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of current projects, and the third will be on the significance of food-borne viruses as a source of disease.

Food additives

The major portion of BSR's research program in this area has been based upon exposure of animals to food additives in short-term (acute) or long-term (chronic) studies. Even the acute tests are quite time consuming; many tests take anywhere from 2 to 7 years to complete. Emphasis in food-additive research will continue to be placed on the search for more subtle "early warning" signs of toxicity that will reveal harmful effects more quickly than current methods do.

Four additional positions are requested in this area: Three are for comprehensive studies on the effects of selected additives on experimental animals, including swine, that are fed these substances on a controlled basis. Some of the results of these studies can be applied to pathological research programs in other areas, such as drugs or pesticides. The other position is for a project on the development of multiple detection procedures for antioxidant food additives that will be expanded to identify and determine alteration and reaction products of these chemicals in foods.

Two extramural studies totaling $60,000 are proposed, an increase of $35,000 over fiscal year 1966. One is for the synthesis of certain food additives that may cause cancer, to be used in developing methods to detect substances of this type in foods. The other will utilize the facilities and techniques of the medical college previously mentioned for research on the effects of food additives on man. New approaches in food research

The need for a "speculative" research program that will seek novel approaches to the solution of scientific problems has been explained in the introduction to BSR's request. Five additional positions are needed to determine if the multiple detection procedures that have been developed to analyze pesticides can be applied as successfully in other areas-to analyze mycotoxins, food additives, and toxic inorganic elements, for example. Three other new positions are needed for studies in a new area: "gnotobiotics." This is the field of nutrition in germ-free animals, and FDA scientists hope to obtain valuable data on the role that intestinal organisms play in making nutrients available to their host. It appears that many of these intestinal flora are vital to the processes of food metabolism. One other position is requested to support a search for microbiological methods to determine the hazards associated with the use of new food-processing techniques, such as gaseous sterilization, dehydro-freezing, and hermetically sealed containers.

Two cooperative studies totaling $60,000 are proposed: an increase of $60,000 over fiscal year 1966. These will involve investigation of two potentially more rapid and more accurate multiple-detection procedures for the analysis of pesticides. Since the instruments used in these studies are quite expensive and still in the experimental stage as far as FDA use is concerned, it is more economical to contract for the equipment and scientific skills needed in their use until the Bureau has enough information to determine if it can apply these new methods to its own research and enforcement programs.

1966 estimate:

Positions..

Amount..

1967 estimate:

Positions
Amount

1967 increase:

Positions..
Amount...

Pesticides

72 $1,025, 000 78 $1, 118, 100

6 $93, 100

Research in this area has been directed toward three major problems: improvement of methodology, studies of pesticide metabolism, and toxicological studies. Improved methods, beyond those used in industry tests, are needed to insure that pesticide residues in foods are within the tolerances established by law. FDA must also determine whether the original pesticide chemical has been transformed within a plant or animal into a different compound (called a metabolite) that may be more harmful, or whether exposure of the pesticide to light and air has produced harmful changes. Finally, tests must be conducted to measure the toxic effects of these substances on animals and, to the extent feasible, on manparticularly over a long period of time.

The six additional positions requested in this area will be used on two new projects. One will involve a study of the chemical and biological behavior of pesticides after they are assimilated into an animal's body. Of particular interest is the possibility that altered pesticide chemicals exist in milk. The other project will involve the exploration of the possible advantages of miniature swine otver other animal species used in pesticide tests, since there is reason to believe hat in many instances the pigs' responses more nearly resemble those of man.

A total of $170,000 is requested for cooperative research: an increase of $20,000 over fiscal year 1966. The most significant of these projects is a continuing contract with a medical college, where unique and important work is being performed. Very low levels of the pesticide parathion have been fed under careful medical supervision to human volunteers. Chemical and electron microscopic əxamination of their blood and tissue has failed to reveal any significant abnormal effects, even though the parathion level in their diets was considerably higher than that established for this chemical in human food. This study provides FDA with its only means of obtaining first hand information on the direct effect of toxic chemicals on man. In fiscal years 1966 and 1967, this program will be expanded to include food additives and aflatoxins, as well as the pesticide chemicals TDE, Captan, and Dalapon.

Two other cooperative studies will involve a literature search in the pesticide field and a study of the effects of food processing on pesticide residues.

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To insure the purity, potency, and efficacy of drugs, FDA must continually improve its capability to detect and measure drug components, even in microscopic quantities. Methods to detect and isolate various adulterants must also be developed. In addition to research on the composition and strength of drugs, more emphasis will be placed on research to determine their efficacy, so that FDA can judge whether or not manufacturers' claims are presented truthfully and fairly. Seven new positions are requested for drug research.

Among the new techniques for identification and determination of drug substances to be investigated in fiscal year 1967 are vapor phase and reflectance infrared spectroscopy and the analysis of fluorescence spectra. More sensitive methods must also be devised to assay single tablets and capsules, since recent experience has shown that the potency of individual tablets varies significantly within a lot that appears to be satisfactory on the average. Such extremes in the potency of powerful drugs like digitoxin or thyroxin present a serious hazard to users. Other new projects for fiscal year 1967 include the examination of cardiovascular, antiviral, and anticancer drugs, as well as experiments to design systems for predicting the storage stability of drugs. A $15,000 study is proposed to apply new techniques to analyze drugs that contain fluorine.

Another important aspect of drug research is the study of drug mechanisms. Methods are sought to disclose early signs of toxic reaction to drugs. Three additional positions are requested in fiscal year 1967 to examine tissues and cells in hormone and enzyme systems for these warning signs. In addition, a position is needed for an expansion of the program to investigate skin sensitization caused by drugs. Guinea pigs injected with sensitizing substances will be observed for manifestations of shock, and their blood, skin, thymus, and lymph nodes will be examined to detect any subtle enzyme or biochemical changes.

New approaches in drug research

Six new positions are requested to support an investigation of the possible application to drug analysis of complex approaches which enable the scientist to detect, isolate, and measure microscopic amounts of drug components. Tissue culture techniques for the assay of anticancer and antiviral drugs, and for the detection of toxic reactions to drugs will also be explored. Two studies totaling $55,000 will involve the application of new or advanced analytical

techniques to drug analysis. Since these are entirely new research areas, it is preferable at the present time to employ the talents of scientists outside of FDA who have already made progress in their investigations.

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It is likely that FDA controls over common psychotoxic drugs like the amphetamines and barbiturates will make these drugs more and more difficult to obtain. Drug abusers and profiteers will then search for substitutes: unusual drugs or combinations of drugs that will produce the same effects on the central nervous system. In anticipation of this development, FDA must find methods to identify drugs with psychotoxic properties and to establish their dose content and manufacturing source. These methods should be suitable for routine field use and acceptable as evidence in court. One additional position is requested to expand methodology research begun in fiscal year 1966. Four other positions are needed for research into the mechanisms of psychotoxic drug action, since very little experimental evidence is available in this area. FDA plans to recruit a specialist in psychopharmacology in fiscal year 1966 who will outline a modest research program for expansion in fiscal year 1967. This kind of research differs in many ways from pharmacological studies now conducted in FDA: it involves the study of far subtler reactions in the body to drugs. Psychological effects, such as changes in animal behavior and attitudes, are observed, rather than gross physical reactions like organ damage, loss of weight, or death. Furthermore, current drug research programs are aimed at the side effects of drugs taken as directed, while this kind of research must explore the effect of drugs when they are deliberately taken in excessive amounts-in other words, when they are abused. These factors necessitate new ideas and new approaches. The staff must be well versed in the investigation of animal behavior as it is influenced by drugs, and it must also be skilled in relating the results of animal experiments to man.

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Evidence continues to mount that certain combinations of chemical substances in cosmetics can be harmful to humans. Research in this area has chiefly been confined to the evaluation in experimental animals of the ability of cosmetic components to produce skin and eve irritancy, skin sensitization, and tumors. Two additional positions are requested to broaden the program on the effects of cosmetics on the eyes and to initiate a new program on the effects of inhaling "spray-on" cosmetics. This latter study, designed to determine the possible long-term effects of allegedly inert substances that may remain fixed in the tissues for years, will include research on substances that are purposely introduced into the body as a cosmetic improvement, such as silicone wrinkle removers. It is also essential to understand the composition of cosmetics, and the major emphasis in the cosmetic research program in BSR has been on the development of methods to analyze them. To support this program, four new positions are needed to apply special separation and identification methods with advanced instrumentation to the analysis of the ingredients in cosmetics, perfumes, and flavors. Two other positions are needed to expand the study of the chemistry of marketed hair dyes to include new investigations of the mechanism of hair dyeing and into the composition of the products as they are actually applied to the hair.

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BSR performs many functions in support of the regulatory program: routine sample analyses when no other facilities are available in field labs (as in the performance of drug and aflatoxin bioassays); consultation on the scientific content of petitions, standards, new drug applications, regulatory program pians, monographs, and compendia of analytical methods; and the training of fieid scientists. The one position requested for regulatory support is needed for microbiological examination of food samples.

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The Bureau's responsibilities in this area range from sample analyses when no other facilities are available to consultation on various complex scientific matters. The volume of effort expanded in the past on vitamin analyses will diminish. slightly in fiscal year 1967 as the District laboratories assume greater responsibility for this work, and the manpower that thus becomes available can be used to absorb the workload impact of a larger inspection staff in the field. Cosmetics

A large proportion of the cosmetic samples examined by FDA is collected on the basis of consumer complaints; all analyses of these samples are performed in BSR laboratories and include chemical analyses to detect unusual and potentially toxic substances, and biological tests to determine any adverse effects on the eyes, SKIL, or hair of animals.

1966 estimate:

Positions.

Amount..

1967 estimate:

Positions.

Amount

1967 increase:

Positions__
Amount

Administrative direction

Bureau support

30 $345,000

46 $544, 000

16

$199,000

The positions requested in this budget for BSR, plus those authorized in fiscal year 1966, comprise a staff increase of 26 percent over fiscal year 1965. During that same period of time, BSR's administrative staff was reduced by two to provide positions for the central laboratory services operation in fiscal year 1966. One additional administrative officer is requested for fiscal year 1967 to provide more effective management and coordination of BSR's expanded programs.

Support

Twelve positions are requested in this area to implement the Bureau's responsibilities under the FDA science information program which is described in a separate section of this budget, on page 78. Another position is needed to provide technical service in repairing and adapting BSR's augmented arsenal of complex and often highly delicate instruments. The Bureau will purchase almost $3 million worth of new equipment in a 3-year period. The rising volume of investigations, tracing directly to the increase in the number of research scientists I BSR, has led to a concomitant increase in workload for the statistical and editorial staff. Biological and microbiological investigations, in particular, involve a great deal of statistical computations. The entire FDA scientific editorial staff is assigned to ESR for administrative direction, and this staff has remained constant during a period when the size of the agency's scientific staff has increased considerably. Research findings become useful to the scientific community only when they are widely disseminated in clear language, in scientific journals or other publications. One editorial and one statistical position are requested for fiscal Year 1967.

Nonstaff costs of $75,000 are requested for the "research breakthrough" fund outlined in the introduction to BSR activities. A specific example of the need for such funds was a recent development in the virus reseach program that appeared to warrant immediate attention. Several thousand dollars were needed to provide an adequate laboratory environment for a repetition and extension of some significant experiments. Without the research breakthrough funds, such expenses can only be absorbed by the Bureau at the expense of other on-going programs, and often this is not possible.

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There are two premises underlying this request that are worthy of special mention: the necessity for timely review of industry submissions, and the necessity for supporting research. In almost every program area, BSSE must base its plans on estimate of input from industry: petitions, drug applications, proposals, appeals, etc. In the past requests for additional resources have pointed primarily toward estimated increases in the number of these industry submissions. In this budget, consideration is given to another factor in the review process: time. Among FDA's most important responsibilities is timely and scientifically sound handling of matters requiring scientific review (such as investigational and new drug submissions, food additive and pesticide petitions). One of the agency's long-range goals is to reach a decision on 75 percent of these submissions within 45 days and another 20 percent within 90 days. Currently, drug submissions are coming in at a rate which requires that BSSE handle them on a priority basis, processing the ones with safety problems before the others. Many of them are delayed, not because of difficulties involved in analyzing them, but because nobody is available to analyze them. Part of BSSE's request for increases in its evaluation programs is based on an estimate of the additional resources required to perform review tasks on a timely basis without sacrificing quality in its analyses. More positions are needed in several areas where the workload is not expected to increase greatly, but where it must be handled in less time. This is particularly true in the areas where drug applications and pesticide petitions are processed.

In addition to its responsibility for administrative and scientific processing of data supporting regulations and industry submissions, the Bureau conducts a research program designed to aid in the solution of many scientific problems that are immediate and specific: particularly, questions about the hazards to public health inherent in various products under consideration by FDA and questions about the methods that manufacturers have used to evaluate the safety of their products. Reviewing and evaluating these methods and industry's tests of safety are frequently not enough; BSSE must investigate the same products from many other different angles, sometimes exploring far beyond the limits of industry submissions to insure that no potential dangers have been overlooked.

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