Abstract:
:The use of physiologically based pharmacokinetic (PBPK) models has been proposed as a means of estimating the dose of the reactive metabolites of carcinogenic xenobiotics reaching target tissues, thereby affording an opportunity to base estimates of potential cancer risk on tissue dose rather than external levels of exposure. In this article, we demonstrate how a PBPK model can be constructed by specifying mass-balance equations for each physiological compartment included in the model. In general, this leads to a system of nonlinear partial differential equations with which to characterize the compartment system. These equations then can be solved numerically to determine the concentration of metabolites in each compartment as functions of time. In the special case of a linear pharmacokinetic system, we present simple closed-form expressions for the area under the concentration-time curves (AUC) in individual tissue compartments. A general relationship between the AUC in blood and other tissue compartments is also established. These results are of use in identifying those parameters in the models that characterize the integrated tissue dose, and which should therefore be the primary focus of sensitivity analyses. Applications of PBPK modeling for purposes of tissue dosimetry are reviewed, including models developed for methylene chloride, ethylene oxide, 1,4-dioxane, 1-nitropyrene, as well as polychlorinated biphenyls, dioxins, and furans. Special considerations in PBPK modeling related to aging, topical absorption, pregnancy, and mixed exposures are discussed. The linkage between pharmacokinetic models used for tissue dosimetry and pharmacodynamic models for neoplastic transformation of stem cells in the target tissue is explored.
journal_name
Environ Health Perspectjournal_title
Environmental health perspectivesauthors
Krewski D,Withey JR,Ku LF,Andersen MEdoi
10.1289/ehp.94102s1137subject
Has Abstractpub_date
1994-12-01 00:00:00pages
37-50eissn
0091-6765issn
1552-9924journal_volume
102 Suppl 11pub_type
杂志文章,评审abstract:BACKGROUND:Although indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) and pyrethroids effectively controls malaria, it potentially increases human exposure to these insecticides. Previous studies suggest that prenatal exposure to these insecticides may impact human neurodevelopment. OBJECTIVES:...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/EHP2129
更新日期:2018-04-06 00:00:00
abstract::This report reviews the recent literature on the adverse effects of occupational factors on fertility and related reproductive outcomes. Few studies fulfill the criteria of good study design because of small sample size, insensitive measures of effect, selection, recall, and observation bias, weak if any control of co...
journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
doi:10.1289/ehp.93101s281
更新日期:1993-07-01 00:00:00
abstract::As part of a detailed experimental study of the pathogenicity of disease of slate dust workers, the early biochemical changes in rat lung from 1 to 90 days after intratracheal inoculation of slate dust of particle size below 5 micron were investigated. A severalfold increase in free cell population (initially macropha...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8351305
更新日期:1983-09-01 00:00:00
abstract::In vivo detection of free radicals on a quantitative basis is essential for an establishment of their role in membrane, protein, and cell and tissue damage. This article compares optical methods, including chemiluminescence, electron paramagnetic resonance (EPR) and NMR methods for the study of free radicals and free ...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.94102s1029
更新日期:1994-12-01 00:00:00
abstract::In this study, we explored the efficacy of upper-room ultraviolet germicidal irradiation (UVGI) in reducing the concentration of Serratia marcescens and Mycobacterium bovis bacille Calmette-Guérin (BCG) aerosols in enclosed places. We constructed a facility (4.5 m x 3 m x 2.9 m) in which both ceiling- and wall-mounted...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.0211095
更新日期:2002-01-01 00:00:00
abstract::The historical exposures to aromatic amines of various occupational groups are briefly reviewed. Modern studies indicate that other occupational groups might have risks worth investigating; these include machinists and workers in the chemical industry. Details of a recent investigation into the exposure of dye workers...
journal_title:Environmental health perspectives
pub_type: 历史文章,杂志文章
doi:10.1289/ehp.834913
更新日期:1983-03-01 00:00:00
abstract::The decline of many amphibian species could be caused by their susceptibility to environmental pollutants that cause cellular stress and cell death. A variety of intracellular signal transduction pathways are activated by environmental stress factors, which result in cell death. Mitogen-activated protein kinases are i...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.02110641
更新日期:2002-07-01 00:00:00
abstract:BACKGROUND:Adverse cardiorespiratory health is associated with exposure to ambient particulate matter (PM). The highest PM concentrations in London occur in proximity to waste transfer stations (WTS), sites that experience high numbers of dust-laden, heavy-duty diesel vehicles transporting industrial and household wast...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.0901303
更新日期:2010-04-01 00:00:00
abstract::Much public health research has been directed to studies of cancer risks due to chemical agents. Recently, increasing attention has been given to adverse reproductive outcomes as another, shorter-term biologic indicator of public health impact. Further, several low-level ubiquitous physical agents have been implicated...
journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
doi:10.1289/ehp.8981193
更新日期:1989-05-01 00:00:00
abstract::The results of our previous and recent work on cadmium metabolism in relation to age and diet are presented. Experiments were performed on albino rats aged 1-26 weeks. In some experiments rats were given different foods (milk, meat, bread) instead of standard rat diet. Some animals received trisodium calcium salt of d...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.845451
更新日期:1984-03-01 00:00:00
abstract::Mineral fibers and particulates represent one of the best documented, economically important, and ubiquitously occurring categories of human carcinogens. Yet, while a wealth of information exists concerning the mechanism of action of physical, chemical, and viral carcinogens, virtually nothing is known relative to the...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.803459
更新日期:1980-02-01 00:00:00
abstract::Chronic exposure to oxidants is associated with an increased incidence of malignancy; however, the mechanism(s) by which oxidants contribute to carcinogenesis is unknown. Since oncogene activation plays an important role in carcinogenesis, we hypothesized that hydroxyl radical-induced DNA damage might contribute to ca...
journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
doi:10.1289/ehp.94102s10155
更新日期:1994-12-01 00:00:00
abstract::The role of the knowledge of high risk groups in the standard-setting process is examined. The overall conclusion is that many potential high risk segments of the population have not been studied adequately and that this deficiency in our knowledge markedly reduces the ability of decision makers to derive appropriate ...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8352257
更新日期:1983-10-01 00:00:00
abstract::[This corrects the article DOI: https://doi.org/10.1289/EHP507.]. ...
journal_title:Environmental health perspectives
pub_type: 杂志文章,已发布勘误
doi:10.1289/EHP3422
更新日期:2018-02-20 00:00:00
abstract:BACKGROUND:The mechanisms governing the correlation between exposure to ultrafine particles and the increased incidence of cardiovascular disease remain unknown. Ultrafine particles appear to cross the pulmonary epithelial barrier into the bloodstream, raising the possibility of direct contact with the vascular endothe...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8497
更新日期:2007-03-01 00:00:00
abstract::During a 2-year chronic inhalation study on methylene chloride (2000 or 0 ppm; 6 hr/day, 5 days/week), gas-uptake pharmacokinetic studies and tissue partition coefficient determinations were conducted on female B6C3F1, mice after 1 day, 1 month, 1 year, and 2 years of exposure. Using physiologically based pharmacokine...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.96104858
更新日期:1996-08-01 00:00:00
abstract::Direct studies of the function of a given cell type often require that the cell type be obtained in pure culture. A number of different specific metabolic activities have been attributed to pulmonary endothelial cells, yet with few exceptions the conclusions were based on indirect evidence. Thus, to improve our abilit...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8035171
更新日期:1980-04-01 00:00:00
abstract::The development of inhalation toxicology as a distinct discipline can be traced back well over one hundred years. The technology has advanced in terms of materials and designs used to construct inhalation chambers and the equipment used to generate controlled test atmospheres of a wide variety of gases, vapors, dusts,...
journal_title:Environmental health perspectives
pub_type: 杂志文章,评审
doi:10.1289/ehp.85-1568347
更新日期:1990-04-01 00:00:00
abstract:INTRODUCTION:Ambient particulate pollution and traffic have been linked to myocardial infarction and cardiac death risk. Possible mechanisms include autonomic cardiac dysfunction. METHODS:In a repeated-measures study of 46 patients 43-75 years of age, we investigated associations of central-site ambient particulate po...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.0901003
更新日期:2010-03-01 00:00:00
abstract::A co-culture clonal survival assay was developed to measure the cytotoxicity of test chemical treatments to BALB/c-3T3 cells because the standard clonal survival assay using 200 wild type (WT) cells frequently overestimates chemical cytotoxicity when compared with identical treatment doses in high-density cultures. Th...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.93101s2311
更新日期:1993-07-01 00:00:00
abstract::Most published environmental remediation interventions have been directed at single allergens and have employed demanding strategies; few have been performed in the homes of inner-city children disproportionately burdened by asthma. Our objective was a) to describe the allergen sensitivities, environmental tobacco smo...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.02110939
更新日期:2002-09-01 00:00:00
abstract::This subject concerns the complex interrelationship of a genetically determined protein deficiency, enzymes which are inhibited by that protein, environmental challenges such as cigarette smoke and industrial pollutants, and the occurrence of obstructive lung disease (Fig. 1). Unequivocal establishment of an etiologic...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.792957
更新日期:1979-04-01 00:00:00
abstract::It has been estimated that 4 of 1,000 live births and 35% of spontaneous abortions are aneuploid and that an important proportion of embryo and newborn aneuploidy is of paternal origin. Exposure to organophosphorous pesticides (OP) has been associated with sperm hyperploidy/polyploidy. Therefore, we aimed to assess th...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.011091237
更新日期:2001-12-01 00:00:00
abstract::There is concern about the human health effects of inhalation of acid compounds found in urban air pollution. It was the purpose of this study to investigate three of these acid compounds, sulfur dioxide (SO2), sulfuric acid (H2SO4), and nitric acid (HNO3) in a group of allergic adolescent subjects. Subjects were expo...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8979173
更新日期:1989-02-01 00:00:00
abstract::Isoflavonoids and related compounds such as coumestrol have classically been categorized as phytoestrogens because these environmentally derived substances bind to the estrogen receptor (ER) and increase uterine wet weight in immature rats and mice. Assessment of the binding affinities of isoflavonoids for ER and subs...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.95103574
更新日期:1995-06-01 00:00:00
abstract:BACKGROUND:Concern persists over endocrine-disrupting effects of persistent organic pollutants (POPs) on human growth and sexual maturation. Potential effects of toxicant exposures on testosterone levels during puberty are not well characterized. OBJECTIVES:In this study we evaluated the relationship between toxicants...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.1205984
更新日期:2014-03-01 00:00:00
abstract::Cofactors involved in respiratory tract carcinogenesis were studied in Syrian golden hamsters or in rats using benzo(a)pyrene as the carcinogenic agent. These factors included severe tissue damage induced by electro-coagulation, glass fibers administered by intratracheal instillation, acetaldehyde as irritant vapor, f...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8350275
更新日期:1983-04-01 00:00:00
abstract:BACKGROUND:Sex-specific associations have been reported between phthalates, bisphenol A (BPA), and child behavior. No data on large study populations are available for other phenols with possible endocrine-disrupting properties. OBJECTIVES:We aimed to study associations between prenatal exposure to phthalates and seve...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/EHP1314
更新日期:2017-09-15 00:00:00
abstract::Polychlorinated dibenzo-p-dioxins (PCDDs, dioxins), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) are environmental endocrine disruptors that have half-lives of 7-10 years in the human body and have toxicities that probably include carcinogenesis. A high ratio of 4-hydroxyl estradiol (4-O...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.8809
更新日期:2006-05-01 00:00:00
abstract::During 1992 and 1993 the Wisconsin Division of Health investigated five cases in which copper-contaminated drinking water was suspected of causing gastrointestinal upsets. Each of these case studies was conducted after our office was notified of high copper levels in drinking water or notified of unexplained illnesses...
journal_title:Environmental health perspectives
pub_type: 杂志文章
doi:10.1289/ehp.94102958
更新日期:1994-11-01 00:00:00