Is the role of the environment in carcinogenesis overestimated?

Medical

IS THE

Hypotheses

ROLE

OF THE

5:

5-14,

1979

ENVIRONMENT

IN CARCINOGENESIS

OVERESTIMATED?

Edward J. Calabrese, Division of Public Health, University of Massachusetts, U.S.A. 01003 Amherst, Massachusetts ABSTRACT The dominant role of the physical and chemical environment in the developAnalyses of the etiology of skin, bladder, ment of cancer is challenged. respiratory and gastric cancersare presented which demonstrate the considerable extent to which one's health status may modify the initiation and promotion of It is concluded that although environenvironmentally associated cancers. mental factors may initiate and/or promote 85 to 90 percent of all cancers this is misleading since it neglects the critical role of the individual's health status as a factor modifying carcinogenesis. Key Words:

carcinogenesis, heredity, nutrition, ultraviolet light. aryl hydrocarbon hydroxylase, arylamine, bladder cancer, skin cancer, gastric cancer, benzo(a)pyrenc,environment, dietary deficiencies. INTRODUCTION

Much has been written in both the scientific and lay press concerning the "fact" that 85 to 90 percent of all cancers are environmentally related (l-5). The concept of environmentally induced cancer is not new. In fact, it probably had its origin with the work of Sir Percival Pott on the occurrence of scrotal cancer in chimney sweeps in the later part of the 18th century (6). Numerous supportive examples have emerged durin g the subsequent 200 years to clearly demonstrate the role of the environment, both physical and chemical, as a factor in carcinogenesis (l-5). In the past decade considerable emphasis has been directed toward further clarifying the links between environment and cancer and developing policy to deal with this issue (7). In dealing with cancer, especially its causes, one is faced with more than a scientific problem but also with economic and political considerations. To a certain extent, the claim that a large percentage of human cancers are caused by environmentalfactorshas provided not only a focus but also a rallying point around which environmentalists, both professional and otherwise, may gather. Despite the fact that environmental factors may initiate and/or promote carcinogenesis, the claim that 85-90 percent of all cancers are environmentally related, while probably accurate, is truly misleading because it neglects the role of the individual's health status in such a situation. The response of the

5

individual to any environmental stressor depends not only on the type and quantity of toxic agents but also on the adaptive capacity of the individual. Consequently, the intention of this paper is to demonstrate the importance of one's health status as influenced by genetic and nutritional factors in affecting one's susceptibility to environmentally associated carcinogenesis. By so doing it is hoped that the popular and professional notions of environmental carcinogenesis will assume their proper perspective. To accomplish this objective five cases where it is generally acknowledged that an environmental factor (i.e. physical or chemical stressing agent) is responsible for initiating carcinogenesis will be specified. However, it will then be demonstrated how the frequency of these environmentally induced cancers within the population is dramatically affected by the health status of the individual. &le

1 - ultra-violet

induced skincancer as a function of racial ancestry -

Numerous studies have clearly demonstrated that midultraviolet radiation The evidence supporting the (250-320 nm) possesses carcinogenic activity. hypothesis that ultraviolet radiation may induce skin cancer is impressive,with a long history, stretching from the 1890's to the present (8-11). Evidence supporting the ultraviolet - skin cancer association has been derived from complementary areas of research, including animal studies and human epidemiological and clinical findings. For example: 1.

Animal experimentation (e.g. usually in mice)has often shown that skin cancer can be produced by repeated exposure to wavelengths between 250-320 nm,with 280-320 nm the most carcinogenic (12,13).

2.

Skin cancer develops most frequently on those portions of the body which have greatest exposure to the sunlight (e.g. the head, neck, arms, and hands) (14-16). These results are consistent with studies indicating a higher incidence of skin cancer in outdoor workers (17,18).

d.

Finally, for similar skin-types the incidence of skin cancer increases significantly as the latitude decreases (11,19). Thus, without clear that midultraviolet belaboring the point, it seems abundantly radiation is a causative agent in the development of many human skin cancers.

In a recent article Wynder and Gori (1) have commented that the most striking example which demonstrates the effect of environmental factors in carcinogenesis is the relationship of sunlight to skin cancer. However, it is equally well known that certain racial groups, particularly those of Celtic origin, are significantly more predisbnsed to the development of skin cancer than other whites. More specifically, those with little skin pigmentation, scattered freckles, light colored hair, blue or gray eyes and a tendency Furthermore, Negroes to sunburn easily are the most susceptible. and Orientals are considerably less susceptible than Caucasians (17,20-22). It has been noted that skin cancer is 45 times more common among in Honolulu, Hawaii (17). Other Caucasians as compared to non-Caucasians individuals, although less numerous, who are also predisposedto the development of ultraviolet induced skin cancer would include people with birth marks (e.g. moles),the elderly (14,15), those with genetic disorders such as occulocutaneous aibinism including both tyrosinase positive and negative phenotypes (23) 6

and those with xeroderma pigmentosum, which is characterized by a reduced capacity to repair DNA damaged by ultraviolet radiation (24,25). Consequently, genetic factors are exceptionally important in modifying the development of ultraviolet induced skin cancer. Example 2 - the role of heredity in the development- of bladder I___ cancer --__.Urinary bladder carcinomas make up the majority of cancers of the lower An estimated 30,000 new cases were predicted to have urinary tract epithelium. occurred in the U.S. during 1977 (26,27). Numerous studies have demonstrated that there is a strong association between human urinary bladder cancer and exposure to chemical agents in the general environment and certain occupations. The earliest report of an occupationally associated bladder cancer was uublished Forty-three by Rehn in 1895 (28) with workers at a German chemical dye plant. years later Hueber et al (29) were able to induce bladder cancers in dogs Over the subsequent years following exposures to the dye 2-amino-naphthalene. considerable epidemiological and toxicological evidence has emerged to substantiate these early observations that arylamines are bladder carcinogens (30,31). Thus, a number of high risk occupations have been recognized and include The chemical, dye, textile and rubber workers, painters, and hairdressers. extent to which occupation is associated with bladder cancer is highly variable (32-34) but thollght to range up to 60 percent (26). Furthermore, the occurrence of the human bladder carcinogen, 2_aminonapththalene, a product of tobacco pyrolysis, in the urine of heavy smokers clearly suggests additional risks of bladder cancer from environmental means (35). Despite the overwhelming evidence that environmental chemicals (e.g. arylamines) are causative agents in human bladder cancer,evidence also exists which implicates genetic susceptiblity to these carcinogenic agents. Carcinogenic arylamines must be bioactivated by enzyme systems within the host before the ultimate carcinogen is formed (30). Susceptibility to bladder carcinogenesis in the dog requires enzymatic activation via N-hydroxylation to proximate N-hydroxyarylamines (36). In contrast, species (e.g. guinea pigs) which lack the ability to N-hydroxylate arylnitrogen compounds do not develop arylamine induced bladder cancer (37). Other studies with dogs have revealed that when the N-hydroxyarlyamines become acetylated these substances become carcinogenic to the liver but cease their carcinogenicity to the bladder (38). Furthermore, the capacity to deacetylate carcinogenic acetylated arylamides is related to the development of bladder cancer (39). Thus, as Lower (26) has succintly concluded "N-hydroxylating enzyme systems can be viewed as components of activation pathways with respect to both arylamine bladder carcinogenesis and arylacetamide hepatocareinogenesis, while N-acetyltransferase enzyme systems can be viewed as components of activation pathways with respect to arylamine hepatocarcinogenesis and as components of detoxication pathways with respect to arylamine bladder carcinogenesis. Similarly. arylacetamide deacetylase enzyme systems can be viewed as components of detoxification pathways with respect to arylacetamide hepatocarcinogenesis and as components of activation pathways with respect to arylacetamide bladder carcinogenesis... it is probable that activating and detoxifying enzyme systems might also act as partial determinants of human susceptibility to b.Ladder scarcinogenesis by arylamines."

Humans differ in their capacity to regulate the activity of hepatic N-acetyltransferase enzyme systems according tomendelianratios (40). The net result with North American Caucasians is a 50:50 polymorphic distribution, with one group of individuals exhibiting either a slow or rapid acetyThe individuals with a slow capacity to acetylate have lation phenotype. been predicted to be at relatively greater risk to arylamine bladder cancer (26). Epidemiological investigations of occupationally exposed individuals Despite the need for are needed to test this hypothesis. epidemiological validation, the toxicological evidence clearly supports the position that one's genotype plays a potentially important role in modifying one's susceptibility to arylamine induced bladder cancer. Example 3 - genetic susceptibility to bronchogenic _-_to aromatic hydrocarbons such as benzo(a)py rene --

carcinoma following ---___ exposure

Kellermann et al (41) have reported that there are differences in susceptiThis differenbility to aromatic hydrocarbon induced bronchogenic carcinoma. tial susceptibility is a function not only of variations in environmental exposure but also in the capacity to activate the procarcinogen to the ultimate form via the action of mixed function oxidase enzymes like arylhydrocarbon hydroxylase (AHH). It is well known that individuals differ in their capacity to metabolize the procarcinogen, ben.zo(a)pyrene (BaP). Furthermore, individuals whoselymphocytes metabolize BaP via AHH at a high rate following exposure to inducers are suspected of having increased risk of lung cancer development following long term exposure to cigarette smoke. The activity of AHH is genetically regulated and has the phenotypic frequencies of 53% for low, 37% for intermediate and 10% for high inducibility. (41). In support of the hypothesis that the genetic capacity for inducing AHH is associated with the development of respiratory cancer, Kellermann et al (41) found that amongst groups with bronchogenic carcinoma those with intermediate and high AHH inducibility had 16 and 36 times greater risk of such cancers than the low group - assuming a risk of 1.0 in the low group. All the patients with bronchogenic carcinoma had smoked for 20-40 years with an average cigarette consumption of about two packages per day. Although three did not smoke cigarettes, two smoked lo-15 cigars per day while the third was a heavy pipe smoker. According to Calabrese (23), the work of Kellermann et al (41) strongly supports the hypothesis of Tokuhata (42) that Tokuhata (42) had noted susceptibility to lung cancer is partially inherited. that familial clustering could be separated from environmental factors and that both heredity and smoking are important factors affecting the incidence of bronchogenic carcinomas. Fxample 4 - the role of dietary vitamins A and B as factors in modifying hydrocarbon-induced cancer -

aromatic

In addition to genetic factors playing an important role in environmental carcinogenesis so too does the adequacy of one's diet. This has been widely noted (43) and recently emphasized by Wynder and Gori (1) who stated that one's diet is of considerable importance as a source of procarcinogens and as a modifying factor in the expression of carcinogenesis. Dietary adequacy muSt be viewed as one of several factors which contribute to the maintenance of one's adaptive capacity.

8

Considerable information has accumulated which indicates that dietary deficiencies of vitamin A enhance the development of epithelial cancers in animal models exposed to carcinogenic aromatic hydrocarbons. For example, Rowe and Gorlin (44) noted that in the hamster cheek pouch, which is lined with a thin squamous epithelium, vitamin A deficiency results in a higher incidence of squamous tumors after DMBA topiral treatment. Further research has indicated that the induction of squamous cell carcinomas in the uterine cervix and vagina of hamsters topically painted with DMBA was inhibited when 105 vitamin A palmitate was added to the olive oil employed as a vehicle for the carcinogen (45). Similar inhibitory responses were also noted in the occurrence of DMRA or BaP induced squamous cell tumors of the esophagous and forestomach when vitamin A palmitate was added to the carcinogen (45). These results are in fundamental agreement with other research (46,47) which demonstrated the inhibitory effect of dietary vitamin A on the development of epithelial tumors. More recently, epidemiological studies (48) have supported the vitamin A respiratory cancer relationship. For instance, a study of 8,000 men revealed that a relatively low dietary intake of vitamin A correlated with a relatively high incidence of lung cancer after matching men for similar smoking habits. Deficiencies of riboflavin have also been reported to enhance the carcinogenicity of polycyclic aromatic hydrocarbon compounds in similar fashion to the vitamin A deficiency (49-51). For example, riboflavin deficient mice are more susceptible to the carcinogenic effects of DMBA as compared to mice with normal riboflavin levels. &le 5 - gastric cancer and the protective effect of --___.--... vitamin C ~~.--.__-----Various epidemiological studies have demonstrated the existence of an inverse association between the incidence of gastric cancer and theconsumption of food high in vitamin C (52-55). Preliminary attempts to establish the toxirologica basis for this inverse association have recently been noted by Marquardt et al (56). These investigators reported that extracts of Japanese raw fish treated with nitrite, a common preservative, are mutagenic in the -_Salmonella -tsmurium --__test. However, when the extracts were treated with ascorbate, the mutagenic activity is prevented. The authors (56) suggest that these data support the hypothesis that the high incidence of stomach cancer among the Japanese (i.e. 10 times more frequent in Japan than the United States) may be due to specific dietary factors. Marquardt et al (56) thus concluded that vitamin C and foods rich in this essential micronutrient may be important as an early available means of gastric cancer prevention. CONCLUSIONS From the above examples it can be seen that one's adaptive capacity may be a critical factor affecting the development of environmentally related skin, bladder, respiratory and gastric cancers. In order to accurately assess the role of environmental factors in the process of carcinogenesis care should be taken to properly characterize the individual and/or group under study. By realizing that their are biological (e.g. genetic and nutritional) factors affecting the predisposition to the initiation and development of environmentally

associated cancers those in regulatory agencies have another practical avenue for dealing with carcinogen exposures. Consequently, the regulatory agencies must recognize that the incidence of environmentally related cancer can be diminished in two ways: one is to reduce the levels of carcinogen exposure assuming the existence of a non-threshold effect and secondly, to increase one's capacity to resist such carcinogenic agents. It is quite clear that a strong effort must be made to reduce and eliminate all exposures to carcinogenic agents where possible. However, it is equally clear that human exposure to carcinogens from natural sources (e.g. W light and hydrocarbon emissions from plants as well as forest fires), industrial processes and personal habits (e.g. smoking and certain dietary preferences) will continue. Thus, it would seem that equally strong efforts should be made to reduce the influence of biological predispositions as a factor in carcinogenesis. One practical example where industry has attempted to reduce the respiratory cancer has been the decision of Johns-Manville, a leading producer of asbestos products (57), not to hire anyone who smokes because of the greatly increased incidence of respiratory cancer resulting from a synergistic relationship between smoking antiasbestos exposure. Although this is an extremely controversial issue and has been challenged in the U.S. courts, it represents a potential strategy for dealing with this problem. Other possible approaches, although equally controversial, could involve pre-employment screening of all workers in order to identify those with genetic factors which may predipsose carcinogenesis in high risk industries. Less controversial approaches would be the development of nutritional education programs, nutritionally balanced breakfasts and lunches in schools and to the elderly. It is also well known that certain industries have given dietary supplements of vitamin C to workers exposed to high levels of lead (58,591 and benzene (60,61) since it reduced toxicity from these agents. Thus, attempts to reduce carcinogenesis by specifically dealing with biological predispositionsmay offer a legitimate type of preventive medicine which may complement but not substitute for, the reduction of the carcinogenic agents in the environment. REFERENCES 1.

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