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CLINICAL TOXICOLOGY, 15( 5), pp. 571-582 (1979)

Research Design from the Academic ToxicologicaI Viewpoint

HANSPETER WITSCHI, M.D. De'partement de pharmacologie Faculte' de me'decine Universite' de Montre'al Montreal, Que'bec, Canada

Before discussing research design from the academic toxicological viewpoint, I find it necessary to define two possible types of research i n toxicology. Both a r e likely to be tackled within an academic institution. One line of work consists of unraveling and of understanding mechanisms of toxicity; I might call it basic research, done by independent investigators. The other a r e a is the collecting of information on the effectiveness and safety of drugs and chemicals. This could be called testing. It is mostly contract research, and is done by qualified scientists who agree to answer a specific question for a sponsor. I then have to precise another point: whatever research is being done in a university has to be done according to the highest scientific and ethic standards. And this can only be accomplished by adhering to good laboratory practice. But now I find it necessary to draw a very sharp line between basic research in toxicology and testing. In doing so, I do not want to imply that one type of research is superior to the other; as toxicologists we have the responsibility to do both, and to do them both well. My talk will have two parts. In the first I propose to maintain that it is not practicable and might even be counterproductive to regulate the material and intellectual aspects of fundamental research. I hope to illustrate this by drawing largely on my own experiences as a university-associated toxicologist. In the second part, I will have to talk about testing i n universities. 57 1 Copyright 0 1980 by Marcel Dekker, Inc.

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Here I must start from a different point: I will assume that regulations on how to do testing a r e going to stay with us, whether we like it o r not. And this means that university laboratories will have to comply if we want to make a useful contribution. I feel that compliance might have its special problems for universities, and I intend to point out some potential areas of concern. First, basic research, I want to recall once more why we need it. Toxicology is a predictive science; so said the program of the first International Congress of Toxicology. In its opening session, my former teacher W. N. Aldridge reasoned a s follows: Chemicals a r e with us to stay, although they can be health hazards. Now we might and actually have encountered obvious difficulties i n the early detection of disease caused by toxic agents except when an unusual medical condition occurs. He then went on: "We cannot afford to wait for this, and this places a very heavy burden of responsibility on those of u s engaged in experimental work. We must generate a more basic understanding of the underlying biology so that we may be more accurately predictive. For this purpose more research is required on the early responses to chemical injury. An acceptance that we must forever rely on experiments involving longer and longer exposure of more and more animals is a gesture of defeat." Research on mechanisms of toxicity is done by individuals o r small teams. One begins quite often out of curiosity with a question, then does the appropriate experiment, decides what the answer means and, more important, formulates the next question. Research means to do one experiment after another and, while doing so, to keep open eyes and an open mind. A good example of this kind of research is the nitrosamine story. It started out with the observation by a medical officer in a British chemical plant that a few workers, working with dimethylnitrosamine, developed acute liver damage. This led to some studies on acute and chronic animal toxicity, and this was how the necrogenic and carcinogenic properties of the compound were discovered. At the same time, molecular biology revolutionized biochemistry and soon the effects of DMN, first on protein synthesis, then on nucleic acid metabolism, were discovered. This in turn triggered interest on the chemistry of other nitrosamines. A s a result of all this basic work, nitrosamines are now recognized to be a definite health hazard. It is even feasible to think of conditions where such compounds might originate in the alimentary tract from otherwise harmless products and so cause cancer. And although we still do not know all we should know, this is a fascinating story of how basic research went from description to understanding of mechanisms and eventually to prediction. Why is it not necessary to regulate this kind of research? I think there a r e three essential elements to guarantee success and to make the work sound The intellectual pleasure and satisfaction the investigator has i n doing his work.

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The opinion and valued judgment of his peers, be they on grant committees o r on the editorial board of high-calibre journals. And, finally, the most vital criterion for good research: the data must be reproducible and be reproduced by others. If an investigator is content to build his reputation and career on those three criteria, he need not adhere to rigid protocol nor need he have a quality assurance unit breathing down his neck. He also should be completely free to make whatever changes he wants in his experimental design. More important, he uses his own scientific judgment when he decides what problems are worthwhile to pursue further. In this kind of work there are no standard experiments nor are there standard operating procedures-on the contrary, the researcher, in testing his hypothesis, will select, develop, modify, and improve his experimental design and methods until h e has found what he knows is scientifically sound and acceptable evidence. The independent investigator enjoys this freedom most of the time because he seeks positive answers to a question and not negative ones-for him, absence of evidence is never evidence of absence. At this point I hate to admit that I know of one incident where this approach somewhat backfired. The late John Barnes once told me how, around 1938, in Oxford, England, a colleague asked him to determine the toxicity of a new drug. Barnes was less than enthusiastic about this pedestrian experiment and wanted to pursue his own work, s o he did not bother to devise a full protocol nor to keep any close observation, let alone records, on how this drug acted o r even was supposed to act. A l l he did was to give it to a few mice and saw whether they survived. They did, there was no FDA regulations, and Dr. Barnes encouraged his colleagues to give the drug to patients. Having done this, he gladly abandoned the project. Had he been forced to follow GLP regulations, he might have had to do more work on this drug with his colleagues and shared a Nobel Prize-because his colleagues were Florey and Chain and the drug w a s penicillin. I now want to turn to another point why basic research in toxicology might be very difficult to regulate: Universities teach undergraduate and graduate students. In doing this, we want to provide them with an education and not simply a training in certain toxicological procedures. Let me illustrate this in somewhat more detail. Graduate students have to be taught how to ask relevant questions in research, because in research it is much more important to know how to a s k questions than to answer them. In other words, everybody can solve problems; the difficult part lies in finding them. Bruce Ames did not and still does not answer the question whether the Salmonella test will allow to define carcinogens within 48 hr. For this, we will need an immense amount of data comparing the Ames test with animal studies. Everybody can do this. However, Ames found the right question: Can a point mutation o r a frameshift mutation in a bacterium be indicative of carcinogenic potential ? If we want to educate students and to bring them to the stage where

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they can ask such questions, we cannot make them follow a predetermined protocol. A graduate student, in his thesis work, will have to develop his own protocol. The supervisor has to check it, to s e e that it is feasible and, equally important, to s e e that the student does not become frustrated by experiments which by faulty design cannot be successful. He provides guidance-but guidance not by saying: now you do this experiment; but by saying: what is it you want to do next? And if once in a while a protocol is inadequate and provides bad data, this can be quite educational for both student and teacher. Another important aspect is methodology. GLP regulations call for standard operating procedures. The biggest disservice one can do to any graduate student would be to provide him with such SOPS. In my opinion, students need to be taught two essentials: to take a method, for example an enzyme assay, out of the published literature and to translate it into practice. For the beginner, and even for the accomplished researcher, it takes some thinking to figure out how much chemicals he has to weigh out every day to run his assay o r even how to make a buffer at a defined pH and molarity. On the other hand, it is also difficult to translate a laboratory method, written in SOP form o r "cookbook form,'' into a description that is acceptable to a scientific journal. To learn this, however, i s part of the education of a graduate student, GLP regulations put much emphasis on record keeping and data retrieval. This cannot be regulated f o r students. In my experience, one of the most important skills one has to develop as a researcher is to keep meaningful and useful laboratory notebooks. It would be possible, of course, to provide students with data sheets to be filled out. But I rather prefer to let them find their own way and to help them by first checking every day, later every week, whether their record keeping is adequate for developing experiments and writing up a thesis. Good bookkeeping will be rewarded, whereas a sloppy job simply will send the student back to the bench. This can be expensive-but it can be quite an education, too. In summary then, what I have meant to say so far is that GLP regulations are incompatible with nonmission-oriented research and with the education of future scientists. This has also been recognized in the preamble of the FDA proposed regulations for GLP: although universities a r e defined as testing facilities, it is acknowledged that not all work going on in universities might necessarily fall under GLP regulations, provided more extensive studies in compliance with the regulations will follow. This brings me to the second part of my talk. FDA regulations also say: "When a sponsor conducting a nonclinical laboratory study intended to be submitted to o r reviewed by the FDA utilizes the services of a consulting laboratory, contractor, o r grantee to perform an analysis o r other service, it shall notify the consulting laboratory, contractor, o r grantee that the service is part of a nonclinical laboratory study that must be conducted in compliance with the provisions of this part. I'

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In these days, with the granting situation being what it is, people i n universities have become more and more inclined to solicit contract work. In this time the sponsor must realize that research at a university is usually not done the same way as i n a commercial testing facility. And the scientist has to realize that to accept and to carry out contract work may be much more difficult and complex than he thought it would be. It is certainly no easy way-if it is possible at all-to finance some extra technician, students, postdoctoral fellows, o r even experiments he could not afford otherwise. I do see a few points which can promise good contract work in a university setting. A big asset is undoubtedly personnel. Scientists taking on this kind of work a r e usually knowledgeable, conscientious, and interested i n the particular problem. For example, somebody who is doing research on the basic aspects of pathogenesis of lung cancer might be quite interested to find out what man-made synthetic fibers do to the lung. Technicians in a university are usually well trained and likely to stay a long time on the same job because salaries a r e often quite good and the work load i s not too excessive. The same applies to animal caretakers, And finally it is more likely than not that one individual will handle only a very limited amount of contract work, but out of this he hopes to get not only the data needed by the sponsor, but one o r several publications as well. A l l this tends to assure quality work. Next I see some problems where a contract arrangement between a sponsor and a university may become frustrating and irritating for both partners. Out of lack of experience, university scientists may fail to come up with crisp, detailed proposals; may fail to complete studies on time o r to estimate costs realistically. This can be learned. However, I think one point could be a major drawback: in animal studies academic scientists usually do not have data on, nor do they want to rely on so-called "historic controls.'' You simply do not do any experiment -dose response, time response, o r even LDSo, histopathology, or electron microscopy-without including an adequate and often substantial number of control animals. And if a n experiment is to be repeated, be it 1 day, 1 month, o r 1 year after the original one, an appropriate number of controls is again automatically included. This could make studies quite expensive. I can also see potential problems where a university laboratory could run afoul of GLP regulations and thus make a study invalid. One such thing could be simply the lack of knowledge of how to design properly the necessary protocols. To design protocols is routine in testing laboratories, but scientists in universities might not bother to ask for advice. Also, to the best of my knowledge, very few real long-term studies a r e done in the average university department, and lack of experience about how to do this properly could cause problems. Data collecting and record keeping could be another weak point in university contract work. A student o r technician tends to and usually gets away with writing down his readings at the spectrophotometer onto a paper towel, to transcribe it later into some notebook, to make calcu-

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lations on a loose sheet, and to provide data in yet another form. This practice would be disastrous in a study regulated by GLP. Also, according to regulations, original data should remain available in the testing facility for a certain number of years. However, notebooks are very personal diaries which not only contain data, but also reflections, references, ideas. They belong to the student o r researcher, and if he leaves the university he takes them with him. I still haveand consult-all the notebooks I filled since I began working in the laboratory. Another critical point might be proper instrument calibration and maintenance, likely to be somewhat neglected in a university laboratory. It is also conceivable that someone will embark on a study without being thoroughly familiar and experienced with all methods to be used. A big problem can also be the animal house. Quite often a university department has no jurisdiction on how, when, and with what chemicals the floors, walls, and windows in an animal house are scrubbed down o r how pests are controlled. The diet can be another factor: Universities usually simply buy chow, the composition of which may vary from batch to batch without being controlled. I probably could mention many other details where universities, the way I know them, could come into conflict with regulations. Just one last puzzling question: Who, in a university, is the quality assurance unit? The director of the department o r the dean? They would hardly want to do this. But then who is going to pay for one o r several full-time professionals who could do the job? Presumably, the sponsor would have to provide it, but how, in a university, is a foreign unit to function the way it is supposed to according to the regulations 7 Now I do not want to say that it is impossible for universities to comply with GLP. If a university laboratory elects to do research regulated by, for example, the FDA regulations, then it has to follow them as any other testing facility would. It will probably be more difficult than we, in universities, like to think, and it might even be traumatic on occasion. But this is a problem we have to deal with in a positive way if we want to assume responsibility f o r this type of work. I am aware that I might be accused of having double standards, since I essentially said that basic research in toxicology can and should not be regulated, whereas there is nothing wrong with regulations concerning testing. I am afraid there is some justification to take this view. In my opinion, experiments in which the safety of a chemical is evaluated lack almost by definition two elements of basic research: they try to prove the negative-to provide evidence for absence-and they a r e seldom checked o r duplicated in other places by other independent investigators. I know it would not be practical to do this, but this is why two of the best possible quality controls of basic research-positive proof and reproducibility-have been replaced by what seems to be a second best approach: regulations. In basic research we a r e still fortunate that we have freedom, although I want to remind you that people working on recombinant DNA have begun to lose some of this freedom. I just hope that we will con-

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tinue to make good use of this privilege i n order to make toxicology a truly predictive science. In the final analysis, after all, there is only one goal in, which we a r e all interested, whether our research is regulated o r not. That is to do responsible toxicology.

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Q U E S T I O N AND A N S W E R S E S S I O N

Q: I just wonder if you might have any suggestions, accepting the fact that some universities will be participating in testing programs, as to the internal mechanisms of meeting the quality assurance of these programs ? A: No, I am sorry I don't have any idea of how this could be practically carried out. I would be at a loss to come up with some quick suggestions right now. Comment: We had someone mention yesterday the economic impact of GLPs on industry. Let me assure you the universities a r e trying to meet GLPs. It is having a definite economic impact on the university. We can tell you some of those. Q: I'd like to ask you if you don't think that a testing facility o r a basic research laboratory could cooperate and work together, when they are physically located reasonably close together, in the particular training of students, don' t you believe that a student who is doing basic research should have the experience of working part of the time in a testing facility and don't you think that would be a beneficial training experience for the student who later on may become a supervisor of a testing facility? A: I think this is a very good question. It depends upon the program a student is enrolled in. For example, in our department students do not get a Ph.D. in toxicology, they are getting a Ph.D. in pharmacology. They have to follow courses and the ones who a r e specializing i n toxicology are simply doing their research on a problem associated with toxicology. The second point is they a r e on the program for about 4 years. In this time they not only have their course work to complete, but also to write first their master thesis and then the Ph.D. thesis. Although I think it might be good to send a student into a testing lab, it could be simply that perhaps there would not be enough time to do this, But if someone wants the experience in order to become a supervisor, then maybe he should spend his postdoctoral time in a very high quality testing lab to learn the trade. Comment: Here is another obligation perhaps for our universities to dwell more upon in academic work-the concepts of good laboratory practices. I think perhaps, after all, all of us came from that environment at one time. I think many of us could look back and wonder how much of our time was properly spent in the details of protocol design, laboratory notebook handling, procedures of documentation, and so forth. The universities are the source of our personnel. A: I will agree with you that we will have to pay more attention to these aspects. For example, notebook control is handled by the thesis

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supervisor. My students don't get away with just writing things on paper towels. In other places they do. But you are right. We should train students by talking about protocols and other practical aspects. Comment: The question of basic research at the universities versus testing research, as you've described it, I think was covered yesterday. I think Dr. Van Houweling touched on this when he responded to a question about what was really the intent of good laboratory practice regulations and I think the response was clear that it was directed toward those studies which were used to demonstrate safety of regulated products. So I think there is a distinction in the preamble and in the attendant regulations although I think certain aspects of good laboratory practices extend throughout research regardless of what kind it is. Q: Are there other comments on the problems related to the research in the university with respect to G L P s ? Comment: We have some quality control people here who possibly might want to comment on the quality control aspect o r quality assurance aspect of the university activity. I think that's one of the focal points that has been difficult to grasp with respect to university research. Comment: This certainly i s the point of the whole thing, the structure of the university is not that of a formalized testing laboratory which is an essentially dedicated service to the testing functions and in talking about problems, if you will just stop and think about the general university situation i n simple matters, let's just say logs for instrumentation, you actually have one deck, and in archives and so forth the records of central servicing and acquisition and calibration and this kind of thing, in a way that you can go back and demonstrate that the machine actually was properly calibrated on the day of that particular test was performed. Many of these things, the columnization of note records of the personnel that come in a university situation where you've got the staff, you've got the technicians, you've got anybody in the room and just how do you handle this? The other thing particularly on the animal side of the testing, is the actual access and service arrangements with the university to assure that the proper handling of animals in the university complex where you' ve got laboratories carrying out all kinds of things in addition, perhaps, to the testing function. So it is really quite a broad spectrum of both problems that the university faces which can be, in certain respects, directly dealt with in the commercial testing laboratories. The other side of it is i n the acceptance of contracts from the government. L e t ' s be frank about it, the government will, lots of times, go to the university because the university will do it much cheaper than a commercial testing laboratory. In other words, the university is going to be faced with the situation of updating the entire facility and you might say raising contract cost. If there is anyone in the audience that has any ideas about the proper cost arrangements relative to the government contract, I would certainly be interested in hearing this. The university situation also frequently absorbs overhead in a way that does not really constructively come back to, you might say, capital improvements of the labs.

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Q: You raised an interesting point about data that leaves with the stu-

dent when he does. I want to know what the responsibilities are after he leaves, with the FDA inspectors. In industry it is a very good thing that you can go back and find the person and recreate that information and the data so that he can reconstruct what happened. I think that is a problem you have to face, that the student leaves after a period of time and even though you may have his records you don' t have someone to help you decipher those records. A: Actually, I could be a bit more direct in rephrasing what you have said. I strongly feel, personally, that if in a university you elect to do contract work, it is not your student who should do it. First of all, he is not trained to do it and second, by putting him on such a rather rigid protocol, you are taking away the chance from him to develop and follow h i s own ideas. Comment: There is one aspect of this which is directly in contrast with what some of you have been talking about relating to the basic research functions and the testing functions. It is a kind of historical fact of life that once formalized in principle that there is no question that good laboratory practices is something good. A l l right? Whether we a r e talking about basic research o r testing. But I think the thing that we have to recognize and be concerned about is that once this is formalized on the testing side it is going to be very easy for the government agencies to say that the grants a r e subject to the university o r whatever other agency also conforming, at least trying to protect the basic science in universities. Comment: F i r s t of all, we do follow good procedures in the universities. We follow, for example, the procedures for good animal care, the procedures drawn up with regard to protection from chemicals and protection against radiation. Criteria on how to do good work are imposed upon u s by the peer review system. I don't think you have to be apprehensive about the quality of research in universities as long as the government is prepared to s e t money aside which is under the jurisdiction of scientists and distributed according to good science. But, on the other hand, if something more is implied, then research might well fall under stringent regulations. Molecular biologists, doing work on recombinent DNA, may face regulations that toxicologists haven't even seen yet. They a r e essentially told, these experiments you a r e not allowed to do. But this is a completely different ball game because I wouldn't comment on whether the regulations on recombinent DNA are necessary; I am not qualified to do this. But apparently people who call for such regulations have the impression that the implications of this research reach far out of the university laboratory and that's why society has to step in. Comment: I know there is a lot of concern among the university people and obviously among the industrial people about contract research with universities. I know that we talk about that there are no such things as double standards. There are some problems in which we train graduate students in the use of instruments, etc., but one thing that I think we must accept at universities and that i s if we accept contract work

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for a regulated industry, the universities must meet GLP with those contracts. Otherwise the data are absolutely worthless to the contracting agency. I know you agree, Peter, because we've discussed this: there is no doubt that you must meet GLPs o r the data are worthless. Comment: I think we should remember that first, these are proposed regulations which are in the process of being reviewed and hopefully changed somewhat. P a r t of the dilemma that is being discussed here is obvious, Quality is, according to the regulations, not to state that you will have a quality assurance unit which is composed of one o r more persons responsible to do such and such but you shall have a system which will attain the accomplishments which are necessary. It hasn' t resolved the problem for the university because the university is not in a position to s e t the quality assurance unit while, with certain industrial laboratories, that may be the best system to set up. So that if the regulation permits the freedom to set up a usable o r workable system to accomplish the objectives rather than spelling out one single system which is imposed on everybody whether it works for them o r not, we would all be much better off. After all, we must recognize that much of the GLP regulations are intended to create a trail which can be followed backwards by an investigator who is not trained as a scientist but trained to investigate record keeping. He is an auditor much like the financial auditor is, and if we set down, again, objectives and say, "Okay, your system must be auditable, we must be able to trace it back to what you did," and if the guys who create the trail in the first place a r e aware of that, it will be workable. One of the problems with the proposed regulations is that they set down too many specifics on ways of doing things rather than objectives. Comment: I have a comment to make on this. I think your point is extremely well taken. The regulations as they are now proposed may be on some points too much detailed. I was, in September, at a Society of Toxicology committee sitting f o r a full week on the proposed regulations and the main apprehension with the FDA regulations was that when your auditor comes, he might not be trained as a scientist. He then might find some problems which are honest differences of opinion or see questions which cannot simply be answered with yes o r no, according to today' s standards or according to today's science. The big problem then is to resolve such questions. The regulations, as they are right now, do not provide any mechanism for this. Who is going to be the Court of Appeal? But this would probably be one of the most important things to have. Comment: Your comments on the verification of basic research interested me for two reasons. One is, I had the experience of working under several rather hard-boiled professors in my younger days and one kept notebooks to the very standards which I don't think would be good science even now 15 or 20 years later. The second point is that the verification of basic research, as you pointed out, h a s traditionally been the reproducibility in another area like this h a s been a verification of science. The GLPs are attempting to find another way around

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this and will probably find some difficulty in doing so. But many of the basic research data a r e reported, acted on, passed into regulations which have never been verified. In other words, somebody will report they have found' a certain situation, with a certain chemical, in a certain test, this goes into the regulating agency, decisions are made, and some time later somebody may get around to attempting to confirm this in another laboratory. Of course, by then it is accepted and the professor is very unwilling to do that work because it has already been accepted and it is essentially repeating plowed ground. So I think that the point that basic research is always verified o r usually verified in an independent laboratory by independent individuals is rapidly changing, at least as far a s the regulatory field goes. Comment: You a r e right but I see this thing as follows: Whenever anybody is doing basic research and he comes up with some data, it then becomes important to make new decisions for future research. This you do based on the data you have now. If I said, "basic research needs to be reproducible by others," this is simply so you can keep your credibility aa a researcher. You finish a certain piece of work and hope somebody else will find it interesting. The other, of course, has his own ideas and would like to go a step further. If he now finds out that you went the wrong way and your ideas a r e not sound, in other words, if he can't repeat your basic experiments, this will badly hurt your reputation as a scientist. If you are testing a compound, basically at the end of the test we a r e in a similar situation. The end of the test must provide us with the means to make a decision. Now, except i n this case, the decision is a fundamentally different and more complex one. The question is no longer: What research do I do next? But rather the decision is now, "Can we and society at large use these compounds, yes o r no, for this and that purpose?'' This decision is, of course, a very difficult one to make, and I fully understand and endorse that it must be based on the very best evidence available. G L P hopes to assure the quality of this evidence. Comment: What you could call a dual standard was addressed from the floor yesterday in asking whether the agency would accept data from laboratories which do not abide by good laboratory practices and show problems with a substance as well as those which show safety of a substance done according to good laboratory practices, I think there is a real problem with that, a s we all know. Comment: Recently, the device legislation was passed, well not passed, but it has been proposed for manufacturers of devices, and many of the devices i n factories in the United States, and I guess a r e good, a r e very, very small companies also and have what you might call sophisticated quality assurance departments and they also will have great difficulty in meeting those good manufacturing practices. One of the alternatives that they have looked at in many of their meetings and discussions on the subject was third party auditing. In other words, they a r e facing the need for troops to spring up throughout the United States that can be at the disposal of someone who does not have a quality assurance unit to come in and provide that service.

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Q: I want to speak a word on what Dr. Witschi was saying. If I under-

stood him correctly, he was concerned about inspectors coming in to inspect testing programs and that there would be a difference of opinion between the inspector and the scientist who was conducting the work, was that correct? A: Yes. Comment: I think I should reassure you that the inspector is not going to make important decisions in regard to the validity of the accuracy o r whatever of the work. They will not be entering into those basically what you might call scientific decisions. Those reports w i l l be sent into the bureaus and the scientists who are working at the bureaus will be looking at those reports and those kinds of things will not be decided by the inspectors. The inspectors really make observations and they report. Significance of the deviations a r e not their area, theirs to decide and make decisions on. That will be decided by other people who, we hope, a r e scientifically competent to make those kinds of decisions and judgments. Comment: I' m sorry I expressed myself somewhat badly. The concern wasn't s o much the difference of opinion between the investigator and the scientist, the question rather is: if the scientist in the regulatory agency does not agree with the scientist in industry, who is going to be the final Court of Appeal? W e all know that regulatory agencies and industry and universities have not always the same viewpoint on the same fact. That is what I meant. Q: The comment made earlier about quality assurance is really a very significant one because this is something that is being done i n many other regulated industries. The nuclear industry, for instance, under its regulatory requirements has a large number of third-party inspection agencies, third-party audit agencies, and third-party quality assurance programs as such. This works very well in industry, both for the small organization and the large organization. If you think about the aspect of going into an audit of a major organization, that is one of the functions that some of these third-party organizations a r e providing, in the other case actually providing the service. For instance, in a university it would appear that they could come in periodically to perform the function rather than have a staff function on the university,

Note added in proof. The author's present address is Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37830.

Research design from the academic toxicological viewpoint.

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