sdl1.d by:
MIKE SLABAUGH Weber State College Ogden,UT 84408
Carcinogens in Nature Elizabeth K. Weisburger Laboratory of Carcinogen Metabolism National Cancer Institute Bethesda, MD 20205 There is much publicity in newspapers or magazines regarding industrial intermediates which are carcinogenic. The implication is often present that natural materials are not carcinogenic. This is not the case; Nature is not always kind in several respects. The tremendous destructive Dower of hurricanes, tohadoes, and other natural phenomena is well known. Less well known is the fact that Nature also provides more suhtle dangers-various types of carcinogens. Some of croups, these contact only limited . population . . . but others affect everyone. One such carcinogenic factor which contacts all is the background radiation originating from various cosmic sources and the trace amounts of radioactive elements found in soils and rocks, or materials made from such sources, like bricks or tiles. Thus, living in a stone or brick house may increase verv .sliehtlv .. . the level of radiation one receives. Estimates vam. .. but up to 'LOO millirems of radiation may be received yearly through such means. Sittine in hieh-flvine aircraft or living , koiata, Columbia, or a t a high altitude, as in ~ e n v e rUSA, Nepal, increases the risk somewhat. The opposite, descending into the depths of the earth in mines, is likewise hazardous. Besides the usual dangers of mines, the ores in some mines contain traces of uranium or radium which decompose to radon gas ( I ) . These radioactive elements are a cause of cancer, especially noticeable among uranium miners (2). However, workers in other types of mines, especially asbestos or un-
Introducing the Column Editor Mike Slabaugh received his BS degree in chemistry at Purdue University in 1965 and his doctorate in organic chemistry at Iowa State University in 1970. His interest in biochemistry and natural products '' research (alkaloids)led to a year of postdoctoral study in biochemistry at Texas . A&M University in 1971. Dr. Slabaugh is now Professor of G Chemistry at Weher State College, where t -1 ' ' 8 in 1979 he was recognized as the "Pro-. fessar of the Year." His professional interests and goals are directed toward chemical education and community involvement in science activities. He has been particularly active in directing regional science fairs. Mike is a member of the American Chemical Society; the Utah Academy of Sciences, Arts and Letters; Sigma Xi; the National Science Teachers Association; Utah Science Teachers Association and the Society for College Science Teachers. He is a eo-author of the text "Introductory Chemistry: General, Organic and Biological" published by Scott, Foreman and Co. He has also authored over twelve other publications.
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This feature presents relevant applications of chemistryt o everyday life. The information presented might he used directly in class, posted on bulletin hoards or otherwise used to stimulate student involvement in activities related to chemistry. Contributions should be sent to the feature editor.
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dereround hematite mines. also run a ereater risk of developing cancer than the overall population (3-5). Another factor that influences everyone is the ultraviolet component of sunlight. The ironic dichotomy is that some sunlight is needed for production of vitamin L)in the skin. but too much sunlight eientually leads to an increase in skin cancer, usually in susceptihle, light-skinned individuals. People exposed recreationally or o&upationally to sunlight, especially in the southern portions of the USA, show higher than average incidence of skin cancer. Therefore, the fad for excessive sunbathing or tanning for recreational or cosmetic purposes may eventually be harmful (fi).Available protective measures include using UV-ncreening lotions and the wearing of lightweight, loose clothing to avoid overexposure to sunlight. An increase in the incidence of skin cancer has also been associated with higher than usual levels of arsenic in drinking water supplies. Other inorganic compounds are also thought t o be carcinogenic in humans, but the exposure is largely occupational as ih the processing of chromates and the refining of nickel. Less well-documented causes of cancer are exposure t o compounds of cadmium or beryllium (7). Overall, though, carcinogenic organic compounds are of even greater interest because of the possibility for widespread human exposure and the tremendous variety of stru&ures they represent. Benzo[a]pyreue, a carcinogenic polycyclic aromatic hydrocarbon, (See Fig. I),is formed in combustion processes and therefore occurs in the atmosphere of cities, along highways, and near airports or similar installations. I t has been found in charcoal-broiled meat and in smoked or well-roasted foods. On the other hand. it also occurs in forest soils, is expelled by volcanoes, and can be synthesized by some ~ l a n t sand aleae. I t has been found in d e e ~ e lavers r of soil ahich are ove;10,000 old. This indicates thai there may be some natural origin for benzolalnvrene. Soil bacteria de. ..grade it to bome extent so that a balance between formation and breakdown exists (8). Plants also make small but measurable quantities of a few compounds usuallv considered to be industrial ~roducts. Ethylene oxide is a large scale intermediate used in the manufacture of ethylene glycol, other glycols, and surfactants. I t is also a fumigant for treating items which cannot he sterilized by other means. Although there are no relevant carcinogenicity tests of ethylene oxide in animals, the compound is under sus~icionbecause it causes hacteria to mutate and has other toxic effects. However, ethylene oxide is produced by broad beans when they are exposed to ethylene (9).In turn
Figure 1.
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724 / Journal of Chemical Education
Srmcture of benro[cc]pyrene. a widespread environmental carcin-
SAFROLE
J - Ararone
Ertragole
Figure 4. A. Structure of elaiornycin. produced by the fungus Sfrepfomyces hepatic^. 8. KMeIhyl-Kformylhyhazine and its hychzom, with acetaldehyde (gyrornitrin)are both produced by the false morel (Gyromitroesculsnta)which is also a type of fungus.
Figure 2. A. B. 8 C: Three structurally related mmpounds, presem in flavoring or perfumery ingredients
(glucose) Cycasin
(primeverose)
Figure 5. Shuctwes of two typical carcinogenic pynoliridine a l k a l o by cerlain plants.
Macrozamin Figure 3.
Carcinogens produced by membws fo the cycad family.
ethylene is formed by ripening fruits and vegetables and is often used commercially to hasten artificial ripening. Similarlv. ". benzene. the laree volume industrial intermediate and solvent is under question as a possible carcinogen. A substantial number of case reports and epidemiologic surveys suggest that long-term exposure of people to benzene is associated with the development of leukemia. However, traces of benzene are present in eggs, fruits, vegetables, dry beans, nuts, beverages, cooked or irradiated meats and fish, and dairy products (10). Since many hydrocarbons are present in plant material, the benzene in milk products may. originate in the . grasses eaten by dairy cattle. A seaweed (Asparagopsis taxiformis), used as a food in Hawaii, contains many brominated or iodinated compounds. Some are close analogs of toxic or carcinogenic compounds usually considered to-be industrial materials, namely phosaene, chloroform, carbon tetrachloride, and 1,2-dibromoethane (11). Plants are responsible for a series of structurally similar carcinoeenic substances which either once were or are oresent in flavoring agents (See Fig. 21. Sat'role ie the chief ingredient of oil ofsassafras obtained from the sassafras tree. Svnthetic safrole was once a root beer flavoring. However, a t high levels i t caused liver tumors in laboratory animals. Likewise, &asarone, isolated from an Indian (Jammu) variety of the calamns plant and used to flavor vermouth, caused intestinal tumors in rats. The third member of the series, estragole, is the chief constituent of oil of tarragon, a flavoring and perfumery material from the tarragon pl&t. I t caused~livertumorsin very young mice (12). The FDA has removed safrole and Jammu calamus from the list of substances which are allowed to be used as food flavorings. Other plants from both tropical and temperate regions of the world produce carcinogens, some of known structure, others unknown. Tronical or subtronical . nlants . of the Cvcad family produce compounds of relatively unusual structure (Fig. 3). The nuts of the cycad plant, which resembles a small
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palm tree, are used in some Pacific islands as an emergency source of starch. The nuts are first soaked in water to remove the toxin, cycasin, which is the glucose conjugate (glycoside) of methylazoxymethanol. In addition to exerting a toxic action on the nervous svstem, cvcasin causes intestinal, kidney, or liver tumors in many laboratory animals. In leaves or kernels from other memhers o i the Cycad family, namely the Zarnia or Encephalartos species, thk methyla~oxymethanolis conjugated with the sugar primeverose which is a xylose-glucose disaccharide. This compound, macrozamin, is similar to cycasin in that i t is also carcinogenic and toxic. One might surmise that i t is the methylazoxymethanol in the conjugate which is the actual carcinogen, and laboratory experiments have confirmed this (13). Interestingly, closeiy related structures exist in elaiomycin which is a nroduct of the microoreanism Streutomvces hepaticus and in gyromitrin, isolated from the false morel which is a delicious mushroom (See Fie. 4). Both elaiomvcin and gyrommin show weak to moderate carcinogenic activity in m b or mice (14. 151. 'lhe false morel is a nourmet t w e food; due to its expense, it fortunately is not e a k n very of&n. A series of very similar alkaloids has been identified in diverse types of plants, many of which are used in herbal or folk medicines around the world (Fig. 5). Seneciojacobae (aragwort type plant), contains r e t r o h e , isstidi& and lasi&pine, which cause liver cancer in rats (14). Various plants of the coltsfoot family, also used as vegetahles or herbal remedies in Japan or Sweden contain petastenine or senkirkine, which have similar structures and also are liver carcinogens (16). The comfrey plant, Symphytum officinale, used as a tea or poultice, congins symphytine, again very similar both in structure and carcinogenic effect in animals t o the other alkaloids (17). Many books on wild plants mention that the "fiddlebeads" or croziers of bracken and other ferns can be eaten as a vegetable. This practice is especially prevalent in Japan and some parts of the USA and Canada. However, bracken fern contains a still unidentified carcinogenic compound (12). This becomes a problem in areas such as Turkey where cattle graze heavily on bracken; a consequence is that bladder tumors often develop in such animals. Volume 57, Number 10, October 1980 1 725
Aflatoxin B, Figure 6. Isms.
sn,,gmflorynm
Structures of two similar carcinogens farmed by fungal organ.
T o add to the nitrosamine dilemma, it has been shown that hoth bacteria and fungi can svnthesize nitrosamines of various r y p ~ s Some . of these nitroso compounds may he responsible for the hirh esophareal . . cancer incidence in partsof China or Africa. ~ i t r o s a m i n e scan he changed to noncarcinogenic substances by the action of sunlight. Some hacteria also convert them back to the parent amine and nitrite, illustrating that a balance between formation and breakdown of substances often exists (22). However, microorganisms are also capable of producing other types of carcinogens. Some of these affect more persons than any other unintentionally ingested natural carcinogen. The fungus, Aspergillus flaws, which often infests oil seeds (rice, cottonseed meal, peanuts)'produces many compounds, hut one called aflatoxin B1 is the most potent liver carcinogen known in experimental animals (Fig. 6). In warm humid areas of the world, there seems to he a direct correlation between the incidence of liver cancer in the population and aflatoxin contamination of the normal diets. A carcinogen closelv related to aflatoxin in structure is sterigmatocys%n, formed by Aspergillus uersicolor or Aspergillus nidulans (23). Aflatoxin B1 can he degraded by hacteria or by relatively simple chemical methods which are being tried as a means to salvage animal feed contaminated with aflatoxin (Fig. 7) 1 7 A,. \-.
Figure 7.
Degradation of atlatoxin B, by
a relatively simple chemical pro-
cess.
Still other plant products have caused tumors in animals subjected to large doses. One is the red chili pepper used heavily as a cooking spice, almost worldwide. However, the animals also had a poor diet low in protein. Thus, there is little relevance t o the typical American diet, although it may he more pertinent for other countries. o f all naturally occurring carcinogenic plants, the tobacco plant probably has the ereatesr exposure. During the hurnine. bf tobacco be&o[a]pyr&e and similar compoun& are formed as pyrolysis products. Many other toxic and carcinogenic substances have also been identified in the gaseous or particulate phases of tobacco smoke-vinyl chloride, nitrosamines, aromatic amines, hydrazine, HCN, and CO, to name a few. More damaging is that unburned tobacco contains several nitrosamines. several of which were carcinoeenic in rats (18. . . 19). Nitrosamines (RR'-N-N=O) are the most versatile carcinogenic compounds known fo; they can cause tumors in many organs, depending on the nature of the R groups. There is much concern over nitroso compounds since they form endogenously in the mammalian organism, usually in the stomach, from nitrite and secondary (or in some cases tertiary) amines. However, ascorhic acid or . ~ r o.. o v-gallate l can inhibit this reaction. ~ e d u c t i o nof dietary nitrate, present in vegetables or grains, to nitrite is accomplished by the hacteria in the salivary plaque (20). Thus each person carries apersonal nitrite source. Furthermore, some nitrosamines can form in meats that have been cured with nitrite. A prime example is bacon, where the nitrite reacts with proline, yielding nitrosoproline which is not carcinogenic. However, on cooking the bacon, the nitrosoproline decarhoxylates, forming nitrosopyrrolidine, a carcinogen, which concentrates in the fatty part of the bacon drippings. Thus, if one eats bacon, i t is best to drain i t well before eating. Nitrosamines also form in other unexpected places: in cutting fluids used in machine shop operations, in cosmetics where ethanolamines and a preservative react, and in pesticide or herbicide mixtures. In most cases the formation has been explained by the presence of nitrite or a precursor (21).
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726 1 Journal of Chemical Education
It is evident that natural structures, from very large to very small, are capable of producing various types of chemical carcinoeens. However. most of the natural &inoeens. , excent for aflatoxin, are relatively weak. Exposure to some of these environmental carcinoeens is unavoidable. hut others can he avoided-moldy foods, certain plants, tobacco, and excess sunlight. Limiting exposure allows the nornial processes of the cell to repair any possible damage from carcinogens. Furthermore, a protective action against carcinogens has been noted with vegetables used as foods. These include cabbage, Brussels sprouts, alfalfa, and lettuce. Even the potent liver carcinogen aflatoxin showed much less effect in animals also fed cauliflower (25). Avoiding undue exposure to carcinogens, hoth natural and synthetic, and maintaining a moderate hut varied diet, are positive steps each individual can take t o prevent becoming a cancer patient (26).
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Literature Cited (1) Wekhach. H.. Botezatu, E., and Gradinaru, M.. Rodioprotocfian. 14.41 (19791. I21 Areher, V. E.. Gillam, J. D., end Wagoner. J. K.. Ann. N Y Acod. S c i , 271, 280
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