Biomedical subjects
D P Rall
Publications and source records attributed to D P Rall.
Problems remain to be resolved in the area of quantitative risk assessment.
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Soviet-American cooperation in environmental health science.
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Environmental health research and regulation.
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Relevance of animal experiments to humans.
The best evidence of an adverse human health effect is a properly conducted epidemiological study. But human beings should not be the sole test animal. Properly conducted animal studies have been shown to be preductive for carcinogenicity and toxicologic responses in human populations. We need to develop more efficient predictive animal tests for all the common serious toxic effects caused by chemicals. One particularly important use of epidemiological studies is to validate (or invalidate) the laboratory animal experiments. There is no more powerful tool than the combination of well conducted animal experiments and well conducted epidemiological experiments.
The role of laboratory animal studies in estimating carcinogenic risks for man.
The extent to which biological processes predict those in humans is discussed and illustrated by analysis of data presented in the first 16 volumes of the IARC Monograph series. Other examples are given to show that if there is sufficient evidence that a chemical is carcinogenic in appropriate animal test systems it must be treated as if it were carcinogenic in humans. A quantitative correlation between data in animals and in humans is more difficult to establish, although there is tentative evidence that such a relationship exists. Society should attempt to keep 'inevitable' exposures to carcinogens to a minimum; social need should be balanced against social risk. Biomedical research can help to estimate this role.
Comparative aspects of brain barrier systems for nonelectrolytes.
Blood-brain and blood-CSF barriers to inulin were compared in 11 vertebrate species. Twenty hours after systemic administration, [14C]inulin penetrated into the central nervous system to an equivalent extent in mudpuppy, salamander (adult and larval), red sculpin, big skate, little skate, southern stingray, and Atlantic stingray with values for RB (dpm/g brain divided by dpm/ml plasma) in the range 0.01- 0.04 and for RCSF (dpm/ml CSF divided by dpm/ml plasma) from 0.02 to 0.04. These values are similar to those reported for mammals. For dogfish, nurse shark, and lemon shark, RB ranged from 0.04 to 0.09 and RCSF from 0.08 to 0.29 and for hagfish RB=0.12, indicating that barrier systems to inulin are poorly developed in sharks and possibly absent in hagfish. Analyses of radiolabeled urea and sucrose penetration into brain and CSF revealed further differences in shark barrier function. Brain barriers to insulin in dogfish and little skate developed with age; in nurse shark there was no detectable change in the inulin ratios over the weight range, 0.2-110 kg.
Environmental hazards and neurological disease.
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Brain-tumor chemotherapy. Pharmacological principles derived from a monkey brain-tumor model.
An implnated choriocarcinoma growing inthe brains of monkeys was used as a brain-tumor model for the study of the cerebral distribution of two commonly used physiological markers, inulin and albumin; tissue samples were obtained from the tumor, adjacent brain, and distant brain. An extravascular inulin space was calculated by subtracting the albumin (plasma) space from the total inulin spaces. The extravascular inulin space in the tumor was found to be 24%, a value significantly larger than that in distant brain (0.6%). The large inulin space of the tumor was probably the result of increases on both capillary permeability and the extracellular space within this area. Determination of the inulin space in 1 to 2-mm thick samples of tissue taken serially from the tumor center to the distant brain indicated a gradual decline in inulin concentration from the tumor's edge to distant brain. This distribution pattern could be the result of either a continuous decrease, running from the tumor to distant brain, in capillary permeability to inulin, or a diffusional flow of inulin from the tumor into the adjacent tissue. The failure of drugs to inhibit such a tumor in view of these observations is discussed.
Tissue distribution of (14C) methyl mercury in the lobster, Homarus americanus.
[14C] Methyl mercury was administered by three different routes: intravascular (iv) injection, ingestion, and absorption from the ambient water. After iv administration (0.1 mg/kg) [14C] methyl mercury was rapidly removed from the plasma, followed by slow loss from the hepatopancreas and a strikingly persistent increase in the amount of radioactivity in the tail muscle. Most (80-90%) of the radioactivity in the hepatopancreas was shown by TLC methods to be the parent compound, and approximately 10% of this persisted for 6 days after injection. The half-life in this organ was found to be 21 days. One month after iv treatment with methyl mercury, the only organs that contained more than 0.1 ppm of this xenobiotic were egg masses, male gonads, heart, brain, intestine, and tail muscle. The half-lives for disappearance from sexual organs were greater than 1 month. After ingestion of [14C] methyl mercury (0.1 mg/kg) in food the hepatopancreas contained most of the administered dose at 6 days (68%), while the stomach (10%), tail muscle (8%), and carcass (15%) contained less. A unique distribution pattern emerged 6 days after exposure to [14C] methyl mercury-containing ambient water (0.1 ppm). The tail muscle contained most (50%) of the absorbed dose, whereas the hepatopancreas and carcass contained only 23 and 10%, respectively. In view of the small molecular size and high lipid solubility of methyl mercury and the lipophilic properties of the chitin-protein exoskeleton of the lobster, it is likely that significant uptake directly from the water as well as storage of absorbed methyl mercury occurred in the tail region. Residue analysis on untreated lobsters indicated that the egg masses contained the largest amount of methyl mercury (0.1 ppm). The hepatopancreas and carcass (muscle) levels were less than 0.05 ppm.
Occupational carcinogenesis. Toward an integrated program of government action.
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Soviet-American cooperation on fundamental problems in environmental health.
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The blood-brain barrier and ventricular system of Myxine glutinosa.
Comparison of the rate and extent of penetration of test compounds from plasma into brain and muscle of the hagfish, Myxine glutinosa, indicates that the blood-brain barrier is poorly developed or absent in this species. We examined a series of hagfish brains in the light and electron microscope in order to relate the structure of the brain to the physiology of the blood-brain barrier and cerebrospinal fluid. The ventricular system consists of an ependymal cell-lined central canal extending from the spinal cord to the midbrain and two or more ependymal cell-lined cavities located more rostrally. A preoptic and an infundibular recess were present in the diencephalons of all brains and were isolated from each other and from the primary ventricular system. Since a typical choroid plexus could not be identified, this suggests that cerebrospinal fluid must be formed entirely by brain in this species. Cerebral capillaries differ significantly from those of other vertebrates in possessing large numbers of cytoplasmic vesicles and in the relative rarity of tight junctions between endothelial cells. These capillaries do not, therefore, appear to be morphologically specialized for barrier functions.