Physiologically based pharmacokinetic (PBPK) tool kit for environmental pollutants--metals.

The Agency for Toxic Substances and Disease Registry (ATSDR) is mandated by the US Congress to identify significant human exposure levels, develop methods to determine such exposures, and design strategies to mitigate them. Physiologically based pharmacokinetic (PBPK) models are increasingly being used to evaluate toxicity of environmental pollutants through multiple exposure pathways. As part of its translational research project, ATSDR is developing a human 'PBPK model tool kit' that consists of a series of published models re-coded in a common simulation language. The tool kit currently consists of models, at various stages of development, for priority environmental contaminants including solvents and persistent organic pollutants. Presented here are results of translational activities of re-coding models for cadmium, mercury, and arsenic. As part of this work, following re-coding each new model was evaluated for fidelity followed by sensitivity analysis. Good agreement was generally obtained for all three models when predictions of original and re-coded model simulations were compared. Also presented is an application of the cadmium toxicokinetic model to interpret biomonitoring data from the National Health and Nutrition Examination Survey (NHANES). The PBPK tool kit will enable ATSDR scientists to perform simulations of exposures from contaminated environmental media at sites of concern and to better interpret site-specific biomonitoring data.

Variability in mammography screening legislation across the states.

Before passage of the Federal legislation, National Breast and Cervical Cancer Screening Act (NBCCSA) in 1991, over half the states (65%) had preexisting laws requiring health insurers, for example, Blue Cross/Blue Shield and HMOs, to provide services beyond the federal coverage for mammography screening and care following breast cancer. This study examined mammography screening legislation across the states. Data were derived from telephone interviews with six NBCCSA program directors or coordinators from July 1999 to October 1999. A review of existing documents from the Institute for Women's Policy Research, online data from the Centers for Disease Control and Prevention, and state laws provided by the Governmental Affairs Division of the American Cancer Society was undertaken. There was considerable variability in relation to factors potentially related to the extent of state laws. The states with the lowest age-adjusted breast cancer mortality rates among black women had the least comprehensive state legislation. Several states with the least percent of women above the federal poverty threshold also had the least comprehensive legislation. Some states had a wide gap between the provision of health insurance coverage and scope of legislation to ensure care following breast cancer. Some states were more aggressive in their efforts to ensure care following breast malignancy at diagnosis. Lessons could be learned by states that enacted the least comprehensive legislation. With the passage of the federal legislation nearly a decade ago, more women are receiving timely and available mammography screening, resulting in earlier diagnosis of breast cancer. Greater efforts must be undertaken by all states to provide the full array of breast cancer treatment for women in the millennium.

Mechanisms of nephrotoxicity from metal combinations: a review.

The common environmental pollutants arsenic, lead, and cadmium are each known to induce chronic renal disease and the molecular mechanisms of such toxic events are being clarified. Nephrotoxicity of these metals is due to the fact that urinary elimination is a main route of excretion, and the proximal tubules are especially sensitive due to their high reabsorptive activity. Renal pathological effects of these metals vary with the chemical form of the metal, the dose, and whether the exposure is acute or chronic in nature. The few isolated studies of combined metal exposures indicate that these pathological effects may be altered due to unknown interactions of these metals within the kidney. Biological factors within the cell such as metal binding proteins and inclusion bodies may also influence metal-metal interactions. Further research is needed to specify the parameters or criteria by which metal interactions is to be assessed for unique biological response patterns to aid in the risk assessment analysis of environmental and occupational metal exposures.

Combining traditional and RN students in a senior capstone experience: the student perspective.

BACKGROUND: This study explored the students' perspective related to combining traditional and RN student populations in a senior capstone course. METHOD: In the final semester in a senior baccalaureate program, nursing students (N = 340) completed an investigator-designed 5-item survey. Data were reviewed independently by three investigators for emergent themes. RESULTS: While the course content was applied differently by two student populations, both appreciated a seminar format that allowed increased creativity, autonomy, and flexibility. CONCLUSIONS: Merits of an integrated course were more explicitly stated by traditional students, who viewed the RNs as a source of reality-based learning. Faculty sensitivity to the unique learning needs of each student population is recommended.

Roles of lead-binding proteins in mediating lead bioavailability.

The intracellular bioavailability of lead (Pb) at low dosage levels in major target organs such as the kidney and brain appears to be largely determined by complexation with a group of low molecular weight proteins. These proteins are rich in aspartic and glutamic dicarboxyl amino acids. The proteins are chemically similar but not identical across all species examined to date and the brain protein appears to be different from that found in the kidney. These proteins possess dissociation constant values for Pb on the order of 10(-8) M and appear to normally bind zinc. In rats, these proteins attenuate the Pb inhibition of the heme pathway enzyme delta-aminolevulinic acid dehydratase by a mechanism involving both Pb chelation and zinc donation to this highly Pb-sensitive zinc-dependent enzyme. Other studies in rats have shown that the kidney protein facilitates the intranuclear movement of Pb in vitro followed by chromatin binding, suggesting that this protein may be involved in alterations of the pathognomonic Pb intranuclear inclusion bodies in renal gene expression associated with the mitogenic effects of Pb in the kidney.

High-affinity renal lead-binding proteins in environmentally-exposed humans.

Chronic low level lead (Pb) exposure is associated with decrements in renal function in humans, but the molecular mechanisms underlying toxicity are not understood. We investigated cytosolic Pb-binding proteins (PbBP) in kidney of environmentally-exposed humans to identify molecular targets of Pb and elucidate mechanisms of toxicity. This study is unique in that it localized PbBPs based on physiologic Pb that was bound in vivo. Two Pb-binding polypeptides were identified, thymosin beta 4 (T beta 4, 5 kDa) and acyl-CoA binding protein (ACBP, 9 kDa, also known as diazepam binding inhibitor, DBI). These polypeptides, which have not been previously recognized for their metal-binding capabilities, were shown to bind Pb with high affinity (Kd approximately 14 nM) and to account for an estimated > 35% of the total Pb in kidney cortex tissue. Both T beta 4 and ACBP (DBI) occur across animal species from invertebrates to mammals and in all major tissues, serving multiple possible functions (e.g. regulation of actin polymerization, calmodulin-dependent enzyme activity, acyl-CoA metabolism, GABA-A/benzodiazepine receptor modulation, steroidogenesis, etc.). Thus, these data provide the first evidence of specific molecular targets of Pb in kidney of environmentally-exposed humans, and they suggest that low-level Pb toxicity may occur via alteration of T beta 4 and ACBP (DBI) function in renal and other tissues, including the central nervous system.

Geriatric bone lead metabolism in a female nonhuman primate population.

A geriatric rhesus monkey (Macaca mulatta) population, previously exposed to lead, was investigated using 109Cd K X-ray fluorescence (K XRF) to determine whether metabolism of lead in bone was similar to that in human populations. The accumulation rate of lead into the tibia in this group of monkeys was determined to be 0.10-0.13 micrograms Pb (g bone mineral)-1 (microgram dl-1 year)-1, which compares well with human data, where the rate has been found to be 0.05-0.10 microgram Pb (g bone mineral)-1 (microgram dl-1 year)-1. In addition, bone lead changes over a 10-month time period were investigated, but no statistically significant difference was found. A halflife for lead in "bone" was calculated by fitting a single exponential model to serial blood lead data; the mean half-life of lead in bone was found to be 3.0 +/- 1.0 years. Both endogenous and exogenous lead exposure were found to be low at the present time, 10 years after cessation of lead intake. It is concluded that rhesus monkeys are an extremely good animal model of human bone lead metabolism and, in addition, that further research is needed to provide a more complete understanding of lead metabolism in geriatric populations.

Cytotoxicity, zinc protection, and stress protein induction in rat proximal tubule cells exposed to cadmium chloride in primary cell culture.

Primary cell culture was utilized to study the relationships between stress protein induction by zinc in vivo and cadmium toxicity in vitro. Effects of cadmium on cell viability were evaluated by the alamar blue assay, in conjunction with the ultrastructural morphology of cells by transmission electron microscopy. The expression of stress protein gene products was evaluated by 35S two-dimensional gel electrophoresis. The results showed cytotoxicity of CdCl2 at and above 129 microM (14.55 micrograms cadmium/mL medium) following 4 h of exposure. Prior zinc administration (20 mg zinc/kg, s.c., two daily doses) in vivo significantly protected the cells in vitro as demonstrated by improved cell viability. The 35S labeling of proteins induced by CdCl2 exposure clearly demonstrated for the first time that gene product of the 70-kDa family was induced in cultured rat proximal tubule cells which are the target cells for cadmium toxicity in vivo. Zinc in vivo pretreatment of animals induced proteins in the 90-, 70-, and 38-kDa families, which may act together with metallothionein to protect cells against cadmium toxicity. The results also indicate that the protective effect of zinc remains after the cells have been put in culture and thus provides a system in which we can study the changes that occur as a result of zinc exposure that decreases cadmium toxicity.

Lead-binding proteins in brain tissue of environmentally lead-exposed humans.

This study reports the partial purification and characterization of cytosolic lead binding proteins (PbBPs) in human brain tissue of environmentally Pb-exposed subjects. The isolated proteins were initially characterized based upon the presence of endogenously associated Pb. Following partial purification (Sephadex G-75 and A-25 DEAE anion-exchange chromatography), the isolated PbBPs (contained within a single DEAE peak) showed a single class of high affinity binding sites with an apparent Kd of 10(-9) M, based upon competition assays using radioactive 203Pb and Hill and Scatchard analysis. The presence of endogenously bound Pb with the isolated proteins indicated the association of Pb with the protein(s) in vivo in these environmentally Pb-exposed subjects, since the samples were prepared in an ultraclean lead analysis laboratory. Moreover, the persistence of Pb-protein binding throughout the initial two steps (Sephadex G-75 and A-25 DEAE) of the purification scheme is consistent with the high affinity and stability of binding measured with the radiolead competition assays. The DEAE isolated PbBPs were further purified by denaturing reversed-phase HPLC analysis, resulting in the isolation of two proteins, thymosin beta 4 (5 kDa, pI 5.1) and a second as yet unidentified protein with an approximate molecular mass of 20 kDa and a pI of 5.9. Qualitative 203Pb-binding analysis of these HPLC purified proteins suggested that they may be primarily responsible for the observed Pb binding in the single DEAE peak. Nearly identical results were obtained in brain cytosols from male and female, and young and adult individuals, although further quantitative analyses are needed to investigate possible sex and age relationships. These data are significant because they contribute to a better understanding of the presence of PbBPs in a sensitive target organ for Pb toxicity in humans, suggesting a possible role of these or similar proteins as sensitive biomarkers of Pb exposure and toxicity.

Alterations in the heme biosynthetic pathway from the III-V semiconductor metal, indium arsenide (InAs).

The effects of indium and arsenic on the heme biosynthetic pathway have been well documented but the effects of indium arsenide (InAs), the next possible generation of the III-V semiconductors, are unknown. Male Syrian golden hamsters were given s.c. injections of sodium arsenite (As3+), indium chloride (In3+) or indium arsenide (InAs). Erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity was inhibited in all exposure groups, while hepatic ALAD activity was not significantly changed. In contrast, the activity of renal ALAD was found to be statistically decreased by As3+ at 10 days, but increased at 30 days, while In3+ and InAs inhibited this enzyme activity at all time points. In vitro studies showed that hepatic ALAD activity was more sensitive to In3+ than As3+, suggesting that the effects of InAs in vivo on this enzyme are due primarily to the In rather than the As moiety. Studies of urinary porphyrin excretion patterns in animals treated with InAs showed marked, early 2-4-fold increase in the excretion of the penta-, hexa- and heptacarboxyl porphyrin at 1-5 days which continued through day 30 of the study. In contrast, there was a slow and steady rise in the excretion of coproporphyrin I and III which reached a maximum at day 30. The results of these studies indicate that both the In and As moieties of InAs are biologically active following InAs exposure and that the enzymes in the heme pathway, such as ALAD, may have great utility as markers of exposure/toxicity for these agents.

Health promotion services and evaluation in the workplace: pragmatic issues.

1. Nurses in the workplace can positively affect employee health and wellness, which ultimately affects productivity and profit. 2. Evaluative research about health promotion services provides useful data about programs and cost effectiveness. 3. Knowing the issues and variables affecting the provision of health promotion services and the evaluation of program outcomes helps nurses plan appropriate services and programs as well as valid and reliable research projects. 4. Major issues include: system entry, management support and commitment, environmental context, ethical considerations, program variables, research design, instruments and equipment, program sites and times, type of program/services, and recordkeeping.

Prenatal outreach: an approach to reduce infant mortality of African American infants.

Infant mortality is a pernicious and disturbing problem in the African American community. Research and public health reports clearly demonstrate the importance of early and ongoing prenatal care in reducing the incidence of low birth weight (LBW) infants, especially for indigent and racial/ethnic minority groups (American Nurses Association 1987, Hogue & Yip, 1989; McCormick, 1985, National Commission to Prevent Infant Mortality 1988, Institute of Medicine 1985, 1989; United States Department of Health and Human Services [USDHHS], 1990). LBW is a known risk factor for perinatal morbidity and mortality in the first year of life (USDHHS, 1993). Prenatal outreach and home visiting programs have shown effectiveness in assisting African American pregnant women and other racial/ethnic minority groups to access and participate in needed prenatal care. Brooten, Gennaro, Knapp, Jovene, Brown, and York's (1991) research also confirmed the importance of early discharge and home followup of very low birthweight infants. Nurses are challenged to participate in grass-roots initiatives and community-based approaches to improve the prenatal outcomes of African American teens.

Role of lead-binding proteins in renal cancer.

High-dose lead exposure in rodents has been shown to produce pathognomonic lead intranuclear inclusion bodies and to result in an increased incidence of renal adenocarcinomas. Studies from this laboratory and others have demonstrated the presence of high-affinity renal lead-binding proteins in rat kidneys which act as tissue sinks for lead at low dose levels. Cell-free nuclear translocation studies have shown that these molecules are capable of facilitating the intranuclear movement of lead and that they are associated with chromatin. These data suggest that renal lead-binding proteins may play a role in mediating known alterations in renal gene expression associated with formation of intranuclear inclusion bodies. More recent studies from this laboratory have demonstrated the presence of chemically similar lead-binding proteins in kidneys of both monkeys and humans. Such observations suggest that a similar mechanism may be operating in primates since lead intranuclear inclusion bodies are also observed in these species. These data provide a testable mechanistic approach for assessing the possible role(s) of lead-binding proteins in mediating the intranuclear movement of lead and lead-induced renal cancer in primate species.

Ideological shifts needed in primary care delivery: removing barriers through reform.

Black Americans is one of the fastest growing segments of the population, yet the incidence of illness and mortality are higher and survival from the leading causes of death is poorer than for White Americans (Jaynes & Williams, 1989; U.S. Department of Health and Human Services [DHHS], 1990). In achieving the Year 2000 national health promotion and disease prevention objectives, health care systems must provide universal access to high quality, affordable, comprehensive, and coordinated primary health care services. It is crucial to initiate new approaches to health care delivery, including linking primary care providers (PCPs) in communities where people live and work to eliminate barriers and improve access to culturally-sensitive primary health care in Black communities. Nursing can play an important leadership role in redirecting the education of PCPs and shaping public policy to reflect the primary health care philosophy.

A health promotion program evaluation in a minority industry.

Wellness or health promotion programs (HPP) in the worksite are beneficial to both employer and employee. Companies report reduced absenteeism and improved job performance and productivity (O'Donnell & Ainsworth, 1984; Glantz & Orr, 1986). These programs are vital for Black Americans who experience distressing disparity in the leading causes of mortality and morbidity when compared to White Americans. Black Americans also experience poorer health as a result of racism, prejudice, discrimination, economic issues, and social ills such as poverty and lack of access to health care. The major purpose of this study was to examine the effects of a nurse-delivered six-month pilot HPP on the health awareness and reported health behaviors of Black Americans in the workplace. Approximately 50 employees participated in the HPP. The overall health screening and evaluation survey results indicated that the HPP was effective in increasing health awareness and in changing health behaviors. Nurses can play an important leadership role in improving the health of Black Americans in the workplace.

Health policy reform initiatives to improve the health of black Americans.

Black Americans comprise 12.4 percent of the United States (U.S.) population and is one of the fastest growing minority groups (U.S. Bureau of the Census, 1992). Recent health statistics indicate, however, that the life expectancy for Black Americans has lagged dramatically behind other minorities and White Americans throughout the century (DHHS, 1990). Economic, legislative and social factors hinder access to care and the provision of services within the current structure of health care in the U.S. Under health care reform, these three factors must be redefined to promote access to comprehensive health care services for Black Americans. Nursing is being challenged to provide the vision and leadership that will influence the key players to support a reform in health policy.