Paul Rademacher UniversitBt Munster Mlinster (Westf.),Germany translator Hans-Georg Gilde Marietta College Marietta, Ohio 45750
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Chemical Carcinogens
In Germany every fifth person dies of cancer. In almost all countries cancer, as a cause of death, is second only to heart and circulatorv diseases. Although for years there has been talk of a worldkde "crusade against cancer," research, despite some noteworthy promess, has as yet made no real hreakthrough toward &understanding of the origin and treatment of cancer. Many conditions that lead to malignant tumors have, however, become well-known in recent times. This article presents an overview of such known causes and explains just how cancer is believed to develop. Furthermore, the consequences of our current knowledge on the reduction of the cancer .-~ - risks for chemists and all others working .in chemical laboratories shall be emphasized. Cancer is desienated as a cellular ahnormalitv, at fust local, which causes a few other cells to lose their essential specific functions for the organism and to multiply uncontrollably. The developing tumor penetrates and destroys surrounding tissue and can bv metastasis spread to other organs. The body is unable to tolerate this grow&g virulent tumor; the hindering effect uvon vital functions, the destruction of irreplaceable organs, hemorrhages, and the removal of nutrients invariably lead to death. Transformation of normal cells into cancerous cells occurs in at least two steps (l,2). ~~~~
~
~
(Coearoinonen)
Carcinogen
normal cell
Initial *has*
precancerous cell
Romotion~phase
cancerous cell In the first. irreversible stem a normal cell is changed into a so-called p;ecancerous celliiatent tumor cell) by means of a carcinogen. This initial phase is followed by the development or promotions phase where cocarcinogens may participate and which may persist up to 50 years in humans despite the absence of the original carcinogen. This second step is viewed as reversible since not all individuals become iU after exposure to a carcinogen. Cowcinogens merely strengthen or accelerate the effect of carcinogens without themselves being able to initiate a tumor. Considered as carcinogensare both endogenous factors, that is those that originate within the organism, as well as thost, exorenousonei that come from theorga~lismi'environment. ~xoienousNoxen, which can he as much physical as chemical in nature and to which the onkogenen (cancer causing) viruses belong, account for approximately 90% of all cancer cases. The chemical carcinogens alone account for 60%of the cases (I, 3). People in industrial countries especially are exposed to harmful chemicals. Therefore, with the increase in industrialization over the last few decades, the risk of cancer has significantly risen. Cancer, however, is by no means the exclusive result of industrialization for it was known 5000 years ago and was recognized in the old Indian and Egyptian medicine. Cancer Stimulating Chemical Compounds The high proportion of chemical carcinogens brings forth the supposition that people who, for professional reasons, work with chemicals, are exposed to a higher cancer risk. An Permission to publish a translated version of this article, which was published originally in Chernie in unserer Zeit,[9,79 (197511, was granted by Verlag Chemie and ishereby gratefully acknowledged.
analysis of the death causes of members of the American Chemical Society between 194M967 confirms this suspicion: The cancer mortality rate for chemists is around 25% above the statistically expected value ( 4 ) . Since the effect of a carcinogen is irreversible, it is possible that a single dose would be sufficient; also, effects of small and seemingly harmless amounts over a period of time accumulate and are not detoxified by the body like other poisons. For this reason there exists no safe limit for carcinoeens. As long - as we cannot treat cancer cases more successfully, avoidance of any contamination with carcinogens is the onlv wav to . ~ossible . reduce the cancer risk. In experimental work in chemical laboratories. we must a v d v safetv precautions that measure up to these dangers. ~ h e k f o r ewe-need , to know which suhstances are carcinogenic and how they act. T o date approximately 1000 carcinogenic chemicals are known and an additional 1000 are suspect (3). Not all of them can he listed here individually,but the more important and dangerous ones shall be mentioned as well as the classes to which many of these compounds belong (5). Chemical carcinogens are prevalent in aromatic hydrocarbons, aromatic amines, nitro- and azo-compounds. In the aliphatic series we have primarily the hydrazines, azo-compounds, azoxy-compounds and practically all alkylating agents. There are also some inorganic compounds and some naturallv occurrine substances which are cancer causing, e.e., .~ -. of back& metabolism, fungi, and plants. The table indicates with an asterisk the com~oundsdaneerous for man. Among those listed are also common laboratory substances. The Evidence For Carcinogenic Properties Oft he many known wmpou~ldswith carcinogenic properties, thus far only a relativelv small number ~approxi~nateIs : ~ I I Ihave been shown as definite. or hiehlv ~ r o l ~ a h ldaneers e. " .. to man. Along with the consequences of accidents, ignorance, and folly, the occupationally caused cancer cases have led to the identification of human carcinogens. The first clear case of cancer resulting- from the effect of chemical compounds goes back 200 years when the British physician, Sir Percival Pott, recognized the so-called chimney sweeper's cancer which occurred in many English chimney sweepers. Often having practiced this profession since early youth, the sweeps by working in narrow chimneys had direct skin contact with soot and tar. Later investigations demonby aromatic strated this type of cancer to be caused hydrocarbon (1,2,8). Also the recognition of the first causal relationship of arsenic to various forms of cancer goes back to the beginning of the 19th century. Thus, J. A. Pars reports in 1820 of skin damaze caused by chronic arsenic poisoning to workers and draught animals~incopper smelt& and tin foundries in Cornwall. Similarly, J. Hutchinsou in 1888 diagnosed skin cancer as a result of thera~euticallvused arsenic-coutaininemedication. Despite these experiences, the German wine, tobacco, and fruit growers have since 1925 used arsenic compounds for pest control. Besides frequently acute and chronic poisonings, which led to a ban of these preparations for the vineyards in 1942, numerous vineyard workers (especially of the Kaiserstuhl and Mosel regions) developed tvpical arse.. nic-type cancers. However, since the latent period for arsenic Volume 53,Number 12,December 1976 / 757
Chemical Caminowns AS*., ~ e . - ,
Ino~gonieCompounds CO*.. Ni*., Ti- corn~ound9.Asbestos' Aromatic Hydrocorbona and Ns O-. S-Andops
Cd-, cr0,'-*-.
Aromatic Amines, Niho and A20 Compounds
c4
Aliphatic Hydmrine. A m and Azoxy Compounds
are the causes of these illnesses (1.2). Also the carcinoeenicitv of the a m dyes was recognized relatively late, despiteihe f a d that earlv and clear indications existed.. e.e.. - . after 4-dimethylaminoazobenzene (butter-yellow) had been used to color butter and margarine (1,2). That the problem of occupational cancer exists even today, was demonstrated most recently by the discovery of the socalled vinyl chloride illness (fia). Vinyl chloride, CHeCHC1, has been produced since the thirties on a large scale for the production of polyvinyl chloride (PVC); a t present the annual world nroduction amounts to over 10 million tons. For a lone time vinyl chloride was considered harmless; even in 1966 the standard reference "Chernie und Toxikologie der Kumtstoffe" stated: "Vinyl chloride is a mildly poisonous gas. At hieher concentrations it acts as an anesthetic and irritates the eyes" (fib).Only in the early sixties was vinyl chloride recognized as by nomeans so harmless. In the Federal Republic of Germany alone, by the end of 1974, 167 workers from PVC plants showed severe illness symptoms, ex., bone atrophy a t fingers and toes (~knmsteolo&),~a derrease in the number of plarelets, incerference with the operation of the lung and spleen, as well as varicose veins in the throat and liver cirrhosis. On the basis of these alarming results the MAKvalue (maximal concentration level), set in 1966 a t 500 ppm, was gradually reduced further so that it is now 50 ppm in the FRG. However. with the knowledee that vinvl chloride can also produce liver cancer, this value is no longer considered harmless. By the end of 1974, more than 30 workers in PVC plants-worldwide-succumbed to a rare liver cancer caused bv vinvl chloride, and in animal experiments it was demonskated that even concentrations below 50 ppm are still carcinogenic. While in the USA and Sweden the MAK value was drastically reduced on January 1,1975 to 1ppm, in other countries discussion about a "no detectable level" continues. It is being reported from Norway that the firm "Norsk Hydro" has terminated its PVC production. Cancer-causing properties in animals have been demonstrated by all compounds unstarred in the table as well as approximately 1000 substances not listed here. As experimental animals. rodents. es~eciallvrats and mice, are most suitahle since they are relat;vely s e k t i v e toward chemicals. Rut also rabbits. doas, - ..v i-m monkeys, and fish are beinc used for these tests. The experiments arevery expensive and &ways last several years, since with some weak carcinogens the effect does not manifest itself in the experimental animal until old age. A few values from the USA (3), where presently 450 compounds are being studied, illustrates this point. The cost is supposed to run approximately $70,000 per compound, and 500 animals are used for each compound. I t is estimated that in the USA a maximum of only 700 compounds could he tested ner vear even if all nossibilities were utilized. I t would. , therefore, take years before the few thousand compounds which are introdured each vear could he tested. It is hopeless to even examine all of the "presently existing compou~dsby these means. More effective, cheaper, and, above all, faster methods of analvsis are needed. The use of cell cultures seems to be a prwnising solution to these problems; they will not, however, comvletelv replare animal exwriments (3).It would be hetter to know the mechanism of n~imitld-Forsch. 1191 Lijinsky, W., Conrad, E.,andBopart, R.vande,Nature, 239,165(1972).
Volume 53,Number 12 December 1976 / 761
