Document zQ8zmNek3JO0Y88BZRokqXMma

22 ECN technology a (T European Chemical News^Juiy 22, 1977 EC- 2250 Dow research shows way out he waits to see better evidence that it is a carcinogen. This lack of correlation with animal of chemical carcinogen problems results he suspects, despite the common suggestion that humans don't neces that chemical companies worldwide are urgently researching short-term toxicology tests (such as that developed by Bruce Ames of California Univer sity) indicates the significance of the "chemical carcinogen problem" and partly reflects the requirements of legis lation coming into force in the US overwhelm natural detoxification pro cesses. this being so with vinyl chloride, styrene, carbon disulphide. /S-naphthylamms and 1,4-dtoxane. This is one reason why in vitro or short-term tests are so divorced from the real situation, notes Gehring. Be cause the cell cultures used to detect sarily exhibit the same effects as test animals. Asbestos, VCM and d-naphthylamine, have all shown good correla tion in this respect, he notes. ' Nevertheless, Gehring believes that a threshold effect will be detected with acrylonitrile, with detoxification pro cesses operating in the blood and lungs. and being formulated in Europe. Although still at an early stage of development the tests are already being incorporated into new legislation (such as the UK Health and Safety Com mission's notification scheme) as a means of quickly screening compounds and as an indicator of whether animal tests should be carried out. The techniques will be the major topic of discussion at an industrial toxicology conference being held at Surrey University next week,' but they are indeed only short-term and not entirely reliable indicators as to whether a chemical is likely to be a carcinogen, however desirable a sub stitute they may be for long-term feeding trials. One of those who hold reservations about the true value or these techniques and who are more concerned with the broader problem of how to deal with carcinogens once they have been identi fied is Dow's head of toxicological research Perry Gehring. He will be speaking at the Surrey conference on the need for an understanding of the mechanisms of action of carcinogens before any extrapolation on the results of high-dose animal tests to humans is carried out (in this case examining vinyl chloride). This reflects work done at Dow Chemical's Michigan laboratories which is helping to overcome one of the big gest theoretical obstacles to ,a rational approach to chemical carcinogens--the fact that it has never been possible to show that there exist any safe ex posure levels, although such "threshold" levels of exposure have been long accepted for substances which are simply toxic. By understanding the detoxification or excretion processes which can allow man and animals to cope with small doses of carcinogens, but which are overwhelmed by large doses, Dow Chemical has shown that the normal statistical extrapolation of high-dose re sults, to produce an indication of cancer incidence resulting from real-life exposure, leads to great uvercstimations. Gehring doesn't suggest that this means an early introduction of a "threshold" conepet for all carcinogens, but there is already evidence, he says, that high doses of some compounds whether a compound causes mutation Duplicated Legislation represent an artificial environment, the situation excludes the natural excretion and repair processes. The detoxification processes occur in different ways, sometimes involving ex cretion of the chemical itself or some times action on the active metabolite (the adduct, between the carcinogen and a macromolecule, which is usually the true carcinogenic agent). In the case of vinyl chloride, he says, These rapid developments in the state of the toxicological art come at a lime when the chemical industry is being criticized for not detecting such chemi cal hazards earlier, although the means have not been available to allow such an understanding. In contrast, the US legislature's answer to the problem, the Toxic Sub stances Control Act, according to Gehring has only duplicated existing the detoxification process involves a substance produced in the liver (gluta thione) which is only in limited supply, and it is therefore not surprising that the process proceeds faster at lower doses, ft would require unrealistic numbers of test animals to show a noeffect level experimentally in feeding trials, but Gehring's work characteriz ing the dose-response data of VCMinduced angiosarcoma in rats has encouraged him to venture estimates of levels of exposure which he regards as likely to result in no greater occurrence of human angiosarcoma than would be expected to. occur spontaneously. Geh ring suggests around 25ppm as being such a level. Neglecting the possibility that a threshold level might exist and the fact that rats have been shown to._be_5.-50. times mri susceptible io VCM-induced tumours than human;, Gehring's calculations baseef on rat aata show that chronic exposure to VCM at the I com level wopltTbe expected to rc^u'* case ot angiosarcoma in l(X)m. subjects -Tovfer--Bran ffie spontaneous oc- currence. Acrylonitrile, which has more re cently come under scrutiny as a car cinogen, is already characterized by Gehring as combining directly with the basic life molecule DNA, rather than via a metabolite, like VCM. According to the evidence from Dow's long-term rat-feeding trials which first raised the suspicion about acrylonitrile, the compound is also more potent because it causes tumours in the brain, where detoxification proces-.es do not operate. But the fact that an excess of brain tumours was not revealed by Du Pom's recent epidemio logical study at its plant at Camden. legislation which has never been implemented. Although incidents such as the kepone pollution at Hopewell, Virginia, were cited as indications of the need for such new law. it simply reflected the result of ineffective implementation of existing laws, according to Gehring. Gehring maintains that 90 per cent of the new law's aims could be achieved with existing legislation, the only neg lected area having previously been law controlling disposals of solids on land. The strength of Dew's belief in this led not just to efforts to modify its contents. Gehring admits, but to try and prevent its ever reaching the statute book. What makes Dow's toxicological work so important is not legislation but the rate at which industrial chemicals are being labelled carcinogenic, often as a result of the massive-dose tech niques which Gehring calls "solid state toxicology". Thus the US National Cancer Insti tute's bioassay programme, originally conceived a decade ago to examine highly bioactive compounds, particu larly pesticides, is now committed to re porting animal test data on more than - 200 suspect chemicals at the rate of three a week. The "Chemical carcinogen of the year" phenomenon of the recent past, notes Gehring, threatens to be come the "Chemical carcinogen of the week" in the near future. What can the industry do to put new evidence in perspective and ensure a fair "trial by media" in such cases? The recent release by the NCI of test data linking perchlorethylene with liver cancer in mice provides an illustration of Dow's efforts. The fact that Dow South Carolina, leads Gehring to be suspicious of that study's validity, and c nttnued on page 23 ti ^ ,/' EVopear* Chemical News, July 22 1977 ECN technology i-*. Research ^budget trends show regulatory pressures in/US assessment of the impact ol govern billion on H&D in 1976. with a 9-2 ment regulation on the US Wtemical per cent increase planned for 1977. industry will considerably reinforce But the example of Du Pont, whose existing trends away from innovative budget was 4-2 per cent of turnover research and towards lower earaings last yea/ serves to illustrate the trend. growth shown by companies, according The company recently announced that to New York analysts, Salomon research on new products would repre Brothers. sent/ess than 25 per cent of the total Salomon's review of controls both'1' on chemical product marketing and on the production side, in pollution stand ards and worker protection, lead to the conclusion that the chemical indus-/ try will suffer in this respect mt than any other. R&D budget in the coming years, down . fnSm a level of 34 per cent in the past. 'The need to improve yields and manufacturing costs to compensate foi escalating feedstock, energy and capit costs, encourages a greater concentriitionNon existing products and reflects the decreasing rate of major disco/eries Investors will tend to pay a Wwer and the, higher risk of exploratory new multiple price for chemical stooKs to product'research. reflect the greater uncertainty and risk, One oh the biggest factors Sfalomon with a preference for large companies considers lb this assessment is the Toxic whch have more diversified /portfolios Substances'Control Act and tre uncer of products. tainty abou^ its implementation. Its The trend is illustrated7 by the in implications include greater public in creasing proportion of A&D budgets volvement in BPA hearings l ecause the being devoted to safety testing and act authorizes \ citizens' pel tions and compliance with government regula provides federal funds fo citizens' tions. Salomon coints out. The tOD groups to allowytieir parti ipation in 20 US companies /Spent nearly $1-4 hearings. sweetener study the fret world market for a non nutritive sweetener equivalent either to cydamate in. acceptability or saccharin in cost of sweetness would be about SlOOm./year according to the latest multi-client study'ppblished by Arnold Services, UK. The study. /entitled^Non-hfutritive Sweeteners, analyses over ^sweetening compounds in terms of technical accept ability and Safety. Among the most promising sweeteners are acetosulfam, ethyl / cyclohexyl aspartylaminoma- lopaWT-'Sbdium ' `2'^hydroxy--4^methyl Valerate and stevioside. Other 'groups worthy of further study include chloro- sugars. thiophen saccharins, oximes/ . nitriles and sweetener of Lo Han Kuo. \ Dow toxicology continued \ studies reported two years ago had failed to show that the widely used dry cleaning solvent represented any hazard to man was predictably ignored in many reports of the new "threat". But Dow had made an effort to ensure a balanced response by pre-empting the release of the NCI's data with a re-release of its own findings of 1975, which it stresses had been carried out with far more reasonable doses. \ GLYCIDYL TRIMETHYL AMMONIUM CHLORIDE for the introduction of cationic functional groups. CH2-CH. CH,N.(CH05+Cr o Key Properties Epoxide content Free epichlorohydrin 91% (typ.) 200ppm(typ.) Applications Photographic chemistry Cationic starch modification Surfactant manufacture Textile fibre treatment Biocide manufacture Whatever your need in fine chemicals, it's probable that we can help. Contact your Shell company today. Another Shell Fine Chemical EC- 2251