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The use of animal models for the study of human disease is, for the most part, a recent development. This discussion of the use of animal models for human diseases directs attention to the sterile period, early advances, some personal experiences, the human as the model, biological oddities among common laboratory animals, malignancies in laboratory animals, problems created by federal regulations, cancer tests with animals, and what the future holds in terms of the use of animal models as an aid to understanding human disease. In terms of early use of animal models, there was a school of rabbis, some of whom were also physicians, in Babylon who studied and wrote extensively on ritual slaughter and the suitability of birds and beasts for food. Considerable detailed information on animal pathology, physiology, anatomy, and medicine in general can be found in the Soncino Babylonian Talmudic Translations. The 1906 edition of the "Jewish Encyclopedia," has been a rich resource. Although it has not been possible to establish what diseases of animals were studied and their relationship to the diseases of humans, there are fascinating clues to pursue, despite the fact that these were sterile years for research in medicine. The quotation from the Talmud is of interest: "The medical knowledge of the Talmudist was based upon tradition, the dissection of human bodies, observation of disease and experiments upon animals." A bright light in the lackluster years of medical research was provided by Galen, considered the originator of research in physiology and anatomy. His dissection of animals and work on apes and other lower animals were models for human anatomy and physiology and the bases for many treatises. Yet, Galen never seemed to suggest that animals could serve as models for human diseases. Most early physicians who can be considered to have been students of disease developed their medical knowledge by observing the sick under their care. 1 early medical investigator proposed that an aggressive invasive cancer of the dog that he had observed be used to study cancer in a generic sense. Other researchers who recognized the value of animals in medical research were Jenner, Claude Bernard, and Pasteur. The human can also serve as an animal model. Some of those situations are presented, and in all a common theme exists. There was no known animal model that could be used, and in some cases the situation has not changed today. In all cases the discoveries must be regarded as serendipitous. The state of the art of the pathology of laboratory animal diseases and neoplasia is unsatisfactory. There is much empirical speculation and little substance. Cancer studies with mice and rats as now conducted are of minimal value. Although a tradition of excellence in the use of animal models to help understand human disease has been established, much remains to be learned.

A 3-month dose range finding study in preparation for a 2-yr carcinogenicity study of potassium prorenoate (SC-23992), a steroid with an antihypertensive profile, is reported. The drug was administered by gavage once daily at doses of 10, 30, and 100 mg/kg/day to Charles River CD rats. Treatment was terminated at 13 weeks and 10 randomly selected animals from each treatment group were killed and necropsied. The remaining 10 animals in each dose group, including controls, were maintained for an additional 4 weeks, in order to investigate reversibility of changes, and then were killed and necropsied. Dose-related increases in thyroid-stimulating hormone (TSH) levels were observed in treated animals of both sexes during the dosing period and the changes were statistically significant and correlated with an increased thyroid weight in females at 13 weeks. Dose-related morphologic changes in the thyroid, observed by light and electron microscopy, were compatible with the effects of TSH stimulation. Liver weights, which increased, were dose-related. In females the increase was statistically significant at the high dose at 2, 4, and 13 weeks. In males it was significant at the high dose at 13 weeks. Microsomal enzyme levels were increased in a time- and dose-related manner with higher values in females than in males. The pattern of enzyme induction was of the type exemplified by pregnenolone-16-α-carbonitrile. Morphologic changes in the liver showed centrilobular hepatocyte enlargement with smooth endoplasmic reticulum membrane proliferation confirmed by electron microscopy. All positive findings returned to normal after the 4-week treatment-free period. The relationship between the thyroid stimulation to liver enzyme induction is of interest. Evidence is presented here that in the presence of SC-23992, TSH stimulation and liver enzyme induction occurred. The possibility that the liver metabolism stimulates the thyroid T3, T4 elimination with secondary TSH activity is a possible explanation, but on the basis of existing information, direct action by SC-23992 on the thyroid cannot be excluded.

The response of man and animals to whole-body irradiation is of major interest. Due to obvious experimental difficulties, observations of large animals have been limited in comparison to those on small laboratory species. Tullis et al. (1) have reported lethal dose investigations with swine, and Prosser et al. (2) mention a lethal dose study with goats but give no details. Some data are also becoming available from various field experiments performed in conjunction with atomic bomb tests (3, 4). So far as is known, there have been reported no other similar studies with animals having a tissue mass or body volume approaching that of man. There is little or no information dealing with such interrelated problems as significance of depth dosage, time-intensity relationships, gamma rays vs. x-rays, radiosensitivity of various species, extrapolation from small to large animals, and sublethal physiological effects. The burro (Equus asinus asinus) was chosen for initial whole-body irradiation investigations becau...

Real and simulated particulate fallout and solutions of Sr85Cl2 and Cs(134)Cl2 were fed to 102 healthy volunteers. Absorption and retention of ingested radioactivity was measured by whole body counting using the gamma-ray spectrometer at the Argonne Cancer Research Hospital. An average of 3 per cent of the radioactivity of week-old local fallout was absorbed: the range was 0 to 9 per cent. Strontium and cesium leached or dissolved from simulated fallout behaved in the same way, metabolically, after absorption as they did when the tracer was swallowed in a solution or injected intravenously. The large number of subjects studied provided additional information on the range of variation of intestinal motility, biological availability of strontium, cesium and barium following ingestion of fallout, and retention of the radionuclides of these elements. (Author)

Summary and Conclusions1. Nine burros exposed to a lethal dose of whole body gamma radiation were observed. The burros had symptoms and pathologic changes characteristic of the irradiation syndrome. Four died during the first week and the remaining 5 died before the 30th post irradiation day. These 5 showed hemorrhagic symptoms. 2. There was a retardation of whole blood clotting time. A clotting defect was demonstrated in recalcified oxalated plasmas of burros tested 2 weeks after irradiation. 3. All irradiated burros developed a severe thrombocytopenia and a lessening of clot retraction was noted on the after 4th post irradiation day, with no clot retraction after the 16th day when the platelet count was approaching zero. 4. There was a pronounced diminution of prothrombin utilization rate after irradiation. The first change was noted 22 hours after irradiation or 3 hours after the animals were removed from the exposure field. 5. There was no demonstrable circulating anticoagulant. The possible relation ...

There is a reduction in the amount of urea catabolized to carbon dioxide. Information based upon this study and other sources leads us to believe that there is a much greater reduction in the glycogen synthesized from urea in the total-body irradiated rat than one would expect. These observations would seem to be related to an increased barrier of the liver cell to plasma urea after total body irradiation or, in our opinion, more likely to a disturbance in the carbon dioxide pool of the hepatic cells or a transcarbonation mechanism.

SummaryA study has been made of the response of the burro to 200 r fractional Co60 gamma ray whole body irradiation. The response is similar to but slower than that observed with a daily dose of 400 r. The response of the platelets to irradiation with 200 r daily corresponded most closely with that seen when an acute LD50 dose had been given and correlated with the bleeding tendency which developed on the ninth irradiation day. A significant hyperferremia was observed in the burro one hour after receiving a total dose of 600 r but the maximum response was not obtained until 1800 r had been administered. Most animals had significantly elevated plasma iron values prior to exitus.

SummaryRabbit pituitaries from animals exposed to 750 and 1100 r of total body Cobalt-60 gamma irradiation showed an early suppression of gonadotropin principles as measured by the chick gonad response. The 750 r group showed the depression on the 8th day after irradiation while in the 1100 r group the suppression was evident by day one and was sustained through day 7. After this time the gonadotropin activity in both groups returned to the normal level.

For periods of 3,6, and 12 months, 104 feral rhesus monkeys (Macaca mulatta) were on test. At the time of necropsy, 26 had caseous granulomatous lesions in the submucosa of the colon consistent with oesophagostomiasis. Five also had histologically identified granulomatous lesions without caseation of various colonic and more distant arterioles. The lesions were seen in the submucosa and subserosa of the colon, the kidney, the adventitial tissue of the prostate, the pancreas, and the heart. Presumptive evidence of the migration of the parasite was found in the adventitial tissue of the esophagus. Fragments of the larvae in arterioles and the caseous submucosa of the colon were consistent morphologically with the species Oesophagostomum. Acellular masses of what was interpreted as cuticle of a molting parasite were found in the lung. A mature female nematode was found encysted in the lung. The identity of that parasite and the cuticle has not been established.

Bioassays of amosite, short-range (SR), intermediate-range (IR) or intermediate-range chrysotile asbestos in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted with male and female Syrian golden hamsters. Amosite and both forms of chrysotile asbestos were administered at a concentration of 1% in pelleted diet for the entire lifetime of the hamsters starting with mothers of the test animals. Group sizes varied from 125-254. There was no adverse effect on body weight gain or survival by either type of asbestos or by IR chrysotile asbestos in combination with DMH. A significant increase (p less than 0.05) in adrenal cortical tumors was observed in male hamsters exposed to SR and IR chrysotile asbestos and in females treated with IR chrysotile asbestos when compared to the pooled control groups. However, statistical significance (p less than 0.05) was lost when these dosed groups were compared with temporal control groups. Neither of the male or female amosite asbestos groups showed increased neoplasia in any tissue or organ compared to the control groups. The cocarcinogen studies using IR chrysotile asbestos and 1,2-dimethylhydrazine dihydrochloride were considered inadequate because there was no increase in intestinal neoplasia in the DMH group.

The primary and secondary immune responses to thrice-crystallized jackbean urease have been studied in three horses. Antibody to urease was readily detectable by hemagglutination in a hyperimmunized colt for 120 days after a secondary challenge. Antisera from these animals following hyperimmunization caused a 30% reduction of in vitro urea hydrolysis at equivalence by precipitate and supernatant fluid when these fractions were assayed separately after centrifugation. Extrapolation of the curves indicates that inhibition of total enzymtic activity in the precipitate and supernatant fluid is impossible, and that a maximum total inhibition would approach 70% with an antigen-antibody ratio of slightly less than 0.6. The evidence indicates that inhibition of enzymtic activity is due to steric hindrance. At antigen-antibody ratios greater than 1.0 the slopes of inhibition were negative for the precipitate and supernatant fluid. Patterns of immunoelectrophoresis for urease antisera were studied and compared with antisera to other antigens. The specific urease antibody in horse antisera to thrice-crystallized jackbean urease and in rat antisera to water extracts of jackbean meal, once-crystallized urease, or thrice-crystallized urease was found in a relatively anodal immunoglobulin fraction. There was no evidence that the purification steps changed the immunologic nature of the enzyme. Over several years of investigation the thrice-crystallized enzyme consistently showed one anodal immunologic component in multiple preparations.

A LD 50/30 value of 651 r was previously reported for the burro exposed to whole-body tantalum-182 irradiation (1). Comparison of that value with those in the literature was impractical because of the species difference and variations in the conditions of exposure. This paper presents the LD 50/30 for burros and swine exposed under similar conditions except that cobalt-60 was used as the source of radiation instead of tantalum-182. These data, together with some physical factors, will be discussed in terms of lethal response as a function of species and of various physical factors. Method The method of selection of the burros was described in previous reports. Forty males and 10 females, two and a half to three and a half years old, weighing from 115 to 164 kg., were selected. All were in good health. For five groups of 10 burros each the mean exposures were 605, 690, 750, 790, and 945 r (Table I) (1). For this study the exposure field was activated with cobalt-60 instead of tantalum-182 (2). About 37 cur...

The object of these experiments is to ascertain whether a single dose of 200 r of x-radiation delivered to male or female mice would produce effects on (a) life span of offspring, and (b) litter size, when these irradiated animals were mated to untreated animals. For this purpose it was thought desirable to carry out the studies on hybrids between dba and C{sub 57} strains in order to minimize the spontaneous and radiation-induced lymphomas which are a major source of mortality in CF{sub 1} mice. C{sub 57} mice irradiated with 200 r of x-rays produced approximately normal litter sizes in crosses with unirradiated animals. Life span data on these offspring will be reported later. 5 refs., 1 tab.

This book is claimed by the publisher to be "a balanced and understandable account of nuclear weapons and the multiple hazards they have created for mankind." It is questionable whether or not the book accomplishes the objectives of the publisher on either count. The chapters by Machta and List (The Global Pattern of Fallout), Crow (Radiation and Future Generations), and Andrews (Radiation Accidents) are excellent and informative. Rosenfeld (Detection of Bomb Tests) has an especially good resume with possible solutions. Holifield (Civil Defense) faithfully presents the discouraging picture of our civil defense program. If for no other reason this book should be read for these chapters. The content of the remainder of the book is not adequate for an evaluation or understanding of the problem created by fallout. Oceanographic, soil, plant physiology, and animal physiology for example are considerations that are inadequately presented. Most glaring of all is the failure to present an evaluation of the real (or estimated) hazards to man from the low levels of radioactivity presently in his environment. Dr.; Andrews' chapter is not an adequate substitute since he deals largely with high level exposures. No place is it evident that the recent work of Hiyama, Scott Russell, Frederickson, Comar, Schuffelen, Cronkite, Jacobson, Loutit, and the many other busy investigators is considered. From internal evidence it is believed that the manuscripts designed to consider the critical disciplines these men embrace were prepared from data available from 12 to 18 months before the publication date. If so it is a serious fault. Research on fallout is moving much too fast for a pedestrian approach. Discarded concepts and hypotheses tend to freeze misinformation-via such widely read books as this-into our scientific folklore. Most unfortunately it is often the scientific folklore from which many public actions and policies are derived. Every effort should be exerted to prevent this. The editor and the publisher unquestionably were governed by the best intentions when they ventured into the production of this book. Unfortunately the state of the discipline of radiation hygiene is changing so rapidly that it was fore-ordained that their manuscripts would be outdated by the time they reached the printers' hands. This book as a consequence does not replace as a source book the voluminous record of the Holifield hearings on the same subject taken in May, 1959. JOHN H. RUST

The LD50(30) for burros irradiated at a rate of 15 r/hr with gamma radiation from Zr95/Nb95 sources was 585 r with a 95% confidence interval of 530 to 627 r. The mode of death was characterized by an absence of early deaths and occasional prolonged survival time beyond 30 days, of lethally irradiated animals. A variable I131 uptake by thyroid, decreased iron uptake, increased blood pyruvic acid and pancytopenia were measured in circulating blood of irradiated animals. The lethality of gamma irradiation from Zr95/Nb95 was greater than that of gamma radiations fronm Co60 or Ta182 if the free-in-air doses were compared. The midline doses necessary to produce the same biological effects were about equal, however, for the various sources when all factors were considered.

Forty-eight hours after irradiation of rats in the lethal dose range, the amount of CO/sub 2/ in expired air decreased to 75% of the control value. To investigate the reason for this decrease, some aspects of intermediary metabolism were studied by using C/sup 14/-labeled substrates. The fraction of substrate carbon recovered as C/sup 14/O/sub 2/ in expired air (ARO) was significantly reduced postirradiation when the tracers were acetate, ribose, glucose, and fructose. At earlier times, andd with lower doses of radiation, there was either no effect, or there was a decrease that was not statistically significant. The movement of CO/sub 2/ was not affected when NaHC/sup 14/O/sub 3/ was the tracer. The ARO of formate was increased. Irradiation had no influence on the C/sub 6//C/ sub 1/ ratio in C/sup 14/O/sub 2/ when the tracers were glucose-1 and glucose-6. Incorporation of glucose and pyruvate (as alanine) into glycogen was increased severalfold. The transfer of carbon from glucose into urea was impaired by radiation, but that from alanine was not affected. With bicarbonate as the tracer, fixation of CO/sub 2/ in liver glycogen was more than seventy times as great in the irradiated rats as in the controls. These findings aremore » interpreted as follows: the reduced output of CO/sub 2/ in expired air postirradiation is not satisfactorily accounted for by impairment of oxidatton of the substrates used; liver glycogen is increased as a resuit of enhanced glycogenesis and gluconeogenesis; and the increased fixation of CO/sub 2/ in liver glycogen suggests that fat may become an important precursor for gluconeogenesis in the irradiated rat. It was concluded that irradiation in the lethal dose range has an influence on intermediary metabolism the significance of which cannot be evaluated fully with the data at hand.« less

A group of 10 male burros was exposed to a total of 350 r weekly in six daily doses of 58.3 r of cobalt-60 y-radiation until death. These will be identified by the term "50 r/day." A second group of 10 male burrows was exposed to 25 r daily until death. The exposure rate was 48 r/hr. The exposure device and dosimetry have been previously described (4). Hemoglobins were determined colorimetrically by the method of Dupray as modified by Wong and Hanzel (5-7). Platelet counts were made by the BrecherCronkite method (8), and the remainder of the hematologic values were obtained by methods described by Wintrobe (9). Plasma irons were determined by the method of Kitzes et al. (10). Electrocardiographic records were made with a Sanborn cardette, model 70, with an attached universal lead selector. The total hay and water consumption of all the animals was recorded daily.

Thyroids of burros and rats studied at this laboratory increased their storage of '131 after irradiation with lethal and sublethal levels of -y-rays to the whole body. This led to an investigation of the 02 consumption, the C02 production, and the calculated respiratory quotient of the irradiated burro which is herein reported. An increase in metabolic activity or oxygen consumption after irradiation has been reported (1-3) for rats and dogs. No change in 02 consumption was noted by others in rats (4), mice (5), or guinea pigs (6). Three species of small animals show considerable difference in weight response after irradiation (7) which seem to indicate a difference in their metabolic activity. In mice a reduced CO2 production, to 80'% of normal, had been reported (8). These varied results in small animals led to the present study of the respiratory exchange in the chronically irradiated burro, in conjunction with other observations made at the time.