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Biomedical subjects

K G Brown

Publications and source records attributed to K G Brown.

At least 19 recordsLinked to original sources
PubMed1995

Significance of exposure assessment to analysis of cancer risk from inorganic arsenic in drinking water in Taiwan.

The primary source of evidence that inorganic arsenic in drinking water is associated with increased mortality from cancer at internal sites (bladder, liver, lung, and other organs) is a large ecologic study conducted in regions of Southwest Taiwan endemic to Blackfoot disease. The dose-response patterns for lung, liver, and bladder cancers display a nonlinear dose-response relationship with arsenic exposure. The data do not appear suitable, however, for the more refined task of dose-response assessment, particularly for inference of risk at the low arsenic concentrations found in some U.S. water supplies. The problem lies in variable arsenic concentrations between the wells within a village, largely due to a mix of shallow wells and deep artesian wells, and in having only one well test for 24 (40%) of the 60 villages. The current analysis identifies 14 villages where the exposure appears most questionable, based on criteria described in the text. The exposure values were then changed for seven of the villages, from the median well test being used as a default to some other point in the village's range of well tests that would contribute to smoothing the appearance of a dose-response curve. The remaining seven villages, six of which had only one well test, were deleted as outliers. The resultant dose-response patterns showed no evidence of excess risk below arsenic concentrations of 0.1 mg/l. Of course, that outcome is dependent on manipulation of the data, as described. Inclusion of the seven deleted villages would make estimates of risk much higher at low doses. In those seven villages, the cancer mortality rates are significantly high for their exposure levels, suggesting that their exposure values may be too low or that other etiological factors need to be taken into account.

Adult↗
PubMed1991

Cyclical disturbance of diabetic control in girls before the menarche.

Seven diabetic girls who presented with cyclical disturbance of diabetic control before the menarche are described. In six girls cyclical hyperglycaemia occurred and in one cyclical hypoglycaemia. The index case is described in detail, and is then included in a description of the main clinical features of all seven cases. Cyclical disturbance of diabetic control may present in diabetic girls from age 9 years onwards. Home blood glucose monitoring records may reveal cyclical disturbance, usually hyperglycaemia, and usually occurring at 21-34 day intervals and lasting for two to five days. Serious illnesses and hospital admission can be averted by educating parents to make appropriate changes to insulin regimen or diet. Our hypothesis is that the disturbance of diabetic control is caused by the onset of cyclical hormonal changes, a 'menstrual' cycle before menstruation. The precise mechanism for the changes in carbohydrate tolerance is unknown.

Adolescent↗
PubMed1989

Statistical uncertainty in the no-observed-adverse-effect level.

The no-observed-adverse-effect level (NOAEL) is a dose value that U.S. EPA reduces by uncertainty factors (UF) and modifying factors (MF) to obtain a reference dose (RfD) for input to regulatory decision making. Whether the true added risk at the NOAEL is below an acceptable level, however, is a source of statistical uncertainty itself. As several authors have previously noted, the probability that added risk at the NOAEL is not negligibly small increases as sample sizes decrease. This is because the definition of the NOAEL statistically controls for the chance of a false-positive error, but not for a false-negative error. The false-positive rate is the test level set by the user in testing for a statistically significant dose effect, typically 0.05. When it is held fixed, the increase in statistical uncertainty as sample size decreases produces an increase in the false-negative rate. Hence, the fewer data available for statistical inference, the higher the expected value of the NOAEL and the less toxic an agent is likely to appear. The solution lies in calculating the probability that a statistical procedure used will detect the maximum added risk acceptable for health regulation (the "power" at that added risk). If the observed response in a dose group is not significantly elevated relative to the control group, and the power for detecting a difference is low as well, then the statistical evidence is inconclusive. In such a case, additional data or other sources of information are needed for evaluating added risk. These concepts are illustrated for examples from the literature with dichotomous (quantal response) data and categorical (severity) data, using a new statistical procedure.

Research Design↗
PubMed1989

A dose-response analysis of skin cancer from inorganic arsenic in drinking water.

A study of the prevalence of skin cancer among 40,421 persons consuming arsenic-contaminated drinking water in Taiwan was used for a cancer dose-response assessment of ingested arsenic. The numbers of persons at risk over three dose intervals and four exposure durations were estimated from the data in order to apply the method of maximum likelihood to a multistage-Weibull time/dose-response model. A constant exposure level since birth for each of the exposure categories was assumed. It was found that the cumulative hazard increases as a power of three in age, and is linear or quadratic (with a linear coefficient) in dose. Observations from a smaller epidemiologic survey in Mexico were similar to what would be predicted from the model of the Taiwan data. Assuming that the skin cancer risk from ingested arsenic in the American population would also be similar to the Taiwan population, an American male would have a lifetime risk of developing skin cancer of 1.3 x 10(-3) (3.0 x 10(-3] if exposed to 1 microgram/kg/day for a 76-year lifespan (median lifespan in the U.S.).

Adult↗
PubMed1987

Effect of vitamin D supplementation during pregnancy on the vitamin D status of ewes and their lambs.

Pregnant ewes were injected intramuscularly with 300,000 iu of vitamin D3 in a water miscible vehicle either 10, seven or four weeks before the expected lambing date and the effects on plasma concentrations of 25-hydroxyvitamin D3 were monitored. The concentrations increased quickly and remained high at parturition but at no time were they outside the normal physiological range. The concentrations in the plasma of the newborn lambs were higher than in uninjected controls and were well correlated with the concentrations in their mothers. Dosing pregnant ewes with 300,000 iu of vitamin D3 in a rapidly available form, approximately two months before lambing, provided a safe means of increasing the vitamin D status of the ewe and the newborn lamb by preventing the seasonally low concentrations of 25-hydroxyvitamin D3.

Animals↗
PubMed1987

Altitude, radiation, and mortality from cancer and heart disease.

The variation in background radiation levels is an important source of information for estimating human risks associated with low-level exposure to ionizing radiation. Several studies conducted in the United States, correlating mortality rates for cancer with estimated background radiation levels, found an unexpected inverse relationship. Such results have been interpreted as suggesting that low levels of ionizing radiation may actually confer some benefit. An environmental factor strongly correlated with background radiation is altitude. Since there are important physiological adaptations associated with breathing thinner air, such changes may themselves influence risk. We therefore fit models that simultaneously incorporated altitude and background radiation as predictors of mortality. The negative correlations with background radiation seen for mortality from arteriosclerotic heart disease and cancers of the lung, the intestine, and the breast disappeared or became positive once altitude was included in the models. By contrast, the significant negative correlations with altitude persisted with adjustment for radiation. Interpretation of these results is problematic, but recent evidence implicating reactive forms of oxygen in carcinogenesis and atherosclerosis may be relevant. We conclude that the cancer correlational studies carried out in the United States using vital statistics data do not in themselves demonstrate a lack of carcinogenic effect of low radiation levels, and that reduced oxygen pressure of inspired air may be protective against certain causes of death.

Altitude↗
PubMed1986

Atomic and Raman spectroscopy of the dipalmitoylphosphatidic acid-calcium complex and phase transitions.

Calcium binding measurements by atomic absorption spectroscopy and temperature-dependent phase transitions studies by Raman spectroscopy were combined in order to investigate the effect of Ca2+ binding on dipalmitoylphosphatidic acid (DPPA) dispersed in CaCl2 solutions of varying concentration at pH 7. The peak heights for the Raman CH stretch bands observed at 2885 cm-1 and 2935 cm-1 were used as a measure of hydrocarbon chain randomization and aggregate ultrastructure. Two transitions were observed for both pure DPPA and DPPA-Ca2+ mixtures. Ca2+ binding caused greatly increased DPPA chain rigidity in the melted state above Tm, but had much less effect on the solid phases below Tm. The increase in rigidity in the fluid state was observed to vary linearly with the molar ratio of bound Ca2+ to total DPPA throughout the range 0 to 1. The results of the Raman and Ca2+ binding measurements are explained by a model in which two populations of DPPA co-exist in the fluid state when Ca2+ binding has not reached saturation. One population consists of the Ca2+-bound DPPA complex with stoichiometric 1:1 binding ratio (determined from an atomic absorption Ca2+ binding study), and the second population is free DPPA. We propose that Ca2+-induced clustering and separation of the two components occurs chiefly because of differences in chain fluidity of the two components.

Calcium↗
PubMed1986

Statistical modeling of animal bioassay data with variable dosing regimens: example--vinyl chloride.

We consider animal bioassay experiments with variable dosing regimens in which groups of animals are dosed beginning at different ages and for varying durations. Two response models are discussed and then applied to data from an experiment on vinyl chloride exposure of F-344 rats, B6C3F1 and Swiss CD-1 mice, and Syrian Golden hamsters. The multistage model of Armitage and Doll, as extended by Whittemore, Day and Brown, and Crump and Howe, is used to estimate the dose effect on the ordered stages of tumor development. The data for all endpoints and species/strains examined consistently indicate a predominant effect on the first stage, suggesting that vinyl chloride is primarily a tumor initiator. This is consistent with evidence from two-stage experiments on this chemical. The second response model, new to this article, adjusts for survival nonparametrically. It is used to test for an age difference in susceptibility, to evaluate alternative exposure durations, and to compare the effectiveness of alternative dosing regimens for detecting carcinogenicity.

Animals↗
PubMed1985

Risk assessment of laboratory rats and mice chronically exposed to formaldehyde vapors.

Experimental data from the Chemical Industry Institute of Toxicology (CIIT) are used to estimate the risk of squamous cell carcinoma of the nasal cavity in Fischer 344 (F344) rats over a range of ambient air concentrations of formaldehyde that includes current exposure guidelines for the workplace and home. These values are presented as a best estimate envelope obtained from five mathematical dose-response formulation. The response of Sprague-Dawley (SD) rats dosed at 15 ppm in a separate study at New York University is consistent with the predicted lifetime response for F344 rats at a slightly lower concentration (13-14 ppm). A dose-related mortality effect beyond what is attributable to the occurrence of nasal carcinomas is found in F344 rats at all CIIT exposure levels (2, 6, and 15 ppm). There is no evidence of a mortality effect in B6C3F1 mice of the CIIT study, and data for SD rats of the NYU experiment are inconclusive. In the CIIT study, rats exposed to 15 ppm exhibited a high incidence of nasal cavity squamous cell carcinomas and polypoid adenomas. Polypoid adenomas were also observed with increased incidences at 2 ppm and 6 ppm. Statistical comparisons with matched controls, and the low historical rate of spontaneous occurrence both suggest that polypoid adenomas may be a risk to F344 rats at exposure levels below the current Occupational Safety and Health Administration (OSHA) standard of 3 ppm. Squamous cell carcinomas were observed in two mice exposed to 15 ppm. This finding may be biologically significant since this tumor is rare and has not been previously reported in 4932 untreated B6C3F1 mice from recent National Toxicology Program (NTP) feeding studies.

Animals↗
PubMed1984

Phase transitions in combined rabbit muscle sarcoplasmic reticulum lipids by Raman spectroscopy.

Using Raman spectroscopy, we found that the sarcoplasmic reticulum lipids of combined muscles from rabbit leg undergo at least two reversible temperature phase changes, centered at about -15 and 13 degrees C. Below the first transition, the lipid Raman CH st region is characteristic of the hexagonal lamellar gel phase. Above the second transition, the Raman CH stretch region is that of a "melted" lamellar phase, somewhat more rigid than a monophasic lipid system. The composition of the lipids was determined and the possibility of a relation between the major head group types and the phase transitions is discussed. Since SR Ca2+ATPase activity is enhanced at about 14-19 degrees C, the Raman studies suggest that ATPase activity is enhanced when the 13 degrees C transition is complete.

Animals↗
PubMed1977

The nephrotic syndrome in Malawian blacks.

This study deals with the nephrotic syndrome in 34 Malawian Blacks, Plasmodium malariae infection and the use of mercury-containing skin lightening creams (Butone 3) must be included among the usual causes of nephrotic syndrome in the Malawian Black.

Adolescent↗
PubMed1975

Cardiac disease in Malawi.

A prospective clinical study of 114 Malawian patients with cardiac disease seen at Queen Elizabeth Central Hospital, Blantyre, is presented. Rheumatic and hypertensive heart disease, cardiorenal failure and severe anaemia were the most common causes. Pericardial disease, mainly due to tuberculosis, was an important treatable cause of cardiac disease. Endomyocardial fibrosis was not diagnosed with certainty and cardiomyopathy was relatively uncommon. Ischaemic heart disease was not seen.

Adolescent↗