State attorney general is a "people's lawyer," then in that role he may sue a State agency. What then is to prevent a State attorney general from suing a Federal regulatory agency in order to protect the citizens of his State? An appropriate test case for this could well be a suit to enjoin the FDA from permitting existing stocks of DES cattle feed to be used until January 1, 1973. This approach could be developed independently of or complementarily with other appropriate

actions in this matter.

4. THE NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH, PINE BLUFF This Center was created by presidential order on January 27, 1971. The FDA is the operating agency for the Center, which will be supported fiscally by the EPA and FDA, equally. The Center is considered to be a national resource, besides a research resource for the FDA and EPA in regulating drugs, food additives, pesticides and other consumer products.

While it is difficult to comment on the Center's programs, as these have not yet been initiated, there is cause for concern that the intended functions of the Center may be subverted. The basis for these concerns largely derives from statements made by representatives of the FDA and industry at the 1971 Annual Meeting of the Flavor and Extract Manufacturers Association, Palm Beach, Fla., as quoted in Food Chemical News, May 10, 1971. The FDA official (Kolbye, 1971) stated:

Not only will the Center provide a testing facility so that we can catch up on a priority basis with the testing for substances not previously tested, but also we can begin to explore this brave new world of doseresponse relationships as related to carcinogenesis, teratogenesis, and mutagenesis. . . one of the major thrusts of the National Center will be to test large populations of animals with relatively low-level, long-term exposures to chemicals that have been currently identified as being potentially carcinogenic, such as DDT.

We have good reasons to suspect that man can tolerate exposure to certain substances without adverse effect ensuing. By this, I do not mean to imply that we are going to abrogate our responsibility to protect public health, nor do I mean to challenge some of the good intentions behind the Delaney amendment. However, we must face reality in that there are many potential carcinogenic substances naturally to be found in our food supply for which we must develop a meaningful regulatory posture.

Fortunately, the Delaney amendment does not directly apply to pesticide residues, otherwise we might be faced with the technical absurdity of having to ban most of our nation's food supply because of minute residues of DDT. Of course, in the last decade since the Delancy amendment was enacted, we have developed new and much more sensitive techniques of analytical chemistry, which will detect residues down to the part per billion, and, in some instances, the part per trillion level.

***for certain substances used in the food supply which are of little economic value to private industry, yet are beneficial from the public's standpoint, the taxpayer will probably have to pick up the bill for additional testing-we do not intend to extend this principle to doing all the safety testing that will be necessary to be accomplished in the future.

At the same meeting, an industry representative (Hall of McCormick Co.) expressed the hope that the Pine Bluff work may convince more scientists that "no-effect levels can be set for carcinogens."

At hearings before Congressman Whitten's Subcommittee on Agriculture, as quoted in Food Chemical News, April 26, 1971, Commissioner Edwards confirmed these suspicions on the FDA's attitude to Pine Bluff. He suggested that: "The Pine Bluff testing facility will provide FDA with the scientific basis on which the Delaney anti-cancer clause may be changed,' "*** reiterating his long held view that the agency is "locked into an all-or-nothing" position because of the Delaney box. He said "FDA didn't want to make it more difficult by recommending changes until it has the scientific data to justify a modification." In other words, plans are being made to develop data at the taxpayer's expense, which will be used to challenge the law, the Delaney amendment, designed to protect him. Apart from the propriety of this approach, scientifically the large scale "megamouse" animal studies planned will certainly not provide the data needed to challenge the concept of zero tolerance for dietary carcinogens.

Referring to the "megamouse" studies planned at Pine Bluff, Dr. Saffiotti, Associate Director for Carcinogenesis at the NCI, stated in recent congressional hearings (Saffiotti, 1971):

I personally believe that certain approaches to the problem of identifying a "safe threshold" for carcinogens are scientifically and economically unsound. I have in mind some proposals to test graded doses of one carcinogen, down to extremely low levels, such as those to which a human population may be exposed through, say, residues in food. In order to detect possible low incidences of tumors, such a study would use large numbers of mice, of the order of magnitude of 100,000 mice per experiment ("megamouse experiment"). This approach seems to assume that such a study would reveal that there is a threshold dose below which the carcinogen is no longer effective, and therefore that a "safe dose" can be identified in this manner. Now, there is presently no scientific basis for assuming that such a threshold would appear. Chances are that such a "megamouse experiment" would actually confirm that no threshold can be determined. But let us assume that the results showed a lack of measurable tumor response below a certain dose level in the selected set of experimental conditions and for the single carcinogen under test. In order to base any generalization for safety extrapolations on such a hypothetical finding, one would have to confirm it and extend it to include other carcinogens and other experimental conditions such as variations in diet, in the vehicles used, in the age of the animals, their sex, etc. Each of these tests would then imply other megamouse experiments. The task would be a formidable one: suffice it to say that an experiment on 100,000 mice would cost about $15 million; if one did 20 such experiments, it would cost $300 million. All this to try and estimate the possible shape of a dose response curve, which would still leave most of our problems in the evaluation of carcinogenesis hazards unsolved. This effort would also block the Nation's resources for long-term bioassays for years to come and actually present the use of such resources for the detection of potent carcinogenic hazards from yet untested environmental chemicals. If 2 million mice are made available as a resource, they can be used effectively to test 4,000 new compounds, each on 500 mice, thereby detecting among them those that are highly carcinogenic in the test conditions.

These general concerns are by no means alleviated by the statement of the Associate Commissioner for Science of the FDA, Dale Lindsay (as quoted in Food Chemical News, Nov. 9, 1970) that the FDA was working on the Pine Bluff plans primarily through the Society of Toxicology.

(a) Senate bill S. 76

5. COMMENTS ON PROPOSED LEGISLATION

I would recommend that the proposed amendment in section 3 (lines 10-19) be modified to read as follows:

That no food additive shall be deemed to be safe if it is found to induce cancer, congenital deformities, or genetic mutation, when ingested by man or animal, or if it is found after tests which are appropriate for the evaluation of the safety of food additives to induce cancer, birth defects or genetic mutation in man or animal.

The proposed modification excludes the concept of "chronic biological injury or damage in any respect. Chronic toxicity per se is nonspecific and can be induced by any natural or synthetic chemical when administered to man or animals at high enough doses for prolonged periods of time. Carcinogenesis (induction of cancer) mutagenesis (induction of mutations), and teratogenicity (induction of birth defects) are however unique and irreversible manifestations of chronic toxicity. For these reasons, it is appropriate to extend the concept of the Delaney amendment to include both mutagenic and teratogenic effects of food additives, but not to chronic toxicity per se. No valid data exist indicating the existence of threshold levels for mutagens or teratogens, as indeed is the case for carcinogens.

(b) Senate bill S. 3163

i. Section 410 (a) (i): There is an ambiguous implication that the Secretary will bear financial responsibility for:

. . . having new tests or investigations conducted on additives which have been approved prior to the enactment of this section, in order to determine whether or not approval of such additives should be withdrawn. The financial onus for safety evaluation of food additives has been placed on the manufacturer by law. Therefore, it would appear unreasonable for the taxpayer to assume financial responsibility for the testing of currently used profitable food chemicals, alleged to be Generally Recognized As Safe.

ii. Section 410(c): The phrase "effectiveness of food additives" requires clarification and definition.

Effectiveness can be defined restrictively from a Federal Trade Commission (FTC) standpoint to indicate that use of the additive will achieve the stated objective, or alternatively from a broad standpoint of societal and economic utility. The term "effective" could be used for the former requirement, and the term "necessary" for the latter requirement (see bill section 3(q)). The narrow FTC type definition would allow, safety apart, the use of monosodium glutamate in baby food, as glutamate is effective in that it does enhance taste, but it is not necessary as babies have not developed a sense of taste; it would allow a wide range of cosmetic food colors, which are effective in coloring foods which the public has been influenced by advertising pressures into "demanding," although there is no broad societal or economic benefit or necessity in this; and, it would allow nitrites to be added for cosmetic purposes, even in those instances where botulinus hazards cannot be substantiated.

Clearly, efficacy or necessity must be defined broadly, and requirements for efficacy, now generally accepted for drugs, should be extended to food additives and all other synthetic chemicals in consumer products and otherwise used in

commerce.

Inherent in toxicological and regulatory philosophy and practice is lip service to the concept of balancing benefit and benefit to the public not to industry, against risk, and risk to public health or environmental integrity and not economic risk to industry. If the chemical in question does not serve a broad socially and economically useful purpose for the general population, why introduce it and force the public-at-large to accept potential hazards without general matching benefits? Such questions should be vigorously directed to cosmetic food coloring agents, besides to food additives in general.

These concepts were emphasized at a recent White House conference on nutrition, where it was recommended by a leading industrial spokesman that food additives be excluded from products unless they either significantly improve the quality or nutritive value of the food or lower its cost as well as being safe (Kendall, 1969).

Additionally, I would recommend that there be consideration of developing a new subsection of the bill to reflect the concept of "third party testing" developed earlier in my testimony. This would also relieve the Secretary from the invidious responsibility of selecting and certifying qualified experts.

iii. Section 410(d): The requirement that the Secretary notify applicants, to that effect, when a period of more than one year is necessary to develop requisite data is unrealistic. Carcinogenicity tests take a minimum of 2 years to conduct, quite apart from the time needed for evaluation. I recommend substituting "more than 3 years", instead of "more than 1 year".

iv. Section 410(e): Rather than requiring the Secretary, on request, to supply the sponsor with details of test procedures used in testing his product, I would recommend the requirement "that all procedures and protocols be based on those promulgated in the Federal Register." This would of course compel such overdue promulgation.

v. Section 410(h) (i): I would recommend that the phrase "liable for the direct costs incurred", be changed to "liable for the direct and indirect costs incurred." vi. Section 410(k) (i): I would recommend that the requirement for public access to data on new food additives be extended to food additives in current use.

6. REFERENCES

Ad Hoc Committee on the Evaluation of Low Levels of Environmental Chemical carcinogens. Report to the Surgeon General, Apr. 22, 1970.

Bickwit, L. A Senate Counsel's Response to a Paper on "Pollution and Health by Epstein, S. S. Chapter XI, pp. 218-227, in, The New Genetics and the Future of Man, ed. M. Hamilton, Pub. W. B. Eerdmans, Grand Rapids, Mich., 1972. Bingham, E., and Falk. H. L. 1969. Environmental Carcinogens. Modifying Effect of Carcinogens on the Threshold Response, Arch. Env. Health, 19:779-783. Brooks, H. CPR National Journal, p. 224, January 30, 1971.

Crow, J. F. 1968. Chemical risk to future generations. Scientist and Citizen. 10:113-117.

Darby, J. W. Hearings on Color Additives before the House Committee on Interstate and Foreign Commerce, 86th Cong., 2d sess., 501, 1960.

Department of Health, Education and Welfare, Food and Drug Administration [21] CFR Part [21], Federal Register [32] F.R. 11443, Aug. 8, 1967. Environment, 1969. Diminishing returns. Staff Report. 11:6-36.

Epstein, S. S., Hollaender, A., Lederberg, J., Legator, M., Richardson, H. and Wolff, A. H. 1969. Wisdom of Cyclamate Ban. Science. 166:1575. Epstein, S. S. 1971. Testimony on adverse human effects due to chemical pollutants. U.S. Senate Hearings Before the Subcommittee on Executive Reorganization and Government Research. Committee on Government Operations, Apr. 6, 1971.

Epstein, S. S. 1972. Environmental Pathology. A Review, Am. J. Path. 66: 352-374.

Flemming, A. Hearings on Color Additives before the House Committee on Interstate and Foreign Commerce, 86th Cong. 2d sess., 501, 1960. Friedman, L., Kunin, C. M., Nelson, M., Whittenberger, J. L. and Wilson, J. G. 1970. Food and Drug Administration, Advisory Committee on Protocols for Safety Evaluation; Panel on reproduction studies in the safety evaluation of food additives and pesticide residues. Toxicol. Appl. Pharmacol. 16:264-296. Herbst, A. L., Ulfeder, H. and D. C. Poskanzer. 1971. "Adenocarcinoma of the vagina: association of maternal stilbestrol therapy with tumor appearance in young women. New Eng. J. Med. 284:878-881.

Herbst, A. L. Personal Communication, 1971.

Hueper, W. C. Occupational and Environmental Cancers of the Urinary System, University Press, New Haven, 1969.

Innes, J. R. M., Ulland, B. M., Valerio, M. G., Petrucelli, L., Fishbein, L., Hart, E. R., Pallotta, A. J., Bates, R. R., Falk, H. L., Gart, J. J., Klein, M., Mitchell, I., and Peters, J. 1969. Bioassay of Pesticides and Industrial Chemicals for Tumorigenicity in Mice: A preliminary Note. J. Nat. Cancer Inst., 43:

1101-1114.

Kalter, H. Teratology of the Central Nervous System. University of Chicago Press, 1968.

Kendall, D. M. A Summary of Panel Recommendations: Report of a Panel on Food Safety to the White House Conference on Food Nutrition and Health, (19) Nov. 22, 1969.

King, C. J. 1965. Antihistamines and Teratogenicity in the Rat. J. Pharm. Exp. Therap., 147:391–398.

Legator, M. 1972. Personal Communication.

Loomis, T. A. 1970. Editorial. Constructive Criticism-a tool for influencing some national problems in toxicology. Toxicol. Appl. Pharmacol. 17:i-iii. Marvin, R. 1972. Personal communication.

Miller, R. W. 1966. Relation between cancer and congenital defects in man. New Eng. J. Med. 275:87-93.

Montesano, R., Saffiotti, U., and Shubik, P. The Role of Topical and Systemic Factors in Experimental Respiratory Carcinogenesis. p. 353. In, Inhalation Carcinogenesis. U.S. Atomic Energy Commission, April 1970.

National Academy of Sciences, National Research Council. Food Protection Committee Task Force. Guidelines for estimating toxicologically insignificant levels of chemicals in food, April 1969.

Preussmann, R., Druckrey, H., Ivankovic, S., and Hodenberg, A. V. 1969. Chemical studies and carcinogenicity of aliphatic, hydrazy, azo and azoxy compounds and triazenes. Potential in vivo alkylating agents. Ann. N.Y. Acad. Sci. 163; article 2, 697-716.

Reports of the Advisory Panels on Carcinogenicity, p. 459; on Mutagenicity, p. 565; on Teratogenicity, p. 655; Report of the Secretary's Commission on

Pesticides and Their Relationship to Environmental Health, U.S. Department of Health, Education, and Welfare, December 1969.

Report of the National Institute of Environmental Health Sciences Task Force on Research Planning in Environmental Health Sciences, U.S.P.H.S. Mar. 10, 1970.

Saffiotti, U. Statement Before the Subcommittee on Executive Reorganization and Government Research, Senate Committee on Government Operations, Apr. 7, 1971. Schwetz, B. A., Sparsch, G. L., and Gehring, P. J. 1971. The effect of 2,4-D and esters of 2,4-D on rat embryonal, foetal and neonatal growth and development Fd. Cosmet. Toxicol., 9:801-817.

Schubert, J., 1972. A Program to Abolish Harmful Chemicals. Ambio (Sweden) 1:79-89.

Sinhuber, R. O., Wales, J. H., Ayers, J. L., Engebrecht, R. H., and Amend, D. L. 1968. Dietary Factors and Hepatoma in Rainbow Trout (Salmo gairdneri). 1. Aflatoxins in Vegetable Protein Feedstuffs. J. Nat. Cancer Inst. 41:711-718. Turner, J., 1972. Personal Communication.

Wilson, R. CPR National Journal, p. 107, Jan. 16, 1971.

Wodicka, V. O. 1972. The Current Status of Food Regulations. FDA Papers

6:10-16.

Yerushalamy, J., and Milkovich, L. 1965. Evaluation of the Teratogenic Effects of Meclizine. Amer. J. Obstet. Gynecol. 93:553–562.

(a) Personal curriculum vitae.

7. APPENDIXES

(b) Internal FDA Memorandum of Mr. A. T. Spiher, Dec. 5, 1969.

(c) Address by William D. Ruckelshaus at The American Society of Toxicology, Washington, D.C., Mar. 9, 1971, and subsequent correspondence relating to the refusal of the Society to publish this speech.

(d) Letter of Dr. A. T. Schramm, chairman of the Industry Committee of the Industrial Liaison Panel, NAS-NRC to Dr. W. J. Darby, chairman of the Food Protection Committee of the NAS-NRC, Oct. 30, 1969.

(e) Letter by Dr. S. S. Epstein and Dr. Legator to Dr. E. Mrak, Chairman, HEW Secretary's Commission on Pesticides, Nov. 21, 1969.

(f) Correspondence with Foster D. Snell, Inc., Mar. 28, 1972-May 15, 1972. (g) Congressmen "contacted" by the Society of Toxicology, June 28, 1972.

Born April 13, 1926, Middlesborough, Yorkshire, England. Naturalized U.S.
citizen, married, three children.

Professional address: Case Western Reserve University, School of Medicine,
Cleveland, Ohio 44106.

Qualifications:

1947, B.Sc. (physiology) London University, England.

1950, M.B.B.S. (bachelor of medicine, bachelor of surgery) (double honors) London University, England.

1952, D.T.M.H. (diploma of tropical medicine and hygiene, bacteriology and parasitology) London University.

1954, D.Path. (diploma of pathology) London University,

1958, M.D. (doctorate of medicine, thesis in pathology and bacteriology) London University, England.

1963, Diplomate, in public health and medical laboratory microbiology, of the American Board of Microbiology.

Positions held:

1950, Demonstrator, morbid anatomy, Guy's Hospital, London.

1951, House physician, St. John's Hospital, London.

1952, Postgraduate student in tropical medicine, pathology, bacteriology, and parasitology, Royal Army Medical College, London.

1952-55, Specialist in pathology, Royal Army Medical Corps.

1955-58, Lecturer in pathology and bacteriology, Institute of Laryngology and Otology, University of London.