Abstract:
:Objective: To develop a physiologically based pharmacokinetic (PBPK) model for chloroprene in the mouse, rat and human, relying only on in vitro data to estimate tissue metabolism rates and partitioning, and to apply the model to calculate an inhalation unit risk (IUR) for chloroprene.Materials and methods: Female B6C3F1 mice were the most sensitive species/gender for lung tumors in the 2-year bioassay conducted with chloroprene. The PBPK model included tissue metabolism rate constants for chloroprene estimated from results of in vitro gas uptake studies using liver and lung microsomes. To assess the validity of the PBPK model, a 6-hr, nose-only chloroprene inhalation study was conducted with female B6C3F1 mice in which both chloroprene blood concentrations and ventilation rates were measured. The PBPK model was then used to predict dose measures - amounts of chloroprene metabolized in lungs per unit time - in mice and humans.Results: The mouse PBPK model accurately predicted in vivo pharmacokinetic data from the 6-hr, nose-only chloroprene inhalation study. The PBPK model was used to conduct a cancer risk assessment based on metabolism of chloroprene to reactive epoxides in the lung, the target tissue in mice. The IUR was over100-fold lower than the IUR from the EPA Integrated Risk Information System (IRIS), which was based on inhaled chloroprene concentration. The different result from the PBPK model risk assessment arises from use of the more relevant tissue dose metric, amount metabolized, rather than inhaled concentrationDiscussion and conclusions: The revised chloroprene PBPK model is based on the best available science, including new test animal in vivo validation, updated literature review and a Markov-Chain Monte Carlo analysis to assess parameter uncertainty. Relying on both mouse and human metabolism data also provides an important advancement in the use of quantitative in vitro to in vivo extrapolation (QIVIVE). Inclusion of the best available science is especially important when deriving a toxicity value based on species extrapolation for the potential carcinogenicity of a reactive metabolite.
journal_name
Inhal Toxicoljournal_title
Inhalation toxicologyauthors
Clewell HJ 3rd,Campbell JL,Van Landingham C,Franzen A,Yoon M,Dodd DE,Andersen ME,Gentry PRdoi
10.1080/08958378.2020.1715513subject
Has Abstractpub_date
2019-01-01 00:00:00pages
468-483issue
13-14eissn
0895-8378issn
1091-7691journal_volume
31pub_type
杂志文章abstract::Halomethanes (HMs) can be formed during the chlorination process to obtain drinking water. In liver cells, HMs had been shown to be mutagenic and carcinogenic; however, their bioactivation by CYP 2E1 and GSTT1 is required. Although inhalation is the most common pathway of exposure, reports on the toxic effects induced...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2012.716871
更新日期:2012-09-01 00:00:00
abstract::Studies have shown associations between acute ambient particulate matter (PM) levels and increases in morbidity and mortality from cardiovascular diseases. We have previously reported in 24 healthy adults that exposure to concentrated ambient particles plus ozone (CAP + O(3)) caused a mean decrease of 0.09 mm in brach...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370490439489
更新日期:2004-06-01 00:00:00
abstract::The lung toxicity of inhalable polymer materials is normally carried out by evaluation of the histopathology responses of rat lungs to repeat, nose-only, exposures of an inhalable aerosol of material in a 13-wk subchronic repeat dose toxicity study. The introduction of transcriptomics into toxicology has allowed the c...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370500444304
更新日期:2006-04-01 00:00:00
abstract:INTRODUCTION:Several experimental and epidemiological studies have demonstrated the neurological adverse effects caused by exposure to air pollution, specifically in relation to pollutant particulate matter (PM). The objective of this study was to investigate the direct effect of PM in increased concentrations in diffe...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2015.1060278
更新日期:2015-01-01 00:00:00
abstract::The irritants acrolein, acetaldehyde, and acetic acid induce a rapid sensory nerve-mediated nasal vasodilatory response in the rat. The aim of the current study was to examine acute nasal sensory nerve-mediated acute responses to an irritant ester vapor, ethyl acrylate. For this purpose, the upper respiratory tract of...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370290084511
更新日期:2002-06-01 00:00:00
abstract:OBJECTIVE:The significance of lung function as an independent risk factor for lung cancer remains unclear. The objective of the study is to answer the question if spirometry can identify patients at risk for lung cancer among people occupationally exposed to asbestos dust in the past. METHODS:In order to identify a gr...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958378.2016.1272652
更新日期:2017-01-01 00:00:00
abstract::Objective: Ethanol is used as a solvent for flavoring chemicals in some electronic cigarette (e-cigarette) liquids (e-liquids). However, there are limited data available regarding the effects of inhalation of ethanol on blood alcohol concentration (BAC) during e-cigarette use. In this study, a modified physiologically...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958378.2020.1720867
更新日期:2020-01-01 00:00:00
abstract:CONTEXT:Particulate air pollution, for example, from ultrafine (UF) particles, has negative health effects. However, there is still limited knowledge regarding the fate of inhaled particles in the human body. OBJECTIVES:To describe the normal lung deposition and 1 week particle retention of indium-111 labeled UF carbo...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2012.708065
更新日期:2012-08-01 00:00:00
abstract::Ozone (O₃), a commonly encountered environmental pollutant, has been shown to induce pulmonary fibrosis in different animal models; the underlying mechanism, however, remains elusive. To investigate the molecular mechanism underlying O₃-induced pulmonary fibrosis, 6- to 8-week-old C57BL/6 male mice were exposed to a c...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2011.584919
更新日期:2011-07-01 00:00:00
abstract::Epidemiological studies have shown an association between microbial growth in buildings and increased risk of respiratory symptoms and disease related to inflammatory reactions in the inhabitants96. The current study examined the affects of growth conditions of Streptomyces anulatus, isolated from indoor air of a mold...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/089583701459065
更新日期:2001-01-01 00:00:00
abstract::It is well documented that inhalation of sulfur mustard causes injury of the respiratory system. While all of the reports and surveys thoroughly document long-term pulmonary effects after significant exposure to mustard, there is no direct evidence that addresses the issue of long-term respiratory effects in individua...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370490442421
更新日期:2004-07-01 00:00:00
abstract:OBJECTIVES:Rodents used in scientific research are typically housed in cages containing natural bedding materials. Despite extensive evidence of biological harm from inhaled particulate matter (PM), relatively little work has been performed to measure bedding-generated PM exposure in caged animals used in basic science...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958378.2019.1694109
更新日期:2019-08-01 00:00:00
abstract::Hypersensitivity pneumonitis (HP) represents the immunologically mediated lung disease induced by repeated inhalations of a wide variety of certain finely dispersed organic antigens. In susceptible subjects, these inhalations provoke a hypersensitivity reaction characterized by intense inflammation of the terminal bro...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2013.827284
更新日期:2013-09-01 00:00:00
abstract::Concurrent exposure to SO(2) and benzo(a)pyrene (B(a)P) resulted in an increased incidence of lung tumors in rodents compared to exposure to B(a)P alone. A synergistic effect on the expression of c-fos and c-jun between SO(2) and B(a)P was observed in lungs after SO(2) and B(a)P exposure. However, tumorigenesis occurs...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958370903341891
更新日期:2010-03-01 00:00:00
abstract:CONTEXT:There have been no animal studies of the health effects of repeated inhalation of mixtures representing downwind pollution from coal combustion. Environmental exposures typically follow atmospheric processing and mixing with pollutants from other sources. OBJECTIVE:This was the fourth study by the National Env...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2011.572932
更新日期:2011-05-01 00:00:00
abstract::Nonhuman primates are often the animal models of choice to study the infectivity and therapy of inhaled infectious agents. Most animal models for inhaled infectious diseases use aerosol/droplets generated by an atomization technique such as a Collison nebulizer that produces particles in the size range of 1 to 3 micro...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370802105413
更新日期:2008-09-01 00:00:00
abstract:BACKGROUND:Nanoparticles are being rapidly assimilated into numerous research fields and consumer products. A concurrent increase in human exposure to such materials is expected. Magnetic nanoparticles (MNPs) possess unique and beneficial features, increasing their functionality and integrative potential. However, MNP ...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2011.592869
更新日期:2011-08-01 00:00:00
abstract::In recent years, a physiology-oriented multicompartmental kinetics (POCK) model was developed to simulate pulmonary retention data of biopersistent, noncytotoxic aerosols in long-term inhalation exposures of rats. Experimental data were successfully simulated for submicrometer-sized aerosols like carbon black, diesel ...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/089583799197096
更新日期:1999-04-01 00:00:00
abstract::A combination of high fuel prices, bus maintenance costs, and the health and safety of school children, along with a consideration of federal and state regulations, prompted Medford Township school district in southern New Jersey to explore the use of alternative fuels, specifically biodiesel. The school district owns...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370701533467
更新日期:2007-09-01 00:00:00
abstract::Endotoxin causes an inflammation at the bronchial and alveolar level. The inflammation-induced increase in permeability of the bronchoalveolar epithelial barrier is supposed to cause a leakage of pneumoproteins. Therefore, their concentrations are expected to increase in the bloodstream. This study aimed at examining ...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370601144456
更新日期:2007-04-01 00:00:00
abstract::An approach to identify causal components of complex air pollution mixtures was explored. Rats and mice were exposed by inhalation 6 h daily for 1 week or 6 months to dilutions of simulated downwind coal emissions, diesel and gasoline exhausts and wood smoke. Organ weights, hematology, serum chemistry, bronchoalveolar...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2014.920440
更新日期:2014-09-01 00:00:00
abstract::Particle research has been historically closely connected to industrial activities or materials, such as coal, asbestos, man-made mineral fibers, and more recently ambient particulate matter (PM). It is the purpose of this review to combine insights and developments in particle toxicology with the historical context o...
journal_title:Inhalation toxicology
pub_type: 历史文章,杂志文章,评审
doi:10.1080/08958370252809086
更新日期:2002-03-01 00:00:00
abstract::This article addresses results of two 13-wk inhalation toxicity studies in Wistar rats with aerosolized 1,6-hexamethylene diisocyanate (HDI) homopolymers using either the isocyanurate (HDI-IC) type or biuret (HDI-BT) type. Groups of 10 rats/sex/level were exposed nose-only to breathing zone concentrations of 0.5, 3.3,...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370118600
更新日期:2001-06-01 00:00:00
abstract::Epidemiological studies suggest that diabetics may be more susceptible to the adverse health effects from exposure to high ambient concentrations of ozone, the primary oxidant gas in photochemical smog. While increased morbidity and mortality from ozone inhalation has been linked to disruption of normal cardiovascular...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958378.2016.1146808
更新日期:2016-01-01 00:00:00
abstract::This study was designed to investigate effects of sulfur dioxide (SO(2)) and its derivatives (bisulfite and sulfite) on the rat blood pressure. The blood pressures of male Wistar rats exposed to SO(2) and its derivatives at various doses were measured. Findings were that: (1) with acute-one time exposure to SO(2) for ...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370390215785
更新日期:2003-08-01 00:00:00
abstract::Objective: Humidifier-disinfectant-induced lung injury is a new syndrome associated with a high mortality rate and characterized by severe hypersensitivity pneumonitis, acute interstitial pneumonia, or acute respiratory distress syndrome. Polyhexamethylene guanidine phosphate (PHMG-P), a guanidine-based antimicrobial ...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958378.2019.1707912
更新日期:2019-01-01 00:00:00
abstract::The effects of low-level ozone exposure (0.08 ppm) on pulmonary function in healthy young adults are well known; however, much less is known about the inflammatory and immunomodulatory effects of low-level ozone in the airways. Techniques such as induced sputum and flow cytometry make it possible to examine airways in...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.3109/08958371003596587
更新日期:2010-06-01 00:00:00
abstract::A method for inhalative exposure of minipigs to aerosols and gases has been developed. Minipigs are exposed via mask inhalation to the test substance using a computer-controlled exposure system that permits simultaneous exposure of groups of four animals in parallel to different controlled dose levels. We studied inha...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958370150502476
更新日期:2001-03-01 00:00:00
abstract::In February 2006, an IARC Monographs Working Group reevaluated the carcinogenic hazards to humans of carbon black, titanium dioxide, and talc, which belong to the group of poorly soluble, low-toxicity particles. The review of the relevant literature and the evaluations by the Working Group will be published in Volume ...
journal_title:Inhalation toxicology
pub_type: 杂志文章,评审
doi:10.1080/08958370701497903
更新日期:2007-01-01 00:00:00
abstract:OBJECTIVE:Dimethyl sulfide (DMS, CAS 75-18-3) is an industrial chemical. It is both an irritant and neurotoxicant that may be life-threatening because of accidental release. The effects of DMS on public health and associated public health response depend on the exposure concentration and duration. However, currently, p...
journal_title:Inhalation toxicology
pub_type: 杂志文章
doi:10.1080/08958378.2018.1551444
更新日期:2018-01-01 00:00:00