Biomedical subjects

S M Hays

Publications and source records attributed to S M Hays.

13 recordsLinked to original sources

PubMed2006

Biomonitoring equivalents: a screening approach for interpreting biomonitoring results from a public health risk perspective.

Advances in both sensitivity and specificity of analytical chemistry have made it possible to quantify substances in human biological specimens, such as blood, urine, and breast milk, in specimen volumes that are practical for collection from individuals. Research laboratories led by the Centers for Disease Control and Prevention (CDC) in its series National Report on Human Exposure to Environmental Chemicals [Centers for Disease Control and Prevention (CDC), 2005. Third National Report on Human Exposure to Environmental Chemicals. NCEH Pub. No. 05-0570.] are dedicating substantial resources to designing and conducting human biomonitoring studies and compiling biomonitoring data for the general population. However, the ability to quantitatively interpret the results of human biomonitoring in the context of a health risk assessment currently lags behind the analytical chemist's ability to make such measurements. The traditional paradigm for human health risk assessment of environmental chemicals involves comparing estimated daily doses to health-based criteria for acceptable, safe, or tolerable daily intakes (for example, reference doses [RfDs], tolerable daily intakes [TDIs], or minimal risk levels [MRLs]) to assess whether estimated doses exceed such health screening levels. However, biomonitoring efforts result in measured chemical concentrations in biological specimens (the result of absorption, distribution, metabolism and excretion of administered doses) rather than estimated intake doses. Quantitative benchmarks of acceptable or safe concentrations in biological specimens (analogous to RfDs, TDIs, or MRLs) needed to interpret these levels exist for very few chemicals of environmental interest. This paper discusses issues inherent in converting existing health screening benchmarks based on intake doses to screening levels for evaluating biomonitoring data, and presents methods and approaches that can be used to derive such screening levels (termed "Biomonitoring Equivalents," or BEs) for a range of chemicals and biological media.

Animals↗

PubMed2003

Rapid communication: partitioning of persistent lipophilic compounds, including dioxins, between human milk lipid and blood lipid: an initial assessment.

A systematic program of sampling and analysis of blood serum for dioxins, furans, and dioxinlike polychlorinated biphenyls (PCBs) has been initiated in the United States through the National Health and Nutrition Examination Survey (NHANES) program. While such data could potentially be used to estimate population-level changes in human milk lipid concentrations of chemicals, such estimates would depend on understanding the relationship between human blood lipid and milk lipid concentrations of the compounds of interest. For dioxins and furans, extremely limited data in humans currently exist for paired blood/milk samples. These data reviewed in this article, support the hypothesis that, over a population and across time, human milk lipid levels of these compounds generally reflect blood lipid levels. However, these data also suggest that significant variations in these ratios are possible among individuals and at various times.

Dioxins↗

PubMed2001

A physiologically based model for the ingestion of chromium(III) and chromium(VI) by humans.

A physiologically based model of human chromium kinetics has been developed, based on an existing physiologically based model of human body and bone growth (O'Flaherty, 1993, Toxicol. Appl. Pharmacol. 118, 16-29; 1995a, Toxicol. Appl. Pharmacol. 131, 297-308; 2000, Toxicol. Sci. 55, 171-18) and an existing physiologically based model of chromium kinetics in rats (O'Flaherty, 1996, Toxicol. Appl. Pharmacol. 138, 54-64). Key features of the adapted model, specific to chromium, include differential absorption of Cr(VI) and Cr(III), rapid reduction of Cr(VI) to Cr(III) in all body fluids and tissues, modest incorporation of chromium into bone, and concentration-dependent urinary clearance consistent with parallel renal processes that conserve chromium efficiently at ambient exposure levels. The model does not include a physiologic lung compartment, but it can be used to estimate an upper limit on pulmonary absorption of inhaled chromium. The model was calibrated against blood and urine chromium concentration data from a group of controlled studies in which adult human volunteers drank solutions generally containing up to 10 mg/day of soluble inorganic salts of either Cr(III) (chromic chloride, CrCl(3)) or Cr(VI) (potassium dichromate, K(2)Cr(2)O(7)) (Finley et al., 1997, Toxicol. Appl. Pharmacol. 142, 151-159; Kerger et al., 1996, Toxicol. Appl. Pharmacol. 141, 145-158; Paustenbach et al., 1996, J. Toxicol. Environ. Health 49, 453-461). In one of the studies, in which the chromium was ingested in orange juice, urinary clearance was observed to be more rapid than when inorganic chromium was ingested. Chromium kinetics were shown not to be dependent on the oxidation state of the administered chromium except in respect to the amount absorbed at these ambient and moderate-to-high exposures. The fraction absorbed from administered Cr(VI) compounds was highly variable and was presumably strongly dependent on the degree of reduction in the gastrointestinal tract, that is, on the amount and nature of the stomach contents at the time of Cr(VI) ingestion. The physiologically based model is applicable to both single-dose oral studies and chronic oral exposure, in that it adequately reproduced the time dependence of blood plasma concentrations and rates of urinary chromium excretion in one of the subjects who, in a separate experiment, ingested daily 4 mg of an inorganic Cr(VI) salt in 5 subdivided doses of 0.8 mg each for a total of 17 days. The high degree of variability of fractional absorption of Cr(VI) from the gastrointestinal tract leads to uncertainty in the assignment of a meaningful value to this parameter as applied to single Cr(VI) doses. To model chronic oral chromium exposure at ambient or moderately above-ambient levels, the physiologically based model in its present form should be usable with urinary clearance set to a constant value of 1-2 liters/day and the gastrointestinal absorption rate constants set at 0.25/day for Cr(III) and 2.5/day for Cr(VI). The model code is given in full in the Appendix.

Administration, Oral↗

PubMed2000

A toxicokinetic study of inhaled ethylene glycol ethyl ether acetate and validation of a physiologically based pharmacokinetic model for rat and human.

The solvents ethylene glycol monoethyl ether acetate (EGEEA) and ethylene glycol monoethyl ether (EGEE), at sufficiently high doses, are known to be rodent developmental toxicants, exerting their toxic effects through the action of their metabolite 2-ethoxyacetic acid (2-EAA). Thus risks associated with exposure to these compounds are best evaluated based on a measure of the internal dose of 2-EAA. The goals of the work reported here were to develop physiologically based pharmacokinetic (PBPK) models of EGEEA and EGEE for pregnant rats and humans. These models were used to identify human exposure levels (ppm in air) equivalent to the rat no observed effect level (NOEL) and lowest observed effect level (LOEL) for developmental effects (Hanley et al., 1984). We exposed pregnant Sprague-Dawley rats to concentrations of EGEEA corresponding to the NOEL and LOEL. Maternal blood, urine, and fetal tissue concentrations of EGEE and 2-EAA measured in these experiments were used to validate the rat EGEEA and EGEE models. Data collected by other researchers were used to validate the capabilities of the rodent EGEEA and EGEE models to predict the kinetics in humans. The models for estimating circulating blood concentrations of 2-EAA were considered valid based on the ability of the model to accurately predict 2-EAA concentrations in rat blood, urine, and fetal tissue. The human inhaled concentration equivalent to the rat NOEL for EGEEA (50 ppm) was predicted to be 25 ppm using the maternal blood average daily area under the curve (AUC) and 40 ppm using the maximum concentration achieved in maternal blood (C(max)). The human inhaled concentration equivalent to the rat LOEL for EGEEA (100 ppm) was determined to be 55 ppm using the maternal blood average daily AUC and 80 ppm using the maternal blood C(max).

Animals↗

PubMed2000

A toxicokinetic study of inhaled ethylene glycol monomethyl ether (2-ME) and validation of a physiologically based pharmacokinetic model for the pregnant rat and human.

Exposures to sufficiently high doses of ethylene glycol monomethyl ether (2-methoxyethanol, 2-ME) have been found to produce developmental effects in rodents and nonhuman primates. The acetic acid metabolite of 2-ME, 2-methoxyacetic acid (2-MAA), is the likely toxicant, and, as such, an understanding of the kinetics of 2-MAA is important when assessing the potential risks to humans associated with 2-ME. A previously described physiologically based pharmacokinetic (PBPK) model of 2-ME/2-MAA kinetics for rats exposed via oral or iv administration was extended and validated to inhalation exposures. Pregnant Sprague-Dawley rats were exposed for 5 days (gestation days 11-15), 6 h/day, to 2-ME vapor at 10 and 50 ppm. Validation consisted of comparing model output to maternal blood and fetal 2-ME and 2-MAA concentrations during and following 5 days of exposure (gestation days 11-15). These concentrations correspond to a known no observed effect level (NOEL) and a lowest observed effect level (LOEL) for developmental effects in rats. The rat PBPK model for 2-ME/2-MAA was scaled to humans and the model (without the pregnancy component) was used to predict data collected by other investigators on the kinetics of 2-MAA excretion in urine following exposures to 2-ME in human volunteers. The partially validated human model (with the pregnancy component) was used to predict equivalent human exposure concentrations based on 2-MAA dose measures (maximum blood concentration, C(max), and average daily area under the 2-MAA blood concentration curve, AUC, during pregnancy) that correspond to the concentrations measured at the rat NOEL and LOEL exposure concentrations. Using traditional PBPK scale-up techniques, it was calculated that pregnant women exposed for 8 h/day, 5 days/week, for the duration of pregnancy would need to be exposed to 12 or 60 ppm 2-ME to produce maternal 2-MAA blood concentrations (C(max) or average daily AUC) equivalent to those in rats exposed to the NOEL (10 ppm) or LOEL (50 ppm), respectively.

Acetates↗

PubMed2000

Development of a physiologically based pharmacokinetic model of 2-methoxyethanol and 2-methoxyacetic acid disposition in pregnant rats.

An accurate description of developing embryos' exposure to a xenobiotic is a desirable component of mechanism-based risk assessments for humans exposed to potential developmental toxicants during pregnancy. 2-Methoxyethanol (2-ME), a solvent used in the manufacture of semiconductors, is embryotoxic and teratogenic in all species tested including nonhuman primates. 2-Methoxyacetic acid (2-MAA) is the primary metabolite of 2-ME and the proximate embryotoxic agent. The objective of the work described here was to adapt an existing physiologically based pharmacokinetic (PBPK) model for 2-ME and 2-MAA kinetics during midorganogenesis in mice to rats on gestation days (GD) 13 and 15. Blood and tissue data were analyzed using the extrapolated PBPK model that was modified to simulate 2-ME and 2-MAA kinetics in maternal plasma and total embryo tissues in pregnant rats. The original mouse model was simplified by combining the embryos and placenta with the richly perfused tissue compartment. The model includes a description of the growth of the developing embryo and changes in the physiology of the dam during pregnancy. Biotransformation pathways of 2-ME to either ethylene glycol (EG) or to 2-MAA were described as first-order processes based on the data collected from rats by Green et al., (Occup. Hyg. 2, 67-75, 1996). Tissue partition coefficients (PCs) for 2-ME and 2-MAA were determined for a variety of maternal tissues and the embryos. Model simulations closely reflected the biological measurement of 2-ME and 2-MAA concentrations in blood and embryo tissue following gavage or iv administration of 2-ME or 2-MAA. The PBPK model for rats as described here is well suited for extrapolation to pregnant women and for assessment of 2-MAA dosimetry under various conditions of possible human exposure to 2-ME.

Acetates↗

PubMed2000

Improving cancer dose-response characterization by using physiologically based pharmacokinetic modeling: an analysis of pooled data for acrylonitrile-induced brain tumors to assess cancer potency in the rat.

Historically, U.S. regulators have derived cancer slope factors by using applied dose and tumor response data from a single key bioassay or by averaging the cancer slope factors of several key bioassays. Recent changes in U.S. Environmental Protection Agency (EPA) guidelines for cancer risk assessment have acknowledged the value of better use of mechanistic data and better dose-response characterization. However, agency guidelines may benefit from additional considerations presented in this paper. An exploratory study was conducted by using rat brain tumor data for acrylonitrile (AN) to investigate the use of physiologically based pharmacokinetic (PBPK) modeling along with pooling of dose-response data across routes of exposure as a means for improving carcinogen risk assessment methods. In this study, two contrasting assessments were conducted for AN-induced brain tumors in the rat on the basis of (1) the EPA's approach, the dose-response relationship was characterized by using administered dose/concentration for each of the key studies assessed individually; and (2) an analysis of the pooled data, the dose-response relationship was characterized by using PBPK-derived internal dose measures for a combined database of ten bioassays. The cancer potencies predicted for AN by the contrasting assessments are remarkably different (i.e., risk-specific doses differ by as much as two to four orders of magnitude), with the pooled data assessments yielding lower values. This result suggests that current carcinogen risk assessment practices overestimate AN cancer potency. This methodology should be equally applicable to other data-rich chemicals in identifying (1) a useful dose measure, (2) an appropriate dose-response model, (3) an acceptable point of departure, and (4) an appropriate method of extrapolation from the range of observation to the range of prediction when a chemical's mode of action remains uncertain.

Acrylonitrile↗

PubMed1997

A proposed approach to study the toxicology of complex mixtures of petroleum products: the integrated use of QSAR, lumping analysis and PBPK/PD modeling.

Mixture toxicity is a topic that has become a matter of concern during the last two decades. One of the major problems with assessing the toxicity of mixtures and the associated human and environmental risk is the large number of possible mixtures, as well as the fact that the actual mixture effect for a given set of constituents might strongly depend on the actual composition of the mixture, i.e., the ratios of the constituent, as well as their nature. This paper presents a possible approach to describe and thereby better understand the pharmacokinetics and dynamics of complex mixtures by combining quantitative structure-activity relationships to predict needed parameters, lumping to reduce the complexity of the problem, and physiologically based pharmacokinetic/pharmacodynamic modeling to integrate all this information into a complete toxicological description of the mixture. It is our hope that by presenting this conceptual approach we might be able to stimulate some criticisms and discussions in the toxicology community regarding this complex and yet very important area of research.

Animals↗

PubMed1996

Observation of steady state in blood and urine following human ingestion of hexavalent chromium in drinking water.

The uptake and elimination of Cr(VI) in a male volunteer who ingested 2 L/d of water containing 2 mg/L for 17 consecutive days was measured. Total chromium was measured in urine, plasma, and red blood cells (RBCs) for 4 d prior to and 2 wk after dosing (34 d total). The estimated bioavailability (2%) and the plasma elimination half-life (36 h) were consistent with our previous studies of Cr(VI) ingestion in humans. Steady-state chromium concentrations in urine and blood were achieved after 7 d of Cr(VI) ingestion. Both plasma and red blood cell (RBC) chromium concentrations returned rapidly to background levels within a few days after cessation of dosing. Since the concentration of chromium in the RBC should not decrease quickly if the chromium had entered the RBC as Cr(VI), these data support our prior work suggesting that concentrations of 10 mg Cr(VI)/L or less in drinking water of exposed humans appears to be completely reduced to Cr(III) prior to systemic distribution. Clinical chemistry data indicate that no toxicity occurred.

Administration, Oral↗

PubMed1996

Using PBPK modeling and comprehensive realism methodology for the quantitative cancer risk assessment of butadiene.

The National Academy of Sciences and many others have noted the need for quantitative health risk assessment methodology that goes beyond a simple screening analysis based on upper bounds on risk. The Academy recommended adoption of methodologies which provide a higher-tier analysis based on realistic estimates of risk which reflect more of the available biological information. In recent years, scientists have challenged the assumption of low-dose linearity and other default assumptions in cancer risk assessment. These challenges have stimulated the continued evolution of quantitative risk assessment methodologies, because effective risk management requires accurate characterizations of uncertainty and greater utilization of cost-benefit analyses for decision making. "Comprehensive Realism" is an emerging quantitative weight-of-evidence based risk assessment methodology for both cancer and noncancer health effects which utilizes probability distributions and decision analysis techniques to reflect more of the available human and animal dose-response data. The current state of knowledge about the relative plausibility of alternative dose-response analyses is also addressed in this approach. The framework discussed here should lead to a higher-tier assessment of butadiene.

Butadienes↗

PubMed1991

Exposure to airborne asbestos associated with simulated cable installation above a suspended ceiling.

Installing cable above a suspended ceiling in the presence of asbestos-containing fireproofing is an example of an activity that may disturb in-place asbestos and associated dust and debris. Two simulations of cable installation were conducted in a room of an unoccupied school to test the extent of such disturbance and resulting elevations in airborne asbestos. Average airborne asbestos concentrations in the room increased over 500-fold during the simulations, with several samples exceeding 50 structures per cubic centimeter (s/cm3), as measured by transmission electron microscopy (TEM) with an indirect preparation technique. Elevated concentrations persisted during a subsequent cleaning of horizontal surfaces in the room and for several hours thereafter. Personal samples collected on the cable installers yielded TEM measurements averaging approximately 68 s/cm3 for the two simulations.

Air Pollutants↗

PubMed1990

Spatial patterns of attendance at general practitioner services.

Geographical theory suggests that consumers will travel to the centre nearest to their residence which offers a particular service. This is a weak indicator of surgery attendance patterns in Gisborne, New Zealand. Nearby surgeries were attended, rather than the nearest available. Various attributes of the practices and the patients were examined to discover their influence on attendance patterns. The distribution of the practices themselves had a significant effect upon relative surgery attendance. Prior knowledge of services was particularly important in determining surgery selection and continued attendance. This accounted for the spatially unconstrained attendance of many Maori. Greater personal mobility enabled higher income households to travel further to attend. Conversely, the less mobile were spatially bounded.

Catchment Area, Health↗

PubMedDate not supplied

The relative susceptibility of animals and humans to the carcinogenic hazard posed by exposure to 2,3,7,8-TCDD: an analysis using standard and internal measures of dose.

An analysis of the carcinogenic dose-response for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in humans and animals was performed based on measured tissue and serum concentrations and using alternatives to administered dose as the dosimetric. The TCDD-related carcinogenic response in rats (female rat liver tumors from Kociba et al., using revised pathology from Goodman and Sauer, was compared to that in humans (lung cancer rates in Fingerhut et al.,). Three dosimetries were used: serum lipid TCDD area-under-the-curve (AUC), peak serum lipid concentration (Cpeak) and average serum lipid concentration (Cavg). Rat serum concentration-time profiles were estimated based on measured adipose lipid TCDD concentrations at the end of the Kociba et al. bioassay, assuming first-order elimination and a half-life of 25 days. Human concentration-time profiles were estimated based on measured serum lipid TCDD concentrations and known dates of first and last exposure, with an assumed 7.5 year half-life and first-order elimination. Comparison of rat and human responses indicated that, using all three of these dosimetries, humans are much less sensitive than rats to the carcinogenic effects of TCDD. Regardless of the dosimetric chosen, the cancer mortality in humans in the NIOSH cohort, if due to TCDD, is relatively insensitive to dose as defined in Fingerhut et al., [3]. Our analysis indicates that human exposure to background levels of TCDD (about 5 ppt serum lipid concentration) is not likely to produce an incremental cancer risk.

Adipose Tissue↗