SEPTEMBER/OCTOBER 1992 VOLUME 5, NUMBER 5 0 Copyright 1992 by t h e American Chemical Society
Perspectives Environmental Carcinogens That May Be Involved in Human Breast Cancer Etiology Karam El-Bayoumy Division of Chemical Carcinogenesis, American Health Foundation, Valhalla, New York 10595 Received July 16, 1992
Introduction Exposure to exogenous carcinogens is an accepted cause of various types of cancer in humans, but the carcinogens that may actually play a role in the etiology of breast cancer have not as yet been clearly defined. This perspective is based on literature data pertaining to the occurrence of carcinogens in the human environment and their relative tumorigenic effects in laboratory animals. This examination of the data purports to stimulate further research into the role of environmental carcinogens in the initiation and development of human breast cancer. It is estimated that there will be approximately 180 000 new cases of breast cancer in American women in 1992 and 46 000 deaths due to this disease (I). Breast cancer is second only to lung cancer as the leading cause of death from cancer in American women (1). A vast body of literature describes risk factors for breast cancer and proposes hypotheses for ita etiology based on epidemiologic and experimental studies (2, 3). Endogenous hormones are believed to play a significant role as are nutritional factors such as dietary fat and caloric intake (4-8). Interactions between dietary exposures and endogenous factors may be critical in modifying one's risk for breast cancer development (9). Other suspected etiologic factors include ethanol and cholesterol epoxide (10-13). Genetic predisposition is also likely to be of importance in the onset of breast cancer (14). Among exogenous stimuli, ionizing radiation is a known cause of breast cancer in humans (15-1 7). Most chemical carcinogensto which humans are exposed require metabolic activation to electrophilic intermediates that can bind to cellular macromolecules (18-21). Inter-
actions of these electrophiles with nucleophilic sites in DNA are considered of paramount importance in the carcinogenic process. Multiple genetic changes such as activation of oncogenes, or inactivation of tumor suppressor genes resulting from these DNA interactions, are now believed to be critical in the process of transforming a normal cell into a cancer cell (22). Thus, chronic exposure to trace amounts of chemical carcinogens in the diet, in polluted air, or in tobacco smoke can be important in the etiology of cancer in the presence of host factors that favor the transformation process. Bioassays in laboratory animals can provide important information on the role of chemicals in the induction of particular types of cancer. Mechanistic studies with these chemicals lead to insights into the nature of the DNA interactions associated with carcinogenesis. This information can be applied in examining human tissues, cells, or fluids to assess the role of specific carcinogens in cancer etiology (23). Thus, a better understanding of the ability of chemicals to induce mammary tumors in rodents may provide important leads toward understanding the role of environmental agents in human breast cancer. DMBA' and its derivatives, as well as several alkylnitrosoureas, are known to induce mammary tumors in rodents (24). The mechanisms by which these compounds 'Abbreviations: PAH, polycyclic aromatic hydrocarbons; NO*-PAH, nitro polycyclic aromatic hydrocarbons; AA, aromatic amines; HAA, heterocyclic aromatic amines; DMBA, 7,12-dimethylbenz[alanthracene; B[alP, benzo[a]pyrene; DB[a,l]P, dibenzo[a,llpyrene; PhIP, P-aminol-methyl-6-phenylimidazo[4,5blpyridine; 4-ABP, 4-aminobiphenyl; IQ, 2-amino-3-methylimidazo[4,5-flquinoline; AAF, 2-(acetylamino)fluorene; 1-NP, l-nitropyrene; 2-NP, 2-nitropyrene; 4-NP, 4-nitropyrene; l,SDNP, l,&dinitropyrene.
0 1992 American Chemical Society
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Chem. Res. Toxicol., Vol. 5, No. 5, 1992
El- Bayoumy Table I. Levels of Representative Mammary Carcinogens Present in Different Sourcesa compound
PAH :
source B [a1p HAA :
DB[a,l] P
%iH3 0 N+NH2
cookedfoodsb cigarettesmokeC urban aird W NdC NHH 2 3 combustion systemse IQ
PhlP
AA: 4-ABP
1 -NP
4-NP
1,E-DNP
Figure 1. Classes of environmental agents known to induce mammary tumors in rodents.
interact with cellular DNA, and the resulting oncogene activation, are fairly well understood (25). Both of these carcinogens have been widely used as model compounds in the study of factors potentially involved in breast cancer etiology (24);yet neither DMBA nor methylnitrosoureas occur in the human environment, or as a result of endogenous formation in humans. A thorough search of the series “Survey of Compounds Which Have Been Tested for Carcinogen Activity” up to 1990, and of the “IARC Monographs on the Evaluation of Carcinogenic Risks to Humans” published to date, reveals two main classes of chemical carcinogens in the human environment that have consistently induced mammary tumors in rodents, namely, polycyclic aromatic hydrocarbons (PAH)and aromatic amines (AA) (26,27). Related mammary carcinogens recognized more recently are the nitro polycyclic aromatic hydrocarbons (N02-PAH) and heterocyclic aromatic amines (HAA). Some representative compounds of these classes of chemicals are illustrated in Figure 1. Several halogenated hydrocarbons and azo dyes have also been shown to induce mammary tumors in rodents, as have certain other environmental chemicals such as butadiene (29-33). The doses of these compounds required to elicit mammary tumors were generally considerably higher, and the specificity for mammary tumor induction was less pronounced than that among the groups of compounds mentioned above. Some examples of environmental occurrence and mammary tumorigenicity of PAH, AA, HAA, and N02-PAH are discussed below to provide an assessment of their potential roles in human breast cancer induction.
Environmental Mammary Carcinogens Human PAH exposure comes from a wide variety of occupational, environmental, and dietary sources (34). PAH are products of combustion and pyrolysis and are common contaminants of processed food (35;cf. Table I). B[alP, a relatively strong carcinogenic PAH, and several
DBB[alP [a,l]P PhIP 1-200 20 400 2.2
NAf g
NA NA
15-69 16.4 NA NA
IQ 0.02-28 0.3 NA NA
4-ABP 1-NP NA 4 NA NA
0.4-11 h 70-100 28-84
Data are from the following references: B[alP and DB[a,l]P (21,35,36);PhIP and IQ (44);4-ABP (48);and 1-NP(53,63).* Values reported in ng/g. Values reported in ng/cigarette. Values reported in pg/m3. e Values reported in ppm (pg/g particulate). f NA, not available. 8 Present but not quantified. Was not found (detection limit, 1-10 ngicigarette).
other carcinogenic four- and five-ring PAH have also been found in cigarette smoke condensate as well as in other respiratory environments (21, 36). The presence in cigarette smoke of the highly potent mammary carcinogen DB[a,llP has been reported, but requires confirmation (37). While DB[a,llP could be present in other environmental sources, it would probably be a relatively minor contributor to the spectrum of PAH (21, 36, 37). A comparison of the tumorigenic potency toward rat mammary gland of B[alP and DB[a,llP, as representative environmental PAH, with that of the synthetic DMBA is presented in Table I1 (37-40; and earlier studies, cf. ref 24). The order of relative potency is as follows: DB[a,Z]P > DMBA > B[alP. Cavalieri and co-workershave assessed the activity of several other PAH as rat mammary tumorigens (41,421. Further studies are required to more clearly define the structural requirements associated with tumorigenicity of PAH in the rat mammary gland. If a person consumes 200 g of broiled steak per day, the daily intake of B[alP amounts to 10 pg, on the basis of analytical determination of 50 ppm B[a]P in charcoalbroiled steak (35). A smoker of 20 cigarettes per day inhales 0.4-0.8pg of B[alP daily (21,36). Daily exposure to B[alP via inhalation of ambient air may amount to 9-40 ng, while intake from drinking water may be 1 ng (43). Evidently, cooked foods are amajor source of B[alP ingestion (43). The possible presenceof DB[a,l]P in foods has not been examined. As is the case for PAH, exposure to environmental AA and HAA also occurs principally by ingestion of food and by inhalation of cigarette smoke. Cooked foods are responsible for higher levels of exposure to HAA than is cigarette smoke. More than 17 HAA have been identified in the pyrolysis products of amino acids and proteins and as a result of cooking foods (44-46). Among them, PhIP frequently occurs in the highest concentration; ita levels in fried beef can be as high as those of B[alP. Thus, exposure to PhIP and B[alP by eating cooked foods may be comparable. The contribution of cigarette smoke to PhIP exposure is relatively low (47). To our knowledge, levels of 4-ABP, as a representative AA, have not been determined in cooked foods;it is present at relatively low levels (approximately one-fourth of those of PhIP) in mainstream cigarette smoke, and at higher levels in the sidestream smoke of cigarettes (48). The tumorigenic potencies of PhIP and I&, as representative HAA, and 4-ABP, as a representative AA, in rat mammary carcinogenesis model systems are compared in Table I11 (49-52). AAF, a widely studied nonenvironmental AA, is included for comparison (24, 39). The differences in
Chem. Res. Toxicol., Vol. 5, No. 5, 1992 587
Perspectives
Table 11. Mammary Tumors Induced by Polynuclear Aromatic Hydrocarbons ~~
species and strain
comDd
source
DB[a,Z]P
cigarette smoke, urban air (?)
route
8 wk old female SD rats
total doselrat (pmol)
mammary tumor incidence (% )
8 8
100 100 0
37
2 200
5 67
38
8
100 17 10 100 88
intramammary
2
BbIP
DMBA
urban air, foods, cigarette smoke, combustion
8 wk old female SD rats
intramammary
urban air, foods, cigarette smoke, combustion synthetic
50 day old inbred virgin female LEW/MAI rats 8 wk old female SD rats
gavage (8 fractions) intramammary
2
synthetic
8 wk old female SD rats
gavage (once)
3.9 78
synthetic
8 wk old female SD rats
gavage (once)
19.5
ref 37
37 39 40
Table 111. Mammary Tumors Induced by Aromatic Amines and Heterocyclic Aromatic Amines
compd 4-ABP
source cigarette smoke
PhIP
foods, cigarette smoke foods, cigarette smoke synthetic
IQ
2-AAF
species and strain 6-8 wk old female SD rats (12 months) 6 wk old female SD rats 6 wk old female F344 rats female SD rats 6 wk old female SD rats
total doseirat (mmol)
route
mammary tumor incidence (%)
ref
dietary supplements
9-12
63
49
gavage dietary supplements (52 wks) 6 wk old gavage weekly (31 wks) gavage (once)
2.4 7-10 4.4 0.3-0.5
56 47 44 30
52 50 51,52 39
Table IV. Mammary Tumors Induced by Nitro Polynuclear Aromatic Hydrocarbons ~~~
~
compd 1-NP
4-NP 1,8-DNP 5-NAc
~
source urban air, foods, combustion urban air, foods, combustion urban air, foods, combustion urban air, foods, combustion urban air urban air, foods, combustion urban air, foods, combustion urban air, combustion
species and strain newborn female SD rats newborn female SD rats weanling female SD rats weanling female SD rats weanling female SD rats weanling female SD rats weanling female SD rats weanling inbred female Wistar rats
route gavage weekly for 16 wks sc injection weekly for 8 wks ip 3X weekly for 4 wks ig intramammary (direct injection) ip 3X weekly for 4 wks
'9.
dietary supplement 1% for 4 months
~~~
total doseirat (pmol) 800 250 16 16 12 16 16 121 x 103
mammary tumor incidence (% ) 63 31 30 46 82" 42 61 42
ref 67 66 80 80 69 80 80 68
In this bioassay 1-NP and 2-NP were inactive.
experimental protocols preclude a ranking of the tumorigenic potencies of the compounds in Table 111. However, cooked foods as a major source of HAA could make a significant cntribution to the exposure of humans to these mammary carcinogens. NOz-PAH are formed in combustion processes and are therefore widely distributed in the environment (53-58). For instance, 1-NP,a representative example of this class, has been detected in foods such as grilled chicken, grilled corn, mackerel, pork, beef, and tea (59). Levels of 1-NP in grilled chicken were found to range from 0.4 to 11nglg. 1-NP has also been detected in the extracts of emissions from diesel, gasoline, and airplane engines (60, 61). In urban atmospheres, the levels of 1-NP were 0.02-0.11 ngl m3 for a wide range of locations in the United States and worldwide. Levels of 2-NP and 4-NP in urban air appear to be comparable; however, they are much lower than those of 1-NP (62). In combustion systems, only 1-NP was detected. 1-NP was not detected in cigarette smoke (detection limit 1-10 nglcigarette) (63). Ohnishi et al. have calculated that exposure to nitropyrenes by oral intake is higher than by inhalation of air that is polluted with diesel engine exhaust (64). Thus, food appears to be the most significant source of N02-PAH exposure. While simultaneous exposure to PAH and nitrogen oxide gas appears to lead to endogenous formation of N02-PAH
(65),further studies are required to verify this finding. The carcinogenicpotencies toward the rat mammary gland of representative N02-PAH are compared in Table IV: all of them occur in the environment and induce mammary tumors independent of the route of administration (6669).
Epilogue On the basis of available data, exposure to PAH, NOZPAH, and HAA through cigarette smoking appears to be far lower than exposure through the diet. This is consistent with the general observation that smoking is not related to human breast cancer (70),although involuntary inhalation of tobacco smoke was implicated as a possible initiator of breast cancer in one study (71). On the basis of the levels of PAH, N02-PAH, and HAA in polluted air, it can be proposed that the latter is also a minor source of exposure. Cooked foods are the major source of exposure to all of these agents, except perhaps for 4-ABP. Reviews by Lijinsky, Felton, and Adamson, have described modifications of cooking practices that can reduce exposure to HAA and PAH (35,44,45).Modified cooking procedures are also expected to reduce levels of N02-PAH (64). However, a detailed analysis of N02-PAH in cooked foods has not yet been conducted. On the basis of available data, it has been hypothesized that PhIP, a representative
588 Chem. Res. Toxicol., Vol. 5, No. 5, 1992
El- Bayoumy 200 umol
1,BDNP
1-NP
IO
PhlP
4-ABP
B(a)P
Figure 2. Mammary tumor incidence following the administration of environmental agents. Compounds were given by either gavage (l,&DNP, 1-NP, IQ, B[a]P) or in the diet (PhIP, 4-ABP) a t the doses shown. 2 umol
1-NP
2-NP
4-NP
B(a)P
DB(a,l)P
Figure 3. Mammary tumor incidence following intramammary administration of environmental agents a t the doses shown.
HAA, is involved in human breast cancer etiology (44). Because of their presence in the environment and relatively strong carcinogenic potencies, an equally valid case can be made for PAH and N02-PAH. Therefore, a thorough evaluation of these different classes of compounds as potential human breast carcinogens needs to be undertaken. To assess risks associated with human exposure to environmental mammary carcinogens, it is essential to initially determine their relative carcinogenic potency in rodents under identical conditions. Unfortunately, experiments described in the literature have divergent protocols, which prevent direct comparisons. However, in order to make some use of existing data, a comparison was made of tumor incidence obtained with compounds of different classes in assaya with similar routes of administration such as gavage or dietary supplement (Figure 2). The differences in dosage, diets, and strains of rats in previous studies make it impossible to rank each agent according to its true carcinogenic potency. At best, assumptions can be made by considering the following: (1)a linear dose-response relationship for each compound administered and (2) that the response of weanling rats is similar to that of 6-week-old rats. With these assumptions, the order of carcinogenicpotency would be as follows: l,&DNP> 1-NP>> B[a]P > IQ N PhIP. Usingadifferent route of administration (i.e., intramammary, direct injection under each nipple) and a similar set of assumptions, another comparison can be made (Figure 3). In this case, the order of carcinogenic potency would be as follows: DB[a,ll P >> 4-NP > B[a] P N 1-NP N 2-NP. Clearly, further animal studies are needed to establish more reliable comparative data. Another approach is to examine the combined effects of multiple agents belonging to the same or to different classes of carcinogens. For example, when HAA were
mixed in the diet at levels comparable to those encountered by humans and given to rats, tumor incidences suggested that the effect of simultaneous administration of multiple carcinogens was not merely additive (72). This, too, will require further studies. More knowledge about human intake and metabolism of PAH, NO*-PAH, and HAA needs to be gathered to enable us to understand how these compounds may function as human breast carcinogens. Development of biochemical markers for these agents is an exciting area of research (23). Although refinement and further development are still needed, sensitive analytical methods are available to monitor protein adducts, DNA adducts, and urinary metabolites of PAH, AA, and HAA after human exposure (44, 73-75). Similar studies on NOzPAH are lacking. DNA adducts are potentially the most accurate markers that not only reflect metabolism and uptake but also could provide knowledge of possible risks. Such adducts could be detected in human blood or in target cells or tissues obtained during surgical procedures or autopsies. Putative PAH-DNA adducts have been detected in human mammary epithelial cells by means of the 32P-postlabeling technique; however, none of these potential adducts corresponded to those derived from B[alP, and their structures are unknown (76). Adduct markers derived from HAA and N02-PAH should be useful for quantitatively assessing human exposure to these agents. DNA adducts derived from representative HAA have already been reported in the literature (44). Representative DNA adducts derived from nitroreduction and ring oxidation of nitrated pyrenes are also available (7779). In future studies on human exposure, these markers should provide the epidemiologist with a potentially powerful risk assessment tool.
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