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The Delaney “anti-cancer” clause
PREVENTIVE
MEDICINE
2, 133-139
(1972)
Dr.Jukes, a versatile writer on a number of scientific subjects dealing with the inte$ace of chemicals, man, and animals, discusses the difficulties associated with a rigid interpretation of the Delaney Clause, although he feels that this legislation will not be modified.
The Delaney The
“Anti-Cancer”
Delaney
Clause
Amendment
THOMAS H. JUKES Division
of Me&cd Physics, University Berkeley, California 94720
of California,
The Delaney Clause of the 1958 Food Additives Amendments is popularly termed the “Delaney Amendment.” We shall refer to it as “the Clause.” It states that “no (food) additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animals.” The same law also provides that no such additive may be used in animal feeds unless no residue of it can be found in food products obtained from the animal after slaughter. The good intentions of the Clause are unquestioned, Rather than having the temerity to oppose the Clause, I shall attempt, as a student of our times, to analyze its background and its portent. According to its author, Hon. James J. Delaney of New York (4), the Clause followed the recommendation of the International Union Against Cancer at its Rome meeting, 1956, and was “strongly endorsed by a number of top-ranked cancer experts.” Delaney says further that “carcinogens are subtle, stealthy, sinister saboteurs of life, They have no place in our food chain,” and that the F.D.A. has announced the toxicity of “stilbestrol, mercury, lead, plasticisers, monosodium, glutinate (sic) and many others. From the outset, the proponents of the Clause emphasized that no level of carcinogen was “safe” (3). The argument that many “natural” food additives and components produce cancer in experimental animals was met by the customary rejoinder that it was dangerous to add to the existing burden of carcinogens to which consumers are exposed, In 1960 Flemming (3) (then Secretary of Health, Education and Welfare) emphasized a quotation from Mider, as follows: No one at this time can tell how much or how produce cancer in any human being, or how
little long
of a carcinogen it would take
would be required to the cancer to develop.
In this statement, the term “how little” can be interpreted as referring to a single molecule; and “how long” may mean a lifetime or even a carry-over into offspring (see below, in discussion of DES). Applied to situations other than food additives, the statement could include the exposure of consumers to carcinogens produced by pyrolysis and cooking of foods, such as by toasting, Copyright All rights
@ 1973 by Academic Press, Inc. of reproduction in any form reserved.
133
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roasting and prolonged heating; carcinogens “naturally” present in foods; and the effects of ionizing radiation, including sunlight. There are indications that the doctrine of the absence of a threshold or a tolerable level is being extended to other chemicals, such as mutagens, even though mutation is a normal biological process. The principle formulated by Mider together with the Delaney Clause, and the recent remarkable improvements in analytical techniques, are sufficient to exclude a substance as a food or animal feed additive when reported as a carcinogen, even though the same substance or one with very similar pharmacodynamic properties is inherently present in foods. The Clause originated in Congress rather than in a federal agency of the executive branch of the government. Two contrasting scientific viewpoints have been developed on the subject embraced by the Clause. The first (15) is similar to that enunciated by Mider. It says: No level of exposure to a chemical carcinogen cant for man. For carcinogenic agents a “safe tion of our present knowledge.
should be considered level for man” cannot
toxicologically be established
insignifiby applica-
It is equally logical to say, of course, that the liminal value of an “unsafe for man” cannot be established by application of our present knowledge. statement continues: The
concept
of a “socially
acceptable
risk”
represents
a more
realistic
The concept that a risk of cancer would be socially acceptable ceptable. The statement appears somewhat cynical. The other viewpoint has been expressed:
level The
notion.
is itself unac-
The conclusion that a chemical agent either is or is not a carcinogenic hazard to man based on animal experimentation, regardless of the dose, route of administration, mechanisms of translocation and particularly the biotransformation mechanisms which are involved in the species under study, is basically inconsistent with established fundamental concepts of the science of toxicology. In spite of the lack of complete knowledge of the subject of chemicalinduced carcinogenesis, it is possible to define the limits of chemical-induced carcinogenesis much along the lines that have been utilized by the regulatory agencies for food additives when any other form of toxicity is under consideration. This is, basically, starting with a concept of the existence of a no-effect or of a toxicologically insignificant dose level (6).
The final sentence seems reasonable, for there must be a molecular level at which the effects of a “carcinogen” reach the point of insignificance by comparison with the omnipresent background of other carcinogenic stimuli. But we have another factor to consider; this is the effect of public pressure upon lawmakers and regulatory agencies. In my opinion, this is the overweening issue in discussions of the Clause. Most scientists in the field of cancer will almost certainly evaluate the slightest risk from cancer as outweighing any need for suspected food additives, and the consuming public will unquestionably side with this evaluation. Furthermore, with a division of scientific opinion, the public will vote for “safety.” In addition, consumers have for more than a decade been subjected to adverse publicity regarding the alleged carcinogenicity of “poisoned” cranberries (3), insecticides (2,20), cyclamates, and diethylstilbestrol (DES) in meat (23). Attempts to repeal or reduce the Clause will meet with resistance and suspicion.
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Certain substances in the diet either (a) can be made to elicit a carcinogenic response in a susceptible laboratory animal when administered orally in a suitable vehicle and at a high dosage level, or, (b) are undisputable strong carcinogens, although they are present at extremely low concentrations, such as the background of radioactive elements which occurs in all biological materials. The Clause, if zealously enforced, can virtually stop the production of food by modern scientific technology. Let us apply “Occam’s Razor” to this complex discussion, and ask three questions: (i) Is there a no-effect level for carcinogenesis?; (ii) can “similar” carcinogens be compared quantitatively with each other?; and (iii) is there a threshold level for certain tumor-inducing stimuli? The first question probably relates to DNA; it is often stated that a single nucleotide change in one DNA molecule may be sufficient to start a carcinogenic train of events. Since all animals do not die of cancer in their old age, there must be a no-effect level in terms of the average life span. (ii) As an example, can diethylstilbestrol be weighed against estrone? Since their carcinogenic effects are the direct result of their estrogenic properties, the answer is yes, but species specificity and tissue or organ specificity must be reckoned with. (iii) The goitrogenic stimulus, discussed below, provides an affirmative answer to this. DDT
Potentially the most devastating possibility of the Clause is its application to DDT. This substance has saved more lives and prevented more disease than any chemical in history (18). Life expectancy in India increased from 32 to 47 years during 1953 to 1961; this was attributed to the decline in malaria resulting from the DDT house-spraying program (14). DDT was exhaustively examined for toxicity in laboratory animals during 1944-1965, after which it was stated to be noncarcinogenic (12). Nevertheless, the induction of tumors in certain strains of mice by sublethal continuous dosage with DDT over a lifetime has been reported. The experimental evidence in this field is conflicting (8); rodents, but not other experimental animals, have developed tumors when they have received massive doses of DDT for prolonged periods. As recounted by Yannacone (24), the Environmental Defense Fund (EDF) decided to use the Delaney Clause against DDT. Yannacone’s version is as follows: There appeared four papers in various journals inferring that DDT might induce tumors, not cancer, but tumors in some particularly susceptible strains of mice . . . the leader of the (EDF) scientific team in the DDT fight, decided that we should hire a public relations firm, call a press conference, announce that DDT causes cancer, and demand, under the Delaney Amendment, that the FDA-USDA cancel the use of DDT immediately (24).
To heighten the emotional impact of their campaign, the EDF linked the DDT content of breast milk with the carcinogenic@ allegation. Primarily as a result of this and similar publicity, and contrary to testimony as summarized in the findings of the Examiner in the recent hearings on DDT, (19) Ruckelshaus (17) has issued a ban on the few remaining uses of DDT in the U.S.A. and has reinforced his ban, by stating that:
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JUKES DDT is a potential human carcinogen. (a) Experiments demonstrate that DDT causes tumors in laboratory animals; (b) there is some indication of metastasis of tumors attributed to exposure of animals to DDT in the laboratory; (c) responsible scientists believe tumor induction in mice is a valid warning of possible carcinogenic properties; (d) there are no adequate negative experimental studies in other mammalian species; (e) there is no adequate human epidemiological data on the carcinogenicity of DDT, nor is it likely that it can be obtained; (f) not all chemicals show the same tumorigenic properties in laboratory tests on animals. DDT presents a carcinogenic risk.
Two years ago, however, Ruckelshaus, as Assistant Attorney General, filed a brief in the U.S. Court of Appeals on behalf of the Secretary of Agriculture (16). The brief states: DDT is not endangering the public health and has an amazing and exemplary record of safe use. DDT, when properly used at recommended concentrations, does not cause a toxic response in man or other mammals and is not harmful. The carcinogenic claims regarding DDT are unproved speculation.
Ruckelshaus has extended his present involvement with oncology luating two other pesticides, aldrin and dieldrin, according to Science folIows:
to eva(22), as
The committee’s cancer expert, Stephen S. Stemberg of Sloan-Kettering Institute, noted that the closest dieldrin comes to causing cancer is in increasing the incidence of a naturally occurring tumor in a single strain of mice. “No carcinogenic action has been demonstrated for dieldrin in rats, dogs, or primates” Sternberg says. In last week’s decision to reaffirm the cancellations of aldrin and dieldrin, Ruckelshaus stated that he had found DDT to be a potential human carcinogen and that “appraisal of similar laboratory evidence concerning dieldrin leads me to make the same finding here.”
Apparently Ruckelshaus’ opinions on carcinogenesis vary. Ottoboni (13) fed dogs 10 and 100 mg of DDT per kilo of body weight per day through four generations. No harmful effects on reproduction, growth or viability, and no tumors were found. Females on the higher level of DDT reached puberty about 60 days earlier than the controls. The long-term continuous exposure of many human beings to DDT dates back to 1945. In 1967, Hayes (9) commented that the length of time was equivalent to a generation in terms of human life span. Many subjects have been exposed to DDT, often for long terms at high dosage rates, without any cases of cancer attributable to this exposure being reported. We may expect that, triggered by adverse American publicity against DDT, a revulsion against the use of DDT and other pesticides will sweep the “malaria belt.” Suffering and death from malaria and other insect-borne diseases throughout the tropics will result. DIETHYLSTILBESTROL
(DES)
This substance, like all estrogens, will produce mammary tumors in mice, and is hence definable as a carcinogen. DES has been used since the 1930s for estrogen replacement therapy, and for other clinical purposes such as treatment of prostatic cancer in human patients. DES is used extensively to increase the production of lean meat in beef cattle, because estrogens augment the formation of messenger RNS, leading to an increase in the synthesis
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of muscle proteins. The authorization for using DES in animal feeds was based on a withdrawal period that would result in a “zero residue” in the beef at the time of slaughter. Beef contains “natural” steroid estrogens, of course. The availability of improved assay procedures make about 2 ppb of DES detectable in beef. Herbst et al. (10) reported eight cases of vaginal adenocarcinema in young women. While these patients were in utero, their mothers had been treated with DES. The dosage was not stated, but large amounts of DES were recommended at that time for treating threatened interruptions of pregnancy. Greenwald et al (7A) noted that 5 adenocarcinomas of the vagina were reported during 1950 to 1970 in women under 30, in the New York State Cancer Registry. Four of the mothers of these patients received DES in doses ranging up to 125 mg per day during pregnancy; the fifth received dienestrol, 5 mg daily, and intramuscular estrone. A dose of 50 mg of DES would be present in 25 tons of beef liver containing 2 ppb of DES. Herbst’s report received much comment uis-a-uis the use of DES for beef production, for example, in a colorful article by Wade (23). The crux of the matter would seem to be a quantitative evaluation: is the maximum daily intake of DES to be expected from the consumption of beef, including beef in which the statutory withdrawal period of the drug had not been observed, sufficient to produce a significant increase in the endogenous level of estrogens in human subjects? An estimate quoted in Nature (5) was that 500 lbs of liver containing 2 ppb of DES would be equivalent in terms of DES (about 0.5 mg) to the daily production of estrogen by a nubile woman. In contrast, Wade (23) states that 0.3 pg of DES, i.e., about 0.06% of 0.5 mg,” represents an appreciable addition to a woman’s own natural supply of estrogen.” This is saying that 0.3 pg would be an appreciable addition to 500 pg. Congressman L. H. Fountain has asked whether consumers “would be willing to risk exposure to a cancer-producing drug for $3.85 a year,” so it seems that the recent ban on DES in cattle feed will not be changed by any scientific evidence that may be presented at hearings. GOITROGENS
(ANTI-THYROID
COMPOUNDS)
These compounds are of unusual theoretical interest as carcinogens because they are produced by edible plants, and because their effects are simulated by iodine deficiency. The latter circumstance makes it necessary to recognize the existence of a threshold or no-effect level for the goitrogenic (and hence “carcinogenic”) stimulus. Inhibition of iodine uptake by the thyroid gland sets in motion a feedback mechanism for its stimulation by increased production of the pituitary thyrotropic hormone. The stimulus leads to a hyperplasia that ultimately produces thyroid neoplasma. This is the basis for designating goitrogens as carcinogenic, and “natural” goitrogens, as found in plants of the cabbage family, may be expected to produce neoplasia just as with iodine deficiency, or with synthetic goitrogens such as thiourea. Astwood (1) has found that natural goitrogens are present in many common foods, as shown by depression of iodine uptake by the human thyroid gland in vivo when these foods are eaten.
138
JUKES
Since iodine deficiency on an otherwise “normal” diet produces thyroid tumors, there must be a threshold value of iodine deprivation at which these tumors are first producible, unless it is concluded that all dietary regimes are “carcinogenic,” including regimes with amply adequate iodine levels. This conclusion, i.e., that a normal diet produces cancer of the thyroid gland, is, however, not usually held, unless it is conceded that the act of alimentation is inherently carcinogenic. If a threshold exists for the goitrogenic stimulus of iodine withdrawal, it must also exist for a low level of the stimulus as produced by adding specific antithyroid substances. Moreover, this purely theoretical conclusion can be reached without experimental verification: For if a deficiency will produce cancer, there must be a threshold of partial deficiency at which the carcinogenic stimulus will be dormant. NUTRITIONALLY
ESSENTIAL
SUBSTANCES
Selenium and vitamin A have been reported as being carcinogenic at high levels, although the effects of selenium in this regard are being debated. This discussion has postponed approval of inorganic selenium, e.g., sodium selenite, as an animal feed additive, although frank selenium deficiency is common in farm livestock in many countries. In our laboratory, selenium deficiency in young pigs produced “hobnail livers” (27), these might indicate a condition that is precirrhotic and hence, perhaps, precancerous. The Clause may be legally side-stepped by using fishmeal as an animal feed supplement. Marine fish contain selenium of “natural” origin and are therefore beyond the regulatory scope of the Clause. It is unlikely that vitamin A will be banned. In summary, the Delaney Clause, although avowedly protective of the consumer, leads to paradoxes in the realm of enforcement. Scientific resolution is needed of certain points regarding chemical carcinogenesis. Some of these points are: Is there a no-effect level of a carcinogen? What is “the practical equivalent of zero” for the residue of a food additive? Is there a threshold level for any carcinogenic stimulus? Can the naturally present level of a carcinogen, such as endogenous estrogens, be sufficient to render traces of an estrogenic additive insignificant? However, the emotion engendered by the question of carcinogenesis is likely to override the resolution of such questions, and no repeal or modification of the Delaney Clause may be expected, especially in the current climate of “environmentalism.” No food additive should be used that increases the probability of cancer under the conditions of its use. This protective provision of safety is included in the law without the Delaney Clause. The regulatory powers of the Food and Drug Administration are therefore not enhanced by the Clause. Its force is to prevent the evaluation for safety, at any level, of any additive that has been found to produce cancer in experimental animals at any dosage rate. Substances with such properties are inherently present in foods (21) and in
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the body. The Clause is in the law; any attempts to repeal or modify it are widely interpreted as likely to diminish the protection of the public against environmental cancer. REFERENCES 1. ASTWOOD, E. G., GREER, M. A., AND ETTLINGER, M. G. L-5-Vinyl-2-Thiooaxazolidone, an Antithyroid compound from Yellow Turnip and from Brassica Seeds. I, Biol. Chem. 181, 121 (1949). 2. CARSON, R. L. “Silent Spring,” pp. l-368. Houghton Mifflin, Boston, MA, 1962. 3. Color Additives, Hearings on H.R. 7624 and S. 2197, Committee on Interstate and Foreign Commerce, House of Representatives, 86th Congress, 1960, pp. 38-69. Government Printing Office, Washington, D. C., 1960. 4. DELANEY, J. J. Congressional Record, pp. E952-E958, Feb. 9, 1972. 5. Anon. DES-another black sheep? Nature (London) 238,67-68 (1972). 6. Editorial, Toxicol. App. Phnrmacol. 17,485 (1970). 7. EGGERT, R. G., PATTERSON, E. L. AKERS, W. T., AND STOKSTAD, E. L. R. The role of vitamin E and selenium in the nutrition of the pig. J. Anim. Sci. 16, 1037 (1957). 7A. Greenwald, P., Barlow, J. J., Masca, P. C. and Burnett, W. S. Vaginal cancer after maternal treatment with synthesis estrogens. N. Engl. J. Med. 285, 390 (1971). 8. HAYES, W. J., JR. Pharmacology and Toxicology of DDT. In “DDT The Insecticide Dichlorodiphenyltrichlorethane and Its Significance,” Vol. II, Human and Veterinary Medicine (P. Muller, Ed.), p. 252 Birkhauser Verlag, Basel, 1959. 9. HAYES, W. J., JR. Toxicity of pesticides to man: Risks from present levels. Proc. Roy. Sot. B. 167, 101 (1967). 10. HERBST, A. L., ULFELDER, H., AND POSKANZER, D. C., Adenocarcinoma of the Vagina. Association of Maternal Stilbestrol Therapy with Tumor appearance in Young Women. N. Engl. J. Med. 284,878 (1971). II. LAWS, E. R., JR. Men with intensive occupational exposure to DDT: A clinical and chemical study. Arch. Enuiron. Health 15, 766-775 (1967). 12. LEHMAN, A. J., “Summaries of Pesticide Toxicity,” Association of Food and Drug Officials of the U. S., 1965. 13. OTTOBONI, A., as cited by Staley, G. A. “California’s Health” May 1972, pp. 2-3. 14. PAL, R. Contributions of insecticides to public health in India. Would Rev. Pest Control I, 6 (1962). 15. Report of Ad Hoc Committee, Congressional Record, February 9, 1972. 16. RUCKELSHAUS, W. D. Brief for the Respondents, U. S. Court of Appeals for The District of Columbia Circuit, No. 23813, on Petition for Review of an Order of the Secretary of Agriculture, August 31,197O. 17. RUCKELSHAUS, W. Opinion of the Administrator, Environmental Protection Agency, Consolidated DDT Hearings, June 2, 1972. 18. SIMMONS, S. W. The Use of DDT Insecticides in Human Medicine. In “DDT. The Insecticide Dichlorodiphenylchloroethane and Its Significance.” Vol. II, Human and Veterinary Medicine (P. Muller, Ed.), p. 251. Birkhauser Verlag, Basel, 1959. 19. SWEENEY, E. M. Hearing Examiner’s Recommended Findings, Conclusions and Orders, Consolidated DDT Hearings, April 25, 1972. 20. TALLIAN, L. Police Gazette, “A Brand New Food Spray That Can Kill You,” p. 13, September 1962; p. 5, December 1962. Publication 1354, National Academy of Sciences, 21. “Toxicants Occurring Naturally in Foods,” National Research Council, Washington, D. C., 1966. 22. WADE, N., Aldrin and dieldrin follow DDT. Science 177,43 (1972). 23. WADE, N. DES: A case study of regulatory abdication. Science 177, 335-337 (1972). 24. YANNACONE, V. J., JR. Speech to Paper Industry PR Luncheon Group, New York, May 20, 1970.
MEDICINE
2, 133-139
(1972)
Dr.Jukes, a versatile writer on a number of scientific subjects dealing with the inte$ace of chemicals, man, and animals, discusses the difficulties associated with a rigid interpretation of the Delaney Clause, although he feels that this legislation will not be modified.
The Delaney The
“Anti-Cancer”
Delaney
Clause
Amendment
THOMAS H. JUKES Division
of Me&cd Physics, University Berkeley, California 94720
of California,
The Delaney Clause of the 1958 Food Additives Amendments is popularly termed the “Delaney Amendment.” We shall refer to it as “the Clause.” It states that “no (food) additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animals.” The same law also provides that no such additive may be used in animal feeds unless no residue of it can be found in food products obtained from the animal after slaughter. The good intentions of the Clause are unquestioned, Rather than having the temerity to oppose the Clause, I shall attempt, as a student of our times, to analyze its background and its portent. According to its author, Hon. James J. Delaney of New York (4), the Clause followed the recommendation of the International Union Against Cancer at its Rome meeting, 1956, and was “strongly endorsed by a number of top-ranked cancer experts.” Delaney says further that “carcinogens are subtle, stealthy, sinister saboteurs of life, They have no place in our food chain,” and that the F.D.A. has announced the toxicity of “stilbestrol, mercury, lead, plasticisers, monosodium, glutinate (sic) and many others. From the outset, the proponents of the Clause emphasized that no level of carcinogen was “safe” (3). The argument that many “natural” food additives and components produce cancer in experimental animals was met by the customary rejoinder that it was dangerous to add to the existing burden of carcinogens to which consumers are exposed, In 1960 Flemming (3) (then Secretary of Health, Education and Welfare) emphasized a quotation from Mider, as follows: No one at this time can tell how much or how produce cancer in any human being, or how
little long
of a carcinogen it would take
would be required to the cancer to develop.
In this statement, the term “how little” can be interpreted as referring to a single molecule; and “how long” may mean a lifetime or even a carry-over into offspring (see below, in discussion of DES). Applied to situations other than food additives, the statement could include the exposure of consumers to carcinogens produced by pyrolysis and cooking of foods, such as by toasting, Copyright All rights
@ 1973 by Academic Press, Inc. of reproduction in any form reserved.
133
134
JUKES
roasting and prolonged heating; carcinogens “naturally” present in foods; and the effects of ionizing radiation, including sunlight. There are indications that the doctrine of the absence of a threshold or a tolerable level is being extended to other chemicals, such as mutagens, even though mutation is a normal biological process. The principle formulated by Mider together with the Delaney Clause, and the recent remarkable improvements in analytical techniques, are sufficient to exclude a substance as a food or animal feed additive when reported as a carcinogen, even though the same substance or one with very similar pharmacodynamic properties is inherently present in foods. The Clause originated in Congress rather than in a federal agency of the executive branch of the government. Two contrasting scientific viewpoints have been developed on the subject embraced by the Clause. The first (15) is similar to that enunciated by Mider. It says: No level of exposure to a chemical carcinogen cant for man. For carcinogenic agents a “safe tion of our present knowledge.
should be considered level for man” cannot
toxicologically be established
insignifiby applica-
It is equally logical to say, of course, that the liminal value of an “unsafe for man” cannot be established by application of our present knowledge. statement continues: The
concept
of a “socially
acceptable
risk”
represents
a more
realistic
The concept that a risk of cancer would be socially acceptable ceptable. The statement appears somewhat cynical. The other viewpoint has been expressed:
level The
notion.
is itself unac-
The conclusion that a chemical agent either is or is not a carcinogenic hazard to man based on animal experimentation, regardless of the dose, route of administration, mechanisms of translocation and particularly the biotransformation mechanisms which are involved in the species under study, is basically inconsistent with established fundamental concepts of the science of toxicology. In spite of the lack of complete knowledge of the subject of chemicalinduced carcinogenesis, it is possible to define the limits of chemical-induced carcinogenesis much along the lines that have been utilized by the regulatory agencies for food additives when any other form of toxicity is under consideration. This is, basically, starting with a concept of the existence of a no-effect or of a toxicologically insignificant dose level (6).
The final sentence seems reasonable, for there must be a molecular level at which the effects of a “carcinogen” reach the point of insignificance by comparison with the omnipresent background of other carcinogenic stimuli. But we have another factor to consider; this is the effect of public pressure upon lawmakers and regulatory agencies. In my opinion, this is the overweening issue in discussions of the Clause. Most scientists in the field of cancer will almost certainly evaluate the slightest risk from cancer as outweighing any need for suspected food additives, and the consuming public will unquestionably side with this evaluation. Furthermore, with a division of scientific opinion, the public will vote for “safety.” In addition, consumers have for more than a decade been subjected to adverse publicity regarding the alleged carcinogenicity of “poisoned” cranberries (3), insecticides (2,20), cyclamates, and diethylstilbestrol (DES) in meat (23). Attempts to repeal or reduce the Clause will meet with resistance and suspicion.
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Certain substances in the diet either (a) can be made to elicit a carcinogenic response in a susceptible laboratory animal when administered orally in a suitable vehicle and at a high dosage level, or, (b) are undisputable strong carcinogens, although they are present at extremely low concentrations, such as the background of radioactive elements which occurs in all biological materials. The Clause, if zealously enforced, can virtually stop the production of food by modern scientific technology. Let us apply “Occam’s Razor” to this complex discussion, and ask three questions: (i) Is there a no-effect level for carcinogenesis?; (ii) can “similar” carcinogens be compared quantitatively with each other?; and (iii) is there a threshold level for certain tumor-inducing stimuli? The first question probably relates to DNA; it is often stated that a single nucleotide change in one DNA molecule may be sufficient to start a carcinogenic train of events. Since all animals do not die of cancer in their old age, there must be a no-effect level in terms of the average life span. (ii) As an example, can diethylstilbestrol be weighed against estrone? Since their carcinogenic effects are the direct result of their estrogenic properties, the answer is yes, but species specificity and tissue or organ specificity must be reckoned with. (iii) The goitrogenic stimulus, discussed below, provides an affirmative answer to this. DDT
Potentially the most devastating possibility of the Clause is its application to DDT. This substance has saved more lives and prevented more disease than any chemical in history (18). Life expectancy in India increased from 32 to 47 years during 1953 to 1961; this was attributed to the decline in malaria resulting from the DDT house-spraying program (14). DDT was exhaustively examined for toxicity in laboratory animals during 1944-1965, after which it was stated to be noncarcinogenic (12). Nevertheless, the induction of tumors in certain strains of mice by sublethal continuous dosage with DDT over a lifetime has been reported. The experimental evidence in this field is conflicting (8); rodents, but not other experimental animals, have developed tumors when they have received massive doses of DDT for prolonged periods. As recounted by Yannacone (24), the Environmental Defense Fund (EDF) decided to use the Delaney Clause against DDT. Yannacone’s version is as follows: There appeared four papers in various journals inferring that DDT might induce tumors, not cancer, but tumors in some particularly susceptible strains of mice . . . the leader of the (EDF) scientific team in the DDT fight, decided that we should hire a public relations firm, call a press conference, announce that DDT causes cancer, and demand, under the Delaney Amendment, that the FDA-USDA cancel the use of DDT immediately (24).
To heighten the emotional impact of their campaign, the EDF linked the DDT content of breast milk with the carcinogenic@ allegation. Primarily as a result of this and similar publicity, and contrary to testimony as summarized in the findings of the Examiner in the recent hearings on DDT, (19) Ruckelshaus (17) has issued a ban on the few remaining uses of DDT in the U.S.A. and has reinforced his ban, by stating that:
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JUKES DDT is a potential human carcinogen. (a) Experiments demonstrate that DDT causes tumors in laboratory animals; (b) there is some indication of metastasis of tumors attributed to exposure of animals to DDT in the laboratory; (c) responsible scientists believe tumor induction in mice is a valid warning of possible carcinogenic properties; (d) there are no adequate negative experimental studies in other mammalian species; (e) there is no adequate human epidemiological data on the carcinogenicity of DDT, nor is it likely that it can be obtained; (f) not all chemicals show the same tumorigenic properties in laboratory tests on animals. DDT presents a carcinogenic risk.
Two years ago, however, Ruckelshaus, as Assistant Attorney General, filed a brief in the U.S. Court of Appeals on behalf of the Secretary of Agriculture (16). The brief states: DDT is not endangering the public health and has an amazing and exemplary record of safe use. DDT, when properly used at recommended concentrations, does not cause a toxic response in man or other mammals and is not harmful. The carcinogenic claims regarding DDT are unproved speculation.
Ruckelshaus has extended his present involvement with oncology luating two other pesticides, aldrin and dieldrin, according to Science folIows:
to eva(22), as
The committee’s cancer expert, Stephen S. Stemberg of Sloan-Kettering Institute, noted that the closest dieldrin comes to causing cancer is in increasing the incidence of a naturally occurring tumor in a single strain of mice. “No carcinogenic action has been demonstrated for dieldrin in rats, dogs, or primates” Sternberg says. In last week’s decision to reaffirm the cancellations of aldrin and dieldrin, Ruckelshaus stated that he had found DDT to be a potential human carcinogen and that “appraisal of similar laboratory evidence concerning dieldrin leads me to make the same finding here.”
Apparently Ruckelshaus’ opinions on carcinogenesis vary. Ottoboni (13) fed dogs 10 and 100 mg of DDT per kilo of body weight per day through four generations. No harmful effects on reproduction, growth or viability, and no tumors were found. Females on the higher level of DDT reached puberty about 60 days earlier than the controls. The long-term continuous exposure of many human beings to DDT dates back to 1945. In 1967, Hayes (9) commented that the length of time was equivalent to a generation in terms of human life span. Many subjects have been exposed to DDT, often for long terms at high dosage rates, without any cases of cancer attributable to this exposure being reported. We may expect that, triggered by adverse American publicity against DDT, a revulsion against the use of DDT and other pesticides will sweep the “malaria belt.” Suffering and death from malaria and other insect-borne diseases throughout the tropics will result. DIETHYLSTILBESTROL
(DES)
This substance, like all estrogens, will produce mammary tumors in mice, and is hence definable as a carcinogen. DES has been used since the 1930s for estrogen replacement therapy, and for other clinical purposes such as treatment of prostatic cancer in human patients. DES is used extensively to increase the production of lean meat in beef cattle, because estrogens augment the formation of messenger RNS, leading to an increase in the synthesis
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of muscle proteins. The authorization for using DES in animal feeds was based on a withdrawal period that would result in a “zero residue” in the beef at the time of slaughter. Beef contains “natural” steroid estrogens, of course. The availability of improved assay procedures make about 2 ppb of DES detectable in beef. Herbst et al. (10) reported eight cases of vaginal adenocarcinema in young women. While these patients were in utero, their mothers had been treated with DES. The dosage was not stated, but large amounts of DES were recommended at that time for treating threatened interruptions of pregnancy. Greenwald et al (7A) noted that 5 adenocarcinomas of the vagina were reported during 1950 to 1970 in women under 30, in the New York State Cancer Registry. Four of the mothers of these patients received DES in doses ranging up to 125 mg per day during pregnancy; the fifth received dienestrol, 5 mg daily, and intramuscular estrone. A dose of 50 mg of DES would be present in 25 tons of beef liver containing 2 ppb of DES. Herbst’s report received much comment uis-a-uis the use of DES for beef production, for example, in a colorful article by Wade (23). The crux of the matter would seem to be a quantitative evaluation: is the maximum daily intake of DES to be expected from the consumption of beef, including beef in which the statutory withdrawal period of the drug had not been observed, sufficient to produce a significant increase in the endogenous level of estrogens in human subjects? An estimate quoted in Nature (5) was that 500 lbs of liver containing 2 ppb of DES would be equivalent in terms of DES (about 0.5 mg) to the daily production of estrogen by a nubile woman. In contrast, Wade (23) states that 0.3 pg of DES, i.e., about 0.06% of 0.5 mg,” represents an appreciable addition to a woman’s own natural supply of estrogen.” This is saying that 0.3 pg would be an appreciable addition to 500 pg. Congressman L. H. Fountain has asked whether consumers “would be willing to risk exposure to a cancer-producing drug for $3.85 a year,” so it seems that the recent ban on DES in cattle feed will not be changed by any scientific evidence that may be presented at hearings. GOITROGENS
(ANTI-THYROID
COMPOUNDS)
These compounds are of unusual theoretical interest as carcinogens because they are produced by edible plants, and because their effects are simulated by iodine deficiency. The latter circumstance makes it necessary to recognize the existence of a threshold or no-effect level for the goitrogenic (and hence “carcinogenic”) stimulus. Inhibition of iodine uptake by the thyroid gland sets in motion a feedback mechanism for its stimulation by increased production of the pituitary thyrotropic hormone. The stimulus leads to a hyperplasia that ultimately produces thyroid neoplasma. This is the basis for designating goitrogens as carcinogenic, and “natural” goitrogens, as found in plants of the cabbage family, may be expected to produce neoplasia just as with iodine deficiency, or with synthetic goitrogens such as thiourea. Astwood (1) has found that natural goitrogens are present in many common foods, as shown by depression of iodine uptake by the human thyroid gland in vivo when these foods are eaten.
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Since iodine deficiency on an otherwise “normal” diet produces thyroid tumors, there must be a threshold value of iodine deprivation at which these tumors are first producible, unless it is concluded that all dietary regimes are “carcinogenic,” including regimes with amply adequate iodine levels. This conclusion, i.e., that a normal diet produces cancer of the thyroid gland, is, however, not usually held, unless it is conceded that the act of alimentation is inherently carcinogenic. If a threshold exists for the goitrogenic stimulus of iodine withdrawal, it must also exist for a low level of the stimulus as produced by adding specific antithyroid substances. Moreover, this purely theoretical conclusion can be reached without experimental verification: For if a deficiency will produce cancer, there must be a threshold of partial deficiency at which the carcinogenic stimulus will be dormant. NUTRITIONALLY
ESSENTIAL
SUBSTANCES
Selenium and vitamin A have been reported as being carcinogenic at high levels, although the effects of selenium in this regard are being debated. This discussion has postponed approval of inorganic selenium, e.g., sodium selenite, as an animal feed additive, although frank selenium deficiency is common in farm livestock in many countries. In our laboratory, selenium deficiency in young pigs produced “hobnail livers” (27), these might indicate a condition that is precirrhotic and hence, perhaps, precancerous. The Clause may be legally side-stepped by using fishmeal as an animal feed supplement. Marine fish contain selenium of “natural” origin and are therefore beyond the regulatory scope of the Clause. It is unlikely that vitamin A will be banned. In summary, the Delaney Clause, although avowedly protective of the consumer, leads to paradoxes in the realm of enforcement. Scientific resolution is needed of certain points regarding chemical carcinogenesis. Some of these points are: Is there a no-effect level of a carcinogen? What is “the practical equivalent of zero” for the residue of a food additive? Is there a threshold level for any carcinogenic stimulus? Can the naturally present level of a carcinogen, such as endogenous estrogens, be sufficient to render traces of an estrogenic additive insignificant? However, the emotion engendered by the question of carcinogenesis is likely to override the resolution of such questions, and no repeal or modification of the Delaney Clause may be expected, especially in the current climate of “environmentalism.” No food additive should be used that increases the probability of cancer under the conditions of its use. This protective provision of safety is included in the law without the Delaney Clause. The regulatory powers of the Food and Drug Administration are therefore not enhanced by the Clause. Its force is to prevent the evaluation for safety, at any level, of any additive that has been found to produce cancer in experimental animals at any dosage rate. Substances with such properties are inherently present in foods (21) and in
THE
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the body. The Clause is in the law; any attempts to repeal or modify it are widely interpreted as likely to diminish the protection of the public against environmental cancer. REFERENCES 1. ASTWOOD, E. G., GREER, M. A., AND ETTLINGER, M. G. L-5-Vinyl-2-Thiooaxazolidone, an Antithyroid compound from Yellow Turnip and from Brassica Seeds. I, Biol. Chem. 181, 121 (1949). 2. CARSON, R. L. “Silent Spring,” pp. l-368. Houghton Mifflin, Boston, MA, 1962. 3. Color Additives, Hearings on H.R. 7624 and S. 2197, Committee on Interstate and Foreign Commerce, House of Representatives, 86th Congress, 1960, pp. 38-69. Government Printing Office, Washington, D. C., 1960. 4. DELANEY, J. J. Congressional Record, pp. E952-E958, Feb. 9, 1972. 5. Anon. DES-another black sheep? Nature (London) 238,67-68 (1972). 6. Editorial, Toxicol. App. Phnrmacol. 17,485 (1970). 7. EGGERT, R. G., PATTERSON, E. L. AKERS, W. T., AND STOKSTAD, E. L. R. The role of vitamin E and selenium in the nutrition of the pig. J. Anim. Sci. 16, 1037 (1957). 7A. Greenwald, P., Barlow, J. J., Masca, P. C. and Burnett, W. S. Vaginal cancer after maternal treatment with synthesis estrogens. N. Engl. J. Med. 285, 390 (1971). 8. HAYES, W. J., JR. Pharmacology and Toxicology of DDT. In “DDT The Insecticide Dichlorodiphenyltrichlorethane and Its Significance,” Vol. II, Human and Veterinary Medicine (P. Muller, Ed.), p. 252 Birkhauser Verlag, Basel, 1959. 9. HAYES, W. J., JR. Toxicity of pesticides to man: Risks from present levels. Proc. Roy. Sot. B. 167, 101 (1967). 10. HERBST, A. L., ULFELDER, H., AND POSKANZER, D. C., Adenocarcinoma of the Vagina. Association of Maternal Stilbestrol Therapy with Tumor appearance in Young Women. N. Engl. J. Med. 284,878 (1971). II. LAWS, E. R., JR. Men with intensive occupational exposure to DDT: A clinical and chemical study. Arch. Enuiron. Health 15, 766-775 (1967). 12. LEHMAN, A. J., “Summaries of Pesticide Toxicity,” Association of Food and Drug Officials of the U. S., 1965. 13. OTTOBONI, A., as cited by Staley, G. A. “California’s Health” May 1972, pp. 2-3. 14. PAL, R. Contributions of insecticides to public health in India. Would Rev. Pest Control I, 6 (1962). 15. Report of Ad Hoc Committee, Congressional Record, February 9, 1972. 16. RUCKELSHAUS, W. D. Brief for the Respondents, U. S. Court of Appeals for The District of Columbia Circuit, No. 23813, on Petition for Review of an Order of the Secretary of Agriculture, August 31,197O. 17. RUCKELSHAUS, W. Opinion of the Administrator, Environmental Protection Agency, Consolidated DDT Hearings, June 2, 1972. 18. SIMMONS, S. W. The Use of DDT Insecticides in Human Medicine. In “DDT. The Insecticide Dichlorodiphenylchloroethane and Its Significance.” Vol. II, Human and Veterinary Medicine (P. Muller, Ed.), p. 251. Birkhauser Verlag, Basel, 1959. 19. SWEENEY, E. M. Hearing Examiner’s Recommended Findings, Conclusions and Orders, Consolidated DDT Hearings, April 25, 1972. 20. TALLIAN, L. Police Gazette, “A Brand New Food Spray That Can Kill You,” p. 13, September 1962; p. 5, December 1962. Publication 1354, National Academy of Sciences, 21. “Toxicants Occurring Naturally in Foods,” National Research Council, Washington, D. C., 1966. 22. WADE, N., Aldrin and dieldrin follow DDT. Science 177,43 (1972). 23. WADE, N. DES: A case study of regulatory abdication. Science 177, 335-337 (1972). 24. YANNACONE, V. J., JR. Speech to Paper Industry PR Luncheon Group, New York, May 20, 1970.