female offspring of the
F, and F2 generations.  At 1 ppm, Aroclor 1254 caused increased
liver weights in F-^ male  weanlings.  At 20 ppm Aroclor 1254
the number of pups in the F-^^ and F2 generations was reduced
while 100 ppm resulted in increased mortality in F-,b offspring
and decreased the mating  performance of F-,b adults.  Aroclor
1260 produced increased liver weights  in Fj_ offspring at
5 ppm but did not affect  reproduction at 100 ppm.  At 500
ppm litter sizes were reduced and survival was decreased
                               C-48

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in F, litters.  Pregnant rats given 100 mg/kg/day Aroclor
1254 on days 7 to 15 had grossly normal litters but only 30.1
percent survived to weaning.  Dosage rates of 50 mg/kg/day
Aroclor 1254 or 100 mg/kg/day Aroclor 1260 did not affect
reproduction or pup survival.
     Rabbits fed 0.1 or 1.0 rag/kg body weight Aroclors 1221
or 1254 showed no significant decrease in number of pregnancies
or number of fetuses per litter  (Villeneuve, et al. 1971a).
No induction of fetal liver enzymes could be detected.
However, administration during gestation of 600-2, 500 ppm
Aroclor 1254 in the diet resulted in resorptions, abortions,
maternal death and, in two fetuses, asymmetric skulls  (Ville-
neuve, et al. 1971b).
     Reproductive effects in mice were investigated in animals
treated for ten weeks with 0.025 mg/day Clophen A60 (Orberg
and Kihlstrom, 1973).  The length of the estrus cycle was
increased from 6.6 days in controls to 8.7 days in experimental
animals.  Also the percentage of implanted ova was reduced
from 87.0 to 79.5.  In a second  study the reproductive effects
of neonatal exposure to PCBs in milk were examined by  injecting
lactating female mice with Clophen A60.  On the day of partu-
rition and at weekly intervals for three weeks, the females
were injected with 50 mg of PCB.  When treated male and
female offspring were mated with each other, the percent
implantation dropped from a control level of 94 percent
to 75 percent (Kihlstrom, et al. 1975).
                             C-49

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     In female Rhesus monkeys exposure to 25 ppm Aroclor



1248 in the diet for two months lead to the typical effects



of PCB intoxication for monkeys including edema, alopecia,



and acne.  One animal ingesting a total of 450 mg PCB died



two months after exposure ended and was found to have hyper-



plastic gastritis and bone marrow hypoplasia.  The remaining



five animals were bred three months after treatment.  Three



were thought to have conceived but resorbed or aborted the



embryos in the first two months of pregnancy.  One delivered



a fully developed but small infant (Allen, et al. 1974).



     In a more fully developed study both male and female



Rhesus monkeys were fed either 2.5 or 5.0 ppm Aroclor 1248



in the diet (Barsotti and Allen, 1975; Barsotti, et al.



1976) .  The total intake in the first 6 months for the females



was 180 and 364 mg for the 2.5 and 5.0 ppm diets, respectively.



Untreated females bred to treated males had normal rates



of conception  (Barsotti and Allen, 1975).  Treated females



bred to normal males produced the following rates of conception:



control, 12/12; 2.5 ppm, 8/8; 5.0 ppm, 6/8.  Live births



resulting from the conceptions were:  control, 12/12; 2.5



ppm, 5/8; 5.0 ppm, 1/6.  In the 2.5 ppm group, three fetuses



were resorbed shortly after conception.  In 5.0 ppm group



three pregnancies aborted at 46, 67, and 107 days of gestation,



one fetus was resorbed, one was stillborn, and one normal



birth occurred.  The two females who failed to conceive



were subsequently bred five times without conception.  The



live born infants were of low birth weight and showed signs



of PCB intoxication after nursing their mothers for less





                               C-50

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than two months.   Three infants died 44 to 112 days after



birth (Barsotti,  et al. 1976).   The mothers'  breast milk



contained 0.154 to 0.397 ppm PCBs and one contained 16.44



ppm (fat basis) (Allen and Barsotti, 1976).  It should be



noted that the dose levels producing these rather striking



effects are within the range of contamination of the human



diet observed until the mid 1970's.



     Recently, adipose tissue levels of PCBs in infant Rhesus



monkeys exposed in utero and via breast milk have been corre-



lated with behavioral effects (Bowman, et al. 1978).  Three



of five infants born to mothers exposed to 2.5 ppm Aroclor



1248 in the diet during pregnancy and lactation survived



over four months.   PCB levels in fat tissue in the infants



declined with a first order rate constant over a period



of 8 to 23 months of age.  Extrapolated maximum PCB levels



were 21, 114, and 123 ug/g fat.  A battery of eleven behavioral



tests was conducted with the three exposed animals and four



controls over this time period and a positive correlation



between reduced performance and PCB body burden was observed



for seven tests.



     Mink have been found to be exceedingly sensitive to



PCB-induced reproductive failure.  A marked increase in



kit mortality was observed in commercial mink in the mid-



1960 's after fish meal derived from spawning Great Lakes



Coho salmon was incorporated into the diet.  Laboratory



studies confirmed that the reproductive losses were related



to the ingestion of Great Lakes fish  (Aulerich, et al. 1971)



and subsequent investigation showed that PCBs contaminating
                              C-51

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the fish meal were the probable toxic agents (Ringer,  et
al. 1972).  When fed 10 ppm each of Aroclors 1242, 1248,
and 1254  (30 ppm total) 11/11 adult female mink died prior
to the end of the normal whelping (delivery) period (Ringer,
et al. 1972).  Aroclor 1254 fed at 10 ppm resulted in no
offspring among six females.  At 5 ppm, Aroclor 1254 fed
for four months prior  to whelping depressed reproduction
with only 3 of 12 females whelping and 3 of 9 kits born
alive.  At 1 ppm Aroclor 1254, 8 of 10 females whelped and
35 of 43  kits were born alive.  Among control animals 11
of 11 whelped and 56 of 66 pups were alive  at birth.  The
reproductive toxicity  of Aroclor 1254 becomes pronounced
between 1 and 5 ppm in the diet  (Ringer, et al. 1972).
At 2 ppm  in a nine month feeding trial, Aroclor 1254 signifi-
cantly reduced reproduction while Aroclors  1016,  1221,  and
1242 did  not  (Aulerich and Ringer, 1977).   Assuming a food
intake of 150 gm/day  (Schaible,  1970)  the  total PCB intake
in the two  trials would have  been 90 mg at  5 ppm  for four
months or 61 mg at  2 ppm  for  nine months  (Aulerich and  Ringer,
1977) .
      Human  exposures  to PCBs  resulting in  toxic  effects
have  almost all resulted  from the  ingestion of  rice oil
contaminated  with  Kanechlor  400  in  Japan  or from industrial
exposure.  While  absorption through the gut was  the route
of exposure in  the  former  case,  occupational exposures  occur
largely  by  inhalation  or  absorption through the skin.
      Yusho, the  disease  resulting from the ingestion of
contaminated rice oil in  Japan,  has been  the subject of
continuing  study  since the episode of exposure in 1968.
                               C-52

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Periodically, special reports on these continuing studies

have been published in Fukuoka Acta Med (Vol.  60, 1969;

Vol. 62, 1971; Vol. 63, 1972; Vol. 65, 1974; Vol 66, 1975;

Vol. 68, 1977).  These results, largely published in Japanese,

have been reviewed in English by the Japanese investigators

both early in the study (Kuratsune, et al. 1972; Kuratsune,

1972) and more recently (Kuratsune, et al. 1976).  The cause
          l
and scope of the exposure of the Japanese public has been

described above (See Ingestion from Food).  The initial

symptoms of Yusho included increased eye discharge and swelling

of upper eyelids, acne-form eruptions and follicular accentua-

tion, and pigmentation of the skj.n.  Other symptoms including

dermatologic problems, swelling, jaundice, numbness of limbs,

spasms, hearing and vision problems, and gastrointestinal

disturbances were prominent among the complaints of patients

seen within the first eight months after exposure (Kuratsune,

et al. 1972).  The first patients were seen almost immediately

after the release of the contaminated oil in February 1968.

Of a group of patients seen between October 1968 and January

1969, 55 percent became ill between June and August.  It

was ultimately determined that as many as 63.9 percent of

those who consumed contaminated oil became ill.  Among a

group of 146 known users of the oil, 80 consumed less than

720 ml and 88 percent of these users were affected.  Among

those who used more than 720 ml, 100 percent were affected.

The clinical severity of symptoms did not differ by sex

but the age group 13 to 29 was more affected than others

(Kuratsune, et al. 1972).
                               C-53

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     The analysis of the oil indicated that it contained
between 2 and 3 mg/kg of Kanechlor 400 (Kuratsune, et al.
1972).  It was later discovered that Kanechlor 400 contained
18 ppm of polychlorinated dibenzofurans (PCDFs) and that
the PCDF concentration in "Yusho Oil" was about 5 ppm .(Nagayama
et al. 1975).  The PCDF level in the oil was 250 times greater
than would be expected based on the level in fresh Kanechlor
400, leading Kuratsune, et al. (1976) to suggest that the
concentration increased with PCB use as a heat transfer
med ium.
     The amounts of Kanechlor 400 ingested were estimated
for the original 146 person study group.   The average amount
ingested was estimated to be 2 g while the minimum amount
ingested by a patient was about 0.5 g (Kuratsune, et al.
1972).
     Laboratory evaluations of patients during the early
period were summarized by Kuratsune  (1972).  Several changes
in blood were noted, including decrease in erythrocyte count,
increase in leukocyte count, and increase in serum lipids,
particularly triglycerides.  Blood proteins, electrolytes,
and enzyme activities were normal in most instances.  Some
increases in urinary ketosteroid excretion were observed.
The "cheesy" material from Yusho acne contained more steric
and oleic acids than did "normal acne", but less myristic
palmitic and palmitoleic acid.  Linoleic acid was present
in Yusho acne but not "normal acne."  Liver biopsy indicated
hypertrophy of the smooth endoplasmic reticulum, reduction
of the rough endoplasmic reticulum,  filamentous inclusions,

                              C-54

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and mitochondrial abnormalities.  Skin changes included
hyperkeratosis, cystic dilatation of the hair follicles
and marked increase of melanine in basal cells of the epidermis
Decreased sensory nerve conduction velocities were observed
in 9 of 23 patients.  Abnormalities of the eyes included
hypersecretion of the meibomian gland, and abnormal pigmenta-
tion of the conjunctiva.
     Thirteen women/ 11 with Yusho and 2 without, but married
to men wi'th Yusho, 'delivered ten live and two stillborn
infants between February 15 and December 31, 1968.  Nine
of the ten had grayish-dark stained skin, and five had similar
pigmentation of the gingiva and nails.  Eye discharge was
common.  A stillborn fetus had marked hyperkeratosis, atrophy
of the epidermis, and cystic dilatation of the hair follicle.
Increased melanin pigment in the blood cells and the epidermis
was also noted.  Twelve of the 13 fetuses were small for
date of birth.  The growth of children affected by Yusho
was significantly lower than Japanese national standards.
A detailed clinical study of four Yusho babies showed that
they were small for their age, had dark pigmentation on
skin and mucous membranes, and gingival hyperplasia.  Teeth
were erupted at birth, spotted calcification of the parietooc-
cipital skull, wide fontanels, and saggital suture was present,
along with facial edema and exophthalmic eyes (Yamashita,
1977).
     By three years after the episode about half the patients
were improving while 40 percent were essentially unchanged
and 10 percent were becoming more severely affected.  Even
                             C-55

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among those said to be improving, many still complained



of persistant headaches, general fatigue, weakness and numbness



of limbs, weight loss, and other problems (Kuratsune, et



al. 1972).



     An evaluation of the longer-term effects of Yusho has



been summarized by Kuratsune, et al. (1976).  In 1972 Masuda



noted a peculiar gas chromatographic pattern of PCB fractions



which was common to blood, tissues and breast milk of Yusho



patients  (Koda and Masuda, 1975) .  A pattern seen in about



60 percent of Yusho patients contained a larger amount of



a late eluting peak than PCB-containing tissues resulting



from other types of exposures.  This pattern was referred



to as type A.  A similar pattern seen in about 37 percent



of Yusho patients was referred to as type B.  These two



patterns  (types A and B) have never been observed in individuals



(human or animal) exposed to PCBs in other situations.



These types appear unique to Yusho.  Tissue levels of PCBs



in patients undergoing surgery or who died and were autopsied



were followed over several years.  Adipose tissue levels



were high (13 to 76 ppm) shortly after the end of exposure



but were  substantially lower by  the next year.  By 1970



and beyond, tissue levels were within the normal range in



the cases studied.  Blood levels were not determined until



1972 by which time they were in  the normal range.  Patients



whose plasma PCB pattern was type A had higher levels than



those with type B.
                               C-56

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     The discovery of substantial levels of PCDF in Yusho
oil has been discussed.  Levels of PCDFs in control individuals
and Yusho patients were determined.  No detectable ( 0.1
ppb)  PCDFs were found in controls while tissues of patients
who died in 1969 and 1972 contained .009 and .013 ppm in
adipose and liver respectively.  Ratios of PCB/PCDF were
144 and 4 for adipose tissue and liver, respectively.  PCDF
levels were higher in liver than adipose on a fat basis.
Although the sample was small, the levels in whole adipose
tissue appeared to have dropped to about 1/3 of the 1969
level by 1972.
     By 1972 the dermal and mucosal signs which were most
marked in the initial stages of toxicity were gradually
improving.  Symptoms considered to be due to internal distur-
bances, such as fatigue, poor appetite, abdominal pain,
headache, pain and numbness in the limbs, and cough and
expectoration of sputum, have become more prominent.  Between
March 1973 and April 1974, 79 patients were examined and
blood PCBs evaluated (Koda and Masuda, 1975).  Of patients
with type A or B plasma PCB chromatographic patterns a majority
exhibited some or all of the typical spectrum of dermatological
symptoms with frequencies in type A patients being higher
than in type B patients.  Because  PCB levels in type A patients
were higher than in type B, the severity of symptoms was
correlated with blood PCB levels.
     Serum triglyceride levels in males did not decline
significantly between 1969 and 1974 (Okumura, et al. 1974) .
Levels in female patients declined but were still above
                               c-57

-------
normal.  The elevation of triglycerides correlated with
increased blood PCB levels and the type A pattern.
     Serum bilirubin in patients was lower in 121 patients
than in 257 controls, indicating an accelerated rate of
disposal (Hirayama, et al. 1974) .
     Long-term effects continued to be observed in children
born to Yusho mothers,.  Nine infants with dark brown skin
pigmentation were born to Yusho mothers between 1969 and
1972, three of them to a patient between 1969 and 1971
(Yoshimura, 1974).  The plasma PCB levels of 30 children
born to 18 Yusho mothers were significantly above control
levels but lower than maternal levels  (Abe, et al. 1975).
Children nursed by their mothers had higher levels than
children who were not breast fed.  One case was reported
by Yoshimura  (1974) in which a baby was thought to have
acquired Yusho solely as a result of breast milk  intake.
     Masuda, et al.  (1974) found PCB levels in breast milk
of five Yusho women between 0.03 and 0.06 ppm which was
just within the normal range.  A recent study of  PCB levels
in the breast milk in 400 Japanese women detected average
levels of 0.033, 0.026, and 0.029 ppm  in three measurements
made at two month  intervals  (Yakushiji, et al. 1977).  Based
on these levels, they calculated that  daily intake by a
nursing infant would be 24 /jg/day.  This can be compared
to an average dietary intake by Japanese adults of 21>ug/day
or 9 jug/day by U.S. adults.  By April  30, 1975, 29 of 1,291
Yusho patients had died.  Among 22 who died before September,
1973, 9 deaths resulted from malignant neoplasms  (Urabe,
1974) .
                              C-58

-------
     The occurrence of Yusho symptoms after modest PCB intake



coupled with the similarity of many of the symptoms to those



seen in animals, particularly primates,  suggests that the



toxic effects observed in animals must be considered potentially



accurate models for humans.  The persistence of symptoms



in Yusho patients is a particular source of concern.  The



major uncertainty regarding toxicity in Yusho patients rests



with the unknown effects of the PCDFs present in unusually



high concentrations in Yusho oils.



     Early reports of toxic effects of occupational PCB



exposure are not easily interpreted because a mixture of



compounds including chloronaphthalenes was present.  A fatal



case resulted from exposure to a mixture of 90 percent chloro-



naphthalenes and 10 percent PCBs  (Drinker, et al.  1937).



The subject developed chloracne, followed by jaundice and



abdominal pain, and was found to have cirrhosis of the liver



at autopsy.



     Many studies of occupational exposure have shown varying



degrees of toxicity under different conditions.  The following



discussion will highlight studies which indicate the types



of toxic reactions commonly observed in occupational exposures



and the levels of sensitivity in different situations.  A



detailed review of occupational exposure to PCBs has recently



been prepared (Natl. Inst. Occup. Safety Health, 1977).



     Elkins (1959) found that average PCB concentrations



in the workroom air of several plants in Massachusetts ranged



from 0.1 to 5.8 mg/m  while peak concentrations were between



0.2 and 10.5 mg/m .  No immediate toxic effects were seen;
                              C-59

-------
however, exposure to 10 mg/m  was said to be unbearably



irritating.  Three cases of severe chloracne were reported



in a work environment in which PCS air levels were found



to be between 5.2 and 6.8 mg/m .  The workers developing



chloracne had been exposed for 2 to 4 years.  No alterations



in liver function or other abnormalities were found (Puccinelli,



1954).



     An analysis of the health effects of PCBs on eight



laboratory workers involved in testing dielectric fluids



was made by Levy, et al. (1977).  The workers, all males



25 to 49 years of age, had been employed 2.5 to 18 years.



Breathing zone, point source, and general work area samples



were collected on three occasions.  The ranges observed



were:  breathing zone, 0.014 to 0.073 mg/m ; point source



(near an oven), 0.042 to 0.264 mg/m ; and room area, 0.013



to 0.15 mg/m .  Blood PCB concentrations were 36 to 286



ppb which is substantially above the range in several studies



of general populations  (Finklea, et al. 1972).  Workers



complained of dry sore throat (6/8), skin rash (3/8), gastro-



intestinal disturbances  (3/8), eye irritation and headache



(2/8).  Examination disclosed one patient with skin rash,



two with nasal irritation, one showing rales, and four with



high blood pressure, but no abnormalities in  liver function.



     Toxic effects from a low level exposure  were reported



by Meigs, et al.  (1954) .  A leaking heat exchanger in a



chemical plant discharged PCB vapors.  No employees worked



routinely at the point of leakage but breathing zone levels



in work areas were found to be 0.1 mg/m  .  The period of



exposure was 19 months.  Seven of 14 exposed  workers developed
                              C-60

-------
mild to moderate chloracne after exposure durations of 5  -



to 14 months.  Liver function tests showed normal serum



bilirubins, 24- and 48-hour cephalin flocculations, thymol



turbidities and serum alkaline phosphatase activities in



six of the seven workers, but borderline increases in cephalin



flocculation and thymol turbidity in the seventh.  After



thirteen months, the thymol turbidity but not the cephalin
           i


flocculation had improved.



     A study of PCB exposure in six Japanese industrial



plants has been reported  (Hasagawa, et al. 1972; Kara, et



al. 1974,  1975).  Although the original publications are



in Japanese, a detailed description in English  is available



(Natl. Inst.  Occup. Safety Health, 1977).  PCBs were manu-



factured in one plant, used in manufacturing capacitors



in four plants, and had been used in a fifth plant until



one month  before the study began.  The sixth plant used



biphenyls, not PCBs.  PCB concentrations in air as both



vapor and  particulates were determined.  The lowest levels


                               3                 3
in one plant were 13 to 15 pg/m  vapor and 4 >ug/m  particulate



while the  highest levels  in a single plant were 95 to 965



/ag/m  vapor, 73 to 650 >ug/m  particulate.  Except  in the



instance of a spill, vapor concentrations always exceeded



particulate concentrations.  Blood PCB levels in 99 workers



were found to average 370 ppb as compared to values in 20



controls averaging 20 ppb.  No correlation between duration



of exposure and blood level could be found in data from



three of the plants.  Dermal effects found were chromoderm-



atosis of  the dorsal joints of the hands and fingers and



of the nail bed, and acneform exanthema.  Dermal effects
                              C-61

-------
seemed unrelated to blood levels, suggesting that they resulted



directly from skin contact.  Changes in fat metabolism and



mild disturbances in liver function were found.  The con-



sequences of termination of PCS exposure were examined by



following 38 current and 80 former workers from 1972 to



1975 who were from the plant which had discontinued PCB



use.  During the period of PCB exposure, 17 capacitor immersion



process workers had blood levels of 7 to 300 ppb, which



were closely related to years of exposure.  One year after



cessation of exposure, blood PCB levels decreased but not



uniformly.  The average decrease was about 75 percent of



the original value.  The blood half-lives of PCBs were determined



and found to be related to the number of years of exposure.



For 1 year of exposure, T*s = 3 months, while for 10 to 15



years exposure, T^s = 30 months.  The investigators concluded



that blood served only as a PCB carrier while fat served



as the depot tissue.  Many of the employees complained of



blackheads, acne, and skin irritation while working with



PCBs; however, these conditions cleared markedly after exposure



ceased.  Serum triglyceride levels in workers were elevated



in correlation with blood PCB levels.



     A study in Australia by Ouw, et al.  (1976) examined



two groups of workers with different levels of exposure



in a capacitor manufacturing facility.  One group  (inside)



worked in an impregnation process where exposure to heated



(70 C) Aroclor 1242 occured.  The second group  (outside)



assembled cool Aroclor-dipped components in a location separate



from the first group.  The entire group had an average blood
                               C-62

-------
PCB level near 400 ppb.   The distribution of individual


Aroclor components differed between the groups with the


outside workers being low in early eluting (on gas chromatO'


graphy) fractions but elevated in late eluting fractions


relative to the inside group.  No abnormalities in liver


function were observed but skin irritation and eczematous


rashes were observed.  One worker had chloracne but no systemJLc


effects.  The severity of dermal effects was not clearly


correlated to blood PCB level.  Breathing zone air concentra-


tions in the impregnation room varied from 2.22 to 0.32


mg/m .  To bring conditions within government guidelines,


improved exhaust ventilation was installed and workers were


encouraged to wear impervious gloves to reduce skin absorption.


These actions reduced atmospheric PCB levels to 0.75 to

         q
0.08 mg/m .  After two months, new blood samples were taken


which indicated that a slight increase in blood levels had


occurred.  Failure to wear gloves was the reason cited for


the failure to improve blood levels.


     A recent study of liver function in Aroclor 1016-exposed


workers illuminates the sensitivity of the liver to exposure


(Alvares, et al, 1977) .   Antipyrene clearance was determined


in five workers who had been occupationally exposed to PCBs


for at least four years and Aroclor 1016 for at least two


years.  None of the workers showed any manifestations of


PCB toxicity.  When compared to five controls matched for


sex, age, and smoking and drinking habits, the antipyrene


half-life was about 2/3 of the control level (10.8 + 0.7


experimental vs. 15.6 + 1.0 control).  The increased rate


of antipyrene clearance was taken to be an indication of
                               C-63

-------
higher levels of metabolic enzymes in the livers of the
exposed workers.
     Data from this limited review of occupational studies
indicate that symptoms much like those seen after PCB inges-
tion can occur after atmospheric or dermal exposure.  Air
PCB concentrations as low as 0.1 mg/m  can produce toxic
effects (Meigs, 1954) and exposure to levels producing no
overt toxicity can affect liver function (Alvares, et al.
1977) .  Recovery after termination of exposure occurs but
is slow and depends upon the amount of PCBs stored in adipose
tissue (Natl. Inst. Occup. Safety Health, 1977).
Synergism and/or Antagonism
     It appears that the synergistic antagonistic effects
of PCBs result from their ability to induce mixed function
oxidases in liver and other tissues, although the effects
of the accelerated metabolism of drugs, such as phenobarbitol
or hormones, such as ketosteroids and thyroxin, have been
discussed above.  The consequences of the PCB induced metabo-
lism of carcinogenic agents such as benzene hexachloride
or aflatoxin will be discussed below in the section on carcin-
ogenicity.
Teratogenicity
     The reproductive effects of PCBs in animals and man
have been discussed above.  It is clear that PCBs readily
cross the placental barrier and accumulate in fetal tissues.
Primate infants exposed to PCBs _iri utero are typically retard-
ed in growth during gestation  (Barsotti and Allen, 1975)
and reproductive failures  (abortions, stillbirths) are common
(Linder, et al. 1974).  Live born animal and human  infants
                              C-64

-------
often display symptoms of toxicity common for the species
(Kuratsune, et al. 1976; Linder,  et al. 1974).  However,
indications of structural malformations or genetic changes
have been rare.  Villeneuve, et al. (1971b)  noted assymetric
skull formation in two rabbit fetuses exposed to high levels
of Aroclor 1254 rn utero.  A written communication by F.L.
Earle (as cited in Natl. Inst. Occup.  Safety Health, 1977)
reported unspecified terata in canine pups born to females
exposed to 48 or 200 ppm but not 20 ppm dietary equivalent,
and in piglets from sows fed the equivalent of 50 ppm.
No additional information was given.
Mutagenicity
     The mutagenicity of different PCB preparations has
been evaluated in several test systems.  The single isomer
4-chlorobiphenyl was found to be highly mutagenic in Salmonella
typhimurium strain TA1538 after liver microsomal enzyme
activation (Wyndham, et al. 1976) .  The products formed
under these activation conditions were 4 chloro-4'-biphenylol
and 4'chloro- 3, 4 biphenyldiol, which, as previously discussed,
are indicative of arene oxide formation  (Safe, et al. 1975).
In the same study, Aroclor 1221 was less mutagenic while
Aroclor 1254, 1268 and 2, 5, 21, 5' tetrachlorobiphenyl
were essentially inactive.  Mutagenic activity decreased
with increasing chlorination.
     Recent attempts to repeat the experiment with different
cultures of the same tester strain have not detected any
mutagenic activity  (S. Safe, personal communication).
     Also 4-chlorobiphenyl was toxic but not mutagenic  to
S. typhimurium TA 1538 with or without activation by Aroclor

                               C-65

-------
1254  (S. Rinkus, personal communication).  4-chlorobiphenyl
has been shown to induce unscheduled DNA synthesis, an indica-
tion of DNA repair, in Chinese hamster ovary cells (S. Safe,
personal communication).
     The Japanese Ministry of Health and Welfare supported
mutagenicity screening program investigated Kanechlors 300
and 500 (Odashima, 1976).  Both compounds were negative
in the Salmonella system but Kanechlor 300 was listed as
positive in a bacterial DNA repair assay and a cytogenetic
analysis with Yoshida sarcoma cells.  Kanechlor 500 was
positive in a mouse bone marrow cell cytogenetic analysis.
     Heddle and Bruce  (1977) reported Aroclor 1254 as negative
in S. typhemurium, the micronucleus test and a sperm morphology
assay.  Aroclor 1254 administered to rats at 50 mg/kg/day
for seven days produced no chromosomal abnormalities in
sperm (Dikshith, et al. 1975) .
     The effects of Aroclor 1254 and 1242 on bone marrow
cells were evaluated in Osborn-Mendel rats  (Green, et al.
1975a).  Animals in groups of eight were given single doses
of Aroclor 1242 at 1250, 2000, or 5000 mg/kg or multiple
doses of 500 mg/kg/day for four days.  Aroclor 1254 was
given for five days at 75, 150, or 300 mg/kg/day.  Aroclor
1242 was more toxic than 1254.  Mitotic  indices were not
reduced by Aroclor 1242 treatment and no increase  in chromoso-
mal abnormalities was observed.  Aroclor 1254 reduced the
mitotic index of bone marrow cells at 150 and 300 mg/kg/day
but not at the low dose.  Again, no increase in chromosomal
abnormalities was seen.  Cytogenetic abnormalities were
found in spermatogonial cells of animals treated at 5000

                               C-66

-------
mg/kg or 500 mg/kg/day Aroclor 1242 but not in statistically



significant numbers.



     A dominant lethal test with Aroclor 1242 and 1254 was



also performed in Osborne-Mendel rats  (Green, et al. 1975b).



Aroclor 1242 was given in single doses of 625, 1250, or



2500 mg/kg or five doses of 125 or 250 mg/kg/day.  Aroclor



1254 was given in five doses of 75, 150, or 300 mg/kg/day.



Treated males were bred to untreated females for the following



10 to 11 weeks.  No significant effect of treatment was



observed on embryo implantation or lethality with any treatment,



     In summary, the only marked genetic effect observed



at any level was with the single isomer 4-chlorobiphenyl.



Kanechlor 300 and 500 produced cytogenetic effects in different



systems but Aroclor 1242 and 1254 did not.  Despite the



apparent weak mutagenicity of most PCBs in the systems used,



the fact that most animals can metabolize many PCB isomers



through an arene oxide intermediate indicates that the muta-



genic potential of PCBs should not be casually dismissed.



Carcinogenicity



     The carcinogenic effects of PCBs have been evaluated



in several animal studies.  The first evidence of carcinogenic



potential in PCBs was reported by Nagasaki, et al.  (1972)



and in more detail by Ito, et al.  (1973).  Male dd mice



were given Kanachlors 500, 400, and 300 mixed in standard-



diets at 500, 250, and 100 ppm for 32 weeks.  Of 12 mice



surviving in the group fed 500 ppm Kanachlor 500, 7  (58.3



percent) had grossly observable nodular hyperplasia with



microscopically observable hepatomas in 5  (41.7 percent).



No tumors were observed in the groups treated with lower
                             C-67

-------
doses of Kanechlor 500,  in any dose of the other Kanechlors,
or in the six control animals.  Kimbrough and Linder  (1974)
treated Bald/cJ mice with Arochlor 1254.  Mice were exposed
to 300 ppm in the diet for 6 or 11 months.  The mice exposed
for six months were fed  control diets for the remaining
five months, and all the animals were killed and examined
at the same time.  All the animals surviving 11 months exposure
had enlarged livers and  adenofibrosis, while 9/22  (41 percent)
were observed to have hepatomas.  Of the 24 mice surviving
six months exposure, most showed some changes ifi liver cell
morphology, and a diffuse interstitial fibrosis was observed
in about 2/3 of them.  One hepatoma  (0.3 cm diam.) was observed.
The details of the mouse experiments are summarized in Table
10.  Kimbrough and Linder (1974) reported subcutaneous abcess
formation in some mice and one sweat gland, adenoma.  Neither
Ito, et al. (1973) nor Nagaski, et al.  (1972) commented
on any pathology other than  in the liver.
     Studies with rats have  been reported by Kimura and
Baba (1973), Kimbrough,  et al.  (1972, 1975), and Ito, et
al.  (1974) .  Kimura and  Baba  (1973) examined the effects
of Kanechlor 400 on the  livers of Donryu strain rats.  Ten
male and ten female animals  were exposed, in a complex protocol,
to amounts of Kanechlor  400  starting at 38.7 ppm in food
and  increasing to 616 ppm as  the animals increased in weight.
Total amounts ingested varied from 450 to 1500 mg  over exposure
periods of 159 to 560 days.   Five control animals  of  each
sex were used.  Fatty degeneration was observed in the livers
of all experimental animals  and two  females  in the control
group.  Adenomatous nodules  were observed in all of the
                               c-68

-------
                                                                TABLE 10



                                          Evidence for Carcinogenic Effects of PCB's in Mice.
n
i
vo

Mouse
Strain
dd
(Ito, et
al. 1973;
& Nagasaki
et al. 1972)






Balb/cJ
(Kimbrough
& Linder,
1974)

No.
Sex Treated
M 12
12
12





6
M 50
50
100
No.
Sur-
viving
12
12
12





6
22
24
58

PCB
Source
Kanechlor 500
n
n
Kanechlor 400
n
a
Kanechlor 300

Control
Aroclor 1254
M
n
Dietary
Level
ppm
500
250
100
500
250
100
500
250
100
300
300
Average Exposure
Daily Dose Time
mg/kg/day (Days)
82. 5a 224
41. 3a
16. 5a
82.5
41.3
16.5
82.5
41.3
16.5
49.8 330
49. 8b 180C
Liver Nodules
Adeno- Neoplastic
fibrosis Nodules Hepatoma
7/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
0/6
22/22 - 9/22
0/24 - 1/24
0/58 - 0/58

Hepatocellular
Carcinoma
5/12
0/12
0/12
0/12
0/12
0/12
0/12
0/12
0/6
<
    Calculated usi.ng food consumption data from Kimbrough and Linder  (1974)  for Balb/cJ mice which  indicates an

    ^average of 165 g/kg/day.

    cNot directly, but assumed to be similar to group exposed 330 d.

     Maintained on control diet for remaining 150 days of experiment.

-------
females which had a cumulative intake of more than 1200


mg Kanechlor 400.  Nodules were seen in none of the males.


A number of histopathological findings were noted in spleen,


lung, adrenal cortex, and brain but no neoplastic changes


outside the liver were mentioned.


     Ito, et al.  (1974) examined the effects of Kanechlors


500, 400, and 300 on male Wistar rats.  Animals were exposed


to dietary levels of 1000, 500, and 100 ppm of each preparation


for 27 to 52 weeks, then killed and examined for pathological


changes.  No hepatocellular carcinoma was observed, but


cholangiofibrosis  (adenofibrosis) was seen at the highest


dose of all three agents  (Table 11).  Nodular hyperplasia


was observed in animals treated with all three agents.


The highest incidence was observed with Kanechlor 500.


No significant changes were observed in organs other than


the liver.


     Kimbrough, et al.  (1975) exposed Sherman strain rats


to Aroclor 1260 at dietary levels of 100 ppm for 21 months.
t

Hepatocellular carcinomas were observed in 26/184 experimental


animals but in only one of the controls (1/173).  Tumors


were observed in  several other tissues of both experimental


and control groups, but they were of low incidence and fre-


quencies were similar  in both groups.  In an earlier study/


Kimbrough, et al.  (1972) fed Aroclor 1254 and 1260 to male


and female rats for eight months.  Adenofibrosis was observed


in animals fed 100 and 500 ppm Aroclor 1254 with the highest


incidence in females.  Aroclor 1260 was associated with


a much lower incidence of adenofibrosis even in animals


fed 1000 ppm.  A  single bladder tumor was observed in a
                              C-70

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                     TABLE  11



Evidence for Carcinogenic Effects of PCB's in Rats.
No.
Strain Sex Treated
Donryue M 10
(Kimura
and Baba, F 10
1973)
M 5
F 5
Wistar M *
(Ito, et
al. 1974)








No.
Sur-
viving
10
10
5
5
13
16
25
10
8
16
15
19
22
18
Dietary
PCB Level
Source ppm
Kanechlor 400
Kanechlor 400
None
'None
Kanechlor 500
N
Kanechlor 400
n
n
Kanechlor 300
n
n
None
38.5-16
38.5-16
-
1000
500
100
1000
500
100
1000
500
100
0
Average Exposure
Daily Dose Time
mg/kg/day (Days)
13. 5C 339a
17. 5d 425b
-
49. Oe 378
24.5
4.9
49.0
24.5
4.9
49.0
24.5
4.9
_
Liver Nodules
Adeno-
fibrosis
-
-
4/13
0/16
0/25
2/10
0/8
0/16
2/15
0/19
0/22
0/18
Neoplastic Hepatocellular
Nodules Carcinoma
0/10
6/10
-
5/13
5/16
3/25
3/10
0/8
2/16
0/15
0/19
1/22
0/18
-
-
;
-
-
-
-
-
-
-
_

-------
Table 11 (Cont.)
Proliferative Changes
No.
No. Sur- PCB
Strain Sex Treated viving Source
Fisher M 25 24 Aroclor 1254
344 rat
(NCI, 1978) 24
24
24
? F 25 23
24
22
24
Dietary
Level
ppm
0
25
50
100
0
25
50
100
Average
Daily Dose
nig/kg/day
0
1.38e
2.75e
5.5e
0
1.38e
2.75e
5.5e
Exposure
Time
(Days)
_
735
735
735
-
735
735
735
Nodular
Hyperplasia
0/24
5/24
8/24
12/24
0/23
6/24
9/22
17/24
Hepatocellular
Carcinoma
and Adenoma
0/24
0/24
1/24
3/24
0/23
1/249
1/22
2/24
Combined
Hematopoietic
and Liver
5/24
2/24
9/24
12/24
4/23
13/24
8/22
9/24

-------
                                                       Table  11  (Cont.)











n
i
-o
u*






Strain Sex
Sherman F
(Kimbrough,
et al. F
1975)
Sherman M
(Kimbrough,
et al. F
1972)



M

F


No.
Treated
200

200

10

10

10

10
10
10
10
10
No.
Sur-
viving
184

174

10

10

8

2
10
10
10
9
Dietary
PCB Level
Source ppm
Aroclor 1260 100

None

Aroclor 1260 1000

- 100

500

1000
Aroclor 1254 100
500
100
500
Average Exposure
Daily Dose Time
mg/kg/day (Days)
4.9f 630

630

71.4 240

7.2

38.2

72.4
6.8
36.4
7.5
37.6
Liver Nodules
Adeno- Neoplastic Hepatocellular
fibrosis Nodules
144/184

0/173

2/10

1/10

1/9

4/7
1/10
10/10
7/10
9/9
Carcinoma
26/184

1/173
•
„

-

-

-
-
-
-
-
grange 159-530
"range 244-560
grange of cumulative intake 450-1800 mg
 range of cumulative intake 700-1500 mg
 Data not provided.  Calculated from Kimbrough, et al. 1975, in which Sherman rats showed similar weight gain over the same
,experimental period.
 Time weighted average calculated from Figure 2 in Kimbrough, et al. 1975.
^Reported as undifferentiated carcinoma of the liver, metastatic.
*290 animals total in 10 groups

-------
treated animal but was probably not the result of PCS exposure



(Kimbrough, et al. 1975) .  The details of the experiments



with rats are summarized in Table 11.



     A report dated November, 1971 described a study made



by Industrial Bio-test Laboratories Inc. A brief summary



of the report was presented at the National Conference on



Polychlorinated Biphenyls  (1976) and a more detailed analysis



presented by the U.S. EPA  (1976a) .  One thousand Charles



river rats were divided  into ten treatment groups.  Fifty



male and 50 female rats  served as a common control group.



Each of nine treated groups contained 50 animals of each



sex.  Groups were fed 1, 10 and 100 ppm of Aroclors 1242,



1254, and 1260 respectively.  Treatment was initiated with



four to six week old animals and continued for a total of



24 months.  Five animals of each sex were sacrificed at



3, 6, and 12 months leaving 35 animals in each group at



the beginning of the second year.  In addition, mortality



was high, leaving only 6 to 21 animals remaining in each



treatment/sex subgroup by  the end of the experiment.  As



seen in the previously described studies, the principal



effects were observed in the liver.  Vacuolar changes and



hyperplasia were the major abnormalities originally noted



in the treated animals.  In addition chromophobe adenomas



of the pituitary were found in 8 of 9 treated groups but



not in the controls.  In 1975 the original liver slides



were re-evaluated with rather different results.  The combined



results for animals treated with 100 ppm of all three Aroclors



included 11 hepatomas, 5 cholangiohepatomas, and 28 nodular



hyperplasias.  No hepatocellular carcinomas were observed.
                              C-74

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     Recently, a bioassay for the possible carcinogenesis
of Aroclor 1254 has been conducted by the National Cancer
Institute (1978).   In this study, 24 Fischer 344 rats of
each sex were orally administered Aroclor 1254 at 25, 50,
or 100 ppm for 104 to 105 weeks.  Matched controls consisted
of 24 untreated rats of each sex.  Mortality among the treated
males was significantly higher than among the controls and
related to dose (P< 0.001) but was not different among the
females (P>0.05).  Interstitial-cell tumors of the testes
in males and leukemias of either granulocytic or lymphocytic
type were observed frequently in both control and treated
animals.  Tumors were observed in several other tissues
but their presence did not correlate with treatment.  Proli-
ferative lesions of the liver were common in treated animals
but were not found in coatrols.  The types and frequencies
of lesions are detailed in Table 11.  They included nodular
hyperplasia in all treated groups increasing in frequency
with dose, adenomas (one male, three females) and hepatocellu-
lar carcinoma  (three males, no females).  In addition, adeno-
carcinomas of the stomach, jejunum or cecum of two treated
males and two treated females but no controls were observed.
Statistical analysis of the frequencies of tumors and prolife-
rative lesions indicated that the combined incidences of
leukemia and lymphoma in treated males were significant
by one test (Cochran-Armitage test for positive dose-related
trend) but not by a more stringent test  (Fisher exact test).
The tumors of the liver and gastrointestinal tract were
not statistically significant; however, the occurrence of
nodular hyperplasia appeared to be related to treatment.
                              C-75

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The study concluded that Aroclor 1254 was not carcinogenic
in Fischer 344 rats; however, the high frequency of hepatocel-
lular proliferative lesions was considered to be a result
of treatment, and the carcinomas of the gastrointestinal
tract possibly associated with the treatment.
     The tumors observed in rodent experiments with PCBs
were predominantly adenofibrosis (cholangiofibrosis) neoplastic
nodules and hepatocellular carcinomas.  Stewart and Snell
(1957) concluded that adenofibrosis cannot be considered
to be a pre-malignant lesion, while Reuber (1968) proposed
that cholangiofibrosis might be a precursor to cholangiocar-
cinoma.  Neoplastic nodules have been observed before the
appearance of carcinomas in several studies with known carcin-
ogens  (Kimbrough, et al. 1975).  Well-differentiated mouse
hepatomas have been shown to be potentially malignant, with
a proportion being transplantable and capable of metastasis
(Andervant and Dunn, 1952).
     Several conclusions can be drawn from the results of
the rodent studies.  A correlation between degree of chlorina-
tion and tumor inducing potential was observed in mice  (Ito,
et al. 1973) and rats (Ito, et al. 1974) with the most highly
chlorinated preparations being most potent.  However, Aroclor
1254 was more potent than Aroclor 1260 in rats (Kimbrough,
et al. 1972).  Where examined, female rats were  found to
be more sensitive than males  (Kimura and Baba, 1973; Kimbrough,
et al. 1972).  No comparisons of sex-related effects were
made in mice.
     It should be noted that none of these studies was a
lifetime study.  In all cases, animals were treated for
                              C-76

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fixed times then killed and examined.  No lifetime studies



with PCBs were found in this survey.  Such studies, if available,



might indicate more clearly the significance of the potentially



preneoplastic lesions induced by PCBs in the studies described



here.



     Data on the possible carcinogenicity of PCBs in humans



are sketchy at this time.  The largest group of exposed



individuals followed longitudinally are the "Yusho" patients.



By late 1973, 2 of 1291-patients had died, 9 of them with



malignant neoplasms (2 stomach cancer, 1 stomach and liver



cancer, 1 liver cancer with cirrhosis, 1 lung cancer, 1



lung tumor, 1 breast cancer, and 1 malignant lymphoma) (Urabe,



1974; Kuratsune, et al. 1976).  The authors did not have



sufficient information to make a detailed epidemiological



analysis but concluded that 9/22 deaths from cancer may



represent an excess of deaths.



     Two cases of malignant melanoma were reported in a



group of 31 industrial workers exposed "heavily" to Aroclor



1254 in the process of its manufacture.  Based on a person-



year analysis and the use of the Third National Cancer Survey



incidence rates (Natl. Cancer Inst. 1978), 0.04 malignant



melanomas would have been expected making these data signi-



ficant at the 0.001 level.  In addition, one of 41 workers



exposed to lower levels of Aroclor 1254 developed a malignant



melanoma (Bahn, et al. 1976).



     Although these studies involve small numbers of indivi-



duals and provide little information about exposure or other



relevant factors, they do suggest that human exposure to



PCBs may be associated with increased risk of neoplasia.





                              C-77

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     In addition to the carcinogenic effects observed with


PCBs, they have been shown to have a significant effect


on the carcinogenic properties of other substances found
                                i

in the environment.  The co-carcinogenic properties of the


PCBs result from their ability to induce the mixed function


oxidases, particularly in liver, as discussed under Acute,


Sub-acute,and Chronic Toxicity.  Ito, et al. (1973) observed


|hat dietary levels of 250 ppm Kanechlor 500 markedly promoted


hepatocellular carcinoma and nodular hyperplasia in mice


exposed to benzene hexachloride at levels of 100 or 250


ppm in the diet.  Kanechlor 400 at 10 or 100 ppm in the


diet failed to promote cervical carcinoma or progression


toward it in mice exposed to 20 methyl cholanthrene saturated


thread implanted in the cervix and uterus (Uchiyama, et


al. 1974) .  Ito, et al. (1978) observed a pronounced increase


in the incidence of preneoplastic, hyperplastic nodules


in N-2-fluorenylacetamide treated rats.  The animals were


fed 1000 ppm PCB (type not specified) for eight weeks following


two weeks exposure to the carcinogen.  This increase in


preneoplastic lesions over a short period was taken to be


a significant indicator of carcinogenic activity.  The ability


of Aroclor 1254 to initiate  (as opposed to promote) tumors


in the two-stage mouse skin system was recently examined


by DiGiovanni, et al.  (1977).  Aroclor 1254 proved to be


a weak initiator of papillomas when a 100 ug treatment of


skin was followed by 32 weeks of treatment with the promoter


27 tetradenanoyl-phorbol-131 acetate.  When used in combina-


tion with the potent initiator dimethylbenzanthracene Aroclor


1254 slightly increased the incidence of papillomas.  Aroclor
                              C-78

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1254 also failed to promote skin tumors initiated by dimethyl-



benzanthracene in the same system (100 >ug Aroclor 1254 applied



twice weekly for 30 weeks) (Berry, et al. 1978).



     Kanechlor 500 promoted hepatocellular carcinoma initiated



by diethylnitrosamine (DENA)  in male Wistar rats  (Nishizumi,



1976).  Promotion was observed when PCB treatment was begun



one week following the end of DENA treatment.  The number



of tumors was significantly higher in rats treated with



DENA and PCB than DENA alone or DENA and phenobarbital although



a promoting effect was observed with the latter drug as well.



     Hepatocarcinogenesis initiated by 3'-methyl - 4-dimethyl-



aminoazobenzene (3'-Me-DAB) in female Donryu strain rats



was promoted by oral administration of PCBs following initia-



tion.  Tumor incidences in animals treated with 3'-Me-DAB



4- PCB, 3'-Me-DAB alone, or PCB alone were 64 percent, 13



percent, and 0 percent, respectively.  PCB treatment preceding



or simultaneous with 3'-Me-DAB treatment did not produce



tumors (Kimura, et al. 1976).



     By contrast to the hepatic co-carcinogenic effects



of PCBs observed by Kimura, et al. (1976) , Nishizumi  (1976) ,



and Ito, et al. (1973; 1978), other investigators have observed



an inhibition of tumor formation or growth in  the presence



of PCBs.  Makiura, et al.  (1974) fed male Sprague Dawley



rats 3'-Me-DAB, 2FAA, or DEN or pairwise combinations of



them for 20 weeks followed by 4 weeks on a stock diet.



Incidence of hepatocellular carcinoma ranged from 65.2 to



92.3 percent, and nodular hyperplasia reached  100 percent



in animals fed pairs of carcinogens.  The addition of 50



ppm Kanechlor 500 to the diet resulted in a large decrease
                              C-79

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in the tumor  incidence and liver weight as compared to carcin-



ogen treatment without PCBs.  PCBs alone induced no tumors



or hyperplastic nodules but did result in an increased liver



weight.  The principal difference between this study and



those of Ito, et al.  (1978), Nishizumi (1976), and Kimura,



et al. (1976) using the same chemicals is that PCS exposure



was delayed until after the initiating treatment in the



latter studies.  This suggests that the induction of mixed



function oxidases by PCS at the time of carcinogen treatment



results primarily in the inactivation of the chemicals and



that the promoting effects observed with sequential exposure



result from some other mechanism.  The co-carcinogenesis



of PCBs with simultaneous exposure to BHC may reflect a



difference in the liver metabolism of this compound.



     In rainbow trout (Salmo gairdnerii)  100 ppm Aroclor



1254 added to the diet reduced the size and frequencies



of liver tumors induced by 6 ppm aflatoxin B, after a one



year exposure (Hendricks, et al. 1977).



     In addition to the inhibition of tumor induction by



some chemicals, PCBs were also shown to inhibit the growth



of experimental tumors in rats.  Sprague-Dawley rats were



inocculated with Walker 256 Carcinosarcoma cells and the



effects of PCBs determined.  Both dietary  (Kerkvliet and



Kimeldorf, 1977a) and injected  (Kervliet and Kimeldorf,



1977b) Aroclor 1254 reduced the size of solid tumors and



increased animal lifespan.  Total dietary PCB intake of



1100 to 2000 mg/kg over a 40-day period reduced tumor weight



to 60 to 40 percent of control in both male and female rats.



Aroclor 1254 injected i.p. reduced the efficiency of tumor






                               C-80

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takes when 10  tumor cells were injected from 81.3 in control
to 50.0 percent in animals receiving 200 mg/kg/day.  Mean
tumor sizes were reduced and lifespans increased by PCBs
in animals inocculated with 10  tumor cells.  Administration
of PCBs for five days preceding tumor inoculation or the
first five days after inoculation was more effective than
administration between days five and ten.
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                    CRITERION FORMULATION
Existing Guidelines and Standards
     The Toxic Substances Control Act (TSCA) (P.L. 94-469)
was signed into law October 11, 1976.  Provisions in section
6(e) of the law specifically regulate the manufacture/ sale/
distribution, and disposal of PCBs*  Manufacture, sale,
or distribution of PCBs was restricted to sealed systems
as of October 11, 1977.  Manufacture was banned as of January
1, 1979 and all processing and distribution in commerce
will cease July 1, 1979.  Allowance for certain exemptions
is provided in the law.  The proposed rules to implement
the terms of section 6(e) of TSCA were released June 7,
1978 (U.S. EPA, 1978b).  Proposed rules on the disposal
of PCBs were released February 17, 1978 (U.S. EPA, 1978a).
The Environmental Protection Agency has proposed a water
quality criterion for  the protection of fresh water and
marine life of 0.001 ug/1 (U.S. EPA, 1976b).  The Food and
Drug Administration established tolerance levels in foods
in 1973 (38 FR 18096)  and proposed new tolerance levels
further restricting levels in 1977  (42 FR 17487).  Both
the current allowed levels and the proposed levels are presented
in Table 3.
     The occupational  exposure limits adopted in 1968 are
based on the recommendations of the American Conference
of Governmental Industrial Hygienists (ACGIH) (1968).  They
set the time-weighted  average eight hour exposure limits
to .1.0 mg/m  for mixtures containing 42 percent  chlorine
and .5 mg/m  for mixtures containing 54 percent  chlorine.
                              C-82

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The newly recommended standard proposed by NIOSH (1977)
is 1.0 ug/m  air TWA over a 10-hour day and 40-hour work
week.
Current Levels of Exposure
     Human exposure to PCBs in the United States has been
broad.  Several studies of tissue and plasma levels of PCBs
have detected them in!a high percentage of randomly chosen
subjects.  Yobs (1972)  detected PCBs in 31.1 percent of
637 human adipose tissue.  The National Human Monitoring
Program for Pesticides in fiscal years 1973 and 1974 found
PCBs in 35.1 and 40.3 percent of adipose tissues tested
(Kutz and Strassman, 1976).  Table 12 indicates the distribu-
tion of PCB concentrations in the population.  A study of
Canadian human adipose tissue PCB levels found 1 ppm or
more in 30 percent of 172 samples  (Grant, et al. 1976).
The eastern provinces, particularly Ontario, had the highest
incidences.  Average adipose tissue PCB levels were just
below 1 mg/kg (ppm) with males having slightly higher accumu-
lations than females.  The same study found human breast
milk to contain about 1 mg/kg on a fat basis.  PCBs were
detected in 8 of 40 samples of breast milk in Colorado at
levels between 40 and 100 ppb (whole milk).  The Japanese
study described earlier found average levels in 400 milk
samples of about 30 ppb  (Yakushiji, et al. 1977).  PCB levels
in plasma in U.S. populations were detected in 43 percent
of 723 samples.  Levels in positive samples ranged from
1.5 to 29 ppb with a mean around 2 to 3 ppb.  White populations
had higher levels than black populations  (Finklea, et al.
1972).
                               C-83

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                                  TABLE 12


        Levels of Polychlorinated Biphenyls in Human Adipose Tissue
 Data        Sample        Percent       Percent      Percent     Percent
source        size       nondetected      1 ppm       1-2 ppm      2 ppm
Yobs,          688          34.2          33.3         27.3         5.2
1972

FY 1973       1277          24.5          40.2         29,6         5.5
Survey

FY 1974       1047           9.1          50.6         35.4         4.9
Survey


From:  Kutz and Strassman  (1976)
                                 C-8'4

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     As discussed in the section on exposure, the median
water levels of PCBs are around 0.1 to 0.3 jug/1 in positive
samples with 0 to 20 percent of samples being positive around
the U.S. (Dennis, 1976).  Average PCB intake in food was
estimated in the mid-1970's to be about 9 jug/day with fish
being the major dietary source.  Ambient air concentrations
are around 100 ng/m  (Kutz and Yang, 1976).
Special Groups at Risk
     The preceding discussion of human exposure makes clear
the fact that a high percentage of the U.S. population has
been and is exposed to low levels of PCBs in food, water,
and air.  Those groups at particular risk for PCB exposure
include industrial workers exposed in the workplace, indivi-
duals consuming large amounts of contaminated fish, such
as sport fisherman (42 FR 17487), and nursing infants who,
per kg body weight, may accumulate significant body burdens
from the levels in human breast milk.  With the cessation
of manufacture of PCBs by Monsanto in 1977 and the great
decline in its use which should result from the implementation
of section 6 (e) of TSCA, industrial exposure should decline
substantially.  Since many PCB-containing sealed systems
can be expected to remain in service for many years continuing
vigilance will be necessary to minimize accidental pollution
of waterways or air and to prevent further occupational
exposure.
                              c-85

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Basis and Derivation of Criterion
     In arriving at .a.criterion for PCB levels in ambient
waters several factors must be taken into account.  First,
PCBs are highly persistent in the environment and accumulate
to a high degree in food webs.  As discussed in the section
Ingestion from Foods, an average bioaccumulation factor
for PCB's in all freshwater fish and shellfish of 46,000
has been determined.  As a consequence, PCBs leave the envi-
ronment very slowly once they have entered it.  Not only
do PCBs persist and accumulate in the environment but in
man as well.  The current environmental levels are not produc-
ing obvious acute ill health in the general population.
However, several animal studies report that PCBs produce
a carcinogenic response and that they may enhance the carcino-
genic activities of other substances.
     Although other adverse effects of PCB exposure could
be used as a basis  for formulating a criterion, carcinogenicity
will be used for a  variety of reasons.  The most extensive
chronic studies with PCBs have identified carcinogenicity
as the major end point.  Although no carcinogenicity studies
have been extended  to more than one generation and firm
data exist only for the female rat, a credible carcinogenic
response to PCBs has been demonstrated and cannot be ignored.
Kimbrough, et al. (1972) observed an incidence of hepatocellular
carcinoma of 26/184 in treated rats compared to 1/173 in
controls.  The NCI  bioassay observed a similar frequency
of hepatocellulor carcinoma at a similar dose level which
was statistically not significant because the number of
animals was low.  In addition, a number of non-malio..
                              C-86

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proliferative processes observed in liver at high frequencies



in the PCB treated animals in these studies were also observed



in both rats and mice in other studies (Ito, et al. 1974;



Kimura and Baba 1973; Kimbrough, et al. 1972; Ito, et al.



1973; Kimbrough and Linder, 1974).  PCBs were classified



as carcinogenic by the International Agency for Research



on Cancer (IARC, 1974).  Evidence from human populations



suggests but does not confirm an increase in cancer frequency



due to PCB exposure  (Kuratsune, et al.  1976; Bahn, 1976).



Finally, a theoretical basis exists for the quantitative



extrapolation of carcinogenic effects in treated animals



to human populations.  Various models, such as the one used



below, can provide quantitative risk estimates based on



animal data, and certain assumptions about the induction



of neoplasia (e.g. one-hit or multi-hit induction).  No



basis exists for extrapolation with mathematical models



from animals to man  for many other kinds of biological effects.



     Although the criterion established below is based on



animal carcinogenicity data it should also be .noted that



other adverse effects have been observed in mammals at levels



below the dose which produces tumors in rats.  The carcinogenic



effect was observed  in rats consuming an average of 4.9



mg/kg/day.  Dietary  levels at 2.5 ppm produced adverse repro-



ductive effects in Rhesus monkeys  (Allen and Barsotti, 1976).



If a food intake of  350 g/day is assumed, the PCB dose is



146 ug/kg/day in 6 kg animals.  At this time no data are



available to indicate the minimal level in  the diet at which



PCBs produce toxic effects in Rhesus monkeys.
                               C-87

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     in mink, ingestion of as little as 61 mg of Aroclor
1254 over nine months or 90 mg of Aroclor over four months
resulted in sharply reduced reproduction (Aulerich and Ringer,
1977) .   Assuming a weight of 1 kg for adult mink and a food
intake of 150 g/day, the PCB dose at 2 ppm was about 300
ug/kg/day which is similar to the level producing reproductive
toxicity in monkeys.
     These data can be used in one approach to developing
an ambient water quality criterion.  If 300 jug/kg/day is
taken as the lowest-observable-effect-level (LOEL) than
an Acceptable Daily Intake (ADI) can be calculated for a
70 kg man using an uncertainty factor of 100:
                     7°
     Assuming that exposure to PCBs is based on the consumption
of 2 liters of drinking water, 18.7 grams  (0.0187 kg) of
fish and shellfish, and a bioconcentration factor of 46,000;
then the following calculation can be made:
           (2 liters) X +  (0.0187 x 46,000) = 210 jug
                                         X = .244 jug/1
                                               or 244 ng/1)
     As will be seen later, the carcinogenicity criterion
methodology gives a lower and presumably more cautionary
level.
     An assessment of carcinogenic risk will be made by
extrapolation from animal data using a linear  (non-threshold)
model.  The model used takes  into account  the bioaccumulation
of PCBs in fish and shellfish.  It is assumed that an average
of 2 liters/day of water are  consumed along with 18.7 g
of fish taken from that water source.  Exposures from  ~>t-her
                               C-88

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food sources, air or occupational exposure are not included
in the criterion level derived by this model.
     Among the studies reviewed by this document, only one
appears suitable for use in the cancer risk assessment.
None of the mouse studies involved feeding for most or all
of a lifetime and are therefore unsuitable.  Of the rat
studies, the only one involving long term exposure and adequate
numbers of animals is the study of Sherman rats by Kimbrough,
et al.  (1975).
     This study has some drawbacks in that it lacks any
evidence of a dose-response (due to the use of only one
dose level), it tests only one sex of the species, and only
one commercial mixture of PCBs was tested.  Yet the experi-
mental design is a good one in many ways:  the treatment
was given over a good proportion of the lifespan; there
was an appropriate route (food) and distribution of exposure
(uniform dose over time); the authors provided good documenta-
tion of the actual intake dose; a sufficiently large number
of experimental and control animals were used to detect
a statistically significant increase in tumors; and there
was a thorough and well documented description of the pathology
(hepatocellular carcinoma).  The NCI study (1978) was the
only other study involving a long-term exposure and was
suggestive of a carcinogenic effect; however, the lack of
an adequate number of animals renders it unsuitable as a
study upon which to base an estimate of carcinogenic risk.
     Under the Consent Decree in NRDC vs. Train, criteria
are to state "recommended maximum permissible concentrations
(including where appropriate,  zero) consistent with the
                              C-89

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      protection of aquatic organims, human health, and recreational

      activities."  PCBs are suspected of being human carcinogens.

      Because there is no recognized safe concentration for a

      human carcinogen, the recommended concentration of PCBs

      in water for maximum protection of human health is zero.

           Because attaining a zero concentration level may be

      infeasible in some cases and in order to assist the Agency

      and States in the possible future development of water quality

      regulations, the concentration of PCBs corresponding to

      several incremental lifetime cancer risk levels have been

      estimated.  A cancer risk level provides an estimate of

      the additional incidence of cancer that may be expected

      in an exposed population.  A risk of 10   for example, in-

      dicates a probability of one additional case of cancer for

      every 100,000 people exposed, a risk of 10   indicates one

      additional case of cancer for every million people exposed,

      and so forth.

           In the Federal Register notice of availability of draft

      ambient water quality criteria, EPA stated that it is con-

      sidering setting criteria at an interim target risk level

      of 10~5, 10~6 or 10~7 as shown in the table below.

Exposure Assumptions            Risk Levels and Corresponding Criteria (1)
        (per day)                      _7           _fi          -
                                0_   1£  '         10 °       1£ D

2 liters of drinking water      0   0.0026 ng/1  0.026 ng/1 0.26 ng/1
and consumption of 18.7
grams fish and shellfish.  (2) .

Consumption of fish and         0   0.0026 ng/1  0.026 ng/1 0.26 ng/1
shellfish only.
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(1)   Calculated by applying  a modified "one-hit" extrapolation
     model described in FR 15926,  1979.   Appropriate bioassay
     data used in the calculation  are presented in Appendix
     I.   Since the extrapolation model is linear at low
     doses, the additional lifetime risk is directly propor-
     tional to the water concentration.   Therefore, water
     concentrations corresponding  to other risk levels can
     be derived by multiplying of  dividing one of the risk
     levels and corresponding water concentrations shown
     in the table by factors such  as 10, 100, 1,000, and
     so forth.
(2)   Approximately 99.8 percent of the PCS exposure results
     from the consumption of aquatic organisms which exhibit
     an average bioconcentration potential of 46,000 fold.
     The remaining 0.2 percent of  PCB exposure results from
     drinking water.
     Concentration levels were derived assuming a lifetime
exposure to various amounts of PCBs,  (1) occurring from
the consumption of both drinking water and aquatic life
grown in waters containing the corresponding PCB's concentra-
tions and, (2) occurring solely from consumption of aquatic
life grown in the waters containing the corresponding PCB
concentrations,  although total exposure information for
PCBs is discussed and an estimate of the contributions from
other sources of exposure can be made, this data will not
be factored into ambient water quality criteria formulation
until additional analysis can be made.  The criteria presented,
therefore, assume an incremental risk from ambient water
exposure only.
                               C-91

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     These criteria are exceedingly low. Although sharp



restriction of open PCB use in 1970 resulted in notable



declines in water PCB levels in the next several years (Dennis,



1976), the residual levels remaining are still two to three



orders of magnitude above the extrapolated level indicated



by the model.  The major source of PCBs in water today is



probably not new effluents from industrial or domestic sources,



but the PCB containing sludges underlying waterways which



typically contain 100 to 1000 fold higher concentrations



than the water itself (Dennis, 1976).  Efforts to reduce



water levels significantly by eliminating current pollution



sources will probably have little effect on average water



PCB concentrations.



     The very low limits suggested by this risk estimate



are due in large part to the very large bioaccumulation



factor in fish (46,000).  This figure is an average for



a wide variety of saltwater and freshwater organisms  (see



section on Ingestion from foods).



     As possible strategies to reduce human exposures to



PCBs are considered, the relative contributions of ingested



water and fish should be kept in mind.  At the assumed consump-



tion rate of 2 1 of drinking water and 18.7 g of fish/day,



over 99 percent of the dietary PCBs will be obtained  from



fish.  Strategies which focus separately on the reduction



of PCB levels in water and fish for human consumption might



be more practical and productive than a single standard



for water which takes bioaccumulation in fish into account.



     A final comment about the risk level derived from this



study is that it is based on animal data which are st.~t.is-





                              C-92

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tically weak.   The weight of evidence indicates that PCBs
are carcinogenic in rodents.  However, the carcinogenic
activities of  these compounds are not great.   An acceptable
noncarcinogenic level could be established with greater
certainty if better quantitative data on carcinogenicity
were available.  Studies with larger numbers of animals
designed to measure relatively small effects are needed.
Also, the rat  appears to be much less sensitive to the acute
and subacute effects of PCBs than man or non-human primates.
Further investigation of the effects of PCBs in Rhesus monkeys,
particularly with reference to the gastric lesions produced,
would be useful.
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                          APPENDIX  I



   Summary and Conclusions Regarding  the  Carcinogenicity  of



                  Polychlorinated Biphenyls*



     Polychlorinated biphenyls (PCBs) are prepared by the



chlorination of biphenyl and are complex mixtures containing



isomers of chlorobiphenyls with different chlorine content.



     Because of the widespread industrial use of PCBs, their



long half-life, and the documented disease-producing capability



of these compounds in several species, regulations have



been promulgated banning most of the manufacturing, processing,



and distribution of PCBs in the United States (FEDERAL REGISTER



Vol. 44, No. 106, May 31, 1979).



     Human studies concerning the possible carcinogenicity



of PCBs have involved small numbers of individuals and provide



little information about exposure.   Although these studies



are only marginally useful in describing the carcinogenicity



of PCBs, the incidence of malignant neoplasms in "Yusho"



patients and in industrial workers exposed to Aroclor 1254



suggests that human exposure to PCBs is  associated with



an increased risk of neoplasia.



     In two separate studies, PCBs have  been reported to



induce hepatocellular carcinomas in both mice and rats (male



mice fed Kanechlor 500 at 500 ppm and female Sherman rats



fed Aroclor 1260 at 100 ppm).



     In an NCI bioassay, Aroclor 1254 was not carcinogenic



in Fischer 344 rats, but the high frequency of hepatocellular



proliferative lesions was considered to  be the result of



treatment and carcinomas of the gastrointestinal trac'- oossibly
                               C-94

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associated with treatment.   In one other mouse study and
three other rat studies,  various PCBs induced proliferative
lesions of the liver which  might be indicative of carcino-
genicity.  The most commonly seen lesions were adenofibrosis
(cholangiofibrosis) and neoplastic nodules.
     A correlation between  degree of chlorination and tumor
inducing potential was observed in both mouse and rat species.
The most highly chlorinated preparations were also the most
potent tumor inducers with  the exception of Aroclor 1254
which was more potent than  Aroclor 1260 in one rat study.
Where examined, female rats were found to be more sensitive
than males.  No comparisons of sex related effects were
made in mice.
     PCBs have been reported to be co-carcinogens, initiators,
and promotors in both mouse and rat species.
     The mutagenicity of different PCB preparations has
been evaluated in several test systems with conflicting
results.  In one study, the single isomer 4-chlorobiphenyl
was reported to be highly mutagenic in Salmonella typhimurium
strain TA 1538 after liver  microsomal activation, while
Aroclor 1221 was reported to be less mutagenic and Aroclors
1254, 1268, and 2,5,2',5'-tetrachlorobiphenyl were inactive.
The fact that mutagenic activity decreased with increasing
chlorination is consistent  with the characteristic insensitivity
of the ames test to chlorinated hydrocarbons.  In other
test systems, Kanechlor 300 inhibited bacterial DNA repair
deficient cells and induced cytogenetic abnormalities in
Yoshida sarcoma cells.  Kanechlor 500 tested positive in
a mouse bone marrow cytogenetic analysis.
                              C-95

-------
     In summary, carcinogenic responses have been induced
in mice and rats.  These results, together with positive
mutagenic responses, and suggestive epidemiologic evidence,
constitute substantial evidence that PCBs are likely to
be human carcinogens.
     The water quality criterion for PCBs is based on the
Kimbrough, et al.  (1975) study on the induction of hepatocellular
carcinomas and neoplastic nodules in female Sherman strain
rats fed 100 ppm Aroclor 1260.  It is concluded that the
water concentration of PCBs should be less than 0.26 ng/1
(~'0.2 ng/1) in order to keep the lifetime cancer risk below
io-5.

*This summary has been prepared and approved by the Carcinogens
 Assessment Group of EPA on June 15, 1979.
                              C-96

-------
                  Summary of Pertinent Data

     The water quality criterion for PCBs is derived from

the hepatocellular carcinoma and neoplastic nodule response

of Sherman strain female rats fed 100 ppm Aroclor 1260 (Kimbrough,

et al.,  1975).  A time-weighted average dose of 88.4 ppm

was administered for approximately 21.5 months and the animals

were observed for an additional six weeks before terminal

sacrifice.  The incidence of hepatocellular carcinoma and

neoplastic nodules was 170/184 in the treated group and

1/173 in the control group.  Assuming a fish bioaccumulation

factor of 46,000, the criterion is calculated from the following

parameters:

     n.  = 170               d = 88.4 x 0.05 = 4.42 mg/kg/day
     N£ = 184               w = 0.4 kg
     n  =   1               L = 730 days
     N:; = 173               R = 46,000
     Le = 730 days          F = 0.0187 kg/day
     le = 645 days

     Based on these parameters, the one-hit slope BH is

3.25  (mg/kg/day)~ .  The resulting water concentration of

PCBs calculated to keep the individual lifetime cancer risk

below 10~  is 0.26 nanograms per liter.
                              C-97

-------
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