Abstract:
:Uncertainty in risk assessment can be reduced by increasing the use of relevant data specific to the particular xenobiotic and exposed organism. We describe the development of a preliminary, mechanism-based exposure response model for chloroform hepatotoxicity consistig of toxicokinetic (TK) and toxicodynamic (TD) submodels. The TK submodel is based on an existing physiologically based toxicokinetic (PBTK) model for chloroform. The TD submodel consists of an empirical function linking tissue dose, defined by the PBTK model, with hepatocyte killing and subsequent regenerative cellular replication. Chloroform-induced cell killing was inferred quantitatively from dose-response hepatic labelling index studies conducted in female B6C3F1 mice and male F344 rats. The overall model was scaled to humans by conventional scaling of the TK submodel and by using the TD submodel as is, i.e. as developed from the rodent data. The resulting human model was used to analyze a case of human poisoning which developed after repeated ingestion of large doses of cough syrup containing chloroform and alcohol. The model predicted the observed toxic response after the capacity for chloroform metabolism was increased by a factor of 3 from the value estimated using human liver microsomes. This is an acceptable adjustment of this parameter, given the uncertainty associated with the extrapolation from microsomes and the coexposure to alcohol. This preliminary result is encouraging, suggesting that the model, at its current stage of development, is able to approximate actual human risks of hepatotoxicity from chloroform exposure. The extensive use of data on chloroform TK and cytolethality-induced regenerative cellular replication for model development suggests that the model has reduced uncertainty relative to the current U.S. EPA oral reference dose (RfD) calculation for chloroform, which does not use any mechanistic or dose-response data.
journal_name
Toxicol Lettjournal_title
Toxicology lettersauthors
Conolly RB,Butterworth BEdoi
10.1016/0378-4274(95)03528-1subject
Has Abstractpub_date
1995-12-01 00:00:00pages
901-6eissn
0378-4274issn
1879-3169pii
0378-4274(95)03528-1journal_volume
82-83pub_type
杂志文章abstract::Free fatty acids (FFA), commonly elevated in diabetes and obesity, have been shown to impair endothelial functions and cause oxidative stress, inflammation, and insulin resistance. Anthocyanins represent one of the most important and interesting classes of flavonoids and seem to play a role in preventing cardiovascula...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2015.09.020
更新日期:2015-12-15 00:00:00
abstract::The distribution of 54Mn in various organs of pregnant rats and of their 19-day-old fetuses and in non-pregnant female rats of various ages has been studied 18 h after an i.v. injection of 54MnCl2. The results indicate that early neonates are more susceptible to manganese (Mn) than the growing rats. The localization o...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(80)90026-0
更新日期:1980-05-01 00:00:00
abstract::A quantitative high-content screening (HCS) was suggested for the real-time monitoring of drug-induced mitochondrial dysfunction-mediated hepatotoxicity. This HCS is very advantageous in that it allows simultaneous observation of drug-induced activations of hepatotoxic pathways using hypermulticolor cellular imaging. ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2012.08.027
更新日期:2012-10-17 00:00:00
abstract::The phototoxic potentials of quinolone derivatives and the possibility of free radical contribution to their phototoxicity were investigated by measuring increments in ear thickness. Balb/c mice, fasted overnight, were orally administered ofloxacin (OFLX), lomefloxacin (LMFX), enoxacin (ENX), ciprofloxacin (CPFX) and ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(91)90176-7
更新日期:1991-10-01 00:00:00
abstract::When cells from the human cell line NHIK3025 were cultured for 4 days, with hexavalent chromium (K2Cr2O7) at a concentration of 8 . 10(-7)M, the relative cell number was reduced to 38%. This effect of hexavalent chromium was abolished if ascorbic acid and chromate were added simultaneously to the incubation medium, bu...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(82)90146-1
更新日期:1982-09-01 00:00:00
abstract::Mouse neuroblastoma cells exposed to 2.5 and 5.0 microM methylmercury for 24 h appeared rounded with the loss of processes. Immunohistochemical staining directed against beta-tubulin revealed severe alterations in microtubular architecture. Non-membrane-bound condensation product was visualized ultrastructurally in th...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(90)90226-c
更新日期:1990-03-01 00:00:00
abstract::Many xenobiotics and carcinogens are oxidized in vitro by prostaglandin-H synthase (PHS) in the presence of arachidonic acid or lipid peroxides. PHS has been suggested to serve as an alternative metabolic activation enzyme to the cytochrome P-450 isoenzymes, particularly in tissues low in monooxygenase activity. This ...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/0378-4274(93)90055-3
更新日期:1993-04-01 00:00:00
abstract::Chloropicrin is an aliphatic volatile nitrate compound that is mainly used as a pesticide. It has several toxic effects in animals and can cause irritating and other health problems in exposed humans. Since the mode of chloropicrin action is poorly understood, the aim of this study was to investigate molecular respons...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2012.04.002
更新日期:2012-06-20 00:00:00
abstract::Manganese (Mn) is an essential trace element required for normal function and development. However, exposure to this metal at elevated levels may cause manganism, a progressive neurodegenerative disorder with neurological symptoms similar to idiopathic Parkinson's disease (IPD). Elevated body burdens of Mn from exposu...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2012.12.024
更新日期:2013-04-26 00:00:00
abstract::In order to elucidate the mechanisms by which long-term treatment with clobazam (CLB), 1,5-benzodiazepine, induces thyroid follicular cell tumors in male rats, male Sprague-Dawley (SD) rats were treated orally with 400 mg/kg of CLB for up to 4 weeks, and the contribution of feedback through elevated thyroid stimulatin...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2003.08.002
更新日期:2003-12-10 00:00:00
abstract::When considering the state of the art in toxicology from an analytical perspective, the key developments relate to three major areas. (1) Forensic horizon: Today forensic analysis has broadened its scope dramatically, to include workplace toxicology, drug abuse testing, drugs and driving, doping, environmental and vet...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/s0378-4274(98)00293-8
更新日期:1998-12-28 00:00:00
abstract::Iron is a unique poison because it is not a xenobiotic. It is an essential element and highly reactive. Because of the critical dependence upon iron and its potential to damage tissues, elaborate mechanisms have evolved for its efficient absorption, transport, cellular uptake, storage and conservation. These are incom...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/s0378-4274(98)00279-3
更新日期:1998-12-28 00:00:00
abstract::We reported earlier that the activation of free-radical-mediated tumor necrosis factor-alpha (TNF-alpha) cascade is the major pathway in the inflammatory lung disease induced by 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog. TNF-alpha induces activating protein 1 (AP-1) activation via phosphorylation of mit...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2008.07.005
更新日期:2008-09-26 00:00:00
abstract::PFAS are man-made compounds that are highly spread in the environment. Human dietary exposure to such contaminants is of high concern as they may accumulate in the food chain. Different studies already demonstrated the importance of the fish consumption in the dietary exposure of these molecules and the potential incr...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2014.07.028
更新日期:2014-12-01 00:00:00
abstract::The aim of this study was to establish a methodology to analyze estrogen quinone-derived adducts, including 17β-estradiol-2,3-quinone (E2-2,3-Q) and 17β-estradiol-3,4-quinone (E2-3,4-Q), in human hemoglobin (Hb). The methodology was then used to measure the levels of these adducts in Hb derived from female breast canc...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2014.01.004
更新日期:2014-03-21 00:00:00
abstract::The tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is the most potent risk factor among tobacco-related carcinogens in lung cancer progression and outcomes. Although genetic mutations and chromosome instability have been detected in NNK-induced lung tumors, the oncogenic mechanisms o...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2017.09.019
更新日期:2017-11-05 00:00:00
abstract::Treatment of young male rats with dipentyl phthalate (DPP) produced significant decreases in testicular cytochrome P-450, cytochrome P-450 dependent microsomal steroidogenic enzymes (17 alpha-hydroxylase, 17-20 lyase) and in the maximal binding of a natural substrate (progesterone) to testis microsomes. No effect was ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(83)90226-6
更新日期:1983-02-01 00:00:00
abstract::The effect of dietary vomitoxin on the serum IgA and IgG responses to two model intestinal antigens, casein and cholera toxin (CT), were assessed in 4 experimental groups: (1) mice fed casein-based diet, (2) mice fed casein-based diet containing 25 ppm vomitoxin, (3) mice fed casein-based diet and immunized with CT, a...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(90)90254-j
更新日期:1990-01-01 00:00:00
abstract::The molecular basis of the interindividual differences of normal individuals to ionizing radiation is poorly understood. Several studies in telomerase KO mice with short telomeres have uncovered an inverse relationship between telomere length and radiation sensitivity. The present work aims to determine if chromosome ...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2007.05.012
更新日期:2007-07-30 00:00:00
abstract::The oxidation of styrene to styrene oxide and the hydration of this metabolite to styrene glycol was investigated in hepatocytes, 9000 x g supernatant (S9) and the microsomal fraction from rat liver. Similar amounts of free styrene oxide were found in microsomes, hepatocytes and S9. However, on the basis of the format...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(84)90120-6
更新日期:1984-11-01 00:00:00
abstract::The cyanobacterial non-proteinogenic amino acid β-N-methylamino-l-alanine (BMAA) is proposed to be involved in the etiology of amyotrophic lateral sclerosis/parkinsonism dementia complex. When administered as single doses to neonatal rats, BMAA gives rise to cognitive and neurodegenerative impairments in the adult ani...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2016.06.015
更新日期:2016-09-06 00:00:00
abstract::In recent years, interesterified fat (IF) has been used to replace hydrogenated vegetable fat (HVF), rich in trans isomers, being found in processed foods. Studies involving IF have shown deleterious influences on the metabolic system, similarly to HVF, whereas no studies regarding its influence on the central nervous...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2017.05.020
更新日期:2017-07-05 00:00:00
abstract::A rat bioassay has been developed to provide an objective approach for the identification and classification of upper and lower respiratory tract irritants, with particular emphasis on the concentration-dependent induction and regression of lesions characteristic of asthma, such as persisting non-specific airway hyper...
journal_title:Toxicology letters
pub_type: 杂志文章,评审
doi:10.1016/0378-4274(96)03688-0
更新日期:1996-08-01 00:00:00
abstract::Regions with heavy industry are in many ways regions of crisis. The health of the population is primarily affected by the different air pollutants. Dust, with all its organic (dioxins and furans) and inorganic (heavy metals) contents, makes up the greatest part of the air-borne pollutants. The influence on health of e...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(96)03731-9
更新日期:1996-11-01 00:00:00
abstract::A single, 50 mg/kg i.p. dose of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) to mice significantly inhibited glutathione reductase activity in liver within 10 min, and in lung and heart within 30 min. Maximal inhibition was reached at 4 h in all tissues and glutathione reductase activity remained significantly depress...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/0378-4274(83)90036-x
更新日期:1983-06-01 00:00:00
abstract::There is a trend towards increasing doses of pralidoxime to treat human organophosphate poisonings that may have relevance in subpopulations. Indeed, pralidoxime is eliminated unchanged by the renal route. This study assesses the effect of renal failure on the kinetics of pralidoxime in a rat model of acute renal fail...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2008.10.022
更新日期:2009-01-10 00:00:00
abstract::Chronic wound healing disorders that occur as a result of a sulfur mustard (SM) exposure present a particular challenge. These chronic wounds are similar to other chronic wounds. In the past, it has been shown that mesenchymal stem cells (MSC) play an important role in the healing of chronic wounds. An important prope...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2017.08.008
更新日期:2018-09-01 00:00:00
abstract::Sulphur mustard (SM) is a blistering agent that causes debilitating damage to the skin, eyes and respiratory system. In cases of severe exposure, immunodepletion can occur as well as death, due to secondary infections. The toxicity of SM is thought to be mediated in part by the alkylation of nucleic acids and proteins...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2011.11.009
更新日期:2012-02-25 00:00:00
abstract::Effective treatments for esophageal squamous cell carcinoma (ESCC), one of the most common cancers in China, are lacking. Longikaurin A (LK-A), an ent-kauranoid diterpenoid isolated from Isodon ternifolius, has been shown to have potent cytotoxic effects on ESCC cells both in vivo and in vitro, mainly by inducing apop...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2017.08.005
更新日期:2017-10-05 00:00:00
abstract::Dioxins are a class of extremely toxic environmentally persistent pollutant, comprised of halogenated dibenzo-p-dioxins, dibenzofurans and biphenyls. Despite significant human exposure via multiple routes, very little is known about toxicity induced by dibenzofuran (DF). Current study shed lights on the potential toxi...
journal_title:Toxicology letters
pub_type: 杂志文章
doi:10.1016/j.toxlet.2012.08.014
更新日期:2012-10-17 00:00:00