all you can do, and at the time she did what he told her. He was merely saving a life.

It is true, in essence, that she should not feel guilty, but I am sure anyone can understand that she would.

Senator KENNEDY. Of course, there was not the information then that would ever suggest to the doctor that recommended that she take this drug that it was in any way going to be a danger to you or to the children.

That information has only been developed in recent times.

Ms. LUDER. Right.

Senator KENNEDY. But we have it now. That is the very major difference. We have that information now, and we are able to avoid the kinds of problems that have affected each of you. I think we can do that now. I think we must, and we have to, and we will.

I think your doctor deserves a great deal of credit, Ms. Luder, for following up and pursuing that.

I think in considering a variety of different issues, he ought to be recognized.

I think it shows the importance of continuing followup. This is something for those who have been affected by the drug. This is extremely important.

I think it is something that we cannot stress or emphasize enough. I want to thank you.

Senator Schweiker?

Senator SCHWEIKER. Thank you, Mr. Chairman.

Mrs. Malloy, I am sure it was not an easy decision for you to make, to come here today and to testify. I am sure you probably decided to help other people who might be confronted with the situation you are confronted with.

What would you expect your Government to do about it? You have obviously come here hoping that we are going to do something, or certainly somebody will do something. I gather that you would feel that the Government does have a responsibility, and that certainly if no one takes it, probably Congress should.

What do you think we should be doing, and is that not why you are here?

Mrs. MALLOY. Yes, Senator. This is why I am here.

I feel rather strongly about DES, naturally. I feel someone has got to safeguard us some way or another from this kind of thing happening. It is inexcusable to me that a drug can be passed out so readily and so easily, and then for us to find out later on it really had no effect anyway. It did not really prevent miscarriages. This is one of the very sad parts of it.

We were given the idea that this was going to help our miscarriages. I think something has to be done, as Mrs. Green said, there has to be more research done before these things are handed out indiscriminately.

I feel very strongly against DES in any way, shape, or form. I am sure all three of us do.

Senator SCHWEIKER. I certainly understand that.

Ms. Luder, what do you think your Government's responsibility is here? You certainly ought to be telling us, I think, in view of what has happened.

Ms. LUDER. I definitely think it should be taken off the market. I think any redeeming value it might have is outweighed by the tragedy it causes.

I think also not only should they try and remove it from the market, from using it in cattle, also, aside from the fact they are distributing it to humans, they should perhaps try and create some kind of campaign, mobile clinics, that can get into remote areas, and check people that might already have it, and keep a close watch on those that might yet contract the cancer.

That I would think would have to be Government funded in that type of situation.

Senator SCHWEIKER. Mrs. Green, would you care to add anything to that?

Mrs. GREEN. No; just that the gynecologist that took care of Susan said he felt we do not usually give young girls internal examinations. but he felt that in any case where there was any idea that DES had been taken, the young girl should be given internal examination so they can watch very carefully, because the earlier they can detect it, of course, the better the treatment.

That would be a followup to what Ms. Luder said, if we could get the mothers to either think back and check records, and have their daughters examined, even very young girls, it might save some lives. Senator SCHWEIKER. Thank you, very much.

Senator KENNEDY. Again we want to thank you. We are very hopeful that this message will go out to all Americans. I think it really comes down to the risk-benefit ratio, and I suppose we will hear a good deal about that this morning. I think we have to measure certainly what it really means in terms of saving lives and the risking of the kinds of tragedies which your families have been exposed to. I think what you have certainly shown for us is what statistics really mean, and they mean human beings, and human tragedy and suffering.

I appreciate very much the fact that you are here and sharing with us your experience. I am sure I speak for all members of the committee in saying we are going to do everything in our power to see that this does not happen to any other Americans, or to any other people in this world, to the extent we can.

Thank you very much.

I hope you can stay for the rest of the hearing.

We will next hear from a panel of witnesses, all of whom have a great deal of expertise regarding the problems associated with DES. Peter Greenwald, M.D., has been director of the Cancer Control Bureau of the New York State Department of Health since 1968. He is a clinical assistant professor of medicine at the Albany Medical School, and an assisting attending physician at the Albany Medical Center Hospital.

Robert H. Pantell, M.D., is a consulting pediatrician and clinical scholar at the Stanford University School of Medicine. Until June of 1974, Dr. Pantell was involved in an effort to persuade the medical boards in the State of Idaho to educate the physicians of that State on the risks of DES.

Ms. Belita H. Cowan is a college instructor of health care in Ann Arbor, Mich. Verv recently, she conducted a survey on the use of DES in Ann Arbor and Detroit, and her findings will be of great interest and assistance to the subcommittee.

We will start off with Dr. Greenwald.

We want to welcome you back, Doctor. We heard you here on this committee, I think, on the same subject 2 years ago.

Since that time we have passed legislation in the Senate, but we were unable to get corresponding action in the House. We saw regulations passed by the FDA, which were then frustrated.

I know the information that has been developed even more recently substantiates your early observations 2 years ago, making the situation even more dangerous.

We want to welcome you. You have been a great help to our committee in the past.

STATEMENTS OF PETER GREENWALD, M.D., DIRECTOR, CANCER CONTROL BUREAU OF NEW YORK STATE DEPARTMENT OF HEALTH, CLINICAL ASSISTANT PROFESSOR OF MEDICINE AT THE ALBANY MEDICAL SCHOOL, AND ASSISTANT ATTENDING PHYSICIAN AT THE ALBANY MEDICAL CENTER HOSPITAL, ACCOMPANIED BY ROBERT H. PANTELL, M.D., CONSULTING PEDIATRICIAN AND CLINICAL SCHOLAR AT THE STANFORD UNIVERSITY SCHOOL OF MEDICINE, AND MS. BELITA H. COWAN, COLLEGE INSTRUCTOR OF HEALTH CARE IN ANN ARBOR, MICH., A PANEL

Dr. GREENWALD. Thank you.

I am Dr. Peter Greenwald, licensed physician in New York State, and director of the Cancer Control Bureau, New York State Department of Health.

I am here at your invitation to present the results of our own studies on diethylstilbestrol (DES) and human cancer, and my opinion about the use of DES as a morning-after pill.

In general, I feel that in this country we should be able to expect proof of safety before a new drug is released, or before an old drug is used in a new way, especially when there is almost no risk to not using the drug. The safety of DES as a morning-after pill has not been proven.

In fact, evidence to date suggests a probable severe cancer risk among at least some daughters born of pregnancies when DES contraceptive treatment failures occur.

The New York State Department of Health Cancer Control Bureau has conducted three studies bearing on the human cancer risk of DES. The first confirms the cause-and-effect relationship and provides some information on dosage and latency, the second assesses the possibility of maternal DES ingestion contributing to cancers other than vaginal or cervical in men or women, and the third evaluates current usage of DES as a morning-after pill in New York State. Results in brief are as follows:

I. VAGINAL CANCER ASSOCIATION

In 1971, five teenage girls reported to the New York State Cancer Registry as having vaginal cancer were investigated. DES therapy to prevent miscarriage had been given during pregnancy to the mothers of four patients, and the fifth took a similar synthetic estrogen, di

enestrol. This was the first confirmation of the work by Dr. Herbst and his colleagues in Boston of the now widely accepted association between maternal use of DES and vaginal cancer.

At the present time, 23 teenagers and young adults have been reported to the New York State Cancer Registry, with this type of vaginal or cervical cancer. Eight have died of advanced disease. All mothers, where our investigations are complete, 20 of 23, are known to have taken DES to prevent spontaneous abortion.

Senator KENNEDY. Do you know what that figure is nationally? Dr. GREENWALD. The last comprehensive registry report was 170 patients. These are patients that have been fully investigated. The number is actually over 200 cases occurring.

Senator KENNEDY. We have the latest figure from Dr. Herbst as being 220.

Dr. GREENWALD. Yes.

Senator KENNEDY. Do you think that this is really the tip of the iceberg, so to speak?

Dr. GREENWALD. Yes; I think I will mention it. I feel that the incidence is still going up. We know from our data, and there is a figure here, that the incidence of vaginal cancer diethylstilbest rol induced is increasing.

As long as it is increasing, we have no way of estimating the ultimate total risk, and there have been more and more patients die with these conditions.

Senator KENNEDY. Well, now, how do you explain that increase in total numbers you are going to develop that during the course of your testimony?

Dr. GREENWALD. Yes.

Senator KENNEDY. OK.

Dr. GREENWALD. The cause and effect relationship between the use of DES by mothers and vaginal cancer in their daughters is suggested in our studies by the facts that all mothers took DES during the first trimester; all patients were born during the peak years of clinical use of DES to prevent miscarriages, by the similar age at diagnosis among patients; the time relationships; and the rather uniform microscopic pattern of these tumors.

The consistency of all of these observations supports the possibility of a common cause. These findings also are in keeping with the independent investigations of others, and are in accord with our biologic knowledge of DES, especially with the fact that DES can be shown to produce cancer in a variety of animals.

It should be noted that "cause-and-effect relationship" means to me that DES is a necessary factor and that the cancer will not develop without it. There are undoubtedly additional factors affecting susceptibility and resistance.

Approximate cumulative dosages of synthetic estrogens taken dur ing pregnancy for 11 mothers of vaginal or cervical cancer patients and 21 mothers of patients whose children did not develop cancer are shown on table 1. Among mothers of patients, the mean dosage was 4,868 milligrams and the range 135 to 15,750 for those whose dosage was known.

Senator KENNEDY. What is the dose for the morning after?

Dr. GREENWALD. It would be 250 milligrams, usual dose; 50 milligrams a day for 5 days.

Senator KENNEDY. So that is greater than actually was being used in the cases

Dr. GREENWALD. Yes. One patient here had an exposure lower than recommended dose for DES contraception, in uteral exposure, and she developed vaginal cancer.

Another point related to that-we found no significant difference in the main dosage for the group whose daughters got vaginal cancer and the other group.

Since very few women in either group received small dosages, we cannot be sure of a dose-response ingredient from this data. However, DES was used over a wide dose range and in the absence of differences it seems very possible that small doses as well as large may induce cancer.

The New York State patients were 8 to 23 years old at time of diagnosis. With prenatal carcinogenic exposures, age at diagnosis is often used to estimate the latent period for cancer development, although with DES the latent period may be influenced by menarchy. Studies of various types of other human carcinogens indicate latent periods of less than 1 year to more than 50 years. While there clearly are differences between DES and other carcinogens in age at exposure, type of carcinogen and mechanism of exposure, this comparison suggests that we may well expect that some patients with longer latency periods will be diagnosed in future years as the interval since the peak years of DES exposure grows longer.

Next is the increase I mentioned before in the figures.

Senator KENNEDY. As I understand what you are suggesting, this amount of dosage, as you mentioned in the paper, it seems possible to you that it does induce cancer, is that right?

Dr. GREENWALD. Yes. In fact it seems likely. The fact that there is one young girl who developed cancer with a dose lower than the dose used, and the fact that we do not find a relationship of dose to risk of cancer, both mean to me that it is fairly likely that small dosages could produce cancer.

Senator KENNEDY. As you made the point earlier, the amount that they are actually taking in terms of the morning-after pill is higher than the amount which were detected in terms of those that actually contracted of

Dr. GREENWALD. Well, for one of them. Most of them had a larger dose than contraceptive. But one patient did have a smaller dose. On the basis of their study, the Mayo Clinic group estimated that the incidence of vaginal cancer or cervical cancer among DES exposed persons could be as high as 4 per 1,000. The 4 per 1,000 is an upper limit estimate for study subjects followed for up to 30 years, whose median age at last followup was 22 years. This estimate could be affected by studying more people.

I do not think we should pass off the incidence rates of this magnitude as trivial. Four per one thousand is equivalent to the annual death rate from heart disease in New York State, is 44 times higher than the annual incidence rate for leukemia, and considerably higher than the annual incidences of breast cancer and colon cancer.

In other words, this means that the DES risk could be as high as a risk for a person developing leukemia over a period of 44 years. That is another way of doing it.

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