Document qadZ4rr3a3n7LOe6eDMXJOB95

1 r j: 2 1 ' ~**rr 'u'Co W0DlE7 John W. Moore Eastern Michigan University, Ypsilanti, Ml 48197 Danger of chemical carcinogens in the envi ronment is becoming increasingly apparent. Widespread exposure to numerous synthetic substances and the fact that cancer does not appear until many years after exposure to a carcinogen make carcinogenesis difficult to detect and often almost impossible to assign unequivocally to a particular compound. Screening tests are expensive, time-consum ing, and results are often suspect (7). The story of vinyl chloride illustrates some of these problems. Vinyl chloride is a colorless gas at ordinary temperatures and pressures, but in industry it is usually handled as liquid under pressure in steel cylinders. It is used as a precursor to the sulfa drugs and, despite its flammability, narcotic effect, and tendency to form solid polymers, as a refrigerant and as a propellant for aerosol sprays. But by far the major use of vinyl chloride is to make vinyl plastics. First step in vinyl plastic production is to synthesize vinyl chloride monomer (VCM), usually from ethylene or acetylene; plants where this is done are usually located close to petroleum refineries which supply their starting materials. Next the monomer is . polymerized to form polyvinyl chloride (PVC) resin, usually in solid form, and the bulk PVC resin is shipped to a large number of manufacturers who extrude, mold, roll, or otherwise form it into a variety of finished products. PVC is easily made into films and sheets, electrical insulation, paper and textile coat ings, phonograph records, and many other products. Because of its versatility it is the second most used polymer after polyethylene (Figure 1). In 1974, PVC plastics and copoly- - J mers accounted for approximately 1% of th .. U.S. gross national product. Major uses of PVC in the United States appear in Table I. . ` _ In the United States, about 700 000 work- - era fabricate products from PVC and about" 6500 persons manufacture vinyl chloride and v convert it to PVC, thus coming into direct . contact with VCM (Table II). j * j J \ j i j { j > The Problem In January 1974 B. F. Goodrich C . volun tarily revealed to federal and state regulatory - officials that since 1971 three workers at its PVC polymerization plant in Louisville, Ky. had died of angiosarcoma of the liver. Be cause this form of cancer is extremely rare (usually no more than 25 cases are reported per year in the U.S.), this disclosure caused immediate alarm. B. F. Goodrich workers = who were in contact with PVC only and not' ' VCM were apparently unaffected, so the ini-: tial hypothesis was that vinyl chloride was ^ the culprit. - -*, + A few weeks later, at the request of the - ' r '- - * rv .- 7 -/ : f*_ 'ft UCC 070600 U.S. Department of Health, Education and Welfare, Britain's Imperial Chemical Indus tries published the results of toxicological studies by Caesare Maltoni of the University of Bologna, Italy (2). In August 1972, Malto ni discovered in a test rat exposed to vinyl chloride a liver angiosarcoma later found to be essentially identical with those that had killed the PVC workers. In January 1973, a team of three scientists representing the U.S. chemical industry visited his laboratory to study his results. The data published in Feb ruary 1974 are shown in Table III. In the experiment, rats were exposed to vinyl chloride in air for four hours a day, five days a week, for 12 months. At all exposure levels above 50 parts per million (ppm), liver cancer was induced. No angiosarcomas were found in controls or in rats exposed similarly to 2500 ppm of vinyl acetate. These results were supplemented at a May 10 to 11, 1974 meeting of the New York Academy of Sci ences and American Cancer Society where Maltoni reported the incidence of angiosar coma in rats at an exposure level of 50 ppm in air. SevesaLQthsxlypae-oLtumen-weK-alse* found. - By May 1974, a cause and effect relation ship between vinyl chloride and human an giosarcoma was generally accepted. Con firmed cases of cancer in workers at PVC plants had risen to 19, 17 of whom were al ready dead. Later, in the United States and nine other countries, a total of 32 cases were diagnosed. A recall of aerosol hair sprays using vinyl chloride as propellant was ordered by the Food and Drug Administration, and the En vironmental Protection Agency (EPA) asked makers of 23 insecticide sprays to reformu late their, products to eliminate vinyl chlo.'tide. The.-EPA order did not recall products , i. Carcinogenic--cancerproducing Mutagenic--producing a significant and permanent change in the hereditary material Teratogenic--produc ing monstroaitiea or malformations in tho developing embryo Molded polyvinyl chloride container* for lubricants, detergents, and edible oils already packaged, and the names of many manufacturers were withheld because the presence of vinyl chloride in their products was deemed to be proprietary information. The Occupational Safety and Health Admin istration (OSHA) of the U.S. Department of Labor set a temporary standard of 50 ppm in air for plants manufacturing vinyl chloride and PVC as well as for PVC fabricating facil ities. EPA set no standards for ambient air outside PVC plants because measurements indicated that the lowest detectable level (1 ppm) of vinyl chloride was rarely exceeded in these locations. In October 1974, OSHA extended the in terim level of 50 ppm to January 1, 1975, after which date a 1 ppm eight-hour average with a maximum of 5 ppm over any period longer than 15 minutes was to be required (5). If such standards could not be met, com panies were required to provide workers with respiratory equipment. On December 14, 1974, the Second U.S. Circuit Court of Ap peals ordered a stay of these rules until it could review them. In early February 1975, it found the rules "clear, definite and ... en tirely feasible" and ordered them put into ef fect by April 1. For the first year workers are required to wear respirators if the concentra tion of VCM exceeds 25 ppm, and respirators must be available at all times. After April 1, 1976, respirators will become mandatory whenever levels exceed the standards. The Society of the Plastics Industry has appealed this Circuit Court decision to the U.S. Su preme Court. ,f '4^ 14 CHEMISTRY VOL 48 NO 6 0 tectlng Ch mlcal Carcinogens More than 40 years elapsed between the introduction of vinyl chloride into commerce and the discovery of its cancer-causing abili ty. During this period production rose until nearly 100 000 tonnes of vinyl chloride were lost to the environment each year. Impor tance of vinyl chloride to the economy had become so great that when OSHA proposed a limit of 1 ppm, one industry spokesman claimed it would "throw two million jobs down the drain." Some observers claim that industry was aware of and withheld the re sults of Maltoni's study of carcinogenicity for some months, postponing regulation for as long as a year (3). But leaving this aside, why did detection of carcinogenic effects take so long? Principal difficulty is the long latency peri od between exposure to a carcinogen and the development of a cancerous tumor. Average length of exposure to vinyl chloride of af fected B. F. Goodrich workers was 19 years, a latency period which falls within the normal range of 15 to 40 years for cancer in humans. Although there is evidence that increasing the dose of a carcinogen increases the inci dence of disease, chronic exposure is not nec essary. Once an individual has received enough of the compound, whether in a single dose or extended over a period of years, can cer may develop. Moreover, there appears to be no threshold concentration below which carcinogenic effects do not occur, although the fraction of the population affected by disease decreases with reduced exposure. As a result of the long latency period, es tablishing a cause and effect relationship be tween a chemical and cancer is difficult Ani mals such as rats are often used to test for carcinogenesis. They have much shorter la tency periods than humans, and the number of animals required for adequate statistics can be reduced if high dosages are used, but this introduces dual difficulties. Data must be extrapolated from high to low doses, and differences in the metabolism of test animals and humana introduce uncertainty in trans lating results from one species to.'another. A substance carcinogenic in rata may be metab olized to a harmless form by humans, and in nocuous substances may be converted into carcinogens. It can be argued effectively that ` humans, because of their greater variety of cell types, may be more susceptible than test animals. -k In view of the difficulties of discovering carcinogens, how did it happen that the ef fect of vinyl chloride on humans was detected at all? Answer is that the cancer induced by f UCC 070602 Figure 2, incidence of cancer of the nervoua lyetem among Swedish children 0 to 4 year* old vinyl chloride is rare enough that even a sin gle case is highly noticeable. Also workers in the PVC plant constituted a well-defined group with well-known exposure to vinyl chloride. Other carcinogens may not produce such obvious effects. Indeed, evidence is that the greatest damage from vinyl chloride itself is not due to liver angiosarcoma but to the other, more common cancers it induces. Studies done at the Harvard School of Public Health indicate that lung cancers and brain cancers occur in vinyl chloride workers at rates 60% and 320% above the national aver age (4). Mutagenic effects have also been dis covered now that angiosarcoma has focused attention on vinyl chloride. A substance which increased the incidence of prevalent cancers such as those of the lung or brain by only 10% and which was not confined to a workplace environment, would be almost im possible to detect. It has been suggested that a substance which reduced IQ by 10% but caused no overt symptoms would be com pletely unnoticed, despite its extremely dele terious effect on human society. Incidence of cancer has increased a good deal during the 20th century and all of the increase cannot be attributed to better meth ods of diagnosis and the fact that other killer diseases have been brought under control.' Even within a particular age group and among the young, cancer is on the rise as is shown by the data in Figure 2 for the 0- to 4year age group in Sweden (1). During the decade 1958 to 1968, incidence of cancer of the nervous system increased threefold in this group. No data are yet available to indicate une quivocally whether this increase is associated with increased levels of industrialization, but / JUNE 1975 CHEMISTRY' 15 Polyvinyl chloride ie used extensively in wir and cable insulation UCC 070603 ,-/V ^ -f/ Vinyl chloride * a a a Cf ?. a a a cr a Polyvinyl chloride orci (:Ctf1-CHCI-)ll. a number of disturbing studies have recently lent weight to this speculation. The National Cancer Institute (NCI) has tabulated deaths due to cancer between 1950 and 1970 in all counties of the United States. Those counties having high rates of cancer deaths correlate well with regions that were heavily industri alized prior to 1940. In view of the 15- to 40year latency period between exposure to a carcinogen and development of cancer, this does not contradict the hypothesis that in creased levels of air and water pollution might lead to increased incidence of malig nant tumors. In another study, EPA discovered a possi ble link between cancer and drinking water supplies (6). Both this and the NCI study in dicate that a major problem may exist along the lower Mississippi River in Louisiana, an area with a high concentration of petrochem ical plants. Known carcinogens have been discovered at low concentrations in the water supply. Some appear to have been released directly from chemical plants, but others are apparently synthesized by combination of in dustrial effluents with chlorine used to disin fect drinking water. Because of such findings, many observers have pointed out that the few cases of angio sarcoma of the liver observed so far may be only the tip of an iceberg. With a 20-year la tency period and the greatly increased num bers of workers exposed, the number of an giosarcomas may well continue to rise for the next two decades, even if all exposure is re duced to the 1-ppm level required by OSHA. Also, because of the increased incidence of carcinogens in the environment over the past few decades, other types of cancer may begin to appear. Cancers caused by vinyl chloride may well be an early warning of problems yet to come. Testing for Carcinogens With testing of carcinogenic and mutagen ic compounds so time-consuming and expen sive, how can we check all the compounds in- JOHN W. MOORE, associate professor of chem istry, has a PhD in physical organic chemistry. Having a special interest in application of audio visual materials and computers, he has developed a series of computer-generated overhead projec tion overlay transparencies showing electron densities in atoms and molecules. He has pub lished more than 50 articles, reviews, and ab stracts in scientific and educational journals. r,` 16 - CHEMISTRY VOL 48 NO 6 troduced into commerce? It seems likely that this will prove impossible, but also unneces sary. Many new chemicals, such as dyes used in food and paper or optical brighteners used in textiles, serve purely cosmetic functions, and little harm to society would be caused by halting production entirely. In other cases, such as that of vinyl chloride, the substance serves a very useful function, and its dangers must be balanced against its benefits before deciding whether to ban it. Here testing must be carried out and at the same time consider able effort made to find substitutes in case production of the material has to be stopped. The Toxic Substances Control Act of 1973 represents a move toward adequate testing. It would require industry to test new chemi cals and notify EPA before producing them in commerical quantities. Although different versions of this bill were passed by the U.S. Senate and House of Representatives in 1973, they became stalled in a House-Senate Conference Committee during the fall of 1974, New bills have been introduced in both legislative bodies this year. The Senate bill and a draft version produced by EPA both require that manufacturers submit test data on a new compound months before beginning commercial production. Compromises be tween the House and Senate may result in action later this year. Others have suggested that better toxico logical testa could be done with less economic disadvantage to small companies if govern ment-supported and -operated regional test ing laboratories, on the model of the Atomic Energy Commission National Laboratories, were established. These labs would provide greater expertise in this area than could be mustered by any but the largest corporations. Whatever approach is taken it will come none too soon. The lesson of vinyl chloride has only begun to unfold, but is quite clear. Spread of synthetic chemicals whose toxic, .v teratogenic, mutagenic, and carcinogenic properties have not been thoroughly evalu ated may have very serious consequences. Moreover, these effects often cannot be read ily detected and once found may not be im mediately reversible. References ^ (1) Ambio, June 1972,88. - (2) Chem. Eng. News, Feb. 25,1974,16. (3) Ibid., Mey 20, 1974, 16; May 27, 1974, 5; Jane 10, 1974,3,12; July 8.1974,21, 37. (4) Ibid., July 22,1974,9, (5) Chemistry, Nov. 1974, 27. . (6) Ibid., Feb. 1975,16. (7) Ibid., May 1975,24. ,,,, ` (8) "Encyclopedia of Polymer Science and Technology.".. 1971,-Vol. 14,452, Wiley-lnteracience, New York, N.Y. ' ; / UCC 070604