Search PubMed⌕ Search

Biomedical subjects

E J O'Flaherty

Publications and source records attributed to E J O'Flaherty.

At least 19 recordsLinked to original sources
PubMed2000

Lessons learned in applying the U.S. EPA proposed cancer guidelines to specific compounds.

An expert panel was convened to evaluate the U.S. Environmental Protection Agency's "Proposed Guidelines for Carcinogen Risk Assessment" through their application to data sets for chloroform (CHCl3) and dichloroacetic acid (DCA). The panel also commented on perceived strengths and limitations encountered in applying the guidelines to these specific compounds. This latter aspect of the panel's activities is the focus of this perspective. The panel was very enthusiastic about the evolution of these proposed guidelines, which represent a major step forward from earlier EPA guidance on cancer-risk assessment. These new guidelines provide the latitude to consider diverse scientific data and allow considerable flexibility in dose-response assessments, depending on the chemical's mode of action. They serve as a very useful template for incorporating state-of-the-art science into carcinogen risk assessments. In addition, the new guidelines promote harmonization of methodologies for cancer- and noncancer-risk assessments. While new guidance on the qualitative decisions ensuing from the determination of mode of action is relatively straightforward, the description of the quantitative implementation of various risk-assessment options requires additional development. Specific areas needing clarification include: (1) the decision criteria for judging the adequacy of the weight of evidence for any particular mode of action; (2) the role of mode of action in guiding development of toxicokinetic, biologically based or case-specific models; (3) the manner in which mode of action and other technical considerations provide guidance on margin-of-exposure calculations; (4) the relative roles of the risk manager versus the risk assessor in evaluating the margin of exposure; and (5 ) the influence of mode of action in harmonizing cancer and noncancer risk assessment methodologies. These points are elaborated as recommendations for improvements to any revisions. In general, the incorporation of examples of quantitative assessments for specific chemicals would strengthen the guidelines. Clearly, any revisions should retain the emphasis present in these draft guidelines on flexibility in the use of scientific information with individual compounds, while simultaneously improving the description of the processes by which these mode-of-action data are organized and interpreted.

Animals↗
PubMed1999

The O'Flaherty model of lead kinetics: an evaluation using data from a lead smelter population.

The O'Flaherty model of lead kinetics is a physiologically based computer model of lead disposition in humans. The model is based on an age-dependent approach to human growth, with particular attention devoted to bone metabolism. As such, model output is well suited for comparison with noninvasive bone lead measurements made via X-ray fluorescence. A subset of workers from a lead smelter population were selected for an initial evaluation of the O'Flaherty model. Detailed blood lead records were used to define input. Simulated bone lead and blood lead output were compared with observation, enabling a refinement of model parameters. A revised version of the O'Flaherty model was then evaluated for the smelter population as a whole. Previously observed trends for the accumulation of lead in cortical bone and the release of lead from bone stores were well explained by the revised model. Model predictions for the accumulation of lead in trabecular bone were not in accord with observed levels in the calcaneus. Model results from the smelter population are consistent with the hypothesis that a polymorphism in the delta-aminolevulinate dehydratase enzyme modifies the kinetics of lead in humans. Further refinements are suggested, which may enhance the ability of the model to explain the underlying relationships between lead exposure and the distribution of lead in the body.

Aging↗
PubMed1998

Evaluation and modification of a physiologically based model of lead kinetics using data from a sequential isotope study in cynomolgus monkeys.

Endogenous (predominantly bone) and exogenous lead were differentially labeled in two 11-year-old female cynomolgus monkeys (Macaca fascicularis) to establish the contributions of the two sources to blood lead. The monkeys had been administered a common lead isotope "mix" at the rate of about 1300 micrograms Pb/kg body wt/day from age 10 months until the start of the study. On day 0, common lead was replaced in sequence by mixes artificially enriched in 204Pb, 206Pb, and 207Pb, given for periods of from 50 to 281 days. Total lead ingestion rate was held constant except during administration of the 207Pb-enriched mix to one of the monkeys, when it was reduced to 650 micrograms/kg/day. Blood and bone were sampled at intervals and analyzed for their content of each of the isotope mixes. A physiologically based model of human lead kinetics was scaled to the cynomolgus monkey and fit to the data to test the correctness of the model structure and to assist with interpretation of study results. Fractional absorption was varied to achieve the best visual fits of the scaled model to blood and bone concentration data for each monkey. The model failed to reproduce the sharp drop in isotope concentrations in blood observed after each exchange of isotope mix. Consequently, it was revised to include a rapid-turnover trabecular bone compartment and a slow-turnover cortical bone compartment, using estimates of trabecular and cortical bone turnover rates from histomorphometric studies in adult cynomolgus monkeys. The revised model fit most of the sets of bone and blood concentrations well. About 17% of the blood lead originated from bone after 11 years of exposure, at blood lead concentrations in excess of 50 micrograms/dl. The rate of return of common lead from bone, as estimated from the model, was 28 micrograms/day just before termination of controlled common lead exposure on day 0. Based on the success of the scaled human model in fitting these data and on the absolute and relative values of bone and blood lead concentrations, the metabolism of lead in the cynomolgus monkey appears to be similar to human lead metabolism.

Americium↗
PubMed1998

Physiologically based models of metal kinetics.

The issues confronting the modeler of metals kinetics are somewhat different from those with which the modeler of organic chemical behavior is faced. Particularly important features of metals kinetics include metal-protein binding and metal-metal interactions. Reduction, and for some metals oxidation, is frequently an intrinsic part of metal metabolism. Alkylation/dealkylation reactions may or may not render the metal less active, and the behavior of alkylated or dealkylated metabolites must often be included in a complete kinetic model. Despite these complexities, the kinetics of metals are as amenable to the techniques of physiologically based modeling as are the kinetics of organic chemicals. Like all models, those for metals kinetics have the potential to organize a variety of observations, sometimes including apparently inconsistent observations, into a coherent framework of behavior, to identify needs for more complete experimental information, and to assist the risk assessor in making judgments concerning dose-response relationships. Development of physiologically based models of the kinetic behavior of metals is in its very early stages. The kinetics of only four metals, arsenic, chromium, mercury, and lead, have been modeled with any degree of completeness. Of these, the lead model is the most fully realized at the present time. The chromium and mercury models are still in the process of development, and experimental data are being gathered to support further development and refinement of the arsenic model. We may expect to see continued progress made on these models and their practical applications, as well as the development of new models for other toxicologically significant metals such as cadmium, manganese, nickel, and aluminum.

Biological Transport↗
PubMed1998

A physiologically based kinetic model for lead in children and adults.

A physiologically based model of lead kinetics in children and adults has been developed and tested. The premises on which the physiologically based model is founded are reviewed in this paper. Because 95% or more of the body burden of lead in adults is found in the bone, bone metabolism is central to the model. Bone volumes are expressed as functions of body weight. Bone formation and resorption rates are estimated from human studies of stable labeled calcium kinetics. Cortical and trabecular bone are modeled separately, with their surface-to-volume ratios taken into account. Standardized growth curves are used to relate body weight to age. Other model features such as organ volumes and physiologic functions are related to body weight based on measurements made in human subjects over a range of ages. Calibrations of the model to two human data sets are shown, and two applications to specific research questions are illustrated. A brief comparison of the structure of this model with that of the Leggett model, and a comparison of the output of this model with that of the integrated exposure uptake biokinetic model of the U.S. Environmental Protection Agency, are also included.

Adult↗
PubMed1996

Measurement of the flux of lead from bone to blood in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead isotopes.

To better understand the kinetics of the transfer of lead from bone to blood, we have developed and tested a method in which sequential doses of lead, each enriched with a different stable isotope, were administered in a nonhuman primate Macaca fascicularis whose skeleton had been previously labeled with lead of known isotopic composition. Lead isotopic ratios of blood and bone samples, analyzed by thermal ionization mass spectrometry (TIMS), were unmixed by isotope dilution techniques. The first label administered allows the contribution from historical bone stores to be measured. Subsequent labels allow measurement of both the historical bone stores and the previous labels that have become recently incorporated into bone. The method may be extended to studies of bone lead mobilization in pregnancy, lactation, menopause, or in disease states such as postmenopausal osteoporosis.

Animals↗
PubMed1996

A physiologically based model of chromium kinetics in the rat.

A physiologically based model of chromium kinetics in rats has been developed. The general structure of the model is similar to that of a model of lead kinetics in rats. Like lead chromium exchanges between plasma and the bone surfaces in contact with plasma, and also like lead, although with much lower efficiency, it can become incorporated into actively mineralizing bone. Both processes are included in the model. Parallel absorption and disposition schemes for chromium(VI) and chromium(III) are linked in the model by reduction processes occurring throughout the body, including the lung and gastrointestinal tract. Examination of a number of data sets from studies in which chromium salts were administered to rats intravenously, orally, or by intratracheal instillation established that intravenous administration, on the one hand, and oral or pulmonary administration, on the other hand, result in different disposition patterns. The model was calibrated based on published oral and intratracheal kinetic studies in rats given soluble chromium(III) and chromium(VI) salts. In the most complete of these studies, chromium concentrations were monitored in individual tissues for 42 days following intratracheal administration of a soluble chromium(VI) salt. Inclusion in the model of a urinary excretion delay was necessary in order to fit excretion data from two other intratracheal studies. Model predictions of blood chromium concentrations are compared with the results of a published kinetic study in which rats were administered a soluble chromium(VI) salt by inhalation.

Animals↗
PubMed1996

Plasma and blood lead concentrations, lead absorption, and lead excretion in nonhuman primates.

In order to assess the comparability of lead disposition in the cynomolgus monkey to that in the human, we determined the relationships among blood lead concentration, plasma lead concentration, and lead excretion in monkeys. Six adult (3-5 kg) female cynomolgus monkeys (Macaca fascicularis) without previous experimental lead exposure were given single intravenous injections of from 750 to 3300 micrograms lead as lead nitrate, labeled with 210Pb, per kilogram body weight. Four additional monkeys, fasted overnight, were administered single oral doses of either 750 or 1500 micrograms lead as lead nitrate, labeled with 210 Pb, per kilogram for the assessment of fractional absorption. Blood and plasma lead concentrations (10 monkeys) and urinary and fecal excretion of lead (2 monkeys) were followed up for up to 16 days after lead administration. Fractional absorption from an oral dose was 44% at the lower of the two doses and 22-28% at the higher dose. The relationship between plasma and blood lead concentrations was found to be similar to that in humans, with plasma lead concentration at most a few percent of total blood lead concentration at low concentrations. Partitioning of lead across the red cell membrane in the 2 monkeys given exceptionally high doses (3300 micrograms/kg) intravenously was distinctly lower than that in the 4 monkeys given lower intravenous doses. Urinary clearance of lead in these 2 monkeys was 19% of the estimated glomerular filtration rate, within the range of efficiencies reported for humans. Fecal clearance, however, was anomalous and appeared to be an artifact of the very high dose. Examination of published data for urinary and fecal lead excretion in three adult baboons showed that both functions in the baboons were quantitatively similar to those in humans. Urinary clearance in the baboons was 14-24% of the estimated glomerular filtration rate, and fecal clearance was 78-85% of the urinary clearance. We conclude that nonhuman and human primates are comparable with respect to the relationship of plasma lead concentration to blood lead concentration and the relative efficiency of lead excretion in urine and feces.

Absorption↗
PubMed1996

Evaluating lead bioavailability data by means of a physiologically based lead kinetic model.

A method of bioavailability estimation is presented in which a physiologically based kinetic model of lead kinetics is fit simultaneously to blood and bone lead concentrations after a period of exposure to dietary lead. Optimization of the simultaneous fit, varying only fractional absorption, gives the best estimate of fractional bioavailability for each treatment group. The analysis was applied to data from three separate studies in which rats were fed for 30 consecutive days purified diets containing lead added as lead acetate, mine waste-contaminated test soils, or mine waste itself. Fractional absorption decreased as lead intake increased, regardless of the source of the lead; but the magnitude of this dose dependence was lead source-dependent. There were no differences in lead absorption by male and female rats when lead intake was expressed per unit body weight. Fractional absorption varied from 4 to 5%, at low exposure rates (1-2 mg lead/kg/day) when lead acetate was added to the diet, to 0.24% at a high exposure rate (24 mg/kg/day) when a mine waste-contaminated test soil was added to the diet. Comparison of the results of this analysis with the results of a more conventional analysis, in which the bone and blood lead concentrations were separately compared with bone and blood lead concentrations in rats given daily injections of lead acetate intravenously for 29 consecutive days, demonstrated that the standard analysis failed to reveal the dose dependence of fractional absorption.

Animal Feed↗
PubMed1995

Chemical mixtures from a public health perspective: the importance of research for informed decision making.

When considered from a public health perspective, the central question regarding chemical mixtures is deceptively simple: Are current approaches to risk assessment for chemical mixtures affording effective (adequate) and efficient (cost-effective) protection for members of our society? Answering this question realistically depends on an understanding of the hierarchical goals of public health (i.e. prevention, intervention, treatment) and an accurate evaluation of the extent to which these goals are being achieved. To allow decision makers to make informed judgments about the health risks of chemical mixtures, adequate scientific knowledge and understanding must be available to support risk assessment activities, which are an integral part of the regulatory decision making process. Designing and implementing relevant research depends on the existence of a feedback loop between researchers and regulators, where the information needs of regulators influence the nature and direction of research and the information and understanding generated by researchers improves the scientific basis for public health decisions. A clear, consistent, commonly accepted taxonomy for describing important mixture-related phenomena is a key factor in creating and maintaining the necessary feedback loop. Ultimately, both researchers and regulators share a common goal with regard to chemical mixtures; improving the state-of-the-science so that we can make informed decisions about protecting public health. A survey of research issues and needs that are crucial to attaining this goal is presented.

Decision Making↗
PubMed1995

Physiologically based pharmacokinetics of methoxyacetic acid: dose-effect considerations in C57BL/6 mice.

Methoxyacetic acid (MAA), a weak acid with a pKa of 3.57, was used to test the broad hypothesis that distribution of weak acids in maternal and fetal tissues is determined principally by the pKa of the acid and the pH values of tissue and fluid compartments and to examine tissue dose-teratogenesis relationships, as well as administered dose-teratogenesis relationships. Five related experimental studies were conducted in pregnant C57BL/6CrIBR mice: a conventional dose-response study of developmental toxicity and transplacental pharmacokinetics in mice, a second dose-response study in which reproductive outcomes in litters from individual dams were related to individual pharmacokinetic behavior, a protein-binding experiment, an embryo tissue localization study, and determination of pH in maternal and embryonic compartments after exposure to MAA. MAA was administered intraperitoneally at 9:00 a.m. on day 10 of gestation, at doses ranging from 88 to 164 mg/kg. Localization within the forelimb bud of the embryo, an MAA target site, was determined by computerized image analysis of the distribution of radiolabeled MAA. The kinetic predictions of a physiologically based model incorporating tissue pH values and MAA pKa agreed well with observed concentrations at the lowest dose. However, at intermediate and higher doses, concentrations in both maternal and embryonic tissues were consistently underestimated. MAA was bound neither to maternal plasma proteins nor to embryonic proteins. Intermediate and higher doses of MAA caused dose-dependent transient depressions in tissue pH, but these were not of sufficient duration to bring predicted tissue concentrations into congruence with the concentrations observed. Distribution of MAA within the forelimb bud was broadly consistent with the pH hypothesis, but MAA concentration was not increased in the distal postaxial sector that is the site of the precursor cells of the missing digits. Internal exposure to MAA, defined as the area under the maternal plasma or embryo concentration curve (AUC), was not proportional to administered dose, but AUC-response relationships generated by the group and individual dose-response studies were comparable. While AUC may be a useful measure of effective MAA dose, it cannot be accurately predicted at teratogenic doses of this agent by the model as it is presently structured.

Abnormalities, Drug-Induced↗
PubMed1995

Influence of lead on mineralization during bone growth.

Lead will inhibit skeletal development and localize in areas of bone formation and resorption, but the mechanisms of lead toxicity in bone are largely unknown. This study used an ectopic bone (plaque) induction method to investigate the effect of lead on mineralization of cartilage in growing bone. Demineralized bone matrix was subcutaneously implanted in male Long-Evans rats to induce plaque formation. Of 64 rats which were provided deionized water, 32 were implanted with control matrix (control group). The remaining 32 rats were implanted with matrix containing a target concentration of 200 micrograms lead/g of plaque tissue as ectopic bone (lead-added group). Another group of 32 rats was continuously exposed to 1000 ppm lead in drinking water and subcutaneously implanted with control matrix (drinking water-lead group). Plaques were taken for analysis on Days 8 and 12 postimplantation. Alkaline phosphatase activity and cartilage mineralization were obliterated in lead-added plaques. However, calcium deposition was markedly enhanced in the lead-added plaques. Decreased alkaline phosphatase in Day 8 drinking water-lead plaques followed increased Day 12 drinking water lead plaque calcification. Enhanced cartilage calcification and reduced alkaline phosphatase activity in the drinking water-lead plaques was consistent with effects observed in the metaphyseal regions of bone in lead-exposed rats and pigs. The results of this study suggest that lead adversely influences bone development through disruption of mineralization during growth.

Alkaline Phosphatase↗
PubMed1995

Physiologically based models for bone-seeking elements. V. Lead absorption and disposition in childhood.

A physiologically based model of lead absorption and disposition, previously developed and validated for adults, has been tested and calibrated for children. The model was modified to incorporate additional information on the age dependence of bone formation rate and to take into account increasing localization of bone modeling activity with age. A bone volume characterized by mature bone metabolic activity increases from zero at birth to the total bone volume by young adulthood. Bone formation rate is high from childhood through adolescence, with peaks at birth and around puberty. Bone resorption rate keeps pace at a rate that allows the orderly increase of bone mass. In general, the model reproduces childhood blood lead observations well, except in instances where lead is ingested at very high concentrations. Both bone and blood lead concentration are labile during early childhood because of the high rate of bone turnover. They respond rapidly to increases in lead exposure, and decrease almost as rapidly to near-preexposure concentrations when exposure returns to background levels. As the child grows, fractional bone formation and resorption rates decline and total bone lead turnover becomes more sluggish. From the time of peak bone mineralization rate in adolescence into early adulthood, the rate of bone turnover drops dramatically and the ability to reverse bone lead accumulation relatively rapidly is lost.

Absorption↗
PubMed1995

PBK modeling for metals. Examples with lead, uranium, and chromium.

Physiologically-based models for metals differ in several key respects from models for organic compounds. Although sequestration by binding to specific metal-binding proteins in liver, kidney, and red cell may be important, neither the magnitude and pattern of metabolism nor potential accumulation in fat is a component of models of metal kinetics. In addition, the long residence times of bone-seeking elements require that bone turnover and metabolism be incorporated into physiologically-based models for these elements. Three mechanism (rapid exchange at bone/blood interfaces, trapping or incorporation with forming bone and loss with resorbing bone, and slow exchange throughout the total bone volume) are potentially important in the overall interchange of bone-seeking elements between blood and bone. Three examples are given of applications of physiologically-based kinetic models for the bone-seeking elements lead, chromium, and uranium to assist in answering practical questions relating to bioavailability, distribution, and data interpretation.

Animals↗
PubMed1994

Structural equation modeling and nested ANOVA: effects of lead exposure on maternal and fetal growth in rats.

This study provided an assessment of the effects of lead on early growth in rats based on structural equation modeling and nested analysis of variance (ANOVA). Structural equation modeling showed that lead in drinking water (250, 500, or 1000 ppm) had a direct negative effect on body weight and tail length (i.e., growth) in female rats during the first week of exposure. During the following 2 weeks of exposure, high correlation between growth measurements taken over time resulted in reduced early postnatal growth. By the fourth week of exposure, reduced growth was not evident. Mating began after 8 weeks of exposure, and exposure continued during gestation. Decreased fetal body weight was detected when the effects of litter size, intrauterine position, and sex were controlled in a nested ANOVA. Lead exposure did not appear to affect fetal skeletal development, possibly because lead did not alter maternal serum calcium and phosphorus levels. The effect of lead on individual fetal body weight suggests that additional studies are needed to examine the effect of maternal lead exposure on fetal development and early postnatal growth.

Analysis of Variance↗
PubMed1994

Effects of lead exposure on skeletal development in rats.

The effects of lead on growth in female rats and on growth and skeletal development in their offspring were investigated. No alteration in growth rate, compared to the growth rate in pair-fed controls, was observed in 48 weanling females continuously exposed to 250 or 1000 ppm lead in drinking water and fed a replete diet. After 49 days of exposure, all rats (24 pair-fed controls, 12 exposed to 250 ppm lead, and 12 exposed to 1000 ppm lead) were mated with control males. At parturition, six lactating dams each from the 250 and 1000 ppm lead groups were removed from lead exposure and given control drinking water, and six lactating dams each from the control group were given either 250 or 1000 ppm lead in drinking water. Exposure conditions for the remaining dams in the control, 250, and 1000 ppm groups were not changed. Maternal blood lead in the continuously lead-exposed groups was higher at the end of lactation than prior to mating. Lead exposure prior to parturition caused greater maternal tibial lead accumulation than lead exposure after parturition. In contrast, lead exposure prior to parturition had a lesser impact on offspring tibial lead accumulation than lead exposure after parturition. Decreases in tibial calcium and phosphorus were observed in dams exposed continuously to 250 or 1000 ppm lead; however, there was no apparent effect of lead on maternal growth-plate morphology or on growth-plate width. Offspring body weight was depressed relative to controls during suckling (Day 11) and after weaning (Day 24) in high-dose and continuously lead-exposed groups. Continuous lead exposure caused a greater decrease in offspring body weight than lead exposure only prior to or after parturition. Decreased tail length growth suggested possible effects of lead on tail vertebral bone growth. While tibial calcium and phosphorus levels were not changed in the weanlings, increased weanling growth-plate width, with disruption of chondrocyte organization, and wider metaphyseal trabeculae were observed. Although the mechanisms of these effects are not known, the results suggest that local lead-related effects on growth-plate chondrogenesis and metaphyseal mineralization may be involved.

Animals↗