Occupational Exposure to Polychlorinated Dioxins and Dibenzofurans

20

O c c u p a t i o n a l E x p o s u r e to P o l y c h l o r i n a t e d

Downloaded by NORTH CAROLINA STATE UNIV on January 7, 2013 | http://pubs.acs.org Publication Date: April 2, 1981 | doi: 10.1021/bk-1981-0149.ch020

Dioxins

and D i b e n z o f u r a n s

CHRISTOFFER RAPPE Department of Organic Chemistry, University of Umeå, S-901 87 Umeå, Sweden HANS RUDOLF BUSER Swiss Federal Research Station, CH-8820 Wädenswil, Switzerland Polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs) are two series of tricyclic aromatic compounds which exhibit similar physical and chemical properties. Some of these compounds have extraordinary toxic properties and were the subject of much concern. They have been involved in accidents like the Yusho accident in Japan 1968 (1), the intoxication at horse arenas in Missouri, USA in 1971 (2) and the accident near Seveso, Italy in 1976 (3). The chemical structures and the numbering of these hazardous compounds are given below.

y The number of chlorine atoms in these compounds can vary between one and eight. In all, there are 75 PCDD and 135 PCDF isomers as shown in Table I, ranging from the mono- to the octachloro compounds. A large number of individual PCDD and PCDF isomers have been synthesized by various methods and characterized mainly by gas chromatography - mass spectrometry (4-7). As a general trend in both series, solubility in most solvents and volatility decrease with increasing number of chlorine atoms. The first synthesis of TCDD was reported by Sandermann et al (_8) using catalytic chlorination of the unchlorinated dioxin. TCDD has also been prepared in good yields by the dimerization of 2,^,5-trichlorophenol salts (9.). PCDDs with symmetrical chlorine substitution (one, two, three or four chlorines in each carbon ring) were prepared by the pyrolyses of different chlorophenates. Unsymmetrically substituted 0097-6156/81/0149-0319$05.75/0 © 1981 American Chemical Society

In Chemical Hazards in the Workplace; Choudhary, G.; ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

CHEMICAL HAZARDS IN THE

320

Table I . PCDFs.

P o s s i b l e number o f p o s i t i o n a l isomers o f PCDDs and

Chlorine substitution


WORKPLACE

Number o f isomers PCDDs PCDFs 2 10 1U 22 Ik 10 2 1 75

monoditritetrâpent ahexaheptaocta-

k 16 28 38 28 16 k 1 135

PCDDs were prepared by a mixed p y r o l y s i s . In t h i s case, the a d d i t i o n a l l y expected s y m m e t r i c a l l y s u b s t i t u t e d PCDDs were a l s o f o r med, see Figure 1 (U.,5.). The most t o x i c and most e x t e n s i v e l y s t u d i e d PCDD and PCDF isomer i s 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 , 8 - t e t r a -CDD or TCDDÎ. The m e l t i n g p o i n t i s 305~3θ6° (10). No b o i l i n g p o i n t has been given f o r TCDD, and the v o l a t i l i t y must be q u i t e low, but i t can be analyzed by gas chromatography. Although TCDD i s l i p o p h i l i c , i t i s o n l y s l i g h t l y s o l u b l e i n most organic s o l vents and very s l i g h t l y s o l u b l e i n water. From a chemical p o i n t o f view TCDD i s considered t o be a s t a b l e compound, but due t o i t s extreme t o x i c i t y , i t s chemistry has not been f u l l y evaluated. However, i t undergoes s u b s t i t u t i o n r e a c t i o n s l i k e c h l o r i n a t i o n t o octa-CDD ( l l ) as w e l l as photo chemical d e c h l o r i n a t i o n (12,13). Thermally, TCDD i s q u i t e s t a b l e , and r a p i d decomposition occurs o n l y at temperatures above 750°C (1ÎLÏ. T o x i c i t y and Metabolism o f PCDDs and PCDFs There i s a pronounced d i f f e r e n c e i n b i o l o g i c a l and t o x i c o l o g i c a l e f f e c t s between d i f f e r e n t PCDD and PCDF isomers which i s c o n t r a d i c t o r y t o the chemical and p h y s i c a l p r o p e r t i e s of these compounds d i s c u s s e d above. The isomers w i t h the highest acute t o x i c i t y are 2,3,7,8-tetra-CDD, 1,2,3,7,8-penta-CDD, 1 , 2 , 3 , ^ , 7 , 8 - , 1 , 2 , 3 , 6 , 7 , 8 - and 1,2,3,7,8,9-hexa-CDD, 2 , 3 , 7 , 8 - t e t r a - C D F , 1 , 2 , 3 , 7 , 8 - and 2,3, +,7,8-penta-CDF and 2,3, +,6,7,8-hexa-CDF, see Figure 2. A l l these isomers have t h e i r f o u r l a t e r a l p o s i t i o n s s u b s t i t u t e d f o r c h l o r i n e , and they a l l have LTJC-Q values i n the range 1-100 ug/kg f o r the most s e n s i t i v e animal species (15~17)· The same isomers have been r e p o r t e d t o have the highest b i o l o g i c a l potency ( l 8 ) . Isomers o f PCDDs and PCDFs vary h i g h l y i n t h e i r acute t o x i c i t y and b i o l o g i c a l a c t i v i t y (15-19). A f a c t o r of 1 000-10 000 i

i



RAPPE

AND

BUSER

Polychlorinated

Dioxins and

Dibenzofurans

Figure 1. Formation of PCDDs by pyrolytic dimerization of chlorophenate


322

CHEMICAL HAZARDS IN THE WORKPLACE


can be found f o r so c l o s e l y r e l a t e d isomers as 2 , 3 , 7 » 8 - and 1,2,3,8-tetra-CDD. Metabolism o f TCDD. No metabolites o f TCDD have been i d e n t i f i e d so f a r . I t has r e c e n t l y been reported by Guenthner et al.(20) that TCDD can be metabolized by the mouse l i v e r cytochrome P-k^0 system t o r e a c t i v e intermediates, which e a s i l y bind c o v a l e n t l y to c u l l u l a r p r o t e i n s . I t i s suggested that t h i s extreme r e a c t i v i t y i n h i b i t s the formation o f normal metabolites l i k e phenols, d i h y d r o d i o l s , o r conjugated p r o d u c t s . ^ Following a s i n g l e o r a l dose o f C-TCDD i n r a t s , Rose et a l . (21I were able t o detect -^C a c t i v i t y only i n feces and not i n u r i n e . The h a l f - l i f e o f -^C a c t i v i t y i n the body was about 31 days and the major part o f the TCDD was stored i n l i v e r and f a t . A f t e r repeated o r a l doses the major route o f e x c r e t i o n was again found t o be f e c e s , but the u r i n contained 3-18JS o f the t o t a l ^ C a c t i v i t y . The h a l f - l i f e o f i ^ C a c t i v i t y i n these r a t s was about 2k days, and most o f TCDD was found i n l i v e r and f a t . The e x p e r i ments i n d i c a t e d that m a t e r i a l s other than TCDD c o n s t i t u t e d a s i g n i f i c a n t f r a c t i o n o f the l ^ C a c t i v i t y excreted i n the feces, but no metabolite was i d e n t i f i e d ( 2 1 ) . Van M i l l e r et a l . (22) reported on the t i s s u e d i s t r i b u t i o n and e x c r e t i o n o f 3H TCDD i n monkeys and r a t s . A marked d i f f e r e n c e was found i n the t i s s u e d i s t r i bution i n the two species. In monkeys, a l a r g e percentage o f the dose was l o c a t e d i n t i s s u e s that had a high l i p i d content, _i.e_. i n s k i n , muscle, and f a t ; whereas i n r a t s these t i s s u e s had much lower l e v e l s o f TCDD. Metabolism o f other PCDDs and PCDFs. Tulp and Hutzinger have studied the r a t metabolism o f a s e r i e s o f PCDDs- (23). 1- And 2-mono-, 2 , 3 - and 2 , 7 - d i - , l,2,U-trî, and 1,2,3,^-tetra-CDD are metabolized t o mono- and dihydroxy derivatives-, w h i l s t i n the cas^ i f the two monochloro isomers, a l s o s-ulphur c o n t a i n i n g metah i l i t e s - are excreted. I tfras^a l s o been shown that the primary hydroxylation e x c l u s i v e l y takes^ place i n the l a t e r a l p o s i t i o n s ( 2 - , 3—, 7 - arid/or 8^-posi.tionsr) i n the molecule. In none o f the experiments- metabolites^ r e s u l t i n g from a f i s s i o n o f the C^Q-C bonds were detected. No metabolites- were found from octa^CDD. The r e s u l t s are r a t i o n a l i z e d i n terms that the metabolism of the PCDDs occurs- mainly v i a 2,3-epoxides. In the octa-CDD as i n 2,3,7,8-tetra-CDD these p o s i t i o n s are blocked, consequently the r e a c t i o n i s l e s s l i k e l y t o take place or takes place at a h i g h l y reduced r a t e ( 2 3 ) . A s i m i l a r r e l a t i o n s i i i p between PCDF isomers r e t a i n e d and apparently excreted has been observed f o r p a t i e n t s with the Yusho disease, an i n t o x i c a t i o n by a r i c e o i l contaminated with PCBs and PCDFs^. The contaminated r i c e o i l and l i v e r s-amples from two o f the p a t i e n t s were analyzed and a l l the major PCDFs were i d e n t i f i e d . A comparison revealed that none o f t h e isomers r e t a i n e d had two v i c i n a l hydrogenated C-atoms i n any o f the two



20.

RAPPE AND BUSER

Polychlorinated

Dioxins

and

Dibenzofurans

323

C-rings o f the benzofuran system. Most o f these isomers had a l l t h e i r l a t e r a l p o s i t i o n s c h l o r i n a t e d . Contrary, a l l the PCDF i s o mers apparently excreted had two v i c i n a l hydrogenated C-atoms i n at l e a s t one of the two rings', and these unblocked p o s i t i o n s are i n v o l v e d i n the metabolism by forming epoxides, see Figure 3 (23). The data discussed here show a s t r i k i n g s i m i l a r i t y between the most t o x i c PCDD and PCDF isomers' and the isomers most e f f i c i e n t l y retained. Kuroki and Masuda have estimated that 0.37$ o f 2 , 3 , 6 , 8 -tetra-,a,QQ.6-O.Q3i o f 2 , 3 , 7 , 8 - t e t r a - and 0.9% o f the 2 , 3 , ^ , 7 , 8 -penta-CDF ingested were r e t a i n e d i n the l i v e r o f one o f the Yusho p a t i e n t s when he died kk months- a f t e r the use o f the r i c e o i l had been discontinued (2k\. A n a l y t i c a l Methods Due t o the extreme t o x i c i t y o f some o f the PCDDs and PCDFs, very s e n s i t i v e and h i g h l y s p e c i f i c a n a l y t i c a l techniques are r e quired. Detection l e v e l s i n b i o l o g i c a l and environmental samples should be orders o f magnitude below the usual d e t e c t i o n l i m i t s obtained i n p e s t i c i d e a n a l y s i s . Any a n a l y s i s at such low l e v e l s i s complicated by the presence o f a multitude o f other, p o s s i b l y i n t e r f e r i n g compounds. The best a v a i l a b l e separation techniques followed by h i g h l y s p e c i f i c d e t e c t i o n means have t o be used f o r an accurate determination of these hazardous compounds. The d i f ferent isomers o f PCDD or PCDF may vary s i n i f i c a n t l y i n t h e i r b i o l o g i c a l and t o x i c o l o g i c a l p r o p e r t i e s and t h e r e f o r e t h e i r sep a r a t i o n and i d e n t i x i c a t i o n becomes important. In recent years, many a n a l y t i c a l methods were developed f o r the a n a l y s i s o f PCDDs, PCDFs and e s p e c i a l l y 2,3,7,8-tetra-CDD i n environmental and i n d u s t r i a l samples, the most s p e c i f i c methods making use of mass spectrometry (25.). P r e r e q u i s i t e s f o r best anal y s e s are e f f i c i e n t e x t r a c t i o n and sample p u r i f i c a t i o n followed by good separation, u l t r a s e n s i t i v e d e t e c t i o n and - very d e s i r a b l y — confirmation. A technique f o r a n a l y z i n g i n d i v i d u a l PCDDs and PCDFs has been described and distrusted i n d e t a i l (26, 27, 28). It involves- one or two steps- by column chromatographic clean-up followed by h i g h - r e s o l u t i o n gas^chromatograplry separation u s i n g glass c a p i l l a r y columns and d e t e c t i o n and q u a n t i t a t i o n u s i n g mass spectrometry (mass chromatography and/or mass fragmentography). A r t i f a c t s u s u a l l y d i s t u r b the a n a l y t i c a l work at these extreme low concentration l e v e l s , but the r i s k can be minimized by a c a r e f u l i n s p e c t i o n o f the complete mas-s spectrum. For a c o r r e c t s t r u c t u r e assignment o f the PCDDs^, the low mass ions have shown to be u s e f u l (h). A d d i t i o n a l information can be obt a i n e d by a comparison o f the r e t e n t i o n times u s i n g h i g h — r e s o l u t i o n GC with authentic standards, but the number o f s y n t h e t i c standards is- s t i l l l i m i t e d . This- a n a l y t i c a l technique has also been used f o r the separation o f the 22 tetra-CDD isomers (5.).



Hexa-CDFs

Penta-CDFs

U3.7,8-Penta-CDD 1.2.3A78-Hexa-CDD 123.6.78+1 e x a - C D D

CI 1.2.37.8,9-Hexa-CDD

Aéc

Figure 3.

1.2.3,4.78 -

Cl

2,3.4.7.8-

C»

m

a

2.3.7.8-

Isomers

1,2,3.7.8-Penta-CDF

CI 2.3A7,8-Penta-CDF

ci CI 2.3.4.6,7,8-He χ a - C D F

N

T

e

•

Occupational Exposure to Polychlorinated Dioxins and Dibenzofurans

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