Biomedical subjects
Publications and source records attributed to E J Calabrese.
The effects of oral supplementation of ascorbic acid (1500 mg d-1) on urinary beta-glucuronidase (beta-G) activity was assessed in a double-blind crossover study design over a 3-week period. The subjects on ascorbic acid treatment displayed a statistically significant (P less than 0.05) decrease in beta-G with an approximate decrease of 25%.
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Since the discovery of superoxide dismutase in 1969, the role of this enzyme in modulating cellular toxicity of superoxide has been well established. Experimentally, cellular damage from compounds or exposures which produce superoxide extracellularly can be prevented or modified by pretreating a cell or organ system with SOD. Likewise, induction of intracellular SOD by exposing the cell system to various types of nonlethal stress will impart resistance or tolerance to further exposures to oxidant and nonoxidant stresses which would normally be toxic. The differences in intracellular SOD activity based on species, age, and organ variability can have a major impact on the interpretation of toxicology data, particularly extrapolation to human toxicology. An awareness of the importance of SOD to the toxicity of xenobiotics which produce superoxide, either directly or indirectly, will enable those conducting toxicology studies to better understand and interpret their results.
Catalase activity is found primarily in peroxisomes although in some species and in some organ systems, cytosolic catalase also may be involved in intracellular oxidant stress protection. Toxicology studies with repeat exposures to xenobiotics producing hydrogen peroxide either directly or indirectly generally indicate that the organisms develop resistance to the toxin (adaptation). This adaptation would result from induction of catalase activity in most target organs. The induction of hepatic peroxisomes accompanied by less than compensatory increase in catalase activity is now recognized as suggesting a potential for hepatotoxic and hepatocarcinogenic effects. Although these effects seem to also require mobilization of fatty acids, it is not clear if such mobilization is an absolute requirement. As would be expected, there are great differences among species in catalase activity thus making animal-human extrapolations difficult. Finally, with the exception of premature and neonatal animals, age-related variations in catalase activity do not seem to be large enough to have toxicological relevance. However, in old animals, their apparent inability to replace lost catalase activity after repeated stress may have major significance in explaining observed young-old differences in toxicity resulting from oxidant stress.
Sixty-four children aged 1-4 years were evaluated for the extent to which they ingest soil. The study followed the soil tracer methodology of S. Binder, D. Sokal, and D. Maughan (1986, Arch. Environ. Health, 41, 341-345). However, the present study included a number of modifications from the Binder et al. study. The principal new features were (1) increasing the tracer elements from three to eight; (2) using a mass-balance approach so that the contribution of food and medicine ingestion would be considered; (3) extending the period of observation from 3 days to 8 days; and (4) validating the methodology by having adult volunteers ingest known amounts of soil in a mass-balance validation study. The principal findings reveal the following. (1) The adult study confirmed the validity of the tracer methodology to estimate soil ingestion. (2) Of the eight tracers employed in the adult study, only Al, Si, and Y provided sufficient recovery data that was directly acceptably stable and reliable. (3) If food ingestion determinations were taken into consideration, the median estimates of soil ingestion from the eight tracers ranged from a low of 9 mg/day (Y) to a high of 96 mg/day (V); the median values of Al, Si, and Y, the three most reliable tracers, ranged from 9 mg/day to 40 mg/day. (4) One child had soil ingestion values ranging from 5 to 8 g/day, depending on the tracer. (5) If food ingestion had not been considered, the estimates of soil ingestion would have increased about two- to sixfold, depending on the tracer with Ti and Y being most affected by food intake. (6) Since soil and dust samples did not significantly differ in their levels of tracer elements, no reliable differentiation between the contribution of ingestion of dust and soil could be made. (7) These findings are generally consistent with the previously reported findings of Binder et al. (1986) and P. Clausing, B. Brunekreff, and J.H. van Wijnen (1987, Int. Arch. Occup. Med., 59, 73) if these latter studies are corrected for ingestion of tracers in food and medicine. The findings also account for the apparent discrepancy between the estimates from Al and Si and estimates based on Ti in previous studies. Thus the elevated estimates of soil ingestion by Ti were substantially reduced when food ingestion is considered.
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1. A retrospective epidemiological study was conducted to assess the hypothesis that sex differences exist with respect to selected lead-induced red blood cell parameters. The study utilized data previously collected in the Boston Childhood Lead Poisoning Prevention Program. 2. This study revealed no statistically significant difference between males and females (n = 1548) aged 1-6 years for blood FEP levels when blood lead levels were similar. 3. These findings are in contrast with previously published research with human adults, which has suggested that adult females display significantly greater FEP values at identical blood level values as similarly aged men.
This paper assesses the capacity of animal models to predict human response to carcinogenic agents with consideration for the heterogeneity of humans. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. Conventional rodent models are usually highly inbred and valued for their ability to display characteristic homogeneity. Current practice assumes that the homogeneity of response to toxic agents, including carcinogens, in the rodent model will be representative of humans. The issue then becomes, To which of the broad spectrum of human responses are specific animal models likely to be related? This paper examines the extent of human heterogeneity over a broad range of biochemical characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, beta-glucuronidase activity, debrisoquine hydroxylation, DNA-adduct formation) with emphasis on those biochemical characteristics that affect responses to carcinogens. Examples are presented to compare the heterogeneity of selected animal models for these biochemical characteristics as they relate to the spectrum of human responses noted above. The paper presents a theoretical perspective for determining to which part of the human population response spectrum common animal models are most likely to be extrapolated.
The risk of adverse reproductive outcomes was examined among semiconductor manufacturers. Personal interviews were conducted with manufacturing workers, spouses of male manufacturers, and an internal comparison group of non-manufacturing workers. Elevated spontaneous abortion ratios were observed for females working in the "diffusion" (38.9%; relative risk = 2.18, 95% confidence interval estimate = 1.1, 3.6) and photolithographic process (31.1%; relative risk = 1.75, 95% confidence interval estimate = 0.8, 3.3). Analysis of potential confounding did not substantially alter the findings. The potential for recall bias was also assessed; although the confidence interval for the comparison of diffusion and non-manufacturing workers no longer excluded 1.0, an excess risk was still reflected. No substantive differences in other reproductive outcomes were identified. Various general health symptoms were examined and reported more frequently among manufacturers than non-exposed. These results should be viewed as tentative until studies with larger numbers and more detailed exposure data are carried out.
This paper will provide an overview of the potential general applicability of chemical hormesis. Evidence will be presented on the occurrence of chemical hormesis by chemical classes studied (e.g. heavy metals, polycylic aromatic hydrocarbons, etc.), by affected biological and toxic end points (e.g. growth enzyme activities, DNA-repair capacity, life span, tumor incidence) and by biological/taxonomic systems. Several specific examples of possible hormetic effects with respect to agents of environmental concern, such as chloroform, will be presented along with a discussion of future research directions.
Fifty-two adult male subjects were randomly assigned to one of three possible treatment groups: supplemental ascorbic acid at one of two levels, 500 mg or 1000 mg, or a placebo. Hair and blood samples were taken before vitamin C or placebo supplementation was started and at monthly intervals thereafter for three months. Samples were analyzed for cadmium, lead, and mercury. Results indicate that vitamin C did not significantly affect levels of these metals in either hair or blood samples.
The capacity of animal models to predict the responses of humans to carcinogenic agents in light of the occurrence of human heterogeneity is assessed in this paper. It is widely accepted that human susceptibility to toxic substances, including carcinogens, is highly variable. At the same time, it is believed that the conventional rodent models, which are usually highly inbred and reared in standard ways, display a very homogeneous response to toxic agents, including carcinogens. The question then becomes, To which narrow band of the broad spectrum of human responses can specific animal models likely be extrapolated? First, the occurrence of human heterogeneity is examined with respect to a broad range of biological characteristics (e.g., aryl hydrocarbon hydroxylase activity, epoxide hydrase activity, glutathione S-transferase activity, beta-glucuronidase activity, debrisoquine hydroxylation, and DNA adduct formation), with particular emphasis on those which affect responses to carcinogens. Second, the occurrence of heterogeneity for selected animal models for these characteristics is assessed and the outcomes are related to the spectrum of human responses noted above.
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The validity of deriving ambient air quality standards or levels via threshold level values (TLVs) is assessed via two methodologies: (1) using current U.S. standards for ambient air standards and occupational standards where the data base is very robust and (2) using Soviet occupational and community air standards where the standards are based on experimentally derived toxicological endpoints. The analysis indicates that the TLV-derived approach using TLV/420 and the appropriate averaging time is in wide disagreement with both validating methodologies.
The effect of age on the metabolism of pentobarbital in mice and rats was investigated following exposure to 0.3 ppm of ozone for 3.75 hr. Young animals were 2.5 months of age and the mature were 18 months. The pentobarbital sleeping time was significantly prolonged following the ozone exposure in both the mice and rats when compared with an air control. No ozone effect on sleeping time was found in the young animals. The results indicate that there may be an age-related sensitivity to the occurrence of ozone-related inhibition of pentobarbital metabolism.
This paper will provide an introduction to the concept of ecogenetics, including its historical foundations. Specific genetic conditions (more than 30), including those involving RBCs and liver conditions, serum proteins, skin disorders, DNA repair diseases, and others that either theoretically or experimentally have been shown to enhance susceptibility to toxic substances, will be identified and evaluated with respect to their capacity to enhance risk, their frequency in the population, and their ability to be identified in screening tests.
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