United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 27711
EPA-600/1-80-012
January 1980
Research and Development
Chronic Toxicity of
Lead and Cadmium
I.  Changes in  the
Central Nervous
System of the
Parental
Generation of Rats
After Chronic
Intoxication with
Lead and Cadmium


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                RESEARCH REPORTING SERIES

Research reports of the Office of Research and Development, U.S. Environmental
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ances of man for unhealthful substances or conditions.  This work is generally
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                                                                EPA-600/1-80-012
                                                                January  1380
                CHRONIC TOXICITY OF LEAD AND CADMIUM

I.   Changes in the Central Nervous System of the Parental Generation
    of Rats After Chronic Intoxication With Lead and Cadmium
                                  By

  Zbigniew. S. Herman, Krystyna Kmieciak-Kolada, Ryszard Szkilnik,
       Ryszard Brus, Kornel Ludyga, Romana Winter, Jan Jonek,
              Janusz Konecki, Jan Kusz, Jakub Bodziony,
               Barbara Hebrewska, Kazimierz Kaminski,
                Marie Ostrowska, Janwiga Wyrebowska,
                          and John Laskey

              Departments of Pharmacology, Biochemistry
                       Cytology and Histology
           Central Animal Farm of Silesian Medical Academy
                             in Katowice
                            Project Officer

                              John Laskey
                 Health Effects Research Laboratory
                U.S. Environmental Protection Agency
                  Research Triangle Park, NC  27711
                 HEALTH EFFECTS RESEARCH LABORATORY
                 OFFICE OF RESEARCH AND DEVELOPMENT
                U.S. ENVIRONMENTAL PROTECTION AGENCY

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                               DISCLAIMER

     This report has been reviewed by the Health Effects Research Laboratory,
U.S. Environmental Protection Agency, and approved for publication.   Approval
does not signify that the contents necessarily reflect the views and policies
of the U. S. Environmental Protection Agency, nor does mention of trade names*
or commercial products constitute endorsement or recommendation for use.

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                                ABSTRACT

     This paper examines the effects  of chronic  exposure  to trace amounts of
lead and cadmium on the central  nervous system of  male Wistar rats.   Treat-
ments consisted of two levels of lead (5  or  50 ppm),  two  levels  of cadmium
(0.1 or 5 ppm), and two combined dosages  (5  ppm  lead  and  0.1 ppm cadmium,
or 50 ppm lead and 5 ppm cadmium).  Treatments were administered in buffered
drinking water.

     The lower dosages generally produced hyperactivity,  while higher
dosages produced hypoactivity.   Effects of lead  and cadmium on biogenic
amines varied with dose and area of the brain.   Biochemical  analysis of
blood and urine showed no changes in  the  hematocrit or hemoglobin,  but the
activity of Delta-ALA dehydratase and serum  phosphatase were differentially
affected.  Concentrations of lead and cadmium in the  liver  and kidney
increased, and positive interaction effects  were noted.

     The results suggest that the level of biogenic amines  in discrete
brain areas is a very sensitive indicator of central  nervous system
toxicity to lead and/or cadmium.

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                                SECTION 1

                              INTRODUCTION


     Coal is a major source of energy in the USA and Poland.   During
processing, the hazardous trace elements contiguous with coal  ore, such
as lead (Pb) and cadmium (Cd), may be transferred to rivers and drinking
water sources resulting in chronic human exposure.   In recent years, the
Pb and Cd content in the environment and in man has increased progres-
sively (12,13,14,15,16,20).  In 1971, the annual averages of Cd,concentration
in air from ten cities in Poland ranged from 0.002 to 0.05 ug/m  (16).
The brain, reproductive system and other organ systems may be targets
for the potentially toxic effects of these elements (14,17,18,19).
Taking into account the possible individual and synergistic effects of
chronic exposure to Pb and/or Cd, it seemed practical to study the
functional physiology of the central nervous and reproductive systems in
rats chronically exposed to trace amounts of Pb and/or Cd in the drinking
water.

     In this paper we report the influence of these elements on the
central nervous system.

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                                SECTION 2

                          MATERIALS AND METHODS

     Experiments were carried out on male Wistar rats, 40 days old, from
the Central Animal Farm of the Silesian Academy of Medicine.   With the ex-
ception of the control group which contained 40 animals, the animals were
divided into groups consisting of 20 rats each and received via drinking
water (buffered with 0.005 M acetate) the following treatments.
     Group I (Control)

     Group II - 5 ppm lead

     Group III - 50 ppm lead

     Group IV - 0.1 ppm cadmium

     Group V - 5 ppm cadmium

     Group VI - 5 ppm lead and 0.1 ppm cadmium

     Group VII - 50 ppm lead and 5 ppm cadmium
Behavioral Measurements

     Because of the large numbers of animals to be tested, 24 hour
locomotor activity was assessed in two waves.  Wave I consisted of a
control, 5 ppm Pb, 0.1 ppm Cd and 5 ppm Pb plus 0.1 ppm Cd; and Wave II
consisted of control, 50 ppm Pb, 5 ppm Cd and 50 ppm Pb plus 5 ppm Cd.
Rats were placed for 24 hours in a photocell actometer (1) and for the
next 24 hours in a motimeter (2).  They had access to standard laboratory
feed and water for 1/2 hour following 6, 12 and 24 hours in each measuring
device for the length of the experiment.  Impulses elicited by locomotor
activity were noted from counters every 12 hours.

Biogem'c Amine Assays

     Rats were killed by cervical dislocation at the end of experiments.
The brains were quickly removed and placed on Petri dishes filled with

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ice and dissected into the hypothalamus, medulla oblongata plus pons,
hippocampus with nucleus accumbens and striatum essentially according to
Glowinski and Iversen (3).  Spectrophotofluorometric analysis of noradren-

aline (NA), 5-hydroxytryptamine (5-HT), and 5-hydroxyindoleacetic acid
(5-HIAA) levels were done according to Miller et aj.  (4) and dopamine
(DA) according to Cox et aJL  (5).

Biochemical Studies

     Blood samples were collected by heart puncture into heparinized
syringes under light ether anesthesia.  The brain was perfused through
the subclavian and carotid arteries with 60 ml of saline cooled to 4C.
The brain was removed and immediately frozen in dry ice, weighed and
homogenized in 5 parts of 0.067 M sodium phosphate buffer, pH 7.4 in a
teflon homogenizer and placed in a beaker filled with ice.  Blood levels
of hemoglobin (6) and 6-aminolevulinic acid dehydratase E.G.4.2.1.24
(ALA-D) (7) were measured.  Lactate dehydrogenase E.C.I. 1.1.27 (LDH)
activity was measured spectrophotometrically, alkaline phosphatase
E.C.3.1.3.1 (Al.Ph.) activity was estimated according to Bessey et aj.
(3), brain acetycholinesterase E.C.3.1.1.7 (AChE) activity was measured
according to Ellman et a_L (9), and brain monoamine oxidase E.C.I.4.3.4.
(MAO) activity was measured according to McEven and Cohen (10) using
benzylamine as a substrate.  The level of coproporphyrin in the urine
was estimated according to Haeger-Aronsen (11).  Lead and cadmium concentra-
tions in 1 gram aliquots of liver, kidney and drinking water were determined
on a Pye-Unicain SP90A Series 2 atomic absorption spectrophotometer.

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                                SECTION 3

                                 RESULTS

Locomotor Activity

     Continuous (40 days) exposure to Pb and/or Cd (5 ppm Pb or 5 ppm Pb
plus 0.1 ppm Cd) produced hyperactivity when measured in the photocell
apparatus or in the motimeter (Table 1).  The 0.1 ppm Cd exposure group,
however, was hyperactive in the photocell apparatus and hypoactive in
the motimeter.  Animals exposed to higher levels of Pb and/or Cd (50 ppm
Pb, 5 ppm Cd or 50 ppm Pb and 5 ppm Cd) were hypoactive in both measuring
devices.  Ratios of diurnal-nocturnal activity did not show consistent
dose-related changes.

Neurochemical Analyses

     NA and DA concentrations in brain areas are'presented in Tables 2
and 3.  Chronic exposure to 5 ppm Pb did not change the NA concentrations
in the brain areas examined, but a decrease in DA concentrations in the
striatum were noted.  Cd at 0.1 ppm decreased the level of NA in all
brain areas except the striatum, but lowered DA level in this area.
After simultaneous exposure to Pb and Cd (5 ppm Pb and 0.1 ppm Cd) only
a decrease in the NA level in hypothalamus was observed.

     Pb at 50 ppm in the water resulted in a decrease in the NA con-
centration in all areas except the limbic system (hippocampus with
nucleus accumbens) and lowered DA levels in the striatum.  Cd at 5 ppm
increased NA concentration in the hypothalamus.  After exposure to 50 ppm
Pb + 5 ppm Cd, there was an increase in NA concentration in the hypothalamus
and a decrease in DA concentration in the striatum.

     5-HT and 5-HIAA concentrations in brain areas are presented in Tables
4 and 5.  Lead at 5 ppm resulted in increased concentration of both
5-HT and 5-HIAA in the hypothalamus.  Cadmium at 0.1 ppm increased 5-HT
concentrations in the brain stem and 5-HIAA concentrations in the hypo-
thalamus and the striatum.  Simultaneous administration of 5 ppm Pb +
0.1 ppm Cd increased the concentrations of both 5-HT and 5-HIAA in the
brain stem, 5-HT levels in the limbic system and 5-HIAA concentrations
in the hypothalamus and striatum.

     Lead at 50 ppm decreased the 5-HT and 5-HIAA concentrations in the
hypothalamus and striatum.  Five ppm Cd decreased the concentration of
5-HT fn the striatum.  Simultaneous exposure to 50 ppm Pb and 5 ppm Cd
decreased the concentrations of both of 5-HT and 5-HIAA in the hypothalamus
and striatum.

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          TABLE 1.   LOCOMOTOR ACTIVITY (COUNTS/24 HR) FOLLOWING 40 DAYS EXPOSURE
                    TO Pb AND/OR Cda
Control
Photocell
Apparatus
(Day 1) 322
Mot i meter
(Day 2) 349
Control
Photocell
Apparatus
(Day 1) 1172
Moti meter
(Day 2) 304
5 ppm Pb
717*d
433
50 ppm Pb
723
89**
5 ppm Pb
+
0.1 ppm Cd 0.1 ppm Cd
696* 787*
201 395
50 ppm Pb
+
5 ppm Cd 5 ppm Cd
972 476*
156* 122*
b ANOVAC
SD P Value
P
83 <.01
51 <.05
ANOVA
SD P Value
129 <.01
32 <.01
a-N = 10 for each group.
b-SD  = pooled standard deviation.
c-Significance level for the analysis of variance (ANOVA).
d-Values significantly different from control values by Dunnett's multiple comparison test
 (**p<.01, *p<-05).

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         TABLE 2.  NORADRENALINE CONCENTRATION (ug/g) IN DISCRETE BRAIN AREAS .FOLLOWING LEAD AND/OR
                   CADMIUM EXPOSURE8
Brain area
Hypothal amus
Pons with Medulla
Oblongata
Hippocampus with
Nucleus Accombens
Striatum

Hypothal amus
Pons with Medulla
Oblongata
Hippocapmus with
Nucleus Accombens
Striatum
Control
2.79
0.78
0.55
0.20
Control
2.71
0.76
0.77
0.20
Pb 5 ppm
2.80
0.79
0.54
0.24
Pb 50 ppm
1.62**
0.68
0.75
0.13
Cd 0.1 ppm
2.50
0.66**d
0.47
0.21
Cd 5 ppm
5.83**
0.80 ,
0.69 ,
0.19
Pb 5 ppm + Cd 0.1 ppm
2.46
0.73
0.51
0.22
Pb 50 ppm + Cd 0.1 ppm
5.83**
0.71
0.71
0.19
SD b ANOVAC P Value
P
.28 <.05
.06 <.01
.28 N.S.
.09 N.S.
SDpb ANOVAC P Value
.44 <.01
.06 <.01
.13 N.S.
.09 N.S.
a-N - 10 for each group.
b-SD  = pooled standard deviation.
c-Significance level from the analysis of variance (ANOVA).
d-Values significantly different from control values by Dunnett's multiple comparison test (**p<.01).

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       TABLE 3.   DOPAMINE CONCENTRATION (ug/g) IN STRIATUM FOLLOWING LEAD
                 AND/OR CADMIUM EXPOSURE3
Control
7.13
Control
9.27
Pb 5 ppm
6.05
Pb 50 ppm
6.39*
Cd 0.1 ppm
4.79*d
Cd 5 ppm
10.68
Pb 5 ppm
+ Cd 0.1 ppm
5.85
Pb 50 ppm
+ CD 5 ppm
7.51
V
1.74
V
2.34
ANOVAC P Value
<.01
ANOVA P Value
<.01
a-N = 10 for each group.
b-SD  = pooled standard deviation.
c-Significance level from the analysis of variance (ANOVA).
d-Values significantly different from control values by Dunnett's multiple
 comparison test (*p<.05).

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Biochemical Analyses

      No significant changes in hematocrit of hemoglobin were noted
in animals on any exposure regimen.  Delta-ALA dehydratase activity in
erythrocytes was significantly decreased by exposure to 50 ppm Pb, 50
ppm Pb plus 5 ppm Cd, and 5 ppm Pb plus 0.1 ppm Cd but not by exposure to
5 ppm Pb.  Neither serum AChE nor serum LDH were altered by any treatment.
Serum alkaline phosphatase activity was increased by treatment with 0.1
ppm Cd, 5 ppm Cd and 50 ppm Pb plus 5 ppm Cd.

     Brain MAO activity was reduced by both Cd treatments and Pb-Cd
treatments, however, only the 5 ppm Pb treatment caused reduced activity
(Table 6).  Brain AChE activity was significantly reduced by 50 ppm Pb
and 50 ppm Pb-5 ppm Cd combination (Table 6).

     Twenty-four hour urinary coproporphyrin was unaffected by the low
doses of Pb and/or Cd treatment but decreased more than 50% by 50 ppm Pb
and increased more than 250% by the 50 ppm Pb-5 ppm Cd combination.

Concentration of Pb and Cd in Tissues

     Cadmium and Pb concentrations in the liver and kidney are presented
in Table 7.  It should be noted that the Pb treated animals when simul-
taneously treated with Cd showed increased liver and kidney Pb concentra-
tions over that resulting from Pb treatment alone.  Likewise, when Cd
treated animals are simultaneously treated with Pb, liver and kidney Cd
concentrations are higher than with Cd treatment alone.  No measurable
quantities of Pb or Cd were found in the drinking water.
                                   8

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      TABLE 4.   5-HYDROXYTRYPTAMINE CONCENTRATIONS (jig/g) IN DISCRETE BRAIN AREAS FOLLOWING LEAD AND/OR
                CADMIUM EXPOSURE3
Brain area
Hypothalamus
Pons with Medulla
Oblongata
Hippocampus with
Nucleus Accombens
Striatum

Hypothal amus
Pons with Medulla
Oblongata
Hippocapmus with
Nucleus Accombens
Striatum
Control
2.50
1.04
0.61
1.07
Control
2.72
1.03
0.99
1.09
Pb 5 ppm
3.01**d
1.08
0.61
1.00
Pb 50 ppm
1.95
0.98
0.99
0.70**
Cd 0.1 ppm
2.59
1.25**
0.67
1.02
Cd 5 ppm
2.73
1.11
i
1.03
0.83*
Pb 5 ppm + Cd 0.1 ppm
2.54
1.30**
0.68
1.18
Pb 50 ppm + Cd 5 ppm
2.04**
1.04
0.98
0.86
SO,, ANOVAC P Value
P
.28 <.01
.09 <.01
.32 N.S.
.32 N.S.
SO b ANOVAC P Value
.32 <.01
.13 N.S.
.09 N.S.
.19 <.01
a-N - 10 for each group.
b-SD  = pooled standard deviation.
c-Significance level from the analysis of variance (ANOVA).
d-Values significantly different from control values by Dunnett's multiple comparison test (**p<.01, *p<.05).

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      TABLE 5.  5-HYDROXYINDOLEACETIC ACID CONCENTRATION (ug/g) IN DISCRETE BRAIN AREAS FOLLOWING LEAD
                AND/OR CADMIUM EXPOSURE3

Brain area
Hypothal amus
Pons with Medulla
Oblongata
Hippocampus with
Nucleus Accombens
Striatum



Control
2.

0.

0.
0.

27

70

99
98

Control
Hypothal amus
Pons with Medulla
Oblongata
Hippocapmus with
Nucleus Accombens
Stri atum
2.

0.

0.
0.
33

72

61
98

Pb
2.

0.

1.
0.

Pb
1.


5 ppm
88**d

73

08
94

50 ppm
75**

0.74

0.
0,

65
77

Cd
2.

0.

1.
1.

Cd
1.

0.

0.
0.

0.1 ppm
85*

64

06
12

5 ppm
87**

88

79
82


Pb 5 ppm + Cd 0.1 ppm
2.

0.

1.
1.

Pb 50 ppm
1.

0.

0.
0.
69*

83

00
37

+ Cd 5 ppm
47**

76

78
69
b
SDP
.35

.32

.25
.44
b
SDP
.28

.09

.13
,44

ANOVAC P Value
<.05

N.S.

N.S.
N.S.

ANOVAC P Value
<.01

N.S.

N.S.
N.S.
a-N - 10 for each group.
b-SD  = pooled standard deviation.
c-Significance level from the analysis of variance (ANOVA).
d-Values significantly different from control values by Dunnett's multiple comparison test (**p<.01,  *p<.05).

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   TABLE 6.   MONAMINE OXIDASE AND ACETYLCHOLINE ESTERASE (ug/min/g) CONCENTRATIONS IN WHOLE BRAIN FOLLOWING
             LEAD AND/OR CADMIUM EXPOSURE3
Analysis
Monoamine Oxidase

Acetylcholine
Esterase
Control
1.49
Control
1.61
Control
10.3
Control
12.0
Pb 5 ppm
0.70
Pb 50 ppm
1.57
Pb 5 ppm
9.1
Pb 50 ppm
4.2**d
Cd 0.1 ppm
0.51
Cd 5 ppm
0.76
Cd 0.1 ppm
10.7
Cd 5 ppm
10.4
Pb 5 ppm + Cd 0.1 ppm
1.00
Pb 5 ppm + Cd 5 ppm
0.33
Pb 5 ppm + Cd 0.1 ppm
10.4
Pb 50 ppm + Cd 5 ppm
8.7*
b
SDP
1.14
 P
1.55
SDpb
2.86
2.66
ANOVA0 P Value
N.S.
ANOVA P Value
N.S.
ANOVAC P Value
N.S.
ANOVA P Value
<.01
a-N - 10 for each group.
                                                    i
b-SD  = pooled standard deviation.

c-Significance level from the analysis of variance (ANOVA).


d-Values significantly different from control values by Dunnett's multiple comparison test (**p<.01,  *p<.05).

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     TABLE 7.   LIVER AND KIDNEY LEAD OR CADMIUM CONCENTRATIONS  FOLLOWING
               40 DAYS EXPOSURE3
                                    5 ppm Pb +                      50 ppm Pb
                     5 ppm Pb       0.1 ppm Cd     50 ppm Pb       +5 ppm Cd


Liver Pb                                     .               .                 .
  Concentration,    2.3   0.2     2.7   0.3    2.7   0.3      3.2   0.5
  M9/9

Kidney Pb                                                                    .
  Concentration,    2.1   0.3     2.4   0.3     2.3   0.2       2.7   0.4
  pg/g
                                  0.1 ppm Cd                       5  ppm Cd
                   0.1 ppm Cd     +5 ppm Pb       5 ppm Cd        + 50 ppm Pb


Liver Cd                                                                      h
  Concentration,    0.52  0.10    0.59  0.08    0.63  0.18      0.68  0.11
Kidney Cd                                     h              K                 h
  Concentration,    0.59  0.05    0.80  0.07   0.75  0.11      0.95   0.23
a-N for each group =10.

b-Significantly different from the low dose by Dunnett's multiple
  comparison test (p<0.05).
                                        12

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                                SECTION 4

                               DISCUSSION

     These results indicate that chronic exposure to 50  ppm Pb and 5 ppm
Cd for 40 days in drinking water to young  rats  is deleterious  to CNS
function.  Higher concentrations of Pb generally lowered both  NA and DA
concentrations in brain areas measured.  Exposure to 5 ppm Pb  increased
the concentration of 5-HT in the hypothalamus,  and the concomitant
treatment of the 5 ppm Pb group with 0.1 ppm Cd had the  same effect in
the brain stem.  Inversely it seem that treatment with 50 ppm  Pb decreased
5-HT in the hypothalamus and striatum.  The higher Cd exposure level
depressed the 5-HT concentration in the striatum.

     These results indicate that estimation of  the level of biogenic
amine levels in discrete brain areas is a  very  sensitive indicator of
CNS toxicity to Pb and/or Cd.  Both agents have a different profile of
action on adrenergic and serotoninergic neurons in the discrete brain
areas measured in this study.  No relationship  between the levels of
biogenic amines and MAO activity was seen.  The decrease of AChE activity
observed in animals exposed to high Pb levels may be interpreted as an
influence of this metal on cholinergic neurons.  Shih and Hanin (24), in
a study with rats exposed from infancy to  4% lead acetate in chow, showed
a decrease in acetylcholine concentrations in  cortex, hippocampus, midbrain
and striatum by 35, 54, 51 and 33%, respectively.  This  finding provides
evidence for an inhibitory effect of Pb on the  central cholinergic
function jn vivo.  There is some experimental  evidence that biogenic
amines in the CNS act by the adenylcyclase-315'cyclic AMP system (27,28,29,30,31).
Very low concentrations of Pb or Cd inhibited  adenylate  cyclase activity
in homogenates and particulate fractions of rat cerebellum and cerebral
cortex.  On the other hand, Pb stimulated  and  Cd inhibited phosphodies-
terase activity (25).

     Our results indicate that both heavy  metals penetrated the brain.
It was stated by others (26) that Pb penetrates the brain and is
concentrated in cortical grey matter and basal  ganglia whereas Cd does
not readily penetrate the brain.  All of these  effects appear to be species
dependent.  Biochemical examinations carried out in our  experiments have
shown some typical signs of Pb and Cd intoxication.  They also indicate
that LDH and /'ihE activity in serum have no value as a diagnostic factor
in Pb and Cd intoxication in rats.  A dose dependent increase in serum
alakaline phosphatase activity was seen with Cd treatment.  The sig-
nificance of this will be confirmed in studies  currently in progress.
Our data suggest that a brief Pb and/or Cd exposure affects the subtle
functions of the CNS.  The toxicological importance of these changes
requires further elucidation.
                                  13

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                               LITERATURE

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     Cleveland, Ohio 60-  .

16.  Just, J., Kelus, J. (1971).  Cadmium in Atmosphere Air of 10 Delected
     Towns in Poland (In Polish with English.  Summary.)  Roczn. PZH, 22,
     249-256.

17.  Sakurai, II., Sugita, M., Tsuchiya, K. (1974).  Biological Response
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     Health, 29, 157.

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     Human Health.  Environmental Affairs, 2, 222-235,

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     Catecholamines in Lead-Exposed Developing Rats.   Sci., 182, 1022-1024.

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     Metal Toxicity.  Mol. Pharmacol. 12, 390-398.
                                  15

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                                  16

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                                    TECHNICAL REPORT DATA
                            (Please read Instructions on the reverse before completing)
1. REPORT NO.
    EPA-600/1-80-012
                             2.
                                                            3. RECIPIENT'S ACCESSION NO.
 CHRONIC TOXICITY OF  LEAD AND CADMIUM  I.  Changes  in the
 Central Nervous System of the Parental Generation  of
 Rats After Chronic  Intoxication With Lead and  Cadmium.
                                                            5. REPORT DATE
                                                             January  1980
                                                            6. PERFORMING ORGANIZATION CODE
7HerTnanR, Kmieciak-Kolada,  Szkilnik, Brus, Ludyga,
 Winter, Jonek,  Konecki,  Kusz, Bodziony, Hebrowska,
 l^am-incb-i  He-f-yrii.ic I/a   Uf\/yohr\uiclf a  anH I aglf py.
                                                             8. PERFORMING ORGANIZATION REPORT NO.
9.
. PERFORMING ORGANIZATION NAME AND ADDRESS
Departments of Pharmacology, Biochemistry,  Cytology
   and Histology
Central Animal  Farm of Silesian Medical  Academy in
Katowice,  Poland.
                                                             10. PROGRAM ELEMENT NO.

                                                                  1AA817
                                                             11. CONTRACT/GRANT NO.

                                                              JB5-531-1
12. SPONSORING AGENCY NAME AND ADDRESS
 Health Effects  Research Laboratory
 U.S. Environmental  Protection Agency
 Research Triangle Park, NC  27711
 John W. Laskey  -  Project Officer
                                                            13. TYPE OF REPORT AND PERIOD COVERED
                                                             Interim Report
                                                            14. SPONSORING AGENCY CODE
                                                             EPA/600/11
15. SUPPLEMENTARY NOTES
16. ABSTRACT
      This paper examines the effects of  chronic exposure to trace  amounts of lead and
 cadmium on  the central nervous system  of male Westar rats.  Treatments  consisted of
 two levels  of lead (5 or 50 ppm), two  levels of cadmium (0.1 or  5  ppm), and two combined
 dosages (5  ppm lead and 0.1 ppm cadmium, or 50 ppm lead and 5 ppm  cadmium).  Treatments
 were administered in buffered drinking water.

      The lower dosages generally produced hyperactivity, while higher dosages produced
 hypoactivity.   Effects of lead and cadmium on biogenic amines varied with dose and area
 of the brain.   Biochemical analysis of blood and urine showed no changes in the hemato-
 crit or hemoglobin, but the activity of  Delta-ALA dehydratase and  serum phosphatase
 were differentially affected.  Concentrations of lead and cadmium  in the liver and
 kidney increased, and positive interaction effects were noted.

      The results suggest that the level  of biogenic amines in discrete brain areas
 is a very sensitive indicator of central nervous system toxicity to lead and/or
 cadmium.
17.
                                 KEY WORDS AND DOCUMENT ANALYSIS
                  DESCRIPTORS
                                              b.IDENTIFIERS/OPEN ENDED TERMS  C. COSATI Field/Group
  Lead
  Cadmiurn
  Intoxication
                                                                           06, T,C
18. DISTRIBUTION STATEMENT

  Release to Public
                                              19. SECURITY CLASS (This Report)
                                                Unclassified
21. NO. OF PAGES
  20
                                               20. SECURITY.CL.ASS
                                                 Unclassified
                                                              (This page)
22. PRICE
EPA Form 2220-1 (Rv. 4-77)   PREVIOUS EDITION is OBSOLETE
                                              17

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