Pediatric Annals

A Pediatrician's View

Milton I Levine, MD

Abstract

This is the second issue of PEDIATRIC ANNALS devoted to environmental hazards affecting infants and children and, as was the previous issue (December, 1979), is under the guest editorship of Dr. Jay M. Arena, Professor of Pediatrics at Duke University Medical School and director of the Duke University Poison Control Center.

The authors in this symposium continue the discussion with articles on hazards to children from contaminants in breast milk, food, and other areas of the environment. One of the authors considers the controversy concerning the use of animal surrogates rather than human beings in experimental toxicology. Dr. Daniel B. Menzel answers the question of why animal experiments are necessary in the first paragraph of his article: such experimentation is needed because "the hazards of assessment of new drugs and experimental compounds in man are too great."

I must admit that I was intimately involved myself in an animal-versus-human experiment years ago, and even today I remain shaken when I think of it. The year was 1927. We were in our fourth year at Cornell Medical College and were given three months for elective studies. I turned to Dr. Oscar Schloss, Professor of Pediatrics at that time, for his advice.

"To be a good pediatrician," Dr. Schloss said to me, "one should have more than an understanding of simple clinical medicine. Learn something about physiological research methods. A pediatrician needs to have a deeper understanding of the functions of the human body, particularly in terms of nutrition."

Dr. Schloss sent me to Dr. Graham Lusk, Professor of Physiology, the world-famous experimental nutritionist. I spent my three months with him.

At that time Dr. Lusk was interested in the metabolism of diabetes and was experimenting with insulin, which had recently been discovered (1923). In the studies dogs were depancreatized, developed diabetes, and were maintained in good health by insulin injections.

One day Dr. Lusk presented me with a little oblong box. As I remember, there was a colorful picture on the cover of the box, depicting mountains, green trees, and streams. The box came from Germany and to the best of my recollection was labeled "Synthalin."

Tm going to present you with a simple but interesting problem," Dr. Lusk said to me. "You are aware, I know, that the great difficulty with insulin is that it must be given by injection. It cannot be taken by mouth."

According to the manufacturer, "Synthalin" served the same purpose as insulin but it could be taken by mouth. Dr. Lusk said he had to be away for a week and suggested that during the time he was away I should experiment with the "Synthalin" to determine if it would really reduce blood sugar as reported.

I was sure I could work it out and approached the assignment with eagerness. I read the directions specifying the number of the silver pellets to be given in proportion to the weight of the patient. The normal procedure was to feed the drug to experimental dogs. But I had a better idea: I would use myself as the subject of the study. I would take the prescribed dose for my weight and take my blood sugar at the outset of the experiment and at intervals of three hours for a period of 48 hours. If my blood sugar dropped too low or I developed symptoms, I could always take orange juice or some other sugar solution.

I outlined my plan to Dr. Ade Milhorat, Dr. Lusk's assistant, and to my surprise he seemed disappointingly unimpressed. "It's a new drug," he said; "we don't know how it works. You'd…

This is the second issue of PEDIATRIC ANNALS devoted to environmental hazards affecting infants and children and, as was the previous issue (December, 1979), is under the guest editorship of Dr. Jay M. Arena, Professor of Pediatrics at Duke University Medical School and director of the Duke University Poison Control Center.

The authors in this symposium continue the discussion with articles on hazards to children from contaminants in breast milk, food, and other areas of the environment. One of the authors considers the controversy concerning the use of animal surrogates rather than human beings in experimental toxicology. Dr. Daniel B. Menzel answers the question of why animal experiments are necessary in the first paragraph of his article: such experimentation is needed because "the hazards of assessment of new drugs and experimental compounds in man are too great."

I must admit that I was intimately involved myself in an animal-versus-human experiment years ago, and even today I remain shaken when I think of it. The year was 1927. We were in our fourth year at Cornell Medical College and were given three months for elective studies. I turned to Dr. Oscar Schloss, Professor of Pediatrics at that time, for his advice.

"To be a good pediatrician," Dr. Schloss said to me, "one should have more than an understanding of simple clinical medicine. Learn something about physiological research methods. A pediatrician needs to have a deeper understanding of the functions of the human body, particularly in terms of nutrition."

Dr. Schloss sent me to Dr. Graham Lusk, Professor of Physiology, the world-famous experimental nutritionist. I spent my three months with him.

At that time Dr. Lusk was interested in the metabolism of diabetes and was experimenting with insulin, which had recently been discovered (1923). In the studies dogs were depancreatized, developed diabetes, and were maintained in good health by insulin injections.

One day Dr. Lusk presented me with a little oblong box. As I remember, there was a colorful picture on the cover of the box, depicting mountains, green trees, and streams. The box came from Germany and to the best of my recollection was labeled "Synthalin."

Tm going to present you with a simple but interesting problem," Dr. Lusk said to me. "You are aware, I know, that the great difficulty with insulin is that it must be given by injection. It cannot be taken by mouth."

According to the manufacturer, "Synthalin" served the same purpose as insulin but it could be taken by mouth. Dr. Lusk said he had to be away for a week and suggested that during the time he was away I should experiment with the "Synthalin" to determine if it would really reduce blood sugar as reported.

I was sure I could work it out and approached the assignment with eagerness. I read the directions specifying the number of the silver pellets to be given in proportion to the weight of the patient. The normal procedure was to feed the drug to experimental dogs. But I had a better idea: I would use myself as the subject of the study. I would take the prescribed dose for my weight and take my blood sugar at the outset of the experiment and at intervals of three hours for a period of 48 hours. If my blood sugar dropped too low or I developed symptoms, I could always take orange juice or some other sugar solution.

I outlined my plan to Dr. Ade Milhorat, Dr. Lusk's assistant, and to my surprise he seemed disappointingly unimpressed. "It's a new drug," he said; "we don't know how it works. You'd better try it out on dogs first."

So I set about using a dog instead of myself for the investigation. I took the blood sugar level of a normal dog to start with and then administered the "Synthalin" orally as prescribed. The réaction was startling. Within half an hour the dog suddenly went into a severe convulsion. Fifteen minutes later the dog was dead.

I was shocked but felt there might have been some extraneous cause of the reaction. After all, the drug had been used on human beings in Germany. So Dr. Milhorat gave me another dog. This time I administered a reduced dosage of the drug. The results, however, were almost identical - convulsions within a half hour and death 15 minutes later.

Since then I have been a firm believer in animal experimentation with drugs before their use in human beings. How could I ever have been so scientifically naïve?

Today, much is being written on environmental hazards - the PCBs, the PPBs, the environmental lead and mercury, the various pesticides, the radiationinduced dangers, among others. As pediatricians, we must realize that our patients are in most instances the ones primarily affected by these hazards. Not only is the baby often assaulted by these substances through the placenta prenatally and through breast milk postnatally, but his body during infancy has great difficulty metabolizing damaging toxins and his kidneys have not yet developed their full excretory capability. Reading through the articles in this issue of Pediatric Annals, one is impressed with the realization that our infants and children are also being constantly bombarded by toxic agents in the air they breathe from lead, mercury vapor, cadmium, dust, asbestos, and various pesticides ----- and in foods and other substances they ingest, which so often contain polychlorinated biphenyls (PCBs); lead, mercury, cadmium, and various food dyes and preservatives.

The PCBs are used in many industries and contamination from them is almost universal. The discharge from commercial concerns has so contaminated the waters of the Great Lakes, the Hudson River, and the St. Lawrence waterway that fish taken from these waters contain high levels oí these compounds. A 1975-1976 survey by the Environmental Protection Agency revealed that breast milk of most mothers contained PCB levels exceeding the tolerance limits allowed for commercially sold cow's milk.

In the September issue of Pediatrics Dr. Edward Kendrick notes that the Wisconsin State Department of Health has just recommended that lactating mothers have their milk analyzed for levels of PCBs and insecticides. The Department believes that breast-feeding should not be attempted if the mother's milk contains levels of these substances that are above the FDA tolerance levels allowed for commercially sold cows' milk. Dr. Kendrick criticizes such advice as premature, since breast-feeding has documented beneficial effects, and no adequate and conclusive data on adverse effects of contaminated mother's milk are yet available. In the meantime, he suggests preventive measures pregnant women can take to lessen the risk of such contamination, and also urges proper handling of commercial wastes that can contaminate human milk.

All of this impresses us with the necessity of having pediatricians in the forefront of efforts to curtail the discharge of hazardous substances into the environment from side products of modern technology. It was largely through the efforts of pediatricians that lead paint was eliminated from children's cribs, beds, and toys and its use gready reduced in indoor decorating. Now this crusade has been taken over by the American Academy of Pediatrics through its Committee on Environmental Hazards, which, among its many projects, is studying problems relating to the contamination of food.

This issue of PEDIATRIC ANNALS should prove of great interest to all pediatricians, who are so frequently asked questions by parents regarding potential dangers. The first article, "Drugs and Chemicals Excreted in Breast Milk," is by Dr. Arena. He discusses and lists the numerous drugs a mother might take and describes the milk/ plasma ratio and the effect on the infant. This article is of special value, since occasionally nursing mothers develop infections and it is of great importance to give the mothers drugs that are either not detectable in the milk or of very low levels and have no adverse effects on the infants.

The second paper deals with poisoning from heavy metals and has been written by Dr. J. Julian Chisolm, Jr., Associate Professor of Pediatrics at Johns Hopkins University. Dr. Chisolm is an authority on lead poisoning and serves as a consultant to the Committee on Environmental Hazards of the American Academy of Pediatrics. The heavy metals discussed are lead, mercury, and cadmium* and there is a full and detailed description of the manner of dissemination of these metals, whether through the atmosphere or in paints, plaster, and dust, or in food. Symptoms of toxicity from these substances are also described.

Dr. Chisolm also discusses chelation therapy for each of these substances and notes which of these heavy metals readily crosses the placenta. He points out that chelation therapy may be lifesaving in severe acute inorganic mercury poisoning but has no beneficial role in chronic poisoning. Chelation therapy also can be lifesaving in severe acute lead poisoning but does not prevent severe sequelae once symptoms have appeared. Chelation therapy is contraindicated for treating the toxic effects of cadmium.

The third contribution - "X-ray, Microwave, and Ultrasound: The Real and Unreal Hazards" - is presented by Dr. Robert L. Brent, chairman of the Department of Pediatrics, Jefferson Medical College. Dr. Brent discusses these three techniques individually, presenting the possible risks associated with each. Realizing that radiation, such as that from x-rays, can at times damage tissue and produce long-term effects, he advises that radiation exposure be kept as low as possible - but that necessary diagnostic x-rays that have a high benefit-to-risk ratio should be continued.

In addition, Dr. Brent points out that in the nuclear accident at Three Mile Island the incidence of subsequent radiation-induced disease should be practically nil. Microwave and ultrasound energy are also discussed. Both of them show no indication of being dangerous to the human being as used in America today.

The final article, discussing the accuracy of animal studies in determining potential carcinogens and teratogens, is by Dr. Daniel B. Menzel, Professor of Pharmacology and Medicine at Duke University Medical Center. This is a highly scientific article, but it is worth including in this symposium for it presents the modern approach to estimating potential hazards of new drugs and other compounds.

Dr. Menzel first notes the four sources of information that can be used to estimate the hazard of a new substance to human beings. Animal studies are first, for the basic biochemical effects of toxicants on animals are very little different from what they are in man. Dr. Menzel then discusses the "reactive intermediate theory," which he calls the greatest single predittive advance in toxicology that has been made. The theory is based on the observation that certain carcinogens must be activated metabolically. Some portion of a carcinogen is excreted unchanged, some is detoxified, and smaller amounts get into lipids, protein, and deoxyribonucleic acid (DNA). Breaks in DNA can at times be detected and correlated with the amounts of reacted foreign compound, which can be detected with as little as 10"12 gm. But although such mutagenic effects can be noted in animals, Dr. Menzel feels that positive results cannot be considered final until further confirmatory experiments are conducted. However, he states that carcinogenesis by organic compounds in animals provide sure evidence that it will occur in man.

The practicing pediatrician, who may find some of the chemical discussion too difficult, is advised to carefully read the author's conclusions, which are clear and well worth reading.

10.3928/0090-4481-19801201-02

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