_-
Critical Reviews In
Carcinogenicity of Polyhalogenated Biphenyls: PCBs And PBBs Eric M. Silberhorn, Howard P. Glauert, and Larry W. Robertson
Critical Reviews in Toxicology Downloaded from informahealthcare.com by University of Auckland on 11/10/14 For personal use only.
ABSTRACT Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) are compounds whose physicallchemical properties led to their widespread commercial use. Although their production has been banned or severely limited in most countries since the 1970s, the persistence and stability of these compounds have resulted in a worldwide distribution, especially of PCBs. PBB contamination is limited principally to the state of Michigan, where a series of tragic errors eventually resulted in the accumulation of residues in livestock and the general human population. Long-term exposure to PCBs and PBBs in animals has been associated with the induction of neoplastic nodules in the liver and in some cases hepatocellular carcinoma. This review discusses the role of PCBs and PBBs in the process of carcinogenesis. The mutagenicity/genotoxicity of these compounds, as well as their initiatiodpromotion potential is discussed. The epidemiology of PCB and PBB exposure is reported along with an estimation of the risk of cancer to humans. Finally, possible molecular mechanisms of action are suggested for polyhalogenated biphenyls in cancer development.
1. INTRODUCTION Polychlorinated biphenyls (PCBs) have been commercially manufactured since 1929 for a variety of applications, including use as dielectrics in transformers and capacitors and as cooling fluids i n hydraulic systems. PCBs have also been used in the formulation of lubricating and cutting oils, in pesticides and flame retardants, and as plasticizers in paints, copying paper, adhesives, sealants, and plastics.285Apart from the suitability of PCB. for a number of commercial applications, their stability (i.e., resistance to chemical and biological breakdown) contributed to their widespread commercial use. Unfortunately, the stability and persistence of these compounds have also resulted in the worldwide distribution of PCBs in the environment: the global distribution of PCBs was first recognized and reported in 1066 by Jensen."' The production of PCBs peaked in I970 and declined steadily thereafter as many countries throughout the world banned their use or limited their production. ''Ic Although only limited commercial manufacture of PCB continues (e.g , in Czechoslovakia), these compounds remain in OUT environment and represent a potential human health hazard
440
PCBs are manufactured commercially by the chlorination of biphenyl. The number of chlorine atoms introduced into the biphenyl molecule and their placement determines the structure of each PCB (Figure 1). There are 209 possible PCB congeners or homologs. lsomeric PCBs are those thdt have the same molecular weight. For example, there are 46 different isomeric pentachlorobiphenyls, 42 hexachlorobiphenyls, etc. (see Table 1). Commercial PCB formulations are not composed of a single congener, but rather are complex mixtures of many individual PCBs. Aroclor 1242, for example, a PCB formulation manufactured by Monsanto Chemical Company, contains 42% chlorine by weight and is composed of 1% monochlorobiphenyls, 13% dichlorobiphenyls, 45% trichlorobiphenyls, etc. (Table 2). As more chlorine is introduced, the % weight of chlorine increases as does the average number of chlorine atoms per biphenyl. Commercial formulations vary in chlorine content and have different physical characteristics that suit them for their various applications. Whereas most individual PCBs are solids at room temperature, commercial PCB formulations are viscous liquids or sticky resins due to melting point depression. l o ' Although attention has been focused on PCBs as a result of their persistence and worldwide distribution, two major human poisoning incidents have occurred involving these industrial chemicals. In both cases, PCB-contaminated rice oil was the vehicle for human intoxication, which occurred in 1968 in Japan (known as Yusho) and in 1979 in Taiwan (known as Yu-Cheng). Information on these poisoning episodes may be ~~ and S h a p i r ~ ,and ' ~ ~Kimfound in K u r a t s ~ n e , 'Kuratsune brough and Jensen, I3O In contrast to the PCBs, polybrominated biphenyl (PBB) formulations were minor industrial products used as fire retardants. About 5 million kg of PBBs were commercially produced during the period 1970 through 1975, primarily by Michigan Chemical Corporation, St. Louis, MI.166The com-
E. M. Silberhorn received B.S. and M.P.H. degrees from the University of Michigan in Ann Arbor. Mr. Silberhom is a Doctoral Candidate and Research Assistant at the Graduate Center for Toxicology at the University of Kentucky in Lexington. H. P. Glauert received an A.B. degree from the University of Missouri in Columbia, and a Ph.D. degree from Michigan State University in East Lansing. Dr. Glauert is currently an Assistant Professor in the Department of Nutrition and Food Science, and the Graduate Center for Toxicology at the University of Kentucky in Lexington. L. W. Robertson received a B.A. degree from Stetson University in Deland, Florida; a M.S. degree from the University of Florida in Gainesville; M.P.H. and Ph.D. degrees from the University of Michigan in Ann Arbor. Dr. Robertson is currently an Associate Professor of Toxicology in the Graduate Center for Toxicology at the University of Kentucky in Lexinaton.
Volume 20. Issue 6
Toxicology mercial product fireMaster@ BP-6 is composed primarily of hexabromobiphenyls (see Table 3) and has the physical form of light brown chunks or flakes. A ground-up form of fireMasteP BP-6, which contained 2% calcium silicate as an anticaking agent, white or off-white in appearance, was sold under the tradename fireMaster@FF-1 .66 It was the latter product that was involved in the Michigan PBB episode. In 1973, a series of tragic errors occurred that focused national attention on this minor product. An undetermined number of bags of fireMaster@FF-1 were included in shipments of magnesium oxide and were delivered to a large feed mill near Battle Creek, MI, where fireMaster,@mistaken for magnesium oxide, was mixed directly into animal feeds. Two periods of the direct addition of fireMaster@to animal feed were identified: AugusVSeptember 1973 and MarcWApril 1974. Feed manufactured subsequently was also contaminated by virtue of coming into contact with contaminated mixing equipment, bins, augers, and trucks. PBBs were also transported via dust throughout the feed mill. The distribution of highly contaminated feed as well as the subsequent distribution of crosscontaminated feed ultimately resulted in the widespread contamination of the food hai in,'^^^'^' and PBB residues were detected in wildlife and the human population of Michigan. PBBs have been identified in human blood, fat, and breast milk. 6 1 Most scientific evaluations have not determined that commercial PBBs or PCBs are particularly acutely toxic, but be-
4'
-
5
6
6'
5'
FIGURE 1. Biphenyl structure with sites of possible halogen
Critical Reviews in Toxicology Downloaded from informahealthcare.com by University of Auckland on 11/10/14 For personal use only.
substitution.
Table 1 Number of Possible Isomers of Halogenated Biphenyls such as PCBs or PBBs Halogen substitution
Number of possible isomers
MonoDiTriTetraPentaHexaHeptaoctaNonaDeca-
3 12 24 42 46 42 24 12
3
-1
Total
209
Table 2 Molecular Weight, CI Content, and the Chlorobiphenyls Present in Commercial PCB Preparations % in Kanechlor'
% in Clophenb
% in Aroclor'
~
Chlorobiphenyl Monochlorobiphenyls Dichlorobiphenyls Trichlorobiphenyls Tetrachlorobipheny 1s Pentachlorobiphenyls Hexachlorobiphenyls Heptachlorobiphenyls Octachlorobiphenyls Nonachlorobiphenyls % CI by weight Approximate molecular weight a
1242 1 13 45 31 10
-
40-42 26 1
1248
1 21 49 21 2
48 288
1260
A 30
A 60
300
400
-
-
-
-
-
-
-
-
1254
1 15 53 26 4
52-54 327
20 52 22 3 1
12 42 38
-
-
-
4 W 2 26 1
60 312
4-2 26 1
-
I 1 60 372
1 16 51 28 4
17 60 23 1
3 33 44 16
500
-
5
5 26 55 13
-
-
-
-
-
-
48 288
52-54 327
Aroclor is the commercial name for PCB mixtures produced by Monsanto Company, St. Louis, MO (Brinkman and de K o and ~ ~ manufacturer's specifications as cited in Hutzinger et a! . I o 1 ) . Clophen is the commercial name for PCB mixtures produced by Bayer, Leverkusen, FRG (Schulte and M a l i s ~ h These . ~ ~ ~compositional ,~~~ data vary slightly from those reported by Schaeffer et aL2"). Kanechlor is the commercial name for PCB mixtures produced by Kanegafuchi Chemical Company, Ltd. Osaka, Japan (Ito et al.'Oh).
1990
~
44 1
Critical Reviews In
__
Table 3 Composition of fireMaster@BP-6 and fireMaster@ FF-1 No."
BP-6b 1%)
Structure
FF-1'
Dhromobtpheny 1s
Critical Reviews In
Carcinogenicity of Polyhalogenated Biphenyls: PCBs And PBBs Eric M. Silberhorn, Howard P. Glauert, and Larry W. Robertson
Critical Reviews in Toxicology Downloaded from informahealthcare.com by University of Auckland on 11/10/14 For personal use only.
ABSTRACT Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) are compounds whose physicallchemical properties led to their widespread commercial use. Although their production has been banned or severely limited in most countries since the 1970s, the persistence and stability of these compounds have resulted in a worldwide distribution, especially of PCBs. PBB contamination is limited principally to the state of Michigan, where a series of tragic errors eventually resulted in the accumulation of residues in livestock and the general human population. Long-term exposure to PCBs and PBBs in animals has been associated with the induction of neoplastic nodules in the liver and in some cases hepatocellular carcinoma. This review discusses the role of PCBs and PBBs in the process of carcinogenesis. The mutagenicity/genotoxicity of these compounds, as well as their initiatiodpromotion potential is discussed. The epidemiology of PCB and PBB exposure is reported along with an estimation of the risk of cancer to humans. Finally, possible molecular mechanisms of action are suggested for polyhalogenated biphenyls in cancer development.
1. INTRODUCTION Polychlorinated biphenyls (PCBs) have been commercially manufactured since 1929 for a variety of applications, including use as dielectrics in transformers and capacitors and as cooling fluids i n hydraulic systems. PCBs have also been used in the formulation of lubricating and cutting oils, in pesticides and flame retardants, and as plasticizers in paints, copying paper, adhesives, sealants, and plastics.285Apart from the suitability of PCB. for a number of commercial applications, their stability (i.e., resistance to chemical and biological breakdown) contributed to their widespread commercial use. Unfortunately, the stability and persistence of these compounds have also resulted in the worldwide distribution of PCBs in the environment: the global distribution of PCBs was first recognized and reported in 1066 by Jensen."' The production of PCBs peaked in I970 and declined steadily thereafter as many countries throughout the world banned their use or limited their production. ''Ic Although only limited commercial manufacture of PCB continues (e.g , in Czechoslovakia), these compounds remain in OUT environment and represent a potential human health hazard
440
PCBs are manufactured commercially by the chlorination of biphenyl. The number of chlorine atoms introduced into the biphenyl molecule and their placement determines the structure of each PCB (Figure 1). There are 209 possible PCB congeners or homologs. lsomeric PCBs are those thdt have the same molecular weight. For example, there are 46 different isomeric pentachlorobiphenyls, 42 hexachlorobiphenyls, etc. (see Table 1). Commercial PCB formulations are not composed of a single congener, but rather are complex mixtures of many individual PCBs. Aroclor 1242, for example, a PCB formulation manufactured by Monsanto Chemical Company, contains 42% chlorine by weight and is composed of 1% monochlorobiphenyls, 13% dichlorobiphenyls, 45% trichlorobiphenyls, etc. (Table 2). As more chlorine is introduced, the % weight of chlorine increases as does the average number of chlorine atoms per biphenyl. Commercial formulations vary in chlorine content and have different physical characteristics that suit them for their various applications. Whereas most individual PCBs are solids at room temperature, commercial PCB formulations are viscous liquids or sticky resins due to melting point depression. l o ' Although attention has been focused on PCBs as a result of their persistence and worldwide distribution, two major human poisoning incidents have occurred involving these industrial chemicals. In both cases, PCB-contaminated rice oil was the vehicle for human intoxication, which occurred in 1968 in Japan (known as Yusho) and in 1979 in Taiwan (known as Yu-Cheng). Information on these poisoning episodes may be ~~ and S h a p i r ~ ,and ' ~ ~Kimfound in K u r a t s ~ n e , 'Kuratsune brough and Jensen, I3O In contrast to the PCBs, polybrominated biphenyl (PBB) formulations were minor industrial products used as fire retardants. About 5 million kg of PBBs were commercially produced during the period 1970 through 1975, primarily by Michigan Chemical Corporation, St. Louis, MI.166The com-
E. M. Silberhorn received B.S. and M.P.H. degrees from the University of Michigan in Ann Arbor. Mr. Silberhom is a Doctoral Candidate and Research Assistant at the Graduate Center for Toxicology at the University of Kentucky in Lexington. H. P. Glauert received an A.B. degree from the University of Missouri in Columbia, and a Ph.D. degree from Michigan State University in East Lansing. Dr. Glauert is currently an Assistant Professor in the Department of Nutrition and Food Science, and the Graduate Center for Toxicology at the University of Kentucky in Lexington. L. W. Robertson received a B.A. degree from Stetson University in Deland, Florida; a M.S. degree from the University of Florida in Gainesville; M.P.H. and Ph.D. degrees from the University of Michigan in Ann Arbor. Dr. Robertson is currently an Associate Professor of Toxicology in the Graduate Center for Toxicology at the University of Kentucky in Lexinaton.
Volume 20. Issue 6
Toxicology mercial product fireMaster@ BP-6 is composed primarily of hexabromobiphenyls (see Table 3) and has the physical form of light brown chunks or flakes. A ground-up form of fireMasteP BP-6, which contained 2% calcium silicate as an anticaking agent, white or off-white in appearance, was sold under the tradename fireMaster@FF-1 .66 It was the latter product that was involved in the Michigan PBB episode. In 1973, a series of tragic errors occurred that focused national attention on this minor product. An undetermined number of bags of fireMaster@FF-1 were included in shipments of magnesium oxide and were delivered to a large feed mill near Battle Creek, MI, where fireMaster,@mistaken for magnesium oxide, was mixed directly into animal feeds. Two periods of the direct addition of fireMaster@to animal feed were identified: AugusVSeptember 1973 and MarcWApril 1974. Feed manufactured subsequently was also contaminated by virtue of coming into contact with contaminated mixing equipment, bins, augers, and trucks. PBBs were also transported via dust throughout the feed mill. The distribution of highly contaminated feed as well as the subsequent distribution of crosscontaminated feed ultimately resulted in the widespread contamination of the food hai in,'^^^'^' and PBB residues were detected in wildlife and the human population of Michigan. PBBs have been identified in human blood, fat, and breast milk. 6 1 Most scientific evaluations have not determined that commercial PBBs or PCBs are particularly acutely toxic, but be-
4'
-
5
6
6'
5'
FIGURE 1. Biphenyl structure with sites of possible halogen
Critical Reviews in Toxicology Downloaded from informahealthcare.com by University of Auckland on 11/10/14 For personal use only.
substitution.
Table 1 Number of Possible Isomers of Halogenated Biphenyls such as PCBs or PBBs Halogen substitution
Number of possible isomers
MonoDiTriTetraPentaHexaHeptaoctaNonaDeca-
3 12 24 42 46 42 24 12
3
-1
Total
209
Table 2 Molecular Weight, CI Content, and the Chlorobiphenyls Present in Commercial PCB Preparations % in Kanechlor'
% in Clophenb
% in Aroclor'
~
Chlorobiphenyl Monochlorobiphenyls Dichlorobiphenyls Trichlorobiphenyls Tetrachlorobipheny 1s Pentachlorobiphenyls Hexachlorobiphenyls Heptachlorobiphenyls Octachlorobiphenyls Nonachlorobiphenyls % CI by weight Approximate molecular weight a
1242 1 13 45 31 10
-
40-42 26 1
1248
1 21 49 21 2
48 288
1260
A 30
A 60
300
400
-
-
-
-
-
-
-
-
1254
1 15 53 26 4
52-54 327
20 52 22 3 1
12 42 38
-
-
-
4 W 2 26 1
60 312
4-2 26 1
-
I 1 60 372
1 16 51 28 4
17 60 23 1
3 33 44 16
500
-
5
5 26 55 13
-
-
-
-
-
-
48 288
52-54 327
Aroclor is the commercial name for PCB mixtures produced by Monsanto Company, St. Louis, MO (Brinkman and de K o and ~ ~ manufacturer's specifications as cited in Hutzinger et a! . I o 1 ) . Clophen is the commercial name for PCB mixtures produced by Bayer, Leverkusen, FRG (Schulte and M a l i s ~ h These . ~ ~ ~compositional ,~~~ data vary slightly from those reported by Schaeffer et aL2"). Kanechlor is the commercial name for PCB mixtures produced by Kanegafuchi Chemical Company, Ltd. Osaka, Japan (Ito et al.'Oh).
1990
~
44 1
Critical Reviews In
__
Table 3 Composition of fireMaster@BP-6 and fireMaster@ FF-1 No."
BP-6b 1%)
Structure
FF-1'
Dhromobtpheny 1s
