ChlorodioxinsâOrigin and Fate

7

Toxicology of Chlorinated Dibenzo-p-dioxins

B. A. S C H W E T Z , J. M . NORRIS, G . L . SPARSCHU, V. K. R O W E , and P. J. G E H R I N G

Downloaded by UNIV OF ARIZONA on January 10, 2013 | http://pubs.acs.org Publication Date: March 1, 1973 | doi: 10.1021/ba-1973-0120.ch007

Chemical Biology Research, The Dow Chemical Co., Midland, Mich. 48640 J. L . E M E R S O N and C . G . G E R B I G Human Health Research and Development Center, The Dow Chemical Co., Zionsville, Ind., 46077

Severe toxicological responses have been attributed to cer tain

chlorodibenzo-p-dioxins.

Therefore,

the

acute and

subacute toxicities of several of these compounds have been determined and these results provide information for eval uating potential health hazards. -p-dioxin (2,3,7,8-TCDD) -p-dioxin studied,

having

an LD

(HCDD)

μg/kg

range.

was less toxic than

but more toxic than either 2,7-dichlorodi

benzo-p-dioxin (OCDD).

in the

50

Hexachlorodibenzo-p-dioxin 2,3,7,8-TCDD

2,3,7,8-Tetrachlorodibenzo

was the most toxic chlorodibenzo

(2,7-DCDD)

or

Both 2,3,7,8-TCDD

octachlorodibenzo-p-dioxin

and HCDD

were acnegenic,

highly embryotoxic, and positive for the chick edema factor. 2,7-DCDD

and OCDD

were not chloracnegenic,

little or no embryotoxicity, lethality; OCDD

caused

and were low in acute oral

was negative for the chick edema factor.

O e v e r e t o x i c o l o g i c a l responses h a v e b e e n associated w i t h c e r t a i n c h l o r o^

d i b e n z o d i o x i n s . O n e of these responses

is c h l o r a c n e , a f o l l i c u l o s i s

first associated w i t h s k i n c o n t a m i n a t i o n b y c h l o r o h y d r o c a r b o n s i n 1899 (3).

Serious outbreaks

a w a y reactions

o f c h l o r a c n e - l i k e lesions associated

with

run

i n t h e p r o d u c t i o n of 2 , 4 , 5 - t r i c h l o r o p h e n o l o c c u r r e d i n

G e r m a n y i n t h e e a r l y 1950's ( 5 ) . 2 , 4 , 5 - T r i c h l o r o p h e n o l itself does n o t cause a c n e ( 8 ) , b u t t h e c o n t a m i n a n t s

w h i c h m a y be formed i n the

u n c o n t r o l l e d p r o d u c t i o n of 2 , 4 , 5 - t r i c h l o r o p h e n o l acnegens

( 5 ) . 2,3,7,8-Tetrachlorodibenzo-p-dioxin

a r e extremely

potent

a n d t r i - a n d tetra-

55

In Chlorodioxins—Origin and Fate; Blair, E.; Advances in Chemistry; American Chemical Society: Washington, DC, 1973.

56

CHLORODIOXINS

chlorodibenzofuran

were

isolated

ORIGIN A N D F A T E

f r o m the contaminants

formed i n

2 , 4 , 5 - t r i c h l o r o p h e n o l p r o d u c t i o n a n d w e r e d e m o n s t r a t e d to b e s t r o n g l y p o s i t i v e acnegens w h e n a p p l i e d t o r a b b i t ears (8).

U s i n g t h e r a b b i t ear

test, t h e a c n e g e n i c p o t e n c y of 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o - p - d i o x i n (2,3,7,8TCDD)

w a s c o n f i r m e d i n 1962 (6).

I n a d d i t i o n , 2 , 3 , 7 , 8 - T C D D is ex

t r e m e l y toxic i n t h e c h i c k e m b r y o assay (4) i n rats

(12).

a n d is h i g h l y e m b r y o t o x i c

Another chlorodibenzodioxin, hexachlorodibenzo-p-dioxin

( H C D D ), is k n o w n to b e p o s i t i v e for t h e c h i c k e d e m a factor, a c o n d i t i o n


c h a r a c t e r i z e d b y h y d r o p e r i c a r d i u m , ascites, a n d anasarca (1,

4).

Experimental Materials. T h e c h l o r o d i b e n z o d i o x i n samples u s e d i n these studies are i d e n t i f i e d a n d d e s c r i b e d i n T a b l e I. Studies w e r e l i m i t e d i n some cases b y a v a i l a b i l i t y of p u r e samples. Acute Lethality. S a m p l e s of 2 , 7 - d i c h l o r o d i b e n z o - p - d i o x i n , 2,3,7,8tetrachlorodibenzo-p-dioxin, hexachlorodibenzo-p-dioxin, a n d octachloro d i b e n z o - p - d i o x i n w e r e e v a l u a t e d f o r acute o r a l l e t h a l i t y i n t h e f o l l o w i n g animals. Test Material Test Animal

Strain

Rat Rat Mouse Rabbit Guinea pig Dog

Sprague-Dawley S h e r m a n (Spartan) Swiss W e b s t e r N e w Zealand albino Hartley Beagle

2 7DCDD

2 3 7 8TCDD HCDD

Χ

OCDD

X

X

X X

X

X X X X

T e s t materials w e r e a d m i n i s t e r e d as suspensions i n c o r n o i l o r as c o r n o i l : a c e t o n e ( 9 : 1 ) solutions i n single doses b y gavage. T h e a n i m a l s w e r e d e p r i v e d of f e e d f o r 16 h o u r s b e f o r e d o s i n g . A f t e r d o s i n g t h e y w e r e o b s e r v e d f o r signs of t o x i c i t y i n c l u d i n g b o d y w e i g h t changes f o r t w o to eight weeks. L e t h a l i t y o f 2 , 3 , 7 , 8 - T C D D via s k i n a b s o r p t i o n w a s tested o n r a b b i t s of m i x e d sexes w i t h doses of 31.6, 63, 126, 252, a n d 5 0 0 /xg/kg b o d y w e i g h t . T h e c o m p o u n d w a s a p p l i e d as a 0 . 0 1 % s o l u t i o n i n acetone t o the a b d o m i n a l s k i n w h i c h h a d b e e n s h a v e n . A f t e r t h e acetone e v a p o r a t e d , t h e t r u n k of e a c h r a b b i t w a s w r a p p e d i n c o t t o n to p r e v e n t i n g e s t i o n . T h e r a b b i t s w e r e h o u s e d i n i n d i v i d u a l h o l d i n g cages a n d w e r e o b s e r v e d f o r signs of t o x i c i t y i n c l u d i n g b o d y w e i g h t changes f o r three weeks. P a r e n t e r a l l e t h a l i t y w a s d e t e r m i n e d b y i n j e c t i n g r a b b i t s of m i x e d sexes i n t r a p e r i t o n e a l l y w i t h 31.6, 63, 126, 252, a n d 5 0 0 /xg/kg of 2,3,7,8T C D D as a 0 . 0 1 % c o r n o i l s u s p e n s i o n ; c o n t r o l r a b b i t s w e r e injected w i t h c o r n o i l . T h e r a b b i t s w e r e h o u s e d i n i n d i v i d u a l h o l d i n g cages a n d w e r e o b s e r v e d f o r signs of t o x i c i t y f o r f o u r weeks. T h e L D o S w e r e c a l c u l a t e d b y t h e W e i l m o d i f i c a t i o n of t h e T h o m p s o n m e t h o d (14, 15) or b y the L i t c h f i e l d a n d W i l c o x o n m e t h o d ( 9 ) . T h e a c u t e l e t h a l i t y studies w e r e t e r m i n a t e d w h e n i t w a s e v i d e n t that t h e survivors w e r e n o t s h o w i n g signs of t o x i c i t y . 5


7.

SCHWETZ

E T

AL.

Table I.

57

Toxicology of Chlorinated Dioxins

Purity of Samples Used in the Toxicology Studies Purity

Sample Identification"

b

2,7-Dichlorodibenzo-p-dioxin a. N o . 104, shelf 142 b. AR-570 c. 340-2-13A d . 340-2-69A 2,3,7,8-Tetrachlorodibenzo-p-dioxin a. C a u s t i c insoluble isolate 1965 b . 851-142-24 c. S k e l l y 11/11/64 d . 340-2-54B 1,2,3,4-Tetrachlorodibenzo-p-dioxin a. F D A - F 9 9 0 Hexachlorodibenzo-p-dioxin a. 252-44-12B-AL22

Tests"

99.6% >99%

1,2,3 3 1,2,3 4

96.4% 98% 91% >99%

1 1 1,3,5 1,2,3,5

99.8%


d

b.

252-44-12B-AL11

c.

340-2-82A

d.

FDA-F911

Octachlorodibenzo-p-dioxin a . 251-1-142A b . 340-2-29A c. A R - 5 7 0 d . 340-2-57A

98.5%

3

65:35, 2 isomers 9 9 % , 65:35, 2 isomers > 9 9 % , 89:11, 2 isomers 95.1%, 3 isomers

1,3 3 1,2,

98% 94%

e

98.86%

3,4,1 3

1,2,3 1,3 3 1,3,4,5

° All samples are from The Dow Chemical Co. except 3a and 4d, which are from the Food and Drug Administration. Based on gas-liquid chromatographic (GLC) or GLC-mass spectrophotometric analysis. Test identification: 1 = LD o, 2 = eye irritation, 3 = chlorance, 4 = teratogenicity, 5 = chick edema. Photolysis product of la. Photolysis product of 5a. b

c

5

d

e

Eye Irritation. R a b b i t eyes w e r e e x a m i n e d p r i o r to experiments a n d f o u n d to b e free of defects or i r r i t a t i o n . A p p r o x i m a t e l y 2 m g of 2 , 7 - D C D D , 2 , 3 , 7 , 8 - T C D D , H C D D , or O C D D w e r e i n s t i l l e d i n the c o n j u n c t i v a l sac of one eye; the c o n t r a l a t e r a l eye served as a c o n t r o l . T h e eyes w e r e e x a m i n e d at v a r i o u s times after treatment f o r c o n j u n c t i v a l redness a n d chemosis, iritis, a n d c o r n e a l i n j u r y . Responses w e r e catag o r i z e d a c c o r d i n g to intensity. Rabbit Ear Bioassay for Acnegenic A c t i v i t y . A c n e g e n i c a c t i v i t y of 2 - 7 - D C D D , 1 , 2 , 3 , 4 - T C D D , 2 , 3 , 7 , 8 - T C D D , H C D D , a n d O C D D w a s tested b y a p p l y i n g 0.1 m l of either a solvent s o l u t i o n or the supernatant of a solvent suspension of e a c h c o m p o u n d to the i n n e r surface of the rabbit's ears five days a w e e k f o r f o u r weeks. T h e ears w e r e e x a m i n e d w e e k l y f o r signs of c h l o r a c n e , i n f l a m m a t i o n , a n d h y p e r k e r a t o s i s . The responses w e r e d i v i d e d i n t o five categories: ( 1 ) none, ( 2 ) v e r y slight, ( 3 ) slight, ( 4 ) moderate, a n d ( 5 ) severe.



58

CHLORODIOXINS

ORIGIN

A N D

FATE

Responses i n the first three categories i n c l u d e no response to m i l d i r r i t a t i o n , i n c r e a s e d ear thickness, slight enlargement of the f o l l i c u l a r a p e r t u r e , s l i g h t e x f o l i a t i o n , a n d slight crust f o r m a t i o n . T h e s e responses alone are not c o n s i d e r e d i n d i c a t i v e of c h l o r a c n e g e n i c a c t i v i t y . C a t e g o r i e s 4 a n d 5 are i n d i c a t i v e of acnegenic response a n d are c h a r a c t e r i z e d b y c o m e d o f o r m a t i o n , i n c r e a s e d ear thickness, a n d hyperkeratosis. Teratology. P r e g n a n t a d u l t S p r a g u e - D a w l e y ( S p a r t a n strain) fe m a l e rats w e i g h i n g a p p r o x i m a t e l y 250 grams w e r e u s e d to s t u d y tera t o g e n i c i t y of the c h l o r i n a t e d d i b e n z o - p - d i o x i n s . T h e d a y s p e r m w e r e first present i n a v a g i n a l smear was c o n s i d e r e d d a y zero of p r e g n a n c y . T h e a n i m a l s w e r e h o u s e d i n d i v i d u a l l y i n w i r e - b o t t o m cages i n a r o o m c o n t r o l l e d f o r t e m p e r a t u r e , h u m i d i t y , l i g h t c y c l e , a n d noise. C o m m e r c i a l l a b o r a t o r y rat c h o w a n d w a t e r w e r e p r o v i d e d w i t h choice. C o r n o i l : a c e t o n e ( 9 : 1 ) solutions, w i t h v a r y i n g amounts of test m a t e r i a l w e r e g i v e n i n 2.5 m l / k g dosages b y gavage. Dosages w e r e c a l c u l a t e d u s i n g d a i l y b o d y w e i g h t s . Rats w e r e treated w i t h 100 m g of 2 , 7 - D C D D / k g / d a y , 0.1, 1.0, 10, or 100 /xg H C D D / k g / d a y a n d 100 or 500 m g O C D D / k g / d a y o n days 6 t h r o u g h 15 of gestation. C o n t r o l rats r e c e i v e d 2.5 m l / k g of c o r n o i l : a c e t o n e ( 9 : 1 ) o r a l l y . A l l rats w e r e o b s e r v e d d a i l y t h r o u g h o u t p r e g n a n c y a n d w e r e w e i g h e d o n days 6, 13, a n d 21 of gestation. P r e g n a n t females w e r e sacrificed b y c a r b o n d i o x i d e anesthesia o n d a y 21 of gestation; the u t e r i n e horns w e r e e x t e r i o r i z e d t h r o u g h a m i d l i n e i n c i s i o n i n the a b d o m i n a l w a l l , a n d the n u m b e r a n d p o s i t i o n of l i v e , d e a d , a n d r e s o r b e d fetuses w e r e n o t e d . A f t e r b e i n g w e i g h e d a n d sexed, the fetuses w e r e e x a m i n e d for external anomalies; the c r o w n - r u m p l e n g t h was m e a s u r e d w i t h a v e r n i e r c a l i p e r . H a l f of each litter w a s p r e s e r v e d i n B o u i n ' s s o l u t i o n a n d later e x a m i n e d for soft tissue anomalies (16); the other h a l f was p r e s e r v e d i n a l c o h o l , c l e a r e d a n d stained w i t h A l i z a r i n red-S, a n d e x a m i n e d for skeletal a b n o r m a l i t i e s (2). A 2 X 2 c o n t i n g e n c y t a b l e was u s e d to evaluate the f r e q u e n c y of anomalies a n d resorptions w i t h i n the fetal p o p u l a t i o n a n d b e t w e e n litters. B o d y w e i g h t a n d b o d y measurements w e r e statistically a n a l y z e d b y a n A n a l y s i s of V a r i a n c e a n d T u k e y ' s test (13). I n a l l cases, the l e v e l of significance was Ρ < 0.05. Chick Bioassay for Chick Edema Factor. T h e bioassay for c h i c k e d e m a factor w a s c o n d u c t e d a c c o r d i n g to the " O f f i c i a l M e t h o d s of A n a l y sis," 10th E d . , Sections 26.087-26.091, A s s o c i a t i o n of O f f i c i a l A g r i c u l t u r a l C h e m i s t s . T h r e e - d a y - o l d w h i t e l e g h o r n , s i n g l e - c o m b cockerels w e r e u s e d . 2 , 3 , 7 , 8 - T C D D , H C D D , and O C D D were the compounds studied. T h e d i e t u s e d i n the s t u d y was f o r m u l a t e d s p e c i f i c a l l y for c o n d u c t i n g the c h i c k e d e m a bioassay ( " N u t r i t i o n a l B i o c h e m i c a l s , " I n t e r n a t i o n a l C h e m ical and Nuclear Corp., Cleveland, O h i o ) . B o d y weights were recorded t w i c e w e e k l y f o r the o r a l i n t u b a t i o n studies a n d at the start a n d t e r m i n a t i o n of the d i e t a r y study. T h e chicks w e r e o b s e r v e d d a i l y for signs of t o x i c i t y , a n d f o o d c o n s u m p t i o n was r e c o r d e d w e e k l y . A f t e r 20 or 21 days of treatment, a l l chickens w e r e sacrified b y c e r v i c a l d i s l o c a t i o n a n d e x a m i n e d f o r gross lesions. T h e a m o u n t of p e r i c a r d i a l a n d p e r i t o n e a l f l u i d w a s m e a s u r e d , a n d a l l gross lesions w e r e r e c o r d e d . If the c a l c u l a t e d "t" w a s greater t h a n + 1 . 3 , the m e a n l o g a r i t h m (100 X m l p e r i c a r d i a l f l u i d ) was greater t h a n 1.1461 for the c h i c k s r e c e i v i n g the test c o m -


7.

SCHWETZ

E T

AL.


59


p o u n d , a n d the m e a n l o g a r i t h m of the negative c o n t r o l w a s less t h a n 1.1460, the c o m p o u n d was c o n s i d e r e d p o s i t i v e for c h i c k e d e m a . Pathology. T o x i c o l o g y studies w e r e not d e s i g n e d to s t u d y the p a t h o l o g i c a l changes associated w i t h c h l o r o d i b e n z o d i o x i n a d m i n i s t r a t i o n , b u t i n some cases, gross p a t h o l o g i c a l a n d h i s t o p a t h o l o g i c a l examinations w e r e p e r f o r m e d . F o r m i c r o s c o p i c e x a m i n a t i o n , tissues w e r e fixed i n 1 0 % b u f f e r e d f o r m a l i n a n d w e r e s t a i n e d w i t h h e m a t o x y l i n a n d eosin. Sections of fetuses of c o n t r o l dams a n d d a m s treated w i t h 100 m g 2 , 7 - D C D D / k g / d a y w e r e s t a i n e d w i t h h e m a t o x y l i n a n d eosin, h e m a t o x y l i n - p h l o x i n e saffron, Masson's t r i c h r o m e stain, a n d M a l l o r y ' s p h o s p h o t u n g s t i c a c i d h e m a t o x y l i n stain. Results Acute Lethality. T a b l e II.

The

l e t h a l i t y of 2 , 3 , 7 , 8 - T C D D

T h e d a t a r e v e a l that the single o r a l L D

5 0

is p r e s e n t e d

in

ranges f r o m 0.0006

m g / k g i n m a l e q u i n e a pigs to 0.115 m g / k g i n r a b b i t s of m i x e d sex.

Data

o n rats a n d g u i n e a pigs i n d i c a t e that

than

males

are m o r e sensitive

females; l e t h a l i t y is essentially the same f o l l o w i n g i n t r a p e r i t o n e a l , o r a l , or s k i n a d m i n i s t r a t i o n for rabbits.

L i m i t e d d a t a s h o w that dogs are less

sensitive to 2 , 3 , 7 , 8 - T C D D t h a n r a b b i t s . F o r f e m a l e a n d m a l e m i c e , single o r a l doses r a n g i n g f r o m 0.001

to 0.130 m g / k g p r o d u c e d a f e w s p o r a d i c

deaths w i t h o u t a n y d e f i n i t i v e dose-response

r e l a t i o n s h i p ; therefore

the

d a t a are not p r e s e n t e d i n the table. L i m i t e d l e t h a l i t y d a t a are a v a i l a b l e for 2 , 7 - D C D D , H C D D , OCDD.

and

H C D D ( s a m p l e c ) k i l l e d 1 of 2 a n d 0 of 2 m a l e rats g i v e n o r a l

doses of 100 a n d 10 m g / k g , respectively.

N o deaths o c c u r r e d i n f o u r

m a l e m i c e g i v e n 2.0 g r a m s / k g of 2 , 7 - D C D D ( s a m p l e a or b ) o r a l l y or i n t w o f e m a l e rats g i v e n 1 g r a m / k g ( s a m p l e a ) .

F o r O C D D , o r a l doses

of 1 g r a m / k g ( s a m p l e d ) to five female rats d i d not cause d e a t h ; i n f o u r m a l e m i c e , doses of 4 g r a m s / k g also d i d not cause d e a t h . toxicity were OCDD.

observed

i n a n i m a l s treated

with

either

N o signs of

2 , 7 - D C D D or

T h e o n l y s i g n of t o x i c i t y a m o n g animals treated w i t h

HCDD

was loss of b o d y w e i g h t . W h i l e a l l species lost b o d y w e i g h t f o l l o w i n g treatment w i t h 2,3,7,8T C D D , other signs of t o x i c i t y w e r e species d e p e n d e n t .

Ascites w a s seen

i n m i c e . A n o r e x i a , d e h y d r a t i o n , depression, e m a c i a t i o n , i n t e s t i n a l h e m o r rhage, a n d a l o p e c i a w e r e seen i n dogs.

C e r t a i n r a b b i t s treated i n t r a -

p e r i t o n e a l l y w i t h 2 , 3 , 7 , 8 - T C D D d e v e l o p e d s k i n lesions t y p i c a l of those associated w i t h acnegens. Rabbit Eye Irritation. I n s t i l l a t i o n of the c h l o r o d i b e n z o d i o x i n s i n t o the c o n j u n c t i v a l sac caused slight, transient p a i n a n d c o n j u n c t i v a l i n flammation,

i n i t i a l l y . T r e a t m e n t w i t h 2 , 3 , 7 , 8 - T C D D w a s associated w i t h

d e l a y e d c o n j u n c t i v a l chemosis 1 3 - 2 2 days later. B y d a y 27, the chemosis h a d s u b s i d e d , b u t the r i m of the e y e l i d w a s t h i c k e n e d a n d

encrusted.


60

CHLORODIOXINS

Table II. Species, Sex

Administration

b

R a t , male

A N D

F A T E

Lethality of 2,3,7,8-

Time of Death, Days Postadministration

b

Oral

9-27

Oral Oral Oral Oral Skin Intraperitoneal

13-43 5-34 9-42 6-39 12-22 6-23

Dogs, male

Oral

9-15

D o g s , female

Oral

—

R a t , female Guinea pig, male G u i n e a p i g , female Rabbit, mixed


ORIGIN

Responses to individual doses are given in those cases in which an LD o could not be calculated. The LD o for oral administration to rabbits was calculated using the method of Litchfield and Wilcoxon (9) ; the remaining values were calculated using the Weil modification of the method of Thompson (14, 15). a

5

5

I n r a b b i t s t r e a t e d w i t h H C D D , the r i m of the e y e l i d w a s e n c r u s t e d 27 days after treatment.

N e i t h e r c o r n e a l i n j u r y nor iritis w a s o b s e r v e d i n

a n y of the a n i m a l s f o l l o w i n g i n s t i l l a t i o n of the c h l o r o d i b e n z o d i o x i n s i n the c o n j u n c t i v a l sac. Acnegenic

Response.

Both

2,3,7,8-TCDD

and

HCDD

produced

c h l o r a c n e i n the r a b b i t ear bioassay as i n d i c a t e d b y t h e f o r m a t i o n of come dones.

S o l u t i o n s of 2 , 3 , 7 , 8 - T C D D

(sample

c o n c e n t r a t i o n f r o m 0.04 μ%/ml to 400 fig/ml

c)

i n benzene

ranging in

p r o d u c e d a p o s i t i v e response

w i t h severity i n c r e a s i n g w i t h c o n c e n t r a t i o n .

A n e g a t i v e response

was

o b t a i n e d w i t h a s o l u t i o n of 0.004 /xg/ml. I n contrast, a c h l o r o f o r m solu t i o n of 1 , 2 , 3 , 4 - T C D D , 50 ^g/m\ With H C D D

(samples

d i d not p r o d u c e a p o s i t i v e response.

a, b , c, a n d d ) , a response w a s p r o d u c e d b y

solutions of 10 to 50 pg/m\

i n chloroform and dimethoxyethane.

Chloro

f o r m extracts f r o m 1 0 % suspensions of 2 , 7 - D C D D or O C D D w e r e nega t i v e , i n d i c a t i n g that these h a v e a l o w o r d e r or p o s s i b l y no

acnegenic

activity. Teratogenicity.

The

effects of c h l o r o d i b e n z o d i o x i n s o n

maternal

a n d f e t a l b o d y measurements, i n c i d e n c e of f e t a l resorptions, a n d a n o m alies are g i v e n i n T a b l e s I I I a n d I V .


7.

SCHWETZ

E T

Tetrachlorodibenzo-^-dioxin LD , b0

a

Dose, mg/kg

mg/kg

0.022


61

Toxicologij of Chlorinated Dioxins

A L .

Number Deaths/ Number Treated

0.008 0.016 0.032 0.063

0/5 0/5 10/10 5/5

0.032 0.063 0.126 0.252 0.500

0/5 2/5 2/5 2/5 3/5

0.30 3.00

0/2 2/2

0.03 0.10

0/2 0/2

0.045 (0.030-0.066) 0.0006 (0.0004-0.0009) 0.0021 (0.0015-0.0030) 0.115 (0.038-0.345) 0.275 (0.142-0.531)

All samples used are from 2c in 2d in Table I. b

2,7-DCDD.

I except guinea pig, female, which is from

Rats treated w i t h 100 m g / k g / d a y o n days 6 t h r o u g h 15

of gestation g a i n e d s l i g h t l y m o r e w e i g h t d u r i n g p r e g n a n c y t h a n controls b u t s h o w e d no t o x i c i t y . T h e r e w a s n o effect o n f e t a l b o d y measurements, or i n c i d e n c e of resorptions, or gross, soft tissue, or skeletal a n o m a l i e s . HCDD.

A d m i n i s t r a t i o n of 0.1-100 μg H C D D / k g / d a y w a s associated

w i t h a dose-related decrease i n m a t e r n a l w e i g h t - g a i n d u r i n g G r o s s n e c r o p s y e x a m i n a t i o n at the t i m e of cesarean

gestation.

section

revealed

e v i d e n c e of m a t e r n a l t o x i c i t y o n l y a m o n g d a m s r e c e i v i n g 100 ttg/kg/day ( p a l e , f r i a b l e l i v e r 3/20 d a m s ; serous a t r o p h y of fat, 1/20 d a m s ) . T r e a t m e n t w i t h 10 or 100 ^g H C D D / k g / d a y w a s h i g h l y l e t h a l to fetuses d u r i n g late gestation.

W h i l e the i n c i d e n c e of e a r l y resorptions

was not i n c r e a s e d at a n y dose l e v e l of H C D D

( 5 - 7 % i n the t r e a t e d vs.

7 % i n the c o n t r o l s ) , there w a s a significant increase i n late resorptions (0%

at 0.1 /xg/kg/day to 7 9 % at 100 ^ g / k g / d a y ) .

T h e weight and

l e n g t h of s u r v i v i n g fetuses w e r e s i g n i f i c a n t l y decreased. A significant increase i n t h e i n c i d e n c e of f e t a l soft-tissue a n d skeletal anomalies w a s seen f o l l o w i n g t r e a t m e n t of p r e g n a n t rats w i t h H C D D at the 100 μg/kg/day

dose l e v e l . T h e i n c i d e n c e of cleft palate, subcutaneous

e d e m a , vertebrae w i t h s p l i t or u n f u s e d centra, a n d s p l i t sternebrae w a s s i g n i f i c a n t l y greater t h a n a m o n g c o n t r o l litters or the c o n t r o l f e t a l p o p u -


62

CHLORODIOXINS

Table III.

„ Compound s i

(Sample)

Ί

a


Maternal Weight Gain on Gestation Days —

ΛΤ

Litters 30

2,7-Dichlorodibenzo-p-dioxin, 100.0 7 Hexachlorodibenzo-p-dioxin, 0.1 19 1.0 19 10.0 18 100.0 19

A N D

FATE

Effect of Treatment with Chlorinated Measurements and the

„ No. of

Control

ORIGIN

6

6-13

13-21

6-21

36 =fc 2

101 ± 6

137 =fc 8

(d), mg/kg/day 31 =t= 1 122 (c), Mg/kg/day 28 =b 2 102 27 =fc 3 99 22 =1= 3 ' 97 6 ± 2 ' 13

O c t a c h l o r o d i b e n z o - p - d i o x i n , (d), mg/kg/dav 100.0 12 32 ± 2 500.0 17 35 =h 3

± 4

152 ±

5

=fc 5 =fc 5 =fc 5 ± 7

130 126 119 19

5 6 6 9'

f

100 =fc 8 115 ± 4

=±= ± =fc =fc

131 =fc 7 150 =fc 5

Sample identified in Table I; administered on days 6-15 of gestation as a corn oil: acetone (9:1) solution. Mean ± S.E. Mean of litter means d= S.E. a

b

c

Table I V .

Effect of Treatment with HexachlorodibenzoPQ/ty/day on Days

Soft Tissue Anomalies Cleft Palate

0.1

0 Ρ L

a b

0 0

(0/156) (0/28)

1 5

(1/104) (1/19)

0.6 4

(1/156) (1/28)

0 0

(0/104) (0/19)

Dilated Renal Pelvis

Ρ L

Subcutaneous E d e m a

Ρ L

5 21

(8/156) (6/28)

6 32

(6/104) (6/ 19)

Ρ L

6 19

(9/158) (5/27)

2 5

(2/103) (1/19)

(1/158) (1/27)

1 5

(1/103) (1/19)

(18/158) (12/27)

28 74

(29/103) (14/19)

Skeletal Anomalies Split Vertebral Centra S p l i t Sternebrae

Ρ L

D e l a y e d Ossification of Sternebrae

Ρ L

Incidence among fetal population; % examined). α

0.6 4 11 44

(number of affected fetuses/number


7.

SCHWETZ

E T

A L .

63


Dibenzo-/>-dioxins on Maternal and Fetal Body Incidence of Fetal Resorptions Fetal Body Weight,


9

Fetal Crown-Rump Length, mm

% Fetal Resorptions

c

Population

d

Litter

e

5.68 =b 0.05

44.5 d= 0.1

7

(22/337)

47

(14/30)

5.80 dz 0.09

44.2 d= 0.2

6

(5/86)

57

(4/7)

5.73 5.93 5.12 3.65

43.8 45.7 42.6 35.2

dz d= =b db

0.04 0.16 0.05' 0.28'

5.73 d= 0.09 5.69 =h 0.05

± =b d= ±

0.1 0.5 0.2' 0.7'

43.6 db 0.4 44.5 ± 0.2

5 (10/217) 9 (20/218) 2 5 ' (57/229) 85 ' (194/227) 8 5

(11/131) (9/199)

47 (9/19) 74 (14/19) 9 4 ' (17/18) 1 0 0 ' (19/19) 42 41

(5/12) (7/17)

% (number resorptions/number implantations). % (number litters with at least one resortion/number litters). Significantly different from control by an Analysis of Variance and Tukey's test (measurements) or the 2 X 2 contingency table (resorptions), P

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