Abstract: The theory and practice of the thermal-dye indicator-dilution method for measurement of EVLW has been discussed, and all available animal data from our laboratory correlating EVTV and gravimetric EVLW have been presented. The method appears to function well over the entire range of edema seen , and to be minimally dependent on cardiac output. Thermal-indicator loss does not seem to be a significant problem and does not impair the accuracy of this method. Out results are consistent with earlier works in the field in identifying significant differences between the isotopic EVLW methods and the thermal-dye method, and it seems likely that these differences are due to the much greater diffusion rate of the thermal indicator.

Abstract: The problem of polychlorinated biphenyls (PCBs) became a national concern in 1971 when several accidental contaminations of foods were reported. Extensive efforts were undertaken by FDA to reduce the residues of PCBs in food. However, the PCB levels in several species of fresh-water fish have raised concern about the PCB residues from environmental contamination, and it is this concern which has prompted a reassessment of the human risk involved from consumption of such fish. The human epidemiology and animal toxicity of PCB exposure are reviewed, as well as risk assessment in general. Specific examples to risk assessment involving extrapolation of animal data to humans, based on several levels of human exposure to PCBs in fish, are presented.

Abstract: We have tested 74 teratogenic and 28 nonteratogenic agents in a recently developed in vitro teratogen assay system. The assay identifies teratogens by their ability to inhibit attachment of ascites tumor cells to plastic surfaces coated with concanavalin A. There is a qualitative agreement between in vivo animal data and in vitro activity for 81 of the 102 agents (79%). Quantitative analysis shows a highly significant correlation coefficient of 0.69 between the inhibitory in vitro dose and the lowest reported teratogenic dose for 54 of the 60 inhibitory teratogens. The doses analyzed ranged over 5 orders of magnitude. We interpret these results to mean that attachment inhibition in concert with other, complementary, in vitro assay systems can become a useful method for the assessment of the teratogenic potential of environmental agents.

Abstract: Inflammatory bowel disease (IBD) commonly affects women of childbearing age, leading to concerns about the effects of the disease on fertility and pregnancy, the effect of pregnancy on the disease, and the diagnosis and treatment of IBD in the pregnancy women The literature regarding these issues is reviewed, and a representative case report is discussed Ulcerative colitis has no effect on fertility Crohn's disease appears to be associated with an increased risk of infertility "Subfertility," a temporary inability to conceive associated with chronic disease activity, is perhaps a more suitable description There have been no studies regarding infertility and males with IBD, although sulfasalazine has recently been reported to cause reversible infertility in men Ulcerative colitis is not associated with a higher spontaneous abortion rate than the general population, although it is not clear whether certain subgroups of patients have a higher rate of abortion A similar conclusion has been reached for Crohn's disease, although reported abortion rates of 10-25% are somewhat higher than the general population Approximately 30-50% of pregnant women with ulcerative colitis have exacerbations during their pregnancy or postpartum, a figure that is applicable to Crohn's disease as well, and which is no different than a control population of nonpregnant women with IBD Patients with active ulcerative colitis at conception have a higher incidence of disease exacerbation than those with quiescent disease Postpartum recurrences are more frequent in Crohn's disease, occurring in up to 40% of patients, but respond to standard medical therapy Women who have had an ileostomy for ulcerative colitis consistently and successfully carry pregnancy to term There is no data regarding women who have had an ileostomy for Crohn's disease The approach to the women with abdominal pain during pregnancy is reviewed, including the use of radiographic procedures No amount of radiation exposure can be considered safe, but the judicious use of standard radiographic tests when considered necessary for the health of the mother appear to be associated with little risk for the fetus The medial treatment of IBD during pregnancy is the same as that for the nonpregnant patient Despite animal data to the contrary, the bulk of human data suggests that steroids, when used to treat a variety of conditions including IBD, pose little risk to the human fetus Similarly, despite the theoretical risk of kernicterus, sulfasalazine appears to be a safe drug even when used during the third trimester of pregnancyU

Abstract: Chloroform and other trihalomethanes are contaminants of drinking water that have been demonstrated to be carcinogenic in laboratory animals. Determination of the mechanism of carcinogenicity of chloroform is required so that the animal data can be extrapolated to estimate the human health hazard. The extent of the binding of chloroform to rat liver and kidney DNA was approximately 0.1% the level of binding found for dimethylnitrosamine. Neither chloroform nor bromoform, in contrast to diethylnitrosamine-initiated GGTase-positive foci in either intact or partial hepatectomized rats, promoted with phenobarbital. Tumor-promoting activity of chloroform was indicated by the slight significant increase, compared to untreated controls, in the incidence of GGTase-positive foci in rats initiated with diethylnitrosamine (DENA) followed by the administration of chloroform twice weekly for a total of 15 doses. In this study, rats administered only the DENA or the chloroform did not contain an increased incidence of GGTase-positive foci compared to untreated controls. However, the incidence of foci in the group that received DENA followed by chloroform was not statistically different from that in either the group that received only the DENA or only the chloroform. In conclusion, we were unable to demonstrate tumor-initiating activity for chloroform, and the tumor-promoting activity of chloroform indicated by our results requires further confirmation.

Abstract: 1 The pharmacological characteristics of β-adrenoceptor subtypes on adipocytes of various mammalian species, including man, are reviewed. 2 Rat adipocytes possess a homogeneous population of β-adrenoceptors with properties that clearly distinguish them from `classic' β1- and β2-adrenoceptors, although they share certain features with both. Thus, rat adipocyte β-adrenoceptors should be considered as non-β1-non-β2 receptors, like the atypical β-adrenoceptors found on erythrocytes of turkey, chicken and frog. 3 Preliminary data suggest that adipocyte β-adrenoceptors of guinea pig and swine are different from `classic' β1- and β2-adrenoceptors as well, whereas in the dog and possibly in the cat, a mixture of β1- and β2-receptors mediates catecholamine induced lipolysis. 4 Human adipocyte β-adrenoceptors probably also consist of at least two subtypes. Insufficient data are available to decide if these β-adrenoceptors are identical with `classic' β1- and β2-receptors, or share some hybrid characteristics with rat adipocyte β-adrenoceptors. 5 In vivo studies in animals as well as in man, tend to corroborate in vitro results. Cardioselective β-adrenoceptor blocking agents, like atenolol, metoprolol and practolol are not as effective in blocking catecholamine induced lipolysis as non-cardioselective agents like propranolol and pindolol. The relatively low potency of cardioselective β-adrenoceptor blocking agents is found using either isoprenaline, adrenaline or exercise as the agonist, suggesting that β2-adrenoceptors are involved. On the other hand, cardioselective agents, though less effective than non-cardioselective compounds, have a significant inhibitory effect on catecholamine induced lipolysis at doses that have only minimal effect on other β2-adrenoceptor mediated responses, which argues for participation of β1-adrenoceptors. 6 Thus, human in vitro and in vivo data are consistent with, but not proof of the hypothesis that a mixture of β1- and β2-adrenoceptors mediates lipolysis induced by sympathetic activation. 7 Species differences in β-adrenoceptor subtype characteristics may complicate the interpretation of the relevance of animal data for the understanding of β-adrenoceptor mediated effects in human adipocytes.

Abstract: This articie is based upon a paper which was presented at the SRP meeting on the Biological Bases of Radiation Protection Standards, October 1981. It is suggested that experimental radiation carcinogenesis data derived from animal studies will probably never provide numerical evidence of risk that is applicable to man. The uncertainties involved in any extrapolation of risk estimates from mice to men surely outweigh the uncertainties in the human epidemiological data. It is also suggested that at least in the foreseeable future animal data will not solve the perennial problem of the shape at low doses of the dose response curve for radiogenic cancer. At most the data may clarify the debate over linearity-non linearity and over the existence or otherwise of a threshold. However, the paper does suggest a very positive role for animal data in providing semi-quantitative generalizations for radiological protection concerning such variables as dose rate, radiation quality, partial body/organ exposure and in situations where the dose is received in a highly inhomogeneous fashion, e.g. the special problems of internal emitters.

Abstract: 1 The pharmacological characteristics of β-adrenoceptor subtypes on adipocytes of various mammalian species, including man, are reviewed. 2 Rat adipocytes possess a homogeneous population of β-adrenoceptors with properties that clearly distinguish them from `classic' β1- and β2-adrenoceptors, although they share certain features with both. Thus, rat adipocyte β-adrenoceptors should be considered as non-β1-non-β2 receptors, like the atypical β-adrenoceptors found on erythrocytes of turkey, chicken and frog. 3 Preliminary data suggest that adipocyte β-adrenoceptors of guinea pig and swine are different from `classic' β1- and β2-adrenoceptors as well, whereas in the dog and possibly in the cat, a mixture of β1- and β2-receptors mediates catecholamine induced lipolysis. 4 Human adipocyte β-adrenoceptors probably also consist of at least two subtypes. Insufficient data are available to decide if these β-adrenoceptors are identical with `classic' β1- and β2-receptors, or share some hybrid characteristics with rat adipocyte β-adrenoceptors. 5 In vivo studies in animals as well as in man, tend to corroborate in vitro results. Cardioselective β-adrenoceptor blocking agents, like atenolol, metoprolol and practolol are not as effective in blocking catecholamine induced lipolysis as non-cardioselective agents like propranolol and pindolol. The relatively low potency of cardioselective β-adrenoceptor blocking agents is found using either isoprenaline, adrenaline or exercise as the agonist, suggesting that β2-adrenoceptors are involved. On the other hand, cardioselective agents, though less effective than non-cardioselective compounds, have a significant inhibitory effect on catecholamine induced lipolysis at doses that have only minimal effect on other β2-adrenoceptor mediated responses, which argues for participation of β1-adrenoceptors. 6 Thus, human in vitro and in vivo data are consistent with, but not proof of the hypothesis that a mixture of β1- and β2-adrenoceptors mediates lipolysis induced by sympathetic activation. 7 Species differences in β-adrenoceptor subtype characteristics may complicate the interpretation of the relevance of animal data for the understanding of β-adrenoceptor mediated effects in human adipocytes.

Abstract: Doses of 3 mg/kg Ro 10-9359 (in arachis oil) were daily administered to adult female Wistar rats by gastric tube for a period of 10 days. Control animals received corresponding quantities of arachis oil only. The body weight of all rats was registered daily. Samples of jejunum and ileum were processed for quantitative histochemical analysis of neutral α-glucosidase kinetics and for three-dimensional evaluation of the mucosal architecture. In addition, mucosal scrapings were prepared from these intestinal segments, and the specific sucrase activity was determined. For each animal data were pooled and analyzed by Wilcoxon (Wn) test.

Abstract: Animal data suggest that angiotensin II may directly affect renal sodium retention independent of aldosterone (4,6). Additionally there is evidence to suggest that the hormone can stimulate protein synthesis in a variety of tissues and that indeed it may be a vasculotoxin (5,7). We describe here experiments designed to elucidate the role of angiotensin II in renal sodium retention in normal man. Additionally we present preliminary evidence suggesting that unlike the rapid sodium retaining effect, some delayed (trophic) actions of the hormone may be generated by a hitherto unappreciated mechanism.

Abstract: Sulphate ester and glucuronic acid conjugations are major pathways of Phase 2 drug metabolism. Their comparative study, in normal and tumour tissues, was undertaken, using various in vitro systems. The major xenobiotic used was 1-naphthol, its conjugation by UDP-glucuronosyl-transferase and sulphotransferase to 1-naphthyl-beta-D-glucuronide and 1-naphthyl sulphate respectively, being investigated. Normal human lung and colon tissue in short-term organ culture formed more 1-naphthyl sulphate, whereas tumours from these organs produced more 1-naphthyl-beta-D-glucuronide, there being a change in conjugation pathways from normal to tumour tissue. Such biochemical differences in human tissues could be exploitable in cancer chemotherapy. Possible reasons for this shift in metabolism include: changes in enzyme protein; availability of cofactors; alterations in hydrolysing enzymes. It may even be connected to alterations in cell-surface glycosaminoglycans. Normal peripheral human lung in organ culture formed almost exclusively 1-naphthyl sulphate, whereas tumour tissue from squamous carcinomas gave predominantly 1-naphthyl-beta-D-glucuronide. Normal colon produced a different pattern of conjugation from colorectal tumours. Subcellular fractions, from lung specimens, reflected the metabolism seen in culture, while those from colonic samples did not. Human bronchial carcinoma cell lines, but not those from human colon adenocarcinomas, generally produced a conjugation pattern suggesting a reasonable model for surgical tumour samples in culture. Xenografts derived from human lung and colon tumours gave a similar conjugation pattern as surgical samples in culture. Species differences occurred with short-term organ cultures from normal rodent lung and colon tissues, which produced conjugation patterns unlike those obtained from normal human tissues. For these pathways, rodent tissues would provide unsatisfactory models for humans. These results emphasised the difficulties in extrapolating from animal data to man and the importance of studying human tissues. Thus, using organ culture of human tissue, improved understanding of human metabolism, target organ toxicity and individualising treatment by testing chemosensitivity of drugs may be obtained.

Abstract: Useful animal models are indispensable in drug research, in which the extrapolation of animal data to humans is essential. Two approaches of the extrapolation are expected to be useful; simulation of human physiology or pathology and a comparative approach in which the various species of animals are lined phylogenetically and compared. The analysis of the present status of laboratory animal science indicates that the development of new experimental animals and disease models is necessary for the establishment of the principles and the methods of the extrapolation of animal data to humans. Four methods of developing new experimental animals are presented. They are 1) from domestic and wild animals, 2) from mutants, 3) from toxicology and 4) by developmental engineering.

Abstract: The earliest studies of induced atherosclerosis involved the feeding of milk and eggs (1) or of pure cholesterol to rabbits (2). The choice of the rabbit for this type of study has been criticized on the grounds that this species is normally herbiverous and thus we are studying a cholesterol storage disease in an animal that cannot detoxify excess cholesterol. The criticism is justifiable but, in fact, any animal species used differs metabolically from man to some extent. While direct extrapolation of animal data to man is generally unwarranted these experiments provide clues which may be useful in assessing dietary or drug treatment.

Abstract: It is now well documented from human and animal data that asbestos exposure is associated with the development of two kinds of diseases: 1/ Fibrosis, not only of lung parenchyma (asbestosis) but also of pleura (pleural plaques); 2/ Cancer, mostly bronchogenic carcinoma and pleural or peritoneal mesothelioma, and also laryngeal cancer, gastro-intestinal tumors and perhaps cancer of other site (1, 2). Initially, such diseases were observed only in asbestos workers, some of them such as mesothelioma or lung cancer after a long latency period of 20 to 40 years (3). At present, with the increasing consumption and accumulation of asbestos dusts in our environment, the asbestos-related diseases increase steadily in incidence and are also observed in association with moderate para-occupational (domestic) or environmental exposures (3, 4). More recently, other fibres, either natural (zeolite) or man made fibres (glass fibres) were shown to have the same potential hazards! (5)

Abstract: Significant reduction in brain weight and in the number of cortical neurons with increase of astroglia in aging brain and SDAT are associated with decreased synthesis and turnover of some neurotransmitters, particularly affecting the DAergic system. Progressive loss of TH activity reaching in SDAT almost the low levels of Parkinson disease is associated with progressive decline in DA concentration in the nigro-striatal system. Increase in MAO-B activity and in the ratio of MAO-B: MAO-A reported by some authors in aging brain and SDAT, however, was not confirmed in human frontal cortex in both Parkinson disease and SDAT. However, the location of both types of MAO in human brain is debatable, since preliminary studies indicate that, unlike in rat brain, MAO-B appears to be the major degradating enzyme of biogenic amines in human brain, while MAO-A might be associated, at least in part, with neuronal structures. Reduction in DAergic parameters in aging brain are also reflected in a decrease of adenylate cyclase activity and of D2 DA receptors. Animal data on decrease of DA-receptor density in the striatum with age were confirmed in human Parkinson disease and Alzheimer disease. These disturbances in neuronal feedback systems may be responsible for pathophysiological and behavioral changes in old age.

Abstract: Pharmacokinetic alterations in drug disposition have been demonstrated for a variety of hepatic disease states, but there is little information concerning the effects of elevated hepatic venous pressure on hepatic drug metabolism. A rat model of hepatic congestion which was characterized by significantly elevated hepatic venous pressure, marked prolongation of prothrombin time, reduced total hepatic blood flow and histological changes of marked pericentral fibrosis and central vein dilation was used to study the effects of liver congestion on hepatic microsomal biotransformation and in vivo disposition of morphine and pentobarbital. No significant differences in levels of microsomal cytochrome P-450 or NADPH-dependent cytochrome c reductase were seen between the two groups. Total hepatic microsomal capacity for glucuronidation of morphine and hydroxylation of pentobarbital was not altered by elevated hepatic vein pressure and no change in in vivo systemic clearance was seen for either drug in response to hepatic venous congestion. These animal data demonstrate that hepatic congestion produces minimal alterations in hepatic metabolism of morphine and pentobarbital and may not have the severe detrimental effects on drug biotransformation and disposition which would be predicted.

Abstract: Cognitive performance declines moderately with normal aging and severely with pathological aging. A similar range of intellectual impairment has been described in association with prolonged alcohol consumption. It is doubtful that all types and degrees of alcohol-associated impairments of cognitive function are attributable only to thiamin deficiency. Evidence from human and animal data indicates increasingly that alcohol per se has direct CNS toxic effects as well, and it is dangerous to suggest that adequate thiamin consumption alone would prevent all CNS toxic effects of chronic alcohol consumption. If a direct role of ethanol in CNS toxicity is accepted, it becomes important to study the molecular basis of the behavioral impairment caused by both aging and alcohol abuse in order to develop rational treatment and prevention. An entire spectrum of relationships is possible between aging and alcohol-related CNS changes. At the one end of the spectrum could simply be deficits additive at the behavioral level but caused by different molecular events. Conversely, molecular processes of biological aging could interact with molecular effects of ethanol, potentiating each other and culminating in an accelerated aging process. Many pathological mechanisms could lead to an irreversible loss of neuronal cell bodies. However, changes in peripheral cell processes, including the synapses, may be equally important in limiting interneuronal communications that result in behavioral deficits. Some changes could even be limited to a decrease of numbers or affinity of synaptic receptor molecules of a particular region. From the human and animal data reviewed, chronic ethanol consumption appears to increase some behavioral deficits caused by aging. What the exact interrelationships are at the molecular basis for the behavioral changes is not yet clear.